A Phase II, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of M5049 in Hospitalized Participants With COVID-19 Pneumonia (ANEMONE)
Phase: PHASE2
Conditions: Coronavirus Disease 2019
Sponsor: EMD Serono Research & Development Institute, Inc.



M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 9 5
Cli nical St u d y  Pr ot oc ol Versi o n: 
0 1 Marc h
2 0 2 1 / Versi o n 4. 0
Re places
Cli nical 
St u d y Pr ot oc ol 
Versi o n:
1 3 Oct o ber 2 0 2 0 / Versi o n 3. 0
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
4. 0
Gl o b al
0 1 M ar 2 0 2 1
3. 0
Gl o b al
1 3 O ct 2 0 2 0
2. 0
Gl o b al
2 4 J ul 2 0 2 0
1. 0
Ori gi n al Pr ot o c ol
2 6 M a y 2 0 2 0
Pr ot oc ol Versi o n 4 . 0 (0 1 M arc h
2 0 2 1)
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
O ver all R ati o n ale f or t he A me n d me nt
T he t hree maj or p ur p oses of t he a me n d me nt are t o ( 1) re place t he pri mar y efficac y e n d p oi nt, ( 2) 
a da pt t he pr ot oc ol t o t he c ha n gi n g la n dsca pe a n d l ocal sta n dar d of care f or C O VI D-1 9 p ne u m o nia , 
a n d (3 ) t o ali g n wit h t he ne w versi o n of t he I n vesti gat or’s Br oc h ure 
 
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e ; A p p x. 6
S p o n s or S i g n at ur e 
P a g e
U p d at e d M e di c al R e s p o n si bl e
C h a n g e of M e di c al R e s p o n si bl e .
1. 1 S y n o p si s;
3. 2 P art B 
O bj e cti v e s; 
9. 1. 2 Effi c a c y 
A s s e s s m e nt s;
1 0 St ati sti c al 
C o n si d er ati o n s 
R e pl a c e d pri m ar y effi c a c y e n d p oi nt 
t o “ti m e t o re c o v er y” a n d r e or g a ni z e d 
t h e st ati sti c al c o n si d er ati o n s , si n c e 
t h e ori gi n al pri m ar y e n d p oi nt i s 
c o v er e d wit hi n a s e c o n d ar y e n d p oi nt .
At t h e b e gi n ni n g of t h e p a n d e mi c (d at a c oll e ct e d 
fr o m 1 8 J a n 2 0 2 0 t o 0 3 F e b 2 0 2 0 ), p ati e nt s 
h o s pit ali z e d d u e t o C O VI D -1 9 p n e u m o ni a o n 
st a n d ar d of c ar e ( S o C) h a d b ot h a m e di a n 
d ur ati o n of h o s pit ali z ati o n a n d m e di a n ti m e t o 
cli ni c al i m pr o v e m e nt ( ≥2 p oi nt s i m pr o v e m e nt o n 
a 7 -c at e g or y or di n al s c al e) of 1 6 d a y s
(C a o 2 0 2 0 ).
I n N o v 2 0 2 0 t h e fi n al r e p ort o n t h e u s e of 
r e m d e si vir f or tr e at m e nt of C O VI D -1 9 s h o w e d 
t h at t h e m e di a n ti m e t o r e c o v er y f or p ati e nt s 
r e c ei vi n g r e m d e si vir w a s 1 0 d a y s ( c o m p ar e d t o 
1 5 - d a y s f or p ati e nt s r e c ei vi n g S o C), a n d t h e 
m e di a n ti m e t o r e c o v er y i n p ati e nt s h o s pit ali z e d 
r e q uiri n g a n y s u p pl e m e nt al o x y g e n w a s 7 t o 
9 d a y s (B ei g el 2 0 2 0 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
I n li g ht of t hi s r a pi dl y c h a n gi n g C O VI D-1 9 S o C
( e. g., r e m d e si vir, ot h er tr e at m e nt o pti o n s
c urr e ntl y a v ail a bl e a n d t h o s e t h at mi g ht b e 
a v ail a bl e wit hi n t h e n e xt m o nt h s ), t h e c urr e nt 
pri m ar y effi c a c y e n d p oi nt “ ali v e a n d n ot r e q uiri n g 
s u p pl e m e nt al o x y g e n ati o n at D a y 1 4” m a y n ot 
all o w a diff er e nti ati o n b et w e e n t h e A N E M O N E 
tr e at m e nt gr o u p s. B y c o ntr a st , ti m e t o r e c o v er y i s 
a n e n d p oi nt t h at w o ul d c a pt ur e a n e arli er h o s pit al
di s c h ar g e or s h ort er d ur ati o n of h o s pit ali z ati o n 
c o m p ar e d t o t h e b e gi n ni n g of t h e p a n d e mi c.
M or e o v er, t i m e t o r e c o v er y b ei n g a wi d el y u s e d 
e n d p oi nt i n C O VI D-1 9 cli ni c al tri al s w o ul d 
f a cilit at e t h e i nt er pr et ati o n of t h e A N E M O N E 
r e s ult s.  
I n a d diti o n, thi s n e w pri m ar y e n d p oi nt i s d eri v e d 
fr o m t h e s a m e W H O or di n al s c al e f or cli ni c al 
st at u s a s s e s s m e nt a s t h e f or m er pri m ar y 
e n d p oi nt, b ut n o w all d at a p oi nt s c oll e ct e d will b e 
u s e d.
1. 1 S y n o p si s; 
3. 2 P art B 
O bj e cti v e s;
1 0. 4. 3 . 9 A n al y si s of 
T ot al D a y s i n t h e 
H o s pit al a n d Ti m e 
t o H o s pit al 
Di s c h ar g e
F or t h e o bj e cti v e “t o a s s e s s t h e 
l e n gt h of h o s pit al st a y”, a n e w 
e n d p oi nt “ti m e t o h o s pit al di s c h ar g e 
fr o m D a y 1 t hr o u g h D a y 2 8” w a s 
a d d e d.
T o c o n d u ct a d diti o n al a n al y si s wit h t h e c oll e ct e d 
d at a a n d g ai n a b ett er u n d er st a n di n g o n
h o s pit ali z ati o n l e n gt h.
1. 2 S o A .
E m p h a si z e d t h e r e q uir e m e nt f or 
st u d y sit e s t o r e c or d d ail y t h e cli ni c al 
st at u s b y t h e W H O 9- p oi nt or di n al 
s c al e d uri n g p arti ci p a nt s 
h o s pit ali z ati o n a n d t h e cli ni c al st at u s 
c h a n g e aft er h o s pit al di s c h ar g e .
A d d e d D a y 3 a n d D a y 5 a s e x a m pl e s
of a d diti o n al st u d y vi sit s t o t a k e pl a c e 
if p arti ci p a nt i s di s c h ar g e b y t h e n ( at 
a p pli c a bl e a s s e s s m e nt s).
T o a v oi d c o nf u si o n, m a ki n g s ur e t h at t h e st u d y 
sit e s r e c or d d at a r e q uir e d p er pr ot o c ol.
1. 2 S o A.
A d d e d cl arifi c ati o n t h at pri nt-o ut or 
p a p er c o p y of E C G t el e m etr y i s 
r e q uir e d a s s o ur c e d o c u m e nt .
T o pr o vi d e i n str u cti o n s o n c orr e ct s o ur c e 
d o c u m e nt ati o n.
1. 2 S o A;
A p p x. 4 Cli ni c al 
L a b or at or y T e st s.
S p e cifi e d el e ctr ol yt e s t o b e 
m e a s ur e d , s p e cifi e d ti m e wi n d o w f or 
D a y 1 l a b or at or y t e st s a n d a d d e d 
gl u c o s e a n d d el et e d r eti c ul o c yt e s .
T o pr o vi d e d et ail e d i nf or m ati o n t o sit e s a n d 
cl arif y di s cr e p a n ci e s .
1. 2 S o A; 
4. 1. O v er all D e si g n; 
5 St u d y P o p ul ati o n; 
5. 1 I n cl u si o n 
Crit eri a;
9. 2. S af et y a n d 
Ot h er A s s e s s m e nt s; 
1 3 R ef er e n c e s.
A d d e d cl arifi c ati o n t o all o w o x y g e n 
s at ur ati o n m e a s ur e m e nt b y p ul s e 
o xi m et er f or S p O 2 / Fi O2 a s s e s s m e nt 
i n st e a d of art eri al bl o o d g a s 
(i n cl u di n g r ef er e n c e s) f or P a O2 / Fi O2
a s s e s s m e nt i n sit e s w h er e art eri al 
bl o o d g a s i s n ot st a n d ar d of c ar e or 
a v ail a bl e.
T o a d a pt t o t h e S o C wit h o ut i m p a cti n g o n t h e 
s af et y of p arti ci p a nt s n or st u d y o ut c o m e. T h e 
c orr el ati o n b et w e e n S p O 2 / Fi O2 r ati o a n d 
m e a s ur e d P a O
2 / Fi O2 r ati o i s hi g h w h e n r e stri ct e d 
t o p ati e nt s wit h S p O2 ≤9 6 %, a s s u b st a nti al 
v ari ati o n of P a O 2 i s pr e s e nt i n hi g h er S p O2 r a n g e 
(Br o w n 2 0 1 6 ). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
2. 2 B a c k gr o u n d ;
4. 1 O v er all D e si g n;
1 3 R ef er e n c e s.
U p d at e d wit h c h a n g e s i n C O VI D -1 9 
l a n d s c a p e ( e. g., n u m b er of 
S A R S -C o V -2 c a s e s) .
U p d at e t h e pr ot o c ol t o t h e r a pi d c h a n gi n g 
C O VI D -1 9 l a n d s c a p e.
2. 3. 1 Ri s k 
a s s e s s m e nt
Ali g n wit h u p d at e d I n v e sti g at or’ s Br o c h ur e .
5. 2 E x c l u si o n 
Crit eri a;
7. 4 C o n c o mit a nt 
T h er a p y;
A p p x. 3 M e di c ati o n 
G ui d a n c e
I n cl u d e d S A R S-C o V -2 v a c ci n ati o n a s 
e x cl u si o n crit eri a a n d pr o hi bit e d 
t h er a p y t hr o u g h D a y 2 8 ( e arli er 
v a c ci n ati o n mi g ht b e p er mitt e d aft er 
c o n s ult ati o n wit h M e di c al M o nit or or 
d e si g n e e). 
S A R S -C o V -2 v a c ci n e s w er e n ot a v ail a bl e at t h e 
ti m e of pr e vi o u s pr ot o c ol a m e n d m e nt. S e v er al 
effi c a c y e n d p oi nt s ar e m e a s ur e d u p t o D a y 2 8. 
S A R S -C o V -2 v a c ci n ati o n pri or t o D a y 2 8 c o ul d 
p ot e nti all y c o nf o u n d t h e cli ni c al o ut c o m e of 
p arti ci p a nt s ( e. g., l e s s s e v er e di s e a s e if 
v a c ci n at e d ). F l e xi bilit y t o all o w pri or v a c ci n ati o n 
i s h o w e v er k e pt b y S p o n s or, i n c a s e of f urt h er
d e v el o p m e nt s i n t h e r a pi d l y c h a n gi n g C O VI D -1 9 
l a n d s c a p e.
5. 2 E x cl u si o n 
Crit eri a
S p e cifi e d t h e e x cl u si o n of s e pti c e mi a, 
a s a n e x a m pl e of t h e e x cl u si o n 
crit eri a ( alr e a d y pr e s e nt i n pri or 
v er si o n s) u n c o ntr oll e d a cti v e 
i nf e cti o n. 
Cl arifi c ati o n t o a v oi d pr ot o c ol d e vi ati o n s.
5. 2 E x cl u si o n 
Crit eri a
I n cl u d e d cl arifi c ati o n t h at I n v e sti g at or 
mi g ht p erf or m t u b er c ul o si s t e st a s 
p er cli ni c al j u d g e m e nt.
Cl arif y t h at, alt h o u g h n ot r e q uir e d a s S cr e e ni n g 
a s s e s s m e nt, I n v e sti g at or h a s fl e xi bilit y t o t e st f or 
t u b er c ul o si s i nf e cti o n a s p er cli ni c al j u d g e m e nt.
5. 2 E x cl u si o n 
Crit eri a;
7. 4. 2 
H e m o p erf u si o n;
A p p x. 3 M e di c ati o n 
G ui d a n c e
I n cl u d e d h e m o p erf u si o n a s e x cl u si o n 
crit eri a a n d pr o hi bit e d t h er a p y
H e m o p erf u si o n c o ul d r e d u c e t h e l e v el s of I L -6, 
T y p e I I F N or T N F, w hi c h i s t h e e x p e ct e d 
tr e at m e nt eff e ct of M 5 0 4 9. T h er ef or e, 
h e m o p erf u si o n w o ul d c o nf o u n d t h e st u d y 
tr e at m e nt o ut c o m e a n d t h er ef or e i s e x cl u si o n ar y 
a n d pr o hi bit e d f or t hi s st u d y.
6. 1. 1. 2 D o si n g a n d 
A d mi ni str ati o n
A d d e d cl arifi c ati o n r e g ar di n g n u m b er 
of d o s e s a n d t a bl et s.
T o a v oi d c o nf u si o n, e s p e ci all y f or p arti ci p a nt s 
wit h fir st d o s e d uri n g t h e e v e ni n g.
7. 4. 1 
C orti c o st er oi d s
A d d e d wit hi n T a bl e 3 ( Pr e d ni s o n e 
E q ui v al e nt C al c ul ati o n), t h e 
e q ui v al e nt of 1 5 m g pr e d ni s o n e a n d 
m a xi m u m all o w e d d ail y d o s e f or 
ot h er or al c orti c o st er oi d s.
T o f a cilit at e t h e w or k of sit e s, b y a v oi di n g 
c al c ul ati o n s t o d et er mi n e pr e d ni s o n e 
e q ui v al e nt s.
9. 4. Tr e at m e nt of 
O v er d o s e
A d d e d n e w s e cti o n d e s cri bi n g t h e 
d efi niti o n a n d m a n a g e m e nt of 
o v er d o s e
T o pr o vi d e i n str u cti o n o n d efi niti o n a n d 
m a n a g e m e nt of o v er d o s e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1 0. 3 P o p ul ati o n s f or 
A n al y s e s;
1 0. 4. 3 A n al y si s of 
t h e S e c o n d ar y 
E n d p oi nt s
U p d at e d t h e i n I nt e nt -t o-Tr e at 
a n al y s e s s et, fr o m r a n d o mi z e d t o 
tr e at e d p arti ci p a nt s, b ei n g a n al y z e d 
a c c or di n g t o t h e a ct u al tr e at m e nt 
r e c ei v e d, i n st e a d of t h e tr e at m e nt 
r a n d o mi z e d t o. C h a n g e d t h e ti m e 
d efi niti o n f or a n al y s e s, a c c or di n gl y, 
fr o m fir st d o s e i n st e a d of fr o m 
r a n d o mi z ati o n.
T o a c c o u nt f or t h e e v e nt u alit y t h at p arti ci p a nt s 
h a v e b e e n tr e at e d wit h o ut b ei n g r a n d o mi z e d.
E C G = el e ctr o c ar di o gr a m, C O VI D 1 9 = c or o n a vir u s di s e a s e 2 0 1 9, Fi O 2 = fr a cti o n of i n s pir e d o x y g e n, 
P a O 2 = p arti al pr e s s ur e of o x y g e n, S A R S -C o V - 2 = s e v er e a c ut e r e s pir at or y s y n dr o m e c or o n a vir u s, 
S o A = s c h e d ul e of a cti viti e s, S p O 2 = p er i p h er al c a pill ar y o x y g e n s at ur ati o n, T N F = t u m or n e cr o si s f a ct or.
- C o nfi d e nti al –
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 1 b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 9 5
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Ta ble of C o nte nts
.............................................................................................................. 6
Ta ble of Ta bles
............................................................................................................ 1 1
Ta ble of Fi g ures
............................................................................................................ 1 1
1
Pr ot oc ol S u m mar y ..............................................................................1 2
1. 1
S y n o psis ..............................................................................................1 2
1. 2
Sc he d ule of Assess me nts .................................................................... 1 6
1. 3
St u d y  Sc he ma ..................................................................................... 2 5
2
I ntr o d ucti o n......................................................................................... 2 6
2. 2
Bac k gr o u n d ......................................................................................... 2 8
2. 2. 1
P ur p ose of St u d y ................................................................................. 2 8
2. 2. 2
P ote ntial T hera pe utics ........................................................................ 2 8
2. 3
Ris k/ Be nefit Assess me nt .................................................................... 2 8
2. 3. 2
Ris ks t o Pri vac y .................................................................................. 3 0
2. 3. 3
K n o w n P ote ntial Be nefits ................................................................... 3 0
3
O bjecti ves a n d E n d p oi nts ................................................................... 3 0
3. 1
Part A O bjecti ves ................................................................................ 3 0
3. 2
Part B O bjecti ves ................................................................................ 3 1
4
St u d y  Desi g n....................................................................................... 3 3
4. 1
O verall Desi g n ....................................................................................3 3
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................3 5
4. 3
J ustificati o n f or D ose ..........................................................................3 5
4. 4
Earl y H os pital Disc har ge Assess me nts ..............................................3 6
4. 5
E n d of St u d y  Defi niti o n...................................................................... 3 6
4. 6
Earl y Ter mi nati o n of Treat me nt .........................................................3 6
4. 7
S ur veilla nce, Safet y  a n d E n d of St u d y Visits.....................................3 6
4. 8
Rela pse Defi niti o n.............................................................................. 3 7
5
St u d y  P o p ulati o n.................................................................................3 7
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 9 5
5. 1
I ncl usi o n Criteria................................ ................................................3 8
5. 2
E xcl usi o n Criteria ............................................................................... 4 0
5. 3
Lifest y le C o nsi derati o ns..................................................................... 4 3
5. 4
Scree n Fail ures .................................................................................... 4 3
5. 5
Strate gies f or Recr uit me nt a n d Rete nti o n ........................................... 4 3
5. 5. 1
Recr uit me nt ......................................................................................... 4 3
5. 5. 2
C osts ................................................................................................... 4 3
5. 5. 3
St u d y  F oll o w-u p ................................................................................. 4 3
5. 5. 4
H os pital Disc har ge .............................................................................. 4 4
6
St u d y  Inter ve nti o n .............................................................................. 4 4
6. 1
St u d y  Inter ve nti o n a n d A d mi nistrati o n .............................................. 4 4
6. 1. 1
I n vesti gati o nal T hera pe utic a n d Matc hi n g Place b o............................ 4 4
6. 1. 1. 1
St u d y  Inter ve nti o n Descri pti o n ........................................................... 4 4
6. 1. 1. 2
D osi n g a n d A d mi nistrati o n ................................................................. 4 4
6. 1. 2. 1
Ac q uisiti o n a n d Acc o u nta bilit y .......................................................... 4 5
6. 1. 2. 2
Destr ucti o n .......................................................................................... 4 5
6. 1. 3
F or m ulati o n, A p peara nce, Pac ka gi n g, a n d La belli n g ......................... 4 5
6. 1. 5
Pre parati o n .......................................................................................... 4 6
7
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g ................ 4 6
7. 1
Bli n di n g ..............................................................................................4 6
7. 2
E mer ge nc y  U n bli n di n g....................................................................... 4 7
7. 3
St u d y  Inter ve nti o n C o m plia nce .......................................................... 4 7
7. 4
C o nc o mita nt T hera p y .........................................................................4 8
7. 4. 1
C ortic oster oi ds ....................................................................................4 8
7. 4. 2
He m o perf usi o n ................................................................................... 4 9
8
Disc o nti n uati o n t he St u d y I nter ve nti o n or fr o m t he St u d y a n d 
Pre mat ure St u d y  Cl os ure.................................................................... 5 0
8. 1
Te m p orar y  or Per ma ne nt Disc o nti n uati o n of t he St u d y 
I nter ve nti o n f or T o xicit y..................................................................... 5 0
8. 2
Reas o ns f or Disc o n ti n uati o n of St u d y Inter ve nti o n ............................ 5 1
8. 3
Wit h dra wal fr o m t he St u d y  b y t he Partici pa nt...................................5 1
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 9 5
8. 4
St u d y  Ter mi nati o n a n d Cl os ure..........................................................5 2
9
St u d y  Assess me nts a n d Pr oce d ures.................................................... 5 2
9. 1
Scree ni n g a n d Efficac y  Assess me nts.................................................. 5 2
9. 1. 1
Scree ni n g Pr oce d ures .......................................................................... 5 2
9. 1. 2
Efficac y  Assess me nts ......................................................................... 5 3
9. 1. 3
Sec o n dar y  E n d p oi nt Assess me nts ...................................................... 5 3
9. 1. 3. 1
Cli nical Stat us ..................................................................................... 5 3
9. 1. 3. 2
A d diti o nal Cli nical E n d p oi nts, C O VI D -1 9 I nfla m mat or y  
Bi o mar kers, a n d Select Ser u m Bi o mar kers ........................................ 5 4
9. 1. 3. 3
P har mac o ki netics ................................................................................ 5 4
9. 1. 4. 3
Pa rt B: P har mac o ki netic Para meters .................................................. 5 6
9. 2
Safet y  a n d Ot her Assess me nts............................................................ 5 6
9. 2. 1
O n -st u d y Pr oce d ures t o be F oll o we d i n t he E ve nt of A b n or mal 
La b orat or y  Test Val ues or A b n or mal Cli nical Fi n di n gs .................... 5 7
9. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ..................................... 5 7
9. 3. 1
Defi niti o n of a n A d verse E ve nt .......................................................... 5 7
9. 3. 2
Defi niti o n of Seri o us A d verse E ve nt .................................................. 5 8
9. 3. 3
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns ............................ 5 8
9. 3. 4
A d verse E ve nts of S pecia l Interest ..................................................... 5 9
9. 3. 4. 1
I nfecti o n..............................................................................................5 9
9. 3. 4. 2
Seiz ure ................................................................................................ 5 9
9. 3. 4. 3
Ser ot o ni n S y n dr o me ........................................................................... 5 9
9. 3. 4. 4
Cli nicall y  Si g nifica nt Arr yt h mia ........................................................ 5 9
9. 3. 5
Classificati o n of a n A d verse E ve nt ..................................................... 5 9
9. 3. 5. 1
Se verit y  of A d verse E ve nts ................................................................5 9
9. 3. 5. 2
Relati o ns hi p t o St u d y  Inter ve nti o n .....................................................6 0
9. 3. 6
Ti me Peri o d a n d Fre q ue nc y  f or E ve nt Assess me nt a n d F oll o w- u p ...6 0
9. 3. 6. 1
I n vesti gat ors Re p orti n g of A d verse E ve nts........................................6 0
9. 3. 7
A E SI  a n d S A E Re p orti n g...................................................................6 1
9. 3. 7. 1
I n vesti gat ors Re p orti n g of Seri o us A d verse E ve nts...........................6 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 9 5
9. 3. 7. 2
I n vesti gat ors Re p orti n g of A d verse E ve nt of S pecial Interest ............ 6 1
9. 3. 8
Re g ulat or y  Re p orti n g of Seri o us A d verse E ve nts ..............................6 1
9. 3. 9
Re p orti n g of Pre g na nc y ...................................................................... 6 2
9. 4
Treat me nt of O ver d ose ....................................................................... 6 2
9. 5
U na ntici pate d Pr o ble ms ...................................................................... 6 2
9. 5. 1
Defi niti o n of U na ntici pate d Pr o ble ms ................................................ 6 2
9. 5. 2
U na ntici pate d Pr o ble m Re p orti n g ...................................................... 6 3
9. 5. 3
Re p orti n g U na ntici pate d Pr o ble ms t o Partici pa nts ............................. 6 3
1 0. 3
P o p ulati o ns f or A nal y ses .................................................................... 6 4
1 0. 4
Statistical A nal y ses ............................................................................. 6 4
1 0. 4. 1
Ge neral A p pr oac h ............................................................................... 6 4
1 0. 4. 2
A na l ysis of t he Pri mar y Efficac y E n d p oi nt........................................ 6 5
1 0. 4. 3
A nal y sis of t he Sec o n dar y E n d p oi nts................................................. 6 5
1 0. 4. 3. 1
A nal y sis of Ali ve a n d N ot Re q uiri n g S u p ple me ntal O x yge nati o n 
t hr o u g h Da y 2 8................................................................................... 6 5
1 0. 4. 3. 2
A nal y sis of Cli nical Stat us.................................................................. 6 6
1 0. 4. 3. 3
A nal y sis of Ti m e t o S p O 2 of ≥9 4 % S ust ai n e d f or at L e ast 
2 4 h o urs i n R o o m Air ......................................................................6 6
1 0. 4. 3. 4
A nal y sis of All-ca use M ortalit y T hr o u g h Da y 6 0.............................. 6 7
1 0. 4. 3. 5
A nal y sis of Ti me t o I nte nsi ve Care U nit A d missi o n ( Da y 1 
T hr o u g h Da y  2 8)................................................................................. 6 7
1 0. 4. 3. 6
A nal y sis of Ti me t o I n vasi ve Mec ha nical Ve ntilati o n ( Da y 1 
T hr o u g h Da y  2 8)................................................................................. 6 7
1 0. 4. 3. 7
A nal y sis of Ti me t o N o ni n vasi ve Mec ha nical Ve ntilati o n ( Da y 1 
T hr o u g h Da y 2 8) ................................................................................. 6 7
1 0. 4. 3. 8
A nal y sis of T otal Da ys i n IC U ...........................................................6 7
1 0. 4. 3. 9
A nal y sis of T otal Da ys i n t he H os pital a n d Ti me t o H os pital 
Disc har ge ............................................................................................ 6 8
1 0. 4. 3. 1 0
A nal y sis of I nfla m mat or y Bi o mar kers ...............................................6 8
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 /9 5
1 0. 4. 3. 1 2
A nal y sis of Occ urre nce of Rela pse i n Partici pa nts D uri n g t he 
St u d y  Peri o d (if First Disc har ge d Wit hi n t he 6 0-da y  St u d y Peri o d).. 6 9
1 0. 4. 3. 1 3
A nal y sis of Occ urre nce of Re-h os pitalizati o n i n Partici pa nts 
D uri n g t he St u d y  Peri o d (if First Disc har ge d Wit hi n t he 6 0-d a y  
St u d y  Peri o d) D ue t o C O VI D-1 9 Disease C o m plicati o ns .................. 6 9
1 0. 4. 4
Safet y  A nalys is................................................................................... 6 9
1 0. 4. 5
P har mac o ki netic Para meters ...............................................................7 0
1 0. 4. 6
Baseli ne Descri pti ve Statistics ............................................................ 7 0
1 0. 4. 7
Pla n ne d Safet y A nal ys es ..................................................................... 7 0
1 1
S u p p orti n g D oc u me ntati o n a n d O perati o nal C o nsi derati o ns ............. 7 1
1 1. 1
Re g ulat or y , Et hical, a n d St u d y O versi g ht C o nsi derati o ns ................. 7 1
1 1. 1. 1
I nf or me d C o nse nt Pr ocess .................................................................. 7 1
1 1. 1. 2
C o nfi de ntialit y  a n d Pri vac y................................................................ 7 1
1 1. 1. 3
Sec o n dar y  Use of St ore d S peci me ns a n d Data................................... 7 2
1 1. 1. 4
Safet y  O versi g ht ................................................................................. 7 2
1 1. 1. 4. 1
I n de pe n de nt Data M o nit ori n g C o m mittee .......................................... 7 2
1 1. 1. 5
Data Ha n dli n g a n d Rec or d Kee pi n g ................................................... 7 3
1 1. 1. 5. 1
Data C ollecti o n a n d Ma na ge me nt Res p o nsi bilities............................ 7 3
1 1. 1. 5. 2
St u d y  Rec or d Rete nti o n...................................................................... 7 3
1 1. 1. 5. 3
S o urce Rec or ds ................................................................................... 7 3
1 1. 1. 6
Pr ot oc ol De viati o ns ............................................................................ 7 4
1 1. 1. 7
P u blicati o n a n d Data S hari n g P olic y .................................................. 7 4
1 1. 1. 8
C o nflict of I nterest P olic y ................................................................... 7 4
1 2
A d diti o nal C o nsi derati o ns .................................................................. 7 4
1 2. 1
Researc h -relate d I nj uries .................................................................... 7 4
1 3
Refere nces ...........................................................................................7 6
1 4
A p pe n dices ......................................................................................... 7 8
A p pe n di x 1
A b bre viat i o ns......................................................................................7 8
A p pe n di x 2
C o ntrace pti o n ......................................................................................8 0
A p pe n di x 3
Me dicati o n G ui da nce ..........................................................................8 2
A p pe n di x 4
Cli nical L a b orat or y Tests ...................................................................8 4
A p pe n di x 5
Pr ot oc ol A me n d me nts Hist or y ........................................................... 8 5
A p pe n di x 6
S p o ns or Si g nat ure Pa ge ......................................................................9 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 /9 5
A p pe n di x 7
C o or di nati n g I n vesti gat or Si g nat ure Pa ge .......................................... 9 4
A p pe n di x 8
Pri nci pal I n vesti gat or Si g nat ure Pa ge ................................................. 9 5
T a ble of T a bles
Ta ble 1
Sc he d ule of Assess me nts .................................................................... 1 6
Ta ble 2
Fl o w Rates Tra nslate d as I n hale d O x y ge n Perce nta ge (i.e., 
Fracti o n of I ns pire d O x y ge n) ..............................................................3 8
Ta ble 3
Pre d nis o ne E q ui vale nce Calc ulati o n ( T otal Dail y D ose) ................... 4 9
Ta ble 4
Acce pta ble P har mac o ki netic Wi n d o ws f or M 5 0 4 9 ( Part A) .............. 5 6
T a ble of Fi g ures
Fi g ure 1
St u d y  Sc he ma ( Part A) ....................................................................... 2 5
Fi g ure 2
St u d y  Sc he ma ( Part B)........................................................................ 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 /9 5
O B J E C TI V E S
E N D P OI N T S ( O U T C O M E M E A S U R E S)
2.
A m b ul at or y: li mit ati o n of a cti viti e s.
3.
H o s pit ali z e d, mil d di s e a s e: h o s pit ali z e d, n o 
o x y g e n t h er a p y.
4.
H o s pit ali z e d, mil d di s e a s e: o x y g e n b y m a s k or 
n a s al pr o n g s.
5.
H o s pit ali z e d, s e v er e di s e a s e: n o ni n v a si v e 
v e ntil ati o n or hi g h fl o w -o x y g e n.
6.
H o s pit ali z e d, s e v er e di s e a s e: i nt u b ati o n a n d 
m e c h a ni c al v e ntil ati o n.
7.
H o s pit ali z e d, s e v er e di s e a s e: v e ntil ati o n + 
a d diti o n al or g a n s u p p ort – e. g., pr e s s or s, R R T, 
E C M O.
8.
D e at h.
T o a s s e s s n or m ali z ati o n of o x y g e n ati o n st at u s 
wit h M 5 0 4 9 c o m p ar e d t o pl a c e b o i n p arti ci p a nt s 
w h o ar e ali v e a n d n ot o n m e c h a ni c al v e ntil ati o n.
Ti m e t o S p O 2 of ≥9 4 % s u st ai n e d f or at l e a st 2 4 h o ur s i n r o o m 
air fr o m D a y
1 t hr o u g h D a y 2 8.
T o e v al u at e t h e n u m b er s of d e at h s wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.
All -c a u s e m ort alit y ( D a y 1 t hr o u g h D a y 6 0).
T o e v al u at e cli ni c al d et eri or ati o n wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.

Ti m e t o I C U ( D a y 1 t hr o u g h D a y 2 8).

Ti m e t o i n v a si v e m e c h a ni c al v e ntil ati o n ( D a y 1 t hr o u g h 
D a y 2 8).

Ti m e t o n o ni n v a si v e m e c h a ni c al v e ntil ati o n ( D a y 1 t hr o u g h 
D a y 2 8).
T o a s s e s s t h e l e n gt h of st a y i n t h e I C U wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o.
T ot al d a y s i n I C U fr o m D a y 1 t hr o u g h D a y 6 0.
T o a s s e s s t h e l e n gt h of h o s pit al st a y wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o.

