Clinical trial NCT04448756
Conditions: Coronavirus Disease 2019
Keywords: COVID-19 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2020-07-29; Completion date: 2021-08-16
Enrollment: 149 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the safety and efficacy of orally-administered M5049 in Coronavirus disease 2019 (COVID-19) pneumonia participants who are hospitalized but not on mechanical ventilation.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: M5049 intervention 2: M5049 intervention 3: Placebo
Intervention descriptions: intervention 1: Participants received M5049 50 milligram (mg) orally twice daily for 14 days. intervention 2: Participants received M5049 100 mg orally twice daily for 14 days. intervention 3: Participants received placebo tablets matched to M5049 daily for 14 days.

Protocol documents:
Prot_000.pdf: 


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

SAP_001.pdf: 


M5049 
 
 
 
A Phase II Study of M5049 in COVID-19 Pneumonia 
MS200569-0026             
 
 
 
 
 
 
 
Version 2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
2/64 
 
 
Approval Page 
 
Integrated Analysis Plan: MS200569-0026  
 
A Phase II, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety 
and Efficacy of M5049 in Hospitalized Participants with COVID-19 Pneumonia 
 
 
 
Approval of the IAP by all Merck Data Analysis Responsible has to be documented within 
ELDORADO via eSignature. With the approval, the Merck responsible for each of the analysis 
also takes responsibility that all reviewers’ comments are addressed adequately. 
By using eSignature, the signature will appear at the end of the document. 
 


M5049 
 
 
 
A Phase II Study of M5049 in COVID-19 Pneumonia 
MS200569-0026             
 
 
 
 
 
 
 
Version 2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/64 
 
 
1 
Table of Contents 
Approval Page 
 ..............................................................................................................2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................6 
3 
Modification History ............................................................................7 
4 
Purpose of the Integrated Analysis Plan ...............................................8 
5 
Objectives and Endpoints .....................................................................8 
6 
Overview of Planned Analyses ...........................................................12 
6.1 
Analyses for IDMC meeting 1 ............................................................12 
6.2 
Analyses for subsequent IDMC Meetings ..........................................13 
6.3 
Final Analysis .....................................................................................13 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ......13 
8 
Analysis Populations and Subgroups ..................................................13 
8.1 
Definition of Analysis Populations .....................................................13 
8.2 
Subgroup Definition and Parameterization ........................................15 
9 
General Specifications for Data Analyses ..........................................18 
9.1 
Presentation of continuous and qualitative variables ..........................18 
9.2 
Presentation of Pharmacokinetic Results ............................................19 
9.2.1 
Presentation of Pharmacokinetic Concentration Data ........................19 
9.2.2 
Presentation of Pharmacokinetic Parameter Data ...............................19 
9.3 
Definition of Baseline and Change from Baseline .............................20 
9.4 
Study Treatment Day ..........................................................................20 
9.5 
Definition of Duration and ‘time since’ Variables .............................20 
9.6 
Conversion Factors .............................................................................21 
9.7 
Definition of On-treatment Period ......................................................21 
9.8 
Imputation of Missing Data ................................................................21 
9.9 
Analysis visit windows .......................................................................25 
10 
Study Participants ...............................................................................25 
10.1 
Disposition of Participants and Discontinuations ...............................25 
10.2 
Protocol Deviations / Exclusion from Analysis Populations ..............26 
10.2.1 
Important Protocol Deviations ............................................................26 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Population .......27 


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 
M S 2 0 0 5 6 9- 0 0 2 6               
  
  
  
  
  
  
  
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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 4 
 
 
1 1  
De m o gra p hics a n d Ot her Ba seli ne C haracteristics ............................. 2 7 
1 1. 1  
De m o gra p hics ..................................................................................... 2 7  
1 1. 2  
Me dical Hist or y .................................................................................. 2 8  
1 1. 3  
Ot her Baseli ne C haracteristics ............................................................ 2 8  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ............................. 3 0  
1 3  
St u d y Treat me nt: C o m plia nce a n d E x p os ure ..................................... 3 0  
1 4  
Efficac y A nal yses ............................................................................... 3 2  
1 4. 1  
Pri mar y E n d p oi nt: T i me t o Rec o ver y ................................................. 3 2 
1 4. 1. 1  
Pri mar y O bjecti ve: Deri vati o n a n d A nal ysis of t he Pri mar y 
E n d p oi nt Ti me t o Rec o ver y ................................................................ 3 2  
1 4. 2  
Sec o n dar y E n d p oi nts .......................................................................... 3 6  
1 4. 2. 1  
Pr o p orti o n of S u bjects 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 ........................................................................................ 3 6  
1 4. 2. 2  
Cli nical Stat us ..................................................................................... 3 7  
1 4. 2. 3  
Ti me t o S p O2 ≥ 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 fr o m Da y 1 t hr o u g h D a y 2 8  ...................................................... 3 9 
1 4. 2. 4  
All-ca use M ortalit y ............................................................................. 4 1  
1 4. 2. 5  
Ti me t o I C U A d missi o n ( Da y 1 T hr o u g h Da y 2 8) ............................. 4 1  
1 4. 2. 6  
Ti me t o N o n-I n vasi ve Mec ha nical Ve ntilati o n ( Da y 1 T hr o u g h 
Da y 2 8) ............................................................................................... 4 3  
1 4. 2. 7  
Ti me t o I n vasi ve Mec ha nical Ve ntilati o n ........................................... 4 3  
1 4. 2. 8  
T otal Da ys i n I C U ............................................................................... 4 4  
1 4. 2. 9  
T otal Da ys i n t he H os pital a n d Ti me t o H os pital Disc har ge .............. 4 5  
1 4. 2. 1 0  
I nfla m mat or y Bi o mar kers ................................................................... 4 6 
1 4. 2. 1 2  
Occ urre nce of Rela pse ........................................................................ 4 8  
1 4. 2. 1 3  
Occ urre nce of Re- h os pita lizati o n d ue t o C O VI D- 1 9 
C o m plicati o ns ..................................................................................... 4 9  
C CI
C CI
C CIC 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 
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1 5  
Safet y a nal ysis .................................................................................... 5 0  
1 5. 1  
A d verse E ve nts ................................................................................... 5 0  
1 5. 1. 1  
All A d verse E ve nts ............................................................................. 5 1  
1 5. 1. 2  
A d verse E ve nts Lea di n g t o Disc o nti n uati o n of St u d y Treat me nt ...... 5 2  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E ve nts ................................................................................... 5 2  
1 5. 2. 1  
Deat hs ................................................................................................. 5 2  
1 5. 2. 2  
Seri o us A d verse E ve nts ...................................................................... 5 3  
1 5. 2. 3  
Ot her Si g nifica nt A d verse E ve nts ...................................................... 5 3  
1 5. 3  
Cli nical La b orat or y E val uati o n ........................................................... 5 3  
1 5. 4  
Vital Si g ns .......................................................................................... 5 5  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns ............................................ 5 6  
1 6  
A nal yses of Ot her E n d p oi nts .............................................................. 5 7  
1 6. 1  
P har mac o ki netics ................................................................................ 5 7  
1 7  
Refere nces ........................................................................................... 6 2  
1 8  
A p pe n dices ......................................................................................... 6 3  
1 8. 1  
A p pe n di x 1 - N CI- C T C Gra da ble  a n d N o n- Gra da ble Safet y 
La b orat or y Test Para meters a n d Directi o n(s) of A b n or malit y ........... 6 3  
 
C CI


M5049 
 
 
 
A Phase II Study of M5049 in COVID-19 Pneumonia 
MS200569-0026             
 
 
 
 
 
 
 
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C O N F I D E N T I A L 
I N F O R M A T I O N 
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2 
List of Abbreviations and Definition of Terms 
 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical classification  
AVT 
Anti-Viral Therapy 
BLQ 
Below lower limit of quantification 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
COVID-19 
Coronavirus disease 2019 
Ctrough 
Concentration observed immediately before next dosing (corresponding to 
pre-dose or trough concentration for multiple dosing) 
CV 
Coefficient of Variation 
eCRF 
electronic Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ECMO 
Extra Corporeal Membrane Oxygenation 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FiO2 
Fractional Inspired Oxygen 
GeoCV 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
HR 
Hazard Ratio 
IDMC 
Independent Data Monitoring Committee 
IAP 
Integrated Analysis Plan 
ICU 
Intensive care unit 
ITT 
Intention to treat 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 






M5049 
 
 
 
A Phase II Study of M5049 in COVID-19 Pneumonia 
MS200569-0026             
 
 
 
 
 
 
 
Version 2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/64 
 
 
OBJECTIVES 
ENDPOINTS (OUTCOME MEASURES) 
IAP SECTIONS 
2. Ambulatory: limitation of 
activities. 
3. Hospitalized, mild disease: 
hospitalized, no oxygen 
therapy. 
4. Hospitalized, mild disease: 
oxygen by mask or nasal 
prongs. 
5. Hospitalized, severe 
disease: noninvasive 
ventilation or high 
flow-oxygen. 
6. Hospitalized, severe 
disease: intubation and 
mechanical ventilation. 
7. Hospitalized, severe 
disease: ventilation + 
additional organ support – 
e.g., pressors, RRT, ECMO. 
8. Death. 
  To assess the PK of M5049. 
Pharmacokinetic parameters: Cmax, 
tmax, λz, t1/2, AUC0-tlast, AUC0-12h, 
AUC0-∞, CL/F, Vz/F, Cmax/D, 
AUC0-tlast/D, AUC0-12h/D, AUC0-∞/D, 
Racc(AUC0-12h), Racc(Cmax) on Day 1 
and Day 7.. 
16.1 
AESI = adverse event of special interest; CL/F = apparent total body clearance of study intervention following 
extravascular 
administration; 
ECG = electrocardiogram; 
ECMO = extracorporeal 
membrane 
oxygenation; 
IAP = Integrated Analysis Plan; ICU = intensive care unit; λz = elimination rate constant; PK = pharmacokinetic; 
RRT = rapid response team; SAE = serious adverse event; TEAE = treatment-emergent adverse event; 
Vz/F = apparent volume of distribution. 