T ot al d a y s i n t h e h o s pit al fr o m D a y 1 t hr o u g h D a y 6 0.

Ti m e t o h o s pit al di s c h ar g e fr o m D a y 1 t hr o u g h D a y 2 8.
T o e v al u at e m o d ul ati o n of bi o m ar k er s of 
C O VI D -1 9 i nfl a m m ati o n wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.
I nfl a mm at or y bi o m ar k er s ( C R P, d -di m er, a n d f erriti n) 
d uri n g st u d y p eri o d ( D a y 1 t hr o u g h D a y 2 8).
T o e v al u at e m o d ul ati o n of s el e ct 
bi o m ar k er s wit h M 5 0 4 9 c o m p ar e d t o 
pl a c e b o.
Bi o m ar k er s (I L -6, T N F I L-8) d uri n g st u d y p eri o d ( D a y 1 
t hr o u g h D a y 2 8).
T o e v al u at e o c c urr e n c e of r el a p s e wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o.
O c c urr e n c e of r el a p s e i n p arti ci p a nt s d uri n g t h e st u d y 
p eri o d (if fir st di s c h ar g e d wit hi n t h e 6 0 -d a y st u d y p eri o d). 
R el a p s e r ef er s t o w or s e ni n g o x y g e n ati o n, wit h eit h er a 
p o siti v e r e s ult of a n y r e s pir at or y p at h o g e ni c n u cl ei c a ci d 
t e st, or w or s e ni n g l e si o n s o n c h e st i m a gi n g wit h 
r e-h o s pit ali z ati o n.
T o a s s e s s o c c urr e n c e of r e -h o s pit ali z ati o n s 
d u e t o C O VI D -1 9 di s e a s e c o m pli c ati o n s.
O c c urr e n c e of r e -h o s pit ali z ati o n i n p arti ci p a nt s d uri n g t h e 
st u d y p eri o d (i f fir st di s c h ar g e d wit hi n t h e 2 8-d a y st u d y 
p eri o d) d u e t o C O VI D -1 9 di s e a s e c o m pli c ati o n s ( D a y 5 
t hr o u g h D a y 6 0).
A E SI = a d v er s e e v e nt of s p e ci al i nt er e st; C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; C R P = C- r e a cti v e pr ot ei n; 
E C G = el e ctr o c ar di o gr a m; E C M O = e x tr a c or p or e al m e m br a n e o x y g e n ati o n; Fi O2 = fr a cti o n of i n s pir e d o x y g e n; 
I C U = i nt e n si v e c ar e u nit; R R T = r a pi d r e s p o n s e t e a m; S A E = s eri o u s a d v er s e e v e nt; S p O 2 = p eri p h er al c a pill ar y 
o x y g e n s at ur ati o n; T E A E = tr e at m e nt- e m er g e nt a d v er s e e v e nt.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 /9 5
O ver a ll Desi g n: T his is a 2- part, P hase II d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d st u d y t o 
e val uate t he safety of a n d cli nical res p o nse t o M 5 0 4 9 ta blets ta ke n orall y  t wice dail y  for 1 4 d a y s 
i n partici pa nts i nitiall y h os pitalize d beca use of m o derate t o se vere C O VI D -1 9 p ne u m o nia.
Partici pa nts will be ra n d o mize d 1: 1: 1 t o recei ve M 5 0 4 9 5 0 m g, M 5 0 4 9 1 0 0 m g, or place b o t wice 
dail y . Part A a n d Part B of t his e x pl orat or y st u d y will eac h c o nsist of a n u p t o 4 8- h o ur Scree ni n g 
Peri o d, a 1 4 -d a y  treat me nt peri o d wit hi n a 2 8-da y i n patie nt a n d/ or o ut patie nt S ur veilla nce peri o d, 
a n d t he n a 3 2- d a y i n patie nt a n d/ or o ut patie nt Safet y F oll o w -u p Peri o d. St u d y  partici pa nts s h o ul d 
be pr o vi de d t he l ocal sta n dar d/s u p p orti ve care b ut ca n n ot be o n a nti malarial (c hl or o q ui ne-relate d)
m e dicati o ns or ot her i m m u n o m o d ulati n g dr u gs (e xce pt f or c ortic oster oi ds – see eli gi bilit y an d 
c oa d mi nistrati o ns s pecificati o ns). Partici pa nts
o n R E C O V E R Y
T rial de xa met has o ne d osi n g 
e q ui vale nt of c ortic oster oi ds a n d i nitiate d o n a nti viral t hera py a n d/ or c o n valesce nt plas ma f or 
treat me nt of C O VI D- 1 9 ma y  be eli gi ble f or e nr oll me nt.
Sites: Site selecti o n will be deter mi ne d as i nf or mati o n bec o mes a vaila ble a b o ut t he e pi de mi ol o g y 
of C O VI D - 1 9, a n d sites will be acti vate d base d o n t he n u m ber of l ocal/re gi o nal cases a n d t he 
willi n g ness of l ocal I nvesti gat ors t o partici pate i n t he st u d y. M ore s pecificall y, e pi de mi ol o g y is 
defi ne d b y  the e v ol vi n g n u m ber of C O VI D - 1 9 cases, t he n u m ber of h os pitalizati o ns , a n d t he 
n u m ber of i nte nsi ve care u nit a d missi o ns at eac h site.
St u d y  Durati o n: T he st u d y will last a p pr o xi matel y 1 5 m o nt hs. Eac h partici pa nt is e x pecte d t o be 
o n st u d y /i n f oll o w-u p f or 6 0 t o 6 2 da y s.
I n v ol ve me nt of S peci al C o m mittee(s): A n i nter nal I n de pe n de nt Data M o nit ori n g C o m mittee will 
be m o nit ori n g safet y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 /9 5
1. 3
St u d y Sc he m a
Fi g ure 1
St u d y Sc he m a ( P art A)
BI D = t wi c e d ail y; C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; E o S = E n d of St u d y; E o T = E n d of Tr e at m e nt .
Fi g ure 2
St u d y Sc he m a ( P art B)
BI D = t wi c e d ail y; C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; E o S = E n d of St u d y; E o T = E n d of Tr e at m e nt .
D oc u me nt N o. 
O bject N o. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
     
    
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 /9 5
2
I ntr o d ucti o n
2. 1
St u d y R ati o n ale
C or o na vir us disease 2 0 1 9 ( C O VI D-1 9) is a ne w pa n de mic disease c haracterize d b y  pul m o nar y 
i nfla m mati o n fr o m i nfecti o n wit h 
se vere 
ac ute 
res pirat or y 
sy n dr o me 
c or o na vir us 2 
( S A R S-C o V -2). S A R S -C o V -2 is a si n gle -stra n de d ri b o n ucleic aci d (ss R N A) vir us relate d t o b ot h 
S A R S -C o V - 1, w hic h ca use d se vere ac ute res pirat or y sy n dr o me (S A R S ) disease i n 2 0 0 2/ 0 3, a n d 
Mi d dle East res pirat or y sy n dr o me c or o na vir us. W hile a nti viral t hera pies t o treat t he C O VI D- 1 9 
are ur ge ntl y nee de d, treat me nts f or se vere disease wit h e xcessi ve p ul m o nar y  infla m mati o n are als o 
critical t o re d uce C O VI D - 1 9 c o m plicati o ns lea di n g t o i ncrease d m ortalit y  an d t o decrease t he 
b ur de n of t he ra pi dly e v ol vi n g pa n de mic o n t he healt h care s yste m ( Fel d ma n n 2 0 2 0). Gi ve n t hat 
t he i m m u n o pat h ol o g y in reacti o n t o S A R S -C o V -2 i nfecti o n is c o ntri b uti n g t o t he hi g h rate of 
m or bi dit y  an d m ortalit y,  host -directe d i m m u n o m o d ulat or y ap pr oac hes are als o bei n g e val uate d 
(Me hta
2 0 2 0, Ste b bi n g 2 0 2 0 ).
I n t his e x pl orat or y P hase II st u d y, a 1 4-d a y  c o urse of M 5 0 4 9, a p ote nt, selecti ve toll -li ke rece pt or 
( T LR) 7/ 8 a nta g o nist will be e val uate d. T he o pti mal ti mi n g of M 5 0 4 9 d osi n g is h y p ot hesize d t o 
be after t he partici pa nt’s i nitial a nti viral res p o nse (s o as t o n ot i nterfere wit h i nitial h ost c o ntr ol or 
cleara nce of t he vir us) a n d w he n i ncreasi n g p ul m o nar y  infla m mati o n is si g nali n g a n o verl y
a m plifie d h ost i nfla m mat or y res p o nse. Treat me nt of C O VI D- 1 9 p ne u m o nia after t he i m me diate 
h ost i n nate a n d earl y a da pti ve i m m u ne res p o nses c o ul d p ote ntiall y  halt pr o gressi o n t o se vere 
i m m u n o pat h ol o g y wit h o ut c o m pr o misi n g viral cleara nce (Si d di q ui 2 0 2 0 ).
T he safety a n d cli nical res p o nse t o orall y -a d mi nistere d M 5 0 4 9
will be e val uate d f or 1 4 d a y s i n 
partici pa nts wit h m o derate d t o se vere C O VI D - 1 9 p ne u m o nia w h o are mai ntai ne d o n l ocal sta n dar d 
of care a n d h os pitalize d w it h o ut t he nee d f or mec ha nical ve ntilati o n . T he 2- p art st u d y is a 
ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d desi g n. T he st u d y desi g n a n d partici pa nt safety 
m o nit ori n g are base d o n M 5 0 4 9 
data o btai ne d fr o m t he first-i n-h u ma n ( FI H) P hase I si n gle 
asce n di n g d ose a n d 1 4- d a y  
multi ple asce n di n g d ose healt h y v ol u nteer st u d y, n o ncli nical 
e val uati o ns of M 5 0 4 9, 
a n d t he ti mi n g of ot her a nti-i nfla m mat or y age nts f or treat me nt of
C O VI D - 1 9 p ne u m o nia. M 5 0 4 9 de m o nstrates d ose -pr o p orti o nal p har mac o ki netics ( P K), has a 
half -life of a p pr o xi matel y 7 to 1 1 h o urs, a n d is mai nl y  meta b oli ze d b y  al de h yde o xi dase, n ot t he 
c o m m o n c yt oc hr o me P 4 5 0 e nz ymes.
T he s mall m olec ule, M 5 0 4 9 , is a d ual T L R 7/ 8 a nta g o nist s h o w n t o s pecificall y i n hi bit t he acti vity 
of vari o us T L R 7/ 8 li ga n ds s uch as ss R N A, certai n G U -ric h micr o
ri b o n ucleic aci d (R N A ), a n d 
s mall m olec ule rece pt or a g o nists. T L R 7 / 8 is e x presse d i n t he e n d os o mes of cells wit h i n nate 
i m m u ne f u ncti o n, w here acti vati o n b y ss R N A vir uses (e. g., S A R S-C o V -2) sti m ulates secreti o n of 
T y pe I interfer o ns (IF Ns) a n d pr oi nfla m mat or y  cyt o ki nes (i nterle u ki n [IL] 6, t u m or necr osis fact or 
al p ha [T N F α ], a n d ot hers), cell ular mat urati o n a n d acti vati o n of ot her h ost i m m u ne mec ha nis ms 
(C h o w 2 0 1 8, Li 2 0 1 3 ).
T w o d ose le vels of M 5 0 4 9, 1 0 0 m g t wice dail y  an d 5 0 m g t wice dail y , will be e val uate d a gai nst 
place b o. T he d ose selecti o n is g ui de d b y  PK a n d 
 data fr o m t he P hase I 
healt h y  vol u nteer st u d y an d b y  the d oses f o u n d t o be efficaci o us i n precli nical l u p us a ni mal 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 /9 5
m o dels. I n the P hase I st u d y, M 5 0 4 9 
s u p presse d secreti o n of e x vi v o -sti m ulate d c yt o ki nes 
i ncl u di n g I L- 6, T N F α , a n d I F N α i n a n e x p os ure - de pe n de nt ma n ner. Base d o n t hese data, 
preli mi nar y  
mo deli n g 
a n d si m ulati o ns pr ojecte d 
1 0 0 m g 
t wice dail y  
wo ul d 
s u p press 
e x vi v o -sti m ulate d I L-6 pr o d ucti o n b y  90 % i n 8 7 % of healt h y  vol u nteers, a n d 5 0 m g t wice dail y 
w o ul d s u p press I L- 6 pr o d ucti o n b y  50 % i n 9 0 % of healt h y  vol u nteers. As t he ma g nit u de of 
T L R 7 / 8 i n hi biti o n re q uire d f or s u p pressi o n of t he c yt o ki ne pr o d ucti o n i n C O VI D - 1 9 patie nts is 
u n k n o w n, a n d t he M 5 0 4 9 safet y pr ofile has n ot bee n descri be d i n t his patie nt p o p ulati o n, cli nical 
a n d p har mac ol o gic e val uati o n of b ot h t he 5 0 m g a n d 1 0 0 m g t wice dail y  dose s i n partici pa nts wit h 
C O VI D - 1 9 p ne u m o nia is vie we d as j ustifie d.
Gi ve n t he a vaila ble data f or M 5 0 4 9 i n h u ma ns, a 2- part, place b o -c o ntr olle d st u d y is dee me d 
necessar y . T he st u d y will be gi n wit h an assess me nt of safet y in 1 5 partici pa nts ( Part A) bef ore 
e x pa n di n g t o a f ull P hase II cli nical e val uati o n of t he st u d y inter ve nti o n i n a n a d diti o nal 
1 3 5 partici pa nts ( Part B) . St u d y partici pa nts m a y  be mai ntai ne d o n s u p p orti ve care b ut s h o ul d n ot 
be si m ulta ne o usl y enr olle d i n ot her C O VI D - 1 9 st u dies. Ot her i m m u n o m o d ulati n g dr u gs s h o ul d 
n ot be use d wit h M 5 0 4 9 (wit h t he e xce pti o n of c ortic oster oi ds per eli gi bilit y an d c o nc o mita nt 
me dicati o ns 
re q uire me nts) u nless t he partici pa nt dec o m pe nsates, (e. g., re q uires mec ha nical 
ve ntilati o n) .
A d diti o n of a n a nti malarial or a nti-i nfla m mat or y me dicati o n w o ul d u n der mi ne t he e val uati o n o n 
t he r ole of M 5 0 4 9 f or C O VI D -1 9 p ne u m o nia a n d t he vali dit y of t he st u dy. T he st u d y partici pa nt’s 
pri mar y  ma na gi n g cli nicia n ma y  place t he partici pa nt o n t he l ocall y preferre d a nti viral t hera p y
a n d/ or c o n valesce nt plas ma (as pre vi o usl y d eter mi ne d at a site le vel a n d wit h S p o ns or n otificati o n
bef ore st u d y im ple me ntati o n) . Part A partici pa nts will be stratifie d b y prese nce/a bse nce of 
o bstr ucti ve l u n g disease. Part B p artici pa nts will be stratifie d base d o n (1) t he use of c ortic oster oi ds 
at a pre d n is o ne e q ui vale nt dail y  dosa ge of ≤1 5 m g or
> 1 5 m g  wit hi n 4 8 h o urs pri or t o 
ra n d o mizati o n, (2) t he use of a nti viral t hera p y i ncl u di n g c o n valesce nt plas ma ( prese nce or 
a bse nce) wit hi n 4 8 h o urs pri or t o ra n d o mizati o n , a n d (3) c o u ntr y .
T his e x pl orat or y, Phase II, pr o of - of-c o nce pt st u d y will e val uate partici pa nts wit h m o derate t o 
se vere C O VI D -1 9 p ne u m o nia recei vi n g M 5 0 4 9 c o m pare d t o place b o o n t he cli nical res p o nse 
defi ne d as t he pr o p orti o n of partici pa nts w h o are ali ve a n d n ot re q uiri n g s u p ple me ntal o x y ge nati o n 
(i ncl u di n g n o ni n vasi ve or mec ha nical ve ntilati o n a n d E C M O) at D a y 1 4. T he partici pa nts will 
c o nti n ue t o be f oll o we d t o d oc u me nt t heir vital stat us a n d nee d f or o x y ge n or ve ntilat or y  s u p p ort
t hr o u g h D a y 2 8 i n t he M 5 0 4 9 c o m pare d t o place b o gr o u ps. I n a d diti o n t o f oll o wi n g ot her cli nical 
para meters , s uc h as W H O or di nal scale, data o n ti me t o peri p heral ca pillar y ox y ge n sat urati o n 
( S p O2) ≥9 4 % s ustai ne d f or at least 2 4 h o urs i n r o o m air t hr o u g h D a y 2 8 will als o be c ollecte d a n d 
e val uated t o better i nf or m f ut ure st u d y i nter ve nti o n e val uati o n i n t his p o p ulati o n. Partici pa nts will 
be f oll o we d t hr o u g h Da y 6 0 f or vital si g ns.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 /9 5
2. 2
B ac k gr o u n d
2. 2. 1
P ur p ose of St u d y
C or o na vir us es are p ositi ve -se nse si n gle-stra n de d e n vel o pe d R N A vir uses, ma n y  of w hic h are 
c o m m o nl y fo u n d i n h u ma ns a n d ca use mil d s ym pt o ms. O ver t he past t w o deca des, e mer gi n g 
pat h o ge nic c or o na vir uses ca pa ble of ca usi n g life -t hreate ni n g disease i n h u ma ns a n d a ni mals ha ve 
bee n i de ntifie d, na mel y se vere ac ute res pirat or y s yn dr o me c or o na vir us ( S A R S -C o V) a n d Mi d dle 
East res pirat or y sy n dr o me c or o na vir us.
I n Dece m ber 2 0 1 9, t he W u ha n 
M u nici pal 
Healt h C o m mittee ( W u ha n, C hi na) i de ntifie d a n 
o ut brea k of viral p ne u m o nia cases of u n k n o w n ca use. C or o na vir us R N A was q uic kl y i de ntifie d i n 
s o me of t hese patie nts. T his n o vel c or o na vir us has bee n a b bre viate d as S A R S - C o V- 2 a n d has 8 9 % 
n ucle oti de i de ntit y wit h bat S A R S -li ke-C o V Z X C 2 1 a n d 8 2 % wit h t hat of h u ma n S A R S -C o V 
(C ha n 2 0 2 0 ). S A R S -C o V - 2 has n o w res ulte d i n a pa n de mic i nfecti n g o ver 1 0 0 milli o n pe o ple 
w orl d wi de wit h a case fatalit y  rate of ar o u n d 2. 1 % as of e n d of Ja nuar y 2 0 2 1 (W H O
2 0 2 1) .
T here is a n ur ge nt p u blic healt h nee d f or ra pi d de vel o p me nt of n o vel i nter ve nti o ns. Eff orts 
c o nti n ue t o e x pa n d i n e val uati n g e xisti n g a n d n o vel a nti virals a n d t hera pe utic strate gies t hat c o ul d 
be s uccessf ul i n treati n g C O VI D- 1 9 disease.
2. 2. 2
P ote nti al T her a pe utics
T here are se veral a nti virals a n d i m m u n o m o d ulati n g dr u gs u n der i n vesti gati o n f or C O VI D - 1 9. T he 
me dical scie nce is ra pi dl y ev ol vi n g . a n d e. g., t he U S F D A a p pr o ve d t he use of re m desi vir f or t he 
treat me nt of S A R S -C o V - 2 i nfecti o n i n Oct o ber 2 0 2 0 a n d has pr o vi de d E mer ge nc y  
Use 
A ut h orizati o n
t o a n u m ber of treat me nts (e. g., m o n ocl o nal a nti b o dies as a nti viral treat me nts 
tar geti n g S A R S -C o V - 2 i nfecti o n), h o we ver, access t o t hese me dicati o ns f or all h os pitalize d 
patie nts wit h C O VI D -1 9 p ne u m o nia is y et t o be deter mi ne d.
M 5 0 4 9 
is h y p ot hesize d t o be c o m ple me ntar y to a nti viral t hera pies a n d t o be e val uate d f or 
pre ve nti o n a n d treat me nt of t he c yt o ki ne st or m p hase of disease i n p artici pa nts h os pitalize d wit h 
m o derate 
t o se vere C O VI D -1 9 p ne u m o nia ; ot her i n vesti gati o nal a nti-i nfla m mat ories are
c o ntrai n dicate d u nless t he partici pa nt re q uires i n vasi ve 
mec ha nical ve ntilati o n. A nti virals 
i ncl u di n g c o n valesce nt plas ma will be all o we d as bac k gr o u n d t hera p y (acc or di n g t o l ocal sta n dar d 
of care a n d wit h pre vi o us a p pr o val b y  the site Pri nci pal I n vesti gat or [ PI ] a n d t he S p o ns or per eac h 
site).
2. 3
Ris k / Be nefit Assess me nt
D oc u me nt N o
O bject N o. 
C CI
C CIC CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 /9 5
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 /9 5
O B J E C TI V E S
E N D P OI N T S ( O U T C O M E M E A S U R E S)
1 4. H o s pit ali z e d, s e v er e di s e a s e: n o ni n v a si v e 
v e ntil ati o n or hi g h fl o w -o x y g e n.
1 5. H o s pit ali z e d, s e v er e di s e a s e: i nt u b ati o n a n d 
m e c h a ni c al v e ntil ati o n.
1 6. H o s pit ali z e d, s e v er e di s e a s e: v e ntil ati o n + 
a d diti o n al or g a n s u p p o rt – e. g., pr e s s or s, R R T, 
E C M O.
1 7. D e at h.
T o a s s e s s n or m ali z ati o n of o x y g e n ati o n st at u s 
wit h M 5 0 4 9 c o m p ar e d t o pl a c e b o i n p arti ci p a nt s 
w h o ar e ali v e a n d n ot o n m e c h a ni c al v e ntil ati o n.
Ti m e t o S p O 2 of ≥9 4 % s u st ai n e d f or at l e a st 2 4 h o ur s i n r o o m 
air fr o m D a y 1 t hr o u g h D a y 2 8.
T o e v al u at e t h e n u m b er s of d e at h s wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.
All -c a u s e m ort alit y ( D a y 1 t hr o u g h D a y 6 0).
T o e v al u at e cli ni c al d et eri or ati o n wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.

Ti m e t o I C U ( D a y 1 t hr o u g h D a y 2 8).

Ti m e t o i n v a si v e m e c h a ni c al v e ntil ati o n ( D a y 1 t hr o u g h 
D a y 2 8).

Ti m e t o n o ni n v a si v e m e c h a ni c al v e ntil ati o n ( D a y 1 t hr o u g h 
D a y 2 8).
T o a s s e s s t h e l e n gt h of st a y i n t h e I C U wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o .
T ot al d a y s i n I C U fr o m D a y 1 t hr o u g h D a y 6 0.
T o a s s e s s t h e l e n gt h of h o s pit al st a y wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o .

T ot al d a y s i n t h e h o s pit al fr o m D a y 1 t hr o u g h D a y 6 0.

Ti m e t o h o s pit al di s c h ar g e fr o m D a y 1 t hr o u g h D a y 2 8.
T o e v al u at e m o d ul ati o n of bi o m ar k er s of 
C O VI D -1 9 i nfl a m m ati o n wit h M 5 0 4 9 
c o m p ar e d t o pl a c e b o.
I nfl a mm at or y bi o m ar k er s ( C R P, d -di m er, a n d f erriti n) 
d uri n g st u d y p eri o d ( D a y 1 t hr o u g h D a y 2 8).
T o e v al u at e m o d ul ati o n of s el e ct 
bi o m ar k er s wit h M 5 0 4 9 c o m p ar e d t o 
pl a c e b o.
Bi o m ar k er s (I L -6, T N F I L-8) d uri n g st u d y p eri o d ( D a y 1 
t hr o u g h D a y 2 8).
T o e v al u at e o c c urr e n c e of r el a p s e wit h 
M 5 0 4 9 c o m p ar e d t o pl a c e b o.
O c c urr e n c e of r el a p s e i n p arti ci p a nt s d uri n g t h e st u d y 
p eri o d (if fir st di s c h ar g e d wit hi n t h e 6 0 -d a y st u d y p eri o d). 
R el a p s e r ef er s t o w or s e ni n g o x y g e n ati o n, wit h eit h er a 
p o siti v e r e s ult of a n y r e s pir at or y p at h o g e ni c n u cl ei c a ci d 
t e st, or w or s e ni n g l e si o n s o n c h e st i m a gi n g wit h 
r e-h o s pit ali z ati o n.
T o a s s e s s o c c urr e n c e of r e -h o s pit ali z ati o n s 
d u e t o C O VI D -1 9 di s e a s e c o m pli c ati o n s.
O c c urr e n c e of r e -h o s pit ali z ati o n i n p arti ci p a nt s d uri n g t h e 
st u d y p eri o d (i f fir st di s c h ar g e d wit hi n t h e 2 8-d a y st u d y 
p eri o d) d u e t o C O VI D -1 9 di s e a s e c o m pli c ati o n s ( D a y 5 
t hr o u g h D a y 6 0).
D oc u me nt N o. 
O bject N o. C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 /9 5
O B J E C TI V E S
E N D P OI N T S ( O U T C O M E M E A S U R E S)
e v al u at e W B C a s m ar k er s f or di s e a s e 
s e v erit y.
A E SI = a d v er s e e v e nt of s p e ci al i nt er e st; C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; C R P = C- r e a cti v e pr ot ei n; 
C tr o u g h = pr e d o s e o b s er v e d c o n c e ntr ati o n; E C G = el e ctr o c ar di o gr a m; E C M O = e xtr a c or p or e al m e m br a n e o x y g e n ati o n; 
I C U = i nt e n si v e c ar e u nit; I F N = i nt erf er o n; 
; P K = p h ar m a c o ki n eti c; 
 
R R T = r a pi d r e s p o n s e t e a m; S A E = s eri o u s a d v er s e e v e nt; S A R S -C o V = s e v er e a c ut e r e s pir at or y s y n dr o m e 
c or o n a vir u s; S p O 2 = p eri p h er al c a pill ar y o x y g e n s at ur ati o n; T E A E = tr e at m e nt- e m er g e nt a d v er s e e v e nt ; WB C = w hit e 
bl o o d c ell .
4
St u d y Desi g n
4. 1
O ver all Desi g n
T his is a 2- part, P hase II d o u ble-bli n d, ra n d o mize d, place b o -c o ntr olle d st u d y to e val uate t he safety 
of a n d cli nical res p o nse t o M 5 0 4 9 ta blets ta ke n orall y t wice dail y f or 1 4 da y s i n partici pa nts
i nitiall y h os pitalize d beca use of m o derate t o se vere C O VI D - 1 9 p ne u m o nia. Partici pa nts will be 
f oll o we d t o assess t h ose w h o are ali ve a n d n ot re q uiri n g s u p ple me ntal o x y ge nati o n (i ncl u di n g 
n o ni n vasi ve or mec ha nical ve ntilati o n a n d E C M O) at Da y 1 4 i n t he M 5 0 4 9 c o m pare d t o place b o 
gr o u ps. Partici pa nts will c o nti n ue t o be f oll o we d t o d oc u me nt t heir nee d f or ox y ge n or ve ntilati o n 
s u p p ort a n d cli nical stat us t hr o u g h D a y 2 8, a n d c o m plete safety f oll o w-u p (a n d vital si g ns) t hr o u g h 
D a y 6 0.
Eli gi ble st u d y partici pa nts, w h o test S A R S -C o V -2 p ositi ve as esta blis he d b y l ocal g ui deli nes, will 
n ot be o n mec ha nical ve ntila ti o n a n d m ust ha ve a n S p O 2 < 9 4 % i n r o o m air a n d partial press ure 
of o x y ge n ( Pa O 2)/fracti o n of i ns pire d o x yge n ( Fi O 2) ≥1 5 0 wit h a ma xi m u m Fi O 2 0. 4.
Part A partici pa nts will be stratifie d b y  prese nce/a bse nce of o bstr ucti ve l u n g disease. Part B 
partici pa nts will be stratifie d base d o n ( 1) t he use of c ortic oster oi ds at a pre d nis o ne e q ui vale nt 
dail y  dosa ge of ≤1 5 m g or > 1 5 m g wit hi n 4 8 h o urs pri or t o ran d o mizati o n, ( 2) t he use of a nti viral 
t hera py
i ncl u di n g c o n valesce nt plas ma ( prese nce or a bse nce) wit hi n 
4 8 h o urs pri or t o 
ra n d o mizati o n, a n d (3) c o u ntr y .
If t he atte n di n g h os pital p h y sicia n a ntici pates t he partici pa nt m a y  re q uire mec ha nical ve ntilati o n 
i n t he first 2 4 h o urs of e nteri n g i n t he st u d y, t he partici pa nt s h o ul d n ot be a p pr oac he d f or c o nse nt. 
St u d y  partici pa nts s h o ul d be pr o vi de d t he l ocal sta n dar d/s u p p orti ve care b ut ca n n ot be o n 
c hl or o q ui ne-relate d me dicati o ns or ot her i m m u n o m o d ulati n g dr u gs t o e nter t he st u d y (t he 
e xce pti o n is t hat if c ortic oster oi ds are i nitiate d pri or t o or d uri n g t he st u d y  Scree ni n g peri o d [a n d 
pri or t o ra n d o mizati o n], t he y are all o we d b ut t he y must n ot be hi g her t ha n 4 0 m g pre d nis o ne per 
da y  base d o n t he d osi n g re gi me n a n d sc he d ule use d i n t he R E C O V E R Y Trial ( N C T 0 4 3 8 1 9 3 6; 
H o rb y 2 0 2 0 ). If t he l ocal sta n dar d of care i ncl u des use of a n a nti viral t hera p y (a n d/ or c o n valesce nt 
plas ma ), w hic h has bee n u nif or ml y a gree d t o b y t he site, has t he per missi o n of t he l ocal Pri nci pal
I n vesti gat or, a n d t he S p o ns or has bee n n otifie d, partici pa nts o n a nti viral t hera p y ma y be eli gi ble 
f or e nr oll me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 /9 5
Partici pa nts will be ra n d o mize d 1: 1: 1 t o recei ve M 5 0 4 9 5 0 m g, M 5 0 4 9 1 0 0 m g, or place b o ta blets 
orall y  twice dail y (e ver y 12 h o urs) . Part A a n d Part B of t his e x pl orat or y st u d y will eac h c o nsist 
of a n u p t o 4 8- h o ur Scree ni n g Peri o d, a 1 4- d a y  treat me nt peri o d at t he start of t he o verarc hi n g 
2 8- d a y  in patie nt a n d/ or o ut patie nt S ur veilla nce peri o d, a n d u p t o a 3 2 -d a y  i n patie nt a n d/ or 
o ut patie nt Safet y  Foll o w -u p Peri o d. Details of ma na ge me nt of p ote ntial dr u g t o xicit y an d st u d y 
i nter ve nti o n disc o nti n uati o n f or t he partici pa nt are pr o vi de d i n Secti o n 8. 1 .
Part A of t he st u d y will pa use e nr oll me nt after 1 5 partici pa nts ha ve bee n ra n d o mize d t o t he 
st u d y-defi ne d i nter ve nti o n (see Fi g ure 1) . U nless a partici pa nt is ter mi nate d fr o m t he st u d y as a 
treat me nt fail ure or f or safety reas o ns, a n d after c o ns ultati o n wit h t he S p o ns or, partici pa nt s
ra n d o mize d i n Part A m a y  be re place d if t he y ha ve disc o nti n ue d t he st u d y bef ore c o m pleti n g
1 4 da y s of treat me nt. A n i nter nal I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) t hat pr o vi des 
o n g oi n g s ur veilla nce of partici pa nt safet y will re vie w a vaila ble safet y an d cli nical o utc o mes data 
a n d will pr o v i de a rec o m me n dati o n w het her or n ot t he st u d y is safe t o pr ocee d t o Part B. Details 
of t he re vie w ma y  be f o u n d i n t he I D M C c harter.
Part B of t he st u d y will e nr oll a p pr o xi matel y 13 5 partici pa nts (see Fi g ure 2) . D etail a nal ys es 
perf or me d f or t he p ur p ose of ris k/ be nefit m o nit ori n g, t he f ull me m bers hi p, ma n date, a n d pr ocesses 
of t he I D M C m a y  be f o u n d i n t he I D M C c harter. T he I D M C will deci de w het her or n ot t o c o nti n ue 
t he st u d y as per pr ot oc ol or ma ke rec o m me n dati o ns as s pecifie d i n t he I D M C charter. U nless t here 
is reas o n t o halt t he st u d y base d o n I D M C rec o m me n dati o ns, a t otal of 1 5 0 partici pa nts are pla n ne d 
t o be ra n do mize d a n d f oll o we d i n Part A a n d Part B of t his st u d y .
After c o nse nt of t he partici pa nt (a n d/ or if necessar y , t he partici pa nt’s le gall y desi g nate d g uar dia n 
b y  telec o nfere nce as all o wa ble b y  local la ws), data f or t his st u d y will be o btai ne d fr o m t he 
partic i pa nt’s o ut patie nt , e mer ge nc y r o o m a n d/ or h os pital rec or ds. Data t o assess eli gi bilit y  will be 
o btai ne d i n t his ma n ner u nless t he data are u n a vaila ble; t he n t he pr oce d ures as s pecifie d i n Ta ble 1
m ust be perf or me d t o deter mi ne eli gi bilit y . Ot her data n ot a vaila ble fr o m t he partici pa nt’s rec or ds 
ma y  be o btai ne d fr o m t he partici pa nt , o nly wit h o ut i nterfere nce i n t he partici pa nt’s cli nical 
ma na ge me nt a n d wit h per missi o n of t he partici pa nt’s pri mar y  atte n di n g cli nicia n (e. g., p h y sicia n, 
p h y sicia n assista nt, or n urse practiti o ner). If data are n ot o btai na ble, d oc u me ntati o n as t o w h y 
s h o ul d be pr o vi de d.
Partici pa nts will be a d mi nistere d o ne of t w o d ose le vels of t he st u d y inter ve nti o n, M 5 0 4 9 , or 
matc hi n g 
place b o 
ta blets, orall y  
ev er y  
12 h o urs ,
after 
a n y 
re q uire d st u d y 
safet y 
assess me nts/ pr oce d ures ( ot her t ha n p ost -treat me nt P K sa m pli n g a n d E C G s) are perf or me d. U nless 
ot her wise s pecifie d (e. g., arterial bl o o d gas at Scree ni n g acc or di n g t o sta n dar d of care per l ocal 
g ui da nce ), all sc he d ule d bl o o d a n d cli nical assess me nts will be o btai ne d fr o m t he st u d y 
partici pa nt’s rec or d as t he assess me nt w o ul d be part of sta n dar d of care f or ma na gi n g C O VI D -1 9 
p ne u m o nia i n t he h os pital. A s mall n u m ber of researc h bl o o d sa m ples (e. g., P K, ser u m , a n d  
 