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 
M S 2 0 0 5 6 9- 0 0 2 6               
  
  
  
  
  
  
  
Versi o n 2. 0 
 
 
C O N F I D E N T I A L 
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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) 
I A P S E C TI O N S 
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). 
1 4. 2. 4 
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).  
•  
1 4. 2. 5
 
•  
1 4. 2. 7
 
 
•  
1 4. 2. 6
 
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. 
1 4. 2. 8 
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 o D a y 2 8 
1 4. 2. 9 
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 m m 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). 
1 4. 2. 1 0 
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 al p h a, 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). 
1 4. 2. 1 1 
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. 
1 4. 2. 1 2 
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 (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) 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)  
1 4. 2. 1 3 
C CI




M5049 
 
 
 
A Phase II Study of M5049 in COVID-19 Pneumonia 
MS200569-0026             
 
 
 
 
 
 
 
Version 2.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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6.2 
Analyses for subsequent IDMC Meetings 
Additional IDMC meetings were held to review accumulating safety data as defined in the Clinical 
Study Protocol (CSP) and to monitor the overall conduct of the clinical study. Blinded and partially 
blinded outputs were created to support IDMC safety review based on the list reported in the 
“MS200569_0026_TOC_Section15” Excel document. 
6.3 
Final Analysis 
This analysis will be the main analysis. All planned analyses identified in the study protocol and 
in this IAP will be performed only after the last participant has completed the safety follow up 
period with all study data in-house, and the database will be locked for the analysis. 
A data review meeting will be held prior to any database lock.  
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol 
The inclusion of all stratification factors is identified as a potential source of problems in the 
implementation and interpretation of statistical models used to analyze efficacy. For this, use of 
corticosteroids before randomization and country will only be included, as deemed the most 
relevant factors, while presence of obstructive lung disease and use of antiviral therapy before 
randomization will be analyzed as subgroups. 
8 
Analysis Populations and Subgroups 
8.1 
Definition of Analysis Populations 
The analysis populations are specified below. The final decision to exclude participants from any 
analysis population will be made during a data review meeting prior to database lock and 
unblinding. 
Enrolled Analysis Set  
The Enrolled Analysis Set includes all participants who sign informed consent and will be used to 
report disposition data. 
Intent-To-Treat Analysis Set (ITT) 
The ITT consists of all treated participants and it will be used for the primary efficacy analysis. 
Participants will be analyzed according to the actual treatment received, which will be determined 
based on the treatment taken just after randomization, as collected in the electronic Case Report 
Form (eCRF). Occurrences of mistreatment (i.e. a different treatment from the one assigned via 
randomization) will be evaluated on a case by case basis. 
Safety Analysis Set (SAF) 


M 5 0 4 9 
  
  
  
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T he S A F c o nsists of all partici p a nts w h o recei ve d at least o ne d ose of st u d y i nter ve nti o n a n d is 
use d f or e val uati o n of  safet y e n d p oi nts.  
Partici pa nts will be a nal yze d acc o r di n g t o t he act ual treat me nt recei ve d, w hic h will be deter mi ne d 
base d o n t he treat me nt ta ke n j ust  after ra n d o mizati o n, as c ollecte d i n t he e C R F. Occ urre nces of 
mistreat me nt will be e val uate d o n a case b y case basis. 
T heref ore, t he I T T a n d t he S A F are t he sa me p o p ulati o n a n d ca n be use d i nterc ha n gea bl y. 
P h ar m ac o ki netics A n alysis Set ( P K A S) 
T he P K A S will i ncl u de all partic i pa nts w h o recei ve d at least o ne d ose of acti ve treat me nt, f or 
w h o m at least o ne q ua ntifia ble p ost d ose plas ma  c o nce ntrati o n of M 5 0 4 9 is o btai ne d, a n d wit h o ut 
a n y rele va nt pr ot oc ol de viati o ns a n d a bse nce of fact or t hat ma y ha ve a n i nfl ue nce o n P K. It will 
be use d f or t he e val ua ti o n of P K e n d p oi nts. 
Partici pa nts will be a nal yze d acc o r di n g t o t he act ual treat me nt recei ve d, w hic h will be deter mi ne d 
base d o n t he treat me nt ta ke n j ust  after ra n d o mizati o n, as c ollecte d i n t he e C R F. Occ urre nces of 
mistreat me nt will be e val uate d o n a case b y case basis. 
P h ar m ac o dy n a mics A n alysis Set ( P D A S) 
T he P D A S will i ncl u de all partici p a nts w h o recei ve d at least o ne d ose of st u d y i nter ve nti o n, f or 
w h o m at least o ne p ost- baseli ne bi o mar ker res ult is o btai ne d a n d wit h o ut a n y rele va nt pr ot oc ol 
de viati o ns or e ve nts t hat ma y ha ve a n i nfl ue nce o n p har mac o d y na mics. It will be use d f or t he 
e val uati o n of e n d p oi nts relate d t o i nfl a m mat or y a n d  
 bi o mar kers. 
Partici pa nts will be a nal yze d acc o r di n g t o t he act ual treat me nt recei ve d, w hic h will be deter mi ne d 
base d o n t he treat me nt ta ke n j ust  after ra n d o mizati o n, as c ollecte d i n t he e C R F. Occ urre nces of 
mistreat me nt will be e val uate d o n a case b y case basis. 
A n al yses per A n al ysis Sets 
T he f oll o wi n g ta ble s u m marizes t he use of t he a nal ysis sets i n t he differe nt a nal yses.  
 A n al y si s
 S et s
A n al y s e s
 I T T/ S A F
 
P K A S
 
P D A S
B a s eli n e C h ar a ct eri sti c s 
 
 
Pr e vi o u s a n d C o n c o mit a nt T h er a pi e s 
 
 
C o m pli a n c e a n d E x p o s ur e 
 
 
Effi c a c y: Pri m ar y  
 
 
 
Ot h er Effi c a c y  
 
 
 
I nfl a m m at or y 
 Bi o m ar k er s 
 
 
P h ar m a c o ki n eti c s 
 
 
S af et y 
 
 
 
C CI
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8.2 
Subgroup Definition and Parameterization 
The following factors, based on data collected on the eCRF, will be used as cofactors for all the 
stratified analyses: 
• Treatment with corticosteroids therapy within 48 hours from randomization (as collected in 
the ‘Randomization’ eCRF page) 
o Corticosteroids dose ≤ 15 mg of prednisone-equivalent (reference level) 
o Corticosteroids dose > 15 mg of prednisone-equivalent 
 
• Country  
o United States of America (reference level) 
o Philippines 
o Brazil 
The following subgroups then, including the two stratification factors defined above and based on 
information collected at baseline, will be defined: 
Comorbidities: 
• Presence of obstructive lung disease (as collected in the ‘Medical History’ eCRF page) 
o No (reference level)  
o Yes 
• Obesity based on BMI  
o No: Body Mass Index (BMI - derivation described at Section 11.1) < 30 kg/m2 
(reference level) 
o Yes: BMI ≥ 30 kg/m2  
• Diabetes co-morbidity at study entry (as collected in the ‘Medical History’ eCRF page) 
o No (reference level)  
o Yes 
• Heart diseases co-morbidity at study entry (as collected in the ‘Medical History’ eCRF page) 
o No (reference level)  
o Yes 
• Hypertension co-morbidity at study entry (as collected in the ‘Medical History’ eCRF page) 
o No (reference level)  
o Yes 


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•  N u m ber  of  rele va nt  c o m or bi dities  ( deri ve d  f or  eac h  partici pa nt  c o u nti n g  t he  n u m ber  of  
c o m or bi dities a m o n g t he o nes liste d a b o ve, i ncl u di n g o besit y base d o n B MI): 
o  N o (refere nce le vel) 
o  Yes: 1 or 2 
o  Yes: m ore t ha n 2  
Use of Rele v a nt T her a pies at b aseli ne : 
•  Treat me nt wit h c ortic oster oi d s t hera p y wit hi n 4 8 h o urs fr o m ran d o mizati o n (as c ollecte d i n 
t he ‘ Ra n d o mizati o n’ e C R F pa ge) 
o  C ortic oster oi ds d ose ≤ 1 5 m g of pre d nis o ne-e q ui vale nt (refere nce le vel) 
o  C ortic oster oi ds d ose > 1 5 m g  of pre d nis o ne-e q ui vale nt 
•  Treat me nt wit h a nti viral t hera p y ( A V T) i ncl u di n g c o n valesce nt ser u m wit hi n 4 8 h o urs fr o m 
ra n d o mizati o n (as c ollecte d i n t he ‘ Ra n d o mizati o n’ e C R F pa ge) 
o  N o (refere nce le vel)  
o  Yes 
De m o gr a p hic c h ar acteristics : 
•  A ge ( deri vati o n descri be d at Secti o n 1 1. 1 )  
o  A ge < 6 0 (refere nce le vel) 
o  A ge ≥ 6 0 
•  Ge n der  
o  Male (refere nce le vel) 
o  Fe male 
•  Et h nicit y 
o  His pa nic or Lati n o   
o  N ot His pa nic n or Lati n o (refere nce le vel) 
C CI
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Ot her c h ar acteristics : 
•  C o u ntr y  
o  U nite d States of A merica (refere nce le vel) 
o  P hili p pi nes 
o  Brazil 
•  Site 
•  S m o ki n g stat us at st u d y e ntr y (as c ollecte d i n t he ‘ S u bsta nce Usa ge’ e C R F pa ge) 
o  S m o ker (f or mer, or re g ular t o bacc o use) 
o  N o n- S m o ker ( ne ver use d t o bacc o, refere nce le vel) 
S u b gr o u p a nal yses will be perf or me d o n pri mar y a n d selecte d sec o n dar y efficac y e n d p oi nt as 
defi ne d bel o w. 
 
 
F or t he defi niti o n of s u b gr o u p le vel, data as d oc u me nte d i n t he e C R F will be ta ke n. T he cate g or y 
“ missi n g” will n ot be i ncl u de d i n a n y s u b gr o u p a nal ysis.  
F or s u b gr o u ps wit h t w o cate g ories o nl y, i n case of  less t ha n 9 partici pa nts wit hi n eac h cate g or y 
t he s u b gr o u p will n ot be c o nsi dere d f or t he a nal ysis. 
C CI
C CI
C CI


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9  
Ge ner al S pecific ati o ns f or D at a A n al yses 
T his secti o n descri bes a n y ge neral s pecificati o ns n ot i ncl u de d i n s u bse q ue nt secti o ns.  
Part A o bjecti ves will be se paratel y descri be d o nl y i n case of earl y ter mi nati o n of t he st u d y f or 
safet y reas o ns, ot her wise all data fr o m all st u d y partici pa nts fr o m Part A a n d Part B will be 
c o m bi ne d. 
St u d y treat me nt gr o u ps are defi ne d a n d la bele d as Place b o, M 5 0 4 9 5 0 m g BI D, a n d M 5 0 4 9 1 0 0 m g 
BI D. U nless ot her wise i n dicate d, all ta bles will be prese nte d b y st u d y treat me nt gr o u ps. F or 
de m o gra p hics, baseli ne a n d safet y data  a t otal c ol u m n is als o prese nte d. 
T he “start date” f or t his st u d y is  t he first d ose date ( Da y 1). 
U nless ot her wise s pecifie d, c o m paris o ns will be prese nte d f or eac h d ose of M 5 0 4 9 vers us place b o. 
I n t his st u d y t here will be n o h y p ot hesis testi n g: t herefore, all statistical test s me nti o ne d i n t his I A P 
are t o be re gar de d as e x pl orat or y. E x pl orat or y statis tical tests c o m pari n g st u d y treat me nt gr o u ps 
will be perf or me d t w o-si de d a n d c o nfi de nce i nter v als ( CI) will be t w o-si de d wit h a c o nfi de nce 
pr o ba bilit y of 9 5 %, u nless ot her w ise s pecifie d i n t his I A P. 
All a nal yses will be perf or me d usi n g S A S ® S oft ware Versi o n 9. 2 or hi g her, wit h t he e xce pti o n of 
M 5 0 4 9 P K para meters w hic h will be deri ve d usi n g n o nc o m part me ntal  met h o ds wit h t he vali date d 
c o m p uter pr o gra m 
 
  
or hi g her 
 
 
9. 1  
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles 
C o nti n u o us varia bles ot her t ha n P K will be s u m marize d usi n g t he f oll o wi n g descri pti ve statistics, 
i.e.  
•  n u m ber of s u bjects wit h n o n- missi n g val ues ( n) 
•  mea n, sta n dar d de viati o n 
P P D
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• median, 25th Percentile - 75th Percentile (Q1-Q3)  
• minimum (Min) and maximum (Max) 
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”. 
Qualitative variables will be summarized by counts and percentages.                
Mean, median, Q1, Q3, Min, and Max will have the same precision as collected in SDTM datasets 
for non-derived data. Standard deviation will be presented with 1 digit more than the mean. 
Percentage and percent change from baseline will be reported using 1 decimal digit, if not specified 
otherwise.   
Unless otherwise stated, the calculation of proportions will be based on the number of subjects in 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category. 
For variables where a subject may have more than one category due to multiple responses per 
subject (i.e. not mutually exclusive categories), the number of subjects included in each category 
will be summarized as a percentage from all subjects. Therefore, the total frequency across 
categories may not equal the total number of all subjects in the population. 
9.2 
Presentation of Pharmacokinetic Results 
9.2.1 
Presentation of Pharmacokinetic Concentration Data 
M5049 concentration data will be descriptively summarized using: number of non-missing 
observations (n), arithmetic mean (Mean), SD, coefficient of variation (CV%), minimum (Min), 
median (Median), and maximum (Max). In cases with n ≤ 2, only n, Min, and Max will be reported. 
 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data: 
Mean, Min, Median, Max:  
3 significant digits 
SD: 
4 significant digits 
CV%: 
1 decimal place  
9.2.2 
Presentation of Pharmacokinetic Parameter Data 
Pharmacokinetic parameter data will be descriptively summarized using: n, Mean, SD, CV%, Min, 
Median, Max, geometric mean (GeoMean), the geometric coefficient of variation (GeoCV), and 
the 95% CI for the GeoMean (LCI 95% GM, UCI 95% GM). For time to reach maximum observed 


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concentration (tmax), only n, Min, Median, and Max will be reported. In cases with n ≤ 2, only n, 
Min, and Max will be reported. The PK parameter maximum observed plasma concentration (Cmax) 
will be reported with the same precision as the source data. All other PK parameters will be 
reported to 3 significant figures. In export datasets, as well as in the SDTM PP domain, PK 
parameters will be provided with full precision, and will not be rounded. Descriptive statistics of 
PK parameter data will be calculated using full precision values, and rounded for reporting 
purposes only.  
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 Significant digits 
SD: 
4 Significant digits 
CV%, GeoCV%: 
1 decimal place  
 
9.3 
Definition of Baseline and Change from Baseline 
In general, the last non-missing measurement prior to first dose will serve as baseline 
measurement.  
Unless otherwise specified, if a scheduled pre-dose measurement actually occurred post-dose, then 
the corresponding measurement will be analyzed similar to an unscheduled post-dose 
measurement. 
Absolute and percent changes from baseline are defined as:  
 
absolute change = analysis visit value – baseline value 
 
percent change = 100 * (analysis visit value – baseline value) / baseline value 
9.4 
Study Treatment Day 
Day 1 is the day of first study drug administration, the day before is Day -1 (no Day 0 is defined). 
Study day is defined relative to Day 1. 
9.5 
Definition of Duration and ‘time since’ Variables 
Durations in days will be calculated by the difference of start and stop date/time  (e.g. survival 
time (days) = date/time of death – date/time of first dose) if not otherwise specified. 
The time since an event (e.g. time since diagnosis) will be calculated as reference date/time minus 
date/time of event, when available. 


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9.6 
Conversion Factors 
The following conversion factors will be used to convert days into months or years:  
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
If height is recorded in inches, height (cm) = height (in) × 2.54. 
If weight is recorded in pounds, weight (kg) = weight (lbs) ÷ 2.2046. 
9.7 
Definition of On-treatment Period 
The on-treatment period is defined as any time on or after the first dose of study treatment.  
The on-treatment period ends with the date of last contact or death, whichever occurs first. 
9.8 
Imputation of Missing Data 
Unless otherwise specified all data will be evaluated as observed, and no imputation method for 
missing values will be used, with the exception of: 
• Handling of missing data for PK parameter calculations is discussed under Section 16.1; 
• Handling of the following data, for which imputed values will be presented in all 
participant data listings and imputed information will be flagged: 
 
Adverse events 
Incomplete AE-related dates will be imputed as follows: 
• If the AE onset date is missing completely, then the onset date will be 
replaced by the start of study treatment. If the end date or resolution 
date indicates that the AE has stopped before start of treatment, this date 
will be used for imputation instead of start of treatment date. 
• If only the day part of the AE onset date is missing, but the month and 
year are equal to the start of study treatment, then the AE onset date 
will be replaced by the start of study treatment. For example, if the AE 
onset date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. If 
the end date or resolution date indicates that the AE has stopped before 
start of treatment, this date will be used for imputation instead of start 
of treatment date. 
• If both the day and month of the AE onset date are missing but the onset 
year is equal to the start of study treatment, then the onset date will be 
replaced by the start of study treatment. For example, if AE onset date 
is --/---/2014, and study treatment start date is 19/NOV/2014, then the 
imputed AE onset date will be 19/NOV/2014. If the end date or 
resolution date indicates that the AE has stopped before start of 


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treatment, this date will be used for imputation instead of start of 
treatment date. 
• In all other cases the missing onset day and/or missing onset month will 
be replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if 
day is missing only), if not resulting in a date later than the date of 
participant's death. In the latter case the date of death will be used to 
impute the incomplete stop date.  
• In all other cases the incomplete stop date will not be imputed.  If stop 
date of AE is after date of cut-off this date will be kept. 
Incomplete AE-related times will be imputed as follows: 
• If the AE onset time is missing, but the date is equal to the start of study 
treatment, then the AE onset time will be replaced by the start time of 
study treatment. 
• In all the other cases missing start time will not be imputed. 
• Incomplete stop times will not be imputed.   
Concomitant 
Medications 
For identification of previous or concomitant medications/procedures, no 
formal imputation will be performed on missing or incomplete dates. Rules 
presented in Table 2 will be used to define if a medication/procedure is 
considered as a previous, concomitant or both previous and concomitant 
medication/procedure. 
Exposure 
Incomplete exposure times will be imputed as follows: 
• If the first dose time is missing, then:  
o if the first dose date is equal to date of randomization then the 
first dose time will be imputed as the time of randomization. 
o if the first dose date is after the date of randomization then the 
first dose time will be imputed: 
 as 08:00 if timing = “Morning” or unknown 
 as 20:00 if timing = “Evening”  
• If the last dose time is missing, then, it will be imputed: 
o as 08:00 if timing = “Morning” or unknown 
o as 20:00 if timing = “Evening”. 
ICU 
admission 
and discharge 
Incomplete ICU admission dates will be imputed as follows: 
• If the ICU admission day is missing, it will be imputed as the latest 
between 1st day of the month and the date of hospital admission. 
• In all other cases ICU admission date will not be imputed 


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Incomplete ICU times will be imputed as follows: 
• If the ICU admission time is missing, but the date is equal to the start 
of study treatment, then the ICU admission time will be replaced by the 
start time of study treatment. 
• In all the other cases, ICU admission time will be imputed as 00:00. 
• Incomplete discharge times will be imputed as 23:59, if not resulting in 
a date and time later than the date and time of participant's death. In the 
latter case the time of death will be used to impute the incomplete 
discharge time.   
Hospital 
discharge 
Incomplete hospital discharge dates will be imputed as follows: 
• If the hospital discharge day is missing, it will be imputed as the last 
day of the month. 
• In all other cases hospital discharge date will not be imputed 
 




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9.9 
Analysis visit windows 
For endpoints to be reported by visit, the following analysis visit windows will be defined: 
•
Baseline (see Section 9.3 for definition)
•
Analysis Day 2
•
Analysis Day 3
•
Analysis Day 4
•
Analysis Day 5: Day 5 and 6
•
Analysis Day 7: Day 7 and 8
•
Analysis Day 10: from Day 9 to Day 11
•
Analysis Day 14: from Day 12 to Day 17
•
Analysis Day 21: from Day 18 to Day 24
•
Analysis Day 28: from Day 25 to Day 35
•
Analysis Day 44: from Day 36 to Day 52
•
Analysis Day 60: from Day 53 onwards
In case of multiple assessments collected within the same window, the one closest to the target 
date will be used for summary statistics. All the assessments will be used for worst case analyses. 
10 
Study Participants 
The subsections in this section include specifications for reporting participant disposition and 
study treatment/study discontinuations. Additionally, procedures for reporting protocol deviations 
are provided. 
10.1 
Disposition of Participants and Discontinuations 
Disposition information will be collected in the ‘Demography’, ‘Exposure’, ‘End of Study 
Treatment’ and ‘Disposition’ eCRF pages. 
The number and percentage of participants in each of the below disposition categories will be 
presented by actual treatment group for the enrolled analysis set. Percentages will be presented 
with respect to the number of treated participants 
• Total number of participants enrolled (i.e. participants who gave informed consent)
• Number of participants who discontinued from the study prior to randomization overall and
grouped by the main reason (e.g. the failed specific inclusion or exclusion criteria, withdrawal
of consent)


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• Number of randomized participants.
The treatment status will be summarized as follows: 
• Number and percentage of participants who did not receive any dose of study treatment
• Number and percentage of participants who took at least one dose of study treatment.
The end of treatment status will be summarized by: 
• Number and percentage of treated participants who completed study treatment (defined as
participants which completed the full course of the study as per ‘End of Study Treatment’
eCRF page).
• Number and percentage of treated participants who discontinued the study treatment, overall
and by primary reason.
The end of study status will be summarized by number and percentage of treated participants who 
completed or prematurely discontinued the study after randomization, grouped by main reason. 
Additionally, the number of participants enrolled, and treated in each analysis set will be provided 
overall, by country and by site.  
The results of the randomization algorithm (according to IWRS) will be summarized as follows: 
•
Cross tabulation: participants randomized (Placebo / M5049 50 mg BID / M5049 100 mg
BID) vs. treated (Placebo / M5049 50 mg BID / M5049 100 mg BID)
•
Cross tabulation: participants randomized to each stratum according to the IWRS vs.
stratum according to the eCRF
The following listings will be created to report disposition information: 
•
Subject disposition: presenting information related to informed consent signature, protocol
version, randomization and screen failure status for the enrolled analysis set
•
Discontinued subjects: presenting information of treatment and study discontinuation for
the ITT/SAF analysis set
•
Randomization scheme: presenting information on randomization and analysis strata for
all the subjects randomized or treated.
10.2 
Protocol Deviations / Exclusion from Analysis Populations 
10.2.1 
Important Protocol Deviations 
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 