bi o mar ker sa m ples) will be c ollecte d at Da y 1, Da y 3, Da y 7, Da y 1 4 , a n d Da y 2 8 (at t he ti me 
p oi nts i n dicate d i n Ta ble 1 ) o nl y  if t he partici pa nt re mai ns i n t he h os pital. As t h ose assess me nts 
are t o g ui de f urt her st u d y i nter ve nti o n de vel o p me nt a n d e val u ati o n a n d are n ot part of sta n dar d of
care f or C O VI D- 1 9, t he sa m ple assess me nts will n ot be perf or me d real-ti me.
All partici pa nts w h o are disc har ge d bef ore Da y 1 4 will
be pr o vi de d wit h a diar y  car d (see 
Secti o n 6. 1. 1. 2 ) a n d ha ve tele me dici ne visits i n l ocales w here it is le gall y acce pta ble a n d if a n 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 /9 5
o ut patie nt ret ur n visit is n ot feasi ble. O ut patie nt partici pa nt s, w h o pre mat urel y disc o nti n ue t he 
st u d y i nter ve nti o n, u p o n n otificati o n of t heir st u d y site, s h o ul d prefera bl y  c o nti n ue t he st u dy 
f oll o w-u p sc he d ule f or safet y; or if necessar y, ret ur n as s o o n as p ossi ble f or a n Earl y  Ter mi nati o n 
( E T) Visit.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T his P hase II st u dy ai ms t o e val uate t he p ote ntial of M 5 0 4 9 t o treat partici pa nts h os pitalize d wit h 
m o derate t o se vere C O VI D - 1 9 p ne u m o nia bef ore re q uiri n g mec ha nical ve ntilati o n. M 5 0 4 9, a 
selecti ve T L R 7/ 8 i n hi bit or, c o ul d p ote ntiall y  s u p press e xcess c yt o ki ne pr o d ucti o n (e. g., I L-6, 
T N F α) t hat is i n d uce d b y  ss R N A S A R S -C o V - 2 i n partici pa nts wit h C O VI D - 1 9 p ne u m o nia. T he 
ti mi n g of M 5 0 4 9 i nter ve nti o n is pr o p ose d t o be after t he partici pa nt ’s i nitial a nti viral res p o nse (s o 
as t o n ot i nterfere wit h i nitial h ost c o ntr ol or cleara nce of t he vir us) i n t h ose w h o s u bse q ue ntly 
ha ve i ncreasi n g p ul m o nar y  infla m mati o n a n d distress, w he n t he st u d y inter ve nti o n ma y  decrease 
a n o verl y a m plifie d h ost i nfla m mat or y res p o nse re prese nti n g a nti b o d y- de pe n de nt ela b orati o n of 
c yt o ki ne st or m (Si d di q ui 2 0 2 0 ). T he st u d y desi g n is i nf or me d b y t he data o n M 5 0 4 9 ge nerate d i n 
t he FI H P hase I healt h y  v ol u nteer P K st u d y a n d precli nical a ni mal m o del e x peri me nts.
O bser vati o n of a n ass ociati o n of M 5 0 4 9 treat me nt wit h i m pr o ve me nt of cli nical stat us (e. g., n o 
l o n ger re q uiri n g s u p ple me ntal o x y ge nati o n or ve ntilati o n s u p p ort, h os pital disc har ge , etc.) in 
partici pa nts wit h C O VI D- 1 9 p ne u m o nia w o ul d pr o vi de s u p p ort f or f urt her cli nical de vel o p me nt 
of M 5 0 4 9 f or C O VI D - 1 9 (Ca o 2 0 2 0, Va n de n B o o m 2 0 2 0 , Wa n g 2 0 2 0 , Z h o u 2 0 2 0, G ua n 2 0 1 9 ).
4. 3
J ustific ati o n f or D ose
T he pr o p ose d d oses of M 5 0 4 9 f or t he st u d y are 5 0 m g or 1 0 0 m g t wice dail y  in a ne w ta blet 
f or m ulati o n wit h o ut f o o d restricti o n. T he d ose le vels t o be e val uate d are selecte d base d o n safety,  
P K , a n d P D (i n hi biti o n of e x vi v o -sti m ulate d I L-6 c y t o ki ne secreti o n) o bser ve d i n t he si n gle a n d 
m ulti ple asce n di n g d ose ( FI H) st u d y in healt h y  partici pa nts. P har mac o ki netic res ults i n dicate d 
d ose -pr o p orti o nalit y of ma xi mal c o nce ntrati o ns a n d o verall e x p os ure ( A U C) i n t he i n vesti gate d 
d ose ra n ge ( 1 t o 2 0 0 m g si n gle or as dail y  d ose) wit h a ter mi nal half-life of 7 t o 1 1 h o ur s.
T he f oll o wi n g data were c o nsi dere d w he n deter mi ni n g t he d oses of M 5 0 4 9 f or t his st u d y :

Preli mi nar y  mo deli n g a n d si m ulati o ns base d o n t he o bser ve d P K a n d P D (i n hi biti o n of 
e x vi v o -sti m ulate d I L- 6 c yt o ki ne secreti o n) i n t he FI H st u d y su g gest t hat M 5 0 4 9 
tro u g h 
c o nce ntrati o ns at stea dy- state ( Cmi n,ss ) will re mai n a b o ve t he I C9 0 i n 8 7. 3 % of t he partici pa nts 
w h o recei ve a 1 0 0 m g  twice dail y d ose a n d 3 1. 2 % of partici pa nts w h o recei ve a 5 0 m g  twice 
dail y  dose. F or b ot h t he 5 0 m g a n d 1 0 0 m g  twice dail y  doses, M 5 0 4 9 tr o u g h c o nce ntrati o ns 
will re mai n a b o ve t he I C5 0 i n m ore t ha n 9 0 % of partici pa nts.

T he FI H healt h y  vol u nteer st u d y e val uate d a n oral M 5 0 4 9 s ol uti o n u n der faste d c o n diti o n 
e xce pt f or a s mall f o o d effect c o h ort. T he c urre nt st u d y will use a ta blet f or m ulati o n wit h o ut 
f o o d restricti o n. M 5 0 4 9 is c o nsi dere d as a Bi o p har mace utics Classificati o n S y ste m Class 1 
c o m p o u n d a n d ta blet f or mulati o n s h o we d ver y  ra pi d diss ol uti o n pr ofile. It is e x pecte d t hat t he 
ne w ta blet f or m ulati o n has si milar e x p os ure c o m pare d t o t he oral s ol uti o n use d i n t he FI H st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 /9 5

T he e x pecte d A U C 0- 2 4 h,ss a n d C ma x,ss at 1 0 0 m g t wice dail y wit h o ut f o o d restricti o n re mai ns well 
bel o w t he e x p os ures at t he n o o bser ve d a d verse effect le vels i n 4-wee k n o ncli nical t o xic ol o g y 
st u d y i n d o g wit h at least 1 0- f ol d safety mar gi n.

T he A U C was i ncrease d b y  33 % a n d C ma x was decrease d b y  11 % u n der fe d c o n diti o n c o m pare d 
t o faste d c o n diti o ns.
Base d o n t he a b o ve c o nsi derati o ns, b ot h t he 5 0 m g a n d 1 0 0 m g t wice dail y d oses i n t he ne w ta blet 
f or m ulati o n wit h o ut f o o d restricti o ns m a y  pr o vi de t he o p p ort u nit y t o o bser ve a P D effect 
(i.e., su p pressi o n of i nfla m mat or y bi o mar kers, e. g. , I L-6) a n d cli nical res p o nse i n partici pa nts wit h 
C O VI D -1 9 p ne u m o nia w hile als o mai ntai ni n g acce pta ble safet y mar gi n.
4. 4
E arl y H os pit al Disc h ar ge Assess me nts
A partici pa nt w h o is disc har ge d fr o m t he h os pital after Da y 3 a n d bef ore Da y 1 4 s h o ul d ha ve t he 
sa me assess me nts as E T of st u d y  treat me nts as per t he sc he d ule of assess me nts ( Secti o n 1. 2 ), b ut 
c o nti n ue st u d y treat me nt as a n o ut patie nt u ntil Da y 1 4.
4. 5
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he last 
visit or t he last sc he d ule d pr oce d ure s h o w n i n  Ta ble 1.
T he e n d of t he st u d y is defi ne d as t he date of t he last visit of t he last partici pa nt or t he last sc he d ule d 
pr oce d ure s h o w n i n  Ta ble 1 f or t he last partici pa nt gl o bally.
4. 6
E arl y Ter mi n ati o n of Tre at me nt
W he n a partici pa nt is disc o nti n ue d or wit h dra ws fr o m treat me nt bef ore D a y 1 4, t he partici pa nt 
s h o ul d c o m plete t he E T assess me nts as s o o n as p ossi ble a n d re vert t o t he sa me st u d y sc he d ule
(Ta ble 1 ) base d o n t he partici pa nt’s D a y 1; t he partici pa nt s h o ul d be e nc o ura ge d t o c o nti n ue 
f oll o w- u p f or safety a n d cli nical assess me nts o utli ne d i n Ta ble 1 t hr o u g h Da y 6 0.
4. 7
S ur veill a nce, S afet y a n d E n d of St u d y Visits
Si nce i m p orta nt sec o n dar y en d p oi nts are e val uate d at D a y 2 8, s ur veilla nce assess me nts occ ur 
bet wee n D a y 1 4 a n d D a y 2 8, w hic h m a y  be disti n g uis he d fr o m c o nti n ue d safety f oll o w-u p t o 
D a y 6 0. If a partici pa nt is disc har ge d a n d n ot see n at t he st u d y  site (as ma y b e t he re q uire me nt of 
t he state a n d/ or l ocal h os pital/cli nic), e ver y eff ort s h o ul d be ma de t o c ollect w hat i nf or mati o n is 
a vaila ble o ver t he p h o ne or t hr o u g h a tele me dici ne c o ntact after h os pital disc har ge.
As t he maj orit y of st u d y partici pa nts s h o ul d be dis c har ge d b y  Da y 2 8, assess me nts f or visits at 
D a y 4 4 a n d Da y 6 0 ( E n d o f S t u d y) are a ntici pate d t o be b y tele me dici ne or p h o ne c o ntact.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 /9 5
4. 8
Rel a pse Defi niti o n
A partici pa nt w h o has bee n disc har ge d fr o m t he h os pital wit h a n S p O 2 of ≥9 4 % s ustai ne d f or at 
least 2 4 h o urs i n r o o m air, b ut w h o m ust be re-a d mitte d bef ore Da y 6 0 d ue t o w orse ni n g 
o x y ge nati o n (a n S p O 2 < 9 4 % i n r o o m air), wit h eit her a p ositi ve res ult of res pirat or y pat h o ge nic 
n ucleic aci d test ( N A T) or w orse ni n g lesi o ns o n c hest i ma gi n g (c o m pare d t o t he p artici pa nt’s sa me 
m o dalit y  of c hest i ma gi n g [c hest X-r a y or c o m p ute d t o m o gra p hy { C T }] at disc har ge, if a vaila ble)
will be c o u nte d as a res pirator y rela pse. F or S A R S -C o V- 2 or a n y ot her i nfecti o n, rec or d t he
a nat o mic site fr o m w hic h t he i nfecti o n was assesse d i n a d diti o n t o t he i nfecti ng a ge nt. T he 
assess me nts i n  Ta ble 1 f or t he Rela pse V isit will be perf or me d , a n d assess me nts i n Ta ble 1 will be 
res u me d base d o n t he partici pa nt’s Da y 1 of st u d y  e ntr y.
5
St u d y P o p ul ati o n
H os pitalize d patie nts ( ≥1 8 t o ≤7 5 ye ars of a ge) wit h C O VI D- 1 9 p ne u m o nia n ot o n mec ha nical 
ve ntilati o n wit h a n S p O 2 < 9 4 % i n r o o m air A N D
a ble t o mai ntai n a Pa O 2/ Fi O2 ≥1 5 0 ( or 
e q ui vale nt S p O 2/ Fi O2 ≥1 9 0) wit h a ma xi m u m Fi O 2 0. 4. T hese rea di n gs ma y  be o btai ne d after 
e xerti o n b y  the partici pa nt.
Pati e nts o n c o nti n u o us p ositi ve air wa y press ure s h o ul d ha ve 
assess me nts f or eli gi bilit y perf or me d w hile a wa ke.
T he c orrelati o n bet wee n S p O 2/ Fi O2 rati o a n d meas ure d Pa O2/ FiO 2 rati o is hi g h w he n restricte d t o 
patie nts wit h S p O 2 ≤9 6 %, as s u bsta ntial variati o n of Pa O 2 is prese nt i n hi g her S p O 2 ra n ge
(Br o w n 2 0 1 6) . T he relati o ns hi p bet wee n S p O 2/ Fi O2 a n d Pa O 2/ Fi O2 was descri be d b y  the f oll o wi n g 
e q uati o n: S/ F = 6 4 + 0. 8 4 x ( Pa O2/ Fi O2) (Rice 2 0 0 7) . Ma xi m u m i n hale d perce nta ge o x y ge nati o n 
( Fi O2 0. 4) mea ns patie nts s h o ul d be o n a nasal ca nn ula or face mas k wit h o ut n o nre breat her at
≤5 L/ mi n
(see g ui da nce Ta ble 2) . ( N ote: face mas k wit h n o nre breat her will ha ve a hi g her 
esti mate d Fi O 2 [i.e., > 0. 4 0 ] a n d t heref ore w o ul d be i neli gi ble).
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 /9 5
M e dical M o nit or or desi g nee re gar di n g e vi de nce of pr o ba ble C O VI D -1 9 p ne u m o nia f or st u d y 
partici pa nt eli gi bilit y .
5.
N ot o n mec ha nical ve ntilati o n (i n vasi ve or n o ni n vasi ve), or ve ntilati o n , or E C M O , n or ( base d 
o n me dical j u d ge me nt of a d mitti n g p h y sicia n) a ntici pate d t o be i n t he ne xt 2 4 h o urs .
6.
A n S p O 2 < 9 4 % i n r o o m air A N D a ble t o mai ntai n a Pa O 2/ Fi O2 ≥1 5 0 ( or e q ui vale nt S p O 2
/ Fi O2 ≥1 9 0 ) wit h a ma xi m u m Fi O 2 0. 4. T hese rea di n gs ma y  be o btai ne d after e xerti o n b y t he 
partici pa nt. N ote: if partici pa nt is o n c hr o nic l o w O 2 t hera py ( ≤2 L), assess t heir c urre nt 
b aseli ne O 2 re q uire me nts f or eli gi bilit y.
7.
Re q uiri n g h os pitalizati o n (i.e., i n t he pr ocess of h os pital a d missi o n or alrea d y a d mitte d).
Birt h C o ntr ol b ase d o n Se x at Birt h
8.
a. Fe male Partici pa nts:

N ot a w o ma n of c hil d beari n g p ote ntial ( See A p pe n di x 2 ).
O R

If a w o ma n of c hil d beari n g p ote ntial :
o
Is usi n g a de p ot c o ntrace pti ve or e xte n de d c ycle oral c o ntrace pti ve fr o m bef ore t he first 
d ose of t he st u d y i nter ve nti o n(s).
o
A gree n ot t o bec o me pre g na nt or d o nate e g gs ( o va, o oc y tes) f or re pr o d ucti o n f or a f ull 
6 0 da y s.
o
Use a hi g hl y effecti ve c o ntrace pti ve met h o d (i.e., wit h a fail ure rate of < 1 % per year) as 
descri be d i n  A p pe n di x 2 f or t he d urati o n of t he st u d y (a f ull 6 0 d a y s), eit her wit h :

A dail y use h or m o nal c o ntrace pti o n fr o m bef ore t he first d ose of t he st u d y 
i nter ve nti o n(s),
O R

Uses a barrier met h o d d uri n g t he le n gt h of t he st u d y  (a f ull 6 0 d a y s).
b. Male Partici pa nts:

A gree t o refrai n fr o m d o nati n g s per m f or at least 90 da y s.
P L U S, eit her