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They will be identified for all participants by either site monitoring, medical review processes or 
programming and confirmed prior to or at the Data Review Meeting at the latest. 
All important protocol deviations are documented in SDTM datasets whether identified through 
site monitoring, medical review or programming. 
A full list of potential protocol deviations including definition and categorization is maintained in 
the most recent study protocol deviation guide. 
Important protocol deviations will be summarized by category. 
A listing of important protocol deviations will be provided based on the ITT/SAF.  
10.2.2 
Reasons Leading to the Exclusion from an Analysis 
Population 
A listing presenting reasons of exclusion from PK/PD analysis sets will be provided. 
11 
Demographics and Other Baseline Characteristics 
If not stated otherwise, the following analyses will be performed based on the ITT/SAF, by 
treatment groups and overall. 
11.1 
Demographics 
Demographic characteristics and physical measurements will be summarized descriptively using 
the following information from the ‘Demography’ and ‘Screening Vital Signs’ eCRF pages. 
The following demographic characteristics will be included:  
•
Sex: male, female
•
Race: white, black or African American, Asian/ Pacific Islander, American Indian or
Alaska Native, more than one race, other, unknown
•
Ethnic origin: Hispanic or Latino/Not Hispanic or Latino
•
Age (years)
•
Age categories:
o
< 60 years,
o
≥ 60 years
•
Country: Brazil, Philippines, United States of America
•
Site
•
Height (cm) at Baseline


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• Weight (kg) at Baseline 
• BMI (kg/m2) at Baseline 
o < 30 kg/m2, 
o ≥ 30 kg/m2  
Specifications for computation: 
• Age [years] 
o (date of given informed consent - date of birth + 1) / 365.25 
o In case of missing day for at least one date, but month and year available for both 
dates: For the derivation of age, the day of informed consent and the day of birth will 
be set to 1 and the formula above will be used 
o In case of missing month for at least one date, but year available for both dates: For 
the derivation of age, the day and the month of informed consent and the day and 
month of birth will be set to 1 and the formula above will be used 
The integer part of the calculated age will be used for reporting purposes. 
• BMI [kg/m²] = 
୵ୣ୧୥୦୲ [୩୥] 
୦ୣ୧୥୦୲[ୡ୫]మ× 10000 
All demographic data will be reported in listings. 
11.2 
Medical History 
The medical history will be summarized from the “Medical History” eCRF page, using MedDRA 
version 23.0 or higher, preferred term (PT) as event category and system organ class (SOC) body 
term as Body System category. Each participant will be counted only once within each PT or SOC. 
Medical history will be displayed in terms of frequency tables, ordered by primary SOC and PT in 
alphabetical order, and listed. 
11.3 
Other Baseline Characteristics 
Tobacco consumption will be collected in the ‘Substance Usage’ eCRF page. The following 
information will be summarized together with demographic characteristics: 
• Tobacco Status; 
The following disease history characteristics will be summarized overall and by treatment group: 
• Based on data from ‘Medical History” eCRF page 
o Time since COVID-19 symptoms onset (days)  
o Time since diagnosis (days)  


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o
Presence of the following co-morbidities:

Diabetes

Heart disease

Obstructive lung disease

Other lung disease

Chronic liver disease

HIV

Tuberculosis

Central nervous system disease

Hypertension
• Based on data from ‘COVID Symptom Assessment” eCRF page
o
Presence of each of the following COVID-19 symptoms at study entry

Cough

Fever

Myalgia

Diarrhea

Dyspnea

Fatigue/malaise

Loss of appetite

Loss of smell

Loss of taste
 ‘Time since’ disease history characteristics, in days, will be calculated as follows: 
• Time since symptoms onset (days) = (Date of first administration of study treatment - Date of
symptoms onset)
• Time since diagnosis (days) = (Date of first administration of study treatment - Date of
diagnosis)
The following listings will be created: 
•
Tobacco use
•
Co-morbidities




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All dosing calculations and summaries will be based on “Exposure” eCRF page. Each participant 
is expected to be treated with the drug assigned by the randomization system for 14 consecutive 
days, twice per day. 
In case of discharge from the hospital before the end of treatment period, the participant will be 
instructed to take the study treatment at home and a diary card will be handled to collect daily 
dosing information.  
In case the start date is missing or incomplete, it is assumed that the first dose of study treatment 
is given at the randomization date.  
Duration of exposure to study drug (days) = (end date/time – date/time of first dose of study 
drug), where end date/time is the date/time of last dose of study drug.  
Dose administered at each administration will be derived as follows:  
•
Participants randomized to M5049 50 mg = number of tablets administered * 12.5 mg
•
Participants randomized to M5049 100 mg = number of tablets administered * 25 mg
Cumulative dose is the sum of all doses administered. 
Compliance will be derived using information from ‘Drug accountability’ eCRF page. 
Compliance (%) = 100× (Number of tablets taken / Number of planned tablets to be taken)  
where: 
•
Number of tablets taken = (total number of tablets dispensed – total number of tablets
returned)
•
Number of planned tablets = Planned duration of exposure (i.e. 14 days) × Number of
planned tablets per day (i.e. 8 tablets/day) = 112 tablets
In case of study drug not returned and amount returned missing, it will be assumed that all tablets 
have been taken for compliance calculation. Considering that 120 tablets are dispensed to ensure 
the subject has sufficient stock, compliance for subjects not returning any tablet will be 107% = 
120/112*100). 
The summary of treatment exposure will include the following information: 
•
Exposure duration (days)
•
Cumulative dose (mg)
•
Compliance (%)
A separate listing will be presented for: 


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•
Treatment exposure
•
Drug accountability
•
Exposure and compliance parameters
•
Subjects receiving investigational product(s) from specific kits.
14 
Efficacy Analyses 
The following analyses will be performed based on the ITT by treatment group except when 
otherwise stated. 
For the time to event analysis, failure will be defined as follows: 
Definition
eCRF page
Value
Invasive 
or 
Non-
Invasive 
Mechanical 
Ventilation 
Ordinal Scale on Clinical Severity 
Ordinal Scale on Clinical Severity >= 5 
ICU admission leading 
to
treatment
discontinuation (both 
the
following
conditions)  
End of study treatment 
AND 
Hospitalization 
Did the subject complete the full course of 
study treatment? = NO 
AND 
Date of treatment completion/discontinuation 
occurring during ICU/HDU stay 
Relapse
Date of Visit 
Reason for Relapse completed 
14.1 
Primary Endpoint: Time to Recovery 
14.1.1 
Primary Objective: Derivation and Analysis of the Primary 
Endpoint Time to Recovery 
The primary efficacy variable is the time to recovery, defined as the time from first dose (Day 1) 
through Day 28 to first occurrence of WHO 9-point ordinal scale 3 or less, in days: 
•
Time to recovery (days) = (Date/time of first ordinal scale for clinical severity <= 3 – Date/time
of first dose)
The rules for the different types of censoring/event below will be followed: 


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# 
Description 
Date of Response or 
Censoring 
Outcome 
1 
Death from Day 1 up to D60/Study completion 
D28 
Censored 
2 
Failure at any point and time during the study 
from D1 up to D28, defined as: 
* ICU admission leading to treatment
discontinuation
* use of mechanical ventilation
* relapse
D28
Censored
3 
Participant not confirmed to be eligible based on 
inclusion criterion 6 (PDEV05 code)  
Date of first dose of 
study drug 
Censored 
4 
No post-baseline clinical status data 
Date of first dose of 
study drug 
Censored 
5 
Clinical status <= 3 before Day 28 
Date of clinical status 
<=3 
Event 
6 
Clinical status > 3 through Day 28 without death 
or failure 
D28
Censored
7 
Early discontinuation before or on Day 28 
without improvement, failure or death 
Date/time of last 
available result of 
clinical status from Day 
1 through Day 28 
Censored 
Number and percentage of participants with and without recovery will be presented.   
The hypotheses that will be tested for each dose level using a one-sided stratified log-rank test of 
distribution of time to recovery with use of corticosteroids at a prednisone equivalent daily dosage 
of ≤ 15 mg or > 15 mg within 48 hours prior to randomization, and country as stratification factors, 
are: 
• H0i: HRi ≤ 1


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 
M S 2 0 0 5 6 9- 0 0 2 6  
Versi o n 1. 0 
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/ 6 4 
•
H 1i: H Ri > 1
w here  
•
H R i de n otes t he Hazar d Rati o of M 5 0 4 9 d ose i vers us place b o
•
i de n otes M 5 0 4 9 5 0 m g BI D or M 5 0 4 9 1 0 0 m g BI D
•
H R i > 1 de n otes a n i m pr o ve ment c o m pare d t o place b o.
Esti mati o n of t he effect of eac h  treat me nt d ose (a n d 9 5 % t w o-si ded CI) se paratel y c o m pare d t o 
place b o will be base d o n hazar d rati o fr o m stratif ie d C o x- m o del of rec o ver y hazar d rate, wit h 
ter ms f or treat me nt gr o u p (eac h acti ve treat me nt se paratel y a gai nst place b o), use of c ortic oster oi ds 
at  a  pre d nis o ne  e q ui vale nt  dail y  d osa 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, a n d c o u ntr y. Ties will be ha n dle d usi n g t he di screte met h o d.   
C u m ulati ve distri b uti o n f u ncti o n f o r ti me t o rec o ver y will be estimate d via Ka pla n- Meier ( pr o d uct 
li mit) 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 
rec o ver y, rec o ver y rates at Da y 7, Da y 1 4, Day 2 1 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. T he esti mates of t he sta n dar d err or ( S E) will be c o m p ute d usi n g Gree n w o o d’s 
f or m ula. 
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 
M S 2 0 0 5 6 9- 0 0 2 6  
Versi o n 1. 0 
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/ 6 4 
C CI




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•
If clinical status ≥ 4 on analysis Day 14 then the participant will be considered a non-
responder on that day.
The rules below to define responder status in special cases will be followed: 
#
Situation
Outcome
1 
Death on or before Day 28 
Non-responder 
2 
Missing on analysis Day 14 
Missing  
Number and percentage of subjects with response at each analysis visit and the corresponding two-
sided Wilson 95% CI will be presented.  
In addition, summary score estimates of the common difference in proportion, stratified for 
corticosteroids use in the 48h prior to randomization and country will be presented with 95% CIs 
based on stratified Newcombe confidence limits for the differences in proportions (Kim, 2013). 
14.2.2 
Clinical Status 
Clinical status will be based on data collected on the ‘Ordinal Scale for Clinical Status’ eCRF page 
and is assessed with the following ordinal scale: 
0.
Uninfected: no clinical or virological evidence of infection.
1.
Ambulatory: no limitation of activities.
2.
Ambulatory: limitation of activities.
3.
Hospitalized, mild disease: hospitalized, no oxygen therapy.
4.
Hospitalized, mild disease: oxygen by mask or nasal prongs.
5.
Hospitalized, severe disease: noninvasive ventilation or high-flow oxygen.
6.
Hospitalized, severe disease: intubation and mechanical ventilation.
7.
Hospitalized, severe disease: ventilation + additional organ support – e.g., pressors, RRT,
ECMO
8.
Death.
In case of death, the participant will be counted with the clinical status =8 (death) for any scheduled 
timepoint after death date. There will be no imputation of missing data. 


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 
M S 2 0 0 5 6 9- 0 0 2 6  
Versi o n 1. 0 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3 8/ 6 4 
Cli nical stat us is e x pecte d e ver y da y d uri n g h os pi talizati o n a n d t he n at e ver y sc he d ule d visit after 
disc har ge. Da y 1 assess me nt wi ll ser ve as baseli ne meas ure me nt. If missi n g, t he last n o n- missi n g 
meas ure me nt pri or t o ra n d o mizati o n will be use d.  
T he n u m ber a n d perce nta ge of partic i pa nts i n eac h cli nical stat us cate g or y as well as s u m mar y 
statistics f or a bs ol ute a n d c ha n ge fr o m baseli ne stat us will be prese nte d b y treat me nt gr o u p, i n a 
ta b ular a n d gra p hical f or m, usi n g a stac ke d bar c hart. 
A c u m ulati ve l o git m o del will be use d t o c o m pare t he cli nical stat us res ults of eac h M 5 0 4 9 gr o u p 
vers us place b o at t he f oll o wi n g a nal ysis vi sits: Da y 7, Da y 1 4, Da y 2 1, Da y 2 8, Da y 4 4 a n d Da y 
6 0 acc or di n g t o t he or di nal scale descri be d a b o v e. U n der t he ass u m pti o n of pr o p orti o nal o d ds, t he 
o d ds rati o ( O R) a n d its 9 5 % Wal d 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 
sc ore test f or t he pr o p orti o nal o d ds ass u m pti o ns will be re p orte d. 
S h o ul d t he m o del fail, d ue t o a n i ns ufficie nt n u m ber of o bser vati o ns per cate g or y of t he de pe n de nt 
varia ble, t he n rele va nt ca te g ories ma y be c olla pse d. 
I n a d diti o n, t he f oll o wi n g dic h ot o mize d versi o ns of t he cli nical stat us will be deri ve d, o nl y if at 
least 6 partici pa nts i n eac h le vel are prese nt: 
•
Deat h (cli nical stat us = 8) vers us a n y ot her cate g or y (cli nical stat us ≠ 8)
•
W orse ni n g (cli nical stat us ≥ 5) vers us sta ble/i m pr o ve ment (cli nical st at us < 5)
•
I n- h os pital (cli nical stat us ≥ 3) vers us h os pital disc har ge d (cli nical stat us < 3).
A l o gistic re gressi o n m o del will be  use d t o c o m pare t he dic h ot o mize d versi o n of t he cli nical stat us 
at eac h ti me p oi nt of i nterest, wit h ter ms f or treat me nt ar m a n d strata defi ne d b y ra n d o mizati o n 
strata. T he O R a n d its 9 5 % Wal d CI will be esti mate d f or eac h M 5 0 4 9 gr o u p vers us place b o.  
T he sa me l o gistic re gressi o n m o del will be use d t o a nal yze t he cli nical stat us deteri orati o n (c ha n ge 
fr o m baseli ne > 0) vers us sta ble/i m pr o ve me nt (c ha n ge fr o m baseli ne ≤ 0) c o m pare d t o baseli ne. 
N o m ulti plicit y c orrecti o n will be a p plie d. 
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 
M S 2 0 0 5 6 9- 0 0 2 6  
Versi o n 1. 0 
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/ 6 4 
1 4. 2. 3  
Ti me t o S p O2 ≥ 9 4 % s ust ai n e d f o r at l e ast 2 4 h o u rs i n 
r o o m ai r f r o m D a y 1 t h r o u g h D a y 2 8  
Ti me t o 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 will be base d o n data c ollecte d 
o n t he ‘ P ulse O xi metr y’ a n d ‘ Res pirat or y Stat us’ e C R F pa ges fr o m Da y 1 t hr o u g h Da y 2 8. 
T he ti me t o S p O 2 i m pr o ve me nt, defi ne d as t he ti me fr o m first d ose ( Da y 1) t o t he date of first 
S p O 2 ≥ 9 4 % s ustai ne d i n r o o m air, i n da ys: 
•
Ti me t o S p O 2 i m pr o ve me nt ( da ys) = ( Date/ti me of first S p O2 ≥ 9 4 % s ustai ne d i n r o o m air –
Date/ti me of first d ose)
T he r ules f or t he differe nt t y pes of ce ns ori n g bel o w will be f oll o we d: 
#  
Descri pti o n  
D ate of E ve nt or 
Ce ns ori n g  
O utc o me  
1  
Deat h fr o m Da y 1 u p t o D 6 0/ St u d y c o m pleti o n  
D 2 8 
Ce ns ore d 
2  
Fail ure at a n y p oi nt a n d ti me d uri n g t he st u d y 
fr o m D 1 u p t o D 2 8, defi ne d as: 
* I C U a d missi o n lea di n g t o treat me nt
disc o nti n uati o n
* use of mec ha nical ve ntilati o n
* rela pse
D 2 8
Ce ns ore d
C CI


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3 
Participant not confirmed to be eligible based on 
inclusion criterion 6 (PDEV05 code)  
Date of first dose of 
study drug 
Censored 
4 
No post-baseline SpO2 data 
Date of first dose of 
study drug 
Censored 
5 
Sustained SpO2 >= 94% at room air before Day 
28 
Date of first SpO2 >= 
94% sustained at room 
air 
Event 
6 
SpO2 < 94% at room air through Day 28 
without death or failure 
D28
Censored
7 
Early discontinuation before or on Day 28 
without improvement, failure or death 
Date/time of last 
available result of 
clinical status from Day 
1 through Day 28 
Censored 
Of note, the endpoint will not be considered met if the assessment is not done at room air, 
irrespective from the actual SpO2 value. 
Number and percentage of subjects with and without improvement will be presented.   
The hypotheses that will be tested for each dose level using a one-sided stratified log-rank test of 
distribution of time to improvement with use of corticosteroids at a prednisone equivalent daily 
dosage of ≤ 15 mg or > 15 mg within 48 hours prior to randomization, and country as stratification 
factors, are: 
• H0i: HRi ≤ 1
• H1i: HRi > 1
where  
• HRi denotes the Hazard Ratio of M5049 dose i versus placebo
• i denotes M5049 50 mg BID or M5049 100 mg BID
• HRi > 1 denotes an improvement compared to placebo.
Estimation of the effect of each treatment dose (and 95% two-sided CI) separately compared to 
placebo will be based on hazard ratio from stratified Cox-model of improvement hazard rate, with 
terms for treatment group (each active treatment separately against placebo), use of corticosteroids 


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at a prednisone equivalent daily dosage of ≤ 15 mg or > 15 mg within 48 hours prior to 
randomization, and country. Ties will be handled using the discrete method.   
Cumulative distribution function for time to improvement will be estimated via Kaplan-Meier 
(product limit) method by treatment group and presented together with associated statistics 
(median time to improvement, improvement rates at Day 7, Day 14, Day 21 and Day 28) including 
the corresponding two-sided 95% CI. The estimates of the standard error (SE) will be computed 
using Greenwood’s formula. 
14.2.4 
All-cause Mortality 
All-cause mortality analysis will be based on data collected on the ‘Death’ eCRF page. 
All-cause mortality is defined as the proportion of subjects who died during the study, regardless 
of the cause of death.   
Number and proportion of subjects dying through Day 60 and the corresponding two-sided Wilson 
95% CI will be provided by treatment groups based on the ITT analysis set.  
In case more than 6 deaths are observed, the difference in proportion of each dose to placebo will 
be presented with two-sided 95% CIs based on the Miettinen-Nurminen method. In addition, 
summary score estimates of the common difference in proportion, stratified for use of 
corticosteroids at a prednisone equivalent daily dosage of ≤ 15 mg or > 15 mg within 48 hours 
prior to randomization, AVT use in the 48h prior to randomization and country will be presented 
with 95% CIs based on stratified Newcombe confidence limits. 
14.2.5 
Time to ICU Admission (Day 1 Through Day 28) 
Time to ICU admission will be based on data collected on the ‘Hospitalization’ eCRF page. 
Time to ICU admission is defined as the time from first dose (Day 1) to the date/time of ICU 
admission, or death, whichever occurs first, in days: 
•
Time to ICU admission (days) = (Date/time of ICU admission – Date/time of first dose)
The rules below to define censoring/event dates will be followed: 
# 
Description 
Date of Event or Censoring 
Outcome 
1 
Subject 
with 
first 
dose 
administered while in ICU   
Date of first dose of study drug 
Censored 


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2 
ICU admission or Death from Day 
1 up to D28 
Earliest 
between 
date 
of 
ICU 
admission and date of death (in case 
of death) 
Event 
3 
For subjects never admitted to ICU 
and not died 
Earliest between D28 and date of 
discontinuation 
Censored 
Number and percentage of subjects with and without the event will be summarized.   
The hypotheses that will be tested for each dose level using a one-sided stratified log-rank test of 
time to ICU admission with use of corticosteroids at a prednisone equivalent daily dosage of ≤ 15 
mg or > 15 mg within 48 hours prior to randomization, and country as stratification factors, are: 
• H0i: HRi ≥ 1
• H1i: HRi < 1
where  
• HRi denotes the Hazard Ratio of M5049 dose i versus placebo
• i denotes M5049 50 mg BID or M5049 100 mg BID
• HRi < 1 denotes an improvement compared to placebo.
Estimation of effect each treatment dose (and 95% two-sided CI) separately compared to placebo 
will be based on hazard ratio from stratified Cox-model of event hazard rate, with terms for 
treatment arm (each active treatment separately against placebo), use of corticosteroids at a 
prednisone equivalent daily dosage of ≤ 15 mg or > 15 mg within 48 hours prior to randomization, 
and country. Ties will be handled using the discrete method.   
Event-free survival function for time to event will be estimated via Kaplan-Meier (product-limit) 
method by treatment group and presented in a tabular and graphical format together with associated 
statistics (median time to event, event rates at Day 7, Day 14, Day 21 and Day 28) including the 
corresponding two-sided 95% CI. The estimates of the standard error (SE) will be computed using 
Greenwood’s formula. 