A bstai n fr o m i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial .
O R

Use a male c o n d o m f or at least 9 0 da ys:
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 /9 5
W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial , w h o is n ot c urre ntl y 
pre g na nt, a n d a d vise her t o use a hi g hl y effecti ve c o ntrace pti ve met h o d wit h a fail ure rate of 
< 1 % per ye ar (see A p pe n di x 2) , si nce a c o n d o m ma y brea k or lea k.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
A n y  co n diti o n t hat c o ul d i nterfere wit h t he st u d y o bjecti ves, c o n d uct or e val uati o n i n t he 
o pi ni o n of t he I n vesti gat or or S p o ns or or desi g nee.
2.
If pre g na nt ( by p ositi ve hi g h -se nsiti vit y pre g na nc y test) or breastfee di n g.
3.
Cli nicall y  si g nifica nt (i.e., acti ve) car di o vasc ular disease: cere br ovasc ular acci de nt/str o ke 
( < 6 m o nt hs pri or t o e nr oll me nt), m y ocar dial i nfarcti o n ( < 6 m o nt hs pri or t o e nr oll me nt), 
u nsta ble a n gi na pect oris, c o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n Classificati o n 
Class ≥III), or seri o us car diac arr h yt h mia re q uiri n g me dic ati o n (i ncl u di n g c orrecte d Q T 
i nter val pr ol o n gati o n of > 4 7 0 ms a n d/ or pace ma ker) or pri or dia g n osis of c o n ge nital l o n g Q T 
s yn dr o me. N ote: d oc u me nte d, l o n gsta n di n g Left B u n dle Bra nc h Bl oc k ( L B B B) res ulti n g i n a 
l o n g Q Tc
usi n g Fri dericia’s f or m ula, is n ot excl usi o nar y if c orrecte d b y  the Q Tc -L B B B 
{ [ Q T – ( 0. 7 × Q R S – 5 0 )]/s q uare r o ot R R} or J T c ( Q Tc – Q R S d urati o n) f or m ula.
4.
Hist or y  of u nc o ntr olle d ill ness (i n t he o pi ni o n of t he I n vesti gat or) pri or t o S A R S -C o V -2 
i nfecti o n, wit hi n t he 3 m o nt hs pri or t o Scree ni n g, i ncl u di n g b ut n ot li mite d t o:
a.
H y perte nsi o n u nc o ntr olle d b y  sta n dar d t hera pies ( n ot sta bilize d t o 1 5 0/ 9 0 m m H g or 
l o wer), or
b.
U nc o ntr olle d acti ve i nfecti o n (e.g. , se ptice mia), or
c.
Si g nifica ntl y u nc o ntr olle d dia betes mellit us or a n y dia betes t hat has res ulte d i n se vere e n d 
or ga n da ma ge, or
d.
U nc o ntr olle d or se vere ast h ma or ot her c hr o nic o bstr ucti ve p ul m o nar y  disease. N ote: 
u nc o ntr olle d ast h ma/c hr o nic o bstr ucti ve p ul m o nar y  disease is defi ne d as m ore t ha n 
1 e xacer bati o n i n t he pre vi o us 1 2 m o n t hs t hat re q uire d a n e mer ge nc y ro o m visit or 
h os pitalizati o n. N ote: c hr o nic l o w O2 (≤ 2 L) t hera p y is all o we d as l o n g as t he partici pa nt 
meets t he criteria o utli ne d i n I ncl usi o n Criteri o n 6.
5.
H ist or y of e pile ps y, ot her ne ur ol o gical dis or der ass ociate d wit h seiz ures (e. g., cere br o vasc ular 
acci de nt/str o ke, ac ute brai n i nfecti o n, tra u matic brai n i nj ur y, pr o gressi ve brai n disease, 
c o n ge nital brai n disease), or c urre ntl y acti ve a n d u nc o ntr olle d ne ur o ps y c hiatric c o n diti o n (i n 
t he o pi ni o n of t he I nvesti gat or) i ncl u di n g de pressi o n or c urre nt s uici dal i deati o n.
6.
Hist or y  of i nterstitial l u n g disease pri or t o Scree ni n g or c urre nt t hr o m b osis or e m b olis m
prese nt d uri n g Scree ni n g .
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 /9 5
7.
Hist or y  of a pri mar y  im m u n o deficie nc y , or ga n tra ns pla nt, s ple nect o m y or f u ncti o nal as ple nia.
8.
Hist or y of t he f oll o wi n g pri or t o Scree ni n g:
a.
H u ma n i m m u n o deficie nc y vir us i nfecti o n.
b.
U ntreate d
he patitis C (i.e., if he patitis C
a nti b o d y
p ositi ve , he patitis C D N A 
is 
detecta ble ).
c.
U ntreate d he patitis B ( positi ve f or he pati tis B s urface a nti ge n or if he patitis c ore a nti b o d y 
p ositi ve , he patitis B D N A is detecta ble ).
d.
Rec urre nt her pes z oster (t w o or m ore e pis o des wit hi n a 1 0-year peri o d) .
e.
K n o w n acti ve t u berc ul osis ( T B) or u ntreate d late nt T B i nfecti o n.
N ote: la b orat or y c onfir mati o n of i n acti ve i nfecti o n stat us is n ot re q uire d f or st u d y eli gi bilit y.
A p pr o priate T B test ca n be perf or me d t o dia g n ose T B i nfecti o n per cli nical j u d ge me nt.
9.
Hist or y  of mali g na nc y  (he mat ol o gic or s oli d t u m or) t hat is n ot c urre ntl y u n der c o ntr ol or i n 
re missi o n pri or t o Scree ni n g.
1 0. Hist or y  of k n o w n alc o h ol or dr u g a b use i n t he 3 m o nt hs pri or t o Scree ni n g as per I n vesti gat or 
o pi ni o n.
Pri or/ C o nc o mit a nt T her a p y
1 1 . K n o w n h y perse nsiti vit y  t o a n y st u d y treat me nt, c o m p o ne nt, or place b o.
1 2. Hist or y  of vacci nati o n a gai nst S A R S -C o V - 2. Vacci nati o n is all o we d after Da y 2 8 as per l ocal 
sta n dar d of care a n d/ or as per t he I n vesti gat or’s cli nical j u d g me nt a n d mi g ht be per mitte d
bef ore Da y 2 8 after c o ns ultati o n wit h t he Me dical M o nit or or desi g nee.
1 3.
D ail y u se of t he f oll o wi n g me dicati o ns ass ociate d wit h ser ot o ni n s yn dr o me wit hi n 1 4 da y s 
pri or t o ra n d o mizati o n:
a.
A nti de pressa nts: 
selecti ve ser ot o ni n re u pta ke i n hi bit ors, ser ot o ni n n ore pi ne p hri ne 
re u pta ke i n hi bit ors, tric yclic a nti de pressa nts, m o n oa mi ne o xi dase i n hi bit ors, St. J o h n’s 
w ort. E xce pti o n: fl u o xeti ne wit hi n 8 wee ks pri or t o ra n d o mizati o n.
b.
A nal gesics: tra ma d ol, fe nta n yl (i.e., i nter mitte nt use as nee de d pri or t o ra n d o mizati o n is 
all o we d).
c.
L o n g -acti n g anti -e metics e. g., pal o n osetr o n, d olas etr o n. S h ort -acti n g a nti -e metics, e. g, 
o n da nsetr o n, p ote ntiall y ass ociate d wit h ser ot o ni n s yn dr o me ma y  be prescri be d o n a n as 
nee de d basis . If s h ort-acti n g a ntie metics re q uire ar o u n d t he cl oc k a d mi nistrati o n f or m ore 
t ha n 1 day, please c o ntact y o ur M e dical M o nit or or desi g nee t o e ns ure safet y of t he st u d y 
partici pa nt. S h ort -acti n g a nti -e metics s h o ul d n ot be a d mi nistere d wit hi n 3 h o urs of st u d y 
treat me nt.
d.
Li nez oli d, tr y pt o p ha n, b us pir o ne, te diz oli d.
1 4. T he i nitiati o n, use or c ha n ge i n t hera pies wit hi n 1 4 da y s pri or t o ra n d o mizati o n:
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 /9 5
a.
Use of ral o xife ne, ta m o xife n, estra di ol, cl oza pi ne, c hl or pr o mazi ne (str o n g al de h y d e 
o xi dase i n hi bit ors ).
b.
Use of c ortic oster oi ds e xcee di n g 4 0 m g  dail y pre d nis o ne e q ui vale nt (e. g., de xa met has o ne 
6 m g) . Use of 4 0 m g  dail y pre d nis o ne e q ui vale nt (e. g., de xa met has o ne 6 m g) f or m ore 
t ha n 1 0 d a y s d uri n g t he st u d y .
c.
A n y  vacci nati o n i ncl u de d b ut n ot li mite d t o s u b u nit or i nacti vate d vacci nes.
d.
Use of C hi nese her bal / n o n-her bal me dicati o ns (e. g., tri pter ygi u m, t otal gl uc osi des of 
pe o n y , etc.).
e.
Use of plas ma p heresis or he m o perf usi o n (see Secti o n 7. 4. 2 ).
1 5. T he i nitiati o n, or use of t hera pies wit hi n 1 m o nt h pri or t o ra n d o mizati o n:
a.
Vacci nati o n wit h li ve or li ve atte n uate d vir us vacci ne.
b.
Use of a n y me dicati o n c o nsi dere d t o ha ve i m m u n o m o d ulati n g a n d/ or i m m u n os u p pressa nt 
pr o perties i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g: a nti malarials, (e. g., c hl or o q ui ne, 
h y dr o x yc hl or o q ui ne, 
mefl o q ui ne) ,
lefl u n o mi de, met h otre xate, 
6- merca pt o p uri ne, 
s ulfasalazi ne, m y c o p he n olate m ofetil 
or s o di u m, azat hi o pri ne, c ycl o p h os p ha mi de, 
da ps o ne, reti n oi ds, a batace pt, a nifr ol u ma b, t hali d o mi de, le nali d o mi de, a nti-T N F α a ge nts,
s yste mic calci ne uri n i n hi bit ors (e. g., c ycl os p ori ne, tacr oli m us) (alt h o u g h t o pical use of 
calci ne uri n i n hi bit ors are all o we d), Br ut o n’s t yr osi ne ki nase i n hi bit ors, ot her s mall 
m olec ules
s uc h as t ofaciti ni b (i.e., Ja n us ki nase/si g nal tra ns d ucers, acti vat ors of 
tra nscri pti o n pat h wa y  in hi bit ors ), I L- 1 a n d I L-6 pat h wa y  in hi bit ors, T N F α pat h wa y 
i n hi bit ors, I L-1 2/I L -2 3 pat h wa y  in hi bit ors , (e. g., uste ki n u ma b) , or ot her disease 
m o dif y i n g, i m m u n os u p pressi ve or i m m u n o m o d ulat or y t hera pies n ot ot her wise s pecifie d 
i n pr ot oc ol.
c.
Use of B cell de pleti n g/ m o d ulati n g t hera p y suc h as a nti-C D 2 0 a ge nts i ncl u di n g b ut n ot 
li mite d t o
rit u xi ma b, ocreliz u ma b, 
ofat u m u ma b, 
o bi n ut uz u ma b, 
ocarat uz u ma b, 
velt uz u ma b, o r bi osi milars t here of, beli m u ma b, or d ual or ot her a nti-B L y m p h oc y te 
Sti m ulat or/a pr oliferati o n i n d uci n g li ga n d ne utralizi n g t hera pies (e. g., R C T 1 8).
1 6 . C o nc urre nt i nter ve nti o nal cli nical st u d y partici pati o n pri or t o st u d y ra n d o mizati o n t hr o u g h 
D a y 2 8. After Da y 2 8 , ap pr o val t o partici pate m ust be re q ueste d fr o m t he S p o ns or w he n t here 
e xists t he i nte nt of partici pati o n i n a c o nc urre nt st u d y.
Di a g n ostic Assess me nts
1 7. Cli nicall y  si g nifica nt or pre defi ne d a b n or malities i n la b orat or y tests (ser u m c he mistries: 
as partate a mi n otra nsferase [A S T ], ala ni ne a mi n otra nsferase [ A L T] or al kali ne p h os p hatase 
le vel > 5. 0 × u p per li mit of n or mal [ U L N]), or he mat ol o gic test ( he m o gl o bi n < 5. 0 m m ol/ L 
[ 9 g/ d L ], w hite 
bl o o d cells < 1. 5
× 
1 0 9/ L, a bs ol ute ne utr o p hil c o u nt < 7 5 0 / m m3, 
platelets < 5 0 × 1 0 9/ L) at Scree ni n g.
1 8. Esti mate d gl o mer ular filtrati o n rate (e G F R ) < 4 5 m L / mi n/ 1. 7 3 m 2 as calc ulate d b y  the 
M o dificati o n of Diet i n Re nal Disease e q uati o n:
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 /9 5
e G F R = 1 7 5 × (ser u m creati ni ne i n m g / d L)– 1. 1 5 4 × (a ge i n ye ars) – 0. 2 0 3 × 0. 7 4 2 (if fe male) × 
1. 2 1 2 (if race is blac k)
5. 3
Lifest yle C o nsi der ati o ns
N o restricti o ns pertai ni n g t o lifest y le a n d/ or diet be yo n d t he details i n dicate d i n Secti o n 5. 2 .
5. 4
Scree n F ail ures
After t he S cree ni n g e val uati o ns ha ve bee n c o m plete d, t he I n vesti gat or or desi g nee is t o re vie w t he 
i ncl usi o n/e xcl usi o n criteria a n d deter mi ne t he partici pa nt ’s eli gi bilit y for t he st u d y. O nl y t he 
reas o n f or i neli gi bilit y will be c ollecte d o n scree n fail ures. Partici pa nts w h o are f o u n d t o be 
i neli gi ble will be t ol d t he reas o n f or i neli gi bilit y. Partici pa nts w h o d o n ot meet t he criteria f or 
i ncl usi o n i n t his st ud y  (scree n fail ure) m a y  be rescree ne d o nce. Rescree ne d partici pa nts will be 
assi g ne d a ne w partici pa nt n u m ber a n d will u n der g o Scree ni n g pr oce d ures as deter mi ne d b y  th e 
S p o ns or a n d I n vesti gat or.
5. 5
Str ate gies f or Recr uit me nt a n d Rete nti o n
5. 5. 1
Recr uit me nt
It is a ntici pate d t hat partici pa nts wit h C O VI D -1 9 will prese nt t o partici pati n g h os pitals a n d t hat n o 
ot her eff orts t o recr uit p ote ntial partici pa nt s are nee de d. Recr uit me nt eff orts ma y  als o i ncl u de 
disse mi nati o n of i nf or mati o n a b o ut t his st u d y t o ot her me dical professi o nals/ h os pitals.
Partici pa nts w h o are c o nfir me d t o ha ve S A R S -C o V - 2 a n d i n t he pr ocess of h os pital a d missi o n or 
alrea d y i n t he h os pital will be assesse d f or eli gi bilit y .
Scree ni n g will be gi n wit h a brief disc ussi o n wit h st u d y staff. S o me partici pa nt s will be e xcl u de d 
base d o n de m o gra p hic data a n d me dical hist or y  (i.e., pre g na nt, < 1 8 or > 7 5 ye ars of a ge, se vere 
or u nc o ntr olle d c hr o nic o bstr ucti ve p ul m o nar y  disease i ncl u di n g ast h ma, heart disease, ce ntral 
ner v o us s yste m disease, re nal fail ure, etc.). I nf or mati o n a b o ut t he st u d y will be prese nte d t o 
p ote ntial partici pa nt s ( or le gall y aut h orize d re prese ntati ve) a n d q uesti o ns will be as ke d t o 
deter mi ne p ote ntial eli gi bilit y. Assess me nts c o m plete d f or partici pati o n i n t he st u d y ca n be gi n o nl y 
after i nf orme d c o nse nt is o btai ne d.
5. 5. 2
C osts
T here is n o c ost t o partici pa nt s f or t he researc h tests, pr oce d ures/e val uati o ns a n d st u d y i nter ve nti o n
w hile part ici pati n g i n t his st u d y. Pr oce d ures a n d treat me nt f or cli nical care, i ncl u di n g c osts 
ass ociate d wit h h os pital sta y, m a y  be bille d t o t he partici pa nt , partici pa nt ’s i ns ura nce, or t hir d 
part y , if a n d as a p pr o priate.
5. 5. 3
St u d y F oll o w -u p
All partici pa nts will be f oll o we d as a n i n patie nt or o ut patie nt f or u p t o 6 0 da y s after st u d y entr y 
f or a n y C O VI D - 1 9 disease c o m or bi dities, a n y ot her A Es re q uiri n g c ha n ges i n c o nc o mita nt 
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 /9 5
me dicati o ns, seri o us a d verse e ve nts (S A Es ) i ncl u di n g a n y re-a d missi o ns t o t he h os pital , a n d 
c ha n ges i n vital stat us assess me nts i ncl u di n g t he W H O or di nal scale.
Partici pa nts w h o 
are f o u n d t o ha ve acti ve he patitis, h u ma n i m m u n o deficie nc y vir us, or 
t u berc ul osis i nfecti o n after e nr oll me nt i nt o t he st u d y (base d o n a ntici pate d dela y s i n dia g n ostic 
la bs), will be assesse d a n d ma na ge d acc or di n g t o S ecti o n 8. 1 .
5. 5. 4
H os pit al Disc h ar ge
All partici pa nts s h o ul d be e nc o ura ge d t o mai ntai n t he st u d y  sc he d ule of assess me nts (Ta ble 1) , if 
n ot b y  ret ur ni n g t o t he st u d y site t he n t hr o u g h tele me dici ne visits. Rec or d all a vaila ble assess me nts 
per  Ta ble 1 i ncl u di n g n ucleic aci d testi n g f or S A R S- C o V-2 a n d a n y  assess me nts f or c o nti n uati o n 
of viral s he d di n g per l ocal pr oce d ures. A partici pa nt w h o is disc har ge d fr o m t he h os pital after 
D a y 3 a n d bef ore D a y 1 4 s h o ul d ha ve t he sa me assess me nts as E T of st u d y treat me nts as per t he 
sc he d ule of assess me nts ( Secti o n 1. 2 ).
6
S t u d y I nter ve nti o n
6. 1
St u d y I nter ve nti o n a n d A d mi nistr ati o n
6. 1. 1
I n vesti g ati o n al T her a pe utic a n d M atc hi n g Pl ace b o
T he s u p plie d matc hi n g place b o M 5 0 4 9 ta blet is i de ntical i n p h y sical a p peara nce t o t he acti ve 
M 5 0 4 9 ta blet.
6. 1. 1. 1
St u d y I nter ve nti o n Descri pti o n
St u d y  I nt er v e nti o n N a m e:
M 5 0 4 9
M at c hi n g Pl a c e b o
D o s e F or m ul ati o n:
Fil m -c o at e d y ell o wi s h t o y ell o w 
t a bl et
Fil m -c o at e d y ell o wi s h t o y ell o w 
t a bl et
U nit D o s e Str e n gt h( s):
2 5 m g
Pl a c e b o
D o s a g e L e v el( s):
5 0 m g, 1 0 0 m g
Pl a c e b o
6. 1. 1. 2
D osi n g a n d A d mi nistr ati o n
F o ur st u d y inter ve nti o n ta blets will be ta ke n orall y  wit h water t wice dail y  (e ver y 12 h o urs, 
m or ni n g a n d e ve ni n g) f or 1 4 da y s (a t otal of 2 8 d oses, 4 ta blets eac h d ose). D osi n g s h o ul d occ ur 
wit hi n a 2- h o ur wi n d o w. T h ose partici pa nts w h o e nter t he i nte nsi ve care u nit (I C U), m a y  still 
recei ve t he st u d y i nter ve nti o n if a ble t o ta ke t he ta blets b y  m o ut h. If partici pa nts i n t he I CU m a y
recei ve me dici nes o nl y b y  nas o gastric t u be ( N G T), refer t o t he P har mac y Ma n ual f or i nstr ucti o ns 
o n pre pari n g t he st u d y inter ve nti o n ta blets f or a d mi nistrati o n via N G T . N o ot her me dicati o n 
s h o ul d be gi ve n at t he sa me ti me as t he st u d y i nter ve nti o n via N G T .
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 /9 5
F or partici pa nts w h o are disc har ge d pri or t o treat me nt c o m pleti o n, a diar y  car d will be pr o vi de d 
t o rec or d t he n u m ber of st u d y inter ve nti o n ta blets a d mi nistere d dail y as well as a n y s y m pt o ms t he 
partici pa nt ma y  be e x perie nci n g. T his diar y  car d ma y  be ret ur ne d b y  mail or electr o nicall y t o t he 
st u d y site. Date a n d ti me of st u d y inter ve nti o n a d mi nistrati o n will be rec or de d i n t he diar y 
car d/ electr o nic ca se re p ort f or m (e C R F).
6. 1. 2. 1
Ac q uisiti o n a n d Acc o u nt a bilit y
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(i.e., recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
O nl y  partici pa nts e nr olle d i n t he st u d y m a y recei ve st u d y i nter ve nti o n(s) a n d o nl y aut h orize d site 
staff m a y  pr o vi de it. All st u d y inter ve nti o n(s) will be st ore d i n a sec ure, e n vir o n me ntall y 
c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, per t he la bele d st ora ge c o n diti o ns, a n d wit h 
access li mite d t o t he I nvesti gat or a n d a ut h orize d site staff. F urt her g ui da nce a n d i nf or mati o n f or 
t he st u d y i nter ve nti o n acc o u nta bilit y are pr o vi de d i n t he P har mac y  Ma n ual.
Bef ore t he st u d y is i nitiate d, t he l o g-i n i nf or mati o n a n d directi o ns f or t he I nteracti ve We b 
Res p o nse S y ste m (I WR S ) will be pr o vi de d t o eac h site. T he site will c o ntact t he I WR S pri or t o 
starti n g st u dy i nter ve nti o n a d mi nistrati o n f or eac h partici pa nt.
Bli n de d treat me nt kit n u m bers will be o btai ne d t hr o u g h t he I W R S. T he I W R S will be use d t o 
assi g n u ni q ue partici pa nt n u m bers, all ocate partici pa nts t o st u d y inter ve nti o n gr o u p a n d all ocate 
st u d y i nter ve nti o n at t he ra n d o mizati o n visit.
6. 1. 2. 2
Destr ucti o n
Destr ucti o n of use d a n d u n use d st oc k will be perf or me d l ocall y b y t he site at t he e n d of t he st u d y 
as per i nstit uti o ns pr oce d ures a n d sta n dar d o perati n g pr oce d ures . C o nfir mati o n a n d rec or d of 
destr ucti o n will be pr o vi de d t o t he S p o ns or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 /9 5
6. 1. 5
Pre p ar ati o n
M 5 0 4 9 fil m-c oate d ta blets a n d place b o fil m-c oate d ta blets are rea d y f or oral use. N o s pecial 
ha n dli n g is re q uire d u nless t he partici pa n t is u na ble t o recei ve st u d y  i nter ve nti o n b y  m o ut h.
F or t h ose partici pa nts w h o ca n n ot ta ke t he ta blets b y  mo ut h d uri n g Part B of t he st u d y, e. g., 
partici pa nts w h o are mec ha nicall y i nt u bate d, refer t o t he P har mac y  Ma n ual f or i nf or mati o n o n 
pre parati o n of t he ta blets (st u d y inter ve nti o n) a n d a p plicati o n via a n N G T . Partici pa nts i n Part A 
of t he st u d y will nee d t o disc o nti n ue st u d y inter ve nti o n if/ w he n t he y are n o l o n ger a ble t o ta ke 
ta blets b y m o ut h.
7
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
O nce t he partici pa nt meets i ncl usi o n a n d e xcl usi o n criteria, t he I n vesti gat or or dele gate will re q uest 
t he bli n de d st u d y inter ve nti o n treat me nt assi g n me nt usi n g t he I WR S. T he st u d y will ra n d o mize 
partici pa nts 1: 1: 1 t o M 5 0 4 9 5 0 m g, M 5 0 4 9 1 0 0 m g , or place b o t wice dail y.
Part A partici pa nts will be stratifie d b y  prese nce/a bse nce of o bstr ucti ve l u n g disease. Part B 
partici pa nts will be stratifie d base d o n ( 1) t he use of c ortic oster oi ds at a pre d nis o ne e q ui vale nt 
dail y  dosa ge of ≤1 5 m g or > 1 5 m g wit hi n 4 8 h o urs pri or t o ra n d o mizati o n, (2) t he use of a nti viral 
t hera py
i ncl u di n g c o n valesce nt plas ma ( prese nce or a bse nce) wit hi n 
4 8 h o urs pri or t o 
ra n d o mizati o n, a n d (3) c o u ntr y .
Partici pa nt n u m bers will be assi g ne d i n t he a p pr o priate f or mat a n d will reflect st u d y  n u mber, site 
n u m ber a n d partici pa nt i de ntificati o n. Partici pa nt n u m bers will n ot be reassi g ne d t o ot her 
partici pa nts or re use d i n t his st u d y. If a partici pa nt is re place d, t he re place me nt will be e nr olle d 
wit h a u ni q ue partici pa nt n u m ber.
7. 1
Bli n di n g
T he st u d y will be d o u ble - bli n de d wit h t he partici pa nt, t he I n vesti gat or, m o nit ors, a n d st u d y site 
staff bei n g bli n de d t o t he st u d y inter ve nti o n a d mi nistere d. H o we ver, if a partici pa nt is recei vi n g 
me dicati o ns o nl y  via N G T , t he p har macist will p ossi bl y be u n bli n de d i n pre par i n g t he ta blets f or 
a d mi nistrati o n via N G T . Refer t o t he P har mac y  Ma n ual f or met h o ds t o pre ve nt u n bli n di n g of ot her 
h os pital staff w he n partici pa nts are recei vi n g t he st u d y  i nter ve nti o n via N G T .
After c o nfir mati o n of partici pa nt’s eli gi bilit y an d at t he last practical m o me nt pri or t o st u d y 
i nter ve nti o n a d mi nistrati o n, partici pa nts will be ce ntrall y all ocate d t o eit her M 5 0 4 9 or place b o i n 
a 1: 1: 1 rati o usi n g a n I WR S a n d per a c o m p uter-ge nerate d ra n d o mizati o n list. T he I WR S will be 
use d t o assi g n u ni q ue partici pa nt n u m bers a n d t o all ocate partici pa nts t o a st u d y inter ve nti o n gr o u p 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 /9 5
at D a y 1. Bef ore t he st u d y is i nitiate d, t he directi o ns f or t he I WR S will be pr o vi de d t o eac h site. 
T he site will c o ntact t he I W R S pri or t o starti n g st u d y inte r ve nti o n a d mi nistrati o n f or eac h 
partici pa nt.
O nl y  the i nter nal I D M C ma y  re q uest re vie w of u n bli n de d data as nee de d. If a safety c o ncer n arises, 
t he I DM C me m bers are all o we d t o re q uest i m me diate u n bli n di n g of t he partial or c o m plete dataset. 
T he rec o m me n dati o ns of t he I DM C will n ot c o ntai n u n bli n de d data or ot her i nf or mati o n t hat c o ul d 
lea d t o t he I n vesti gat or or st u d y staff bec o mi n g u n bli n de d. A n i n de pe n de nt statisticia n, n ot 
i n v ol ve d wit h st u d y co n d uct n or a me m ber of t he I D M C, will be res p o nsi ble f or pr o d uci n g t he 
u n bli n de d safety data f or t he I D M C re vie w. F u ncti o ni n g of t he I D M C will be descri be d i n t he 
I D M C C harter.
All brea ks of t he st u d y bli n d m ust be a de q uatel y d oc u me nte d .
T he bi oa nal yt ical la b orat or y(ies) res p o nsi ble f or t he bi o a nal ys is of t he P K sa m ples (re q uiri n g 
s hi p me nt of la b orat or y sa m ples fr o m t he site) will be u n bli n de d d uri n g st u d y  co n d uct t o perf or m 
P K bi oa nal ys is o n sa m ples fr o m partici pa nts w h o recei ve d acti ve st u d y inter ve nti o n . T he 
la b orat or y ap plies mas ke d s u bject i de ntifiers t o pre ve nt ass ociati o n of treat me nt c o des wit h a n y 
ot her cli nical data s uc h as efficac y  a n d safety data.
7. 2
E mer ge nc y U n bli n di n g
I n a n e mer ge nc y, t he I n vesti gat or is s olely res p o nsi ble f or deter mi ni n g if u n bli n di n g of a 
partici pa nt’s st u d y inter ve nti o n assi g n me nt is warra nte d. Partici pa nt safety m ust al wa ys be t he first 
c o nsi derati o n i n t his decisi o n. If t he I n vesti gat or deci des t hat u n bli n di n g is warra nte d, t he 
I n vesti gat or s h o ul d ma ke e ver y eff ort t o c o ntact t he res p o nsi ble Me dical M o nit or/ S p o ns o r pri or t o 
t he u n bli n di n g, u nless t his c o ul d dela y emer ge nc y  treat me nt. T he Me dical M o nit or/ S p o ns or m ust 
be n otifie d wit hi n 2 4 h o urs after u n bli n di n g. T he I n vesti gat or m ust pr o vi de t he S p o ns or wit h t he 
reas o n f or u n bli n di n g wit h o ut re veali n g t he st u d y inte r ve nti o n, e xce pt t o t he desi g nate d dr u g safety 
re prese ntati ve via t he E mer ge nc y  Un bli n di n g N otificati o n F or m. T he date of, a n d reas o n f or 
u n bli n di n g m ust be rec or de d i n t he s o urce d oc u me nts a n d e C R F.
7. 3
St u d y I nter ve nti o n C o m pli a nce
W he n partici pa nts are d ose d at t he site, t he y will recei ve st u d y inter ve nti o n directl y  fr o m t he 
I n vesti gat or or desi g nee, u n der me dical s u per visi o n. T he date a n d ti me of eac h d ose a d mi nistere d 
at t he st u d y site will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he eC R F .
W he n 
partici pa nts self-a d mi nister st u d y inter ve nti o n(s) at h o me, c o m plia nce wit h 
st u d y 
i nter ve nti o n will be assesse d at eac h tele me dici ne or st u d y site visit. C o m plia nce will be assesse d 
b y  co u nti n g ret ur ne d ta blets d uri n g t he site vi sits or if p ossi ble, partici pa nt s h o wi n g re mai ni n g 
ta blets via tele me dici ne visit (e. g., scree n of p h o ne, c o m p uter, etc.); site will d oc u me nt n u m bers 
i n t he s o urce d oc u me nts a n d e C R F. A n y de viati o n(s) fr o m t he prescri be d d osa ge re gi me n are 
rec or de d i n t he e C R F.
A rec or d of t he n u m ber of st u d y inter ve nti o n ta blets dis pe nse d t o a n d ta ke n b y  eac h partici pa nt 
will be mai ntai ne d a n d rec o ncile d wit h st u d y inter ve nti o n a n d c o m plia nce rec or ds. I nter ve nti o n 
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 /9 5
start a n d st o p dates, i ncl u di n g dates f or i nter ve nti o n dela y s a n d/ or d ose re d ucti o ns,will be rec or de d 
i n t he e C R F.
7. 4
C o nc o mit a nt T her a p y
A ll c o nc o mita nt t hera pies (e. g., me dici nes a n d n o n dr u g i nter ve nti o ns) use d fr o m t he ti me t he 
partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g a n y c ha n ges (see
A p pe n di x 3 ), m ust be rec or de d i n t he e C R F. F or prescri pti o n a n d o ver -t he-c o u nter me dici nes, 
vacci nes, vita mi ns, a n d her bal s u p ple me nts, rec or d t he na me, reas o n f or use, dates a d mi nistere d, 
a n d d osi n g i nf or mati o n .
C o -e nr oll me nt i n a n ot her i nter ve nti o nal st u d y eval uati n g C O VI D -1 9 treat me nts or S A R S -C o V - 2
vacci ne s is n ot all o we d u ntil after Da y 2 8 , a n d o nl y wit h per missi o n of t he S p o ns or. Off-la bel use 
of a nti viral t hera py a n d/ or c o n valesce nt plas ma is per mitte d if t he t hera p y was i de ntifie d as part 
of t he sta n dar d of care f or t he site pri or t o its e nr olli n g partici pa nts i nt o t he st u d y. Ot her s u p p orti ve 
care i ncl u di n g off -la bel use of ot her dr u gs, de vices, or i nter ve nti o ns t hat mi g ht be use d t o ma na ge 
C O VI D -1 9 (e. g., a ntic oa g ula nts) s h o ul d als o be rec or de d.
T he list of o n -st u d y c o ntrai n dicate d me dicati o ns is t he sa me as t h ose c o ntra dicte d f or st u d y 
eli gi bilit y an d ca n be f o u n d i n A p pe n di x 3 t hr o u g h S t u d y Da y 2 8. Sta n dar d of care vacci nati o ns 
are rec o m me n de d t o be pr o vi de d fr o m Da y 2 8 o n u nless t here is a n i m me diate cli nical nee d (e. g., 
ra bies vacci nati o n).
After St u d y  Da y 28, a n y dr u g is all o we d f or partici pa nt treat me nt.
A d mi nistrati o n of S A R S -C o V -2 vacci nes , as per sta n dar d of care a n d/ or as per t he I n vesti gat or’s 
cli nical j u d ge me nt, is per mitte d after Da y 2 8; earlier a d mi nistrati o n mi g ht be per mitte d after 
c o ns ultati o n wit h t he Me dical M o nit or or desi g nee. 
7. 4. 1
C ortic oster oi ds
C ortic oster oi ds s h o ul d n ot be i nitiate d or t heir d ose c ha n ge d o nce t he partici pa nt has e ntere d t he 
st u d y so as t o n ot i nterfere wit h t he pri mar y o bjecti ve of t his st u d y - e val uati o n of t he 
a nti-i nfla m mat or y effects of t he st u d y dr u g.
C ortic oster oi ds i nitiate d pri or t o or d uri n g t he st u d y Scree ni n g peri o d (a n d pri or t o ra n d o mizati o n) 
m ust n ot be hi g her t ha n 4 0 m g pre d nis o ne per da y base d o n t he d osi n g re gi me n a n d sc he d ule use d 
i n t he R E C O V E R Y
Trial ( N C T 0 4 3 8 1 9 3 6) perf or me d b y  the U ni versit y  of O xf or d, U nite d 
Ki n g d o m (H or b y 2 0 0 2) T he c ortic oster oi d d osi n g (6 m g  of de xa met has o ne, ≤4 0 m g  pre d nis one, 
refer t o Ta ble 3 ) sc he d ule m ust be c o m plete d wit hi n 1 0 d a y s of c ortic oster oi ds i nitiati o n as per t he 
R E C O V E R Y Trial ( mea n da y s of c ortic oster oi d use was 6 d a y s).
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 /9 5
T a ble 3
Pre d nis o ne E q ui v ale nce C alc ul ati o n ( T ot al D ail y D ose)
Or al C orti c o st er oi d 
M e di c ati o n
E q ui v al e nt ( m g) t o 1 m g 
Pr e d ni s o n e
E q ui v al e nt ( m g) t o 1 5 m g 
Pr e d ni s o n e a
M a xi m u m all o w e d 
d ail y  d o s e ( m g)
B et a m et h a s o n e
0. 1 5
2. 3
6
C orti s o n e
5
7 5
2 0 0
D efl a z a c ort
1. 2
1 8
4 8
D e x a m et h a s o n e
0. 1 5
2. 3
6
H y dr o c orti s o n e
4
6 0
1 6 0
M e pr e d ni s o n e
0. 8
1 2
3 2
M et h yl pr e d ni s ol o n e
0. 8
1 2
3 2
Pr e d ni s ol o n e
1
1 5
4 0
Tri a m ci n ol o n e
0. 8
1 2
3 2
a
I n P art B, p arti ci p a nt s will b e str atifi e d b a s e d o n t h e u s e of c orti c o st er oi d s wit hi n 4 8 h o ur s pri or t o 
r a n d o mi z ati o n: pr e d ni s o n e e q ui v al e nt d ail y d o s e of ≤1 5 m g or > 1 5 m g . 
H o we ver, if t he partici pa nt re q uires i n vasi ve mec ha nical ve ntilati o n A N D t he h os pital sta n dar d of 
care rec o m me n ds use of c ortic oster oi ds ( u p t o 4 0 m g pre d nis o ne -e q ui vale nt dail y ) a n d/ or ot her 
a nti-i nfla m mat or y me dicati o ns, t hese dr u gs will be per mitte d. A n y a d diti o nal a nti-i nfla m mat or y 
use i nitiate d at t he sa me ti me of mec ha nical ve ntilati o n s h o ul d als o be rec or de d, i.e., t he na me, 
reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.
7. 4. 2
He m o perf usi o n
T he F D A has gra nte d te m p orar y aut h orizati o n u n der t he E mer ge nc y  Us e A ut h orizati o n pr o gra m 
f or f o ur he m o perf usi o n de vices f or treat me nt of patie nts wit h se vere C O VI D - 1 9, defi ne d as 
h os pitalizati o n, I CU a d missi o n, i nt u bati o n or mec ha nical ve ntilati o n . H o we ver, as t he i nte nt of 
he m o perf usi o n is t o re m o ve i nfla m mat or y cyt o ki nes fr o m t he circ ulati o n, t his pr oce d ure c o ul d 
re d uce t he le vels of I L-6, T y pe I I F N or T N F α , w hic h is t he e x pecte d treat me nt effect of M 5 0 4 9. 
T heref ore, he m o perf usi o n w o ul d c o nf o u n d t he st u d y treat me nt o utc o me a n d t heref ore is 
e xcl usi o nar y an d pr o hi bite d f or this st u d y. S pecificall y , if a partici pa nt is o n he m o perf usi o n at 
S cree ni n g, t his partici pa nt will n ot be eli gi ble f or e nr oll me nt i n t his st u d y. If a n e nr olle d st u d y 
partici pa nt o n st u d y inter ve nti o n nee ds t o recei ve he m o perf usi o n as per I n vesti gat or j u d geme nt , 
t he n it s h o ul d be disc usse d wit h t he st u d y mo nit or. T his partici pa nt s h o ul d disc o nti n ue t he st u d y 
i nter ve nti o n.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 /9 5
8
Disc o nti n u ati o n t he St u d y I nter ve nti o n or fr o m t he St u d y a n d 
Pre m at ure St u d y Cl os ure
8. 1
Te m p or ar y 
or Per m a ne nt Disc o nti n u ati o n 
of t he St u d y 
I nter ve nti o n f or T o xicit y
A n y  ne w cli nicall y rele va nt fi n di n g is re p orte d as a n A E gra de d acc or di n g t o C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) Versi o n 5. 0.
Partici pa nts w h o ha ve t heir st u d y inter ve nti o n hel d f or s us pecte d dr u g t o xicit y, m a y  ha ve t he st u d y 
i nter ve nti o n restarte d wit h a p pr o val of t he S p o ns or if t he p ote ntial be nefit of t he st u d y inter ve nti o n
o ut wei g hs t he ris k of t he t o xicit y . M ore s pecificall y , if a cli nically si g nifica nt fi n di n g is i de ntifie d 
after e nr oll me nt, t he I nvesti gat or or q ualifie d desi g nee will deter mi ne if t he partici pa nt ca n 
c o nti n ue o n t he st u d y inter ve nti o n a n d if a n y c ha n ge i n partici pa nt ma na ge me nt is nee de d i n 
disc ussi o n wit h t he M e dical M o nit or a n d S p o ns or.
T he st u d y inter ve nti o n ma y  not be restarte d if a n y SA E, cli nicall y si g nifica nt A E, persiste nt
Gra de 4 la b orat or y ab n or malit y , i nterc urre nt ill ness, or ot her me dical c o n diti o n occ urs i n dicati n g 
t o t he In vesti gat or t hat c o nti n ue d partici pati o n is n ot i n t he best i nterest of t he partici pa nt .

T he st u d y i nter ve nti o n will n ot be restarte d if t he f oll o wi n g occ urs: seri o us i nfecti o n ot her t ha n 
C O VI D - 1 9, seiz ure, cli nicall y si g nifica nt arrh yt h mia, or ser ot o ni n s yn dr o me .

T he st u d y inte r ve nti o n s h o ul d be wit h hel d if t he partici pa nt de vel o ps Gra de 3 li ver f u ncti o n 
tests (i.e., a n i ncrease i n tra nsa mi nases [A L T or A S T ] > 5. 0 t o 2 0. 0 × U L N if B aseli ne was 
n or mal or > 5. 0 t o 2 0. 0 × Ba seli ne if B aseli ne was a b n or mal re gar dless of t he partici pa nts 
bilir u bi n le vel). If t he A L T a n d A S T d o n ot i m me diatel y tre n d t o t he partici pa nt’s B aseli ne 
val ues wit hi n 2 4 h o urs, t he st u d y  i nter ve nti o n m ust be hel d u ntil t he li ver f u ncti o n tests ret ur n 
t o t he partici pa nt’s B aseli ne val ues . If t he A L T a n d A S T ret ur n t o t he partici pa nt’s B aseli ne 
val ues bef ore Da y 1 5 , t he st u d y i nter ve nti o n ma y be restarte d.

F or partici pa nts w h ose e G F R < 4 0 m L / mi n/ 1. 7 3 m 2 f or 2 4 h o urs , e x perie nce a G ra de 3 i ncrease 
i n ser u m creati ni ne ( > 3. 0 × B aseli ne or > 3. 0 t o 6. 0 × U L N) f or 2 4 h o urs or w h o de vel o p Ac ute 
Ki d ne y  Inj ur y  (re q uiri n g he m o dial ys is), t he st u d y inter ve nti o n m ust 
be per ma ne ntl y 
disc o nti n ue d.

If t he E C G Q Tc
i nter val (c orrecte d b y  Fri dericia’s f or m ula) i ncreases t o > 4 8 0 msec, a n 
i m me diate i n vesti gati o n i nt o p o te ntial dr u g ca uses s h o ul d be perf or me d, a n d t he st u d y 
i nter ve nti o n te m p oraril y wit h hel d. If t he partici pa nt is n ot o n a n y k n o w n dr u gs t o pr ol o n g Q Tc, 
t he n ki d ne y  fu ncti o n s h o ul d be re vie we d a n d als o a p ote ntial dr u g i nteracti o n s h o ul d be 
c o nsi dere d. T he co ntrai n dicate d dr u g list s h o ul d be re vie we d f or st u d y co ntrai n dicate d 
me dicati o ns (e. g., al de h y de o xi dase i n hi bit ors) a n d t he offe n di n g dr u g disc o nti n ue d u nless n o 
alter nati ves are a vaila ble f or ma na ge me nt of t he partici pa nt. If t he Q Tc ret ur ns t o t he 
part ici pa nt’s B aseli ne or t he pr ol o n gati o n is assesse d as relate d t o t he u n derl yi n g S A R S -C o V - 2 
i nfecti o n of t he peri my ocar di u m , i n t he o pi ni o n of t he In vesti gat or, t he st u d y  i nter ve nti o n ma y 
be restarte d a n y ti me bef ore Da y 1 5.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 /9 5
8. 2
Re as o ns f or Disc o nti n u ati o n of S t u d y I nter ve nti o n
A partici pa nt ma y disc o nti n ue st u d y i nter ve nti o n (early ter mi nati o n of st u d y i nter ve nti o n ) f or a n y 
of t he f oll o wi n g reas o ns:

U nacce pta ble t o xicit y .

Occ urre nce of pre g na nc y .

T he partici pa nt re q uests t o disc o nti n ue st u d y  i nter ve nti o n.

Occ urre nce of a n y m e dical c o n diti o n or circ u msta nce t hat e x p oses t he partici pa nt t o s u bsta ntial 
ris k a n d/ or d oes n ot all o w t he partici pa nt t o a d here t o t he re q uire me nts of t he pr ot oc ol.

T he partici pa nt is assesse d as at ris k f or reacti vati o n of T B .

T he par tici pa nt fails t o c o m pl y wit h pr ot oc ol re q uire me nts or st u d y-relate d pr oce d ures.
U nless t he partici pa nt wit h dra ws c o nse nt, t h ose w h o disc o nti n ue st u d y i nter ve nti o n bef ore 
c o m pleti n g t he 1 4- d a y  co urse s h o ul d be e nc o ura ge d t o re mai n i n t he st u d y for f urt her safety 
e val uati o ns a n d t o ascertai n vital stat us t o D a y  6 0. It is critical t o t he st u d y data i nte grity t hat vital 
stat us be c ollecte d at Da ys 1 4, 2 1, 2 8, a n d 6 0 eit her t hr o u g h tele me dici ne c o ntacts or p h o ne calls 
if t he partici pa nt is u na ble t o ret ur n t o the st u d y site (i.e., h os pital area or cli nic). T he reas o n f or 
partici pa nt disc o nti n uati o n of st u d y  i nter ve nti o n s h o ul d be d oc u me nte d i n t he e C R F.
8. 3
Wit h dr a w al fr o m t he St u d y b y t he P artici p a nt
T he partici pa nt will disc o nti n ue t he st u d y  if:

Partici pa nt wit h dra ws 
c o nse nt, partici pa nt’s le gally a ut h orize d re prese ntati ve wit h dra ws 
c o nse nt, or t he partici pa nt re q uests disc o nti n uati o n fr o m t he st u d y f or a n y reas o n.

Partici pa nt dies.

Partici pa nt is l ost t o f oll o w - u p.