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14.2.6 
Time to Non-Invasive Mechanical Ventilation (Day 1 Through 
Day 28) 
Time to non-invasive mechanical ventilation will be based on data collected on the ‘Ordinal Scale 
for Clinical Severity’ eCRF page. 
Time to non-invasive mechanical ventilation is defined as the time from first dose (Day 1) to the 
date/time of clinical status >= 5, in days: 
•
Time to non-invasive mechanical ventilation (days) = (Date/time of clinical status >= 5 –
Date/time of first dose)
The rules below to define censoring/event dates will be followed: 
# 
Description 
Date of Event or Censoring 
Outcome 
1 
Clinical status >= 5 or Death from 
Day 1 up to D28 
Earliest between date of clinical 
status >= 5 and date of death (as 
applicable) 
Event 
2 
For subjects which never started 
mechanical ventilation and not 
died 
Earliest between D28 and date of 
discontinuation 
Censored 
Analyses will be performed as specified in Section 14.2.5. 
14.2.7 
Time to Invasive Mechanical Ventilation 
Time to invasive mechanical ventilation will be based on data collected on the ‘Ordinal Scale for 
Clinical Severity’ eCRF page. 
Time to invasive mechanical ventilation is defined as the time from first dose (Day 1) to the 
date/time of clinical status >= 6, in days: 
•
Time to invasive mechanical ventilation (days) = (Date/time of clinical status >= 6 –
Date/time of first dose)
The rules below to define censoring/event dates will be followed: 


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# 
Description 
Date of Event or Censoring 
Outcome 
1 
Clinical status >= 6 or Death from 
Day 1 up to D28 
Earliest between date of clinical 
status >= 6 and date of death (in case 
of death) 
Event 
2 
For subjects which never invasive 
started mechanical ventilation and 
not died 
Earliest between D28 and date of 
discontinuation 
Censored 
Analyses will be performed as specified in Section 14.2.5. 
14.2.8 
Total Days in ICU 
Total days in ICU will be based on data collected on the ‘Hospitalization’ eCRF page. 
Total days in the ICU are defined as the sum, for all ICU admissions, of the time from ICU 
admission to the date of ICU discharge, in days: 
Total days in the ICU (days) = ∑(Date/𝑇𝑖𝑚𝑒 of ICU discharge –  Date/𝑇𝑖𝑚𝑒 of ICU admission )
௛
  
where h = number of ICU admissions during the study. 
In case of ICU admission and discharge prior to first dose, the occurrence will not be considered 
for derivation of total days in ICU. In case ICU admission prior to and discharge after first dose, 
date and time of first dose will be used in place of date and time of ICU admission for calculation 
of total days in ICU. 
The following information will be presented:  
•
Number and percentage of participants admitted in ICU
•
Number and percentage of participants with more than one ICU admission
•
Number and percentage of participants in the following discharge categories: death in ICU,
discontinuation in ICU, discharged from ICU.
•
Summary statistics of duration of ICU stay.


M5049 
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Participants never admitted to ICU will not be considered for descriptive statistics derivation. 
14.2.9 
Total Days in the Hospital and Time to Hospital Discharge 
Total days in the hospital will be based on data collected on the ‘Hospitalization’ eCRF page. 
Total days in the hospital are defined as the sum, for all hospitalization events, of the time from 
first dose to the date of hospital discharge, in days: 
•
Total days in the hospital (days) =
First hospitalization: Date of hospital discharge – Day 1 + 1
+
Subsequent hospitalization: Date of discharge – date of admission + 1
In other words, in case of hospital admission prior to and discharge after first dose, date of first 
dose will be used in place of date of hospital admission for calculation of total days in the 
hospital. In case of multiple hospitalizations, the total number of days of each event will be 
added up. 
The following information will be presented:  
•
Number and percentage of participants with more than one hospital admission (only non-
consecutive hospitalization will be included in the count)
•
Number and percentage of participants in the following discharge categories: death in
hospital, discontinuation in hospital, discharged from hospital.
•
Summary statistics of duration of hospital stay.
In addition, time to hospital discharge will be based on data collected on the ‘Hospitalization’ 
eCRF page from Day 1 through Day 28. 
The time to hospital discharge, defined as the time from first dose (Day 1) to the date of first 
hospitalization discharge, in days: 
•
Time to hospital discharge (days) = (Date of first hospitalization discharge – Date of first dose)
The rules for the different types of censoring/event below will be followed: 
# 
Description 
Date of Event or 
Censoring 
Outcome 


M 5 0 4 9 
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1  
Deat h fr o m Da y 1 u p t o D 6 0/ St u d y c o m pleti o n  
D 2 8 
Ce ns ore d 
2  
Fail ure at a n y p oi nt a n d ti me d uri n g t he st u d y 
fr o m D 1 u p t o D 2 8, defi ne d as: 
* I C U a d missi o n lea di n g t o treat me nt
disc o nti n uati o n
* use of mec ha nical ve ntilati o n
* rela pse
D 2 8
Ce ns ore d
3  
H os pital disc har ge bef ore Da y 2 8 
Date of h os pital 
disc har ge 
E ve nt 
4  
N o h os pital disc har ge bef ore Da y 
2 8/ disc o nti n uati o n wit h o u t deat h or fail ure 
Earliest bet wee n D 2 8 
a n d date of 
disc o nti n uati o n 
Ce ns ore d 
A nal yses will be perf or me d as s pecifie d i n Secti o n 1 4. 2. 3. 
1 4. 2. 1 0  
I nfl a m m at or y Bi o m ar kers 
I nfla m mat or y  bi o mar ker  a nal ysis  will  be  base d  o n  data  c ollecte d  o n  t he  ‘I nfla m mat or y  
bi o mar kers’ e C R F pa ge a n d will be perf or me d base d o n t he P D A S. 
T he f oll o wi n g i nfla m mat or y bi o mar kers will be c o llecte d f or t his st u d y a n d a nal yze d b y a l ocal 
la b orat or y as per t he sc he d ule of e ve nts re p orte d i n t he pr ot oc ol: 
•
C- Reacti ve Pr otei n, D- di mer, Ferriti n
T he f oll o wi n g s u m maries will be pr o vi de d b y treat me nt gr o u p a n d t otal base d o n t he P D A S f or 
eac h i nfla m mat or y bi o mar ker: 
•
O bser ve d, c ha n ge a n d perce nt c ha n ge  fr o m baseli ne b y a nal ysis visit;
•
B o x a n d w his ker pl ots o ver ti me f or o bser ve d, c ha n ge a n d perce nt c ha n ge fr o m baseli ne
b y treat me nt gr o u p;
•
S pa g hetti pl ots of c ha n ge a n d perce nt c ha n ge fr o m baseli ne b y treat me nt gr o u p
C CI






M 5 0 4 9 
  
  
  
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2.  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 a w orse ni n g lesi o n o n c hest 
i ma gi n g  (i.e.,  c o m pare d  t o  t he  partici pa nt’s  c hest  X-ra y  or  c o m p ute d  t o m o gra p h y  at  
disc har ge)  
N u m ber a n d pr o p orti o n of s u bjects  wit h rela pse d uri n g t he st u d y peri o d (if first disc har ge d) a n d 
t he c orres p o n di n g t w o-si de d Wils o n 9 5 % CI will be pr o vi de d b y treat me nt gr o u p base d o n t he I T T 
a nal ysis set.  
I n case m ore t ha n 6 e ve nts of rela pse are o bserve d, t he differe nce i n pr o p orti o n of eac h d ose t o 
place b o will be prese nte d wit h t w o-si de d 9 5 % CIs base d o n t he Mietti ne n- N ur mi ne n met h o d. I n 
a d diti o n, s u m mar y sc ore esti mates of t he c o m m o n differe nce i n pr o p orti o n, st ratifie d f or use of 
c ortic oster oi ds at a pre d nis o ne  e q ui vale nt dail y d osa 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, A V T use i n t he 4 8 h pri or t o ra n d o mizati o n a n d c o u ntr y will be prese nte d 
wit h 9 5 % CIs base d o n stratifie d Ne wc o m be c o nfi d e nce li mits f or t he differe nces i n pr o p orti o ns. 
1 4. 2. 1 3  
Occ urre nce
 of
 Re- h os pit a liz ati o n
 d ue
 t o
 C O VI D- 1 9
 
C o m plic ati o ns 
T he a nal ysis of occ urre nce of re- h os pitalizati o n d ue t o C O VI D- 1 9 c o m plicati o ns will be base d 
o n data c ollecte d o n t he ‘ H os pitalizati o n’ e C R F pa ge. 
Re- h os pitalizati o n is defi ne d as 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 rea d mitte d bef ore or 
o n Da y 6 0, f or C O VI D- 1 9 relate d c o m plicati o ns. 
N u m ber a n d pr o p orti o n of s u bjects wit h re- h os pitalizati o n d ue t o C O VI D- 1 9 d uri n g t he st u d y 
peri o d (if first disc har ge d) a n d t he c orres p o n di n g t w o-si de d Wils o n 9 5 % CI will be pr o vi de d b y 
treat me nt gr o u p base d o n t he I T T a nal ysis set.  
I n case m ore t ha n 6 e ve nts of re- h os pitalizati o n are o bser ve d, t he differe nce i n pr o p orti o n of eac h 
d ose t o place b o will be prese n te d wit h t w o-si de d 9 5 % CIs base d o n t he Mietti ne n- N ur mi ne n 
met h o d. I n a d diti o n, s u m mar y sc ore esti mates of t he c o m m o n differe nce i n pr o p orti o n, stratifie d 
f or use of c ortic oster oi ds at a pred nis o ne e q ui vale nt dail y d osa 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, A V T use i n t he 4 8 h pri or t o ra n d o mizati o n a n d c o u ntr y will be 
prese nte d wit h 9 5 % CIs base d o n stratifie d Ne wc o m be c o nfi de nce li mits f or t he differe nces i n 
pr o p orti o ns. 
C CI


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1 5  
S afet y a n al ysis 
Safet y a nal yses will be d o ne o n t he S A F a nal ysis  set a n d acc or di n g t o t he act ual treat me nt recei ve d 
(see Secti o n 8. 1 ).  
1 5. 1  
A d verse E ve nts 
A d verse e ve nts i nf or mati o n is c ollecte d  i n t he ‘ A d verse E ve nt’ e C R F pa ge. 
C CI


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Treatment-emergent adverse events (TEAE) are those events with onset or worsening dates 
occurring within the on-treatment period as defined in Section 9.7. 
Adverse events related to study treatment are those events with relationship missing, or yes. 
All analyses described in this section will be based on TEAEs if not otherwise specified. The AE 
listings will include all AEs (whether treatment-emergent or not).  
Unless otherwise specified, TEAEs will be summarized by number and percentage of participants 
with the specific TEAE of interest, by treatment group, primary SOC and PT in alphabetical order.  
Each participant will be counted only once within each SOC or PT. If a participant experiences 
more than one AE within a SOC or PT for the same summary period, only the AE with the strongest 
relationship or the worst severity, as appropriate, will be included in the summaries of relationship 
and severity.  
15.1.1 
All Adverse Events 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 5.0), in 
alphabetical order by MedDRA PT as event category and MedDRA primary system organ class 
(SOC) body term as Body System category, using MedDRA version 23.0 or later.  
In case a participant has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
Incomplete AE-related dates will be handled as specified in Section 9.8. 
The following tables will be created, by treatment group:  
• Overall summary of AEs: it will include the frequency (number and percentage) of 
participants with each of the following: 
o TEAEs 
o TEAEs with NCI-CTCAE Grade ≥ 3, Grade ≥ 4  
o Related TEAEs 
o Related TEAEs with NCI-CTCAE Grade ≥ 3, Grade ≥ 4  
o TEAEs leading to permanent treatment discontinuation  
o Related TEAEs leading to permanent treatment discontinuation  
o Serious TEAEs 
o Related Serious TEAEs  
o TEAEs leading to death  
o Related TEAEs leading to death 