Partici pa nts are free t o wit h dra w fr o m t he st u d y at a n y ti me u p o n re q uest wit h o ut a n y 
c o nse q ue nce. I n t he case of a partici pa nts bec o mi n g l ost t o f oll o w- u p, atte m pts t o c o ntact t he 
pa rtici pa nt s h o ul d be ma de a n d d oc u me nte d i n t he partici pa nt’s me dical rec or ds.
After h os pital disc har ge, a partici pa nt will be c o nsi dere d l ost t o f oll o w-u p if he or s he fails t o 
a p pear f or a f oll o w- u p tele me dici ne c o nfere nce or i n-pers o n assess me nt at t he st u d y site. T he st u d y
site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as p ossi ble, 
c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule a n d ascertai n 
if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y.
Bef ore a partici pa nt is dee me d “l ost t o f oll o w -u p”, t he I nvesti gat or or desi g nee m ust ma ke e ver y  
eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls a n d 2) if 
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 /9 5
necessar y , se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last k n o w n 
maili n g a d dress . T hese eff orts will be d oc ume nte d i n t he partici pa nt’s rec or d.
P artici pa nts w h o wit h dra w fr o m t his st u d y or are l ost t o f oll o w- u p after si g ni n g t he i nf or me d 
c o nse nt f or m (I CF) a n d a d mi nistrati o n of t he st u d y inter ve nti o n will be re place d i n Part A o nl y 
wit h S p o ns or a p pr o val. T he rea s o n f or partici pa nt disc o nti n uati o n fr o m Part A a n d B of t he st u d y 
will be rec or de d o n t he a p pr o priate e C R F.
8. 4
St u d y Ter mi n ati o n a n d Cl os ure
T his st u d y  ma y be pre mat urel y ter mi nate d f or reas o ns i ncl u di n g b ut n ot li mite d t o:

Deter mi nati o n of u ne x pecte d, si g ni fica nt, or u nacce pta ble ris k t o partici pa nts.

I ns ufficie nt c o m plia nce t o pr ot oc ol re q uire me nts.

Data t hat are n ot s ufficie ntl y  c o m plete a n d/ or n ot e val ua ble.

As deter mi ne d b y t he S p o ns or, Re g ulat or y  A ut h orities or t he l ocal I R B/IE C.
If t he st u d y is pre mat urel y ter mi nate d, t he site PI will pr o m ptl y i nf or m st u d y partici pa nts a n d t he 
I RB/I E C as a p plica ble. T he site PI  will ass ure a p pr o priate f oll o w- u p f or t he partici pa nts, as 
necessar y . If t here is ca use f or e mer ge ntl y n otif y i n g partici pa nts f or safet y reas o ns bef ore t he 
I RB/I E C has re vie we d t he i nf or mati o n, t he PI ma y d o s o.
T he S p o ns or will n otif y  Re g ulat or y Aut h orities as a p plica ble .
9
S t u d y Assess me nts a n d Pr oce d ures
9. 1
Scree ni n g a n d Effic ac y Assess me nts
9. 1. 1
Scree ni n g Pr oce d ures
After partici pa nts ga ve i nf or me d c o nse nt, Scree ni n g assess me nts will be c o m plete d as i n dicate d 
i n Ta ble 1 .
Cli nical scree ni n g assess me nts will be perf or me d l ocall y b y  the site la b orat or y. T he o verall 
eli gi bilit y of t he partici pa nt t o partici pate i n t he st u d y will be assesse d o nce all scree ni n g
assess me nts are c o m pleted a n d re viewe d t o c o nfir m t hat p ote ntial partici pa nts meet all eli gi bilit y  
criteria. T he scree ni n g pr ocess ca n be s us pe n de d pri or t o c o m plete assess me nt at a n y ti me if 
e xcl usi o ns are i de ntifie d b y t he st u d y t ea m. St u d y partici pa nt s w h o meet all eli gi bilit y criteria will 
be i m me diately ra n d o mize d. Scree ni n g will be halte d w he n e nr oll me nt n u m bers ha ve bee n reac he d 
w hile all o wi n g f or eli gi ble partici pa nts i n S cree ni n g t o still e nr oll.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 /9 5
9. 1. 2
Effic ac y Assess me nts
F or all Baseli ne assess me nts a n d F oll o w -u p Visits, refer t o  Ta ble 1 f or pr oce d ures t o be d o ne a n d 
details f or eac h assess me nt. T he res pirat or y stat us is assesse d o n a dail y  basis t o get her wit h t he 
cli nical stat us o n t he W H O or di nal scale. T he cli nical res p o nse (efficac y assess me nt) is based o n 
data c ollecte d fr o m t he pri mar y e n d p oi nt ti me t o rec o ver y fr o m first d ose (Da y 1) t hr o u g h Da y 2 8
(defi ne d as first occ urre nce of W H O scale 3 or less) a n d assess me nts of res pirat or y  stat us a n d t he 
cli nical or di nal scale f or sec o n dar y  e n d p oi nts are perf or me d o n Da y s 1 t hr o u g h Da y 2 8.
T he Fi O 2 sc ore a n d met h o d of res pirat or y s u p p ort will be o btai ne d (e. g., nasal ca n n ula, hi g h fl o w 
o x y ge nati o n, n o ni n vasi ve ve ntilati o n, mec ha nical ve ntilati o n, etc.) fr o m t he h os pital c hart a n d 
rec or de d f or t he da y o btai ne d (i.e., o n Da y 4 , Da y 4 res pirat or y stat us is o btai ne d a n d rec or de d as 
D a y  4). F or p artici pa nts w h o are place d o n i n vasi ve mec ha nical ve ntilati o n, d oc u me nt t he reas o n 
f or i nt u bati o n a n d t he l ocal i nstit uti o nal pr ot oc ol f or i nt u bati o n.
I n a d diti o n, b ot h S p O 2 meas ure d b y  p ulse o xi metr y a n d Fi O2 will be rec or de d at t he ti me S p O 2 is 
d oc u me nte d o n a dail y  basis w hile t he partici pa nt is h os pitalize d . W he n S p O 2 reac hes ≥9 4 % i n 
r o o m air a n d is mai ntai ne d f or 2 4 h o urs, t he da y  an d ti me are rec or de d at t he be gi n ni n g a n d 
c o ncl usi o n of t he 2 4 h o urs, as doc u me ntati o n is s u p p orti ve of t he pri mar y e n d p oi nt (i.e., ali ve a n d 
free of res pirat or y s u p p ort).
9. 1. 3
Sec o n d ar y E n d p oi nt Assess me nts
9. 1. 3. 1
Cli nic al St at us
T h e cli nical stat us will be assesse d wit h a n or di nal scale a s t he sec o n d assess me nt of a gi ve n st u d y 
da y . T he sc ore ca n be o btai ne d fr o m t he h os pital c hart usi n g t he last sc ore pri or t o t he ti me of 
assess me nt. T his is rec or de d f or t he d a y  obtai ne d (i.e., o n Da y 3, D a y 3 sc ore is o btai ne d a n d 
rec or de d as Da y 3).
T he W H O or di nal scale is as f oll o ws:
0.
U ni nfecte d: n o cli nical or vir ol o gical e vi de nce of i nfecti o n.
1.
A m b ulat or y : n o li mitati o n of acti vities.
2.
A m b ulat or y : li mitati o n of acti vities.
3.
H os pitalize d, mil d disease: h os pitalize d, n o o x y ge n t hera p y.
4.
H os pitalize d, mil d disease: o x y ge n b y mas k or nasal pr o n gs.
5.
H os pitalize d, se vere disease: n o ni n vasi ve ve ntilati o n or hi g h fl o w-o x y ge n.
6.
H os pitalize d , se vere disease: i nt u bati o n a n d mec ha n ical ve ntilati o n.
7.
H os pitalize d, se vere disease: ve ntilati o n + a d diti o nal or ga n s u p p ort – e. g., press ors, ra pi d 
res p o nse tea m, E C M O.
8.
D eat h.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 /9 5
W he n 
deat hs are rec or de d, data s h o ul d be c ollecte d o n w het her t he deat h occ urre d after 
wit h dra wal of care a n d, if s o, t he reas o n f or wit h dra wal of care.
9. 1. 3. 2
A d diti o n al 
Cli nic al 
E n d p oi nts , C O VI D -1 9
I nfl a m m at or y 
Bi o m ar k ers, a n d Select Ser u m Bi o m ar kers
Data c ollecte d f or ot her cli nical e n d p oi nt a n d i nfla m mat or y  bi o mar kers will be o btai ne d fr o m t he 
partici pa nt’s h os pital c hart a n d s h o ul d be rec or de d f or t he da y o btai ne d. W here rele va nt, data will 
als o be cr oss -c hec ke d wit h t he S A E a n d A E re p orte d data (e. g., all-ca use m ortalit y  as a n S A E 
re p ort).
As part of t he sec o n dar y cli nical e n d p oi nt assess me nts, data o n all-ca use m ortalit y ( Day 1 t hr o u g h 
D a y 6 0), t he ti me t o I CU ( Da y 1 t hr o u g h D a y 2 8), t he ti me t o i n vasi ve mec ha nical ve ntilati o n 
( Da y 1 t hr o u g h Da y 2 8), t he ti me t o n o ni n vasi ve mec ha nical ve ntilati o n ( Da y 1 t hr o u g h Da y 2 8), 
t he t otal da y s i n I CU fr o m Da y 1 t hr o u g h D a y 6 0, a n d t he t otal da y s i n t he h os pital fr o m Da y 1 
t hr o u g h Da y 6 0 will be c ollecte d f or a nal ys is.
I nfla m mat or y bi o mar ker data ( C-reacti ve pr otei n , d-di mer, a n d ferriti n) c ollecte d b y  the site d uri n g 
t he st u d y peri o d ( Da y 1 t hr o u g h Da y 2 8) will als o be r ec or de d as i n dicate d i n Ta ble 1 i n t he st u d y 
cli nical data base. Ot her bi o mar ker data a n d researc h sa m ples a nal yz e d at t he ce ntral la b orat or y are 
n ot esta blis he d as sta n dar d of care a n d will n ot be a vaila ble f or partici pa nt ma na ge me nt.
H os pital re-a d missi o ns (if t he partici pa nt was first disc har ge d wit hi n t he 6 0- da y  st u d y peri o d) 
s h o ul d be re p orte d as S A Es ( u nless t he a d missi o n is electi ve). S peci fically, h os pital re-a d missi o n 
will be c o nsi dere d as a C O VI D -1 9 rela pse if t he partici pa nt is re-a d mitte d d ue t o w orse ni n g 
o x y ge nati o n a n d eit her a p ositi ve res ult of a n y res pirat or y pat h o ge n test or w orse ni n g lesi o ns o n 
c hest i ma gi n g.
9. 1. 3. 3 
P h ar m ac o k i netics
P har mac o ki netic data will be a nal y ze d at a ce ntral la b orat or y a n d are n ot a vaila ble f or partici pa nt 
ma na ge me nt.

T he f oll o wi n g P K para meters f or M 5 0 4 9 will be calc ulate d f or Part A, w he n a vaila ble data 
per mits:
S y m b ol
D efi niti o n
A U C 0- l a st
Ar e a u n d er t h e pl a s m a c o n c e ntr ati o n -ti m e c ur v e ( A U C) fr o m ti m e of d o si n g t o t h e ti m e of t h e l a st 
o b s er v ati o n
A U C 0- l a st/ D
D o s e -n or m ali z e d A U C 0- l a st
A U C 0- 1 2 h
A U C fr o m ti m e of d o si n g t o 1 2 h o ur s p o st d o s e
A U C 0- 1 2 h / D
D o s e -n or m ali z e d A U C 0- 1 2 h
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 /9 5
S y m b ol
D efi niti o n
A U C 0- ∞
A U C fr o m ti m e of d o si n g t o i nfi nit y
A U C 0- ∞/ D
D o s e -n or m ali z e d A U C 0- ∞
C L/ F
T h e a p p ar e nt t ot al b o d y cl e ar a n c e of st u d y i nt er v e nti o n f oll o wi n g e xtr a v a s c ul ar a d mi ni str ati o n.
C L/ F = D o s e/ A U C 0- ∞
C m a x
M a xi m u m o b s er v e d c o n c e ntr ati o n ( P art A a n d B)
C m a x/ D
D o s e -n or m ali z e d C m a x 
C tr o u g h
Pr e d o s e o b s er v e d c o n c e ntr ati o n ( P art A a n d B, D a y 7 o nl y)
λ z
T er mi n al r at e c o n st a nt
R a c c ( A U C0- 1 2 h )
T h e a c c u m ul ati o n r ati o of A U C 0- 1 2 h fr o m D a y 1 t o D a y 7.
R a c c (A U C 0- 1 2 h ) = A U C 0- 1 2 h ( D a y 7)/ A U C0- 1 2 h ( D a y 1)
R a c c ( Cm a x)
T h e a c c u m ul ati o n r ati o of C m a x fr o m D a y 1 t o D a y 7.
R a c c ( Cm a x) = C m a x ( D a y 7)/ Cm a x ( D a y 1)
tm a x
T h e ti m e t o r e a c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n c oll e ct e d d uri n g a d o si n g i nt er v al ( u nl e s s 
ot h er wi s e d efi n e d, t a k e t h e 1 st o c c urr e n c e i n c a s e of m ulti pl e/i d e nti c al C m a x v al u e s)
t1/ 2
A p p ar e nt eli mi n ati o n h alf -lif e
V z/ F
T h e 
a p p ar e nt 
v ol u m e of di stri b uti o n 
d uri n g t h e t er mi n al p h a s e f oll o wi n g e xtr a v a s c ul ar 
a d mi ni str ati o n. V z/ F = D o s e/( A U C 0- ∞ × λ z)

W h ole bl o o d sa m ples of a p pr o xi matel y 3 m L  will be c ollecte d f or meas ure me nt of plas ma 
c o nce ntrati o ns of M 5 0 4 9, as s pecifie d i n Ta ble 1.  T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) 
of eac h sa m ple will be rec or de d t o calc ulate act ual ti me ela pse d si nce t he pri or d ose 
a d mi nistrati o n. Acce pta ble wi n d o ws f or P K c ollecti o n are i n dicate d i n  Ta ble 4.

T he e xact date/ti me of sa m ple c ollecti o n a n d st u d y inter ve nti o n a d mi nistrati o n m ust be 
rec or de d i n t he e C R F a n d will be use d i n t he calc ulati o n of P K para meters. Ti me de viati o ns 
fr o m pla n ne d P K sa m pli n g ti mes will n ot be c o nsi dere d a pr ot oc ol de viati o n pr o vi de d t he e xact 
date/ti me of sa m ple c ollecti o n a n d st u d y i nter ve nti o n a d mi nistrati o n are rec or de d i n t he e C R F.
F or D a y 1, D a y 3 ( Part B o nl y) , a n d D a y 7 P K sa m pli n g, t he ti me of t he meal c o ns u me d cl osest 
t o a d mi nistrati o n of t he st u d y i nter ve nti o n s h o ul d als o be rec or de d o n t his e C R F, i.e., the ti me 
t he last meal is fi nis he d bef ore or t he first meal is starte d after st u d y inter ve nti o n a d mi nistrati o n, 
w hic he ver ti me is cl osest t o sa m pli n g .

T he q ua ntificati o n of M 5 0 4 9 
i n plas ma will 
be perf or me d usi n g a vali date d li q ui d 
c hr o mat o gra p h y -mass s pectr o metr y assa y met h o d. C o nce ntrati o ns will be use d t o e val uate t he 
P K of M 5 0 4 9.

Re mai ni n g sa m ples c ollecte d f or a nal ys es of M 5 0 4 9 c o nce ntrati o n m a y  als o be use d t o e val uate 
safety or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.

Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y  Ma n ual. 
Rete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d of st u d y are s pecifie d i n t he 
res pecti ve I CF.

All sa m ples c ollecte d f or P K (e xce pt fr o m place b o partici pa nts ), as s pecifie d i n Ta ble 1,  still 
wit hi n t he k n o w n sta bilit y of t he M 5 0 4 9 at t he ti me of recei pt b y  the bi oa nal y tical la b orat or y 
ma y be a nal yz e d.
See Secti o n 1 0. 4. 5 f or f urt her details o n t he P K a nal ysis.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 /9 5
T a ble 4
Acce pt a ble P h ar m ac o ki netic Wi n d o ws f or M 5 0 4 9 ( P art A)
S a m pli n g Ti m e
Ti m e fr o m S c h e d ul e d S a m pli n g All o w e d
1 a n d 2 h o ur s p o st d o s e
± 2 0 mi n ut e s
6 h o ur s p o st d o s e
± 3 0 mi n ut e s
1 2 h o ur s p o st d o s e
± 1 2 0 mi n ut e s
9. 1. 4. 1
Ser u m Bi o m ar kers
Bl o o d will be c ollecte d as i n dicate d i n Ta ble 1 f or meas ure me nt of ser u m bi o mar kers, e. g.,
a d diti o nal c yt o ki nes (fr o m I L- 6, I L-8, a n d 
, a nti-S A R S -C o V -2 a nti b o dies.
9. 1. 4. 3
P art B: P h ar m ac o ki netic P ar a meters
Bl o o d will be c ollecte d as i n dicate d i n Ta ble 1 f or dr u g c o nce ntrati o n meas ure me nts a n d/ or 
descri pti ve p o p ulati o n P K a nal ys is.
9. 2
S afet y a n d Ot her Assess me nts
Ti me p oi nts f or st u d y pr oce d ures are s pecifie d i n Ta ble 1.  A st u d y ph y sicia n lice nse d t o ma ke 
me dical dia g n oses will be res p o nsi ble f or all st u d y-relate d me dical decisi o ns.
T he f oll o wi n g safet y assess me nts will be perf or me d:

A Es (see Secti o n 9. 3) .

C o nc o mita nt me dicati o ns.

Brief p h y sical e xa mi nati o n: a brief, s ym pt o m - directe d (tar gete d) p h ysical e xa mi nati o n will be 
perf or me d t o e val uate f or a n y p ossi ble A E t hr o u g h o ut t he st u d y.

Cli nical la b orat or y eval uati o ns : data will be rec or de d fr o m t he partici pa nt’s c hart at t he ti me 
p oi nts i n dicate d i n Ta ble 1.  If t he data is n ot a vaila ble, bl o o d will be c ollecte d wit h o ut 
i nterfere nce i n t he partici pa nt ’s cli nical care. Refer t o A p pe n di x 4 f or cli nical la b orat or y 
assess me nts.

Vital si g ns: incl u di n g res pirati o n rate, p ulse, diast olic a n d s yst olic bl o o d press ure, b o d y  
te m perat ure. Hei g ht a n d wei g ht will be rec or de d as i n dicate d i n  Ta ble 1.

E C G : sta n dar d 1 2 -lea d resti n g E C G will be o btai ne d after t he part ici pa nt has bee n i n 
se mi-s u pi ne p ositi o n f or at least 5 mi n utes
at t he ti me p oi nts i n dicate d i n Ta ble 1. T he E C G 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 /9 5
traci n g m ust be clear f or c o m p uter tra nsfer a n d a nal ys is a n d will be st ore d di gitall y  by t he 
S p o ns or .

Arterial bl o o d gas : will be perf or me d , acc or di n g t o sta n dar d of care per l ocal g u i da nce, at 
Scree ni n g o nl y if n ot a vaila ble fr o m t he partici pa nt’s c hart a n d rec or de d fr o m t he partici pa nt’s 
c hart if perf or me d at ot her ti mes as i n dicate d i n Ta ble 1 , i ncl u di n g n or malizati o n of S p O 2 i n 
r o o m air a n d disc har ge.

S p O 2 a n d Fi O 2.

C hest i ma gi n g will be o btai ne d as per l ocal g ui deli nes a n d rec or de d fr o m t he partici pa nt’s c hart 
if perf or me d at ot her ti mes as i n dicate d i n Ta ble 1.

T u berc ul osis , h u ma n i m m u n o deficie nc y vir us a n d h e patitis assess me nt : data will be c ollecte d 
as per l ocal g ui deli nes fr o m t he partici pa nt’s c hart .

Prese nce of ot her i nfecti o ns or c o nti n ue d S A R S- C o V -2 s he d di n g as per l ocal g ui deli nes .
9. 2. 1
O n- st u d y Pr oce d ures t o be F oll o we d i n t he E ve nt of A b n or m al 
L a b or at or y Test V al ues or A b n or m al Cli nic al Fi n di n gs
T he care of h os pitaliz e d partici pa nts will be u n d er t he ma na ge me nt of t he atte n da nt fl o or 
p h y sicia n; t h us, cli nical fi n di n gs a n d la b orat or y data are t o be c ollecte d fr o m t he partici pa nt’s 
cli nical c hart. If t he data are n ot c ollecte d, d oc u me nt circ u msta nces. If a p h y si ol o gic para meter, 
e. g., vital si g ns, or la b orat or y val ue is o utsi de of t he l ocal la b orat or y-s pecifie d ra n ge, a n d t he 
atte n da nt p h y sicia n has re peate d t he la b orat or y meas ure me nt , b ot h meas ure me nts s h ou l d be 
rec or de d a n d a n acc o m pa n yi n g n ote as t o w h y , i n t he j u d g me nt of t he In vesti gat or, t he a b n or malit y 
is t he res ult of a n ac ute, s h ort-ter m, ra pi dly re versi ble c o n diti o n or was a n err or a n d s h o ul d n ot be 
re p orte d as a n A E.
A p h y si ol o gic para meter ma y  als o be re peate d if t here is a tec h nical pr o ble m wit h t he meas ure me nt 
ca use d b y  malf u ncti o ni n g, or a n i na p pr o priate meas uri n g de vice (i.e., i na p pr o priate-size d bl o o d 
press ure c u ff).
9. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
9. 3. 1
Defi niti o n of a n A d verse E ve nt
A n A E mea ns a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a n i nter ve nti o n i n 
h u ma ns, w het her or n ot c o nsi dere d i nter ve nti o n -relate d. A n A E ca n t heref ore be a n y u nfa v ora ble 
a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s ym pt o m, or disease te m p orall y  
ass ociate d wit h t he use of t he st u d y i nter ve nti o n.
A n y  me dical c o nditi o n t hat is prese nt at t he ti me t hat t he partici pa nt is scree ne d will be c o nsi dere d 
as B aseli ne a n d n ot re p orte d as a n A E. H o we ver, if t he se verit y of a n y pre-e xisti n g me dical 
c o n diti o n i ncreases, it s h o ul d be rec or de d as a n A E.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 /9 5
Gi ve n t he nat ure of se verit y of t he u n derl yi n g ill ness, partici pa nt s will ha ve ma n y s ym pt o ms a n d 
a b n or malities i n vitals a n d la b orat or y. All cli nicall y im p orta nt e ve nts will be ca pt ure d as A Es i n 
t his st u d y.
9. 3. 2
Defi niti o n of Seri o us A d verse E ve nt
A n S A E is defi ne d as a n A E or s us pecte d a d verse reacti o n w hic h is c o nsi dere d seri o us if, i n t he 
vie w of eit her t he I n vesti gat or or t he S p o ns or, it res ults i n a n y  of t he f oll o wi n g o utc o mes:

Deat h.

A life -t hreate ni n g A E.

I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n or re-h os pitalizati o n .

A persiste nt or si g nifica nt i nca pacit y  or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal 
life f u ncti o ns.

A c o n ge nital a n o mal y/ birt h defect.
I m p orta nt me dical e ve nts t hat m a y  not res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n 
ma y  be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y m a y je o par dize 
t he patie nt or partici pa nt a n d m a y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d i n t his d efi niti o n. E x a m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g 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, bl o o d d y scrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a b use.
“ Life-t hreate ni n g” refers t o a n A E t hat at occ urre nce re prese nts a n i m me diate ris k of deat h t o a 
partici pa nt . A n e ve nt t hat ma y  ca use deat h if it occ urs i n a m ore se vere f or m is n ot c o nsi dere d 
life-t hreate ni n g. Si milarl y , a h os pital a d missi o n f or a n electi ve pr oce d ure is n ot c o nsi dere d a S A E.
All S A Es, as wit h a n y  A E, will be assesse d f or se verit y a n d relati o ns hi p t o st u d y i nter ve nti o n.
All S A Es will be rec or de d o n t he a p pr o priate S A E e C R F.
All S A Es will be re vie we d a n d e val uate d a n d will be s e nt t o t he I D M C f or peri o dic re vie w.
All S A Es will be f oll o we d t hr o u g h res ol uti o n or sta bilizati o n b y  a lice nse d st u d y ph y sicia n (f or 
I n vesti gati o nal Ne w Dr u g (I ND) st u dies, a p h y sicia n liste d o n t he F or m F D A 1 5 7 2 as t he site 
Pri nci pal or S u b -I n vesti gat or).
9. 3. 3
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
A sus pecte d u ne x pecte d seri o us a d verse reacti o n (S U S A R ) is a n y SA E w here a ca usal relati o ns hi p 
wit h t he st u d y i nter ve nti o n is at least reas o na bl y p ossi ble b ut is n ot liste d i n t he I n vesti gator ’s
Br oc h ure. T he S p o ns or’s dr u g safety de part me nt will s u b mit a n y SU S A R re p orts t o R e g ulat or y 
A ut h orities a n d et hics c o m mittees wit h u n bli n de d i nf or mati o n, per a p plica ble re g ulati o ns. O nl y 
bli n de d i nf or mati o n will be pr o vi de d t o t he st u d y  tea m.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 /9 5
9. 3. 4
A d verse E ve nts of S peci al I nterest
A d verse e ve nts of s pecial i nterests are i nfecti o ns (seri o us a n d o p p ort u nistic i nfecti o ns), seiz ure,
ser ot o ni n s yn dr o me , a n d cli nicall y si gnifica nt car diac arr yt h mias. All n o nseri o us A E SIs m ust be 
a d diti o nall y d oc u me nte d a n d re p orte d.
9. 3. 4. 1 
I nfecti o n
A n y  CT C A E Gra de ≥3 or S A Es of i nfecti o n a n d o p p ort u nistic i nfecti o n will be c o nsi dere d a n 
A E SI .
9. 3. 4. 2
Seiz ure
A n y  t y pe of seiz ures/e pile ps y of a n y gra de or its c o nse q ue nces are classifie d as A E SIs.
9. 3. 4. 3
Ser ot o ni n S y n dr o me
Ser ot o ni n s y n dr o me a n d its s pe ctr u m of s ym pt o ms are a pr o d uct of t he o veracti vati o n of b ot h t he 
ce ntral a n d peri p heral ser ot o ni n rece pt ors as a res ult of hi g h le vels of ser ot o ni n. S y m pt o ms us uall y 
be gi n wit hi n 2 4 h o urs of a n i ncrease d d ose of a ser ot o ner gic a ge nt, t he a d diti o n of a n ot her 
ser ot o ner gic a ge nt t o a dr u g re gi me n or o ver d osi n g.
9. 3. 5
Cl assific ati o n of a n A d verse E ve nt
T he deter mi nati o n of ser i o us ness, se verit y, a n d ca usalit y will be ma de b y  an o n- site In vesti gat or 
w h o is q ualifie d (lice nse d) t o dia g n ose A E i nf or mati o n, pr o vi de a me dical e val uati o n of A Es, a n d 
classif y AEs base d u p o n me dical j u d g me nt. T his i ncl u des b ut is n ot li mite d t o p h y sicia ns, 
p h y sicia n assista nts, a n d n urse practiti o ners.
9. 3. 5. 1
Se verit y of A d verse E ve nts
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y of eac h A E.
I n vesti gat ors will 
refere nce t he C T C A E, Versi o n 5 . 0 ( p u blicati o n date: 2 7 N o v 2 0 1 7), a descri pti ve ter mi n ol o g y that 
ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity) scale is pr o vi de d at t he
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If t he se verit y for a n A E is n ot s pecifically g ra de d b y  CT C A E, t he I n vesti gat or is t o use t he ge neral 
C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical j u d g me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 /9 5
F or A Es n ot i ncl u de d i n t he pr ot oc ol -defi ne d gra di n g s yste m, t he f oll o wi n g g ui deli nes wil l be use d 
t o descri be se verity.

Mil d ( Gra de 1):
e ve nts t hat are us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal or n o treat me nt 
or t hera pe utic i nter ve nti o n a n d ge nerall y  d o n ot i nterfere wit h t he partici pa nt ’s us ual acti vities 
of dail y  li vi n g.

M o derate ( Grade 2): e ve nts t hat are us uall y  alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n. T he e ve nt i nterferes wit h us ual acti vities of dail y  li vi n g, ca usi n g disc o mf ort b ut 
p oses n o si g nifica nt or per ma ne nt ris k of har m t o t he researc h partici pa nt .

Se ve re ( Gra de 3): E ve nts i nterr u pt us ual acti vities of dail y  li vi n g, or si g nifica ntl y affects cli nical 
stat us, or ma y  re q uire i nte nsi ve t hera pe utic i nter ve nti o n. Se vere e ve nts are us uall y 
i nca pacitati n g.

Life -t hreate ni n g ( Gra de 4): E ve nts t hat re prese nt a n i m me diate ris k of deat h t o a partici pa nt.

Deat h ( Gra de 5).
A Es c haracterize d as i nter mitte nt re q uire d oc u me ntati o n of o nset a n d d urati o n of eac h e pis o de. 
T he start a n d st o p d urati o n of eac h re p orte d A E will be rec or de d o n t he a p pr o priate e C R F. C ha n ges 
i n t he se verit y of a n A E will be d oc u me nte d t o all o w a n assess me nt of t he d urati o n of t he e ve nt at 
eac h le vel of i nte nsit y. A la b orat or y ab n or malit y  of Gra de 4, s uc h as a ne mia or ne utr o pe nia, is 
c o nsi dere d seri o us o nl y if t he c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w.
9. 3. 5. 2
Rel ati o ns hi p t o St u d y I nter ve nti o n
F or eac h re p orte d A E , t he PI  or desi g nee m ust assess t he relati o ns hi p of t he e ve nt t o t he st u d y 
i nter ve nti o n usi n g t he f oll o wi n g g ui deli ne:

Relate d: t he A E is k n o w n t o occ ur wit h t he st u d y i nter ve nti o n, t here is a reas o na ble p ossi bilit y 
t hat t he st u d y i nter ve nti o n ca use d t he A E, or t here is a te m p oral relati o ns hi p bet wee n t he st u dy 
i nter ve nti o n a n d e ve nt. Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t he st u d y i nter ve nti o n a n d t he A E.