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• TEAEs by SOC and PT
• TEAEs by SOC and PT and worst grade
• Treatment related TEAEs by SOC and PT
• Treatment related TEAEs by SOC and PT and worst grade
• TEAEs leading to death by SOC and PT
• Related TEAEs leading to death by SOC and PT
• TEAEs excluding SAEs, with frequency ≥ 5% in any treatment arm by SOC and PT
• TEAEs by age subgroup, as defined in Section 8.2, by SOC and PT
• TEAEs by gender subgroup, as defined in Section 8.2, by SOC and PT.
15.1.2 
Adverse Events Leading to Discontinuation of Study 
Treatment 
TEAEs leading to permanent discontinuation of study drug are those events recorded as “Drug 
withdrawal” on the AE pages of the eCRF. 
The frequency (number and percentage) of participants with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug by treatment group: 
• TEAEs leading to study treatment discontinuation by SOC and PT
• Related TEAEs leading to study treatment discontinuation by SOC and PT
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
15.2.1 
Deaths 
All deaths will be tabulated based on information from the “Death” eCRF page, summarizing the 
following information: 
• Number of Deaths
• Number of Deaths within 30 days after last dose of study treatment
• Primary Reason of Death, among:
o
Progressive disease and/or other disease related condition
o
Event unrelated to study treatment
o
Unknown


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In addition, date and cause of death will be provided in individual participant data listing together 
with selected dosing information (date of first and last administration and number of doses). 
This listing will include: 
• AEs with fatal outcome (list preferred terms of AEs with outcome=fatal) 
• Flag for death within 30 days of last study treatment 
15.2.2 
Serious Adverse Events 
The following overall frequency tables will be prepared for serious treatment-emergent adverse 
events (SAEs):  
• Incidence of serious TEAEs by SOC and PT  
• Incidence of related serious TEAEs by SOC and PT  
The listings of treatment - emergent SAEs will also be provided with the relevant information. 
15.2.3 
Other Significant Adverse Events 
Adverse events of special interest will be identified on the ‘Adverse Event’ eCRF page and using 
Standardized MedDRA queries.  
The frequency (number and percentage) of participants with each of the following treatment 
emergent adverse event of special interest (AESI) will be presented by treatment group: 
• Infections, defined as any Common Terminology Criteria for Adverse Events (CTCAE) 
Grade ≥ 3 or serious adverse events (SAEs) of infection and opportunistic infection; 
• Seizure, defined as any type of seizures/epilepsy of any grade or its consequences; 
• Serotonin syndrome and its spectrum of symptoms; 
• Clinically significant arrythmias. 
All AESIs will be flagged in adverse event listing.  
15.3 
Clinical Laboratory Evaluation 
Clinical laboratory evaluation will be collected on the ‘Local Laboratory Results: Hematology’ 
and ‘Local Laboratory Results: Chemistry’ eCRF pages. 
Laboratory values (including corresponding normal ranges) from the local labs will be used for 
summary statistics and shift tables.  
Quantitative laboratory parameters reported as “< X”, below the lower limit of quantification 
(BLQ), “> X” or above the upper limit of quantification (ULQ), will be converted to X/lower 


M 5 0 4 9 
  
  
  
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li mit/ u p per li mit f or t he p ur p ose of q ua ntitati ve s u m maries ( wit h t he e xce pti o n of e G F R), b ut will 
be prese nte d as rec or de d, i.e. as “ < X”, B L Q, “ > X” or U L Q i n listi n gs.   
T he f ull list of para meters wit h N CI- C T C A E gr a des a vaila ble a n d n ot a vaila ble a n d rele va nt 
directi o ns of a b n or malities of i nterest are liste d i n  A p pe n di x 1 at secti o n 1 8. 1. 
La b orat or y res ults will be classifie d acc or di n g t o t he N CI- C T C A E criteria versi o n 5. 0. S o me of 
t he t o xicit y gra di n gs are base d o n la b orat or y meas ure me nts i n c o nj u ncti o n wit h cli nical fi n di n gs. 
N o n- n u merical q ualifiers w ill n ot be ta ke n i nt o c o nsi derati o n i n t he deri vati o n of C T C A E criteria 
(e. g., h y p o kale mia Gra de 1 a n d Gra de 2 are o nl y disti n g uis he d b y a n o n- n u merical q ualifier a n d 
t heref ore Gra de 2 will n ot be deri ve d). 
A d diti o nal la b orat or y res ults t hat are n ot part of N CI- C T C A E will be prese nte d acc or di n g t o t he 
cate g ories: bel o w n or mal li mit, wit hi n n or mal li mits a n d a b o ve n or mal li mit (acc or di n g t o t he 
la b orat or y n or mal ra n ges). 
F or esti mate d gl o mer ular filtrati o n rate ( m L/ mi n / 1. 7 3 m2) t he val ue c ollecte d i n C R F will be use d 
w he n re p orte d.  W he n missi n g or re p orte d as “ >/ < X”, it will be calc ulate d usi n g t he M o dificati o n 
of Diet i n Re nal Disease e q uati o n:  
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 years)– 0. 2 0 3 × 0. 7 4 2 (if fe male) × 
1. 2 1 2 (if race is blac k)  
T he  f oll o wi n g  s u m maries  will  be  pr o vi de d  b y  treat me nt  gr o u p  f or  eac h of  c he mistr y  a n d  
C CI


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hematology laboratory: 
All parameters: 
• Summary results based on normal ranges by time points will include number and 
percentage of participants below normal limit, within normal limits and above normal limit.   
Non-gradable parameters according to NCI-CTCAE: 
• Shift from baseline to the worst on-treatment value according to normal range criteria 
Gradable parameters according to NCI-CTCAE: 
• Shift from baseline to the worst on-treatment value for each relevant directionality 
(minimum and/or maximum value) according to the CTCAE toxicity grades; the highest 
CTCAE grade during the on-treatment period is considered as the worst grade for the 
summary 
• Summary results based on CTCAE grade by time point will include number and percentage 
of participants with Grade 1, 2, 3, 4, 3/4, and any grade (1 to 4). 
For those parameters which are graded with two directions of toxicities such as potassium 
(hypokalemia/hyperkalemia), the toxicities will be summarized separately. Low direction toxicity 
(e.g., hypokalemia) grades at baseline and post baseline will be set to 0 when the variables are 
derived for summarizing high direction toxicity (e.g., hyperkalemia), and vice versa.   
Spaghetti plots for Aspartate Aminotransferase, Alanine Aminotransferase and Total Bilirubin, 
will be presented by treatment group, including only those participants with any NCI CTCAE 
grade 2 or higher at any point in time during the study. 
The listings of laboratory results will be provided for all laboratory parameters. The listings will 
be sorted by actual treatment, then subject ID, parameters and assessment dates for each 
participant. Laboratory values that are outside the normal range will also be flagged in the data 
listings, along with corresponding normal ranges and CTCAE grades. A listing for laboratory 
normal ranges will also be provided. 
15.4 
Vital Signs 
Vital signs will be collected on the ‘Screening Vital Signs’ and ‘Vital Signs’ eCRF pages. 
The following vital sign parameters will be collected for this study as per the schedule of events: 
• Systolic blood pressure (SBP) (mmHg) 
• Diastolic blood pressure (DBP) (mmHg) 


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• Pulse rate (beats per minute [bpm]) 
• Respiratory rate (breaths/min) 
• Body temperature (⁰C) 
• Weight (kg) at baseline 
• Height (cm) at baseline 
The following summaries will be provided by treatment group based on the SAF analysis set for 
each vital sign parameter: 
• Descriptive statistics and changes from baseline over time by treatment group; 
All vital sign data will be listed. 
15.5 
Other Safety or Tolerability Evaluations 
ECG data will be collected on the ‘ECG’ eCRF page. 
ECG summaries will include all ECG assessments from the on-treatment period.   
The analysis of QT data is complicated by the fact that the QT interval is highly correlated with 
heart rate. Because of this correlation, formulas are routinely used to obtain a corrected value, 
denoted QTc, which is independent of heart rate. This QTc interval is intended to represent the QT 
interval at a standardized heart rate. Several correction formulas have been proposed in the 
literature. For this analysis we will use some of those methods of correction, as described below. 
The QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as  
 , 
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 60/Heart 
Rate.   
QTcF values collected in the eCRF will be used for the analysis. In case those are missing, this 
parameter will be derived based on RR and QT.   
The following analyses will be performed for each of the applicable ECG parameters (ventricular 
rate, denoted as HR in what follows, PR, RR, QRS, QT, QTc and QTcF) by treatment group, 
during the on-treatment period. Unscheduled ECG measurements will not be used in computing 
the descriptive statistics for change from baseline at each post-baseline time point. However, they 
will be used in the analysis of notable ECG changes. 
3 RR
QT
QTcF =




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Day 
Time (h) 
Time from Scheduled Sampling Allowed 
6 
± 30 minutes 
12 
± 120 minutes 
Day 7 
Predose 
Within 60 minutes prior to dose administration 
1 
± 20 minutes 
2 
± 20 minutes 
6 
± 30 minutes 
Note: Samples collected by site when possible. 
Table 4: Pharmacokinetic Sampling Times for Part B 
Day 
Time (h) 
Time from Scheduled Sampling Allowed 
Day 1 
Predose 
Within 60 minutes prior to dose administration 
1 to 2 hours 
N/A 
4 to 6 hours 
N/A 
8 to 12 hours 
N/A 
Day 3 and 7 
Predose 
Within 60 minutes prior to dose administration 
1 to 2 hours 
N/A 
4 to 6 hours 
N/A 
Part A samples that are collected outside the specified time windows will be included in the PK 
parameter estimation (NCA) but will be excluded from the concentration summary and mean 
concentration plots. Part B samples that are collected outside the specified time windows will be 
included in the PK parameter estimation, flagged in the concentration listing, and excluded from 
the concentration summary and mean concentration plots. 
Pharmacokinetic concentrations which are erroneous due to a protocol violation (as defined in the 
CSP), sampling processing or analytical error (as documented in the bioanalytical report) may be 
excluded from the PK analysis if agreed by the Sponsor. In this case the rationale for exclusion 
must be provided in the CSR. Any other PK concentrations that appear implausible to the Clinical 
Pharmacologist/Clinical PK/PD Scientist will not be excluded from the analysis. Any implausible 
data will be documented in the CSR. 
Any PK concentrations or PK parameters excluded from summary statistics will be included in 
subject listings and flagged; a reason for exclusion will be detailed in the CSR (e.g. a footnote or 
a table of exclusions). Any flags should be included in the study specific SDTM and ADaM data 
sets.  
IDMC 1 PK analysis will be based on Part A concentrations (Day 1 and Day 7-predose only) and 
parameters (Day 1 only), as listed below. The PK outputs for IDMC 1 are presented in 
Section 6.1. 


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The following PK parameters will be reported for M5049 on Day 1 and Day 7 in Part A only 
except where noted, where data permit.  
AUC0-tlast 
Area under the concentration-time curve (AUC) from time of dosing to the time of 
the last quantifiable observation. 
AUC0-tlast/Dose The dose-normalized AUC0-tlast. Normalized using the actual dose, using the 
formula AUC0-tlast/Dose.  
AUC0-12h 
AUC from time of dosing to time 12 hours post dose. AUC0-12h (Day 1) will be 
based on the estimated concentration at 12 hours after dosing. AUC0-12h (Day 7) will 
be based on predose Day 7 concentration used for estimated concentration at 
12 hours. 
AUC0-12h/Dose The dose-normalized AUC0-12h. Normalized using the actual dose, using the 
formula AUC0-12h/Dose.  
AUC0-∞ 
AUC from time of dosing extrapolated to infinity on Day 1 only, based on the 
predicted value for the concentration at tlast, as estimated using the linear regression 
from λz determination.  AUC0-∞=AUC0-tlast+Clast pred/λz. 
AUC0-∞/Dose The dose-normalized AUC0-∞. Normalized using the actual dose, using the formula 
AUC0-∞/Dose on Day 1 only.  
CL/F 
The apparent total body clearance of study intervention following extravascular 
administration on Day 1 only, CL/F = Dose/AUC0-∞. 
Cmax 
Maximum observed concentration. 
Cmax/Dose 
The dose-normalized maximum observed concentration. Normalized using the 
actual dose, and the formula Cmax /Dose. 
Ctrough 
The concentration observed immediately before next dosing on Day 7 only. 
λz 
Terminal first order elimination rate constant.  
Racc(AUC0-12h) The 
accumulation 
ratio 
of 
AUC0-12h 
from 
Day 
1 
to 
Day 
7.  
Racc(AUC0-12h)= AUC0-12h12 (Day 7)/AUC0-12h (Day 1) 
Racc(Cmax) 
The 
accumulation 
ratio 
of 
Cmax 
from 
Day 
1 
to 
Day 
7.  
Racc(Cmax) = Cmax (Day 7)/ Cmax (Day 1) 
tmax 
Time to reach the maximum observed concentration Cmax. 
t1/2 
Apparent terminal half-life, t1/2 = ln 2/λz. 
Vz/F 
The apparent volume of distribution during the terminal phase following 
extravascular administration on Day 1 only, Vz/F = Dose/(AUC0-∞ × λz). 
The following PK parameters will be calculated for M5049 for diagnostic purposes and listed, but 
will not be summarized: 


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•  First ( λ z l o w) a n d last (λ z u p) ti me p oi nt of t he ti me of t he l o g-li near re gressi o n t o deter mi ne 
λ z.  
•  N u m ber of data p oi nts i ncl u de d i n t he l o g-li near re gressi o n a nal ysis t o deter mi ne λ z. 
•  G o o d ness of fit statistic ( R s q,a dj) f or calc ulati o n of λ z.  
•  A U C e xtra:  T he A U C fr o m ti me tlast e xtra p olate d t o i nfi nit y gi ve n as perce nta ge of 
A U C 0- ∞. A U Ce xtra = (e xtra p olate d area/ A U C0- ∞) * 1 0 0. 
T he f oll o wi n g P K para meters wi ll be re p orte d f or M 5 0 4 9 o n Da y 1, Da y 3, a n d Da y 7 i n Part B 
o nl y e xce pt w here n ote d, w here data per mit.  
C ma x 
Ma xi m u m o bser ve d c o nce ntrati o n. 
C tr o u g h 
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g o n Da y 3 a n d 7 o nl y. 
tma x 
Ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n C ma x . 
T he calc ulati o n of t he A U C will be perf or me d us i n g t he mi xe d li near-l o g tra pez oi dal met h o d. T he 
act ual ti me of bl o o d sa m pli n g ( 1 4 si g nifica nt di gits or t he S A S f or mat Best 1 2) will be use d f or P K 
para meter calc ulati o n. I n cases w here t he act ual  sa m pli n g ti me is missin g, calc ulati o ns will be 
perf or me d usi n g t he sc he d ule d ti me.  
Val ues bel o w t he l o wer li mit of q ua ntificati o n of  t he assa y ( L L O Q) will be ta ke n as zer o f or 
s u m mar y  statistics  of  P K  c o nce ntrati o n  data,  P K  para meter  esti mati o n,  a n d  f or  gra p hical  
prese ntati o ns. I n case B L Q c o nce ntrati o ns occ ur at t he e n d of t he d osi n g i nter val ( 1 2 h), t hese 
c o nce ntrati o ns will be e xcl u de d fr o m t he calc ulati o n of t he A U C 0- 1 2.   
T he re gressi o n a nal ysis s h o ul d c o nt ai n data fr o m at least 3 differe n t ti me p oi nts i n t he ter mi nal 
p hase c o nsiste nt wit h t he assess me nt of a strai g ht li ne o n t he l o g-tra nsf or me d scale.  
 
 “ best fit” met h o d ol o g y will be use d as sta n dar d. H o we ver, i n s o me cases, f urt her 
a dj ust me nt  ma y  be  ma de  b y  t he  p har mac o ki neticist,  if  warra nte d,  after  a gree me nt  wit h  t he  
S p o ns or. T he last q ua ntifia ble c o nce ntrati o n s h o ul d  al wa ys be i ncl u de d i n t he re gressi o n a nal ysis, 
w hile  t he  c o nce ntrati o n  at  t ma x  a n d  a n y  c o nce ntrati o ns  < L L O Q  w hic h  occ ur  after  t he  last  
q ua ntifia ble data p oi nt s h o ul d n ot be use d.  
T he c oefficie nt of c orrela ti o n ( Rs q,a dj) s h o ul d be ≥0. 8 0 0 0, A U C e xtra s h o ul d n ot be greater t ha n 
2 0 %, a n d t he o bser vati o n peri o d o ver  w hic h t he re gressi o n li ne is esti mate d s h o ul d be at least 
t w of ol d t he res ulti n g t1/ 2 itself. If t hese criteria are n ot met, t he n t he rate c o nsta nt a n d all deri ve d 
para meters ( C L/ F, V z/ F, t1/ 2, A U C0- ∞, a n d A U C0- ∞/ D) will be i ncl u de d i n t he para meter listi n gs 
a n d descri pti ve statistics b ut will be fla g ge d i n listi n gs a n d disc usse d a p pr o priatel y.  
T he f oll o wi n g listi n gs a n d s u m mar y statistics of M 5 0 4 9 P K  c o nce ntrati o n a n d para meter data will 
be pr o vi de d, w here data per mit: 
•  Listi n g of i n di vi d ual P K c o nce ntrati o n data b y part, d ose, da y, a n d sc he d ule d ti me p oi nt 
P P D


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•  Listi n g of i n di vi d ual si n gle d ose P K para meters b y part a n d d ose 
•  Listi n g of i n di vi d ual m ulti ple d os e P K para meters b y part a n d d ose 
•  Descri pti ve s u m mar y ta ble of P K c o nce ntrati o n data b y d ose, da y, a n d sc he d ule d ti me p oi nt 
( Part A) or ti me wi n d o w ( Part B) 
•  Descri pti ve s u m mar y ta ble of P K pa ra meter data b y part, d ose, a n d da y 
•  I n di vi d ual c o nce ntrati o n-ti me pr ofiles (li near a nd se mi-l o garit h mic scales ) will be pl otte d b y 
part, d ose le vel, a n d da y as s pa g hetti pl ots, usi n g act ual ti me p oi nts ( w here a vaila ble).  
•  Arit h metic mea n c o nce ntrati o ns will be pl ot te d o n b ot h li near ( ± S D) a n d se mi-l o garit h mic 
scales usi n g sc he d ule d ti me p oi nts – wit h all d ose le vels o verlai d b y part a n d da y. Part B will 
use t he mi d p oi nt of t he all o we d sa m pli n g wi n d o w f or t he ti me val ue w he n pl otti n g. 
•  Scatter pl ots of d ose- n or malize d C ma x , d ose- n or malize d A U C0- 1 2 h, d ose- n or malize d A U C0-tlast, 
a n d d ose- n or malize d A U C 0- ∞ (as a p plica ble) a gai nst d ose f or eac h c orres p o n di n g da y, w here 
a p plica ble. ( Part A o nl y) 
•  Scatter pl ot of C ma x  a gai nst d ose f or eac h c orres p o n di n g day, w here a p plica ble. ( Part B o nl y) 
All descri pti ve s u m maries of P K data will be pe rf or me d usi n g t he P K A S. I n di vi d ual P K data will 
be liste d usi n g t he I T T A nal ysis Set. T he mea n c o nce ntrati o n-ti me pr ofiles a n d P K para meter pl ots 
will be pl otte d usi n g t he P K A S a n d t he i n di vi d ual s u bject c o nce ntrati o n-ti me pr ofiles will use t he 
I T T A nal ysis Set.  
E x pl orat or y d ose pr o p orti o nalit y a nal ysis f or Part A will be perf or me d b y vis ual i ns pecti o n of t he 
scatter pl ots of C ma x / d ose, A U C0- 1 2 h/ d ose, A U C0-tlast/ d ose, a n d A U C0- ∞/ d ose vers us d ose ( w here 
a vaila ble). 
 N C A C ore O ut p ut will be pr o vi de d i n a se parate listi n g. 
P P D


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17 
References 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4(2):213-26 
Yeonhee Kim and Seunghyun Won. “Adjusted proportion difference and confidence interval in 
stratified randomized trials.” PharmaSUG 2013 - Paper SP04 


M5049 
 
 
 
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18 
Appendices 
18.1 
Appendix 1 - NCI-CTC Gradable and Non-Gradable Safety 
Laboratory Test Parameters and Direction(s) of Abnormality 
NCI-CTC gradable parameters 
Laboratory 
Assessment 
Parameters  
Name in NCI-CTC 
Direction(s) of abnormality 
Hematology 
Hemoglobin 
Anemia / Hemoglobin 
increased 
Low/High 
 
Leukocytes (WBC) 
White blood cell decreased / 
Leukocytosis  
Low/High 
 
Neutrophils 
Neutrophil count decreased  
Low 
 
Eosinophils 
Eosinophilia 
High 
 
Lymphocytes 
Lymphocyte count decreased 
/ increased 
Low/High 
 
Platelets 
Platelet count decreased 
Low 
Biochemistry 
Albumin 
Hypoalbuminemia  
Low 
 
Alanine Aminotransferase (ALT) 
Alanine Aminotransferase 
increased 
High 
 
Aspartate Aminotransferase (AST) 
Aspartate Aminotransferase 
increased 
High 
 
Alkaline Phosphatase (ALP) 
Alkaline Phosphatase 
increased 
High 
 
Bicarbonate 
Blood Bicarbonate decreased 
Low 
 
Total Bilirubin 
Blood bilirubin increased 
High 
 
Creatinine 
Creatinine increased 
High 
 
Creatine Kinase (CK) 
CPK increased 
High 
 
Sodium 
Hyponatremia / 
Hypernatremia 
Low / High 
 
Potassium 
Hypokalemia / Hyperkalemia 
Low / High 
 
Glucose 
Hypoglycemia 
Low 
Note: parameters with both Low and High directions of abnormality are going to be split. For example, Calcium is 
going to be split in Calcium Low and Calcium High. 
 
NCI-CTC non-gradable parameters 
Laboratory 
Assessment 
Parameters 
Direction of interest  
Hematology 
Hematocrit 
 


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Laboratory 
Assessment 
Parameters 
Direction of interest  
 
Mean corpuscular volume (MCV) 
High 
 
Basophils 
 
 
Monocytes 
High 
Biochemistry 
Total Protein 
Low 
 
Chloride 
High 
 
Urea Nitrogen (BUN) 
High 
 
Estimated Glomerular Filtration Rate (eGFR) 
Low