N ot Relate d:
t here is n ot a reas o na ble p ossi bilit y  that t he a d mi nistrati o n of t he st u d y 
i nter ve nti o n ca use d t he e ve nt, t here is n o te m p oral relati o ns hi p bet wee n t he st u d y i nter ve nti o n 
a n d e ve nt o nset, or a n alter nate eti ol o g y  has bee n esta blis he d.
9. 3. 6
Ti me Peri o d a n d Fre q ue nc y f or E ve nt Assess me nt 
a n d 
F oll o w -u p
F or t his st u d y, all Gra de 1 t hr o u g h Gra de 4 A Es a n d all S A Es will be d oc u me nte d, rec or de d a n d 
re p orte d. All A Es a n d S A Es occ urri n g fr o m t he ti me t he i nf or me d c o nse nt is si g ne d t hr o u g h t he 
D a y 6 0 ( E n d of St u d y) visit will be assesse d f or relati o ns hi p t o t he st u d y  i nter ve nti o n.
9. 3. 6. 1
I n vesti g at ors Re p orti n g of A d verse E ve nts
I nf or mati o n o n all A Es s h o ul d be rec or de d o n t he a p pr o priate eC R F. All clearl y relate d si g ns, 
s ym pt o ms, a n d res ults of dia g n ostic pr oce d ures perf or me d beca use of a n A E s h o ul d be gr o u pe d 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 /9 5
t o get her a n d rec or de d as a si n gle dia g n osis. If t he A E is a la b orat or y ab n or malit y  t hat is part of a 
cli nical c o n diti o n or s yn dr o me, it s h o ul d be rec or de d as t he s y n dr o me or dia g n osis rat her t ha n t he 
i n di vi d ual la b orat or y ab n or malit y . Eac h A E will als o be descri be d i n ter ms of d urati o n (start a n d 
st o p date), se verit y, ass ociati o n wit h t he st u d y i nter ve nti o n, acti o n(s) ta ke n, a n d o utc o me.
9. 3. 7
A E SI a n d S A E Re p orti n g
9. 3. 7. 1
I n vesti g at ors Re p orti n g of Seri o us A d verse E ve nts
A n y  AE t hat meets a pr ot oc ol-defi ne d criteri o n as a S A E m ust be s u b mitte d i m me diatel y (wit hi n 
2 4 h o urs of site a ware ness) o n a n S A E f or m t o t he desi g nate d P har mac o vi gila nce Gr o u p, at t he 
f oll o wi n g c o ntact details:
E- mail a d dr ess
Fa x n u m ber: 
Seri o us a d verse e ve nt re p orti n g will be s u b mitte d via pa per f or ms a n d will als o be e ntere d i n t he 
electr o nic data ca pt uri n g s yste m. Ot her s u p p orti n g d oc u me ntati o n of t he e ve nt m a y  be re q ueste d 
b y  the desi g nate d P har mac o vi gila nce Gr o u p a n d s h o ul d be pr o vi de d as s o o n as p ossi ble. T he 
desi g nate d Me dical 
M o nit or 
will re vie w a n d assess t he S A E f or p ote ntial i m pact o n st u d y 
partici pa nt safety a n d pr ot oc ol c o n d uct.
At a n y ti me after c o m pleti o n of t he st u d y, if t he site PI  or a p pr o priate S u b-I n vesti gat or bec o mes 
a ware of a n S A E, t he site PI  or a p pr o priate S u b-I n vesti gat or will re p ort t he e ve nt t o t he desi g nate d 
P har mac o vi gila nce Gr o u p.
9. 3. 7. 2
I n vesti g at ors Re p orti n g of A d verse E ve nt of S peci al I nterest
F or a n o nseri o us A E SI, t he site will c o m plete t he s pecific A E SI re p ort f or m a n d n otif y  the S p o ns or 
i m me diatel y ( wit hi n 2 4 h o urs), usi n g t he sa me pr ocess f or re p orti n g S A Es, as s pecifie d a b o ve.
F o r a seri o us A E SI, t he site will c o m plete a n S A E re p ort f or m, usi n g t he S A E re p orti n g pr ocess, 
as s pecifie d i n Secti o n 9. 3. 7. 1 .
9. 3. 8
Re g ul at or y Re p orti n g of Seri o us A d verse E ve nts
F oll o wi n g n otificati o n fr o m t he site PI  or ap pr o priate S u b-I n vesti gat or, as t he I N D S p o ns or, will 
re p ort a n y S U S A R i n a n I N D safet y re p ort t o t he R e g ulat or y Aut h orit y  an d will n otif y  all 
partici pati n g site PI s as s o o n as p ossi ble. A n y  une x pecte d fatal or life-t hreate ni n g s us pecte d 
a d verse reacti o n will be re p orte d t o t he R e g ulat or y Aut h orit y  as s o o n as p ossi ble, b ut i n n o case 
later t ha n 7 cale n dar da ys after the S p o ns or’s i nitial recei pt of t he i nf or mati o n. If t he e ve nt is n ot 
fatal or life-t hreate ni n g, t he I N D safety re p ort will be s u b mitte d wit hi n 1 5 cale n dar da ys after t he 
S p o ns or deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g. Rele va nt f oll o w- u p i nf or mati o n 
t o a n I N D safet y re p ort will be s u b mitte d as s o o n as t he i nf or mati o n is a vaila ble. U p o n re q uest 
fr o m R e g ulat or y Aut h orit y , t he S p o ns or will s u b mit a n y ad diti o nal data or i nf or mati o n t hat t he 
D oc u me nt N o. 
O bject N o
C CI
C CI
P P D
P P D

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 /9 5
a ge nc y dee ms necessar y, as s o o n as p ossi ble, b ut i n n o case later t ha n 1 5 cale n dar d a y s after 
recei vi n g t he re q uest.
S eri o us a d verse e ve nts t hat are n ot S U S A Rs will be re p orte d t o t he R e g ulat or y Aut h orit y  at least 
a n n uall y i n a s u m mar y f or mat w hic h i ncl u des all S A Es.
Sites ma y  ha ve a d diti o nal l ocal re p orti n g re q uire me nts (t o t he I RB /IE C a n d/ or nati o nal R e g ulat or y 
A ut h orit y ).
9. 3. 9
Re p orti n g of Pre g n a nc y
Pre g na nc y  is n ot a n A E. H o we ver, a n y p re g na nc y t hat occ urs d uri n g st u d y partici pati o n s h o ul d be 
rec or de d i n t he a p pr o priate e C R F a n d s u b mitte d t o t he S p o ns or o n t he ap pr o priate pa per re p orti n g 
f or m wit hi n 2 4 ho urs of lear ni n g of t he pre g na nc y . Pre g na nc y s h o ul d be f oll o we d t o o utc o me.
T he I n vesti gat or will c ollect f oll o w-u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate, a n d t he 
i nf or mati o n will be f or war de d t o t he S p o ns or. Ge nerally, f oll o w -u p will n ot be re q uire d f or l o n ger 
t ha n 6 t o 8 wee ks b e y o n d t he esti mate d deli ver y  date. A n y ter mi nati o n of pre g na nc y  will be 
re p orte d, re gar dless of fetal stat us ( prese nce or a bse nce of a n o malies) or i n dicati o n f or t he 
pr oce d ure. A b n or mal pre g na nc y  outc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na nc y ) are c o nsi dere d S A Es a n d s h o ul d be rec or de d a n d 
re p orte d t o t he S p o ns or acc or di n gly.
9. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose of st u d y inter ve nti o n greater t ha n t he pla n ne d t otal dail y  d ose ( 8 ta blets of 
st u d y inter ve nti o n per d a y ) wit hi n 2 4- h o ur ti me peri o d ( mi d ni g ht t o mi d ni g ht) or t otal 1 4- d a y  
c u m ulati ve st u d y dose (see Secti o n 6. 1. 1. 2 ) f or a partici pa nt i n t he st u d y will be c o nsi dere d a n 
o ver d ose.
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.
E ve n if n ot ass ociate d wit h a n A E or a S A E, a n y  o ver d ose is rec or de d i n t he C R F a n d re p orte d t o 
gl o bal patie nt safety i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a S A E a n d O ver d ose 
Re p ort F or m, f oll o wi n g t he pr oce d ure i n Secti o n  9. 3 .
9. 5
U n a ntici p ate d Pr o ble ms
9. 5. 1
Defi niti o n of U n a ntici p ate d Pr o ble ms
A n u na ntici pate d pr o ble m is a n y  e ve nt, i nci de nt, e x perie nce, or o utc o me t hat meets t he f oll o wi n g 
criteria:

U ne x pecte d i n ter ms of nat ure, se verit y, or fre q ue nc y gi ve n (a) t he researc h pr oce d ures t hat are 
descri be d i n t he pr ot oc ol -relate d d oc u me nts, s uc h as t he I RB /IE C -a p pr o ve d researc h pr ot oc ol 
a n d i nf or me d c o nse nt d oc u me nt; a n d ( b) t he c haracteristics of t he partici pa nt p o p ulati o n bei n g 
st u die d.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 /9 5

Relate d or p ossi b l y relate d t o partici pati o n i n t he researc h (“ p ossi bl y relate d” mea ns t here is a 
reas o na ble p ossi bilit y  that t he i nci de nt, e x perie nce, or o utc o me m a y  ha ve bee n ca use d b y  the 
pr oce d ures i n v ol ve d i n t he researc h).

S u g gests t hat t he researc h places partici pa n ts or ot hers at a greater ris k of har m (i ncl u di n g 
p h y sical, psyc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y  k n o w n or rec o g nize d.
9. 5. 2
U n a ntici p ate d Pr o ble m Re p orti n g
T o satisf y  the re q uire me nt f or pr o m pt re p orti n g, u na ntici pate d pr o ble ms will be rep orte d usi n g t he 
f oll o wi n g ti meli ne:

U na ntici pate d pr o ble m s t hat are S A Es will be re p orte d t o t he st u d y Sp o ns or wit hi n 2 4 h o urs of 
t he I n vesti gat or bec o mi n g a ware of t he e ve nt per t he a b o ve descri be S A E re p orti n g pr ocess.

A n y  ot her u na ntici pate d pr o ble m will be re p orte d t o t he st u d y Sp o ns or wit hi n 3 da y s of t he 
I n vesti gat or bec o mi n g a ware of t he pr o ble m.
9. 5. 3
Re p orti n g U n a ntici p ate d Pr o ble ms t o P artici p a nts
Partici pa nts will be i nf or me d of a n y u na ntici pate d pr o ble ms t hat occ ur as part of t heir partici pati o n 
i n t his st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 /9 5
1 0. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a n y 
a nal ys is p o p ulati o n will be ma de d uri n g a bli n de d data re vie w meeti n g pri or t o data base l oc k a n d 
u n bli n di n g.
A n al y s i s S et
D e s cri pti o n
E nr oll e d 
All p arti ci p a nt s w h o si g n i nf or m e d c o n s e nt.
I nt e nt-t o-Tr e at
T h e I nt e nt-t o-Tr e at A n al y si s S et c o n si st s of all tr e at e d p arti ci p a nt s. P arti ci p a nt s will 
b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt r e c ei v e d.
T h e I nt e nt -t o-Tr e at A n al y si s S et will b e u s e d f or t h e pri m ar y effi c a c y a n al y si s.
S af et y
T h e S af et y A n al y si s S et c o n si st s of all p arti ci p a nt s w h o r e c ei v e at l e a st o n e d o s e of 
st u d y i nt er v e nti o n a n d i s u s e d f or e v al u ati o n of s af et y e n d p oi nt s.
P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e a ct u al tr e at m e nt t h e y r e c ei v e.
P h ar m a c o ki n eti c s
T h e P h ar m a c o ki n eti c A n al y si s p o p ul ati o n will i n cl u d e all p arti ci p a nt s w h o r e c ei v e d at 
l e a st 1 d o s e of a cti v e tr e at m e nt, f or w h o m at l e a st 1 q u a ntifi a bl e pl a s m a
c o n c e ntr ati o n of M 5 0 4 9 i s o bt ai n e d, a n d wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s a n d 
a b s e n c e of f a ct or t h at m a y h a v e a n i nfl u e n c e o n p h ar m a c o ki n eti c s.
P h ar m a c o d y n a mi c s
T h e P h ar m a c o d y n a mi c A n al y si s p o p ul ati o n will i n cl u d e all p arti ci p a nt s w h o r e c ei v e d 
at l e a st 1 d o s e of st u d y i nt er v e nti o n, f or w h o m at l e a st 1 p o st b a s eli n e bi o m ar k er 
a s s e s s m e nt w a s o bt ai n e d a n d wit h o ut a n y r el e v a nt pr ot o c ol d e vi ati o n s or e v e nt t h at 
m a y h a v e a n i nfl u e n c e o n p h ar m a c o d y n a mi c s .
1 0. 4
St atistic al A n al yses
1 0. 4. 1
Ge ner al A p pr o ac h
T his st u d y  is e x pl orat or y.
F or eac h treat me nt gr o u p, c o nti n u o us varia bles will be s u m marize d usi n g descri pti v e statistics, 
w hile q ualitati ve varia bles will be s u m marize d b y  c o u nts a n d perce nta ges.
A n I nte grate d A nalys is Pla n (IA P ) will be de vel o pe d a n d fi nalize d bef ore t he first I D M C meeti n g .
A nal y sis will prese nt t he cli nical o utc o mes of partici pa nts fr o m Part A a n d Part B c o m bi ne d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 /9 5
1 0. 4. 2
A n al ysis of t he Pri m ar y Effic ac y E n d p oi nt
T he pri mar y  en d p oi nt, ti me t o rec o ver y, is defi ne d as t he ti me fr o m first d ose ( Da y 1) t hr o u g h 
D a y 2 8 t o first occ urre nce of W H O 9- p oi nt or di nal scale 3 or less. F or partici pa nts w h o die a n d 
th ose c o nsi dere d as fail ure (t hat i ncl u des use of mec ha nical ve ntilati o n, I C U a d missi o n lea di n g t o 
treat me nt disc o nti n uati o n, a n d rela pse), t he ti me t o rec o ver y will be ce ns ore d at Da y  28. F or 
partici pa nts c o m pleti n g t he st u d y wit h o ut rec o veri n g or fail ure, t he ti me t o rec o ver y will be 
ce ns ore d at D a y 2 8. Partici pa nts wit h dra w n bef ore t he E n d of St u d y  Visit wit h o ut rec o veri n g or 
fail ure will be ce ns ore d at t he last date of a vaila ble cli nical stat us assess me nt.
C u m ulati ve distri b uti o n f u ncti o n f or ti me t o rec o ver y will be esti mate d via t he Ka pla n -Meier 
( pr o d uct-li mit esti mates) met h o d b y  treat me nt gr o u p a n d prese nte d t o get her w it h ass ociate d 
statistics ( me dia n ti me t o rec o ver y, rec o ver y rates at Da y  7, Da y  14, a n d Da y  28) i ncl u di n g t he 
c orres p o n di n g t w o -si de d 9 5 % CI .
T he p ote ntial i nterc urre nt e ve nts t hat c o ul d c o nf o u n d t he pri mar y  e n d p oi nt are:

Inte nsi ve care u nit a d missi o n/in v asi ve mec ha nical ve ntilati o n/ deat h.

Treat me nt disc o nti n uati o n d ue t o A E.

C o nc o mita nt me dicati o n: a nti viral t hera p y i ncl u di n g c o n valesce nt plas ma , c ortic oster oi ds.

F or bi d de n c o nc o mita nt me dicati o n (e. g., c hl or o q ui ne -relate d me dicati o ns, i m m u n o m o d ulati n g 
dr u gs).
S pecific a nal ys es t o acc o u nt f or i nterc urre nt e ve nts a n d stratificati o n fact ors will be descri be d i n 
t he I A P.
1 0. 4. 3
A n al ysis of t he Sec o n d ar y E n d p oi nts
1 0. 4. 3. 1
A n al ysis 
of 
Ali ve 
a n d 
N ot 
R e q uiri n g 
S u p ple me nt al 
O x y ge n ati o n t hr o u g h D a y 2 8
T he n u m ber a n d pr o p orti o n of partici pa nts ali ve a n d d o n ot re q uire s u p ple me ntal o x y ge nati o n or 
ve ntilat or y  su p p ort (i ncl u di n g mec ha nical ve ntilati o n a n d E C M O ) will be descri be d at Da y 7, 
D a y 1 4, a n d at re g ular i nter vals.
T he differe nce of eac h d ose vers us place b o i n pr o p orti o n of partici pa nts w h o are ali ve a n d d o n ot 
re q uire s u p ple me ntal o xy ge n ati o n or ve ntilat or y s u p p ort o n Da y  7, o n Da y 1 4 a n d o n Da y 2 8 will 
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 /9 5
be pr o vi de d gra p hicall y  t o get her wit h t w o-si de d 9 5 % CIs. T he CIs will be base d o n t he Mietti ne n 
& N ur mi ne n met h o d (Mietti ne n
1 9 8 5 ).
1 0. 4. 3. 2
A n al ysis of Cli nic al St at us
T he n u m ber a n d perce nta ge of partici pa nts i n eac h cli nical stat us cate g or y will be prese nte d b y  
treat me nt gr o u p a n d by ti me p oi nt i n a gra p hical ma n ner.
A n or di nal lo gistic re gressi o n m o del will be use d t o c o m pare t he cli nical stat us fr o m Da y 1 t hr o u g h 
D a y 6 0 of M 5 0 4 9 gr o u ps t o place b o. U n der t he ass u m pti o n of pr o p orti o nal o d ds, a s u m mar y o d ds 
rati o a n d its 9 5 % CI will be esti mate d f or eac h M 5 0 4 9 gr o u p vers us place b o. A test f or t he 
pr o p orti o nalit y  ass u m pti o n will als o be ma de.
Se parate o d ds rati os will als o be esti mate d f or dic h ot o mize d versi o n of t he healt h stat us:

Deat h vers us a n y ot her cate g or y .

W orse ni n g vers us sta ble/i m pr o ve me nt .

N ot disc har ge vers us h os pital disc har ge d.
A n e x pl orat or y lo n git u di nal a nal ys is will be r u n t o acc o u nt f or all of t he ti me p oi nts a n d prese nt 
esti mates of treat me nt effect b y ti me p oi nt .
1 0. 4. 3. 3
A n al ysis of Ti me t o S p O2 of ≥9 4 % S ust ai ne d f or at Le ast 
2 4 h o urs i n R o o m Air
T he ti me t o res p o nse is defi ne d as t he ti me fr o m first d ose ( Da y 1) t o t he date of t he first S p O 2
≥9 4 % s ustai ne d f or at least 2 4 h o urs i n r o o m air u p t o Da y 2 8. F or partici pa nts w h o die a n d t h ose 
c o nsi dere d as fail ure (t hat i ncl u des use of mec ha nical ve ntilati o n, I CU a d missi o n lea di n g t o 
treat me nt disc o nti n uati o n, a n d rela pse) t he ti me t o res p o nse will be ce ns ore d at D a y 2 8. F or 
partici pa nts c o m pleti n g t he st u d y wit h o ut meeti n g res p o nse or fail ure, t he ti me t o res p o nse will be 
ce ns ore d at D a y 2 8. Partici pa nts wit h dra w n bef ore the E n d of St u d y  Visit wit h o ut meeti n g 
res p o nse or fail ure will be ce ns ore d at t he last date of S p O2 assess me nt i n r o o m air te m perat ure.
C u m ulati ve distri b uti o n f u ncti o n f or ti me t o res p o nse will be esti mate d via t he Ka pla n -Meier 
( pr o d uct-li mit esti mates) met h o d b y  treat me nt gr o u p a n d prese nte d t o get her wit h ass ociate d 
statistics ( me dia n ti me t o res p o nse, res p o nse rates at Da y 7, Da y 1 4, a n d Da y 2 8) i ncl u di n g t he 
c orres p o n di n g t w o -si de d 9 5 % CI.
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 /9 5
1 0. 4. 3. 4
A n al ysis of All -c a use M ort alit y T hr o u g h D a y 6 0
N u m ber a n d perce nta ge of deat h t hr o u g h Da y  6 0 wit h 9 5 % CI will be prese nte d b y  treat me nt 
gr o u p.
1 0. 4. 3. 5
A n al ysis of Ti me t o I nte nsi ve C are U nit A d missi o n ( D a y 1 
T hr o u g h D a y 2 8)
Ti me t o I C U a d missi o n (hereafter , “e ve nt”) is defi ne d as t he ti me fr o m first d ose ( Da y 1) t o t he 
date of e ve nt u p t o Da y 2 8. Partici pa nts c o m pleti n g or wit h dra wi n g fr o m t he st u d y wit h o ut 
e x perie nci n g t he e ve nt, will be ce ns ore d at t he ti me of c o m pleti o n or wit h dra wal. If deat h occ urs 
bef ore t he e ve nt, it will be c o u nte d as a n e ve nt.
A nal y sis will be base d o n a stratifie d l o g-ra n k test of distri b uti o n of ti me t o e ve nt wit h
strata 
defi ne d b y  ( 1) t he use of c ortic oster oi ds at a pre d nis o ne e q ui vale nt dail y  dose of ≤1 5 m g  or 
> 1 5 m g wit hi n 4 8 h o urs pri or t o ra n d o mizati o n, ( 2) t he use of a nti viral t hera py i ncl u di n g 
c o n valesce nt plas ma (prese nce or a bse nce ) wit hi n 
4 8 h o urs pri or
t o ra n d o mizati o n, a n d 
(3) c o u ntr y.
Esti mati o n of treat me nt effect b y  d ose (a n d 9 5 % t w o-si de d CI) c o m pare d t o place b o will be base d 
o n hazar d rati o fr o m a stratifie d C o x -m o del of res p o nse hazar d rate, wit h ter ms f or treat me nt gr o u p 
a n d strata defi ne d as a bo ve .
E ve nt -free s ur vi val f u ncti o n f or ti me t o e ve nt will be esti mate d via t he Ka pla n -Meier met h o d b y  
treat me nt gr o u p a n d prese nte d t o get her wit h ass ociate d statistics ( me dia n ti me t o e ve nt, res p o nse 
rates at Da y 9, Da y 1 4 a n d Da y 2 8) i ncl u di n g t he c orres p o n di n g t w o-si de d 9 5 % CI.
1 0. 4. 3. 6
A n al ysis of Ti me t o I n v asi ve Mec h a nic al Ve ntil ati o n ( D a y 1 
T hr o u g h D a y 2 8)
Ti me t o i n vasi ve mec ha nical ve ntilati o n will be a nal y ze d i n t he sa me ma n ner as ti me t o I C U.
1 0. 4. 3. 7
A n al ysis 
of Ti me
t o N o ni n v asi ve 
Mec h a ni c al Ve ntil ati o n 
( D a y 1 T hr o u g h D a y 2 8)
Ti me t o n o ni n vasi ve mec ha nical ve ntilati o n will be a nal yz e d i n t he sa me ma n ner as ti me t o I C U.
1 0. 4. 3. 8
A n al ysis of T ot al D a ys i n I C U
T he t otal n u m ber of d a y s i n I CU fr o m Da y  1 thr o u g h Da y 6 0 will be descri be d t o get her wit h 
9 5 % CI  b y treat me nt gr o u p.
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 /9 5
1 0. 4. 3. 9
A n al ysis of T ot al D a ys i n t he H os pit al a n d Ti me t o H os pit al 
Disc h ar ge
T he t otal n u m ber of da ys i n t he h os pital fr o m Da y  1 thr o u g h Da y  60 will be descri be d t o get her 
wit h 9 5 % CI  b y treat me nt gr o u p.
I n a d diti o n, ti me t o h os pital disc har ge will be a nal y ze d. T he ti me t o h os pital disc har ge is defi ne d 
as t he ti me fr o m first d ose ( Da y 1) t hr o u g h Da y 2 8 t o h os pital disc har ge. F or partici pa nts w h o die 
a n d t h ose c o nsi dere d as fail ure (t hat i ncl u des use of mec ha nical ve ntilati o n, I C U a d missi o n lea di n g 
t o treat me nt disc o nti n uati o n, a n d rela pse), t he ti me t o h os pital disc har ge will be ce ns ore d at 
D a y 2 8. F or partici pa nts c o m pleti n g t he st u d y wit h o ut bei n g disc har ge d or fail ure, t he ti me t o 
h os pital disc har ge will be ce ns ore d at Da y 2 8. Partici pa nts wit h dra w n bef ore t he E n d of St u d y 
Visit wit h o ut h os pital disc har ge or fail ure will be ce ns ore d at t he last date of a vaila ble cli nical 
stat us assess me nt.
C u m ulati ve distri b uti o n f u ncti o n f or ti me t o h os pital disc har ge will be esti mate d via t he 
Ka pla n -Meier ( pr o d uct-li mit esti mates) met h o d b y treat me nt gr o u p a n d prese nte d t o get her wit h 
ass ociate d statistics ( me dia n ti me t o h os pital disc har ge, h os pital disc har ge rates at Da y 7, Da y 1 4, 
a n d Da y 2 8) i ncl u di n g t he c orres p o n di n g t w o -si de d 9 5 % CI .
1 0. 4. 3. 1 0
A n al ysis of I nfl a m m at or y Bi o m ar kers
A bs ol ute val ues, a bs ol ute c ha n ges, a n d perce nt c ha n ges fr o m Baseli ne t o eac h ti me p oi n t i n 
i nfla m mat or y bi o mar kers will be s u m marize d b y treat me nt gr o u p.
Descri pti ve statistics will be dis pla y e d usi n g B o x a n d W his ker pl ots.
S pa g hetti pl ots wit h perce nt c ha n ge fr o m Baseli ne as well as a bs ol ute c ha n ge fr o m Baseli ne will 
als o be pr o vi de d b y tr eat me nt gr o u p.
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 /9 5
1 0. 4. 3. 1 2
A n al ysis of Occ urre nce of R el a pse i n P artici p a nts D uri n g t he 
S t u d y P eri o d (if F irst D isc h ar ge d W it hi n t he 6 0 -d a y S t u d y 
P eri o d)
C o u nt a n d perce nta ge of partici pa nts wit h rela pse (see Secti o n 4. 8 f or defi niti o n ) a m o n g 
partici pa nts disc har ge d bef ore Da y 2 8 wit h 9 5 % CI  will be prese nte d by treat me nt gr o u p .
1 0. 4. 3. 1 3
A n al ysis of Occ urre nce of Re -h os pit aliz ati o n i n P artici p a nts 
D uri n g t he St u d y Peri o d (if First Disc h ar ge d W it hi n t he 
6 0 -d a y 
St u d y 
Peri o d) 
D ue 
t o 
C O VI D - 1 9 
Dise ase 
C o m plic ati o ns
C o u nt a n d perce nta ge of partici pa nts w h o are re-h os pitalize d bef ore Da y 2 8 wit h 9 5 % CI  will be 
prese nte d b y treat me nt gr o u p a n d w het her or n ot d ue t o C O VI D -1 9 dis ease c o m plicati o ns.
1 0. 4. 4
S afet y A n al ysis
A d verse e ve nts will be c o de d acc or di n g t o t he Me dical Dicti o nar y  for Re g ulat or y  Acti vities
( Me d D R A). T he 
n u m ber 
a n d 
perce nta ge 
of 
partici pa nts 
e x perie nci n g 
1 
or 
m ore 
treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) will be s u m marize d acc or di n g t o Me d D R A
s yste m 
or ga n classes a n d preferre d ter ms b y  treat me nt gr o u p, relati o ns hi p t o st u d y inter ve nti o n, a n d 
se verity.
Deat hs, S A Es, A E SIs, T E A Es lea di n g t o treat me nt disc o nti n uati o n, a n d T E A Es lea di n g t o 
treat me nt i nterr u ptio n will be s u m marize d b y  treat me nt gr o u p.
S u m mar y  statistics will be use d t o prese nt o bser ve d val ues a n d c ha n ges fr o m Baseli ne i n vital 
si g ns, E C G para meters, a n d a b n or mal la b orat or y para meters.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 /9 5
1 0. 4. 5
P h ar m ac o k i netic P ar a meters
P har mac o ki netic a nal ys es will be specifie d i n t he I AP, w hic h will be fi nalize d bef ore data base 
l oc k. T he P K of M 5 0 4 9 a n d e x p os ure -res p o nse relati o ns hi ps wit h res pect t o bi o mar kers/cli nical 
e n d p oi nts will be descri be d usi n g m o deli n g a n d si m ulati o n. F ull details of t he rele va nt (i nte grate d) 
p o p ulati o n m o deli n g 
a n d si m ulati o n acti vities (i ncl u di n g o bjecti ves, rele va nt e n d p oi nts, 
met h o d ol o g y , s oft ware, etc.) will be defi ne d i n a se parate p har mac o metric a nal ysis pla n f or Part B 
i n a d diti o n t o Part A.
Part A
T he c o nce ntrati o ns a n d deri ve d P K para meters of M 5 0 4 9 will be s u m marize d descri pti vel y b y  
ti me p oi nt a n d d ose gr o u p.
I n di vi d ual a n d mea n c o nce ntrati o n pr ofiles o ver ti me will be pr o vi de d by partici pa nt / d ose gr o u p.
B o x pl ots will be pre pare d f or C ma x , A U C0- 1 2 h, Cma x / D a n d A U C0- 1 2 h/ D b y d ose gr o u p.
1 0. 4. 6
B aseli ne Descri pti ve St atistics
Baseli ne c haracteristics will be s u m marize d b y  treat me nt gr o u p . F or c o nti n u o us meas ures t he 
mea n a n d sta n dar d de viati o n will be s u m marize d. Cate g orical varia bles will be descri be d b y  the 
pr o p orti o n i n eac h cate g or y  ( wit h t he c orres p o n di n g sa m ple size n u m bers).
1 0. 4. 7
Pl a n ne d S afet y A n al yses
T he st u d y will pa use e nr oll me nt after 1 5 partici pa nts i n Part A
ha ve bee n ra n d o mize d t o t he 
st u d y-defi ne d i nter ve nti o n. A n i nter nal I D M C t hat pr o vi des o n g oi n g s ur veilla nce of partici pa nt 
safety w ill re vie w all a vaila ble safety a n d cli nical o utc o mes data , a n d will rec o m me n d w het her t he 
st u d y is safe t o pr ocee d t o Part B.
D uri n g Part B, t he I D M C will pr o vi de o n g oi n g s ur veilla nce of partici pa nt safety, will re vie w 
a vaila ble safety a n d cli nical o utc o mes data , a n d will rec o m me n d w het her t he st u d y is safe t o 
c o nti n ue.
P ur p ose, me m bers hi p, ma n date, a n d pr ocesses of t he I D M C w ill be detaile d i n t he I D M C c harter.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 /9 5
1 1
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns
1 1. 1
Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
T his st u d y will be c o n d ucte d i n c o nf or mit y wit h t he pri nci ples set f ort h i n T he Bel m o nt Re p ort: 
Et hical Pri nci ples a n d G ui deli nes f or t he Pr otecti o n of H u ma n S u bjects of Researc h a n d t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) E 6( R 2).
I RB s/I E Cs will re vie w a n d a p pr o ve t his pr ot oc ol, ass ociate d i nf or me d c o nse nt d oc u me nts, 
recr uit me nt material, 
a n d ha n d o uts or s ur ve ys i nte n de d f or t he partici pa nt s, pri or t o t he 
recr uit me nt, scree ni n g, a n d e nr oll me nt of partici pa nt s. Site I R Bs/I E Cs m a y  ha ve a d ditio nal 
nati o nal a n d l ocal re g ulati o ns.
A n y  ame n d me nts t o t he pr ot oc ol or c o nse nt materials will be a p pr o ve d b y  the I RB /IE C bef ore t he y 
are i m ple me nte d. T he In vesti gat or will n otif y  the I RB /IE C of de viati o ns fr o m t he pr ot oc ol a n d 
S A Es, as a p plica ble t o t he I R B /IE C p olic y .
W he n a p plica ble, a me n d me nts will be s u b mitte d t o t he a p pr o priate Healt h A ut h orities.
1 1. 1. 1
I nf or me d C o nse nt Pr ocess
I nf or me d c o nse nt is a pr ocess t hat is i nitiate d pri or t o a n i n di vi d ual a greei n g t o partici pate i n a 
st u d y a n d c o nti n ui n g t hr o u g h o ut t he i n di vi d ual’s st u d y partici pati o n. I n vesti gat ors or desi g nate d 
researc h staff will o btai n a partici pa nt ’s i nf or me d c o nse nt i n acc or da nce wit h t he re q uire me nts of 
4 5 C o de of Fe deral Re g ulati o ns ( C F R ) 4 6, 2 1 C F R 5 0 a n d 2 1 C F R 5 6 f or F D A -re g ulate d st u dies,
state a n d l ocal re g ulati o ns a n d p olic y , a n d I C H E 6 G C P bef ore a n y st u d y pr oce d ures or data 
c ollecti o n are perf or me d.
Partici pa nts will recei ve a c o ncise a n d f oc use d prese ntati o n of ke y  inf or mati o n a b o ut t he cli nical 
st u d y, ver ball y a n d wit h a writte n c o nse nt f or m. T he k e y  inf or mati o n a b o ut t he st u d y will be 
or ga nize d a n d prese nte d i n la y ter mi n ol o g y an d la n g ua ge t hat facilitates u n dersta n di n g w h y o ne 
mi g ht or mi g ht n ot wa nt t o partici pate.
I CFs will be I RB /IE C -a p pr o ve d, a n d partici pa nt s will be as ke d t o rea d a n d re vie w t he c o nse nt 
f or m. Partici pa nt s ( or le gally a ut h orize re prese ntati ves) m ust si g n t he I CF pri or t o starti n g a n y 
st u d y pr oce d ures bei n g d o ne s pecifically f or t his st u d y. O nce si g ne d, a c o p y of t he I C F will be 
gi ve n t o t he partici pa nt f or t heir rec or ds.
Ne w i nf or mati o n will be c o m m u nicate d b y t he site PI  to partici pa nt s w h o c o nse nt t o partici pate i n 
t his st u d y i n acc or da nce wit h I RB /IE C re q uire me nts. T he i nf or me d c o nse nt d oc u me nt will be 
u p date d, a n d partici pa nt s will be re-c o nse nte d per I R B/IE C re q uire me nts, if necessar y.
1 1. 1. 2
C o nfi de nti alit y a n d Pri v ac y
Partici pa nt c o nfi de ntialit y is strictl y hel d i n tr ust b y t he partici pati n g In vesti gat ors, t heir staff, a n d 
t he S p o ns or(s) a n d t heir a ge nts. T his c o nfi de ntialit y is e xte n de d t o c o ver cli nical i nf or mati o n 
relati n g t o partici pa nts, test res ults of bi ol o gical sa m ples a n d ge netic tests, a n d all ot her i nf or mati o n 
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 /9 5
ge nerate d d uri n g partici pati o n i n t he st u d y. N o i de ntifia ble i nf or mati o n c o ncer ni n g partici pa nts i n 
t he st u d y will be release d t o a n y una ut h orize d t hir d part y . Partici pa nt c o nfi de ntialit y will be 
mai ntai ne d w he n st u d y res ults are p u blis he d or disc usse d i n c o nfere nces.
T he st u d y mo nit or, ot her a ut h orize d re prese ntati ves of t he S p o ns or, re prese ntati ves of t he 
I RB /IE C , a n d/ or re g ulat or y age ncies m a y  in s pect all d oc u me nts a n d rec or ds re q uire d t o be 
mai ntai ne d b y  the In vesti gat or, i ncl u di n g b ut n ot li mite d t o, me dical rec or ds ( office, cli nic, or 
h os pital) a n d p har mac y  rec or ds f or t he partici pa nt s i n t his st u d y. T he cli nical st u d y site will per mit 
access t o s uc h rec or ds i ncl u di n g re m ote access w here a p plica ble .
All s o urce rec or ds i ncl u di n g electr o nic data will be st ore d i n sec ure d s y ste ms i n acc or da nce wit h 
i nstit uti o nal p olicies a n d fe deral re g ulati o ns.
1 1. 1. 3
Sec o n d ar y Use of St ore d S peci me ns a n d D at a
Sec o n dar y  H u ma n S u bject Researc h is t he re -use of i de ntifia ble data or i de ntifia ble bi os peci me ns 
t hat were c ollecte d fr o m s o me ot her ‘‘ pri mar y’ ’ or ‘‘i nitial’’ acti vit y, s uc h as t he data a n d sa m ples 
c ollecte d i n t his pr ot oc ol. A n y  use of t he sa m ple or data f or sec o nd ar y  researc h p ur p oses, h o we ver, 
will be prese nte d i n a se parate pr ot oc ol a n d re q uire se parate I R B /IE C a p pr o val.
Eac h sa m ple will be la belle d o nl y  wit h a barc o de a n d a u ni q ue trac ki n g n u m ber t o pr otect 
partici pa nt c o nfi de ntialit y. Sec o n dar y researc h wit h co de d sa m ples a n d data ma y occ ur, h o we ver, 
partici pa nt c o nfi de ntialit y will be mai ntai ne d as descri be d f or t his pr ot oc ol. A n I RB /IE C re vie w 
of t he sec o n dar y  researc h usi n g c o de d s peci me ns is re q uire d.
T he partici pa nt ’s decisi o n ca n be c ha n ge d at a n y ti me b y n otif y i n g t he st u d y d oct ors or n urses i n 
writi n g. If t he partici pa nt s u bse q ue ntl y cha n ges his/ her decisi o n, t he sa m ples will be destr o y e d if 
t he sa m ples ha ve n ot bee n use d f or researc h or release d f or a s pecific researc h pr oject.
1 1. 1. 4
S afet y O versi g ht
1 1. 1. 4. 1
I n de pe n de nt D at a M o nit ori n g C o m mittee
Safet y  oversi g ht will be c o n d ucte d b y  an i nter nal I D M C c o nsisti n g of me m bers w h o are
i n de pe n de nt of t he st u d y tea m a n d are e x perts i n cli nical trials, ris k/ be nefit, safety, statistical 
c o nsi derati o ns a n d t he rele va nt me dical e x pertise. T he i nter nal ID M C m a y als o re q uest t he c o n d uct
of a f utilit y anal y sis, w he n a p plica ble (e. g., o verl y  pr ol o n ge d st u d y enr oll me nt wit h re q uire me nt 
of a d diti o nal res o urces t o s u p p ort st u d y  c o n d uct).
T he I D M C will o perate u n der t he g ui deli nes of a c harter w hic h will detail a nal y ses perf or me d f or 
t he p ur p ose of ris k/ be nefit m o nit ori n g b y t he I D M C, t he f ull me m bers hi p, ma n date, a n d pr ocesses 
of t he I D M C .
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 /9 5
1 1. 1. 5
D at a H a n dli n g a n d Rec or d Kee pi n g
1 1. 1. 5. 1
D at a C ollecti o n a n d M a n a ge me nt Res p o nsi bilities
All partici pa nt st u d y data will be rec or de d i n e C R Fs or tra ns mitte d t o t he S p o ns or or desi g nee 
electr o nicall y (e. g., la b orat or y data). T he I n vesti gat or is res p o nsi ble f or verif yi ng t hat data e ntries 
are c o m plete, acc urate, le gi ble, a n d ti mel y b y electr o nicall y si g ni n g t he e C R F.
T he I n vesti gat or will mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he i nf or mati o n 
i n t he e C R F.
T he I nvesti gat or will per mit st u d y-relate d m o nit ori n g, q ualit y ass ura nce a u dits, I RB/I E C re vie w, 
a n d re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o t he st u dy file a n d s o urce data.
T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y  
c hec ki n g of t h e d ata a n d mai ntai ni n g a vali date d data base. Data base l oc k will occ ur o nce q ualit y 
c o ntr ol a n d q ualit y  ass ura nce pr oce d ures ha ve bee n c o m plete d. Details will be o utli ne d i n Data 
Ma na ge me nt d oc u me nts a n d pr oce d ures.
St u d y  M o nit ors will perf or m o n g oi n g re m ote so urce data re vie w t o c o nfir m t hat data i n t he eC R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safet y an d ri g hts of partici pa nts are bei n g pr otecte d; 
a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u dy 
a gree ments, I C H G C P, a n d all a p plica ble re g ulat or y  re q uire me nts.
1 1. 1. 5. 2
St u d y Rec or d Rete nti o n
T he I nvesti gat or will retai n rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he 
c o n d uct of t his st u d y for 1 5 years after st u d y co m pleti o n, u nless l ocal re g ulati o ns, i nstit uti o nal 
p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds m a y  be destr o y e d d uri n g t he 
rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds ma y be tra nsferre d t o a n ot her 
l ocati o n or party wit h o ut t he S p o ns or’s writte n n otificati o n.
1 1. 1. 5. 3
S o urce Rec or ds
S o urce data are all i nf or mati o n i n ori gi nal rec or ds (a n d certifie d c o pies of ori gi nal rec or ds) of 
cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical st u d y necessar y  for t he 
rec o nstr ucti o n a n d e val uati o n of t he st u d y. S o urce data s h o ul d be attri b uta ble, le gi ble, 
c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete. Eac h partici pati n g site will 
mai ntai n 
a p pr o priate me dical a n d researc h rec or ds f or t his st u d y, i n c o m plia nce wit h I C H G C P, re g ulat or y, 
a n d i nstit uti o nal re q uire me nts. Data rec or de d i n t he eC R F deri ve d fr o m s o urce d oc u me nts s h o ul d 
be c o nsiste nt wit h t he data rec or de d o n t he s o urce d oc u me nts.
I nter vie w of partici pa nt s is s ufficie nt f or o btai ni n g me dical hist or y . S olicitati o n of me dical rec or ds 
fr o m t he partici pa nt ’s pri mar y care pr o vi der is n ot re q uire d.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 /9 5
1 1. 1. 6
Pr ot oc ol De vi ati o ns
A pr ot oc ol de viati o n is a n y no nc o m plia nce wit h t he cli nical st u d y pr ot oc ol . T he n o nc o m plia nce 
ma y  be eit her o n t he part of t he p artici pa nt , t he In vesti gat or, or t he st u d y site staff. F oll o wi n g a 
de viati o n(s), c orrecti ve acti o ns s h o ul d be de vel o pe d b y  the site a n d i m ple me nte d pr o m ptl y . All 
i n di vi d ual pr ot oc ol de viati o ns will be a d dresse d i n partici pa nt st u d y rec or ds.
It is t he res p onsi bilit y  of t he site PI  an d pers o n nel t o use c o nti n u o us vi gila nce t o i de ntif y an d re p ort 
de viati o ns wit hi n fi ve w or ki n g d a y s of i de ntificati o n of t he pr ot oc ol de viati o n, or wit hi n 5 w or ki n g 
da y s of t he sc he d ule d pr ot oc ol-re q uire d acti vit y. All de viati o ns m ust be pr o m ptl y  re p orte d per t he 
pr ot oc ol de viati o n re p orti n g pr oce d ures. Pr ot oc ol de viati o ns m ust be se nt t o t he l ocal I R B/I E C per 
t heir g ui deli nes. T he site PI  an d pers o n nel are res p o nsi ble f or k n o wi n g a n d a d heri n g t o t heir 
I RB /IE C re q uire me nts. A c o m plete d c o p y of t he Pr ot oc ol De viati o n F or m m ust be mai ntai ne d i n 
t he Re g ulat or y File, as well as i n t he partici pa nt ’s c hart if t he de viati o n is partici pa nt s pecific.
1 1. 1. 7
P u blic ati o n a n d D at a S h ari n g P olic y
T o a v oi d pre mat ure release of data, t his p r ot oc ol s pecifies t hat efficac y data fr o m a st u d y t hat has 
n ot y et bee n c o m plete d d ue t o i ns ufficie nt e nr ol lme nt s h o ul d n ot be release d.
A n i n de pe n de nt m o nit ori n g c o m mittee w o ul d re vie w res ults fr o m a n i nteri m a nal ysis of st u d y data 
t o ma ke rec o m me n dati o ns re gar di n g w he t her t he st u d y sh o ul d c o nti n ue or st o p for safet y as g ui de d 
b y  t he pres pecifie d m o nit ori n g pla n.
1 1. 1. 8
C o nflict of I nterest P olic y
T he i n de pe n de nce of t his st u d y fr o m a n y act ual or percei ve d i nfl ue nce, s uc h as b y  th e 
p har mace utical i n d ustr y , is critical. T heref ore, a n y act ual c o nflict of i nterest of pers o ns w h o ha ve 
a r ole i n t he desi g n, c o n d uct, a nal ysis, p u blicati o n, or a n y as pect of t his st u d y will be discl ose d 
a n d ma na ge d. F urt her m ore, pers o ns w h o ha ve a percei ve d c o nflict of i nterest will be re q uire d t o 
ha ve s uc h c o nflicts ma na ge d i n a w a y  that is a p pr o priate t o t heir partici pati o n i n t he desi g n a n d 
c o n d uct of t his st u d y. P olicies a n d pr oce d ures are esta blis he d f or all st u d y gr o u p me m bers t o 
discl ose all c o nflicts of i nterest as well as a mec ha nis m f or t he ma na ge me nt of all re p orte d d ualities 
of i nterest.
1 2
A d diti o n al C o nsi der ati o ns
1 2. 1
Rese arc h -rel ate d I nj uries
I ns ura nce c o vera ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ura nce 
c o n diti o ns will meet g o o d l ocal sta n dar ds , as a p plica ble.
F or a n y p ote ntial researc h -relate d i nj ur y, t he site PI or desi g nee will assess t he partici pa nt . St u d y 
pers o n nel will tr y to re d uce, c o ntr ol, a n d treat a n y co m plicati o ns fr o m t his st u d y. I m me diate 
me dical treat me nt ma y  be pr o vi de d b y t he partici pati n g st u d y  site.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 /9 5
As nee de d, referrals t o a p pr o priate healt h care facilities will be pr o vi de d t o t he partici pa nt . T he 
site PI s h o ul d t he n deter mi ne if a n i nj ur y occ urre d as a direct res ult of t he tests or treat me nts t hat 
are d o ne f or t his st u d y.
If it is deter mi ne d b y  the partici pati n g site PI  that a n i nj ur y occ urre d t o a partici pa nt as a direct 
res ult of t he tests or treat me nts t hat are d o ne f or t his st u d y, t he n referrals t o a p pr o priate healt h care 
facilities will be pr o vi de d t o t he partici pa nt .
St u d y  pers o n nel will tr y t o re d uce, c o ntr ol a n d treat a n y c o m plicati o ns fr o m t his st u d y. I m me diate 
me dical treat me nt m a y  be pr o vi de d b y  the partici pati n g site, s uc h as gi vi n g e mer ge nc y me dicati o ns 
t o st o p i m me diate aller gic reacti o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 /9 5
1 3
Refere nces
Bei gel J H, T o mas he k K M, D o d d L E, et al. Re m desi vir f or t he Treat me nt of C o vi d - 1 9 - Fi nal 
Re p ort. N E n gl J Me d. 2 0 2 0; 3 8 3( 1 9): 1 8 1 3 - 2 6.
Br o w n S M, Griss o m C K, M oss M, et al. N o nli near I m p utati o n of Pa o 2/ Fi o 2 Fr o m S p o 2/ Fi o 2 
A m o n g Patie nts Wit h Ac ute Res pirat or y  Distress S yn dr o me. C hest. 2 0 1 6; 1 5 0( 2): 3 0 7 - 1 3.
Ca o B , Wa n g Y, We n D, et al. A Trial of L o pi na vir – Rit o na vir i n A d ults H os pitalize d wit h Se vere 
C o vi d -1 9. N E n g J Me d . 2 0 2 0; 3 8 2( 1 9): 1 7 8 7- 9 9.
C ha n J F, Y ua n S, K o k K H, et al. A fa milial cl uster of p ne u m o nia ass ociate d wit h t he 2 0 1 9 n o vel 
c or o na vir us i n dicati n g pers o n -t o-pers o n tra ns missi o n: a st u d y of a fa mil y cl uster. T he La ncet. 
2 0 2 0. S 0 1 4 0 -6 7 3 6( 2 0) 3 0 1 5 4 -9. 1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6( 2 0) 3 0 1 5 4 - 9.
C h o w K, Gale M, L o o Y. RI G- I a n d o t her R N A se ns ors i n anti viral im m u nit y. A n n u Re v I mm u n ol. 
2 0 1 8; 3 6: 6 6 7 -9 4.
Fel d ma n n M, 
Mai ni R N, 
W o o d y  JN
et al. Trials of a nti-t u m o ur necr osis fact or t hera p y for 
C O VI D -1 9 are ur ge ntl y  nee de d. La ncet. 2 0 2 0 ; 3 9 5( 1 0 2 3 4): 1 4 0 7- 9.
G ua n W, Ni Z, H u Y et al. Cli nical characteristics of cor o na vir us d isease 2 0 1 9 i n C hi na. N E n gl J 
Me d. 2 0 2 0.
H or b y
P, Li m W S, 
E m bers o n J R, et al. De xa met has o ne 
i n H os pitalize d 
Patie nts wit h 
C o vi d - 1 9 - Preli mi nar y  Re p ort ( 2 0 2 0 J ul y 1 7). d oi: 1 0. 1 0 5 6/ N EJ M oa 2 0 2 1 4 3 6.
Li Y, C he n M, Ca o H et al. E xtra or di nar y  GU -ric h si n gle-stra n d R N A i de ntifie d fr o m S A R S 
c or o na vir us c o ntri b utes a n e xcessi ve i n nate i m m u ne res p o nse. Micr o b I nfect. 2 0 1 3; 1 5( 2): 8 8 - 9 5.
Mietti ne n O, N ur mi ne n M. C o m parati ve a nal ys is of t w o rates. Stat Me d 1 9 8 5; 4( 2): 2 1 3-2 6.
Me hta P, Mc A ule y  DF, Br o w n M et al. C O VI D -1 9: c o nsi der c yt o kine st or m s yn dr o mes a n d 
i m m u n os u p pressi o n. T he La n cet 2 0 2 0; 3 9 5( 1 0 2 2 9) . 1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6( 2 0) 3 0 6 2 8 - 0.
Rice T W, W heeler A P, Ber nar d G R, et al. C o m paris o n of t he S p O 2/ FI O 2 rati o a n d t he Pa O 2/ FI O 2 
rati o i n patie nts wit h ac ute l u n g i nj ur y or A R D S. C hest. 2 0 0 7;1 3 2( 2): 4 1 0 - 7.
Si d di q u i H K a n d Me hra M R. C O VI D -1 9 Ill ness i n Nati ve a n d I m m u n os u p presse d States A 
Cli nical -T hera pe utic Sta gi n g Pr o p osal. J o ur nal of Heart a n d L u n g Tra ns pla ntati o n ( 2 0 2 0). 
d oi. or g/ 1 0. 1 0 1 6/j. heal u n. 2 0 2 0. 0 3. 0 1 2 .
Ste b bi n g J, P hela n A, Griffi n I et al. C O VI D - 1 9-c o m bi ni n g a nti viral a n d a nti-i nfla m mat or y 
treat me nts. La ncet I nfect Dis 2 0 2 0. 1 0. 1 0 1 6/ S 1 4 7 3-3 0 9 9( 2 0) 3 0 1 3 2 - 8.
Va n de n B o o m W, H o y  M, Sa n kara n J et al. T he Searc h f or O pti mal O x y ge n Sat urati o n Tar gets 
i n Criticall y Ill Patie nts. C hest 2 0 2 0; 1 5 7( 3): 5 6 6 - 5 7 3.
Wa n g 
Y. 
Re m desi vir i n A d ults 
Wit h 
Se vere C O VI D- 1 9: A 
Ra n d o mise d, 
D o u ble- Bli n d, 
Place b o -C o ntr olle d, 
M ultice ntre 
Trial. 
La ncet 2 0 2 0 
M a y  16; 3 9 5( 1 0 2 3 6): 1 5 6 9 - 1 5 7 8. d oi: 
1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6( 2 0) 3 1 0 2 2 -9. E p u b 2 0 2 0 A pr 2 9.
W H O. Wee kl y  e pi de mi ol ogic u p date - 0 2 Fe br uar y 2 0 2 1. 2 0 2 1. [last accesse d Fe br uar y 0 9 2 0 2 1] 
htt ps:// w w w. w h o.i nt/ p u blicati o ns/ m/ite m/ wee kl y -e pi de mi ol o gical-u p date ---2- fe br uar y-2 0 2 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 /9 5
W u 
J T, Le u n g K, Le u n g G M. N o wcasti n g a n d f orecasti n g t he p ote ntial d o mestic a n d 
i nter nati o nal s prea d of t he 2 0 1 9 -n C o V o ut brea k ori gi nati n g i n W u ha n, C hi na: a m o delli n g 
st u d y. T he La ncet . 2 0 2 0. S 0 1 4 0 -6 7 3 6( 2 0) 3 0 2 6 0 -9. 1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6( 2 0) 3 0 2 6 0 -9.
Z h o u F, Y u T, D u R et al. Cli nical c o urse a n d ris k fact ors f or m ortalit y of a d ult i n patie nts wit h 
C O VI D - 1 9 i n W u ha n, C hi na: a retr os pecti ve c o h ort st u d y. T he La ncet. 2 0 2 0; 3 9 5( 1 0 2 2 9): 1 0 5 4 - 6 2.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 /9 5
1 4
A p pe n dice s
A p pe n di x 1
A b bre vi ati o ns
A E
A d verse e ve nt
A E SI
A d verse e ve nt of s pecial i nterest
A U C
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve
C F R
C o de of Fe deral Re g ulati o ns
C L / F
A p pare nt 
t otal b o d y  cleara nce of 
st u d y inter ve nti o n 
f oll o wi n g 
e xtra vasc ular a d mi nistrati o n
C O VI D - 1 9 
C or o na vir us disease 2 0 1 9
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C tr o u g h
Pre d ose o bser ve d c o nce ntrati o n
E C G
Electr ocar di o gra m
E C M O
E xtrac or p oreal me m bra ne o x y ge nati o n
e C R F
Electr o nic case re p ort f or m
e G F R
Esti mate d gl o mer ular filtrati o n rate
E T
Earl y ter mi nati o n of treat me nt
FI H
First -i n-h u ma n
Fi O 2
fracti o n of i ns pire d o xy g e n
H R T
H or m o nal re place me nt t hera p y
I A P
I nte grate d A nalys is Pla n
I CF
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
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 L
I nterle u ki n
I ND
I n vesti gati o nal Ne w Dr u g
I RB
I nstit uti o nal Re vie w B oar d
I W R S
I nteracti ve We b Res p o nse S yste m
L B B B
Left B u n dle Bra nc h Bl oc k
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 /9 5
N A T
N ucleic aci d test
N G T
Nas o gastric t u be
Pa O 2
Partial press ure of o x y ge n
PI
Pri nci pal I n vesti gat or
P K
P har mac o ki netic
Q Tc
C orrecte d Q T i nter val
R N A
Ri b o n ucleic aci d
S A E
Seri o us a d verse e ve nt
S A R S
Se vere ac ute res pirat or y  s yn dr o me
S A R S -C o V
Se vere ac ute res pirat or y  s yn dr o me c or o na vir us
S p O 2
Peri p heral ca pillar y  o x yge n sat urati o n
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
ss R N A
Si n gle -stra n de d ri b o n ucleic aci d
T B
T u berc ul osis
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
T L R
T oll -li ke rece pt or
T N F α
T u m or necr osis fact or al p ha
V Z / F
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase f oll o wi n g 
e xtra vasc ular a d mi nistrati o n
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 /9 5
A p pe n di x 2
C o ntr ace pti o n
Defi niti o ns:
W o me n of C hil d beari n g P ote ntial
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c y cle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.
A w o ma n of c hil d beari n g p ote ntial is n ot:
1.
Pre me narc hal.
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y.

D oc u me nte d bilateral sal pi n gect o m y .

D oc u me nte d bilateral o o p h orect o m y.
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he fe male’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y  i nter vie w.
F or a fe male wit h per ma ne nt i nfertilit y due t o a n alter nate me dical ca use ot her t ha n t he 
a b o ve, (e. g., m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y ), I n vesti gat or discreti o n a p plies t o 
deter mi ne st u d y e ntr y.
3.
A p ost me n o pa usal fe male.

A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use.
o
A hi g h f ollicle-sti m ulati n g h or m o ne le vel i n t he p ost me n o pa usal ra n ge ma y  be 
use d t o c o nfir m a p ost me n o pa usal state i n a fe male n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o n al re place me nt t hera p y (H R T). H o we ver, i n t he a bse nce 
of 
1 2 m o nt hs 
of 
a me n orr hea, m ore 
t ha n 1 f ollicle-sti m ulati n g h or m o ne 
meas ure me nt is re q uire d i n t he p ost me n o pa usal ra n ge.

A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 1 of 
t he n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o 
c o nti n ue her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  e nr oll me nt.
D oc u me nt N o
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 /9 5
C o ntr ace pti o n G ui d a nce:
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y

I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n .

I ntr a ut eri n e d e vi c e.

I ntr a ut eri n e h or m o n e-r el e a si n g s y st e m.

Bil at er al t u b al o c cl u si o n .

V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a w o m a n of c hil d b e ari n g p ot e nti al a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. Ot h er wi s e, u s e 
a n a d diti o n al hi g hl y eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt

C o m bi n e d ( e str o g e n- a n d pr o g e st o g e n -c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n .

Or al.

I ntr a v a gi n al.

Tr a n s d er m al .

I nj e ct a bl e.

Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n .

Or al.

I nj e ct a bl e.

S e x u al a b sti n e n c e: a hi g h l y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e e v al u at e d 
i n r el ati o n t o t h e d ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y.
If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e 
m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st - o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h e a m et h o d ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or t hi s st u d y. 
M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n).
D oc u me nt N o
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 /9 5
A p pe n di x 3
Me dic ati o n G ui d a nce
M e di c ati o n T y p e
M e di c ati o n s
Di s c o nti n u ati o n ( W e e k s) B ef or e 
R a n d o mi z ati o n a n d T hr o u g h D a y 2 8
I m m u n o m o d ul at or s/ 
I m m u n o s u p pr e s s a nt s
A nti m al ari al s: h y dr o x y c hl or o q ui n e, 
c hl or o q ui n e , m efl o q ui n e
4
D a p s o n e or r eti n oi d s
S ulf a s al a zi n e
M et h otr e x at e
L efl u n o mi d e
A z at hi o pri n e 
6- m er c a pt o p uri n e
M y c o p h e n ol at e m of etil or s o di u m
T h ali d o mi d e or l e n ali d o mi d e
J A K i n hi bit or s: e . g., t of a citi ni b, 
b ari citi ni b
B T K i n hi bit or s: e . g., i br uti ni b
C y cl o p h o s p h a mi d e
C al ci n e uri n i n hi bit or s:
e. g., c y cl o s p ori n e, t a cr oli m u s, 
v o cl o s p ori n. I n cl u di n g t o pi c al u s e 
( e. g., t a cr oli m u s, pi m e cr oli m u s)
Pl a s m a p h er e si s
Bi ol o gi c s
A b at a c e pt
4
A nti -I L-6 r e c e pt or (t o cili z u m a b, 
s aril u m a b) or a nti -I L 6 ( silt u xi m a b)
I L-1 2/I L - 2 3 i n hi bit or: u st e ki n u m a b
A nti -I L- 1
I VI G
A nti -T N F : e. g., et a n er c e pt, 
a d ali m u m a b
B eli m u m a b, d u al or ot h er a nti -B 
L y m p h o c yt e Sti m ul at or/ a 
pr olif er ati o n i n d u ci n g li g a n d 
n e utr ali zi n g t h er a pi e s ( e. g., R C T 1 8)
A nti -C D 2 0: e . g., rit u xi m a b, 
o cr eli z u m a b, of at u m u m a b, 
o bi n ut u z u m a b, o c ar at u z u m a b, 
v elt u z u m a b or bi o si mil ar s
A nti -I F N: e. g., a nifr ol u m a b
V a c ci n ati o n ( N ot e: p arti ci p a nt s wit h 
pr e vi o u s S A R S -C o V -2 v a c ci n ati o n 
ar e e x cl u d e d b ut mi g ht b e 
v a c ci n at e d aft er D a y 2 8, or e arli er 
aft er c o n s ult ati o n wit h M e di c al 
M o nit or or d e si g n e e )
I n cl u d e d b ut n ot li mit e d t o s u b u nit or 
i n a cti v at e d v a c ci n e s
2
Li v e or li v e att e n u at e d vir u s v a c ci n e
4
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 /9 5
M e di c ati o n T y p e
M e di c ati o n s
Di s c o nti n u ati o n ( W e e k s) B ef or e 
R a n d o mi z ati o n a n d T hr o u g h D a y 2 8
C hi n e s e 
M e di c ati o n/ H er b al/ N o n -h er b al 
s u p pl e m e nt s
Tri pt er y gi u m, t ot al gl u c o si d e s of 
p a e o n y
2
A nti d e pr e s s a nt s
S el e cti v e s er ot o ni n r e u pt a k e 
i n hi bit or s, s er ot o ni n n or e pi n e p hri n e 
r e u pt a k e i n hi bit or s, tri c y cli c 
a nti d e pr e s s a nt s, m o n o a mi n e 
o xi d a s e i n hi bit or s, St. J o h n’ s w ort
2
Fl u o x eti n e
8
A n xi ol yti c
B u s pir o n e
2
A n al g e si c s
Tr a m a d ol a n d f e nt a n yl, c o nti n u e d 
u s e o nl y
2
A nti -e m eti c s (l o n g-a cti n g)
P al o n o s etr o n, d ol a s e tr o n
2
A nti bi oti c s
Li n e z oli d, t e di z oli d
2
M e di c ati o n s a s s o ci at e d wit h A O X 
i n hi biti o n
R al o xif e n e, t a m o xif e n, e str a di ol, 
cl o z a pi n e, c hl or pr o m a zi n e
2
S u p pl e m e nt
Tr y pt o p h a n
2
H e m o p erf u si o n
H e m o p erf u si o n
2
A O X = al d e h y d e o xi d a s e; B T K = Br ut o n t yr o si n e ki n a s e ; J A K = J a n u s ki n a s e ; I L = i nt erl e u ki n; I VI G = i ntr a v e n o u s 
i m m u n e gl o b uli n; S A R S -C o V - 2 = s e v er e a c ut e r e s pir at or y s y n dr o m e c or o n a vir u s ; T N F α = t u m or n e cr o si s f a ct or 
al p h a.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 /9 5
A p pe n di x 4
C li nic al L a b or at or y Tests
L a b or at or y  
A s s e s s m e nt s
P ar a m et er s
H e m at ol o g y
Pl at el et s
M e a n C or p u s c ul ar V ol u m e
W B C C o u nt wit h 
Diff er e nti al :

N e utr o p hil s

L y m p h o c yt e s

M o n o c yt e s

E o si n o p hil s

B a s o p hil s
H e m o gl o bi n
H e m at o crit
Bi o c h e mi str y
Bl o o d Ur e a 
Nitr o g e n
El e ctr ol yt e s
( s o di u m, 
p ot a s si u m, 
c hl ori d e, 
bi c ar b o n at e)
A s p art at e A mi n otr a n sf er a s e  
Cr e ati ni n e Ki n a s e
Cr e ati ni n e
Al b u mi n
Al a ni n e A mi n otr a n sf er a s e
T ot al Pr ot ei n
e G F R
Gl u c o s e
Ot h er S cr e e ni n g 
T e st s
S er u m h C G or uri n e pr e g n a n c y t e st ( a s n e e d e d f or a w o m a n of c hil d b e ari n g p ot e nti al).
All st u d y -r e q uir e d l a b or at or y a s s e s s m e nt s will b e p erf or m e d b y l o c al l a b or at or y. It i s 
r e q uir e d t h at t h e s e l o c al l a b or at ori e s ar e c ertifi e d, p erf or m a n d d o c u m e nt i nt erl a b or at or y 
t e sti n g at r e g ul ar ti m e i nt er v al s a n d pr o vi d e a li st of n or m al r a n g e l a b or at or y v al u e s 
i n cl u di n g u nit s a s d efi n e d b y i nt er n ati o n al s y st e m of u nit s ( e. g., C LI A-c ertifi e d , U K 
N E Q U A S, et c.).
B a s eli n e T e st s

S er u m vir ol o g y ( h e p atiti s B a n d C s cr e e ni n g, HI V) p er l o c al g ui d eli n e s .

Uri n e dr u g s cr e e n p er l o c al g ui d eli n e s .
C LI A = Cli ni c al L a b or at or y I m pr o v e m e nt A m e n d m e nt s of 1 9 8 8; e G F R = e sti m at e d gl o m er ul ar filtr ati o n r at e; 
h C G = h u m a n c h ori o ni c g o n a d otr o p hi n; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; U K N E Q U A S = U nit e d Ki n g d o m 
N ati o n al E xt er n al Q u alit y A s s e s s m e nt S er vi c e; W B C = w hit e bl o o d c ell.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 /9 5
A p pe n di x 5
Pr ot oc ol A me n d me nts Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is o n t he title pa ge.
C h a n ges fr o m Versi o n 2. 0 t o Versi o n 3. 0 I ncl u de d i n t he A me n d me nt
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 1. 1 S y n o p si s
I n cl u d e d t h at p arti ci p a nt s o n 
R E C O V E R Y Tri al d e x a m et h a s o n e 
d o si n g e q ui v al e nt of c orti c o st er oi d s 
m a y b e eli gi bl e f or e nr oll m e nt.
Cl ar ifi c ati o n of eli gi bilit y f or e nr oll m e nt.
S e cti o n 1. 1 S y n o p si s
I n cr e a s e d t h e d ur ati o n of t h e st u d y t o 
1 5 m o nt h s.
D u e t o pr otr a ct e d e nr oll m e nt ti m e s.
S e cti o n 1. 2 S c h e d ul e 
of A s s e s s m e nt s
I n cl u d e d H o s pit al Di s c h ar g e ( H D) a n d 
H D a s s e s s m e nt d et ail s.
A m e n d e d d et ail s f or r e q uir e m e nt f or 
c h e st i m a gi n g d o c u m e nt ati o n.
U p d at e d E C G s c h e d ul e.
U p d at e d cr o s s r ef er e n c e.
T o g at h er criti c al bi o m ar k er d at a a n d t o ali g n 
wit h v ari o u s l o c al st a n d ar d of c ar e g ui d a n c e 
r e g ar di n g c h e st i m a gi n g.
T o ali g n E C G s c h e d ul e wit h P K s a m pli n g.
S e cti o n 2. 2. 2 P ot e nti al 
T h er a p e uti c s
A m e n d e d d et ail s of a nti vir al s a n d 
i m m u n o m o d ul ati n g dr u g s.
U p d at e d t o d e s cri b e r e c e nt cli ni c al st u d y 
r e s ult s.
S e cti o n 3. 2 P art B 
O bj e cti v e s
I n cl u d e d P K p ar a m et er s o n D a y 3 f or 
P art B.
T o r efl e ct s a m pli n g o n D a y 3 if di s c h ar g e i s 
a nti ci p at e d b ef or e D a y 7.
S e cti o n 4. 1 O v er all 
D e si g n
S e cti o n 9. 1. 3. 3 
P h ar m a c o ki n eti c s
I n cl u d e d pr e a n d p o st d o s e P K 
s a m pl e s o n D a y 3.
T o g u ar a nt e e c oll e cti o n of P art B P K d at a if 
p arti ci p a nt i s di s c h ar g e d b ef or e D a y 7.
S e cti o n 4. 1 O v er all 
D e si g n
S e cti o n 4. 4 E arl y 
H o s pit al Di s c h ar g e 
A s s e s s m e nt s
S e cti o n 5. 5. 4 H o s pit al 
Di s c h ar g e
Cl arifi e d t h at p arti ci p a nt s di s c h ar g e d 
pri or t o D a y 1 4 s h o ul d h a v e H D 
a s s e s s m e nt s p erf or m e d.
T o g at h er criti c al bi o m ar k er d at a.
S e cti o n 4. 4 E arl y 
H o s pit al Di s c h ar g e 
A s s e s s m e nt s
N e w s e cti o n a d d e d.
T o cl arif y a s s e s s m e nt s p erf or m e d at e arl y 
di s c h ar g e.
S e cti o n 5 St u d y 
P o p ul ati o n
S e cti o n 5. 1 St u d y 
P o p ul ati o n
S e cti o n 5. 5. 1 
R e cr uit m e nt
I n cr e a s e d u p p er a g e li mit f or st u d y 
p arti ci p a nt s t o ≤7 5 y e ar s.
B a s e d o n st u d y t o d at e, st u d y i nt er v e nti o n i s 
w ell t ol er at e d; t h er ef or e, t h e a g e r e stri cti o n i s 
e x p a n d e d u p t o 7 5 y e ar s of a g e, t o r efl e ct a 
hi g h er ri s k gr o u p f or C O VI D -1 9 p n e u m o ni a.
S e cti o n 5 St u d y 
P o p ul ati o n
I n cl u d e d a g ui d a n c e c h art f or Fi O2
wit h r e g ar d t o O 2 d eli v er y.
T o f a cilit at e e nr oll m e nt.
S e cti o n 5. 1 I n cl u si o n 
Crit eri a
E x p a n d e d r a n g e of t e st s f or 
S A R S -C o V -2 i nf e cti o n.
T o ali g n wit h t h e r a n g e of t e st s t h at h a v e 
b e c o m e a v ail a bl e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 /9 5
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 5. 1 I n cl u si o n 
Crit eri a
Cl arifi e d i n cl u si o n crit eri a wit h r e g ar d 
t o O2 t h er a p y.
T o f a cilit at e e nr oll m e nt.
S e cti o n 5. 2 E x cl u si o n 
Crit eri a
U p d at e d e x cl u si o n crit eri o n wit h 
r e g ar d t o n e ur ol o gi c al di s or d er s.
T o cl arif y n e ur ol o gi c al di s or d er s t h at ar e 
e x cl u si o n ar y f or t h e st u d y.
S e cti o n 5. 2 E x cl u si o n 
Crit eri a
Cl arifi e d e x cl u si o n crit eri a wit h r e g ar d 
t o l o n g Q T c.
Cl arifi e d t h at p arti ci p a nt s wit h 
si g nifi c a ntl y u n c o ntr oll e d di a b et e s 
m ellit u s will b e e x cl u d e d.
Cl arifi e d e x cl u si o n crit eri a wit h r e g ar d 
t o O2 t h er a p y.
Cl arifi e d t h at c o nti n u e d d ail y u s e of 
m e di c ati o n s a s s o ci at e d wit h 
s er o t o ni n s y n dr o m e wit hi n 1 4 d a y s 
pri or t o r a n d o mi z ati o n i s e x cl u si o n ar y.
A m e n d e d crit eri o n t o i niti ati o n, u s e, or 
c h a n g e i n t h er a p y wit hi n 1 4 d a y s of 
r a n d o mi z ati o n i n st e a d of S cr e e ni n g.
Cl arifi e d e x cl u si o n crit eri o n wit h 
r e g ar d t o c orti c o st er oi d u s e d uri n g 
t he st u d y.
R e m o v al of e x cl u si o n crit eri a f or 
i niti ati o n or c h a n g e i n d o s e of 
a n gi ot e n si n c o n v erti n g e n z y m e 
i n hi bit or s or r e c e pt or bl o c k er s.
A m e n d e d crit eri o n t o i niti ati o n or u s e, 
of t h er a pi e s wit hi n 1 m o nt h of 
r a n d o mi z ati o n i n st e a d of S cr e e ni n g.
Li st of m e d i c ati o n s h a s b e e n u p d at e d 
a n d i nt er mitt e nt u s e of s o m e 
m e di c ati o n s i s all o w e d.
Q u alifi e d c o n c urr e nt cli ni c al st u d y 
p arti ci p ati o n t hr o u g h D a y 2 8 i s 
e x cl u si o n ar y if t h e st u d y i s e v al u ati n g 
a n i nt er v e nti o n.
A m e n d e d e x cl u si o n crit eri a f or 
di a g n o sti c a s s e s s m e nt s ( w hit e bl o o d 
c ell s, a b s ol ut e n e utr o p hil c o u nt, a n d 
pl at el et s) at S cr e e ni n g.
R e m o v al of a hi st or y of si g nifi c a nt 
c h e st i m a gi n g a b n or m aliti e s a s a n 
e x cl u si o n crit eri o n.
All eli gi bilit y crit eri a ar e u p d at e d t o i n cr e a s e 
p ot e nti al t ar g et p o p ul ati o n wit h o ut 
c o m pr o mi si n g s af et y, a n d b a s e d o n f e e d b a c k 
fr o m sit e s r e g ar di n g s cr e e n f ail ur e s.
S e cti o n 6. 1. 1. 2 D o si n g 
a n d A d mi ni str ati o n
Cl arifi e d t h at di ar y c ar d s c a n b e 
r et ur n e d b y m ail or el e ctr o ni c all y.
T o e n a bl e e a si er c oll e cti o n of st u d y -r e q uir e d 
d at a.
S e cti o n 7. 4
C o n c o mit a nt T h er a p y
Q u alifi e d w h e n c o -e nr oll m e nt i n 
a n ot h er o b s er v ati o n al o nl y st u d y i s 
all o w e d.
Cl arifi e d d et ail s f or o n -st u d y 
c o ntr ai n di c at e d m e di c ati o n s a n d 
v a c ci n ati o n s.
Cl arifi c ati o n s of pr ot o c ol pr o c e d ur e s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 /9 5
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 9. 3. 4 A d v er s e 
E v e nt s of S p e ci al 
Int er e st
A d d e d cli ni c all y si g nifi c a nt c ar di a c 
arr yt h mi a s.
F or c o n si st e n c y wit h S e cti o n 2. 3. 1.
S e cti o n 1 0. 3 
P o p ul ati o n s f or 
A n al y s e s
R e m o v e d “r a n d o mi z e d” i n t h e 
d efi niti o n of S af et y A n al y si s S et.
T o all o w f or all p ati e nt s r e c ei vi n g st u d y 
i nt er v e nti o n t o b e e v al u at e d f or s af et y.
S e cti o n 1 0. 4. 3. 1 1 
A n al y si s of O c c urr e n c e 
of R el a p s e i n 
P arti ci p a nt s D uri n g t h e 
St u d y P eri o d (if Fir st 
Di s c h ar g e d W it hi n t h e 
6 0 -d a y St u d y P eri o d)
U p d at e d cr o s s r ef er e n c e.
T o r efl e ct d o c u m e nt str u ct ur e.
A p p e n di x 3 M e di c ati o n 
G ui d a n c e
Cl arifi e d t h at t h e di s c o nti n u ati o n 
p eri o d i s t h e s p e cifi e d n u m b er of 
w e e k s b ef or e a n d t hr o u g h 
r a n d o mi z ati o n.
R e m o v e d di s c o nti n u ati o n p eri o d f or 
c orti c o st er oi d s.
A m e n d e d di s c o nti n u ati o n p eri o d s f or 
a nti d e pr e s s a nt s, a n xi ol yti c s, 
a n al g e si c s, a nti -e m eti c s, a nt i bi oti c s, 
m e di c ati o n s a s s o ci at e d wit h A O X 
i n hi biti o n, a n d s u p pl e m e nt s.
R e m o v e d di s c o nti n u ati o n p eri o d f or 
i n v e sti g ati o n al a g e nt s.
R e m o v e d d et ail s of m e di c ati o n s wit h 
a r e q uir e d d ur ati o n of a st a bl e d o s e.
Cl arifi c ati o n s aft er st u d y dr u g di s c o nti n u ati o n 
t o as si st wit h m e di c al m a n a g e m e nt d uri n g 
t h e f oll o w-u p p eri o d.
T hr o u g h o ut
U p d at e d “ c o n v al e s c e nt s er u m” t o 
“ c o n v al e s c e nt pl a s m a”.
T o r efl e ct st a n d ar d t er mi n ol o g y.
C orr e ct e d d efi niti o n of A O X fr o m 
“ alt er n ati v e” t o “ al d e h y d e” o xi d a s e.
T o r efl e ct c orr e ct d efi niti o n.
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s.
Mi n or, t h er ef or e t h e s e h a v e n ot b e e n 
s u m m ari z e d.
A O X = al d e h y d e o xi d a s e; C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; E C G = el e ctr o c ar di o gr a m; Fi O 2 = fr a cti o n of 
i n s pir e d o x y g e n; H D = H o s pit al Di s c h ar g e; P K = p h ar m a c o ki n eti c; Q T c = c orr e ct e d Q T i nt er v al.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 /9 5
C h a n ges fr o m Versi o n 1. 0 t o Versi o n 2. 0 I ncl u de d i n t he A me n d me nt
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e p a g e 
A d d e d l e g al e ntit y f or all c o u ntri e s, 
e x c e pt t h e U S a n d C a n a d a.
U p d at e d t h e s p o n s ori n g l e g al e ntiti e s t o pr o vi d e 
f or st u d y sit e s i n Br a zil b ei n g i n cl u d e d i n t h e 
st u d y.
A d d e d Cli ni c al Tri al s. g o v r e gi str y 
n u m b er.
R e gi str y n u m b er w a s n ot a v ail a bl e at t h e ti m e of 
V er si o n 1. 0 fi n ali z ati o n.
S e cti o n 1. 1 
S y n o p si s
U p d at e d P K p ar a m et er s t o b e a s s e s s e d 
f or s e c o n d ar y o bj e cti v e s i n P art A.
T o e n s ur e c o n si st e n c y a cr o s s s e cti o n s a n d wit h 
t h e I A P.
S e cti o n 1. 1 
S y n o p si s
A d d e d t h e e v al u ati o n of m o d ul ati o n of 
s el e ct bi o m ar k er s a s s e c o n d ar y 
o bj e cti v e i n P art B.
A v ail a bilit y of s el e ct bi o m ar k er s at t h e s a m e ti m e 
a s t h e cli ni c al o ut c o m e d at a will g ui d e n e xt st e p s 
i n cli ni c al d e v el o p m e nt of M 5 0 4 9.
S e cti o n 1. 2 
S c h e d ul e of 
A s s e s s m e nt s
M o v e d s er u m vir ol o g y a n d uri n e f or 
dr u g s of a b u s e a s s e s s m e nt s t o t h e e n d 
of t h e S cr e e ni n g a n d 
R a n d o mi z ati o n o nl y a s s e s s m e nt s i n 
T a bl e 1.
T o e m p h a si z e t h at t h e s e a s s e s s m e nt s will n ot b e 
e x cl u si o n ar y b ut o nl y f or p arti ci p a nt 
m a n a g e m e nt.
A d d e d t h at art eri al bl o o d g a s s h o ul d b e 
p erf or m e d at S cr e e ni n g if n ot a v ail a bl e 
fr o m t h e p arti ci p a nt c h art.
T o cl arif y t h at art eri al bl o o d g a s will b e o bt ai n e d 
fr o m t h e p arti ci p a nt c h art, a s a v ail a bl e, b ut 
s h o ul d b e p erf or m e d at S cr e e ni n g, if n ot 
a v ail a bl e fr o m t h e c h art.
S p e cifi e d t h at c h e st i m a gi n g will b e 
d o n e a s p er l o c al g ui d eli n e s.
St u d y sit e s mi g ht b e u si n g diff er e nt r a di ol o g y 
g ui d eli n e s b ut n ot ultr a s o u n d a s n ot a c cr e dit e d i n 
U S or Br a zil.
A d d e d t h at t h e ti m e of s a m pl e c oll e cti o n 
f or i nfl a m m at or y bi o m ar k er s will b e 
r e c or d e d o n d a y s a s i n di c at e d.
T o cl arif y t h at t h e d at e a n d cl o c k ti m e of s a m pl e 
c oll e cti o n will b e r e c or d e d a s alr e a d y f o u n d o n 
t h e e C R F.
F or P art B, a d d e d a D a y 3 s a m pl e 
c oll e cti o n f or s er u m a n d  
 
bi o m ar k er s, a n d d o c u m e nt ati o n at 
D a y 3 of i nfl a m m at or y bi o m ar k er s, if 
c oll e ct e d.
T o b ett er e v al u at e m o d ul ati o n of s el e ct 
bi o m ar k er s.
F or P K s a m pli n g, a d d e d t o b ot h P art A 
a n d P art B “ at s el e ct sit e s” w h er e p o st 
P K s a m pli n g m a y b e d e cr e a s e d.
T o e n a bl e m or e sit e s t o p arti ci p at e i n t h e st u d y 
b e c a u s e t h e y c a n p erf or m o nl y li mit e d P K 
s a m pli n g.
A d d t h at t h e ti m e of t h e cl o s e st m e al 
c o n s u m e d pri or t o t h e st u d y i nt er v e nti o n 
a d mi ni str ati o n i. e., w h e n t h e l a st m e al 
w a s fi ni s h e d b ef or e t h e st u d y 
i nt er v e nti o n a d mi ni str ati o n, s h o ul d b e 
r e c or d e d.
T o cl arif y t h e ti m e t o b e r e c or d e d wit h r e g ar d s t o 
m e al c o n s u m pti o n a n d st u d y i nt er v e nti o n 
a d mi ni str ati o n.
A d d e d t h at t h e D a y 1 s a m pl e s f or 
s er u m a n d  
 bi o m ar k er s m u st b e 
c oll e ct e d pri or t o st u d y i nt er v e nti o n 
a d mi ni str ati o n a n d t h at t h e ti m e of e a c h 
c oll e cti o n s h o ul d b e r e c or d e d.
T o e n s ur e t h at a B a s eli n e ( pr etr e at m e nt) v al u e i s 
o bt ai n e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 /9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 2. 2. 2 
P ot e nti al 
T h er a p e uti c s
A d d e d t h at c o n v al e s c e nt s er u m will b e 
all o w e d a s b a c k gr o u n d t h er a p y.
T o cl arif y t h at c o n v al e s c e nt s er u m i s all o w e d if 
u s e d a s i n t h e c o nt e xt of a n a nti vir al.
S e cti o n 2. 3. 1 
P ot e nti al Ri s k s
U p d at e d p ot e nti al ri s k fr o m “ Q T i nt er v al 
pr ol o n g ati o n” t o “ Cli ni c all y si g nifi c a nt 
arr yt h mi a”.
A d d e d n ot e t h at d o c u m e nt e d, 
l o n g st a n di n g L eft B u n dl e Br a n c h Bl o c k 
v ari a nt t h at c orr e ct s wit h Fri d eri ci a’ s 
f or m ul a, i s n ot e x cl u si o n ar y.
T o b e c o n si st e nt wit h S e cti o n 9. 3. 4.
S e cti o n 3. 1 
P art A O bj e cti v e s
U p d at e d P K p ar a m et er s t o b e a s s e s s e d 
f or s e c o n d ar y o bj e cti v e s i n P art A.
T o e n s ur e c o n si st e n c y a cr o s s s e cti o n s a n d wit h 
t h e I A P.
S e cti o n 3. 2 
P art B O bj e cti v e s
A d d e d t h e e v al u ati o n of m o d ul ati o n of 
s el e ct bi o m ar k er s a s s e c o n d ar y 
o bj e cti v e i n P art B.
A v ail a bilit y of s el e ct bi o m ar k er s at t h e s a m e ti m e 
a s t h e cli ni c al o ut c o m e d at a will g ui d e n e xt st e p s 
i n cli ni c al d e v el o p m e nt of M 5 0 4 9.
S e cti o n 4. 1 
O v er all D e si g n
U p d at e d str atifi c ati o n s f a ct or s f or P art B 
p arti ci p a nt s.
T o i n cl u d e st er oi d u s e a s a str atifi c ati o n f a ct or f or 
t h e c a s e s w h er e a d mi ni st er e d d o s e s ar e gr e at er 
t h a n 1 5 m g a n d cl arif y c o n v al e s c e nt s er u m i s 
c o n si d er e d a s a n a nti vir al (tr e at e d a s s u c h o n 
st u d y r a n d o mi z ati o n).
S e cti o n 5 St u d y 
P o p ul ati o n
A d d e d t h at S p O 2 a n d P a O 2 / Fi O2
r e a di n g s m a y b e o bt ai n e d aft er e x erti o n 
b y t h e p arti ci p a nt.
T o cl arif y t h at o bt ai ni n g S p O 2 s at ur ati o n a n d Fi O 2
m e a s ur e m e nt s aft er e x erti o n b y t h e p arti ci p a nt i s 
all o w e d.
S e cti o n 5. 1 
I n cl u si o n Crit eri a
A d d e d t h at S p O 2 a n d P a O 2 / Fi O2
r e a di n g s m a y b e o bt ai n e d aft er e x erti o n 
b y t h e p arti ci p a nt.
T o cl arif y t h at o bt ai ni n g S p O 2 s at ur ati o n a n d Fi O 2
m e a s ur e m e nt s aft er e x erti o n b y t h e p arti ci p a nt i s 
all o w e d.
S e cti o n 5. 2 
E x cl u si o n Crit eri a
A d d e d n ot e t h at d o c u m e nt e d, 
l o n g st a n di n g L eft B u n dl e Br a n c h Bl o c k 
v ari a nt t h at c orr e ct s wit h Fri d eri ci a’ s 
f or m ul a, i s n ot e x cl u si o n ar y.
T o a d dr e s s a fr e q u e nt fi n di n g i n ol d er 
p arti ci p a nt s w h o ot h er wi s e h a v e “ n or m al” E C G s.
S p e cifi e d t h at o nl y p arti ci p a nt s wit h 
s e v er e e n d or g a n d a m a g e d u e t o 
u n c o ntr oll e d di a b et e s m ellit u s or a n y 
di a b et e s will b e e x cl u d e d fr o m t h e 
st u d y.
T o cl arif y t h at p arti ci p a nt s wit h u n c o ntr oll e d 
di a b et e s m ellit u s or a n y di a b et e s will o nl y b e 
e x cl u d e d fr o m t h e st u d y if it h a s r e s ult e d i n 
s e v er e e n d or g a n d a m a g e.
U p d at e d d efi niti o n f or u n c o ntr oll e d 
a st h m a/ c hr o ni c o b str u cti v e p ul m o n ar y 
di s e a s e.
T o cl arif y t h e ti m efr a m e f or h o s pit ali z ati o n i n 
c a s e of e x a c er b ati o n.
U p d at e d e x cl u si o n crit eri a f or t h e u s e of 
t h er a pi e s wit hi n 1 4 d a y s pri or t o or 
d uri n g S cr e e ni n g.
T o a d d p h er e si s a n d u p d at e wit h r e s p e ct t o 
c orti c o st er oi d u s e.
A d d e d t h at c o n v al e s c e nt s er u m will b e 
all o w e d if p art of t h e st a n d ar d of c ar e 
f or t h e l o c al h o s pit al.
T o cl arif y t h at c o n v al e s c e nt s er u m i s all o w e d if 
u s e d a s i n t h e c o nt e xt of a n a nti vir al.
C h a n g e d e G R F a s c al c ul at e d b y t h e 
M o difi c ati o n of Di et i n R e n al Di s e a s e 
e q u ati o n, fr o m < 5 0 m L/ mi n/ 1. 7 3 m
2 t o 
4 5 m L/ mi n/ 1. 7 3 m
2 .
C h a n g e d t o xi cit y crit eri a f or e G F R.
S e cti o n 6. 1. 1. 2 
D o si n g a n d 
A d mi ni str ati o n
U p d at e d t e xt r e g ar di n g t h e 
a d mi ni str ati o n of st u d y i nt er v e nti o n vi a 
N G T.
T o b e c o n si st e nt wit h i n str u cti o n s i n t h e 
P h ar m a c y M a n u al.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 /9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 6. 1. 5 
Pr e p ar ati o n
R e m o v e d t e xt st ati n g t h at t a bl et s will b e 
cr u s h e d if a d mi ni st er e d vi a N G T.
T o b e c o n si st e nt wit h i n str u cti o n s i n t h e 
P h ar m a c y M a n u al.
S e cti o n 7 
M e a s ur e s t o 
Mi ni mi z e Bi a s: 
R a n d o mi z ati o n 
a n d Bli n di n g
U p d at e d str atifi c ati o n s f a ct or s f or P art B 
p arti ci p a nt s.
T o i n cl u d e st er oi d u s e a s a str atifi c ati o n f a ct or f or 
t h e c a s e s w h er e a d mi ni st er e d d o s e s ar e gr e at er 
t h a n 1 5 m g a n d cl arif y c o n v al e s c e nt s er u m i s 
all o w e d if u s e d a s i n t h e c o nt e xt of a n a nti vir al.
S e cti o n 7. 1 
Bli n di n g
U p d at e d t e xt t o st at e t h at t h e 
p h ar m a ci st will p o s si bl y b e u n bli n d e d i n 
pr e p ari n g t h e t a bl et s f or a d mi ni str ati o n 
vi a N G T.
T o w ar n st u d y sit e s i n t h e e v e nt t hi s o c c ur s.
U p d at e d t e xt t o st at e t h at o nl y t h e 
i nt er n al I D M C m a y r e q u e st r e vi e w of 
u n bli n d e d d at a.
Pri or l a n g u a g e w a s v a g u e.
R e m o v e d t e xt d e s cri bi n g t h e u n bli n di n g 
of bi o a n al yti c al l a b or at or y(i e s) 
r e s p o n si bl e f or t h e bi o a n al y si s of P K 
s a m pl e s.
T h e t e xt w a s i n c orr e ct.
S e cti o n 7. 3 St u d y 
I nt er v e nti o n 
C o m pli a n c e
R e m o v e d t e xt st ati n g t h at a p er s o n 
ot h er t h a n t h e p er s o n a d mi ni st eri n g t h e 
st u d y i nt er v e nti o n will c o nfir m t h e d o s e 
of st u d y i nt er v e nti o n a n d st u d y 
p arti ci p a nt i d e ntifi c ati o n at t h e ti m e of 
d o si n g.
T h e i n str u cti o n s w er e i n c orr e ct a n d c arr y o v er 
fr o m W H O t e m pl at e.
S e cti o n 7. 4 
C o n c o mit a nt 
T h er a p y
A d d e d i n str u cti o n s r e g ar di n g t h e u s e 
a n d r e c or di n g of c orti c o st er oi d s.
T o pr o vi d e g ui d eli n e s f or t h e u s e a n d r e c or di n g 
of c orti c o st er oi d s.
S e cti o n 7. 4. 1. 1 
C orti c o st er oi d s
A d d e d a s u b s e cti o n wit h i n str u cti o n s 
r e g ar di n g t h e u s e of c orti c o st er oi d s.
T o pr o vi d e g ui d eli n e s f or t h e u s e of 
c orti c o st er oi d s.
S e cti o n 8. 1 
Di s c o nti n u ati o n 
of t h e St u d y 
I nt er v e nti o n f or 
T o xi cit y
U p d at e d s e cti o n h e a di n g t o i n cl u d e 
t e m p or ary or p er m a n e nt 
di s c o nti n u ati o n.
Cl arifi e d l a n g u a g e u n d er w hi c h c o n diti o n s 
di s c o nti n u ati o n of dr u g o c c ur s wit h r e s p e ct t o 
li v er f u n cti o n t e st s, e G R, a n d E C G Q T c.
A d d e d t e xt t o s p e cif y w h e n st u d y 
i nt er v e nti o n m a y b e r e st art e d aft er 
Gr a d e 3 li v er f u n cti o n t e st s.
C h a n g e d t o xi cit y crit eri a f or e G F R.
A d d e d t o xi cit y crit eri a f or E C G Q T c 
i nt er v al.
S e cti o n 8. 2 
R e a s o n s f or 
Di s c o nti n u ati o n 
of St u d y 
I nt er v e nti o n
A d d e d t e xt t h at t h e vit al st at u s f or 
s u bj e ct s w h o di s c o nti n u e st u d y 
i nt er v e nti o n pr e m at ur el y, will b e 
c oll e ct e d at D a y s 1 4, 2 1, 2 8, a n d 6 0 
eit h er t hr o u g h t el e m e di ci n e c o nt a ct s or 
p h o n e c all s if t h e p arti ci p a nt i s u n a bl e t o 
r et ur n t o t h e st u d y sit e.
T o mi ni mi z e mi s si n g d at a, p arti ci p a nt s w h o 
di s c o nti n u e d st u d y i nt er v e nti o n pr e m at ur el y, will 
b e f oll o w e d f or t h e r e g ul arl y s c h e d ul e d effi c a c y 
a s s e s s m e nt s.
D oc u me nt N o. 
O bject N o
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 /9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S e cti o n 9. 1. 3. 2 
A d diti o n al Cli ni c al 
E n d p oi nt s, 
C O VI D -1 9 
I nfl a m m at or y 
Bi o m ar k er s, a n d 
S el e ct S er u m 
Bi o m ar k er s
U p d at e d h e a di n g a n d t e xt r e g ar di n g t h e 
c oll e cti o n of bi o m ar k er d at a.
T o cl arif y ti mi n g of d a t a a v ail a bl e f or st ati sti c al 
a n al y si s.
S e cti o n 9. 1. 3. 3 
P h ar m a c o ki n eti c s
A d d e d t h at P K d at a will b e a n al y z e d at 
a c e ntr al l a b or at or y a n d will n ot b e 
a v ail a bl e f or p arti ci p a nt m a n a g e m e nt.
T o cl arif y v a g u e l a n g u a g e.
U p d at e d d efi niti o n s f or P K p ar a m et er s.
T o e n s ur e c o n si st e n c y a cr o s s s e cti o n s a n d wit h 
t h e I A P.
A d d e d t h at t h e ti m e w h e n t h e l a st m e al 
w a s fi ni s h e d b ef or e or t h e fir st m e al 
st art e d aft er st u d y dr u g a d mi ni str ati o n, 
w hi c h e v er i s t h e cl o s e st m e al 
c o n s u m e d, s h o ul d b e r e c or d e d.
T o cl arif y t h e ti m e t o b e r e c or d e d wit h r e g ar d s t o 
m e al c o n s u m pti o n.
S e cti o n 1 0. 4. 2 
A n al y si s of t h e 
Pri m ar y Effi c a c y 
E n d p oi nt
U p d at e d str atifi c ati o n s f a ct or s.
U p d at e d of t h e st ati sti c al m et h o d ol o g y 
i n t h e s e n siti vit y a n al y si s t o t a k e i nt o 
a c c o u nt t h e str atifi c ati o n f a ct or s.
T o i n cl u d e st er oi d u s e a s a str atifi c ati o n f a ct or f or 
t h e c a s e s w h er e a d mi ni st er e d d o s e s ar e gr e at er 
t h a n 1 5 m g.
S e cti o n 1 0. 4. 3. 1 
A n al y si s of 
Cli ni c al St at u s
M o difi e d o d d s r ati o s t o b e e sti m at e d f or 
di c h ot o mi z e d v er si o n of t h e h e alt h 
st at u s.
A d diti o n al a n al y si s d e e m e d t o b e i m p ort a nt.
S e cti o n 1 0. 4. 3. 2 
A n al y si s of Ti m e 
t o S p O2 of ≥ 9 4 % 
s u st ai n e d f or at 
l e a st 2 4 h o ur s i n 
r o o m air
U p d at e d c o v ari at e s t o r efl e ct t h e 
c h a n g e s i n r a n d o mi z ati o n str atifi c ati o n 
f a ct or s.
T o a c c o u nt f or c o u ntr y a n d st er oi d u s e f or t h e 
c a s e s w h er e a d mi ni st er e d d o s e s ar e gr e at er 
t h a n 1 5 m g i n t h e a n al y si s.
S e cti o n 1 0. 4. 3. 4 
A n al y si s of Ti m e 
t o I nt e n si v e C ar e 
U nit A d mi s si o n 
( D a y 1 T hr o u g h 
D a y 2 8)
U p d at e d c o v ari at e s t o r efl e ct t h e 
c h a n g e s i n r a n d o mi z ati o n str atifi c ati o n 
f a ct or s.
T o a c c o u nt f or c o u ntr y a n d st er oi d u s e f or t h e 
c a s e s w h er e a d mi ni st e r e d d o s e s ar e gr e at er 
t h a n 1 5 m g i n t h e a n al y si s.
S e cti o n 1 0. 4. 4 
S af et y A n al y si s
U p d at e d t e xt r e g ar di n g t h e s u m m ar y 
st ati sti c s f or s af et y a n al y si s.
T o cl arif y st ati sti c al pr o c e d ur e s.
S e cti o n 1 0. 4. 5 
P h ar m a c o ki n eti c 
P ar a m et er s
U p d at e d t e xt r e g ar di n g t h e pr e s e nt ati o n 
of p o p ul ati o n m o d eli n g a n d si m ul ati o n 
a cti viti e s.
T o e n s ur e c o n si st e n c y wit h t h e I A P.
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt f or m atti n g 
r e vi si o n s.
Mi n or; t h er ef or e, h a v e n ot b e e n s u m m ari z e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 /9 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
C O VI D -1 9 = c or o n a vir u s di s e a s e 2 0 1 9; E C G = el e ctr o c ar di o gr a m; e C R F = el e ctr o ni c c a s e r e p ort f or m; 
e G F R = e sti m at e d gl o m er ul ar filtr ati o n r at e; Fi O 2 = fr a cti o n of i n s pir e d o x y g e n; I A P = I nt e gr at e d A n al y si s Pl a n; 
I D M C = I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e; N G T = n a s o g a stri c t u b e; P a O 2 = p arti al pr e s s ur e of o x y g e n; 
P K = p h ar m a c o ki n eti c; Q T c = c orr e ct e d Q T i nt er v al; R N A = ri b o n u cl ei c a ci d; S A R S- C o V - 2 = s e v er e a c ut e 
r e s pir at or y s y n dr o m e c or o n a vir u s; S p O 2 = p eri p h er al c a pill ar y o x y g e n s at ur ati o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI

M 5 0 4 9
A P h ase II St u d y of M 5 0 4 9
i n C O VI D -1 9 P ne u m o ni a ( A N E M O N E)
M S 2 0 0 5 6 9- 0 0 2 6
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 /9 5
A p pe n di x 8
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A 
P hase 
II, 
Ra n d o mize d, 
D o u ble- bli n d, 
Place b o -c o ntr olle d St u d y  to E val uate t he Safet y  an d 
Efficac y  of M 5 0 4 9 
i n H os pitalize d Partici pa nts wit h 
C O VI D - 1 9 P ne u m o nia
Cli nic al St u d y Pr ot oc ol Versi o n:
0 1 Mar
2 0 2 1 / Versi o n 4 . 0
Site N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site a n d u n dersta n d a n d will c o n d uct it per t he 
cli nical st u d y pr ot oc ol, a n y a p pr o ve d pr ot oc ol a me n d me nts, I nter natio nal C o u ncil 
o n 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n a n d 
s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct a n d 
a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olel y for 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or w it h a n y 
necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  sp o use 
a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet 
Healt h 
A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI