Conditions: COVID
Keywords: COVID-19 pneumonia hyper-inflammation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 814
Healthy volunteers: no

Brief summary:
Interventional, randomized, double-blind, placebo-controlled study encompassing 2 development phases (Phase 2 and Phase 3).

Detailed description:
The Phase 2 portion of the study will evaluate the efficacy and safety of 2 dose levels of mavrilimumab relative to placebo (standard of care) in participants who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with x-ray/computed tomography (CT) evidence of bilateral pneumonia and active or recent signs of hyperinflammation (fever or clinical laboratory results indicative of hyper-inflammation). The Phase 3 portion is intended to confirm Phase 2 efficacy and safety findings. In both Phase 2 and Phase 3, participants will be enrolled into 2 cohorts: Cohort 1 will include non-mechanically ventilated, hospitalized participants who require supplemental oxygen to maintain oxygen saturation (SpO2) ≥ 92% (ie, "non-mechanically ventilated" participants); Cohort 2 will include hospitalized participants for whom mechanical ventilation was recently initiated (ie, "mechanically ventilated" participants). Following Screening, enrolled participants in each cohort will be randomized 1:1:1 to receive one of 2 mavrilimumab dose levels, or placebo as a single intravenous (IV) infusion (Day 1). Participants will undergo primary study assessments through Day 29 and will be followed for safety through Day 90.

Arms:
arm 1: Non-mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion arm 2: Non-mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion arm 3: Non-mechanically ventilated participants administered placebo as a single IV infusion arm 4: Mechanically ventilated participants administered mavrilimumab 10 mg/kg as a single IV infusion arm 5: Mechanically ventilated participants administered mavrilimumab 6 mg/kg as a single IV infusion arm 6: Mechanically ventilated participants administered placebo as a single IV infusion

Interventions: intervention 1: mavrilimumab intervention 2: Placebo
Intervention descriptions: intervention 1: anti-granulocyte-macrophage colony-stimulating factor receptor alpha (GM-CSF-Rα) monoclonal antibody (human isoform immunoglobulin G \[IgG4\]) intervention 2: matching placebo

Protocol document:
Prot_SAP_000.pdf: 
 
 
Cli nic al S tu d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
Gl o b al  Versi o n 6 . 0 ( A me n d me nt 5 ) (0 8  N o v 2 0 2 1 ) 
St u d y Title:  
A P hase 2/ 3, 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 t o 
e val uate t he efficac y a n d safet y of ma vrili m u ma b ( K P L -3 0 1) 
treat me nt i n a d ult s u bjects h os pitalize d wit h se vere C O VI D-1 9 
p ne u m o nia a n d h y per -i nfla m mati o n 
St u d y N u m ber:  
K P L -3 0 1 -C 2 0 3  
U S I N D #  
1 4 9, 3 0 0  
St u d y P h ase:  
2/ 3  
Pr o d uct N a me:  
m a vrili m u ma b ( K P L-3 0 1 ) 
I n dic ati o n: 
Se vere cor o na v ir us d ise ase 2 0 1 9 (C O VI D -1 9 ) p ne u m o nia a n d 
h y per -i nfla m mati o n 
S p o ns or:  
Ki ni ksa P har mace uticals, Lt d .  
  
 
  
 
S p o ns or C o nt act /Me dic al 
M o nit or:  
 
 
Versi o n:  
D ate : 
Ori gi n al  Gl o b al  Pr ot oc ol  - Vers i o n 1  
1 4  Ma y 2 0 2 0  
S o ut h Afric a Versi o n 1 ( A me n d me nt 1)  
2 7 J ul y 2 0 2 0  
Gl o b al Versi o n  2  (A me n d me nt 1 ) 
1 3  A u g ust 2 0 2 0  
Gl o b al Versi o n 3 ( A me n d me nt 2)  
1 5  Dece m ber 2 0 2 0  
B r a zil Versi o n 4 ( A me n d me nt 3)  
2 7 A pril 2 0 2 1  
Gl o b al  Versi o n 5  ( A me n d me nt 4 ) 
1 4 J u ne  2 0 2 1  
Gl o b al Versi o n 6 ( A me n d me nt 5)  
0 8  N o ve m ber 2 0 2 1  
C o nfi de nti al it y St ate me nt 
T he c o nte nts of t his d oc u me nt are c o nfi de ntial a n d bel o n g t o Ki ni ksa P har mace uticals, Lt d. E xce pt as ma y be 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese materials, y o u (i ncl u di n g a n y c ollea g ues or 
s u b or di nates) a gree t o h ol d s uc h i nf or mati o n i n c o nfi de nce a n d n ot t o discl ose it t o ot hers ( e xce pt w here re q uire d b y 
a p plica ble la w), n or t o use it f or u na ut h orize d p ur p oses. I n t he e ve nt of act ual or s us pecte d breac h of t his o bli gati o n, 
Ki ni ksa s h o ul d be pr o m ptl y n otifie d.  


Cli nic al S t u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3
Gl o b al  Versi o n 6 . 0 ( A me n d me nt 5) ( 0 8 N o v 2 0 2 1 )
St u d y Title:
A P hase 2/ 3, 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 t o 
e val uate t he efficac y a n d safet y of ma vrili m u ma b ( K P L- 3 0 1) 
treat me nt i n a d ult s u bjects h os pitalize d wit h se vere C O VI D- 1 9
p ne u m o nia a n d h y per-i nfla m mati o n
St u d y N u m ber:
K P L- 3 0 1- C 2 0 3
U S I N D #
1 4 9, 3 0 0
St u d y P h ase:
2/ 3
Pr o d uct N a me:
ma vrili m u ma b ( K P L- 3 0 1)
I n dic ati o n:
Se vere c or o na vir us dise ase 2 0 1 9 ( C O VI D - 1 9) p ne u m o nia a n d 
h y per -i nfla m mati o n
S p o ns or:
Ki ni ksa P har mace uticals, Lt d .
S p o ns or C o nt act/ Me dic al 
M o nit or:
Versi o n:
D ate:
Ori gi n al  Gl o b al Pr ot oc ol - Vers i o n 1
1 4 Ma y 2 0 2 0
S o ut h Afric a Versi o n 1 ( A me n d me nt 1)
2 7 J ul y 2 0 2 0
Gl o b al Versi o n 2 ( A me n d me nt 1 )
1 3 A u g ust 2 0 2 0
Gl o b al Versi o n 3 ( A me n d me nt 2)
1 5 Dece m ber 2 0 2 0
B r a zil Versi o n 4 ( A me n d me nt 3)
2 7 A pril 2 0 2 1
Gl o b al  Versi o n 5 ( A me n d me nt 4)
1 4 J u ne 2 0 2 1
Gl o b al Versi o n 6 ( A me n d me nt 5)
0 8 N o ve m ber 2 0 2 1
C o nfi de nti alit y St ate me nt
T he c o nte nts of t his d oc u me nt are c o nfi de ntial a n d bel o n g t o Ki ni ksa P har mace uticals, Lt d. E xce pt as ma y be 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese materials, y o u (i ncl u di n g a n y c ollea g ues or 
s u b or di nates) a gree t o h ol d s uc h i nf or mati o n i n c o nfi de nce a n d n ot t o discl ose it t o ot hers ( e xce pt w here re q uire d b y 
a p plica ble la w), n or t o use it f or u na ut h orize d p ur p oses. I n t he e ve nt of act ual or s us pecte d breac h of t his o bli gati o n, 
Ki ni ksa s h o ul d be pr o m ptl y n otifie d.


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2  of 1 0 9  
C o nfi de ntial  
TI T L E P A G E   
 
P R O T O C O L A P P R O V A L  
 
Pr ot oc ol Title:  
A P hase 2/ 3, 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 t o 
e val uate t he efficac y a n d safet y of ma vrili m u ma b ( K P L -3 0 1) treat me nt 
i n a d ult s u bjects h os pitalize d wit h se vere C O VI D-1 9 p ne u m o nia a n d 
h y per -i nfla m mati o n 
Pr ot o c ol N u m ber: 
K P L -3 0 1 -C 2 0 3  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol, I nter nati o nal 
C o u ncil o n Har m o nisati o n (I C H) G o o d Cli nical Practice a n d a p plica ble re g ulat or y re q uire m e nts.  
S p o ns or Si g nat or y : 
 
 
 
 
 
 
 
 
S p o ns or’s electr o nic si g n at ure a p pe n de d 
t o t he e n d of t his pr ot oc ol. 
 
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3  of 1 0 9  
C o nfi de ntial  
I N V E S TI G A T O R’ S A G R E EM E N T  
 
I h a ve recei ve d a n d rea d t he I n v esti gat or’s Br oc h ure f or ma vrili m u ma b  ( K P L-3 0 1) . I ha v e rea d 
t he K P L -3 0 1 -C 2 0 3 Cli nical S t u d y P r ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d. I a gree t o 
mai ntai n t he c o nfi de ntialit y of all i nf or mati o n r ecei ve d or de v el o p e d i n c o n necti o n wit h t his 
pr ot oc ol.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri nte d Na me of I n v esti gat or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g nat ure of I n vesti gat or  
 
 
 
 
 
 
 
 
Date  
 
 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4  of 1 0 9  
C o nfi de ntial  
E M E R G E N C Y  C O N T A C T I N F O R M A TI O N  
T a ble 1 : 
E mer ge nc y C o nt a ct I nf or m ati o n  
R ole i n St u d y  
N a me  
E m ail a n d Tele p h o ne N u m ber  
Cli nical St u d y Lea der /Res p o nsi ble 
P h ysicia n  
 
 
 
Dr u g Safet y P h ysicia n  
  
  
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5  of 1 0 9  
C o nfi de ntial  
1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Ki ni ksa P har mace uticals, Lt d.  
N a me of I n vesti g ati o n al Pr o d uct:  
K P L -3 0 1  
N a me of Acti ve I n gre die nt:  
M a vrili m u ma b  
Title of St u d y:  
A P hase 2/ 3, 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 t o e val uate t he efficac y a n d safet y of 
ma vrili m u ma b ( K P L -3 0 1) treat me nt i n a d ult s u bj ects h os pitalize d wit h se vere C O VI D -1 9 p ne u m o nia 
a n d h y per -i nfla m mati o n 
St u d y ce nter(s):  A p pr o xi matel y 5 0 st u d y ce nters are pla n ne d i n t he U nite d States , E M E A, Lati n 
A merica , a n d Africa  
St u die d peri o d ( ye ars):  
D ate first s u bject e nr olle d:  J ul y 2 0 2 0 
Esti mate d date last s u bject c o m plete d: T B D  
P h ase of de vel o p me nt:  
P hase 2/ P hase 3  
O bjecti ves:  
P ri m ar y:  
T o e val uate t he cli nical efficac y of a si n gle i ntra ve n o us (I V) d ose of ma vrili m u ma b ( 1 0 m g/ k g or 
6  m g/ k g) relati ve t o place b o i n a d ult s u bjects h os pitalize d wit h se vere C O VI D -1 9 p ne u m o nia a n d 
h y per -i nfla m mati o n t o re d uce pr o gressi o n t o res pirat or y fail ure or deat h. 
Sec o n d ar y:  
T o assess t he i m pact of treat me nt o n cli nical stat us , m ortalit y, a n d safet y of a si n gle I V d ose of 
ma vrili m u ma b ( 1 0 m g/ k g or 6 m g/ k g) relati ve t o place b o i n a d ult s u bj ects h os pitalize d wit h se vere 
C O VI D -1 9 p ne u m o nia a n d h y per -i nfla m mati o n. 
Ot her : 
 
Met h o d ol o g y:  
T his is a n i nter ve nti o nal, 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 e nc o m passi n g  2 
de vel o p me nt p hases ( P hase 2 a n d P hase 3). T he P hase 2 p orti o n of t he st u d y is i nte n de d t o e val uate t he 
efficac y a n d safet y of 2 d os e le vels of ma vrili m u ma b  relati ve t o place b o (sta n dar d of care) i n s u bjects 
w h o ha ve teste d p ositi ve f or t he se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 (S A R S -C o V -2 ) wit h  
x -ra y/c o m p ute d t o m o gra p h y ( C T ) e vi de nce of bilateral p ne u m o nia  a n d acti ve or rece nt si g ns of 
h y peri nfla m mati o n (fe ver or  cli nical la b orat or y res ults i n dicati ve of h y per -i nfla m mati o n). T he P hase 3 
p orti o n is i nte n de d t o c o nfir m P hase 2 efficac y a n d safet y fi n di n gs. I n b ot h P hase 2 a n d P hase 3, 
su bj ects will be e nr olle d i nt o 2 c o h orts:  C o h ort 1 will i ncl u de n o n -mec ha nical l y ve ntilate d, 
h os pitalize d s u bjects w h o re q uire s u p ple me ntal o x y ge n t o mai ntai n o x y ge n sat urati o n ( S p O 2) ≥ 9 2 % , 
ie, “n o n -ve ntilate d ” s u bjects; C o h ort 2 will i ncl u de h os pitalize d s u bjects f or w h o m mec ha nical 
ve ntilati o n was rece ntl y i nitiate d ( wit hi n 4 8 h o urs pri or t o ra n d o mizati o n), ie, “v e ntilate d ” s u bjects. 
F oll o wi n g S cree ni n g, e nr olle d s u bjects i n eac h c o h ort will be ra n d o mize d 1: 1: 1 t o recei ve 
ma vrili m u ma b  1 0  m g/ k g or 6  m g/ k g, or place b o  as a si n gle I V i nf usi o n ( Da y 1)  i n a d diti o n t o sta n dar d 
of care as per i nstit uti o nal pr ot oc ol a n d at t he discreti o n of t he i n vesti ga t or ( pr o vi de d t hat t he 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
6  of 1 0 9  
C o nfi de ntial  
me dicati o n/t hera p y is n ot e x plicitl y pr o hi bite d per pr ot oc ol) . T here will be a sea mless tra nsiti o n i n 
e nr oll me nt of s u bjects i n b ot h c o h orts bet wee n t he P hase 2 a n d P hase 3 p orti o n s of t he st u d y. F or eac h 
c o h ort, once t he last s u bj ec t i n P hase 2 is e nr olle d, all s u bse q ue nt s u bjects will be c o nsi dere d P hase 3 
s u bj ects. T his will all o w f or c o nti n ue d e nr oll me nt d uri n g t he a nal ysis of t he P hase 2 c o h ort -s pecific 
data.  O nce t he last s u bj ect i n P hase 2 c o m pletes Da y 2 9 , pri mar y efficac y a n d  safet y a nal yses of t he 
P hase 2 data will be c o n d ucte d b y t he S p o ns or . F oll o wi n g de m o nstrati o n of efficac y a n d safet y i n 
P hase 2, t he P hase 3 p orti o n of t he st u d y will be c o nti n ue d/c o m plete d.  
St u d y Sc he m atic  
 
N u m ber of s u bjects ( pl a n ne d):  
P hase 2:  A p pr o xi matel y 1 7 1  s u bjects 
•  
C o h ort 1:  A p pr o xi matel y 1 2 0  n o n -ve ntilate d s u bj ects  
•  
C o h ort 2:  A p pr o xi matel y 5 1  ve ntilate d s u bj ects  
P hase 3:  A p pr o xi matel y 6 6 5  s u bjects 
•  
C o h ort 1:  A p pr o xi matel y 6 0 0  n o n -ve ntilate d s u bj ects  
•  
C o h ort 2:  A p pr o xi matel y 1 1 7  ve ntilate d s u bjects  (a p pr o xi matel y 6 5 s u bj ects at ti me of 
e nr oll me nt cl os ure ) 
Base d o n re vie w of t he P hase 2 C o h ort 2 res ults of t he pri mar y a n d sec o n dar y e n d p oi nts at da y 2 9 , 
P hase 3 C o h ort 2 is  cl ose d t o f urt her e nr oll me nt , as t here  was n o e vi de nce t hat ma vrili m u ma b pr o vi de d 
cli nical be nefit o ver place b o i n rece ntl y ve ntilate d patie nts.  
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
A d ult s u bjects w h o ha ve teste d p ositi ve f or S A R S-C o V -2 wit h c o nfir me d p ne u m o nia a n d h y per -
i nfla m mati o n 
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n:  
M a vrili m u ma b 1 0 m g/ k g  or  6 m g/ k g  (t otal d ose n ot t o e xcee d 1 0 0 0 m g) a d mi nistere d as a si n gle I V 
i nf usi o n o ver a p pr o xi matel y 6 0 mi n ute s 
D ur ati o n of tre at me nt:  
S u bj ects will recei ve a si n gle I V d ose of ma vrili m u ma b or place b o i nf use d o ver a p pr o xi matel y 6 0 
mi n utes  o n Da y 1 . 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
7  of 1 0 9  
C o nfi de ntial  
Ref ere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
Place b o  a d mi nistere d as a si n gle I V i nf usi o n o ver a p pr o xi matel y 6 0 mi n utes  
Criteri a f or e v al u ati o n :  
T he f oll o wi n g efficac y e n d p oi nts will be use d f or b ot h t he P hase 2 a n d P hase 3  parts  of t he st u d y . 
E n d p oi nts will be e val uate d f or b ot h C o h orts  1 a n d 2 , u nless ot her wise s pecifie d. 
Effic ac y:  
Pri m ary Effic acy E n d p oi nt : 
C o h ort 1 ( n o n -ve ntilate d su bj ects) : 
Pr o p orti o n of s u bjects ali ve a n d free of mec ha nical ve ntilati o n at Da y 2 9. Mec ha nical ve ntilati o n is 
defi ne d as i n vasi ve mec ha nical ve ntilati o n (I M V) or e xtrac or p oreal me m bra ne o x y ge nati o n  ( E C M O).  
M ec ha nical ve ntilati o n stat us will be e val uate d base d o n the Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Diseases ( NI AI D) cli nical o utc o me 8-p oi nt or di nal scale. S u bj ects w h ose cli nical o utc o me 
has met  a n NI AI D score  of  2 will be c o nsi dere d  as usi n g mec ha nical ve ntilati o n .  
Sc ale  
Descri pti o n  
1  
Deat h  
2  
H os pitalize d, o n i n vasi ve mec ha nical ve ntilati o n or E C M O  
3  
H os pitalize d, o n n o n -i n vasi ve ve ntilati o n or hi g h fl o w o x y ge n de vices 
4  
H os pitalize d, re q uiri n g s u p ple me ntal o x y ge n  
5  
H os pitalize d, n ot re q uiri n g s u p ple me ntal o x y ge n - re q uiri n g o n g oi n g me dical 
care ( C O VI D -1 9 relate d or ot her wise)  
6  
H os pitalize d, n ot re q uiri n g s u p ple me ntal o x y ge n - n o l o n ger re q uires o n g oi n g 
me dical care  
7  
N ot h os pitalize d, li mitati o n o n acti vities a n d/ or re q uiri n g h o me o x y ge n  
8  
N ot h os pitalize d, n o li mitati o ns o n acti vities  
C o h ort 2 ( v e ntilate d su bjects) : 
T he pri mar y efficac y e n d p oi nt is m ortalit y rate  at Da y 2 9 , defi ne d as t he pr o p orti o n of s u bj ects w h o 
ha ve die d  b y Da y 2 9 . 
Sec o n d ary E n d p oi nts : 
S ec o n dar y efficac y e n d p oi nts will be e xa mi ne d base d o n t he hierarc hical or der bel o w : 
C o h ort 1 ( n o n -ve ntilate d su bj ects) : 
•  
M ortalit y rate at Da y 2 9  
•  
Ve ntilati o n -free s ur vi val (Ti me t o ve ntilati o n or deat h ) b y Da y 2 9  
D efi ne d as ti me fr o m ra n d o mizati o n t o ve ntilati o n or deat h; s u bj ects still ali ve will be ce ns ore d 
at Da y 2 9 
•  
O verall s ur vi val b y Da y 2 9  
D efi ne d as ti me fr o m ra n d o mizati o n t o deat h; s u bjects still ali ve will be ce ns ore d at Da y 
2 9  


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8  of 1 0 9  
C o nfi de ntial  
C o h ort 2 ( v e ntilate d su bjects) : 
•  
Ti me t o 1 -p oi nt cli nical i m pr o ve me nt b y Da y 2 9  
Defi ne d as ti me fr o m ra n d o mizati o n t o a 1 -p oi nt i m pr o ve me nt o n t he NI AI D 8 -p oi nt or di nal 
scale, or disc har ge fr o m t he h os pital, w hic he ver c o mes first. S u bjects w h o die bef ore Da y 2 9  
will be ce ns ore d at Da y 3 5 . 
Ot her Effic acy E n d p oi nts : 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9  of 1 0 9  
C o nfi de ntial  
 
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
. 
S af et y E n d p oi nts a n d O versi g ht:  
Safet y e n d p oi nts will i ncl u de a d verse e ve nts  ( A Es), la b orat or y para meters, vital si g ns, 
electr ocar di o gra m ( E C G ), a n d ot her c o n diti o n-s pecific e ve nts. Fre q ue nc y a n d s pecific details will be 
descri be d i n t he Cli nical M o nit ori n g Pla n.  
A Safet y Re vie w C o m mittee ( S R C) i ncl u di n g 2 p h ysicia ns fr o m t he S p o ns or, 1  p h ysicia n fr o m t he 
S p o ns or’s c o ntract researc h or ga nizati o n ( C R O), a n d 1 i n de pe n de nt p h ysicia n w h o is a n e x pert i n 
critical care me dici ne, p ul m o nar y dis or ders, i nfecti o us diseases a n d/ or C O VI D -1 9 treat me nt ( S R C 
C hair pers o n)  will meet peri o dicall y t o re vie w A Es/ seri o us A Es (S A Es ), reas o ns f or st u d y 
disc o nti n uati o ns, a n d ke y cli nical a n d la b orat or y assess me nts. T he i nitial S R C meeti n g will be 
tri g gere d o nce 4 s u bjects ha ve c o m plete d Da y 8. S R C me m bers will be bli n de d t o treat me nt 
assi g n me nt.  
A Data M o nit ori n g C o m mittee ( D M C) will be esta blis he d b y t he S p o ns or  t o c o n d uct peri o dic re vie ws 
of u n bli n de d safet y data fr o m st u d y P hases 2 a n d 3. T he i nitial meeti n g will be tri g gere d at 1 m o nt h 
after e nr oll me nt of t he first patie nt . M ore details o n t he D M C are pr o vi de d i n t he pr ot oc ol a n d t he 
D M C c harter.  


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0  of 1 0 9  
C o nfi de ntial  
St atistic al Met h o ds:  
T he P hase 2 a n d P hase 3 parts of t his st u d y a n d t he c o h orts wit hi n eac h p hase will be i n de pe n de ntl y 
a nal yze d u nless ot her wise s pecifie d.  
A n alysis Sets : 
I nte nt-t o-Treat (I T T) A nal ysis Set : 
All ra n d o mize d s u bjects w h o meet eli gi bilit y  criteria  will be i ncl u de d i n t he I T T a nal ysis set.  
M o difie d I T T ( mI T T)  A nal ysis Set : 
All ra n d o mize d s u bjects w h o meet eli gi bilit y criteria  a n d recei ved  st u d y dr u g will be i ncl u de d i n t he 
mI T T a nal ysis set.   
Safet y A nal ysis Set : 
All ra n d o mize d s u bjects w h o recei ve d st u d y dr u g will be i ncl u de d i n t he safet y a nal ysis set.  
Per -Pr ot oc ol ( P P) A nal ysis Set : 
All mI T T/I T T s u bjects wit h o ut pr ot oc ol de viati o ns dee me d t o i m pact efficac y or et hical c o n d uct will 
be i ncl u de d i n t he P P a nal ysis set.  
R a n d o miz ati o n Str at a : 
T here will be 3 stratificati o n fact ors f or ra n d o mizati o n:  
1.  Use of a ut h orize d  sta n dar d of care a nti viral  t hera p y f or C O VI D-1 9  (e g, re md esi vir) : yes vs. n o  
2.  A ge: <  6 5 vs. ≥ 6 5 year s 
3.  Ac ute res pirat or y distress s y n dr o me ( A R D S) stat us  b y partial press ure of o x y ge n t o fracti o nal 
i ns pire d o x y ge n (Pa O 2/ Fi O2) rati o* : n or mal -mil d (> 2 0 0 ) vs. m o derate -se vere (≤ 2 0 0 ). A R D S 
stat us will o nl y be use d f or C o h ort 1 ( n o n-ve ntilate d s u bj ects) . 
*  If P a O2 is u n a vaila ble , use S p O 2/ Fi O2:  n or mal – mi l d (>  2 3 5 ) vs. m o derate– se vere (≤ 2 3 5 ). 
St atistic al A n alysis :  
All statistical a nal yses will be perf or me d usi n g S A S ®  Versi o n 9. 4 or hi g her. Descri pti ve statistics will 
be prese nte d f or all e n d p oi nts a n d will i ncl u de n u m ber of s u bjects ( n), mea n, sta n dar d de viati o n, 
me dia n, i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bles, a n d fre q ue nc y a n d 
perce nta ge f o r cate g orical a n d or di nal varia bles.  
Efficac y A nal ysis : 
All efficac y a nal yses will be base d o n t he mI T T f or t he P hase 2 e n d p oi nts a n d base d o n t he I T T 
a nal ysis set f or t he P hase 3 e n d p oi nts. A nal yses base d o n ot her a nal ysis sets will be c o nsi dere d as 
se nsiti vit y a nal yses. All efficac y c o m paris o ns will be pri mar il y base d o n eac h of t he ma vrili m u ma b 
ar ms vers us t he place b o  ar m.  
Pri m ary Effic acy E n d p oi nt :  
F or t he P hase 2 part of t he st u d y, t he Fis her’s e xact test will be perf or me d f or t he pri mar y efficac y 
e n d p oi nt f or b ot h c o h orts.  T he C oc hra n -Ma ntel -Hae nszel ( C M H) test a dj usti n g f or ra n d o mizati o n 
strata (a ut h orize d  sta n dar d of care a nti viral t hera p y f or C O VI D-1 9  (e g, re m desi vir), a ge, a n d A R D S 
stat us) will be use d as s u p p orti ve a nal ysis of t he pri mar y effi cac y e n d p oi nt f or C o h ort 1.  


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 1  of 1 0 9  
C o nfi de ntial  
F or b ot h c o h orts i n  t he P hase 3 part of t he st u d y, t he C M H test a dj uste d b y ra n d o mizati o n strata will be 
use d t o test t he pri mar y efficac y e n d p oi nt.  
T he n u m ber of s u bjects a n d perce nta ges will be s u m marize d b y treat me nt. T he 8 0 %  (f or P hase 2) a nd  
9 5 % (f or P hase 2 a n d 3) c o nfi de nce i nter vals will als o be pr o vi de d as a p pr o priate.  
Sec o n d ary  a n d Ot her  Effic acy E n d p oi nts :  
V e ntilati o n free s ur vi val, o verall s ur vi val, 
, ti me t o cli nical 
i m pr o ve me nt, a n d all ot her ti me t o e ve nt e n d p oi nts will be a nal yze d usi n g l o g-ra n k test stratifie d b y 
ra n d o mizati o n strata. T he hazar d rati o f or ma vrili m u ma b vs. place b o a n d t he c orres p o n di n g Wal d 8 0 % 
(f or P hase 2) a n d 9 5 %  (f or P hase 2 a n d  3)  CI will be calc ulate d base d o n a C o x pr o p orti o nal -hazar ds 
m o del wit h treat me nt as c o variate, stratifie d b y ra n d o mizati o n strata.  
A ll bi nar y e n d p oi nts i n b ot h c o h orts f or P hase 2 will be a nal yze d b y usi n g pri maril y t he Fis her’s e xact 
test. T he C M H test a dj usti n g f or ra n d o mizati o n strata ( a ut h orize d  sta n dar d of care a nti viral  t hera p y f or 
C O VI D -1 9 [ e g, re m desi vir], a ge, a n d A R D S stat us) will be use d as s u p p orti ve a nal ysis for C o h ort 1 . 
F or t he P hase 3 part of t he st u d y, t he C M H test a dj uste d b y ra n d o mizati o n strata will be use d t o test all 
bi nar y sec o n dar y a n d ot her efficac y e n d p oi nt f or b ot h c o h orts.   
S afety A n alysis  
All safet y s u m maries will be prese nte d f or t he safet y a nal ysis set. N o f or mal statistical a nal ysis of 
safet y e n d p oi nts will be perf or me d. 
Descri pti ve statistics will be use d t o s u m marize all safet y e n d p oi nts b y treat me nt gr o u p a n d/ or st u d y 
visit. Data s u m maries will dis pla y  para meters s uc h as i nci de nce of A Es , cli nical la b orat or y varia bles, 
vital si g ns, b o d y wei g ht a n d b o d y mass i n de x, E C G para meters, a n d p h ysical e xa mi nati o ns, w here 
a vaila ble. 
Ot her A n alys e s 
P har mac o ki netic para meters of ma vrili m u ma b will be s u m marize d.  T he prese nce of  a nti -dr u g 
a nti b o dies will be e x pl ore d. Para meters of mec ha nical ve ntilati o n, res pirat or y stat us, Se q ue ntial Or ga n 
Fail ure Assess me nt ( S O F A )/ quic k S O F A, a n d hea lt h care res o urce utilizati o n (e g, da ys a n d/ or le n gt h 
i n h os pital/I C U/ o x y ge n use) will be s u m marize d.  
I nteri m A n alysis 
T here is n o i nteri m a nal ysis pla n ne d f or t he P hase 2 or P hase 3 part of t h e st u d y. I nstea d, t he S p o ns or 
will c o n d uct a pri mar y  a n d/ or fi nal efficac y a nal ysis  (ie, re vie w of u n bli n d e d st u d y res ults) w he n t he 
last s u bject i n eac h P hase a n d C o h ort  c o m pletes t he Da y 2 9 / Da y 9 0 assess me nts. 
S a m ple Size Esti m ati o n : 
P hase 2 : 
A p pr o xi matel y 1 7 1  s u bjects will be ra n d o mize d t o t he P hase 2 part of t his st u d y.  
Sa m ple size esti mati o n f or C o h ort 1 ( n o n -ve ntilate d s u bj ects) i n P hase 2 is base d o n t he pri mar y 
efficac y e n d p oi nt of pr o p orti o n of s u bjects ali ve a n d free of mec ha nical ve ntilati o n  at Da y 2 9 , usi n g 
t he Fis her’s e xact test.  A p pr o xi matel y 1 2 0  s u bjects will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. 
Ass u mi n g t he pr o p orti o ns of s u bjects ali ve a n d free of mec ha nical ve ntilati o n at Da y 2 9  is 9 5 % a n d 
7 5 % f or t he acti ve treat me nt ar m a n d place b o ar m, res pecti vel y, 4 0  s u bjects per ar m will ac hie ve a 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 2  of 1 0 9  
C o nfi de ntial  
mi ni m u m 8 0 % p o wer f or a pair wise c o m paris o n vers us c o ntr ol w he n t he t w o -si de d al p ha val ue is 0. 2 0, 
after acc o u nti n g f or 1 5 % dr o p o ut . 
Sa m ple size f or C o h ort 2 ( ve ntilate d s u bjects) i n  P hase 2 is base d o n t he pri mar y efficac y e n d p oi nt 
m ortalit y rate at Da y 2 9 , usi n g t he Fis her’s e xact test. A p pr o xi matel y 5 1 s u bjects will be ra n d o mize d 
wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he m ortalit y rate s at Da y 2 9  are 4 0 % a n d 8 0 % f or t he acti ve 
treat me nt ar m a n d place b o ar m, res pecti vel y, 1 7 s u bjects per ar m will ac hie ve a n 8 0 % p o wer f or a 
pair wise c o m paris o n vers us c o ntr ol w he n t he t w o -si de d al p ha val ue is 0. 2 0. 
P hase 3  
A p pr o xi matel y 6 6 5  s u bjects will be ra n d o mize d t o t he P hase 3 part of t his st u d y. 
Sa m ple size f or C o h ort 1 ( n o n -ve ntilate d s u bjects) of t he P hase 3 part  is deter mi ne d base d o n t he 
pri mar y efficac y e n d p oi nt of pr o p orti o n of s u bjects ali ve a n d free of mec ha nical ve ntilati o n at Da y 2 9  
(ma vrili m u ma b 6 m g / k g vs place b o ) usi n g  t he C hi s q uare  test. T he ass u m pti o ns  use d  f or t he 
calc ulati o n are a dj uste d base d o n t he res ults of P hase 2 p orti o n. A p pr o xi matel y 6 0 0  s u bjects will be 
ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he pr o p orti o ns f or t he acti ve ar m a n d place b o ar m 
are 8 7. 5 % a n d 7 4 . 4% res pecti vel y, a p pr o xi matel y 2 0 0  s u bj ects per ar m are s ufficie nt t o ac hie ve at least  
9 0 % p o wer f or t he treat me nt c o m paris o n  at t he t w o-si de d si g nifica nce le vel of 0. 0 5 . 
Sa m ple size f or C o h ort 2 ( ve ntilate d s u bjects) of t he P hase 3 part  is deter mi ne d base d o n t he m ortalit y 
rate at Da y 2 9  usi n g a Fis her’s e xact test. A p pr o xi matel y 1 1 7 s u bj ects will be ra n d o mize d wit h a 1: 1 : 1 
all ocati o n rati o. Ass u mi n g t he m ortalit y rate s f or t he acti ve ar m a n d place b o ar m are 4 0 % a n d 8 0 % 
res pecti vel y, a p pr o xi matel y 3 9 s u bjects per ar m are re q uire d t o ac hie ve a 9 0 % p o wer f or a pair wise 
c o m paris o n vers us c o ntr ol w he n t he t w o -si de d al p ha val ue is 0. 0 2 5.  H o we ver, base d o n re vie w of t he 
P hase 2 C o h ort 2 res ults of t he pri mar y a n d sec o n dar y e n d p oi nts at da y 2 9, P hase 3 C o h ort 2 is cl ose d 
t o f urt her e nr oll me nt (a p pr o xi matel y 6 5 s u bj ects ra n d o mize d at t he ti me of e nr oll me nt cl os ure), as 
t here was n o e vi de nce t hat ma vrili m u ma b pr o vi de d cli nical be nefit o ver place b o i n rece ntl y ve ntilate d 
patie nts.  
M ulti plicit y A dj ust me nt  
T he c o h orts wit hi n t he P hase 2 a n d P hase 3 st u d y parts will be a nal yze d se paratel y u nless ot her wise 
s pecifie d.  
T he  t w o-si de d t y pe I err or rate is 0. 2 f or eac h P hase 2 c o h ort a n d 0. 0 5 f or eac h P hase 3 c o h ort. N o 
m ulti plicit y a dj ust me nt will be d o ne f or t he P hase 2 part  a n d P hase 3 C o h ort 2  (n o f or mal testi n g will 
be d o ne as e nr oll me nt t o c o h ort 2 st o p pe d earl y) .  
M ulti plicit y a dj ust me nt  f or P hase 3 C o h ort 1 will be d o ne t o g uara ntee str o n g c o ntr ol of t he o verall 
T y pe I err or rate at a t w o -si de d al p ha val ue of 0. 0 5. C o n ve nti o nal H oc h ber g met h o d will be use d t o 
a dj ust f or m ulti plicit y i n t he a nal ysis of t he t w o d ose le vels a n d t he se q ue nce of efficac y e n d p oi nts. 
Details are pr o vi de d i n Secti o n  1 3. 4 .  
Eli gi bilit y C riteri a:  
I ncl usi o n Criteria: 
S u bj ects m ust meet all t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt.  


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 3  of 1 0 9  
C o nfi de ntial  
1.  S u bj ect ( or le gall y a ut h orize d re prese ntati ve) is a ble a n d willi n g t o pr o vi de i nf or me d c o nse nt, 
w hic h i ncl u des c o m plia nce wit h st u d y re q uire me nts a n d restricti o ns liste d i n t he c o nse nt f or m. 
C o nse nt m ust be perf or me d per i nstit uti o nal re g ulati o ns . 
2.  A ge of ≥ 1 8 years  
3.  P ositi ve S A R S -C o V -2 ( 2 0 1 9 -n C o V) test  wit hi n 1 4 da ys pri or t o ra n d o mizati o n  
4.  H os pitalize d f or S A R S -C o V -2 ( 2 0 1 9-n C o V)  
5.  Bilateral p ne u m o nia o n c hest x -ra y or C T 
6.  [Ori gi n al Criteri a Delete d ] 
7.  At least o ne of t he f oll o wi n g  wit hi n 7 da ys pri or t o  ra n d o mizati o n:  
•  
Ferriti n >  5 0 0 n g/ m L  
•  
C R P >  5 m g/ d L  
•  
D -di mer > 1, 0 0 0 n g/ m L  
•  
L D H > 2 5 0 U/ L  
•  
Fe ver  - a meas ure d te m perat ure of at least 1 0 0. 4 ° F [ 3 8 ° C]  
8.  F or C o h ort 1:  R ecei vi n g a n y f or m of n o n -i n vasi ve ve ntilati o n O R o x y ge nati o n t o mai ntai n 
S p O 2 ≥ 9 2 % a n d n o n -mec ha nicall y ve ntilate d  (e xa m ples i ncl u de n asal ca n n ula, face mas k, 
ve nt uri mas k, hi g h -fl o w nasal ca n n ula, a n d n o n-i n vasi ve ve ntilati o n or  n o n -i n vasi ve p ositi ve 
press ure ve ntilati o n ) 
9.  F or C o h ort 2:  Rece ntl y ve ntilate d wit h  mec ha nical ve ntilati o n be gi n ni n g wit hi n 4 8 h o urs pri or 
t o ra n d o mizati o n 
1 0.  Fe male s u bjects m ust be:  
•  
p ost me n o pa usal, defi ne d as at least 1 2 m o nt hs p ost cessati o n of me nses ( wit h o ut a n 
alter nati ve me dical ca use), or  
•  
per ma ne ntl y sterile f oll o wi n g d oc u me nte d h ysterect o m y, bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y, or t u bal li gati o n or ha vi n g a male pa rt ner wit h vasect o m y as affir me d b y 
t he s u bject, or  
•  
n o n pre g na nt, n o nlactati n g, a n d if se x uall y acti ve ha vi n g a gree d t o use a hi g hl y effecti ve 
met h o d of c o ntrace pti o n (ie, h or m o nal c o ntrace pti ves ass ociate d wit h i n hi biti o n of 
o v ulati o n or i ntra uteri ne de vi ce [I U D], or i ntra uteri ne h or m o ne -releasi n g s yste m [I U S], or 
se x ual a bsti ne nce) fr o m Scree ni n g Visit u ntil Da y 9 0.  
1 1.  Male s u bjects m ust ha ve d oc u me nte d vasect o m y or if se x uall y acti ve m ust a gree t o use a 
hi g hl y effecti ve met h o d of c o ntrace pti o n wit h t heir p art ners of c hil d beari n g p ote ntial (ie, 
h or m o nal c o ntrace pti ves ass ociate d wit h t he i n hi biti o n of o v ulati o n or I U D, or I U S, or se x ual 
a bsti ne nce) fr o m Scree ni n g u ntil Da y 9 0. Male s u bjects m ust a gree t o refrai n fr o m d o nati n g 
s per m d uri n g t his ti me peri o d. 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 4  of 1 0 9  
C o nfi de ntial  
E xcl usi o n Criteria : 
Ge ner al Excl usi o n Criteri a : 
1.  O nset of C O VI D -1 9 s y m pt o ms > 1 4 da ys pri or t o ra n d o mizati o n 
2.  H os pitalize d > 7 da ys  pri or t o ra n d o mizati o n  
3.  [ F or C o h ort 1 o nl y] Nee d f or i n vasi ve mec ha nical ve ntilati o n  
4.  Nee d f or E C M O  
5.  Seri o us pri or or c o nc o mita nt ill ness t hat i n t he o pi ni o n of t he I n vesti gat or precl u des t he s u bject 
fr o m e nr olli n g i n t he trial, i ncl u di n g ( b ut n ot li mite d t o): 
•  
Hist or y of p ul m o nar y al ve olar pr otei n osis  
•  
Se vere a n d u nc o ntr olle d p ul m o nar y disease ot her t ha n C O VI D -1 9 p ne u m o nia  (e g, ast h ma, 
c hr o nic o bstr ucti ve p ul m o nar y disease, or ot hers)  
•  
Pre -e xisti n g ( pri or t o de vel o p me nt of C O VI D -1 9)  se vere left ve ntric ular s yst olic 
d ysf u ncti o n ( ie, left ve ntric ular ejecti o n fracti o n < 3 5 %) 
•  
He m o d y na mic i nsta bilit y wit h press or re q uire me nts of  n ore pi ne p hri ne at a d ose of 
>  0. 5  mc g/ k g/ mi n or e q ui vale nt (t otal if m ulti ple press ors use d) f or m ore t ha n 1 2 h o urs 
c o nti n u o usl y, m y ocar dial i nfarcti o n, str o ke, a n d car di o ge nic  se ptic s h oc k wit hi n 3 0 da ys 
pri or t o ra n d o mizati o n  
•  
K n o w n acti ve t u berc ul osis ( T B) deter mi ne d b y hist or y a n d l ocal sta n dar d of care, or 
hist or y of i nc o m pletel y treate d T B or at hi g h ris k f or late nt T B (e x p os ure or pri or 
i ncarcerati o n) 
o  If tu berc ul osis testi n g is re q uire d per l ocal re g ulati o ns, o ne p ositi ve ( or t w o 
i n deter mi nate) i nterfer o n ga m ma release assa y test res ults or o ne p ositi ve P C R test is 
e xcl usi o nar y 
•  
C o nc o mita nt u nc o ntr olle d s yste mic bacterial or f u n gal i nfecti o n  
•  
C o nc o mita nt res pirat or y viral i nfecti o n ot her t ha n C O VI D -1 9 a n d i nfl ue nza  t hat, i n t he 
o pi ni o n o f t he I n vesti gat or, re prese nts a hi g her m ortalit y ris k (e g, S A R S, Mi d dle East 
res pirat or y s y n dr o me [M E R S ]) 
6.  Rece nt treat me nt wit h cell -de pleti n g bi ol o gical t hera pies (e g, a nti -C D 2 0) wit hi n 1 2 m o nt hs, 
n o n -cell -de pleti n g bi ol o gical t hera pies (s uc h as a nti -t u mor necr osis fact or [ T N F], a na ki nra, 
a nti -I L-6 rece pt or [e g, t ociliz u ma b], or a batace pt) wit hi n 8 wee ks ( or 5 half -li ves, w hic he ver is 
l o n ger), treat me nt wit h al k ylati n g a ge nts wit hi n 1 2 wee ks, treat me nt wit h c ycl os p ori ne A, 
azat hi o pri ne, c ycl o p h os p ha mi de, m yc o p he n olate m ofetil ( M M F) , or ot her i m m u n os u p pressa nt 
(e xce pt f or c ortic oster oi ds) wit hi n 4 wee ks  pri or t o ra n d o mizati o n .  Me dicati o ns t hat bec o me 
sta n dar d of care f or C O VI D-1 9 a n d/ or recei ve e mer ge nc y use a ut h orizati o n ma y be all o we d 
after disc ussi o n wit h t he me dical m o nit or.  
7.  [ Ori gi n al Criteri a Delete d] 


ma vrili m u ma b ( K P L -3 0 1)  
Ki ni ksa P har mace uticals, Lt d . 
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 5  of 1 0 9  
C o nfi de ntial  
8.  If su bject is recei vi n g or has recei ve d h y dr o x yc hl or o q ui ne wit hi n 3 m o nt hs pri or t o scree ni n g 
visit , a correcte d Q T i nter val b y Fri dericia’s met h o d ( Q T c F) o n Scree ni n g E C G  of  ≥ 5 0 0 ms  is 
e xcl usi o nar y. If s u bj ect has a pace ma ker, t his criteri o n d oes n ot a p pl y.  
9.  [ Ori gi n al Criteri a Delete d] 
1 0.  E nr olle d i n a n ot her i n vesti gati o nal st u d y of a me dical i nter ve nti o n  wit hi n 3 0 da ys pri or t o 
ra n d o mizati o n. Partici pati o n i n o pe n la bel trials i n v ol vi n g i n vesti gati o nal treat me nts f or 
C O VI D -1 9  ma y be all o we d u p o n a p pr o val b y t he S p o ns or . 
1 1.  K n o w n h y perse nsiti vit y t o ma vrili m u ma b or a n y of its e xci pie nts  
1 2.  I n t he o pi ni o n of t he I n vesti gat or, u na ble t o c o m pl y wit h t he re q uire me nts t o partici pate i n t he 
st u d y 
1 3.  [ Ori gi n al Criteri a Delete d] 
1 4.  [ Ori gi n al Criteri a Delete d] 
1 5.  At S cree ni n g bl o o d tests, a n y of t he f oll o wi n g:  
•  
As partate tra nsa mi nase > 1 0  × u p per li mit of n or mal ( U L N ) 
•  
Ala ni ne tra nsa mi nase > 1 0  × U L N  
•  
He m o gl o bi n < 7 .5 g/ d L  
•  
Ne utr o p hils < 1, 5 0 0/ m m 3 
•  
A bs ol ute platelet c o u nt < 5 0, 0 0 0/ m m 3 
•  
Creati ni ne cleara nce < 3 0 m L/ mi n ( b y C oc kcr oft -Ga ult f or m ula ) 
1 6.  Life e x pecta nc y less t ha n 4 8 h o urs, i n t he o pi ni o n of t he In vesti gat or  
1 7.  K n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n (re gar dless of i m m u n ol o gical stat us), k n o w n 
he patitis B vir us s urface a nti ge n p ositi vit y a n d/ or a nti -he patitis C vir us p ositi vit y  


ma vrili m u ma b ( K P L -3 0 1)  
 
Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 6  of 1 0 9  
C o nfi de ntial  
T a ble  2 : 
Sc he d ule of A cti vities  
 
 
St u d y D a y  
 
 
 
Scree ni n g  
St u d y P eri o d  
F oll o w -u p 
P eri o d  
D ate of 
Disc h ar ge 
or U N S 
Visit 3 
Acti vit y  
U p t o 3  d a ys 
pri o r t o 
st u d y dr u g 1  
1  
2  
3  
4  
5  
6  
7  
8  
1 5 2 
± 2  
2 2 2 
± 2  
2 9 2  
+ 4  
6 0  
+ 1 4  
9 0  
+ 1 4  
 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K n o w n c o -m or bi dities (i n cl. C O VI D-1 9 ris k fact ors)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dicati o n hist or y ( 3 0 da ys pri or t o S cree ni n g) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S A R S -C o V -2 T est (C O VI D -1 9 ) 
X 4  
O  
O  
O  
O  
O  
O  
O  
O  
O  
O  
O  
 
 
O  
P h ysical e xa m ( i ncl u di n g b o d y wei g ht & hei g ht) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
q S O F A ( C o h ort 1  o nl y )5 
X 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S O F A ( C o h ort 2 o nl y) 5 
X 5 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
Electr ocar di o gra m  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
C hest X -ra y or C T sca n6 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C hest X -ra y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 7 
Res pirat or y Viral Pa nel 8 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u berc ul osis  scree ni n g9 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y test f or W O C B P ( uri ne or ser u m)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
O  
X  
Ra n d o mizati o n a n d St u d y Dr u g A d mi nistrati o n  
 
X 1 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g ns  
X  
C ollect dail y 1 1 u ntil date of disc har ge  
O  
O  
O  


ma vrili m u ma b ( K P L -3 0 1)  
 
Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 7  of 1 0 9  
C o nfi de ntial  
 
 
St u d y D a y  
 
 
 
Scree ni n g  
St u d y P eri o d  
F oll o w -u p 
P eri o d  
D ate of 
Disc h ar ge 
or U N S 
Visit 3 
Acti vit y  
U p t o 3  d a ys 
pri o r t o 
st u d y dr u g 1  
1  
2  
3  
4  
5  
6  
7  
8  
1 5 2 
± 2  
2 2 2 
± 2  
2 9 2  
+ 4  
6 0  
+ 1 4  
9 0  
+ 1 4  
 
B o d y T e m perat ure ( Celsi us)  
X  
C ollect dail y 1 1 u ntil date of disc har ge  
O  
O  
O  
Ec h ocar di o gra m ( E C H O) 1 2 
O  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical assess me nt ( NI AI D 8 -p oi nt scale) 1 3 
X  
C ollect dail y 1 1 u ntil date of disc har ge  
X  
X  
X 1 4 
Mec ha nical ve ntilati o n para meters
1 5 
X  
C ollect dail y 1 1 u ntil date of disc har ge  
 
 
X  
Res pirat or y f u ncti o n para meters 1 6 
X  
C ollect dail y 1 1 u ntil date of disc har ge  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
He mat ol o g y , C oa g ulati o n, C he mistr y, Li ver 
Pr o file1 7 
X 1 8 
 
 
X  
 
 
 
 
 
X  
 
X  
O  
O  
X  
Li pi d pa nel 1 7 
X 1 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Uri nal ysis 1 7 
X 1 8 
 
 
 
 
 
 
 
 
 
 
O  
O  
O  
X  
P har mac o ki netic sa m ple 2 1 
 
X 2 2 
 
X  
 
 
 
X  
 
X  
 
X  
 
 
X  
A nti -ma vrili m u ma b  a nti b o d y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
A d verse e ve nts 1 3 , 23 
X  
C o nti n u o us c ollecti o n d uri n g h os pitalizati o n  
X  
X  
X  
C o nc o mita nt me dicati o ns 1 3 , 2 4 
 
C o nti n u o us c ollecti o n d uri n g h os pitalizati o n  
X  
X  
X  
Healt h care res o urce utilizati o n 1 3 
X  
C o nti n u o us c ollecti o n d uri n g h os pitalizati o n  
X  
X  
X  
Assess me nt of s ur vi val 1 3 
 
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  


ma vrili m u ma b ( K P L -3 0 1)  
 
Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 8  of 1 0 9  
C o nfi de ntial  
X =  re q uire d assess me nt f or all s u bj ects; m a y be c olle cte d re m otel y if s u bje ct h as bee n disc h ar ge d a n d is u n a ble t o be e v al u ate d at t he cli ni c al site  
O =  o pti o n al ass ess me nt f or s u bj ects, i ncl u di n g t h ose disc h ar ge d fr o m h os pit a l a n d are u n a bl e t o be e v al u ate d at t he cli ni c al site, or as per st a n d ar d of c are  
C R P = C -reacti ve pr otei n; I N R = i nter nati o nal n or malize d rati o; L D H = lactate de h y dr o ge nase; 
; S O F A/ q S O F A = ( q uic k) Se q ue ntial Or ga n 
Fail ure Assess me nt ; T N F = t u m or necr osis fact or; W O C B P = w o me n of c hil d beari n g p ote ntial; U N S = u nsc he d ule d visit  
 
Sc he d ule of Acti vities F o ot n otes  
1  
Scree ni n g acti vities c a n occ ur u p t o 3 da ys pri or t o st u d y dr u g  a d mi nistrati o n,  e xce pt f or C O VI D -1 9 testi n g  (see f o ot n ote # 4), scree ni n g la bs (see f o ot n ote # 1 7)  a n d 
c hest x-ra y or C T sca n  (see f o ot n ote # 6). S u bject eli gi bilit y s h o ul d be c o nfir me d at Da y 1 pri or t o st u d y dr u g a d mi nistrati o n.  
2  
F or h os pitalize d s u bjects, t his visit will i n cl u de acti vities liste d . F or s u bjects disc har ge d bef ore Da y 1 5 , t he Da y 1 5, 2 2 a n d 2 9 visit s ma y  be c o n d ucte d b y p h o ne a n d  
will n ot i ncl u de a n y la b orat or y tests, vital si g ns, or b o d y te m perat ure.  F or s u bjects w h o re mai n h os p italize d after D a y 2 9, t h e sa me ass ess me nt s s h o ul d be c o m plete d 
o n a wee kl y basis . 
3  
At t h e ti me of disc har ge,  c o m plete O N L Y  t h e Date of Disc har ge / U N S visit assess me nts o n t h e disc har ge date  (ie, st u d y da y assess me nts are n ot re q uire d). If a s u bject 
is disc har ge d a n d t h e I n vesti gat or j u d ges t h at it is n ot safe f or t h e s u bject t o ret ur n t o t h e site, or t he s u bject is n ot willi n g t o ret ur n t o t he site, t h e re q uire d visits  ( Da ys 
1 5, 2 2, 2 9, 6 0 a n d 9 0)  t hat occ ur t hereafter ma y be d o ne b y ph o ne call f oll o w -u p a n d la b tests will n ot be perf or me d.  
4  
S u bject s m ust ha ve a p ositi ve S A R S-C o V -2 ( 2 0 1 9 -n C o V) test wit hi n 1 4 da ys pri or t o ra n d o mizati o n . It d oes n ot ha ve t o be t h e first p ositi ve test b ut a p ositi ve test is 
re q uire d wit hi n 1 4 da ys pri or t o ra n d o mizati o n. T he test ma y be perf or me d l o call y (at t h e cli nical site or fr o m a n ot h er i nstit uti o n)  or b y ce ntral la b orat or y  if l o cal testi n g 
is n ot a vaila ble. If S A R S-C o V -2 testi n g is c o m plete d p ost -scree ni n g, please e nter d ata i nt o  t he eC R F . 
5  
If t h ere is a 1-p oi nt w orse ni n g i n NI AI D scale i n a s u bject, it is rec o m me n de d t o re -assess q S O F A ( C o h ort 1) or S O F A ( C o h ort 2) at t h e ti me of w orse ni n g or as per 
sta n dar d of care d uri n g h os pitalizati o n. 
6  
Scree ni n g x -ra y or C T c a n be d o ne wit hi n 7 da ys fr o m ra n d o mizati o n. If perf or me d at a d diti o nal ti me p oi nts b y t h e I n vesti gat or/site staff as part of sta n dar d of care 
t hr o u g h Da y 2 9, res ults will be c ollecte d a n d e ntere d i nt o t h e e C R F . 
7  
T he d isc har ge X -ra y c a n be d o ne wit hi n 7 2 h o urs of disc har ge . 
8  
P a nel i ncl u de s i nfl u e nza –  A/ H 3 N 2, A/ H 1 N 1 p d m 0 9, A/ H 7 N 9 , A/ H 5 N 1 , A , n ot t y pe d, B, or o t her (s pecif y); cor o na vir us  –  n o ve l C o V, M E R S C o V, ot her C o V (s pecif y); 
R S V; a de n o vir us; b acteria; ot h er i nfecti o us res pirat or y dia g n osis (s pecif y); cli nical p ne u m o nia . 
9  
T u berc ul osis scree ni n g is ma n dat or y f or S o ut h Africa sites a n d is at t h e discreti o n of t h e I n vesti gat or  else w here. If re q uire d, o ne p ositi ve ( or 2  i n deter mi n ate) i nterfer o n 
ga m ma releas e assa y test res ults or o ne p ositi ve P C R test is e xcl usi o nar y . 
1 0  
T he  NI AI D sc ore  s h o ul d be rec or de d at t he ti me of ra n d o mizati o n f or all eli gi ble s u bjects. F or s u bjects i n C o h ort 1 o nl y, als o rec or d 1) eit her P a O 2 ( m m H g), if 
a vaila ble, or  S p O 2 ( %) , a n d 2) Fi O 2 ( %)  f or s u bjects o n assisti ve ve ntilati o n or L/ mi n of  o x y ge n  s u p ple me ntati o n f or s u bjects n ot o n assisti ve ve ntilati o n (e.g ., si m ple 
mas k/c a n n ula) . I nitiati o n of st u d y dr u g a d mi nistrati o n s h o ul d occ ur wit hi n 2 4 h o urs of ra n d o mizati o n.  
1 1  
If t h e s u bject re mai ns h os pitalize d after D a y 8 t h ese assess me nts s h o ul d be c ollecte d dail y u ntil t h e da y of disc har ge (i e , D a ys 9 -1 4, 1 6 -2 1, 2 3 -2 8 or after Da y 2 9) . O n 
Da y 1, assess me nts s h o ul d be c ollecte d at t h e ti me cl osest t o a n d pri or t o t h e i nitiati o n of st u d y dr u g a d mi nistrati o n. Dail y c ollecti o n g ui deli nes  after Da y 1 : c ollect 
assess me nt i n t h e m or ni n g at a p pr o xi mat el y  t h e sa me ti me eac h da y a n d cl osest t o t h e c ollecti o n of t he N IAI D s c ore assess me nt , e xce pt f or res pirat or y para meters (see 
f o ot n ote # 1 6) 
1 2  
If a vaila ble, E C H O  perf or me d fr o m 9 0 da y s pri or t o ra n d o mizati o n t hr o u g h Da y 9 0  will  be c ollecte d  (re p ort o nl y). 
1 3  
If d isc har ge d, t h ese assess me nts m ust be perf or me d via p h o ne call at Da ys 1 5,  2 2,  a n d 2 9 . 
1 4  
T he N IAI D at disc har ge  t o h o me s h o ul d reflect stat us i m me diatel y p ost-disc har ge (ie, eit her 7 or 8) . 
1 5  
C ollect ve ntilati o n s u p p orti ve me as ures ( e g, pr o nati o n, nitric o xi d e use, trac he ost o m y ) re cei v e d b y s u bjects o n mec ha nical ve ntilati o n; details i n t h e Site Ma n ual . 
1 6  
Res pirat or y f u ncti o n para meters will be rec or de d dail y u ntil t he date of Disc har ge. Dail y  val u es  base d o n t he hi g hest dail y Fi O 2, i n cl u di n g  P a O 2, Fi O2, S p O2  a n d o x y ge n 
re q uire me nt, O t h er arterial bl o o d gas p ara meters if a vaila ble s h o ul d be rec or de d. I n a d diti o n, ot her s u p p orti ve meas ures i n cl u di n g pr o nati o n, ne ur o m usc ular bl oc ka de, 
trac he ost o m y, E C M O, vas o press or or i n otr o pic t hera p y, i n hale d nitric o xi d e or ot her s h o ul d be rec or de d.     


ma vrili m u ma b ( K P L -3 0 1)  
 
Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 9  of 1 0 9  
C o nfi de ntial  
1 7  
All sa m ples after s cree ni n g m a y b e c ollecte d ± 1 da y fr o m desi g nate d c ollecti o n date , ± 2  da y s after D a y 7. Ad diti o nal sa m ples c ollecte d as sta n dar d of care  t hr o u g h 
Disc har ge will  be c ollecte d . 
 
 
  
1 9  
If sa m ple at Scree ni n g was o btai ne d > 4 8  h o urs pri or t o start of st u d y dr u g i nf usi o n , a n ot h er sa m ple s ho ul d be o btai ne d pri or t o d osi n g o n Da y 1.  
 
 
  
2 1  
Ser u m c ollecte d f or p har mac o ki n etics st u dies t o be c o n d ucte d b y  t he S p o ns or .  N o p har m ac o ki n etic sa m ples are re q uire d after Da y 2 9.  
2 2  
O n Da y 1, p har mac o ki n etic  sa m ple t o be c ollecte d bef ore i nf usi o n a n d w he n i nf usi o n is c o m plete . 
2 3  
C ollect a bl o o d sa m ple f or c yt o ki ne assess me nt if a seri o us i nf usi o n reacti o n occ urs, or  a s u bject e x perie nces n e w s y m pt o ms or  w orse ni n g of s y m pt o ms of c yt o ki n e 
release s y n dr o me (e g, mal aise, na useas a n d v o miti n g, diarr hea) 
2 4  
Pr o hi bite d me dicati o ns i ncl u de a n y c ell -de pleti n g bi ol o gical t h era pies (e g, a nti -C D 2 0) wit hi n 1 2 m o nt hs  pri or t o S cree ni n g; or pre vi o us treat me nt wit h n o n-cell-
de pleti n g bi ol o gical t h era pies (s uc h as a nti -T N F, a na ki nra, a nti -I L-6 rece pt or [ e g, t o ciliz u ma b], or a batace pt) wit hi n 8 wee ks ( or 5 half -li ves, w hic he ver is l o n ger) pri or 
t o Scree ni n g; treat me nt wit h al k ylati ng a ge nts wit hi n 1 2 wee ks pri or t o Scree ni n g ; treat me nt wit h c ycl os p ori n e A, azat hi o pri n e, c ycl o p h os p ha mi d e, M M F, or ot h er 
i m m u n os u p pressa nt (e xce pt f or c ortic oster oids ) wit hi n 4 wee ks of Scree ni n g . Me dicati o ns t h at bec o me sta n dar d of car e f or C O VI D -1 9 a n d/ or recei ve e mer ge nc y us e 
a ut h orizati o n ma y be all o we d aft er disc ussi o n wit h t h e me dical m o nit or.  C o nc o mita nt me dicati o ns t o trac k i n cl u de a nti p yretics, a nti -i nfecti ves relate d t o C O VI D-1 9, 
a n d c ortic oster oi ds. Ot her c o nc o mita nt me dicati o ns rec or de d at Baseli ne Da y  1 a n d ma xi m u m d ose.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 0  of 1 0 9  
C o nfi de ntial  
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F 
FI G U R E S   
T A B L E O F C O N T E N T S  
1.  
S Y N O P SI S  .............................................................................................................. - 5 - 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ...............2 0  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S .............................2 6  
4.  
I N T R O D U C TI O N ......................................................................................................2 8  
5.  
T RI A L O BJ E C TI V E S A N D  P U R P O S E  ....................................................................3 4  
5. 1.  
Pri mar y O bj ecti ve  .......................................................................................................3 4  
5. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 4  
5. 3.  
Ot h er O bjecti ve  ...........................................................................................................3 4  
6.  
I N V E S TI G A TI O N A L P L A N .....................................................................................3 5  
6. 1.  
O verall St u d y Desi g n  ..................................................................................................3 5  
6. 2.  
N u m ber of S u bjects ( pla n ne d)  ....................................................................................3 6  
6. 3.  
Treat me nt Assi g n me nt  ................................................................................................3 7  
6. 4.  
D ose A dj ust me nt Criteria  ...........................................................................................3 7  
6. 4. 1.  
Safet y Criteria f or A dj ust me nt or St o p pi n g D oses  .....................................................3 7  
6. 5.  
Criteria f or St u d y Ter mi nati o n  ...................................................................................3 7  
7.  
S E L E C TI O N C RI T E RI A A N D WI T H D R A W A L O F S U B J E C T S ..........................3 8  
7. 1.  
S u bject I n cl usi o n Criteria  ...........................................................................................3 8  
7. 2.  
S u bject E x cl usi o n Criteria  ..........................................................................................3 9  
7. 3.  
Wit h dra wal of S u bjects  ...............................................................................................4 0  
7. 3. 1.  
Treat me nt St o p pi n g Criteria  .......................................................................................4 0  
7. 3. 2.  
Re place me nt p olic y  ....................................................................................................4 1  
7. 3. 3.  
Wit h dra wal of i nf or me d c o nse nt  ................................................................................4 1  
7. 3. 4.  
L ost t o f oll o w -u p  ........................................................................................................4 1  
8.  
T R E A T M E N T O F S U BJ E C T S  ..................................................................................4 2  
8. 1.  
Descri pti o n of St u d y Dr u g  ..........................................................................................4 2  
8. 1. 1.  
I n v esti gati o nal Pr o d uct ...............................................................................................4 2  
8. 1. 2.  
Descri pti o n  ..................................................................................................................4 2  
8. 1. 3.  
D ose a n d A d mi nistrati o n  ............................................................................................4 2  


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 1  of 1 0 9  
C o nfi de ntial  
8. 2.  
C o nc o mita nt Me dicati o ns  ...........................................................................................4 2  
8. 2. 1.  
Pr o hi bite d Me dicati o ns  ...............................................................................................4 3  
8. 3.  
Treat me nt C o m plia nce  ................................................................................................4 3  
8. 4.  
Ra n d o mizati o n a n d Bli n di n g  ......................................................................................4 3  
8. 4. 1.  
Ra n d o mizati o n  ............................................................................................................4 3  
8. 4. 2.  
Treat me nt Bli n di n g  .....................................................................................................4 4  
9.  
S T U D Y  D R U G M A T E RI A L S A N D M A N A G E M E N T  ...........................................4 5  
9. 1.  
St u d y Dr u g  ..................................................................................................................4 5  
9. 2.  
St u d y Dr u g Pac k a gi n g a n d La b eli n g  ..........................................................................4 5  
9. 3.  
St u d y Dr u g St ora ge  .....................................................................................................4 5  
9. 4.  
St u d y Dr u g Pre p arati o n  ..............................................................................................4 5  
9. 5.  
A d mi nistrati o n  ............................................................................................................4 5  
9. 6.  
St u d y Dr u g A cc o u nta bilit y  .........................................................................................4 5  
9. 7.  
St u d y Dr u g H a n dli n g a n d Dis p osal  ............................................................................4 6  
1 0.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................4 7  
1 0. 1.  
Pri mar y Efficac y E n d p oi nt  .........................................................................................4 7  
1 0. 1. 1.  
C o h ort 1 ( N o n -ve ntilate d S u bjects)  ............................................................................4 7  
1 0. 1. 2.  
C o h ort 2 ( Ve ntilate d S u bjects)  ...................................................................................4 7  
1 0. 2.  
Sec o n dar y Efficac y E n d p oi nts  ....................................................................................4 7  
1 0. 3.  
Ot her Effi cac y E n d p oi nts  ...........................................................................................4 8  
1 0. 4.  
Efficac y Para m eters  ....................................................................................................4 9  
1 0. 4. 1.  
Mec ha nic al Ve ntilati o n Para meters  ............................................................................4 9  
1 0. 4. 2.  
Res pirat or y Para met ers  ...............................................................................................4 9  
1 1.  
A S S E S S M E N T O F P H A R M A C O KI N E TI C S  ...........................................................5 1  
1 1. 1.  
P har mac o ki netic Sa m pli n g a n d Para meter Assess me nt  .............................................5 1  
1 2.  
A S S E S S M E N T O F S A F E T Y  .....................................................................................5 2  
1 2. 1.  
Safet y Para met ers  .......................................................................................................5 2  
1 2. 1. 1.  
De m o gra p hic/ Me di cal Hist or y  ...................................................................................5 2  
1 2. 1. 2.  
Vital Si g ns  ..................................................................................................................5 2  
1 2. 1. 3.  
P h ysical E x a mi nati o n  .................................................................................................5 2  
1 2. 1. 4.  
Electr ocar di o gra m, a n d C hest X -ra y or C T Sca n .......................................................5 2  
1 2. 1. 5.  
La b orat or y Ass ess me nts  .............................................................................................5 2  


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 2  of 1 0 9  
C o nfi de ntial  
1 2. 1. 5. 1.  
Pre g n a nc y Scree n  ........................................................................................................5 4  
1 2. 1. 6.  
Se q ue ntial Or ga n Fail ure Assess me nt ( S O F A) a n d Q uic k S O F A  ..............................5 4  
1 2. 2.  
A d verse a n d Seri o us A d verse E ve nts  .........................................................................5 5  
1 2. 2. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................5 5  
1 2. 2. 1. 1.  
A d verse E v e nt ( A E)  ....................................................................................................5 5  
1 2. 2. 1. 2.  
A d verse Dr u g Reacti o n  ...............................................................................................5 5  
1 2. 2. 1. 3.  
A d verse E v e nts of S peci al I nt erest  .............................................................................5 5  
1 2. 2. 1. 4.  
Seri o us A d verse E v e nt ( S A E)  ....................................................................................5 7  
1 2. 3.  
Relati o ns hi p t o St u d y Dr u g  ........................................................................................5 8  
1 2. 4.  
Rec or di n g A d verse E ve nts  .........................................................................................5 8  
1 2. 5.  
Re p orti n g Seri o us A d v erse E ve nts  .............................................................................6 0  
1 2. 5. 1.  
Pre g n a nc y Re p orti n g  ..................................................................................................6 1  
1 2. 5. 2.  
Re p orti n g of St u d y Treat me nt Err ors  .........................................................................6 1  
1 3.  
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S  ...................................6 3  
1 3. 1.  
A nal ysis Sets  ...............................................................................................................6 3  
1 3. 1. 1.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................6 3  
1 3. 1. 2.  
M o difie d I nte nt -t o-Treat A nal ysis Set  ........................................................................6 3  
1 3. 1. 3.  
Safet y A nal ysis Set  .....................................................................................................6 3  
1 3. 1. 4.  
Per -Pr ot oc ol A nal ysis Set  ...........................................................................................6 3  
1 3. 2.  
Statistical A nal ysis  ......................................................................................................6 3  
1 3. 2. 1.  
Ge neral Met h o ds  .........................................................................................................6 3  
1 3. 2. 2.  
St ratifie d A nal ysis ......................................................................................................6 3  
1 3. 2. 3.  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  ....................................................................6 4  
1 3. 2. 4.  
Efficac y A nal yses  .......................................................................................................6 4  
1 3. 2. 4. 1.  
Pri mar y Efficac y E n d p oi nt  .........................................................................................6 4  
1 3. 2. 4. 2.  
Sec o n dar y a n d Ot her Efficac y E n d p oi nts  ...................................................................6 4  
1 3. 2. 5.  
Safet y A nal ysis  ...........................................................................................................6 5  
1 3. 2. 6.  
Ot her A nal yses  ............................................................................................................6 5  
1 3. 2. 7.  
I nteri m A nal ysis ..........................................................................................................6 5  
1 3. 3.  
Sa m ple Siz e Esti mati o n  ..............................................................................................6 5  
1 3. 3. 1.  
P hase 2  ........................................................................................................................6 5  
1 3. 3. 2.  
P hase 3  ........................................................................................................................6 6  


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 3  of 1 0 9  
C o nfi de ntial  
1 3. 4.  
M ulti plicit y  A dj ust me nt ..............................................................................................6 6  
1 4.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S .........................................6 8  
1 4. 1.  
St u d y M o nit ori n g  ........................................................................................................6 8  
1 4. 2.  
A u di ts a n d I ns p ecti o ns ................................................................................................6 8  
1 5.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................6 9  
1 6.  
E T HI C S  ......................................................................................................................7 0  
1 6. 1.  
Et hics Re vie w  .............................................................................................................7 0  
1 6. 2.  
Et hical C o n d uct of t he St u d y  ......................................................................................7 0  
1 6. 3.  
I nf or me d C o nse nt .......................................................................................................7 0  
1 7.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ......................................................7 1  
1 7. 1.  
I ns p ecti o n of Rec or ds .................................................................................................7 1  
1 7. 2.  
Rete nti o n of Rec or ds  ..................................................................................................7 1  
1 8.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................7 2  
1 9.  
LI S T O F R E F E R E N C E S  ............................................................................................7 3  
2 0.  
S U M M A R Y O F C H A N G E S  ......................................................................................7 6  
2 0. 1.  
C ha n ges fr o m Gl o bal Pr ot oc ol Versi o n 5 ( A me n d me nt 4) t o Gl o bal Pr ot oc ol 
Versi o n 6 ( A me n d m e nt 5)  ..........................................................................................7 6  
2 0. 2.  
C ha n ges fr o m Brazil Pr ot oc ol Versi o n 4 ( A me n d me nt 3) t o Gl o bal Pr ot oc ol 
Versi o n 5 ( A me n d m e nt 4)  ..........................................................................................8 1  
2 0. 3.  
C ha n ges fr o m Gl o bal Pr ot oc ol Versi o n 3 ( A me n d me nt 2) t o Gl o bal Pr ot oc ol 
Versi o n 5 ( A me n d m e nt 4)  ..........................................................................................8 5  
2 0. 4.  
C ha n ges fr o m Gl o bal Pr ot oc ol Versi o n 2 ( A me n d me nt 1) t o Gl o bal Pr ot oc ol 
Versi o n 3 ( A me n d m e nt 2)  ..........................................................................................9 7  
 


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 4  of 1 0 9  
C o nfi de ntial  
LI S T O F T A B L E S  
Ta ble 1:  
E mer ge nc y C o nta ct I nf or mati o n  .............................................................................. - 4 - 
Ta ble  2:  
Sc he d ule of A cti vities  .................................................................................................1 6  
Ta ble 3:  
A b bre viati o ns a n d S peci alist Ter ms  ...........................................................................2 6  
Ta ble  4:  
Sc he d ule of La b orat or y Assess me nts  .........................................................................5 3  
Ta ble  5:  
Cli nical Criteria f or Dia g n osi n g A na p h yl a xis  ............................................................5 6  
 


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2 5  of 1 0 9  
C o nfi de ntial  
LI S T O F FI G U R E S  
Fi g ure 1:  
St u d y Desi g n f or K P L -3 0 1 -C 2 0 3  ...............................................................................3 6  
 


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2 6  of 1 0 9  
C o nfi de ntial  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol.  
T a ble 3 : 
A b bre vi ati o ns a n d S peci alist  T er ms  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
2 0 1 9 -n C o V  
2 0 1 9 n o vel c or o na vir us  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
A L T  
Ala ni ne a mi n otra nsferase  
A R D S  
Ac ute res pirat or y distress s y n dr o me  
A S T  
As partate a mi n otra nsferase  
B A L  / B A L F 
B r o nc h oal ve olar la va ge / br o nc h oal ve olar la va ge fl ui d 
C F R  
C o de of Fe deral Re g ulati o ns  
C M H  
C oc hra n -Ma ntel -Hae nszel  
C O VI D -1 9  
C or o na Vir us Disease 2 0 1 9  
C R F  
Case re p ort f or m  
C R O  
C o ntract researc h or ga nizati o n  
C R P  
C -reacti ve pr otei n 
C R S  
C yt o ki ne release s y n dr o me 
C T  
C o m p uterize d t o m o gra p h y  
DI LI  
Dr u g -i n d uce d li ver i nj ur y 
D M C  
Data M o nit ori n g C o m mittee  
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  
Fi O 2 
Fracti o n of i ns pire d o x y ge n  
G M -C S F  
Gra n ul oc yte -macr o p ha ge c ol o n y -sti m ulati n g fact or 
I C H 
I nter nati o nal C o u ncil o n Har m o nisati o n 
I C U 
I nte nsi ve care u nit 
I E C 
I n de pe n de nt Et hics C o m mittee 
I F N-g  
I nterfer o n-ga m ma  
I g G 
I m m u n o gl o b uli n G 
I L 
I nterle u ki n 
I M V 
I n vasi ve mec ha nical ve ntilati o n 
I N D 
I n vesti gati o nal Ne w Dr u g A p plicati o n 


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2 7  of 1 0 9  
C o nfi de ntial  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
I R B 
I nstit uti o nal Re vie w B oar d 
I S A RI C 
I nter nati o nal Se vere Ac ute Res pirat or y a n d E mer gi n g 
I nfecti o n C o ns orti u m 
I T T 
I nte nt-t o-treat 
I U D 
I ntra uteri ne de vice 
I U S 
I ntra uteri ne h or m o ne-releasi n g s yste m 
I V 
I ntra ve n o us 
I W R S 
I nteracti ve we b -base d res p o nse s yste m  
L D H  
Lactate de h y dr o ge nase  
M E R S  
Mi d dle  East res pirat or y s y n dr o me  
mI T T  
M o difie d i nte nt -t o-treat 
M M F  
M yc o p he n olate m ofetil  
M O D S  
M ulti ple or ga n d ysf u ncti o n s y n dr o mes  
NI AI D  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases 
NI V  
N o n -i n vasi ve ve ntilati o n 
P a O 2 
P artial press ure of o x y ge n  
P C R  
P ol y merase c hai n reacti o n  
P K  
P har mac o ki netics  
R A  
R he u mat oi d art hritis  
R O  
Rece pt or occ u pa nc y  
S A D  
Si n gle -asce n di n g -d ose  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A R S -C o V -2  
Se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  
S D  
Sta n dar d de viati o n  
S O F A  / q S O F A 
Se q ue ntial Or ga n Fail ure Assess me nt  / q uic k S O F A 
S p O 2 
O x y ge 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  
T B  
T u berc ul osis  
T N F  
T u m or necr osis fact or  
U L N  
U p per li mit of n or mal  
U N S  
U nsc he d ule d site visit  
U S  
U nite d States  


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2 8  of 1 0 9  
C o nfi de ntial  
4.  
I N T R O D U C TI O N 
T he 2 0 1 9 n o vel c or o n a vir us ( 2 0 1 9 -n C o V; se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
[S A R S -C o V -2 ]) has s prea d ra pi dl y si nce its rece nt i de ntificati o n i n s u bjects wit h se vere 
p ne u m o nia i n W u ha n, C hi na a n d res ulte d i n a w orl d wi de cor o na v ir us d ise ase 2 0 1 9 ( C O VI D-1 9)  
pa n de mic . Gi ve n t he b ur de n of disease, effecti ve treat me nts are ur ge ntl y re q uire d. 
T he 2 0 1 9 -n C o V has affi nit y f or cells i n t he l o wer res pirat or y tr act a n d ca n re plicate t here, 
ca usi n g ra di ol o gical e vi de nce of l o wer res pirat or y tract lesi o ns i n s u bjects w h o d o n ot prese nt 
wit h cli nical p ne u m o nia. T here see m t o be t hree m aj or patter ns of t h e cli nical c o urse of 
i nfecti o n:  mil d ill ness wit h s y m pt o ms prese nti n g i n t he u p per res pirat or y tr act; n o n -life-
t hreate ni n g p ne u m o nia; a n d se vere p n e u m o nia wit h ac ute res pirat or y distress s y n dr o me ( A R D S) 
t hat be gi ns wit h mil d s y m pt o ms f or 7– 8 da ys a n d t he n pr o g resses t o ra pi d deteri orati o n a n d 
A R D S re q uiri n g a d va n ce d life s u p p ort.  
I n cli nical a n d e pi d e mi ol o gic al data fr o m t he C hi nese Ce nter f or Disease C o ntr ol a n d Pre ve nti o n 
re gar di n g 7 2, 3 1 4 case rec or ds pr o vi di n g a n i m p orta nt ill ustrati o n of t he e pi de mi ol o gic cur ve of 
t he C hi nese o ut brea k, t he o verall cas e-fatalit y rate ( o n c o nfir me d cases) was 2. 3 % (N o vel 
C or o na vir us P ne u m o nia E mer ge nc y Res p o ns e E pi de mi ol o g y Tea m , 2 0 2 0). Of n ote, t he fatal 
cases w ere pri maril y el derl y s u bjects, i n partic ular t h ose a ge d ≥ 8 0 years a n d 7 0 t o 7 9 years (case 
fatalit y rates of 1 4. 8 %  a n d 8. 0 % , res pecti vel y). A p pr o xi matel y h alf ( 4 9. 0 %) of t he critical 
s u bjects w h o were ofte n affecte d b y pree xisti n g c o m or bi dities s uc h as car di o vasc ular diseas e, 
dia betes, c hr o ni c res pir at or y dise ase, a n d o nc ol o gical diseases die d.  
I n o n e of t he first re p orts o n t he disease, H ua n g et al. ill ustrate d t hat s u bjects ( n =  4 1)  s uffere d 
fr o m fe ver, c o u g h, d ys p n ea , a n d m yal gia  or fati g u e  (H ua n g . C hest c o m p uterize d t o m o gra p h y 
( C T) sca ns s h o w e d p ne u m o nia wit h a b n or mal fi n di n gs i n all cas es. T he cli nical s pectr u m of 
C O VI D -1 9 varies fr o m as y m pt o matic or pa u ci -s y m pt o matic f or ms t o cli nical co n diti o ns 
c haracteriz e d b y res pirat or y fail ure t hat n ecessitat es mec ha nical ve ntilati o n a n d s u p p ort i n a n 
i nte nsi ve care u nit (I C U), t o m ulti-or ga n a n d s yste mic ma nifestati o ns i n ter ms of se psis, se ptic 
s h oc k, a n d m ulti ple or ga n d ysf u n cti o n s y n dr o m es ( M O D S). A b o ut a t hir d of s u bjects re q uir e d 
I C U care a n d 1 5 % of cases were fatal. Si milarl y, i n a m ore rece nt r e p ort of 2 0 1 h os pitalize d 
s u bjects, 4 1. 8 % de vel o pe d A R D S a n d 5 2. 4 % of t h ese s u bjects died  (W u Z , 2 0 2 0 ).  
T w o rece nt st u dies pr o vi de val ua ble i nsi g ht i nt o t he nat ural hist or y of h os pitalize d s u bjects wit h 
C O VI D -1 9. T he I nter n ati o nal Se vere Ac ute Res pir at or y a n d E mer gi n g I nfecti o n C o ns orti u m 
(I S A RI C) C O VI D-1 9 R e p ort  is u p date d re g ularl y. As of 2 7 A pril 2 0 2 0, the c o h ort c o nstit ute d 
1 9 , 4 6 3 i n di vi d uals wit h a me dia n a ge of 7 1 years  (ra n ge of 0-1 0 4 years)  fr o m ce nters 
pre d o mi na ntl y i n t he U nite d Ki n g d o m  (I S A RI C, 2 0 2 0). A m o n g s u bjects f or w h o m o utc o me data 
were a vaila ble  ( n =  1 1 ,8 7 3)  there w ere a t otal of 4 ,2 7 8  deat hs ( 1 9. 5 %). T he mea n n u m ber of 
da ys fr o m h os pital a d missi o n t o o utc o me ( deat h or disc har ge) was 8. 7 da ys ( sta n dar d de vi ati o n 
[S D ] =  8. 1 da ys) . A t otal of 3 ,7 5 2  s u bjects were a d mitte d i nt o a n I C U or hi g h de pe n de n c y u nit 
( H D U), a n d of t hese, 9 8 9  die d ( 2 6. 4 %) . A m o n g I C U/ H D U s u bjects f or w h o m o utc o me a n d 
treat me nt details were a v aila ble  ( n =  1 ,8 0 4) , 5 4. 1 %  recei ve d i n vasi ve mec ha nical ve ntilati o n 
(I M V). T h e ris k of deat h i ncreas e d wit h i ncreasi n g a ge. T he  me di a n le n gt h of sta y was 6 da ys.  
B y da y 1 5 f oll o wi n g a d missi o n, t he pr o p orti o n of s u bjects w h o die d, w h o were i n t he I C U, a n d 
w h o were disc har ge d le v ele d o ut, s u g gesti n g t hat t his ti me p oi nt is p ote ntiall y i m p orta nt f or 
deter mi ni n g t he p ossi ble t hera pe utic i m pact of a dr u g.  


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Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
2 9  of 1 0 9  
C o nfi de ntial  
T he sec o n d rece nt  st u d y e x a mi ne d t he use of pr ot ease i n hi bit ors l o pi na vir-rit o na vir i n a d ults 
h os pitaliz e d wit h se vere C O VI D -1 9 i n a  ra n d o mize d, c o ntr olle d, o pe n-la bel trial (Ca o  B, 2 0 2 0 ). 
S u bject s were ra n d o ml y assi g ne d i n a 1: 1 rati o t o recei v e eit her l o pi na vir– rit o na vir ( 4 0 0 m g a n d 
1 0 0 m g, res pecti vel y; n =  9 9) t wice a d a y f or 1 4 d a ys, i n a d diti o n t o sta n dar d care, or sta n d ar d 
care al o ne ( n  =  1 0 0). Treat me nt wit h l o pi na vir – rit o na vir was n ot ass oci ate d wit h a differe nce 
fr o m sta n dar d care i n t he ti me t o cli nical i m pr o ve me nt, w hic h was meas ured usi n g  a 7 -p oi nt 
or di nal scale. M ort alit y at 2 8 da ys w as si milar i n t he l o pi na vir – rit o na vir gr o u p a n d t he sta n dar d-
care gr o u p ( 1 9. 2 % vs. 2 5. 0 %). T he a ut h ors n ote d t hat t he o verall m ortalit y i n t he st u d y ( 2 2. 1 %) 
was hi g h er t ha n i n pr e vi o usl y p u blis he d st u d ies, i n dicati n g t hat t his s u bject p o p ulati o n ha d 
se vere dise ase u p o n a d missi o n.  
T he t w o af ore me nti o ne d st u dies pr o vi de val ua ble i nsi g ht i nt o t he cli nical pr o gressi o n of C O VI D -
1 9 a n d ha ve i nfl ue n ce d t he desi g n of st u d y K P L -3 0 1 -C 2 0 3. Alt h o u g h t he l o pi na vir -rit o na vir 
st u d y di d n ot s h o w a t hera pe utic be n efit f or t he treat me nt c o m pare d t o sta n dar d -care, t h e st u d y 
caref ull y e val uate d cli nic al i m pr o ve me nt usi n g a 7 -p oi nt scale at D a ys 7 a n d 1 4, a n d m ortalit y at 
Da y 2 8. T he m ortalit y rat e re p ort e d b y  I S A RI C was similar t o t he l o pi na vir-rit o na vir st u d y 
( 1 9. 5 % vs. 2 2. 1 %); h o w e ver, ma n y o utc o mes are u na vaila ble i n t he I S A RI C st u d y, a n d he n ce 
m ore deat hs are li kel y. T he me dia n a ge of t he l o pi na vir-rit o na vir st u d y was y o u n ger ( 5 8 vs. 7 1 
years), a n d t he perce nt a ge of mal es w as si milar ( 6 0. 0  vs. 5 6. 6 years)  t o de m o gra p hi cs o bser v e d 
i n t he I S A RI C p o p ulati o n. 
I n It al y, t he case-fatalit y rate has b ee n re p orte d at 7. 2 % (Li vi n gst o n L , 2 0 2 0). F urt her m ore, i n a n 
i nitial U nite d States ( U S ) e x perie nce of 2 1 criticall y ill s u bjects, 1 4  ha d die d at t he ti me of 
p u blicati o n, a n d o nl y 2 s ur vi ve d a n d tra nsferre d o ut of t he I C U, hi g hli g hti n g t he nee d f or 
effecti ve treat me nts bef ore s u bjects bec o me criticall y ill (Are ntz  M, 2 0 2 0 ).  
A m o n g t he s e vere cli nical ma nifestati o ns, t here are se vere p ne u m o nia a n d A R D S. Alt h o u g h t he 
cli nical c o urse of t he dise ase see ms t o pre dict a fa v ora ble tre n d i n t he m aj orit y of s u bjects, i n 
s o me cases, after a b o ut a wee k, t here is a s u d de n w orse ni n g of t heir cli nical c o n diti o ns wit h 
ra pi dl y w orse ni n g res pirat or y fail ure a n d M O DS . Criteria  f or defi niti o n of s pecific 
s u b p o p ulati o ns i ncl u de: 
•  Se vere P ne u m o nia. Fe ver ass ociate d wit h se v ere d ys p nea, res pir at or y distress, 
tac h y p nea, a n d h y p o xia . H o we ver, t he fe v er  s y m pt o m m ust be i nter prete d caref ull y as 
e ve n i n se vere f or ms of t he disease, t he t e m perat ure ma y be o nl y sli g htl y ele vate d, 
fe ver m a y als o be a bs e nt or c o nf o u n de d b y c o nc o mita nt a nti -p yretic use. I n t his 
defi niti o n, t he dia g n osis is cli nical, a n d ra di ol o gic i ma gi n g is use d f or e x cl u di n g 
c o m plicati o ns.  
•  A R D S. T his is a s y n dr o me of res pir at or y fail ure, s u g gesti ve of eit her : 
−  a seri o us ne w -o nset res pirat or y fail ure sec o n d ar y t o differe nt eti ol o g y 
( p ne u m o nia –  viral or b acterial, ac ute pa n creatitis, tra u ma, s u r ger y, etc.) or  
− w orse ni n g res pir at or y fail ure fr o m a pre vi o usl y i d e ntifie d eti ol o g y.  
•  T he dia g n osis re q uires ra di o gra p hi c a n d cli nical criteria  (Ra nieri V M, 2 0 1 2 ). Se verit y 
of A R D S is base d o n partial press ure of o x y ge n ( Pa O 2)/ Fi O2:  a rati o Pa O2/ Fi O2 
≤ 3 0 0 is s u g gesti ve of A R D S. Mil d A R D S: 2 0 0 < Pa O 2/ Fi O2 ≤ 3 0 0. I n n o n -ve ntilate d 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 0  of 1 0 9  
C o nfi de ntial  
s u bjects or i n t h ose ma na ge d t hr o u g h n o n-i n vasi ve ve ntilati o n ( NI V) b y usi n g 
p ositi ve e n d -e x pirat or y press ure  or a c o nti n u o us p ositi ve air wa y press ure  ≥ 5 c m H 2O.  
− M o derate A R D S: 1 0 0 < Pa O
2/ Fi O2 ≤ 2 0 0  
− Se vere A R D S: Pa O 2/ Fi O2 ≤ 1 0 0.  
•  Alter nati vel y, if Pa O 2 is u na vaila ble, a d eter mi nati o n of A R D S se verit y m a y be b ase d 
o n o x y ge n s at ura ti o n (S p O 2)/ Fi O2, w here b y a rati o S p O2/ Fi O2 ≤ 2 3 5  is s u g gesti ve of 
m o derate -s e vere A R D S  (Rice T W, 2 0 0 7 ). 
U nf ort u natel y, n o dr u g or vacci n e has yet b ee n a p pr o ve d t o treat h u ma n c or o na vir uses. Se veral 
o pti o ns ca n be e n visa ge d t o c o ntr ol or pre ve nt e mer gi n g i nfecti o ns of C O VI D -1 9 , i ncl u di n g 
va cci nes, m o n ocl o n al a nti b o dies, oli g o n ucle oti de -base d t hera pies, pe pti des, i nterfer o n a n d s mall -
m olec ules. Alt h o u g h t he p ote ntial re p ur p osi n g of e xisti n g a nti viral a ge nts t o treat C O VI D -1 9 is 
bei n g e val uate d i n cli nical trials, ne w i nter ve nti o ns base d o n dr u gs t hat are directl y acti ve o n t he 
vir us itself are li kel y t o r e q uire m o nt hs t o years t o de vel o p  (Cli nical Trials. g o v , 2 0 2 0 ). 
Acc u m ulati n g e vi de n ce s u g gests t hat a s u b gr o u p of s u bjects wit h se vere C O VI D-1 9 mi g ht ha ve 
a c yt o ki ne st or m s y n dr o me  (Me hta P, 2 0 2 0 ). T he i de ntificati o n a n d t reat m e nt of h y p er -
i nfla m mati o n usi n g e xisti n g t hera pies wit h u n derst o o d safet y pr ofiles is a rele va nt o pti o n t o 
a d dress t he i m me diate n ee d t o re d uce t he risi n g m ortalit y.  
I n t he s etti n g of pat h ol o gical fi n di n gs of p ul m o nar y e d e ma a n d h yali ne me m bra ne f or mati o n, 
ti mel y a n d a p pr o priate us e of dr u gs ai me d at re d u ci n g i nfla m mati o n t o get her wit h ve ntilat or 
s u p p ort s h o ul d be c o nsi dere d f or se vere s u bjects t o pre ve nt a n d treat A R D S. A c yt o ki ne pr ofile 
rese m bli n g s ec o n dar y he m o p ha g o c yti c l y m p h o histi oc yt osis is associate d wit h C O VI D -1 9 
disease se verit y, c haracterize d b y i ncrease d I L -2, I L -7, gra n ul oc yte -c ol o n y sti m ulati n g fact or, 
i nterfer o n-γ i n d uci ble pr otei n 1 0, m o n oc yte c he m oattracta nt pr otei n 1, macr o p ha ge 
i nfla m mat or y pr otei n 1-α, a n d t u m or necr osis fact or  ( T N F)-α. Pre dict ors of fatalit y fr o m rece nt 
st u dies i ncl u de d ele vate d ferriti n, C -reacti ve pr ot ei n (C R P ), D -di mer, a n d I L -6, s u g gesti n g t hat 
m ortalit y mi g ht be d u e t o virall y -dri ve n h y per -i nfl a m mati o n.  
I n h y p er-i nfl a m mati o n, i m m u n om o d ulat i o n is li kel y t o be be nefi cial. I n fact, i n a s u b gr o u p 
a nal ysis of a ra n d o mize d c o ntr olle d trial, s u bjects wit h se psis a n d or ga n d ysf u ncti o n or h y per-
i nfla m mati o n ha d i m pr o ve d s ur vi val wit h I L-1 rece pt or a nta g o nis m, a n d t his t hera p y has n ot 
bee n ass oci ate d wit h a d v erse e v e nts  ( A Es), e ve n at hi g h d oses (Fis her  CJ, 1 9 9 4 ). A m ultice nter, 
ra n d o mize d c o ntr olle d trial of t ociliz u ma b (I L-6 rece pt or bl oc ka d e, lice ns e d f or c yt o ki ne releas e 
s y n dr o me), has bee n a p pr o ve d i n C hi na i n s u bjects wit h C O VI D-1 9 p ne u m o nia a n d ele vate d 
I L-6 ; st u dies of saril u ma b i n C O VI D -1 9 are als o u n der wa y (X u  X,  2 0 2 0 ). 
I n t his st u d y, we ai m t o e nr oll s u bjects wit h se vere C O VI D -1 9 p ne u m o nia a n d h y per -
i nfla m mati o n t o e val uate t he cli nical effi cac y a n d safet y of a si n gle i ntr a ve n o us (I V) d ose of 
ma vrili m u ma b relati ve t o place b o t o re d u ce t he i n ci de nce of pr o gressi o n t o res pirat or y fail ure or 
deat h .  
St u d y K P L -3 0 1 -C 2 0 3 will assess ma vrili m u ma b 1 0  m g/ k g a n d 6  m g/ k g si n gle  I V i nf usi o n vs. 
place b o usi n g a variet y of para m eters at b aseli ne a n d at Da ys 1 -8, 1 5, 2 2, 2 9, 6 0 a n d 9 0 
f oll o wi n g d osi n g. T hese i ncl u de cli nical i m pr o ve m e nt b y t he Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Dise ases ( NI AI D) 8-p oi nt or di nal sc ale  (Cli nical Trials. g o v , 2 0 2 0), mec ha nical 
ve ntilati o n assess me nt, res pirat or y para meters, s ur vi val, c o nc o mita nt me di cati o ns, A Es , a n d 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 1  of 1 0 9  
C o nfi de ntial  
la b orat or y me as ures
). Ot her 
la b orat or y tests (ie, h e mat ol o g y, c oa g ul ati o n, c he mistr y, li ver pr ofile, p h ar mac o ki netics, a nti-
K P L a nti b o d y, 
 will be dra w n less fre q u e ntl y 
t hr o u g h o ut t he st u d y. T h e st u d y will e nr oll s u bjects wit h less-se vere dise as e (ie, n o n-v e ntilate d) 
a n d m ore-se v ere disease (ie, re q uiri n g mec ha nical ve ntilati o n). Ki ni ksa belie ves t hat t his 
a p pr oac h will all o w f or t he detecti o n of a p ote ntial t hera pe utic be n efit i n t he f ull ra n ge of 
se verit y of C O VI D-1 9 s u bjects wit h se vere p n e u m o nia a n d h y per -i nfla m mati o n. T he fre q ue n c y 
of assess me nt f oll o wi n g a d missi o n will all o w f or a nal ysis of s u bjects w h o are disc h ar ge d wit hi n 
t he first wee k a n d f or t h ose w h o re q uir e m ore pr ol o n ge d care. T he e xte nsi o n of p ost treat me nt 
f oll o w-u p u ntil 9 0 da ys p ost d ose acc o u nts f or d urati o n of Ma vrili m u ma b e x p os ure a n d a n 
a d diti o nal 3 0 -da y safet y wi n d o w. Ma vrili m u ma b 6 m g/ k g si n gle d os e I V i nf usi o n s h o we d 
e vi de nce of t hera pe utic b e nefit i n a n E x pa n de d Access Treat me nt Pr ot oc ol fr o m It al y; h o we ver, 
t his was n ot a ra n d o mize d, place b o-c o ntr olle d trial  (De L uca G, 2 0 2 0 ). I n a d diti o n, le nzil u ma b, 
a n a nti -g ra n ul o c yt e-ma cr o p ha ge c ol o n y -sti m ulati n g fact or (G M -C S F ) li ga n d m o n ocl o nal 
a nti b o d y de v el o pe d b y H u ma ni ge n s h o we d pr o misi n g res ults i n a n u nc o ntr olle d c o m passi o nate 
treat me nt pr ot oc ol at t he Ma y o cli nic  (H u ma ni ge n , 2 0 2 0). Of n ote, i n b ot h t he m a vrili m u ma b 
a n d le nzil u ma b treat me nt pr ot oc ols, a hi g h d o s e ai me d at ac hie vi n g l u n g distri b uti o n rat her t ha n 
o nl y peri p h eric bl oc k a ge of G M -C S F was us e d . T he st u d y d esi g n of K P L -3 0 1 -C 2 0 3 b uil ds o n 
t he e nc o ura gi n g res ults of t hese trials a n d utilizes t he data a n d e x perie nce fr o m I S A RI C a n d t h e 
l o pi na vir-rit o na vir st u dies t o esti mate place b o/sta n dar d of care o ut c o me rates .  
R ati o n ale f or m a v rili m u m a b  
G M -C S F is c o nsi dere d t o be a pr o-i nfl a m mat or y c yt o ki ne ass ociate d wit h tiss ue i nfla m mati o n 
t hat pr o m otes b ot h i n nate a n d a da pti ve i m m u ne res p o nses. G M -C S F dri ves t he  acti vati o n a n d 
differe ntiati o n of m acr o p ha ges  al o n g wit h t he acti vati o n of ne utr o p hils , de n dritic cells  a n d 
e osi n o p hils  (Ha milt o n J A, 2 0 0 8 ). G M -C S F rece pt or acti vati o n tri g gers sti m ulati o n of m ulti ple 
d o w nstrea m si g nali n g p at h wa ys, i n cl u di n g J a n us ki nase 2 (J A K 2)/si g nal tra ns d ucer a n d acti vat or 
of tra nscri pti o n 5 ( S T A T 5), t he mit o ge n -acti vate d pr otei n ki nase ( M A P K) pat h wa y, a n d t he 
p h os p h oi n ositi de 3 ki nase ( PI 3 K) p at h wa y, all rele va nt i n acti vati o n a n d differe ntiati o n of 
m yel oi d cells  (Ha milt o n J A, 2 0 0 2; S hi o mi A , 2 0 1 5). I n a d diti o n, G M -C S F ca n als o pr o m ote  
a nti ge n -pre s e ntati o n b y d e n dritic cells (Miller G, 2 0 0 2 ). G M -C S F -acti vate d macr o p ha ges a n d 
ot her m yel oi d cells pr o d uce reacti ve o x y ge n s pecies a n d pr oi nfla m mat or y c yt o ki nes, i ncl u di n g 
T N F , I L-1 β, I L -6, I L -2 3 a n d I L -1 2  (Ha milt o n  J A, 2 0 2 0 ). Ne u tr o p hil s ur vi val a n d f u ncti o n, 
i ncl u di n g t he i n d ucti o n of N E T osis (ie, ne utr o p hil cell deat h) , are als o  m o d ulate d b y G M -C S F  
(Sa ba S, 2 0 0 2 ; Castella ni S , 2 0 1 9 ; R o ot R K, 1 9 9 9 ). 
U n der p h ysi ol o gi c c o n diti o ns, le vels of circ ulati n g G M -C S F are l o w, b ut le vels are ele vate d i n 
i nfla m mat or y c o n diti o ns. Se veral c ell t y pes ca n ser ve as a s o urce of G M-C S F, i ncl u d i n g 
fi br o blasts, e n d ot helial c ells, m o n oc ytes/ macr o p ha ges, de n dritic cells, T cells, ne utr o p hils, 
e osi n o p hils  a n d ca ncer cells, wit h m ost pr o d ucti o n occ urri n g l ocall y at t he site of i nfla m mati o n  
(Ha milt o n J A, 2 0 0 2, R o ot R K, 1 9 9 9 ). A l ve olar macr o p ha ges a n d l u n g e pit h elial cells ha ve als o 
bee n s h o w n t o secrete G M-C S F i n mice (Tra p n ell  B C, 2 0 0 2 ; Ca kar o va  L , 2 0 0 9 , Ya ma m ot o K, 
2 0 1 5 ). T h is secreti o n of G M-C S F  e x acer bates t he i nfla m mat or y reacti o n via c yt o ki ne pat h w a ys 
t hat ha ve bee n ter me d t h e c ol o n y sti m ulati n g fact or net w or k. G M-C S F ca n be i n d uce d b y 
i nfla m mat or y c yt o ki nes a n d i n t ur n i ncreases pr o d ucti o n of ot her pr oi nfla m mat or y c yt o ki n es, 
t h us f u ncti o ni n g as a fee d-f or w ar d i nfla m mat or y a m plifier (X u  X, 2 0 2 0 ). 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 2  of 1 0 9  
C o nfi de ntial  
A rece nt st u d y re p orte d ele vate d le vels of G M -C S F i n t he l u n gs of s u bjects wit h C O VI D-1 9, 
s pecificall y s h o wi n g t hat after t he 2 0 1 9-n C o V i nfecti o n, C D 4 + T l y m p h o c yt es are ra pi dl y 
acti vate d t o bec o m e pat h o ge ni c T hel per ( T h) 1 cells a n d ge n erat e G M -C S F a n d ot her 
pr oi nfla m m at or y c yt o ki n e s (Z h o u  Y, 2 0 2 0 ). T h e c yt o ki ne e n vir o n m e nt i n d uces i nfla m mat or y 
C D 1 4 + C D 1 6 + m o n oc ytes wit h hi g h e x pressi o n of I L -6 a n d accelerates t he i nfla m mati o n. T he 
a ut h ors f urt her c o nte n d t hat t hese a berra nt a n d e x cessi ve i m m u ne cells ma y e nt er t he p ul m o nar y 
circ ulati o n i n h u ge n u m b ers a n d pla y a n i m m u ne -da ma gi n g r ole , ca usi n g l u n g f u ncti o nal 
disa bilit y a n d ra pi d m ort alit y. I ncrease d G M -C S F prese nce i n br o nc h io al v e olar la va ge fl ui d 
( B A L F) i n C O VI D -1 9 patie nts ma y a d diti o nall y pr o m ote  e n ha nce d ne utr o p hil s ur vi val a n d 
N E T osis , c o ntri b uti n g t o t he h y p eri nfla m mati o n o bser ve d i n se v ere p atie nts  (Mat ute -Bell o G, 
2 0 0 0; K o u pe n o va M , 2 0 2 0 ). M ore o ver, B A L F fr o m patie nts wit h se vere C O VI D -1 9 c o nt ai n 
si g nifica nt le v els of cir c ulati n g i nfla m mat or y m o n oc yt e-deri ve d macr o p ha ges a n d G M -C S F ma y 
dri ve t his i nfiltrati o n  (Lia o M , 2 0 2 0; La n g F M , 2 0 2 0). Ele vate d ser u m le vels of G M -C S F , I L 1, 
T N F  al o n g wit h a d diti o nal c yt o ki n es a n d c h e m o ki nes  ha ve rece ntl y bee n descri be d i n C O VI D -
1 9  patie nts as well. T he ele vate d le vels of G M -C S F i n t he l u n gs a n d cir c ulati o n of C O VI D-1 9 
patie nts al o n g wit h its plei otr o pic pr o -i nfla m mat or y effects s u g gest t hat tar geti n g G M-C S F t o 
treat se vere C O VI D-1 9 ma y re d uce h y peri nfl a m mat or y res p o nses.  I n d ee d, G M-C S F ser ves as a 
master re g ulat or of c yt o ki ne e x pressi o n a n d m yel oi d -me diate d h y peri nfl a m mati o n a n d t h us ma y 
m o d ulate se vere C O VI D -1 9  ass ociate d h y p eri nfla m mati o n m ore si g nifica ntl y t ha n si n gl e 
d o w nstrea m  c yt o ki ne tar geti n g a p pr oac h es  (La n g F M , 2 0 2 0). 
G M -C S F si g nals t hr o u g h G M -C S F -R, w hic h c o nsists of a s pecific li ga n d -bi n di n g α -c hai n ( G M 
C S F -R α) a n d a si g n al -tra ns d uci n g β-c hai n ( G M -C S F -R β) t hat is c o m m o n t o I L -3 a n d I L -5 
rece pt ors. He nce, G M-C S F -R si g nali n g ca n be s p ecificall y tar gete d wit h a nti b o dies directe d at 
G M -C S F -R α  (Z h o u  Y, 2 0 2 0 ).  
Ma vrili m u ma b is a n a nti -G M -C S F -R α m o n ocl o nal a nti b o d y ( h u ma n is of or m  i m m u n o gl o b uli n G 
[I g G] 4) pre vi o usl y de vel o pe d b y M e dI m m u ne a n d n o w i n de vel o p me nt b y Ki ni ksa 
P har mace uticals t hat ha s bee n s h o w n t o i n hi bit t he G M-C S F si g nali n g a xis i n h u ma ns a n d 
i m pr o ve cli nical o utc o mes meas ures i n a P has e 2 pr o gra m i n rhe u mat oi d art hritis ( R A) (Cr otti C,  
2 0 1 7 ). 
Rece nt data i n dicate t hat t he be nefit of si n gle c yt o ki ne bl oc ka de, e g, toci liz u ma b a n d saril u ma b, 
c o nferre d mar gi nal t o n o cli nical be nefit  (R oc h e Gr o u p , 2 0 2 0; Re ge ner o n , 2 0 2 0 ). A n u pstrea m 
bl oc ka de of pr o d ucti o n a n d pr oliferati o n of i nf la m mat or y cells, e g, a nti-G M -C S F bl oc ka de,  still 
re mai ns a rele va nt mec ha nis m. At least t w o a nti-G M -C S F a ge nts i n de vel o p me nt, ma vrili m u ma b 
a n d le nzi l u ma b, ha ve s h o w n preli mi nar y cli nical b e nefit . 
R ati o n ale f or D ose a n d R o ute of A d mi nistr ati o n  
T he d ose rati o nal e, a n d b y e xte nsi o n t he I V r o ute of a d mi nistrati o n f or C O VI D -1 9 s u bjects , is 
base d o n a c o m bi nati o n of data fr o m pri or safet y a n d efficac y e v al uati o n of si n gle a n d m ulti ple 
d oses i n R A patie nts , t he assessme nt of m a vrili m u ma b l u n g distri b uti o n a n d p har mac o d y n a mic 
effects i n mice , a n d res ults fr o m t he P hase 2 p orti o n (C o h ort 1) of st u d y K P L -3 0 1 -C 2 0 3 .  
I n a P h ase 1 si n gle-asce n di n g -d ose ( S A D) st u d y , t he p har mac o ki n etics ( P K) of ma vrili m u ma b 
were test e d at I V d os es of 0. 0 1 -1 0 m g/ k g i n s u bjects wit h mild -t o-m o derate R A. Ma vrili m u ma b 
was well t olerat e d at all d ose le vels (B ur mester  G R, 2 0 1 1 ). P har mac o ki netic a n d 
p har mac o d y n a mic si m ulati o ns fr o m st u dies i n s u bjects wit h R A , c o u ple d wit h t he P K data f r om 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 3  of 1 0 9  
C o nfi de ntial  
t he P hase 1 st u d y, i n dicate t hat a si n gl e d ose of ≥3 m g/ k g will pr o vi de E C9 0 (t he c o nce ntrati o n 
t hat lea ds t o 9 0 % ma xi mal res p o nse) f or t he R A e n d p oi nt A C R 5 0 ( A merica n C olle ge of 
R he u mat ol o g y 5 0 % res p o nse criteria; d ata o n file) f or u p t o 2 2 da ys. T h eref ore, at d oses ≥3 
m g/ k g  I V, t he p h ar mac ol o gic pr ofiles i n dicate d s ustaine d peri p heral i n hi biti o n  of t he G M -C S F -
R α si g nali n g a xis f or at least t hree wee ks. I n t he C O VI D-1 9 e x pa n de d access  pr ot oc ol c o n d ucte d  
i n Ital y, a si n gle-d ose I V i nf usi o n of 6 m g/ k g ma vrili m u ma b was well -t olerate d i n 1 3 n o n -
ve ntilate d C O VI D -1 9 s u bjects. T here di d n ot a p p ear t o be a n y a d verse safet y si g nal o n 
la b orat or y me as ures ( e g, li ver f u ncti o n tests) or A Es of s pecial i nterest .   
I n precli nic al st u dies, t he p ote ntial s yste mic effects of ma vrili m u ma b ha ve bee n i n vesti gate d i n 
a 4-wee k a n d a n 1 1 -wee k re peat -d ose c y n o m ol g us m o n ke y st u d y. T here were n o effects 
attri b uta ble t o I V a d mi nistrati o n of ma vrili m u ma b i n d oses u p t o 1 0 0 m g/ k g/ wee k f or 4 wee ks i n 
a st u d y c o n d ucte d i n acc or da nce wit h G o o d La b orat or y Practice ( G L P). I n a n 1 1-wee k 
e x pl orat or y ( n o n -G L P) st u d y t here were n o effects attri b uta ble t o I V a d mi nistrati o n of 
ma vrili m u ma b f oll o wi n g 1 0 m g/ k g/ wee k, a n d t he n o o bser ve d A E  l e vel was 1 0 0 m g/ k g/ wee k. 
A n  i m m u n oc yt oc h e mistr y scree n t o test i n vitr o bi n di n g of ma vrili m u ma b t o a pa nel of n or mal 
h u ma n tiss ues re veal e d n o n o n -s pecific or u na ntici pate d bi n di n g of t he a nti b o d y. F urt her details 
o n safet y st u dies i n a ni mals a n d h u ma ns are pr o vi de d i n t he I n vesti gat or’s Br oc h ure.  
T he effic ac y a n d s af et y res ults fr o m t he K P L -3 0 1 -C 2 0 3, P h ase 2 C o h ort 1  s u bjects, s u p p ort 
use of b ot h d oses of ma vrili m u ma b i n t he o n g oi n g P hase 3 st u d y.  W hile ge nerall y t here are n o 
a p pare nt differe nces bet wee n t he t w o ma vrili m u ma b ar ms f or  efficac y a n d safet y, gi ve n t he 
s mall n u m ber of pri mar y e ve nts of ve ntilati o n a n d/ or deat h a n al yze d t o dat e, t here are s o me 
di ffere n ces b et wee n t h e t w o d oses i n m ortalit y ( 1 0 m g/ k g is n u mericall y efficaci o us ) or 
ve ntilati o n -free s ur vi val ( 6 m g/ k g is n u me ricall y m ore effi caci o us). O verall, b ot h t he 1 0 m g/ k g 
a n d t he 6 m g/ k g a p pear well -t olerate d wit h n o ne w i de ntifie d safet y ris ks i n t he C O VI D-1 9 st u d y 
p o p ulati o n.  I n fact, seri o us i nfecti o ns (e. g., se ptic s h oc k, se psis ) were  s u bsta ntiall y l o wer i n b ot h  
ma vrili m u ma b  d ose a r ms c o m pare d t o place b o, a n d t hr o m b osis e ve nts were o nl y re p orte d i n t he 
place b o ar m.  T here were n o seri o us a d verse e v e nts relate d t o ma vrili m u ma b , n o d ose -relat e d 
a d verse e ve nts  a n d n o i nf usi o n reacti o ns.  
Im p ort a nt p ote ntial ris ks f or ma vrili m u ma b  will c o nti n ue t o be m o nit ore d. T hese  i ncl u de se v ere 
h y perse nsiti vit y reacti o ns, i m m u ne c o m ple x disease, seri o us i nfecti o ns ( viral, bacteri al, a n d 
o p p ort u nistic i nfecti o ns), mali g na n c y, vacci ne i nteracti o ns, p ul m o nar y al ve olar pr otei n osis, 
re pro d ucti ve t o xicit y a n d gra n ul oc ytic effects, i ncl u di n g ne utr o p e nia . Of n ote, t here is n o 
bi ol o gical r ati o nale f or s e veral of t hese p ote ntial ris ks i n t he setti n g of a si n gle d ose 
a d mi nistrati o n. M ore i m p orta ntl y , no ne of t hese p ote ntial ris ks ha ve bee n i de n tifie d i n t he R A 
de vel o p me nt pr o gra m t hr o u g h P hase 2 b wit h a p pr o xi matel y 9 0 0 s u bject-years of e x p os ure.  See 
I n v esti gat or’s Br oc h ure for a d diti o nal details . 
T his cli nical st u d y was d esi g ne d a n d s hall be i m pl e me nte d, e x ec ute d , a n d re p orte d i n acc or da nce 
wit h t he IC H Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble l ocal re g ulati o ns , 
U S  C o de of Fe d eral Re g ulati o ns ( C F R ) 2 1, a n d wit h t he et hical pri nci ples lai d d o w n i n t he 
Declarati o n of Helsi n ki . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 4  of 1 0 9  
C o nfi de ntial  
5.  
T RI A L O B J E C TI V E S A N D P U R P O S E  
5. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bje cti ve of t his st u d y is t o e val u ate t he cli nical efficac y of a si n gle I V d ose of 
ma vrili m u ma b relati ve t o place b o i n a d ult s u bjects h os pitalize d wit h se vere C O VI D -1 9 
p ne u m o nia a n d h y per -i nfla m mati o n t o re d uce pr o gressi o n t o res pirat or y fail ure or deat h.  
5. 2.  
Sec o n d ar y O bjecti ve s 
T he sec o n d ar y o bjecti ve s of t his st u d y are t o assess t he i m pact of treat me nt o n cli nical stat us , 
m ortalit y , a n d safet y of a si n gle I V d os e of ma vrili m u ma b ( 1 0 m g/ k g or 6 m g/ k g) relati ve t o 
place b o i n a d ult s u bjects h os pitaliz e d wit h se vere C O VI D -1 9 p ne u m o nia a n d h y per -
i nfla m mati o n. 
5. 3.  
Ot her  O bjecti ve  
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 5  of 1 0 9  
C o nfi de ntial  
6.  
I N V E S TI G A TI O N A L P L A N 
6. 1.  
O ver all St u d y Desi g n  
T his is a pr os pecti ve, P hase 2/ 3 , i nter ve nti o nal, r a n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d 
st u d y desi g ne d t o e v al uat e t he efficac y a n d safet y of ma vrili m u ma b  ( K P L-3 0 1) treat me nt i n 
a d ult s u bjects h os pitalize d wit h se vere C O VI D -1 9 p ne u m o nia a n d h y per -i nfla m mati o n.  
A p pr o xi matel y 8 3 6 s u bj ects, di vi de d i nt o 2 c o h orts, will be e nr olle d a n d  ra n d o mize d i n a 1: 1: 1 
all ocati o n rati o t o recei ve a si n gle I V inf usi o n of ma vrili m u ma b ( 1 0 m g/ k g or 6 m g/ k g ) or 
place b o  i n a d diti o n t o sta n dar d of care as per i nstit uti o nal pr ot oc ol a n d at t he discreti o n of t he 
i n vesti gat or ( pr o vi de d t h at t he me dicati o n/t hera p y is n ot e x plicitl y pr o hi bite d per pr ot o c ol). 
C o h ort 1 will  i ncl u de n o n-mec ha nic all y v e ntilate d  h os pitalize d s u bjects w h o re q uire 
s u p ple me ntal o x y ge n t o mai ntai n S p O 2 ≥ 9 2 % , ie, “ n o n-ve ntilate d” s u bj ects . C o h ort 2 will 
i ncl u de h os pitaliz e d s u bjects f or w h o m mec ha nical ve ntilati o n was rece ntl y i nitiate d (wit hi n 4 8 
h o urs pri or t o ra n d o mizati on ), ie, “ ve ntilate d” s u bj ects). T he i nitial P hase 2 part of t he st u d y will 
e nr oll a p pr o xi matel y 1 7 1  s u bjects, a n d t he P hase 3 part will e nr oll a p pr o xi matel y 6 6 5  s u bjects. 
T here will be a sea mless tra nsiti o n i n e nr oll me nt of s u bjects i n b ot h c o h orts bet wee n t he P has e 2 
a n d P hase 3 p orti o n s of t he st u d y. F or eac h c o h ort, o nce t he last s u bject i n P hase 2  is e nr olle d, all 
s u bse q ue nt s u bjects will be c o nsi dere d P hase 3 s u bjects. T his will all o w f or c o nti n ue d 
e nr oll me nt d uri n g t h e  a n al ysis of t he P has e 2 c o h ort-s pecific d ata.  O n ce t h e last s u bject i n P hase 
2 c o m pletes Da y 2 9 , pri mar y effi cac y a n d safet y a nal ys es of t he P has e 2 d ata will be c o n d uct e d 
b y t he S p o ns or . F oll o wi n g de m o n str ati o n of effi cac y a n d safet y i n P hase 2, t he P hase 3 p orti o n  
of t he st u d y will be c o nti n ue d/c o m plete d. Base d o n re vie w of t h e P hase 2 C o h ort 2 res ults of t he 
pri mar y a n d sec o n dar y e n d p oi nts at da y 2 9 , P hase 3 C o h ort 2 is cl ose d t o f urt her e nr oll me nt , as 
t here was n o e vi de nce t h at ma vrili m u ma b  pr o vi de d cli nical be nefit o ver place b o i n rece ntl y 
ve ntilate d patie nts.  
T he pri mar y e n d p oi nt  i n b ot h c o h orts will be assesse d f or b ot h  t he P hase 2 a n d P hase 3  parts of 
t he st u d y usi n g t he NI AI D scale f or cli nical im pr o ve me nt . S u bject cli nical stat us will be assess e d 
dail y  us i n g this 8 -p oi nt or di nal scale :  
1.  De at h;  
2.  H os pit alize d, o n i nv asive mec h a nic al ve ntil ati o n or extr ac or p ore al me m br a ne 
oxy ge n ati o n ( E C M O);  
3.  H os pit alize d, o n n o n -i nv asive ve ntil ati o n or hi g h fl o w oxy ge n devices;  
4.  H os pit alize d, re q uiri n g s u p ple me nt al oxy g e n;  
5.  H os pit alize d, n ot re q uiri n g s u p ple me nt al oxy ge n –  re q uiri n g o n g oi n g me dic al c are 
( C O VI D-1 9 rel ate d or ot her wise);  
6.  H os pit alize d, n ot re q ui ri n g s u p ple me nt al oxy ge n –  n o l o n ger re q uires o n g oi n g me dic al 
c are;  
7.  N ot h os pit alize d, li mit ati o n o n activities a n d/ or re q uiri n g h o me oxy ge n;  
8.  N ot h os pit alize d, n o li mit ati o ns o n activities.  


ma vrili m u ma b ( K P L -3 0 1)  
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Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 6  of 1 0 9  
C o nfi de ntial  
Scree ni n g acti vities will be perf or me d u p t o 3 da ys pri or t o ra nd o mizati o n  ( Da y 1). T he st u d y 
f oll o w-u p peri o d will c o ncl u de o n st u d y Da y 2 9, a n d s u bjects will be f oll o we d f or A E s/seri o us 
A Es ( S A Es ), c o nc o mita nt me dicati o ns, m ortalit y , a n d cli nical i m pr o veme nt  ( NI AI D scale) 
t hr o u g h st u d y Da y 9 0 (Fi g ure 1 ). T he S c he d ule of A cti vities is prese nte d i n Ta ble  2 . 
Fi g ure 1 : 
St u d y Desi g n f or K P L -3 0 1 -C 2 0 3  
 
A Safet y Re vie w C o m mittee ( S R C) i ncl u di n g 2 p h ysicia ns fr o m t he S p o ns or, 1 p h ysici a n fr o m 
t he S p o ns or’s c o ntract researc h or ga nizati o n ( C R O), a n d 1  i n de pe n de nt p h ysicia n  w h o is a n  
e x pert i n critical care me dici ne, p ul m o nar y  dis or d ers, i nfecti o us diseas es a n d/ or C O VI D -1 9 
treat me nt (S R C C hair pers o n) will meet peri o dicall y t o re vie w A E s/ S A Es, reaso ns f or st u d y 
disc o nti n uati o ns, a n d ke y cli nical a n d la b orat or y assess me nts. S R C acti vities will be g ui de d b y 
a n S R C C harter . T he i nitial S R C meeti n g will be tri g gere d o n ce t he i nitial 4 s u bjects ha ve 
c o m plete d Da y 8. S R C me m bers will be bli n de d t o s u bject treat me nt assi g n me nt.  
A Data M o nit ori n g C o m mittee ( D M C) has bee n  esta blis he d b y t he S p o ns or  t o c o n d uct peri o dic 
re vie ws a n d m a y meet m ore fre q ue ntl y as nee de d  t o re vie w u n bli n de d safet y dat a fr o m t he P hase 
2 a n d 3  p orti o ns of t he st u d y . T he i nitial meeti n g will be tri g gere d at 1 m o nt h after t he first 
s u bject is e nr olle d. T he D M C  c harter will detail t he c o m p ositi o n, r oles a n d res p o nsi bilities a n d 
a nal ysis pla n f or t he D M C ’s acti vities. 
T he st u d y ma y b e ter mi n ate d if u ne x pecte d, si g nifica nt, or u nacce pta bl e safet y ris ks t o e nr olle d 
s u bjects arise, or if rec o m me n de d b y a p plica ble b oar d(s) after re vie w of safet y data.  
6. 2.  
N u m ber of S u bjects  ( pl a n ne d) 
A t otal of a p pr o xi matel y 8 3 6  s u bjects will be e nr olle d i n t his st u d y. A p pr o xi matel y 1 7 1  s u bjects 
will be ra n d o mize d t o t he P hase 2 part, a n d a p pr o xi matel y  6 6 5  s u bjects will be ra n d o mize d t o 
t he P hase 3 part.  
I n P has e 2: 
C o h ort 1: A p pr o xi matel y 1 2 0  n o n -ve ntilate d s u bjects, a n d  
C o h ort 2: A p pr o xi matel y 5 1  ve ntilate d s u bjects  
I n P has e 3: 
C o h ort 1: A p pr o xi matel y 6 0 0  n o n -ve ntilate d s u bjects, a n d  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 7  of 1 0 9  
C o nfi de ntial  
C o h ort 2: A p pr o xi matel y 1 1 7  ve ntilate d s u bjects  (a p pr o xi matel y 6 5 s u bjects at ti me of 
e nr oll me nt cl os ure)  
6. 3.  
Tre at me nt Assi g n me nt  
Acr oss t he t w o st u d y parts ( P hase 2 a n d P hase 3), a p pr o xi matel y  8 3 6  s u bjects will be 
ra n d o mize d i n a 1: 1: 1 all ocati o n rati o t o recei ve a ma vrili m u ma b  ( 1 0 m g/ k g or 6  m g/ k g) or 
place b o. N o s u bject will recei v e m ore t ha n o ne d ose.   
Details re gar di n g ra n d o miz ati o n  t o treat me nt are pr o vi de d i n Secti o n  8. 4. 1 . 
6. 4.  
D ose A dj ust me nt Criteri a  
Ma vrili m u ma b  will be a d mi nistere d as a si n gle I V  i nf usi o n o ver 6 0 mi n utes. N o d ose 
a dj ust me nts are pla n ne d .  
6. 4. 1.  
S afet y Criteri a f or A dj ust me nt or St o p pi n g D oses  
At a n y t i me d uri n g t he i nf usi o n of st u d y dr u g , sh o ul d a m o derate reacti o n occ ur, t he i nf usi o n will 
be st o p pe d f or a peri o d of at least 3 0 mi n utes a n d restarte d at t he In vesti gat or’s discreti o n  o nl y  
after t he e ve nts ha v e res ol ve d.  T he i nf usi o n rate s h o ul d be re -starte d at a rat e t olerate d b y t he 
s u bject. I nf usi o ns m ust be c o m plete d wit hi n 4 h o urs of st u d y dr u g pre p arati o n (see P har m ac y 
Ma n ual f or m or e details). S h o ul d a se vere reacti o n occ ur, t he i nf usi o n will be st o p pe d 
per ma ne ntl y. Se verit y of i nf usi o n reacti o ns a re t o be deter mi ne d b y t he I n v esti gat or. N o d ose 
a dj ust me nts  are pla n ne d . A d diti o nal details re gar di n g st u d y dr u g d osi n g are pr o vi de d i n 
Secti o n  9. 5 . 
6. 5.  
Criteri a f or St u d y Ter mi n ati o n  
T he st u d y ma y b e ter mi n ate d or te m p or aril y s us p e n de d i n w h ole or i n part  b y t he S p o ns or at a n y 
ti me. Reas o ns f or s uc h acti o n i ncl u de: 
•  U ne x pecte d, si g nifi ca nt, o r u nacce pta ble s afet y ris k t o s u bjects e nr olle d i n t he st u d y 
•  Decisi o n base d o n rec o m me n dati o ns fr o m a p plica ble b oar d(s) after re vie w of safet y 
a n d/ or effi cac y d ata  
•  Disc o nti n uati o n of t he st u d y dr u g d e vel o p me nt pr o gra m b y t h e S p o ns or  
T he I n vesti gat or ma y b e  i nf or me d of a d diti o nal pr oce d ures t o b e f oll o we d i n or der t o e ns ure t hat 
a de q uate c o nsi derati o n is gi ve n t o t he pr ot ecti o n of t he s u bject’s i nterests. T he I n vesti gat or or 
S p o ns or, de pe n di n g o n t h e l ocal re g ul ati o n, will be res p o nsi ble f or i nf or mi n g t he I nstit uti o nal 
Re vie w B o ar d ( I R B) of t he earl y ter mi nati o n of t he trial.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 8  of 1 0 9  
C o nfi de ntial  
7.  
S E L E C TI O N C RI T E RI A A N D WI T H D R A W A L O F S U B J E C T S  
7. 1.  
S u bject I ncl usi o n Criteri a  
S u bjects m ust meet all t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i n t he st u d y.  
1.  S u bject ( or le gall y a ut h oriz e d re prese ntati ve) is a ble a n d willi n g t o pr o vi de i nf or me d 
c o nse nt, w hic h i ncl u des c o m plia nce wit h st u d y re q uire me nts a n d restri cti o ns liste d i n t he 
c o nse nt f or m. C o nse nt m ust be perf or m e d per i nstit uti o nal re g ulati o ns . 
2.  A ge of ≥ 1 8 years  
3.  P o siti ve S A R S-C o V -2 ( 2 0 1 9 -n C o V) test  wit hi n 1 4 da ys pri or t o ra n d o mizati o n  
4.  H os pitalize d f or S A R S-C o V -2 ( 2 0 1 9 -n C o V)  
5.  Bilateral p ne u m o nia o n c hest x -ra y or C T 
6.  [ Ori gi n al Criteri a Delete d] 
7.  A t least o ne of t he f oll o wi n g, wit hi n 7 da ys pri or t o ra n d o mizati o n:  
•  F erriti n > 5 0 0 n g/ m L  
•  C R P >  5 m g/ d L  
•  D -di mer > 1, 0 0 0 n g/ m L  
•  L D H > 2 5 0 U/ L  
•  Fe ver  - a m eas ur e d te m p erat ur e of at least 1 0 0. 4° F [ 3 8° C]  
8.  F or C o h ort 1:  Recei vi n g a n y f or m of n o n -i n v asi ve ve ntilati o n O R o x y ge n ati o n t o 
mai ntai n S p O 2 ≥ 9 2 % a n d n o n -mec ha nicall y v e ntilate d  (e x a m ples i ncl u de nasal ca n n ula, 
face m as k, ve nt uri mas k, hi g h-fl o w n asal ca n n ula, a n d NI V or n o n-i n vasi ve p ositi ve 
press ure v e ntilati o n)  
9.  F or C o h ort 2:  Rece ntl y ve ntilate d wit h mec ha nical ve ntilati o n be gi n ni n g wit hi n 4 8 h o urs 
pri or t o ra n d o miza ti o n 
1 0.  Fe male s u bjects m ust be:  
•  p ost me n o pa usal, defi ne d as at least 1 2 m o nt hs p ost cessati o n of me nses ( wit h o ut a n 
alter nati ve me dical ca us e), or  
•  per ma ne ntl y sterile f oll o wi n g d oc u m e nte d h ysterect o m y, bilateral sal pi n gect o m y, 
bilateral o o p h orect o m y, or t u b al li gati o n or h a vi n g a m ale part n er wit h vas ect o m y as 
affir me d b y t he s u bj ect, or  
•  n o n pre g na nt, n o nlact ati n g, a n d if s e x uall y acti ve ha vi n g a gree d t o use a hi g hl y 
effecti ve met h o d of c o ntrace pti o n (ie, h or m o nal c o ntrace pti ves ass ociate d wit h 
i n hi biti o n of o v ulati o n or i ntra uteri ne de vice [I U D], or i ntra uteri ne h or m o n e -rel easi n g 
s yste m [I U S], or se x ual a bsti ne nce) fr o m Scree ni n g Visit u ntil Da y 9 0.   
1 1.  Male s u bjects m ust ha ve d oc u me nte d vasect o m y or if se x uall y acti ve m ust a gree t o us e a 
hi g hl y effecti ve m et h o d of c o ntrace pti o n wit h t heir part ners of c hil d beari n g p ote ntial (ie, 
h or m o nal c o ntrace pti ves ass ociate d wit h t he i n hi biti o n of o v ulati o n or I U D, or I U S, or 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
3 9  of 1 0 9  
C o nfi de ntial  
se x ual a bsti ne nce) fr o m Scree ni n g u ntil Da y 9 0. Male s u bjects m ust a gree t o refrai n fr o m 
d o nati n g s per m d uri n g t his ti me peri o d. 
7. 2.  
S u bject E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g e x cl usi o n criteria will n ot be eli gi ble f or st u d y 
e nr oll me nt.  
Ge ner al Ex cl usi o n Criteri a  
1.  O nset of C O VI D -1 9 s y m pt o ms > 1 4 da ys pri or t o ra n d o mizati o n  
2.  H os pitaliz e d > 7 da ys pri or t o ra n d o mizati o n  
3.  [ F or C o h ort 1 o nl y] N ee d f or i n vasi ve mec h a nical ve ntilati o n 
4.  Nee d f or E C M O  
5.  Seri o us pri or or c o n c o mita nt ill ness t hat i n t he o pi ni o n of t he I n vesti gat or precl u des t he 
s u bject fr o m e nr olli n g i n t he trial, i ncl u di n g ( b ut n ot li mite d t o): 
•  Hist or y of p ul m o nar y al v e olar pr otei n osis  
•  Se vere a n d u n c o ntr olle d p ul m o nar y dise ase ot her t ha n C O VI D -1 9 p n e u m o nia (e g, 
ast h ma, c hr o nic o bstr ucti ve p ul m o nar y disease, or ot hers)  
•  Pre -e xisti n g ( pri or t o de v el o p me nt of C O VI D -1 9) se vere l eft ve ntric ular s yst olic 
d ysf u n cti o n (ie, left ve ntric ular ejecti o n fracti o n < 3 5 %)  
•  He m o d y n a mic i nsta bilit y wit h press or re q uir e me nts of n ore pi ne p hri ne at a d ose of 
>  0. 5 mc g/ k g/ mi n or e q ui vale nt (t otal if m ulti ple press ors use d) f or m ore t h a n 
1 2  h o urs c o nti n u o usl y, m y o car dial i nfarcti o n, str o ke, a n d car di o ge nic  s e ptic s h oc k 
wit hi n 3 0 da ys pri or t o r a n d o mizati o n  
•  K n o w n acti ve t u berc ul osis ( T B) deter mi ne d b y hist or y a n d l o cal sta n dar d of care, or 
hist or y of i nc o m pletel y tr eate d T B or at hi g h ris k f or late nt T B (e x p os ure or pri or 
i ncarcerati o n) 
o  If t u berc ul osis testi n g is r e q uire d per l ocal r e g ulati o ns, o ne p ositi ve ( or t w o 
i n deter mi nate) i nterfer o n ga m ma release ass a y test res ults or o ne p ositi ve 
p ol y merase c h ai n reacti o n  test is e x cl usi o nar y 
•  C o nc o mita nt u nc o ntr oll e d s yste mic bacterial or f u n gal i nfecti o n  
•  C o nc o mita nt res pirat or y viral i nfecti o n ot her t ha n C O VI D -1 9 a n d i nfl u e nza  t hat, i n 
t he o pi ni o n of t he I n vesti gat or, re prese nts a hi g her m ortalit y ris k (e g, S A R S, Mi d dle 
East res pirat or y s y n dr o me  [M E R S ]) 
6.  Rece nt trea t me nt wit h cell-de pleti n g bi ol o gical t h era pies (e g, a nti -C D 2 0) wit hi n 1 2 
m o nt hs, n o n -cell-de pleti n g bi ol o gical t hera pies (s uc h as a nti -t u m or necr osis fact or 
[ T N F], a na ki nra, a nti-I L-6 rece pt or [e g, t ociliz u ma b], or a batace pt) wit hi n 8 wee ks ( or 5 
half -li ves, w hic he v er is l o n ger), treat me nt wit h al k ylati n g a ge nts wit hi n 1 2 wee ks, 
treat me nt wit h c ycl os p ori ne A, azat hi o pri ne, c ycl o p h os p ha mi de, m yc o p h e n olate m ofetil 
( M M F), or ot h er i m m u n os u p pressa nt (e x ce pt f or c ortic oster oi ds) wit hi n 4 wee ks pri or t o 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 0  of 1 0 9  
C o nfi de ntial  
ra n d o mizati o n. Me dicati o ns t hat bec o me sta n dar d of care f or C O VI D -1 9 a n d/ or recei ve 
e mer ge n c y use a ut h orizati o n ma y be all o we d after disc ussi o n wit h t he me dical m o nit or.  
7.  [ Ori gi n al Criteri a Delete d] 
8.  If s u bject is recei vi n g or has recei ve d h y dr o x yc hl or o q ui ne wit hi n 3 m o nt hs pri or t o 
ra n d o mizati o n, a c orrecte d Q T i nter val b y Fri dericia ’s met h o d ( Q Tc F) o n S cree ni n g 
electr ocar di o gra m ( E C G ) of ≥ 5 0 0 ms is e x cl usi o nar y. If s u bject has a p ace ma ker, t his 
criteri o n d oes n ot a p pl y. 
9.  [ Ori gi n al Criteri a Delete d] 
1 0.  E nr olle d i n a n ot her i n vesti gati o nal st u d y of a me di cal i nter ve nti o n wit hi n 3 0 da ys pri or t o 
ra n d o mizati o n. Partici pati o n i n o pe n la bel trials i n v ol vi n g i n vesti gati o nal treat me nts f or 
C O VI D -1 9 ma y b e all o w e d u p o n a p pr o val b y t he S p o ns or.  
1 1.  K n o w n h y p erse nsiti vit y t o ma vrili m u ma b or a n y of its e xci pie nts  
1 2.  I n t he o pi ni o n of t h e I n vesti gat or, u na bl e t o c o m pl y wit h t he re q uire me nts t o partici pate 
i n t he st u d y 
1 3.  [ Ori gi n al Criteri a Delete d] 
1 4.  [ Ori gi n al Criteri a Delete d] 
1 5.  At Scree ni n g bl o o d tests, a n y of t he f oll o wi n g:  
•  As partate tra nsa mi nase ( A S T) > 1 0 × u p per li mit of n or mal ( U L N ) 
•  Ala ni ne tra nsa mi nas e ( A L T) > 1 0 × U L N  
•  He m o gl o bi n < 7. 5 g/ d L  
•  Ne utr o p hils < 1, 5 0 0/ m m 3 
•  A bs ol ute platelet c o u nt < 5 0, 0 0 0/ m m 3 
•  Creati ni ne cleara n ce  < 3 0 m L/ mi n ( b y C oc kcr oft -Ga ult f or m ula)  (C oc k cr oft  D W , 
1 9 7 6)   
1 6.  Lif e e x pecta nc y less t h a n 4 8 h o urs, i n t he o pi ni o n of t he In vesti gat or  
1 7.  K n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n (re gar dless of i m m u n ol o gical stat us), 
k n o w n he patitis B vir us s urface a nti ge n p ositi vit y a n d/ or a nti -he p atitis C vir us p ositi vit y  
7. 3.  
Wit h dr a w al of S u bjects  
7. 3. 1.  
Tre at me nt St o p pi n g Criteri a  
S h o ul d a m o derate reacti o n occ ur d uri n g i n f usi o n of t he st u d y dr u g, t he i nf usi o n will be st o p pe d 
a n d restart e d at t he In v esti gat or’s discreti o n aft er t he e ve nts ha v e res ol ve d. S h o ul d a se vere 
reacti o n occ ur, t he i nf usi o n will be per ma ne ntl y disc o nti n ue d , b ut s u bjects will c o nti n ue t heir 
partici pat i o n i n t he st u d y. S uc h se vere reacti o ns i ncl u de, b ut are n ot li mite d t o, urticaria, 
h y perse nsiti vit y, h y p ote nsi o n, bra d ycar dia, h y p o xia, ge neralize d ras h, or a c ha n ge i n me ntal 
stat us. If f o ur ( 4) ca us all y relate d  se v ere reacti o ns wit h 2 4 -h o ur of d osi n g o cc ur, st u d y 
e nr oll me nt will be pa use d u ntil t he D M C ca n re vi e w t he cases a n d d eter mi ne if t here is a n 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 1  of 1 0 9  
C o nfi de ntial  
a d verse dr u g-relate d safet y si g nal. D etails re gar di n g st u d y dr u g d osi n g are pr o vi de d i n  
Secti o n  9. 5 .  
7. 3. 2.  
Re pl ace me nt p olic y  
N o s u bject re pla ce me nt will be d o ne, re gar dless of t he reas o n f or st u d y disc o nti n uati o n.  
7. 3. 3.  
Wit h dr a w al of i nf or me d c o nse nt  
S u bjects ma y v ol u ntaril y wit h dra w c o nse nt t o partici pate i n t h e st u d y f or a n y reas o n at a n y ti me. 
Wit h dra wal of c o nse nt o cc urs o nl y w he n a s u bject:  
•  D oes n ot wa nt t o partici p ate i n t he st u d y a n y m ore , 
A N D  
•  D oes n ot all o w f urt her c ollecti o n of pers o nal dat a . 
It is e n c o ura ge d t hat t he s u bject pr o vi des wit h dra wal of c o nse nt i n writi n g.  
I n t his sit uati o n, t he In vesti gat or s h o ul d ma ke a reas o na ble eff ort (e g , tele p h o ne call, e-m ail, 
letter) t o u n dersta n d t h e pri mar y reas o n f or t he s u bject’s decisi o n t o wit h dra w his/ her c o ns e nt 
a n d rec or d t his i nf or mati o n. T he s u bject’s vital stat us ca n be v erifie d u p o n c o ntact wit h s u bject’s 
pri mar y care p h ysicia n or ot her s o urces acc or di n g t o l ocal r ules a n d re g ulati o ns.  
N o f urt her assess me nts m ust be c o n d ucte d, a n d t he data t hat w o ul d ha ve bee n c ollecte d at 
s u bse q ue nt visits will be c onsi dere d missi n g.  
F urt her atte m pts t o c o ntact t he s u bject are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati o n or f oll o w -u p.  
All eff orts s h o ul d be ma d e t o c o m plete t he ass ess me nts pri or t o st u d y wit h dra wal. A fi nal 
e val uati o n at t he ti me of t he s u b ject’s st u d y wit h dra wal s h o ul d be ma d e as detaile d i n t he 
assess me nt ta ble  (T a ble  2 ). 
T he S p o ns or will c o nti n ue t o kee p a n d us e c ollect e d st u d y i nf or mati o n (i ncl u di n g a n y dat a 
res ulti n g fr o m t he a nal ysis of a s u bject’s sa m ples u ntil t he ti me of wit h dra wal) acc or di n g t o 
a p plica ble la w.  
All bi ol o gical sa m ples n ot yet a n al yze d at t he ti me of wit h dra wal ma y still be use d f or f urt her 
testi n g/a nal ysis i n acc or da nce wit h t he ter ms of t his pr ot oc ol a n d t he i nf or m e d c o nse nt f or m  a n d 
wit h l ocal r ules a n d re g ulati o ns . 
7. 3. 4.  
L ost t o f oll o w -u p  
F or s u bjects w h os e stat us is u nclear beca use t h e y fail t o c o m plete st u d y visits wit h o ut stati n g a n 
i nte nti o n t o disc o nti n ue or wit h dra w, t he In vesti gat or m ust s h o w “d ue dili ge nce ” b y 
d oc u me nti n g i n t he s o ur ce d oc u me nts t he ste ps ta ke n t o c o ntact t he s u bject, e g , d ates of 
tele p h o ne calls, re gistere d letters. A s u bject s h o ul d n ot be c o nsi dere d as l ost t o f oll o w-u p u ntil 
t he e n d of t he st u d y w h e n d ue dili ge n ce has b ee n c o m plete d.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 2  of 1 0 9  
C o nfi de ntial  
8.  
T R E A T M E N T O F S U B J E C T S  
8. 1.  
Descri pti o n of St u d y Dr u g  
8. 1. 1.  
I n vesti g ati o n al Pr o d uct 
M a vrili m u ma b ( K P L-3 0 1, f or merl y k n o w n as C A M -3 0 0 1)  is a rec o m bi na nt h u ma n m o n ocl o nal 
I g G 4 a nti b o d y, w hic h m o d ulates acti vit y of gra n ul oc yte-macr o p ha ge c ol o n y -sti m ulati n g fact or 
( G M-C S F) b y bi n di n g t o t he al p ha s u b u nit of its rece pt or ( G M -C S F R α).  
8. 1. 2.  
Descri pti o n  
Ma vrili m u ma b is a sterile, clear t o o palesce nt, c ol orless t o sli g htl y br o w n -yell o w li q ui d, free 
fr o m visi ble particles a n d is f or m ulate d 
 
 It is 
s u p plie d b y Ki ni ksa Phar mace uticals as a li q ui d i n access orize d pre -fille d s yri n ges or i n vials f or 
pare nteral a d mi nistrati o n. Please see t he P har mac y M a n u al f or a d diti o nal details.  
Matc hi n g pla ce b o c o ntai ni n g o nl y pr o d uct dil ue nt/ e x ci pie nts will be pr o vi de d as a li q ui d i n 
access orize d pre-fille d s yri n ges or i n vials f or pare nteral a d mi nistrati o n. 
8. 1. 3.  
D ose a n d A d mi nistr ati o n  
S u bjects will recei ve a si n gle I V i nf usi o n of eit her 1 0 m g/ k g or 6 m g/ k g  ma vrili m u ma b or 
place b o o ver  a p pr o xi matel y 6 0 mi n utes. T h e m a xi m u m d ose ma y n ot e xcee d 1 0 0 0 m g , w hic h 
was  ap pr o xi matel y  t he m a xi m u m d ose a d mi nistere d i n t he P hase 1 st u d y wit h I V i nf usi o n. 
D osi n g will be bas e d o n b o d y w ei g ht  o btai n e d at Scree ni n g . A d diti o nal details re gar di n g 
ma vrili m u ma b d osi n g are pr o vi de d i n Secti o n  9. 5 . 
At a n y ti me d uri n g t he i nf usi o n of st u d y dr u g, s h o ul d a m o derate reacti o n occ ur, t he i nf usi o n will 
be st o p pe d a n d restarte d at t he I n vesti gat or’s  discreti o n o nl y aft er t he e ve nts ha ve res ol ve d. T he 
i nf usi o n rate s h o ul d be re-starte d at a rate t olerate d b y t he s u bject. I nf usi o ns m ust be c o m plete d 
wit hi n 4 h o urs of st u d y dr u g pre parati o n (see P har mac y Ma n ual f or m ore d etails).  
U se of pre -me dicati o n t o a v oi d or treat p ote ntial i nf usi o n-relate d reacti o ns is at t he discreti o n of 
t he In v esti gat or . I n t he e ve nt of a n i nf usi o n reacti o n, t he f oll o wi n g i nter ve nti o ns ca n be 
c o nsi dere d if n ee de d  us i n g a s e parate I V li ne fr o m t hat use d f or t he m a vrili m u ma b  i nf usi o n: 
Na Cl 0. 9 % I V i nf usi o n at 5 0 0 m L/ hr, di p he n h y dra mi ne 5 0 m g I V, h y dr oc ortis o ne s o di u m 
s ucci nate 1 0 0 m g I V, e pi ne p hri ne 1 m g/ m L 0. 3 m g i ntra m usc ul ar. 
8. 2.  
C o nc o mit a nt Me dic ati o ns  
N o f or mal dr u g -dr u g i nteracti o n st u dies ha ve b ee n c o n d ucte d wit h ma vrili m u ma b.  
Use of c o n c o mita nt me dicati o ns i ncl u di n g a nti p yretics, a nti -i nfecti ves a n d a nti -f u n gals, a n d 
c ortic oster oi ds  will be rec or de d . All i n vesti gati o n al a n d off -l a bel t hera pies f or C O VI D -1 9 will be 
rec or de d f or eac h s u bject (e g, c hl or o q ui ne, h y dr o x yc hl or o q u i ne, c ortic oster oi ds, a nti virals 
[re m desi vir, l o pi na vir/rit o na vir]) al o n g wit h t he ti me, d ose, a n d  d urati o n of t heir a d mi nistrati o n.  
Me dicati o n hist or y wit hi n 3 0 da ys of S cree ni n g will be c ollecte d . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 3  of 1 0 9  
C o nfi de ntial  
8. 2. 1.  
Pr o hi bite d Me dic ati o ns  
T he f oll o wi n g m e dicati o ns are als o pr o hi bite d  if use occ urre d  wit hi n t he ti mi n g s pecifi e d: 
•  Treat me nt wit h cell -d e pl eti n g bi ol o gical t hera pies ( e g, a nti-C D 2 0)  wit hi n 1 2 m o nt hs 
pri or t o Scree ni n g ,  
•  N o n -cell-d e pleti n g bi ol o gical t hera pies (s uc h as a nti -T N F, a n a ki nra, a nti -I L-6 
rece pt or [eg , t ociliz u ma b], or a batace pt) wit hi n 8 wee ks ( or 5 half -li ves, w hic he ver is 
l o n ger) pri or t o Scree ni n g,  
•  T reat me nt wit h al k ylati n g a ge nts wit hi n 1 2 wee ks pri or t o Scree ni n g ,  
•  T reat me nt wit h c ycl os p ori ne A, azat hi o pri ne, c ycl o p h os p ha mi de, or M M F, or ot her 
i m m u n os u p pressa nt t hera p y (e x ce pt f or c ortic oster oi ds) wit hi n 4 wee ks of Scree ni n g . 
Me dicati o ns t hat bec o me sta n dar d of care f or C O VI D -1 9 a n d/ or recei ve e mer ge nc y us e 
a ut h orizati o n ma y be all o we d after disc ussi o n wit h t he me dical m o nit or.  Us e of a d diti o nal  
i n vesti gati o nal a ge nts usi n g i m m u n os u p pressi ve t hera p y, as s al va ge/c o m p assi o nate use t hera p y 
of a n alter nati ve a ge nt , m a y b e c o nsi dere d at t he discreti o n of t he In v esti gat or i n c o ns ultati o n 
wit h t he S p o ns or . 
8. 3.  
Tre at me nt C o m pli a nce  
A si n gle I V i nf usi o n of ma vrili m u ma b  or place b o will be a d mi nistere d o v er a p pr o xi matel y 6 0 
mi n utes i n a cli nical setti n g. N o a d diti o nal pr oce d ures f or m o nit ori n g c o m plia nce are necessar y.  
8. 4.  
R a n d o miz ati o n a n d Bli n di n g  
8. 4. 1.  
R a n d o miz ati o n  
After me eti n g all i ncl usi o n/e x cl usi o n criteria a n d o btai ni n g i nf or me d c o nse nt, s u bjects will be 
ra n d o mize d i n a 1: 1: 1 all ocati o n rati o t o recei ve eit her a 1 0 m g/ k g or 6 m g/ k g si n gle I V d os e of 
ma vrili m u ma b , or place b o.  
T here will be 3 stratificati o n fact ors f or ra n d o mizati o n:  
1.  Use of a ut h orize d  sta n dar d of care a nti vir al  t hera p y f or C O VI D-1 9  (e g, re m desi vir): yes 
vs. n o  
2.  A ge: <  6 5 vs. ≥ 6 5 years  
3.  Ac ute res pir at or y distress s y n dr o me ( A R D S) stat us b y Pa O 2/ Fi O2*:  n or mal – mil d ( > 2 0 0 
vs. m o derate -s e vere ( ≤ 2 0 0). A R D S stat us will o nl y be use d f or C o h ort 1 ( n o n-ve ntilate d 
s u bjects). 
*  
If P a O 2 is u n a vaila ble, use S p O 2/ Fi O2:  n or mal– mil d ( >  2 3 5 ) vs. m o derate -se vere (≤ 2 3 5 ) 
A n I nteracti ve We b Res p o nse S yste m (I W R S) will be use d d uri n g t he st u d y f or assi g n me nt of a 
S u bject I d e ntificati o n N u m ber at e nr oll me nt, ra n d o mizati o n t o a treat me nt, a n d assi g n m e nt of 
bli n de d st u d y dr u g. A s u bject is c o nsi dere d ra n d o mize d i nt o t he st u d y w he n t he I n v esti gat or 
c o nfir ms t he eli gi bilit y criteria i n t he I W R S a n d t h e p har macist has bee n pr o vi de d wit h t he 
i n vesti gati o nal pr o d u ct n u m ber.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 4  of 1 0 9  
C o nfi de ntial  
8. 4. 2.  
Tre at me nt Bli n di n g  
S u bjects, In v esti gat or  or desi g nee , a n d t he S p o ns or  or desi g nee  will be bli n de d t o treat me nt. At 
t he site le vel, onl y t he cli ni cal site phar macist  will ha ve access t o t he treat me nt assi g n me nts.  T he 
D M C  will re vie w t he u n bli n de d safet y data  p eri o dicall y . If t he In v esti gat or  deci des t hat 
u n bli n di n g t he s u bject is esse ntial f or t heir cli nical ma na ge me nt, t he n t he s u bject ma y be 
e mer ge ntl y u n bli n de d , eit her bef ore or after a disc ussi o n bet wee n t he S p o ns or ’s safet y p h ysici a n 
or desi g n ee a n d t he Pri nci pal I n v esti gat or.  T he c hair of t he D M C will be alerte d wit hi n 4 8 h o urs 
of a n y u n bli n di n g . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 5  of 1 0 9  
C o nfi de ntial  
9.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
9. 1.  
St u d y Dr u g  
A si n gle I V i nf usi o n of ma vrili m u ma b  1 0 m g/ k g  or ma vrili m u ma b  6 m g/ k g or mat c hi n g pl ace b o 
will be a d mi nistere d t o st u d y s u bjects. T otal ma vrili m u ma b  d ose is n ot t o e x cee d 1 0 0 0 m g.  
9. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
Eac h st u d y site will be s u p plie d wit h st u d y dr u g i n pac ka gi n g as d escri be d i n t he P har mac y 
M a n ual. 
A u ni q ue me dicati o n n u m ber is pr i nte d o n t he st u d y me dicati o n la bel. 
9. 3.  
St u d y Dr u g St or a ge  
All st u d y treat me nt m ust be st ore d as s pecifie d o n t he la bel a n d  i n t he P har mac y M a n ual.  
9. 4.  
St u d y Dr u g Pre p ar ati o n  
I n di vi d ual s u bject i nf usi o ns are t o be pre pare d at t he i n vesti gati o nal site u n der t he a ut h orit y of 
t he In v esti gat or a n d i n a cc or da nce wit h l ocal r e g ul ati o ns. D oses s h o ul d be pre pare d f or 
a d mi nistrati o n via a s yri n ge p u m p. M ore detaile d i nstr ucti o n will be pr o vi de d t o cli nical sites i n 
t he P har mac y Ma n u al (t o be de vel o pe d pri or t o first St u d y I nitiati o n Visit). 
9. 5.  
A d mi nistr ati o n  
Bli n de d st u d y dr u g will be a d mi nistere d as a si n gl e I V i nf usi o n o ver a p pr o xi matel y 6 0 mi n utes 
b y q ualifie d h ealt h care  p ers o n nel.  All i nf usi o ns will be a d mi nistere d i n t he prese nce of q ualifi e d 
healt h care pers o n nel as per  l ocal h os pital re g ul ati o ns u n der t he s u per visi o n of t he I n vesti gat or or 
desi g nee. I m me diat e access t o a n e mer ge nc y cras h cart will be re q uire d. T he i nf usi o n s h o ul d last 
a p pr o xi matel y 6 0 mi n utes. Pre me dicati o n t o a v oi d or treat p ote ntial i nf usi o n -relate d reacti o n is 
at t he discreti o n of t he I n vesti gat or. T he i nitial 1 5 mi n utes of i nf usi o n will be a d mi nistere d at a n 
i nf usi o n rate t o all o w f or deli ver y of a p pr o xi matel y 1/ 6 of t he t otal v ol u me of t he i nf usi o n. If n o 
m o derate or s e vere i nf usi o n reacti o ns are o b ser ve d, t he rate will be d o u ble d f or t he ne xt 1 5 
mi n utes. After t he first 3 0 mi n utes t he rate will be i ncreas e d t o deli ver a n ot her 5 0 % of t h e t otal 
v ol u me if t he i nf usi o n c o nti n ues t o be well t olerat e d. At a n y ti me d uri n g t he i nf usi o n, if a 
m o derate reacti o n occ urs, t he i nf usi o n will be st o p pe d f or a p eri o d of at least 3 0 mi n utes a n d 
restarte d at t he discreti o n of t he I n vesti gat or o nl y after t he e ve nts ha v e res ol ve d. T he i nf usi o n 
s h o ul d be re-starte d a rat e t olerate d b y t he s u bj ect. T he i nf usi o n s h o ul d be st o p pe d per ma ne ntl y 
if a se vere reacti o n is o bs er ve d. M or e detail is pr o vi de d i n Site Ma n ual.  
9. 6.  
St u d y Dr u g Acc o u nt a bilit y  
T he In vesti gat or m ust mai ntai n a n acc urat e rec or d of t he s hi p me nt a n d dis pe nsi n g of st u d y 
treat me nt i n a dr u g acc o u nta bilit y l o g.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 6  of 1 0 9  
C o nfi de ntial  
9. 7.  
St u d y Dr u g H a n dli n g a n d Dis p os al  
St u d y dr u g  m ust be recei ve d b y a desi g nate d pers o n at t he st u d y site , safel y ha n dl e d a n d pr o p erl y 
st ore d i n a sec ure d l oc ati o n t o w hic h o nl y t he In v esti gat or a n d desi g nate d site pers o n nel ha ve 
access. U p o n recei pt, all st u d y dr u g  m ust be st ore d acc or di n g t o t he i nstr ucti o ns s pecifie d o n t he 
la bels a n d i n t he P har mac y M a n ual. Cli nical s u p plies are t o be dis pe ns e d o nl y i n acc or da n ce wit h 
t he pr ot oc ol. Tec h ni cal c o m plai nts are t o be re p orte d t o t he res pecti ve Ki ni ksa Q ualit y 
Ass ura nc e.  
At t he c o ncl usi o n of t he st u d y, a n d as a p pr o pri ate d uri n g t he c o urse of t he st u d y, t he In v esti gat or 
will ret ur n all u n use d st u d y dr u g , p ac k a gi n g, a n d dr u g la bels t o Ki ni ksa or t heir desi g n ee.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 7  of 1 0 9  
C o nfi de ntial  
1 0.  
A S S E S S M E N T O F E F FI C A C Y  
T he f oll o wi n g effi cac y e n d p oi nts will  be use d f or b ot h t he P hase 2 a n d P hase 3  parts  of t he 
st u d y. E n d p oi nts will be e val uate d f or b ot h C o h orts 1 a n d 2, u nless ot her wise s pecifie d.   
1 0. 1.  
Pri m ar y Effic ac y E n d p oi nt  
1 0. 1. 1.  
C o h ort 1 ( N o n -ve ntil at e d S u bjects)  
T he pri mar y effic ac y e n d p oi nt is t he pr o p orti o n of s u bjects ali ve a n d free of mec ha nical 
ve ntilati o n  at Da y 2 9. Mec ha nic al ve ntilati o n is  defi ne d as i n vasi ve m ec ha nical ve ntilati o n or 
E C M O.  
Mec ha nic al ve ntilati o n stat us will be e val uate d b ase d o n t he NI AI D cli nical o utc o me 8-p oi nt 
or di nal sc ale. T h e scal e is use d t o assess  cli nical stat us f or eac h da y, wit h t he w orst sc ore fr o m 
t he pre vi o us da y rec or de d. S u bjects w h ose cli nical o utc o me has met  a n NI AI D  sc ore of 2 will be 
c o nsi dere d as usi n g me c ha nical ve ntilati o n .  
T he NI AI D scal e is as f oll o ws: 
•  De at h;  
•  H os pit alize d, o n i nv asive mec h a nic al ve ntil ati o n or E C M O;  
•  H os pit alize d, o n n o n -i nv asive ve ntil ati o n or hi g h fl o w oxy ge n devices;  
•  H os pit alize d, re q uiri n g s u p ple me nt al oxy g e n;  
•  H os pit alize d, n ot re q uiri n g s u p ple me nt al oxy ge n –  re q uiri n g o ng oi n g me dic al c are 
( C O VI D-1 9 rel ate d or ot her wise);  
•  H os pit alize d, n ot re q uiri n g s u p ple me nt al oxy ge n –  n o l o n ger re q uires o n g oi n g 
me dic al c are;  
•  N ot h os pit alize d, li mit ati o n o n activities a n d/ or re q uiri n g h o me oxy ge n;  
•  N ot h os pit alize d, n o li mit ati o ns o n a ctivities.  
1 0. 1. 2.  
C o h ort 2 ( Ve ntil at e d S u bjects)  
T he pri mar y effic ac y e n d p oi nt is m ortalit y rate at Da y 2 9 , defi n e d as t he pr o p orti o n of s u bjects 
w h o ha ve die d  b y D a y 2 9 . 
1 0. 2.  
Sec o n d ar y Effic ac y E n d p oi nts  
Sec o n dar y effic ac y e n d p oi nt s will be e x a mi ne d base d o n t he hierarc hi cal or der bel o w . 
C o h ort 1 ( N o n -ve ntil at e d S u bjects)  
1.  M ortalit y rat e at Da y 2 9  
2.  Ve ntilati o n free s ur vi val ( Ti me t o ve ntilati o n or deat h ) b y Da y 2 9  
Defi ne d as ti me fr o m ra n d o mizati o n t o ve ntilati o n or deat h; s u bjects still ali ve will be 
ce ns ore d at Da y 2 9.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 8  of 1 0 9  
C o nfi de ntial  
3.  O verall s ur vi val b y D a y 2 9  
D efi ne d as ti me fr o m ra n d o mizati o n t o deat h; s u bjects still ali ve will be ce ns ore d at Da y 
2 9 . 
C o h ort 2  (V e ntil at e d  S u bjects)  
1.  Ti me t o 1 -p oi nt cli nical i m pr o ve me nt b y Da y 2 9  
Defi ne d as ti me fr o m ra n d o mizati o n t o a 1 -p oi nt i m pr o ve me nt o n t he NI AI D 8 -p oi nt 
or di nal scale, or dis c har ge fr o m t he h os pital, w hic he ver occ urs first. S u bjects w h o die 
bef ore Da y 2 9  will be ce ns ore d at Da y 3 5 . 
1 0. 3.  
Ot her Effic ac y E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
4 9  of 1 0 9  
C o nfi de ntial  
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
1 0. 4.  
Effic ac y P ar a meters  
1 0. 4. 1.  
Mec h a nic al Ve ntil ati o n P ar a meters  
Mec ha nic al ve ntilati o n meas ures f or eac h s u bject will be rec or de d dail y u ntil t he date of 
Disc har ge. Ve ntilati o n  a n d o x y ge n at i o n m o de  a n d ass ociate d meas ures  will be c ollecte d .  T his 
will i ncl u de  nee d f or hi g h fl o w o x y ge n, NI V, I M V, or E C M O  a n d will be rec or de d dail y u ntil 
t he date of Disc h ar ge. Eff ort will be ma de t o c ollect ve ntilati o n s u p p orti ve meas ures (e g, 
pr o nati o n, use of nitric o xi de, or trac he ost o m y) recei ve d b y s u bjects o n mec ha nical v e ntilati o n; 
f urt her det ails are pr o vi de d i n t he Sit e Ma n ual . 
1 0. 4. 2.  
Res pir at or y P a r a meters  
Res pirat or y f u ncti o n para meters will be rec or de d at t he ti me of ra n d o mizati o n f or C o h ort 1 
s u bjects (a b bre viate d para meters per t he Sc he d ule of Acti vities) a n d dail y f or all s u bjects u ntil 
t he date of Disc h ar ge. At Da y 1 t h e res pirat or y para meters s h o ul d be c ollecte d at t he ti me cl osest 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 0  of 1 0 9  
C o nfi de ntial  
t o a n d pri or t o t he i nitiati o n of st u d y dr u g a d mi nistrati o n. F or dail y val u es  after Da y 1, c ollect at 
t he ti me of hi g hest d ail y Fi O 2. T he c ollecte d val ues will i ncl u de t he peri p heral o x y ge n s at ur ati o n 
( S p O 2), Pa O2 i n m m H g (if a vaila ble) a n d t he a m o u nt of o x y ge n t he patie nt is re q uiri n g at t he 
ti me. If t h e patie nt is o n mec ha nic al ve ntilati o n, n o ni n vasi ve ve ntilati o n ( C P A P or Bi P A P) or 
hi g h fl o w n asal ca n n ul a, t he o x y ge n re q uir e me nt will be t he  fracti o nal i n halati o n of o x y ge n 
( Fi O2) a n d will be c ollecte d as a perce nta ge. If t he patie nt is o n si m ple nasal ca n n ula, si m ple face 
mas k or trac h c ollar, t he o x y ge n re q uir e me nt t o be c ollecte d is t he liter fl o w e x presse d as liters 
per mi n ute ( L P M). Ot her  arterial bl o o d gas  p ara m eters  i ncl u di n g p H, p C O 2, H C O 3, base e x cess 
s h o ul d be rec or de d if a v aila ble. I n a d diti o n, ot her s u p p orti ve meas ures i ncl u di n g pr o nati o n, 
ne ur o m usc ular bl oc k a de, trac he ost o m y, E C M O , v as o press or or i n otr o pi c t hera p y, i n hale d nitri c 
o xi de or ot her s s h o ul d be rec or de d. 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 1  of 1 0 9  
C o nfi de ntial  
1 1.  
A S S E S S M E N T  O F P H A R M A C O KI N E TI C S  
S u bjects will pr o vi de ser u m sa m ples f or p har mac o ki netic st u dies t o be c o n d ucte d b y Ki ni ksa.  
1 1. 1.  
P h ar m ac o ki netic S a m pli n g  a n d P ar a meter Assess me nt  
Sa m ples will be c ollecte d at Scree ni n g, Da y 1 ( pri or t o t he st u d y dr u g i nf usi o n a n d o nce it is 
c o m plete), a n d at Da ys 3 , 7, 1 5  ±  2, 2 9  + 4 , a n d at t he Disc har ge/ U N S visit. 
T he pla n ne d P K para met ers f or assess me nt i ncl u d e, b ut are n ot li mite d t o, t he f oll o wi n g: 
P ar a meter  
Descri pti o n  
C ma x  
T he ma xi m u m plas ma c o nce ntrati o n  
T ma x  
Ti me of ma xi m u m plas ma c o nce ntrati o n  
A U C last 
Area u n d er t he c ur ve fr o m ti me 0 t o ti me of last meas ura ble pl as ma 
c o nce ntr ati o n, calc ulat e d usi n g li near tra pez oi dal i nte grati o n  
A U C 0 -∞ 
Area u n d er t he c ur ve fr o m ti me 0 e xtra p olate d  t o i nfi nit y 
A U C 0 -∞ = A U C last + C last/z w here C last is t he last q ua ntifia ble 
c o nce ntr ati o n  
C L  
Cleara nce, C L = D ose/ A U C 0 -∞ 
V z 
V ol u me of distri b uti o n, V z = D os e/( z x A U C 0 -∞)   
t1/ 2 
Ter mi nal p hase h alf life, t 1/ 2 = I n( 2)/ z  
z 
Ter mi nal p hase rate c o nsta nt. Esti mate d b y li near re gressi o n of t h e 
ter mi nal l o g-li near p has e of t he l o g-tra nsf or me d c o nce ntrati o n vs. ti me 
data  
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 2  of 1 0 9  
C o nfi de ntial  
1 2.  
A S S E S S M E N T O F S A F E T Y  
1 2. 1.  
S afet y P ar a meters  
Safet y will be assesse d t hr o u g h r o uti ne me dical m o nit ori n g of A E s/ S A Es a n d la b orat or y 
para meters as des cri be d i n t he S c he d ule of A cti vities (Ta ble  2 ). S pecific assess me nts are 
disc usse d i n detail bel o w.  
1 2. 1. 1.  
De m o gr a p hic/ Me dic al Hist or y  
M e dical hist or y a n d me dicati o n hist or y (u p t o 3 0 da ys pri or t o Scree ni n g) , de m o gra p hics, a n d 
k n o w n c o -m or bi dities  will be c ollecte d fr o m all s u bjects at Scree ni n g . T h e n u m ber of da ys 
bet wee n o nset of C O VI D -1 9 s y m pt o ms a n d i nitiati o n of treat me nt will be rec or de d i n all 
s u bjects.  
I n v esti gat ors will ha ve t h e discreti o n t o rec or d a b n or mal test fi n di n gs o n t he me dical hist or y case 
re p ort f or m (C R F ) w he n e ver , i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he 
i nf or me d c o nse nt si g nat ure. 
1 2. 1. 2.  
Vit al Si g ns  
Vital si g ns will be rec or de d at S cree ni n g, Da y 1, a n d t hr o u g h o ut t he st u d y peri o d as s pecifie d i n 
t he Sc he d ule of Acti vities  (Ta ble  2 ). 
1 2. 1. 3.  
P h ysic al E x a mi n ati o n  
A p h ysic al e x a mi nati o n of eac h s u bj ect will be c o n d ucte d at S cree ni n g a n d at t he 
Disc har ge / U N S visit . Hei g ht a n d wei g ht will be c ollect e d at Scree ni n g  o nl y .  
1 2. 1. 4.  
Electr oc a r di o gr a m , a n d C hest X-r a y o r C T Sc a n  
A n E C G will be o btai ne d at Scree ni n g  a n d at t he Disc har ge/ U N S visit . A c hest x -ra y or c hest C T 
sca n will be o btai ne d at S cree ni n g. T he c hest x -ra y will be re peat e d at t he Disc har ge  visit . 
A d diti o nal c hest x -ra ys or C T sca ns ma y be p erf or me d fr o m Scree ni n g t hr o u g h Da y 2 9 at t he 
discreti o n of t he I n v esti gat or  a n d t hese res ults m ust be rec or de d . 
1 2. 1. 5.  
L a b or at or y Assess me nts  
All safet y la b orat or y para meter s i n t he st u d y will be c o n d ucte d at S cree ni n g (as per T a ble  2 ) wit h 
a d diti o nal p ost -d ose ti me p oi nts n ote d i n Ta ble  4 .  
S u bjects w h o are disc h ar ge d s h o ul d c o m plete t he Disc har ge/ U N S visit  (t he st u d y da y 
assess me nts are n ot re q uire d) . If a s u bject is disc h ar ge d a n d t h e I n vesti gat or j u d ges t h at is it n ot 
safe f or t he s u bject t o ret ur n t o t he site, or t he s u bject is n ot willi n g t o ret ur n t o t he site, t he visits 
t hat occ ur t hereafter ma y be d o ne b y tele me di ci ne a n d la b tests a n d ot her proce d ures will n ot be 
perf or me d. A d diti o nal la b orat or y assess me nt ma y be perf or me d fr o m Scree ni n g t hr o u g h Da y 2 9 
at t he discreti o n of t he I n vesti gat or  a n d t hese res ults m ust be rec or de d . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 3  of 1 0 9  
C o nfi de ntial  
T a ble  4 : 
Sc he d ule of L a b or at or y A ssess me nts 
Acti vit y  / P ar a meter 
C ollecti o n Det ail  
C ollecti o n Ti me p oi nts  
C E N T R A L L A B O R A T O R Y  
Res pirat or y P a nel  
A/ H 3 N 2, A/ H 1 N 1 p d m 0 9, 
A/ H 7 N 9, A/ H 5 N 1, A, n ot 
t y pe d, B, or ot her (s pecif y); 
c or o na vir us –  n o vel C o V, 
M E R S C o V, ot her C o V 
(s pecif y); R S V; a de n o vir us; 
bacteria; ot her i nfecti o us 
res pirat or y dia g n osis 
(s pecif y); cli nical p ne u m o nia 
Scree ni n g  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
A nti -ma vrili m u ma b 
a nti b o d y 
 
Scree ni n g a n d t he Disc har ge/ U N S visit  
P har ma c o ki netic  sa m ple 
 
Da y 1 ( bef ore i nf usi o n a n d w h e n i nf usi o n is 
c o m plete ), Da ys 3 ± 1 , 7 ± 1 , 1 5± 2 , 2 9+ 4  a n d at t he 
Dis char ge/ U N S visit  
L O C A L L A B O R A T O R Y  
Pre g na nc y test  ( w o me n of 
c hil d -beari n g p ote ntial)  
Uri ne or ser u m β h C G  
Scree ni n g a n d at t he Disc har ge/ U N S visit;  
Da y 9 0 + 1 4  is o pti o nal 
 
 
 
 
 
  
 
He mat ol o g y  
C o m plete bl o o d c o u nt  + 
differe ntial  
Scree ni n g  ( u p t o 7 da ys pri or t o ra n d o mizati o n), 
Da ys 3 ± 1 , 1 5 ± 2, 2 9+ 4  a n d at t he Disc har ge/ U N S 
visit;  
Da ys 6 0 + 1 4  a n d 9 0 + 1 4  are o pti o nal  
C oa g ulati o n  
P T, P T T, a n d I N R  
C he mistr y  
electr ol ytes, bl o o d urea 
nitr o ge n , gl uc ose a n d C R 
Li ver  Pr ofile  
A S T, A L T, Al b, Al k P, T bili, 
D bili  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 4  of 1 0 9  
C o nfi de ntial  
Acti vit y  / P ar a meter 
C ollecti o n Det ail  
C ollecti o n Ti me p oi nts  
Li pi d P a nel  
C h olester ol, t otal; hi g h -
de nsit y  li p o pr otei n ( H D L) 
c h olester ol; l o w-de nsit y 
li p o pr otei n ( L D L) c h olester ol 
(calc ulati o n); tri gl yceri des; 
ver y l o w -de nsit y li p o pr otei n 
( V L D L) c h olester ol 
(calc ulati o n) 
Scree ni n g  ( u p t o 7 da ys pri or t o ra n d o mizati o n) 
a n d at t he Disc har ge / U N S visit 
Uri nal ysis  
 
Scree ni n g  ( u p t o 7 da ys pri or t o ra n d o mizati o n) 
a n d  Disc har ge/ U N S visit;  
Da y 2 9 + 4 , Da ys 6 0 + 1 4  a n d 9 0 + 1 4  are o pti o nal  
T u berc ul osis  
 
O pti o nal at Scree ni n g - at I n vesti gat or’s discreti o n  
S o ut h Afric a o nl y:  T B testi n g re q uire d f or all 
s u bj ects at Scree ni n g  
S A R S -C o V -2  
C O VI D -1 9  
Scree ni n g *  
Da ys 1, 2, 3, 4, 5, 6, 7, 8, 1 5 ± 2, 2 2  ± 2,  2 9  + 4  a n d 
Disc har ge/ U N S  are o pti o nal  
Scree ni n g = u p t o  3 da ys pri or t o ra n d o mizati o n  
* F or S A R S -C o V -2 testi n g ( C O VI D -1 9), a p ositi ve test wit hi n 1 4 da ys of ra n d o mizati o n is re q uire d. Sites t hat are 
u na ble t o perf or m S A R S -C o V -2 l ocall y  (at t he cli nical site or fr o m a n ot her i nstit uti o n) ma y use Ce ntral La b orat or y 
testi n g.  
T he  f ull S c he d ule of A cti vities  is prese nte d in Ta ble  2 . 
1 2. 1. 5. 1.  Pre g n a nc y Scree n  
All pre -me n o pa us al w o me n w h o are n ot s ur gicall y sterile will ha ve a uri n e or ser u m pre g n a nc y 
test perf or me d at S cree ni n g. Pre g n a nc y testi n g is n ot re q uire d f or p ost -me n o pa usa l w o me n. F or 
fe male s u bjects of c hil d b eari n g p ote ntial w h o are disc har ge d a n d ret ur n t o t he site later, a 
pre g na nc y t est m ust be re peate d at t he last visit t he s u bject c o m pletes o n t he st u d y.  
1 2. 1. 6.  
Se q ue nti al Or g a n F ail ure Assess me nt ( S O F A ) a n d Q uic k S O F A 
Se q ue n tial Or ga n Fail ure Assess me nt ( S O F A) a n d Q uic k S O F A ( q S O F A) are cli nical 
assess me nts  t o i de ntif y s u bjects wit h w orse ni n g h ealt h stat us i n I C U a n d n o n-I C U e n vir o n me nts, 
res pecti vel y. C o h ort 1  (n o n -ve ntilate d ) s u bjects will be assesse d usi n g q S O F A at Scree ni n g. 
C o h ort 2 ( v e ntilate d) su bjects will be assesse d usi n g S O F A at Scree ni n g  a n d at Da y 8 .  
If a s u bject e x perie nces a 1-p oi nt w orse ni n g i n NI AI D, it is rec o m me n de d t o re -ass ess q S O F A 
( C o h ort 1) or S O F A ( C o h ort 2) at t he ti me of w orse ni n g or as per st a n dar d of care d uri n g 
h os pitaliz ati o n.  
A d diti o nal S O F A/ q S O F A assess me nts  ma y be p erf or me d fr o m Scree ni n g t hr o u g h Da y 2 9 at t he 
discreti o n of t he I n v esti gat or  a n d t hese res ults m ust als o be rec or de d.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 5  of 1 0 9  
C o nfi de ntial  
1 2. 2.  
A d verse a n d Seri o us A d verse E ve nts  
1 2. 2. 1.  
Defi niti o n of A d verse E ve nts  
1 2. 2. 1. 1.  A d verse E ve nt ( A E)  
A n A E is a n y u nt o war d me dical occ urre n ce ( e g, 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 b n or mal la b orat or y fi n di n gs], s y m pt o m or diseas e) i n a cli nical i n vesti gati o n s u bject after 
pr o vi di n g writte n i nf or me d c o nse nt f or  partici pati o n i n t he st u d y. T heref ore, a n A E ma y or ma y 
n ot be te m p orall y or ca usall y ass o ciate d wit h t he use of a me dici n al (i n vesti gati o nal) pr o d uct.  
A b n or mal la b orat or y v al ues or test res ults c o nstit ute A E s o nl y if t he y f ulfill at least o ne of t he 
f ollo wi n g criteria:  
•  t he y i n d uc e cli nical si g ns or s y m pt o ms 
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t h era p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val ues o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifi ca nt c ha n ges fr o m 
baseli ne or t he pre vi o us visit, or val ues, w hic h are c o nsi dere d n o n -t y pical i n s u bjects wit h t he 
u n derl yi n g dise ase.  
1 2. 2. 1. 2.  A d verse D r u g Re acti o n   
A n a d vers e dr u g reacti o n is defi ne d as, “ A res p o ns e t o a me dici nal pr o d u ct w hic h is n o xi o us a n d 
u ni nte n de d [ DI R 2 0 0 1/ 8 3/ E C Art 1( 1 1)]. Res p o nse i n t his c o nte xt mea ns t hat a ca us al 
relati o ns hi p bet wee n a m e dici nal pr o d uct a n d a n A E  is at least a reas o na bl e p ossi bilit y” (see 
A n ne x I V, I C H -E 2 A G ui deli ne).  
I nf or mati o n a b out a d v ers e dr u g reacti o ns f or t he i n vesti gati o nal dr u g ca n b e f o u n d i n t he 
I n v esti gat or’s Br oc h ure. 
1 2. 2. 1. 3.  A d verse E ve nts of S peci al I nterest  
A n A E  of s pecial i nterest ( A E SI) is o ne of scie ntific a n d me dical i nterest s pecific t o 
u n dersta n di n g  of t he in vesti gati o n al p r o d uct a n d re q uires cl ose m o nit ori n g a n d c o m m u nicati o n 
b y t he In vesti gat or  t o t he S p o ns or  wit hi n 2 4  h o urs of k n o wle d ge of t h e e ve nt , re gar dless of 
seri o us ness criteria. T he ra pi d re p orti n g of A E SIs all o ws o n g oi n g a n al ysis of t hese e v e nts i n 
or der t o c h aracteriz e a n d u n dersta n d t he m i n ass ociati o n wit h t he use of t his  i n vesti gati o nal 
pr o d uct.  
He p atic F u ncti o n A b n or m alit y  / Dr u g-i n d uce d Li ver I nj ur y 
Dr u g -i n d uce d li ver i nj ur y ( DI LI) is c o nsi dere d a n A E SI a n d s h o ul d be re p orte d wit hi n 2 4 h o urs 
of k n o wle d ge of t h e e ve nt.  I n s u bjects wit h n or mal li ver f u ncti o n at baseli n e, DI LI is defi ne d as 
a n i ncrease i n A L T or A S T t o greater t ha n 3 × U L N wit h  c o nc urrent i ncrease i n bilir u bi n t o 
greater t ha n 2 × U L N, wit h o ut a n ot her e x pla nati o n. I n s u bjects wit h a b n or m al A L T a n d/ or A S T 
a n d/ or bilir u bi n at baseli ne, it is o perati o nall y d efi ne d as a d o u bli n g of A L T or A S T a n d 
bilir u bi n, wit h o ut a n ot her e x pla nati o n . C o nc ur re nt fi n di n gs are t h ose t hat d eri ve fr o m a si n gl e 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 6  of 1 0 9  
C o nfi de ntial  
bl o o d dra w or fr o m se parate bl o o d dra ws ta k e n  wit hi n 8 da ys of eac h ot h er. I n t he e ve nt of 
he patic f u ncti o n a b n or malit y w here t he eti ol o g y is u n k n o w n,  ti mel y f oll o w-u p i n vesti gati o ns a n d 
i n q uiries s h o ul d be i nitiate d b y t h e i n vesti gati o nal site, base d o n me dical j u d g me nt, t o ma ke a n 
i nf or me d decisi o n re gar di n g t he eti ol o g y of t he e v e nt.  
Ac ute a n d Del a ye d H y perse nsiti vit y Re a cti o ns  
Bi ol o gic t h era pi es are k n o w n t o be ass ociate d wit h a n i ncrease d ris k of i m me d iate a n d dela ye d 
h y perse nsiti vit y reacti o ns as well as a n a p h yl a xis. A na p h yl a xis is defi ne d bel o w i n Ta ble  5  usi n g 
Sa m ps o n’s criteria ( Sa m ps o n  H A, 2 0 0 6 ).  A na p h yl a xis a n d se vere h y perse nsiti vit y reac ti o ns are 
re q uire d t o be re p ort e d wit hi n 2 4 h o urs of k n o wle d ge of t he e v e nt. 
T a ble  5 : 
Cli nic al C riteri a f or D i a g n osi n g A n a p h yl a xis  
A n a p h yl a xis is hi g hl y li kel y w he n a n y o ne  of t he f oll o wi n g 3 criteri a are f ulfille d:  
1.  
Ac ute o nset of a n ill ness ( mi n utes t o se veral h o urs) wit h i n v ol ve me nt of t he s ki n, m uc osal tiss ue, 
or b ot h (e g, ge neralize d hi ves, pr urit us or fl us hi n g, s w olle n li ps -t o n g ue-u v ula)  
 
A N D A T L E A S T O N E O F T H E F O L L O WI N G:  
 
a. 
Res pirat or y c o m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, stri d or, re d uce d P E F, 
h y p o xe mia)  
 
b.  
Re d uce d B P or ass ociate d s y m pt o ms of e n d -or ga n d ysf u ncti o n (e g, h y p ot o nia [c olla pse], 
s y nc o pe, i nc o nti ne nce) 
2.  
T w o or m ore of t he f oll o wi n g t hat occ ur ra pi dl y after e x p os ure t o a likely aller ge n f or t h at p atie nt  
( mi n utes t o se veral h o urs): 
 
a. 
I n v ol ve me nt of t he s ki n-m u c osal tiss ue (e g, ge neralize d hi ves, itc h -fl us h, s w olle n li ps-
t o n g ue-u v ula)  
 
b.  
Res pirat or y c o m pr o mise (e g, d ys p nea, w heeze -br o nc h os pas m, stri d or, re d uce d P E F, 
h y p o xe mia)  
 
c. 
Re d uce d B P or ass ociate d s y m pt o ms (e g, h y p ot o nia [c olla pse], s y nc o pe, i nc o nti ne nce)  
 
d.  
Persiste nt gastr oi ntesti nal s y m pt o ms (e g, cra m p y a b d o mi nal pai n, v o miti n g)  
3.  
Re d uce d B P after e x p os ure t o k n o w n aller ge n f or t h at p atie nt  ( mi n utes t o se veral h o urs): 
 
a. 
I nfa nts a n d c hil dre n: l o w s yst olic B P (a ge s pecific) or greater t ha n 3 0 % decrease i n s yst olic 
B P *  
 
b.  
A d ults: s yst olic B P of less t ha n 9 0 m m H g or greater t ha n 3 0 % decrease fr o m t hat pers o n’s 
baseli ne  
P E F, P ea k e x pirat or y fl o w; B P, bl o o d press ure.  
* L o w s yst olic bl o o d press ure f or c hil dre n is d efi n e d as less t h a n 7 0 m m H g fr o m 1 m o nt h t o 1 year, l ess t h a n ( 7 0 m m H g 1 +  
[2  a ge]) fr o m 1 t o 1 0 years,  a n d less t h a n 9 0 m m H g fr o m 1 1 t o 1 7 years.  
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 7  of 1 0 9  
C o nfi de ntial  
Ne utr o pe ni a  
A Es  of ne utr o pe ni a of s p ecial i nterest t o t he S p o ns or (defi ne d as a n A N C  <  1. 0  ×  1 0 9 cells/ L) 
will be c o nsi dere d a n A E SI a n d s h o ul d be re p ort e d wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt . 
Seri o us I nfecti o n  
I nfecti o ns meeti n g S A E  criteria (e g, re q uire d h os pital izati o n) or  i nfecti o ns wit h a se verit y gra d e  
of “ se vere” t h at re q uir e tr eat me nt wit h I V t hera p y (a nti bi otics, a nti viral, or a ntif u n gal) a n d 
o p p ort u nistic i nfecti o ns will be c o nsi dere d A E SI a n d s h o ul d be re p orte d wit hi n 2 4 h o urs of 
k n o wle d ge of t he e ve nt . 
E ver y eff ort s h o ul d be m a de t o i de ntif y t he ca usati ve pat h o ge n t hr o u g h pr o m pt a n d a p pr o priate 
i n vesti gati o n b y t he In v esti gat or or re p orti n g p h ysicia n.  
W orse ni n g of C yt o ki ne Rele ase S y n dr o me  
T here is li mite d e x perie nce wit h ma vrili m u ma b or ot her a nti-G M -C S F a ge nts i n patie nts wit h 
C O VI D -1 9. I n t he e x pa n de d access pr ot oc ol c o n d ucte d b y Italia n i n vesti gat ors wit h 
ma vrili m u ma b ( De L uca G, 2 0 2 0 ), all e x ce pt f or o ne of t he s u bjects tr eate d wit h ma vrili m u ma b 
e x perie nce d a d ecreas e i n C R P a n d I L -6 . Gi v e n t he li mite d e x perie nce, i n t his st u d y [ w orse ni n g 
of] c yt o ki ne releas e s y n dr o me ( C R S) will be assesse d as a n A E SI  a n d s h o ul d be re p ort e d wit hi n 
2 4 h o urs of k n o wle d ge of t he e ve nt . If a s us pecte d C R S occ urs, e g, s y m pt o ms s uc h as malaise, 
na usea a n d v o miti n g, diarr hea , u ns c he d ule d bl o o d sa m ple kits s h o ul d be c ollecte d, w hic h will 
i ncl u de serial c yt o ki nes a n d i nfla m mat or y bi o mar kers. T hese s a m ples s h o ul d be i m me diatel y 
s hi p pe d t o t he ce ntral la b orat or y a n d t he st u d y site s h o ul d c ollect l ocal a vail a ble c yt o ki nes a n d 
i nfla m mat or y bi o mar kers i n parallel. 
1 2. 2. 1. 4.  Seri o us A d verse E ve nt ( S A E)  
A n  S A E is defi ne d as a n y A E  (a p peara n ce of [or w orse ni n g of a n y pre -e xisti n g] u n desira ble 
si g n(s), s y m pt o m(s) or m e dical c o n diti o ns(s)) w hi c h meets a n y o ne of t he f oll o wi n g criteria:  
•  res ults i n deat h  
•  is life-t hreate ni n g 
− Lif e -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he s u bject 
was at ris k of deat h at t he ti m e of t he reacti o n; it d oes n ot refer t o a reacti o n t hat 
h y p ot hetic all y mi g ht ha ve ca use d d eat h if it were m ore se vere ( please refer t o t he 
I C H-E 2 D G ui deli nes)  
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y 
•  c o nstit utes a c o n ge nital a n o mal y/ birt h  defect  
•  re q uires 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, u nless 
h os pitaliz ati o n is f or:  
− r o uti ne treat me nt or m o nit ori n g of t he st u die d i n di cati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n (c or o nar y heart disease, c ere br o vasc ul ar diseas e or 
peri p heral vasc ular disease)  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
5 8  of 1 0 9  
C o nfi de ntial  
− electi ve or pre -pla n n e d tr eat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelat e d t o 
t he i n dicati o n u n der st u d y a n d h as n ot w orse n e d si nce si g ni n g t he i nf or me d 
c o nse nt  
− s ocial reas o ns a n d res pite care i n t he a bse n ce of a n y det eri orati o n i n t he s u bject’s 
ge n eral c o n diti o n  
− treat me nt o n a n e m er ge n c y o ut p atie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E gi v e n a b o ve a n d n ot r es ulti n g i n h os pital a d missi o n  
•  is me dicall y si g nifica nt, e g, d e fi ne d as a n e v e nt t hat je o par dizes t he s u bject or ma y 
re q uire me di cal or s ur gic al i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o u s r eacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y 
life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht je o par dize t he s u bject or mi g ht 
re q uire i nter ve nti o n t o pr e ve nt o ne of t he ot h er o utc o mes liste d a b o ve. S uc h e ve nts s h o ul d be 
c o nsi dere d as “ me dicall y si g nifica nt ”. E x a m ples of s uc h e ve nts are i nte nsi v e treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns t hat d o 
n ot res ult i n h os pitalizati o n or de vel o p me nt of d e pe n de nc y or a b use.  
All mali g na nt ne o plas ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met. 
A n y s us pe cte d tra ns missi o n via a me dici nal pr o d u ct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d vers e reacti o n. 
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d seri o us A E  
irres pecti ve of w het h er  a cli nical e ve nt has o cc urre d.  
1 2. 3.  
Rel ati o ns hi p t o St u d y Dr u g  
A n I n vesti gat or w h o is q ualifie d i n me dici ne m ust ma ke t he deter mi nati o n of relati o ns hi p t o t he 
i n vesti gati o nal pr o d u ct f or eac h A E (N ot R elat e d, U nli kel y Relate d , P ossi bl y Relate d or 
Defi n itel y R elate d). T h e I n v esti gat or s h o ul d deci d e w het her, i n his or her me dical j u d g m e nt, 
t here is a reas o na bl e p ossi bilit y t hat t he e v e nt ma y ha ve bee n ca us e d b y t he i n vesti gati o nal 
pr o d uct. If n o vali d reas o n e xists f or s u g gesti n g a relati o ns hi p, t he n t he A E s h o ul d be classifie d 
as “N ot rel ate d.” If t here is a n y vali d reas o n, e v e n if u n deter mi ne d, f or s us pecti n g a p ossi ble 
ca use-a n d-effect rel ati o ns hi p bet wee n t he i n vesti gati o nal pr o d uct a n d t he o cc urre nce of t he A E, 
t he n t he A E s h o ul d be c o nsi dere d “relate d. ” 
If t he rel ati o ns hi p bet wee n t he S A E a n d t he i n vesti gati o nal pr o d u ct is deter mi ne d t o be 
“P ossi bl y ” or “D efi nitel y” relate d, t h e e ve nt will b e c o nsi dere d relat e d t o t he i n vesti gati o nal 
pr o d uct f or t he p ur p oses of e x pe dite d re g ulat or y re p orti n g.   If t he relati o ns hi p bet wee n t he S A E 
a n d i n vesti gati o nal pr o d uct is dee me d t o be “ u nli k el y relate d, ” t he case is c o nsi dere d e x pe dite d 
i n J a pa n b ut n ot e x pe dite d i n t he U S A or E ur o pea n U ni o n. 
1 2. 4.  
Rec or di n g A d verse E ve nts  
T he In vesti gat or h as t he res p o nsi bilit y f or ma na gi n g t he safet y of i n di vi d ual s u bject a n d 
i de ntif yi n g A E s. 


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Q ualifie d me dical p ers o n nel will be rea dil y a v aila ble t o a d vise o n trial relat e d me dical q uesti o ns 
or pr o ble ms.  
T he occ urre n ce of A E s m ust be s o u g ht b y n o n-directi ve q uesti o ni n g of t he s u bject at eac h visit 
d uri n g t he st u d y. A Es  als o ma y b e detecte d w he n t he y are v ol u nteere d b y t he s u bject d uri n g or 
bet wee n visits or t hr o u g h p h ysical e x a mi nati o n fi n di n gs, la b orat or y test fi n di n gs, or ot her 
assess me nts.  
A Es  m ust be rec or de d i n t he A d verse E ve nts C R F u n der t he si g ns, s y m pt o ms or dia g n osis 
ass ociate d wit h t he m, acc o m pa nie d b y t h e f oll o wi n g i nf or m ati o n (as far as p ossi ble) (if t he e ve nt 
is seri o us refer t o Secti o n  1 2. 2. 1. 4 ): 
1.  T he se verit y gra de:  
•  mil d: us uall y tr a nsie nt i n nat ure a n d ge nerall y n ot i nterferi n g wit h n or m al acti vities  
•  m o derat e: s uffi cie ntl y dis c o mf orti n g t o i nterfere wit h n or mal acti vities  
•  se vere: pr e ve nts n or mal acti vities. 
2.  Its r elati o ns hi p t o t he st u d y treat me nt. If t he e ve nt is d ue t o lac k of efficac y or 
pr o gressi o n of u n derl yi n g ill ness (ie , pr o gressi o n of t he st u d y i n dica ti o n) t he assess me nt 
of ca usalit y will us uall y be ‘ N ot s us pect e d’. T he rati o nale f or t his g ui da nce is t hat t he 
s y m pt o ms of a lac k of efficac y or pr o gressi o n of u n derl yi n g ill ness are n ot ca use d b y t he 
trial dr u g, t h e y ha p pe n i n s pite of its a d mi nistrati o n a n d/ or b ot h lac k of effi cac y a n d 
pr o gressi o n of u n derl yi n g diseas e ca n o nl y b e e v al uate d mea ni n gf ull y b y a n a nal ysis of 
c o h orts, n ot o n a si n gle s u bject . 
3.  Its d ur ati o n (start a n d e n d dates) or if t he e ve nt is o n g oi n g, a n o utc o m e of n ot 
rec o vere d/ n ot res ol v ed m ust be re p orte d.  
4.  W het her it c o nstit utes a S A E (see Secti o n  1 2. 2. 1. 4  f or defi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met. 
5.  Acti o n ta ke n re gar di n g wit h st u d y tr eat me nt. 
All A E s m ust be treate d a p pr o priatel y.  T his st u d y i ncl u des a si n gl e I V d ose 
a d mi nistrati o n. N o d ose a dj ust me nt is a ntici pate d. Acti o ns ma y i ncl u d e : 
•  N ot a p plica ble  
•  D ose  te m p oraril y i nterr u pte d b ut later  c o m plete d  
•  D ose  i nterr u pte d a n d n ot c o m plete d 
6.  Its o utc o me  
•  n ot rec o vere d/ n ot res ol ve d  
•  rec o vere d/r es ol ve d 
•  rec o veri n g/res ol vi n g 
•  rec o vere d/r es ol ve d wit h se q uelae 
7.  fatal; or u n k n o w n. 


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C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n t he 
me dical hist or y of t he s u bject.  
A E s (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri b e d usi n g a dia g n osis 
w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
A E  m o nit ori n g s h o ul d be c o nti n ue d f or at least 6 0 da ys f o ll o wi n g t he l ast d ose of st u d y 
treat me nt. 
O nce a n A E  is detect e d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o be 
per ma ne nt ( e g, co nti n ui n g at t he e n d of t he st u d y), a n d assess me nt m ust be ma de at eac h visit ( or 
m ore fre q u e ntl y, if necessar y) of a n y c ha n ges i n se verit y, t he s us pect e d rel ati o ns hi p t o t he 
i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me. 
T he Me dical Di cti o nar y f or Re g ul at or y Acti vities ( Me d D R A) will be use d t o c o de all A Es . 
1 2. 5.  
Re p orti n g Seri o us A d verse E ve nts  
T o e ns ure s u bject safet y, e ver y S A E, re gar dl ess of ca usalit y, o cc urri n g aft er t he s u bject has 
pr o vi de d i nf or me d c o ns e nt a n d u ntil t he last st u d y visit m ust be re p orte d t o t he S p o ns or  or 
desi g nee , wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. A d diti o nal l y, I n vesti gat or re p orti n g of 
S A Es t o I R B/ E C a n d ot h er  Re g ulat or y Healt h A ut h orities ma y b e re q uir e d  per l ocal r ul es a n d 
re g ulati o ns. F or t he p ur p ose of deter mi ni n g t he e x pecte d ness of Seri o us S us pecte d A d verse 
Reacti o ns i n o n g oi n g st u dies c o n d ucte d b y Ki ni ks a, t he f oll o wi n g Seri o us S us pecte d A d verse 
Reacti o n is c o nsi dere d a n e x pecte d react i o n: P ne u m o nia .   
M ore s pecifi call y, t he I n vesti gat or will re p ort all S A E s t o t he Ki ni ksa P har mace uticals safet y 
C R O ve n d or n o later t ha n 2 4 h o urs after t h e I n vesti gat or’s i nitial recei pt of t his i nf or mati o n . 
T he e ve nt m ust als o be rec or de d o n t h e cli nical d ata base . Preli mi nar y re p orts of S A Es m ust be 
f oll o we d b y detaile d des cri pti o ns as s o o n as p ossi ble i ncl u di n g cl ear a n d re dacte d p h ot oc o pies of 
h os pital case re p orts, c o ns ulta nt re p orts, a ut o ps y re p orts, a n d ot her d o c u me nts w he n re q uest e d a s 
a p plica ble a n d if a vaila bl e.  
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure a n d is t h o u g ht t o be 
relate d t o t he st u d y treat me nt, t he n t he e ve nt is c o nsi dere d a s us pecte d u ne x pecte d seri o us 
a d verse reacti o n ( S U S A R), a n d Ki ni ksa or desi g nee ma y nee d t o iss ue a n I n v esti gat or 
N otificati o n t o i nf or m all I n v esti gat ors i n v ol ve d i n a n y st u d y wit h t he sa m e st u d y treat me nt t hat 
t his S A E has bee n re p orte d. T he sta n dar d t i meli nes f or S U S A R re p orti n g as per I C H E 2 A will be 
f oll o we d.  
T he S p o ns or  or desi g nee  will re p ort all S U S A Rs  t o t he a p plica ble Re g ulat or y A ut h orities  n o 
later t ha n 1 5 cale n dar da ys after t he S p o ns or’s i nitial recei pt of t his i nf or m ati o n. Fatal or life-
t hreate ni n g u ne x pecte d e x perie nces f or w hi c h t here is a p ossi bilit y t hat t he e x perie nce ma y h a ve 
bee n ca use d b y t he dr u g will be re p orte d b y t he S p o ns or  or desi g nee  t o t he Re g ulat or y 
A ut h orities  b y tele p h o n e or facsi mile tra ns missi o n n o later t ha n 7 cale n dar da ys after recei pt of 
t his i nf or mati o n.  
A n y S A Es e x perie n ce d after c o m pleti o n of t he st u d y s h o ul d o nl y be re p orte d t o t he 
S p o ns or/I n vesti gat or.  


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E xce pti o ns t o S A E Re p orti n g  
E ve nts t hat are ca pt ure d as pr ot oc ol -ma n dat e d cli nical o utc o me meas ures ( ie, part of t he 8-p oi nt 
NI AI D s cale) s h o ul d n ot  be re p ort e d as S A Es. T his w o ul d i ncl u de i nitiati o n of i n vasi ve 
mec ha nic al ve ntilati o n a n d/ or E C M O , n o n-i n vasi ve ve ntilati o n or hi g h-fl o w o x y ge n, a n d 
s u p ple me ntal o x y ge n.  I n a d diti o n, pr oce d ures ass ociate d wit h t hese cli nical o utc o me meas ures 
(e g, i nt u bati o n or trac h e ost o m y) s h o ul d n ot be re p orte d as S A Es. E ve nts t h at i n t he j u d g me nt of 
t he i n vesti gat or are clearl y a p art of t he nat ural hist ory of se vere C O VI D -1 9 p ne u m o nia wit h 
h y per -i nfla m mati o n s h o ul d n ot be re p orte d as S A Es (e g, fe v er, el e vate d C R P). All deat hs , 
seri o us i nfecti o ns a n d se vere gra n ul oc yt o pe nia a n d ne utr o pe nia s h o ul d be re p orte d as S A Es.  Per 
t he I n v esti gat or Br oc h ure, p ne u m o nia is t he o nl y e ve nt t hat is i ncl u de d i n t he Refere nce Safet y 
I nf or mati o n ( R SI) a n d w o ul d be c o nsi dere d e x pecte d or liste d. A n y ot h er seri o us relate d a d verse 
dr u g reacti o ns w o ul d be c o nsi dere d u n e x pecte d a n d w o ul d re q uire e x pe dite d re p orti n g.  
1 2. 5. 1.  
Pre g n a nc y Re p orti n g  
F or mal r e pr o d ucti o n t o xic ol o g y testi n g of K P L -3 0 1  has n ot yet b ee n perf or me d.  
Fe male s u bjects of c hil d beari n g p ote ntial m ust t heref ore a gree t o use a hi g hl y effecti ve a n d 
pr ot oc ol -a p pr o ve d c o ntr ace pti ve met h o d ( Secti o n  7. 1 ) f or t he d urati o n of t he st u d y (u ntil Da y 
9 0) , w hic h is 9 0 da ys aft er d osi n g a n d c o v ers 5 ½ half -li ves of ma vrili m u ma b (a p pr o xi matel y 1 5 
da ys) .  Re g ular pre g na n c y tests will be perf or me d f or fe mal e s u bjects of c hil d beari n g p ote ntial, 
as defi ne d i n t he Sc h ed ule of Acti vities ( Ta bl e  2 ). 
Male s u bjects w h o ha v e a fe male p art ner of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y 
effecti ve a n d pr ot o c ol a p pr o ve d  c o ntr ace pti ve m et h o d ( Secti o n  7. 1 ) f or t he d urati o n of t he st u d y 
a n d u ntil 1 6 wee ks aft er l ast st u d y dr u g a d mi nistrati o n u n der t his pr ot oc ol.  
If a s u bject b ec o mes pre g na nt w hile partici pati n g i n t he st u d y, st u d y dr u g d osi n g m ust be 
disc o nti n ue d i m me diatel y.  
A fe male s u bject m ust i m me diatel y i nf or m t he I n vesti gat or if s h e bec o mes pre g na nt d uri n g t he 
st u d y. A male s u bject m ust i nf or m t he I n v esti gat or if his fe male part ner bec o mes pre g na nt 
d uri n g t he st u d y. Pre g n a ncies occ urri n g u p t o 1 6 wee ks after last st u d y dr u g a d mi nistrati o n m ust 
be re p ort e d t o t he I n vesti gat or. T he I n v esti gat or m ust re p ort all pre g n a ncies t o t he S p o ns or or 
desi g nee i m me diatel y a n d n o  later t ha n 2 4 h o urs of t heir first k n o wle d ge of t he pre g na n c y. T he 
I n v esti gat or s h o ul d c o u nsel t he s u bject t hat it is u n k n o w n w hat effects st u d y dr u g mi g ht ha ve o n 
a fet us. M o nit ori n g of t he s u bject s h o ul d c o nti n ue u ntil c o ncl usi o n of t he pre g na nc y.  T he 
n e w b or n s h o ul d be m o nit ore d f or a mi ni m u m of 6 m o nt hs after birt h , or l o n ger as per l ocal 
re q uire me nt. 
I nsta n ces of fetal deat h or c o n ge nital a b n or malit y, if br o u g ht t o t he atte nti o n of t he I n vesti gat or 
at a n y ti me after cessati o n of t he st u d y tr eat me nt a n d  c o nsi dere d b y t he I n v esti gat or t o b e 
p ossi bl y relate d t o t he st u d y treat me nt, m ust be re p orte d t o t he S p o ns or as a n S A E.  
1 2. 5. 2.  
Re p orti n g of St u d y Tre at me nt Err o rs  
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me di ci ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, s u bject or 
c o ns u mer.  


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St u d y treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be c ollecte d i n 
t he e C R F irres p ecti ve of w het her  ass o ciate d wit h a n A E/ S A E a n d r e p orte d t o Safet y wit hi n 2 4 
h o urs of a w are n ess  o nl y if ass ociate d wit h a n S A E . 


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1 3.  
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S  
T he P hase 2 a n d P has e 3 parts of t his st u d y a n d t h e c o h orts wit hi n eac h p hase will be 
i n de pe n de ntl y a nal yze d u nless ot her wise s pecifie d. 
1 3. 1.  
A n al ysis Sets  
1 3. 1. 1.  
I nte nt-t o-Tre at A n al ys is Set 
All ra n d o mize d s u bjects w h o meet eli gi bilit y criteria will be i ncl u de d i n t he i nte nt -t o-treat (I T T) 
a nal ysis s et. Effic ac y a n al yses f or t he P hase 3 p art of t he st u d y will be b ase d o n t he I T T a nal ysis 
set. All I T T a nal yses will be base d o n t he ra n d o mi ze d treat me nt.  
1 3. 1. 2.  
M o difie d I nte n t-t o-Tre at A n al ysis Set  
All ra n d o mize d s u bjects w h o meet eli gi bilit y criteria a n d recei v e st u d y dr u g (ie, i nitiati o n of 
st u d y dr u g i nf usi o n) will be i ncl u de d i n t he m o difie d i nte nt -t o-treat ( mI T T) a nal ysis s et. Efficac y 
a nal ys es f or t h e P hase 2 part of t he st u d y will be base d o n t he mI T T a nal ysis set. All mI T T 
a nal ys es will be base d o n t he ra n d o mize d treat me nt.  
1 3. 1. 3.  
S afet y A n al ysis Set  
All ra n d o mize d s u bjects recei v e st u d y dr u g will be i ncl u de d in t he Safet y a nal ysis set. Safet y 
a nal ys es will be base d o n t he act ual treat me nt recei ve d.  
1 3. 1. 4.  
Per -Pr o t oc ol A n al ysis Set 
All mI T T/I T T s u bjects wit h o ut pr ot oc ol de viati o ns dee me d t o i m pact efficac y or et hical c o n d uct 
will be i ncl u de d i n t he per -pr ot oc ol ( P P) a n al ysis s et.  
1 3. 2.  
St atistic al A n al ysis  
T his secti o n o utli nes t he o verall met h o d ol o gi es. D etails of t he statistical a nal yses, m et h o ds, a n d 
data c o n ve nti o ns will be descri be d i n t he Statistical A nal ysis Pla n ( S A P ). 
1 3. 2. 1.  
Ge ner al Met h o ds  
All statistical a nal yses will be  perf or me d usi n g S A S ®  Versi o n 9. 4 or hi g her. All cli nical st u d y 
data will be pres e nte d i n s u bject data listi n gs. Des cri pti ve statistics will be prese nte d f or all 
e n d p oi nts a n d will i ncl u de n u m ber of s u bjects ( n), mea n, S D, me dia n, i nter q uartile ra n ge, 
mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bl es, a n d fre q u e nc y a n d perce nta ge f or cate g ori cal 
a n d or di nal vari a bles. T h e fi nal S A P will be c o nfir me d i n a se parate d oc u me nt pri or t o st u d y 
u n bli n di n g. A n a b bre viat e d s u m mar y of t he S A P p o p ulati o ns a n d met h o ds is pr o vi de d bel o w.  
1 3. 2. 2.  
Str atifie d A n al ysis  
T here will be 3 stratificati o n fact ors f or ra n d o mizati o n:  
1.  Use of a ut h orize d  sta n dar d of care a nti vir al  t hera p y f or C O VI D-1 9 (e g, re m desi vir) : yes  
vs.  n o  
2.  A ge: <  6 5 vs. ≥ 6 5 year s 


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3.  Ac ute res pir at or y distress s y n dr o me ( A R D S) stat us b y partial press ur e of o x y ge n t o 
fracti o nal i ns pire d o x y ge n ( Pa O2/ Fi O2) rati o *: n or mal-mil d (> 2 0 0 ) vs. m o derate -se vere 
(≤ 2 0 0 ). A R D S stat us will o nl y be use d f or C o h ort 1 ( n o n -ve ntilate d  s u bjects)  
*  
If Pa O2 is u na vaila ble, us e S p O2/ Fi O2:  n or mal– m il d ( > 2 3 5 ) vs. m o derate-s e vere 
( ≤ 2 3 5 ) 
W he n a n a nal ysis is t o be stratifie d b y t h ese varia bles a n d a strat u m has ≤ 5 e ve nts of i nterest i n a 
l o g-ra n k test or t he sa m e res p o nse i n all s u bjects i n a C oc hra n -M a ntel -Hae nszel (C M H ) test, t he 
strata f or t he l ast stratificati o n fact or will be p o ole d. If t he sa me sit uati o n o cc urs, strat a f or t he 
sec o n d fact or will be p o ole d. If t he sa me sit uati o n still e xists, t he a nal ysis will be d o ne wit h o ut 
stratificati o n. 
1 3. 2. 3.  
H a n dli n g of Dr o p o uts  a n d M issi n g D at a 
N o dr o p o uts  will be re pla ce d. E ver y eff ort will be ma de t o a v oi d missi n g data . M issi n g data will 
n ot  be i m p ute d u nless ot her wise s pecifie d. F or ti me -t o-e ve nt a nal yses, s u bjects wit h o ut t he e ve nt 
will be ce ns ore d.  Details o n ha n dli n g missi n g d at a will be s pecifie d i n t he S A P.  
1 3. 2. 4.  
Effic ac y A n al ys es 
All efficac y a n al ys es will be base d o n t he mI T T f or t he P hase 2 e n d p oi nts a n d base d o n t he I T T 
a nal ysis s et f or t he P hase 3 e n d p oi nts. A nal ys es b ase d o n ot her a nal ysis sets will be c o nsi dere d 
as se nsiti vit y a nal ys es. All efficac y c o m paris o ns will be pri maril y base d o n eac h of t he ma vrili m u ma b 
ar ms vers us t he place b o ar m.    
1 3. 2. 4. 1.  Pri m ar y Effic ac y E n d p oi nt  
F or t he P hase 2 p art of t h e st u d y, t he Fis her’s e x act test will be d o ne f or t he pri mar y efficac y 
e n d p oi nt f or b ot h co h orts.  T he C M H test a dj ust i n g f or ra n d o mizati o n strata (a ut h orize d sta n dar d 
of care a nti viral  t hera p y f or C O VI D-1 9 [e g, re m desi vir] , a ge, a n d A R D S stat us) will be use d as 
s u p p orti ve a nal ysis of t he pri mar y efficac y e n d p oi nt f or C o h ort 1.  
F or  b ot h c o h orts i n  t he P hase 3 part of t h e st u d y, t he C M H test a dj uste d b y ra n d o mizati o n strata 
(a ut h orize d  sta n dar d of care a nti vir al  t hera p y f or C O VI D-1 9 (e g, re m d esi vir), a ge, a n d A R D S 
stat us) will be use d t o test t he pri mar y efficac y e n d p oi nt. 
N u m ber of s u bjects a n d perce nt a ges will be s u m marize d b y tr eat me nt. T h e 8 0 %  (fo r P hase 2) 
a n d 9 5 % (f or P hase 2 a n d  3)  c o nfi de n ce i nter vals ( CIs) will als o  be pr o vi de d as a p pr o priat e.   
M issi n g data at D a y 1 5 will be c o nsi dere d as n o n-res p o n der u nless ot her wise s pecifie d. Details 
f or ha n dli n g missi n g data will be s pecifie d i n t he S A P. 
1 3. 2. 4. 2.  Sec o n d ar y a n d Ot her Effic ac y E n d p oi nts  
Ve ntilati o n -free s ur vi val, o verall s ur vi val , 
 ti me t o cli nical 
i m pr o ve me nt, a n d all ot her ti me t o e vent e n d p oi nts will be a nal yze d usi n g l o g -ra n k test stratifie d 
b y ra n d o mizati o n strata. T hese ti me t o e ve nt e n d p oi nts will be s u m marize d wit h t he 2 5t h, 5 0t h 
( me dia n), a n d 7 5t h p erce ntiles usi n g t he Ka pla n-Meier met h o d. T he 8 0 % (f or P hase 2) a n d 9 5 % 
(fo r P hase 2 a n d 3)  CI s f or t he perce ntiles will be calc ulate d usi n g a l o g-l o g tra nsf or mati o n. T he 
perce nt a ge of s u bjects wit h e ve nts a n d its 8 0 %  (f or P hase 2) a n d 9 5 % (f or P hase 2 a n d 3)  CI will 


ma vrili m u ma b ( K P L -3 0 1)  
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be calc ul ate d at Da y 4, 8 , 1 5, 2 2 a n d Da y 2 9  si nc e ra n d o mizati o n as ap pr o p riate, usi n g 
Gree n w o o d’s f or m ula wit h a l o g -l o g tr a nsf or mati o n. 
T he hazar d rati o f or ma vrili m u ma b vs. place b o a n d t he c orres p o n di n g Wal d 8 0 % (f or P hase 2) 
a n d 9 5 %  (f or P hase 2 a n d 3)  CI will be calc ulat e d base d o n a C o x pr o p orti o nal -hazar ds m o del 
wit h treat me nt as c o v ariate, stratifie d b y ra n d o mizati o n strata.  
All  bi nar y e n d p oi nts i n b ot h c o h orts f or P hase 2 will be pri maril y a n al yze d usi n g t he Fis her’s 
e x act test. T he C M H test a dj usti n g f or ra n d o mizati o n strata (a ut h orize d  sta n dar d of care a nti viral  
t hera p y f or C O VI D-1 9 [ e g, re m desi vir], a ge, a n d A R D S stat us) will be use d as s u p p orti ve  
a nal ysis for C o h ort 1  ( n o n-ve ntilate d s u bjects) .  
F or t he P hase 3 p art of t h e st u d y, t he C M H test a d j uste d b y ra n d o mizati o n strata will be use d t o 
test all bi nar y s ec o n dar y a n d ot her  efficac y e n d p oi nt f or  b ot h  c o h orts. 
1 3. 2. 5.  
S afet y A n al ys is 
All safet y s u m maries will be prese nte d f or t he safet y a nal ysis set. N o f or m al statistical a nal ysis 
of safet y e n d p oi nts wi ll be perf or me d. 
Descri pti ve statistics will be use d t o s u m marize all safet y e n d p oi nts b y treat me nt gr o u p a n d/ or 
st u d y visit. Data s u m maries will dis pla y  para meters s uc h as i nci de n ce of A E s, cli nical la b orat or y 
varia bles, vital si g ns, b o d y w ei g ht a n d b o d y mass i n de x, E C G para meters, a n d p h ysic al 
e x a mi nati o ns, w here a vaila ble.  
1 3. 2. 6.  
Ot her A n al ys es 
P har mac o ki netic para met ers of ma vrili m u ma b will be s u m marize d. T he pres e nce of a nti-dr u g 
a nti b o dies will be e x pl ore d. Para meters of mec ha nical ve ntilati o n, res pirat or y  stat us, 
S O F A/ q S O F A, a n d healt h care res o ur ce utilizati o n  (e g, da ys a n d/ or le n gt h i n h os pital/I C U) will 
be s u m mariz e d.  
1 3. 2. 7.  
I nteri m A n al ysis 
T here is n o i nteri m a n al ysis pla n ne d f or t he P hase 2 or P hase 3 part of t h e st u d y.  I nste a d, t he 
S p o ns or will c o n d uct a p ri mar y a n d/ or fi n al effi cac y a nal ysis (ie, re vie w of u n bli n de d st u d y 
res ults) w he n t he last s u bject i n eac h P has e a n d C o h ort  c o m pletes t he Da y 2 9 / Da y 9 0 
assess me nts.  
1 3. 3.  
S a m ple Size Esti m ati o n  
1 3. 3. 1.  
P h ase 2  
A p pr o xi matel y 1 7 1  s u bj ects will be ra n d o mize d t o t he P hase 2 part of t his st u d y.  
Sa m ple siz e esti mati o n f or C o h ort 1  (n o n -ve ntilat e d s u bjects)  i n P hase 2 is base d o n t he pri mar y 
effic ac y e n d p oi nt pr o p orti o n of s u bjects ali ve a n d free of mec h a nical ve ntil ati o n at Da y 2 9 , usi n g 
a Fis her’s e x act test.  
A p pr o xi matel y 1 2 0  s u bj ects will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he 
p r o p orti o n of s u bjects ali ve a n d free of m ec ha ni cal ve ntilati o n at Da y 2 9 is 9 5 % a n d 7 5 % f or t he 
acti ve treat me nt ar m a n d place b o ar m, re s pecti vel y, 4 0  s u bjects per ar m will ac hie ve a mi ni m u m 


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8 0 % p o wer f or a p air wis e c o m paris o n vers us c o ntr ol  w he n t he t w o -si de d al p ha val ue is 0. 2 0, 
after acc o u nti n g f or 1 5 % dr o p o ut . 
Sa m ple siz e f or C o h ort 2  ( ve ntilate d s u bjects) i n P hase 2 is base d o n t he pri mar y effi cac y 
e n d p oi nt  of  m ortalit y rate at Da y 2 9 , usi n g t he Fis her’s e x act test. A p pr o xi matel y 5 1  s u bjects 
will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he m ortalit y rate s at Da y 2 9  are 4 0 % 
a n d 8 0 % f or t h e acti ve tr eat me nt ar m a n d pl ace b o  ar m, res pecti vel y, 1 7  s u bjects per ar m will 
ac hie ve a n 8 0 % p o w er f or  a pairwise c o m paris o n vers us c o ntr ol  w he n t h e t w o -si de d al p ha val ue 
is 0. 2 0. 
1 3. 3. 2.  
P h ase 3  
A p pr o xi matel y 6 6 5  s u bj ects will be ra n d o mize d t o t he P hase 3 part of t his st u d y.  
Sa m ple siz e f or C o h ort 1  ( n o n-ve ntilate d  s u bjects) of t he P hase 3 part  is deter mi ne d base d o n t h e 
pri mar y efficac y e n d p oi nt pr o p orti o n of s u bjects ali ve a n d free of mec ha nical ve ntilati o n at Da y 
2 9  (ma vrili m u ma b  6 m g/ k g vs place b o ), usi n g t he C hi s q uare  test. T he ass u m pti o ns use d f or t he 
calc ulati o n are a dj uste d b ase d o n t he res ults of P hase 2 p orti o n.  A p pr o xi matel y 6 0 0  s u bjects will 
be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he pr o p orti o ns f or t he acti ve ar m a n d 
place b o ar m are 8 7. 5 % a n d 7 4 .4 % res pecti vel y, a p pr o xi matel y 2 0 0  s u bjects per ar m are 
s ufficie nt t o ac hie v e at least  9 0 % p o wer f or t he tr eat me nt c o m paris o n at t he t w o-si de d 
si g nifica n ce le v el of  0. 0 5 . 
Sa m ple siz e f or C o h ort 2  (ve ntilate d s u bjects)  of t he P hase 3 part  is deter mi ne d base d o n t he 
m ortalit y rate at Da y 2 9  usi n g a Fis her’s e x act test. A p pr o xi matel y 1 1 7  s u bjects will be 
ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he m ortalit y rates f or t he acti ve ar m a n d 
place b o ar m are 4 0 % a n d 8 0 % res pecti vel y, a p p r o xi matel y 39  s u bjects p er ar m are re q uir e d t o 
ac hie ve a 9 0 % p o w er f or a pair wise c o m paris o n v ers us c o ntr ol w he n t h e t w o -si de d al p ha val ue is 
0. 0 2 5.  H o we ver, b ase d o n re vie w of t h e P hase 2 C o h ort 2 res ults of t he pri mar y a n d sec o n dar y 
e n d p oi nts at da y 2 9 , P has e 3 C o h ort 2 is  cl ose d t o f urt her e nr oll me nt  (a p pr o xi matel y 6 5 s u bjects 
ra n d o mize d at t he ti me of e nr oll me nt cl os ure), as t here was n o e vi de nce t h at ma vrili m u ma b 
pr o vi de d cli nical be n efit o ver place b o i n rece ntl y ve ntilate d patie nts.  
1 3. 4.  
M ulti plicit y A dj us t me nt 
T he c o h orts wit hi n t he P hase 2 a n d P hase 3 st u d y parts will be a nal yz e d se paratel y u nless 
ot her wise s pecifie d.  
T he t w o -si de d t y pe I err or rate is 0. 2 f or eac h P has e 2 c o h ort  a n d 0. 0 5 f or eac h P hase 3 c o h ort. 
N o m ulti plicit y a dj ust me nt will be d o ne f or t he P h ase 2 part a n d P hase 3 C o h ort 2  (n o f or mal 
testi n g will be d o ne as e nr oll me nt f or t his c o h ort st o p pe d earl y) .  
M ulti plicit y a dj ust me nt f or P hase 3 C o h ort 1 will be d o ne t o g uara ntee str o n g c o ntr ol of t he 
o verall T y pe I err or rat e at a t w o -si de d al p h a val u e of 0. 0 5. F or eac h e n d p oi nt, t he test statistics 
f or t he t w o c o m paris o ns as y m pt oticall y f oll o w a bi variate n or mal distri b uti o n  a n d are p ositi vel y 
c orrel ate d d ue t o s hari n g a c o m m o n c o ntr ol  ar m ( place b o) . T h us, t he c o n ve nti o nal H oc h ber g 
met h o d will be use d t o a dj ust f or m ulti plicit y i n t he a nal ysis of t he t w o d ose le vels a n d t he 
se q ue nce of efficac y e n d p oi nts. Bel o w are t he det ails.   


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C o nsi deri n g t he h y p ot hesis testi n g of b ot h t he 1 0 m g/ k g a n d t he 6 m g/ k g i n di vi d uall y vers us 
place b o f or eac h e n d p oi nt t o be a fa mil y, t h e testi n g o n t he pri mar y e n d p oi nt a n d t he t hree 
or dere d s ec o n dar y e n d p oi nts c orres p o n d t o Fa mil y 1, Fa mil y 2, Fa mil y 3, a n d Fa mil y 4, 
res pecti vel y.  
Testi n g will be d o ne s e q ue ntiall y ( Fa mil y 1, t he n 2, 3, a n d 4) base d o n t h e f oll o wi n g decisi o n 
r ules ( p-val u es are all t w o -si de d):  
•  If b ot h p-val ues i n a fa mil y are ≤ 0. 0 5, statisticall y si g nifica nt treat me nt effects f or t he 
e n d p oi nt ca n be clai me d f or b ot h d ose le vels, a n d testi n g ma y pr ocee d t o t h e ne xt fa mil y 
t o test t h ose h y p ot heses at t w o-si de d si g nifica nce l e vel of 0. 0 5.  
•  If t he lar ger p-v al ue is > 0. 0 5 a n d t he s maller p -v al ue is ≤ 0. 0 2 5, a statisticall y si g nifi ca nt 
treat me nt effect ca n be cl ai me d o nl y f or t he o ne d ose le vel c orres p o n di n g t o t he s maller 
p -val ue. Se q ue ntial testi n g st o ps here, a n d n o f urt h er i nfere ntial testi n g ca n be d o ne. T he 
re mai ni n g d ata a n al yses will be pr o vi de d f or c o m plete ness ( wit h p val ues as n o mi nal) t o 
i nf or m t he disc ussi o n of be nefit-ris k.  
•  If b ot h p-val ues i n t he fa mil y are > 0. 0 5, a statisticall y si g nifica nt treat me nt effect ca n n ot 
be clai me d f or eit her d os e le vel. Se q ue ntial testi n g st o ps here, a n d n o f urt h er i nfere ntial 
testi n g ca n b e d o ne. T h e re mai ni n g d ata a n al yses will be pr o vi de d f or c o m plete ness ( wit h 
p val ues as n o mi nal) t o i nf or m t he disc ussi o n of b e nefit -ris k.  
 


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1 4.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
1 4. 1.  
St u d y M o nit ori n g  
Bef ore a n i n v esti gati o nal site ca n e nr oll a s u bject i nt o t he st u d y, a re pres e nt ati ve of Ki ni ksa  or 
desi g nee  will c o ntact t he i n vesti gati o nal st u d y site t o: 
•  Deter mi ne t he a de q uac y of t he  i n vesti gati o nal st u d y site a n d facilities 
•  Disc uss wit h t he In v esti gat or(s) a n d ot h er pers o n nel t heir res p o nsi bilities wit h re gar d t o 
pr ot oc ol a d here nce, a n d t he res p o nsi bilities of Ki ni ksa  or its re pres e ntati ves. T his will be 
d oc u me nte d i n a Cli nical St u d y A gree me nt bet wee n Ki ni ksa  a n d t he In v esti gat or.  
D uri n g t h e st u d y, a m o nit or fr o m Ki ni ksa  or desi g nee will h a ve re g ular c o ntacts wit h t he 
i n vesti gati o nal site, f or t h e f oll o wi n g: 
•  Pr o vi de i nf or mati o n a n d s u p p ort t o t he In v esti gat or(s)  
•  C o nfir m t hat facilities re mai n acce pta ble  
•  C o nfir m t hat t he i n vesti gati o nal tea m is a d heri n g t o t he pr ot oc ol, t hat data are bei n g 
acc uratel y rec or de d i n t he case re p ort f or ms, a n d t hat i n vesti gati o nal pr o d u ct 
acc o u nta bilit y c hec ks are bei n g p erf or m e d  
•  Perf or m s o urce data v erificati o n  
•  Rec or d a n d re p ort a n y pr ot oc ol de viati o ns n ot pre vi o usl y se nt t o Ki ni ksa  
•  C o nfir m A Es a n d S A Es ha ve bee n pr o perl y d o c u me nte d o n C R Fs a n d c o nfir m a n y S A Es 
ha ve bee n f or w ar de d t o Ki ni ksa  a n d t h ose S A Es t hat met criteria f or re p orti n g ha v e  bee n 
f or war de d t o t he I R B/ E C. 
1 4. 2.  
A u dits a n d I ns pecti o ns  
A ut h oriz e d re pres e ntati ves of Ki ni ksa , a re g ulat or y a ut h orit y, a n I n de p e n de nt Et hics C o m mittee 
or a n I nstit uti o nal Re vie w B oar d ma y visit t he site t o perf or m a u dits or i ns pecti o ns, i ncl u di n g 
s o urce dat a verifi cati o n. T he p ur p ose of a  Ki ni ksa  a u dit or i ns pecti o n is t o s yste maticall y a n d 
i n de pe n de ntl y e x a mi ne all st u d y-relat e d acti vities a n d d oc u me nts t o deter mi ne w het her t hes e 
acti vities were c o n d ucte d, a n d data were rec or de d, a nal yze d, a n d acc uratel y re p orte d acc or di n g 
t o t he pr ot oc ol, G o o d Cli nical Practice g ui d eli nes of t he I nter n ati o nal C o nfere nce o n 
Har m o nizati o n, a n d a n y a p plica ble re g ulat or y re q uire me nts. T he In v esti gat or s h o ul d c o ntact 
Ki ni ksa  i m me diatel y if c o ntacte d b y a re g ulat or y a ge nc y a b o ut a n i ns pecti o n. 


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6 9  of 1 0 9  
C o nfi de ntial  
1 5.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T o e ns ure c o m plia n ce wit h G o o d Cli nical Practices a n d all a p plica ble re g ul at or y re q uir e me nts, 
Ki ni ksa  ma y c o n d uct a q ualit y ass ur a nce a u dit. Please see Secti o n  1 4. 2  f or m ore details 
re gar di n g t he a u dit pr ocess. 


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1 6.  
E T HI C S  
1 6. 1.  
Et hics Re vie w  
Bef ore i nitiati n g a trial, t he In vesti gat or/ Instit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I R B or I n de pe n d e nt Et hics C o m mittee ( IE C) f or t he trial pr ot oc ol, writte n i nf or me d c o nse nt 
f orm, c o nse nt f or m u p dates, s u bject recr uit me nt pr oce d ures a n d a n y ot her writte n i nf or mati o n t o 
be pr o vi de d t o s u bjects.  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble data base s uc h as cli nicaltrials. g o v. I n 
a d diti o n, after st u d y c o m pleti o n a n d fi n alizati o n of t he st u d y re p ort t he res ults of t his trial will be 
s u b mitte d f or p u blicati o n a n d p oste d i n a p u blicl y accessi ble data bas e of cli nical trial res ults.  
T his pr ot oc ol defi nes t he st u d y o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d o n 
st u d y partici p a nts. A d diti o nal assess me nts re q uir e d t o e ns ure safet y of s u bj ects s h o ul d be 
a d mi nistere d as dee me d necessar y o n a case -b y -case basis. I n vesti gat ors will a p pl y d ue dili ge nce 
t o a v oi d pr ot oc ol de viati o ns.  
T he I R B/ E C will be i nf or me d b y t he  I n vesti gat or of a n y c ha n ges t o t he a p pr o ve d pr ot oc ol.  
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val. A n y a d mi nistrati ve 
a me n d me nts t o t he pr ot o c ol will be pr o vi de d t o I R Bs/I E Cs acc or di n g t o I R B/I E C pr oce d ures.  
T he I R B/I E C will be i nf or me d  b y t h e I n vesti gat or of seri o us a n d u ne x pecte d S A Es i n acc or da nce 
wit h t he I R B/I E C re p orti n g re q uire me nts. T h e I n v esti gat or will pr o vi de t he I R B/I E C wit h 
pr o gress r e p orts per I R B/I E C pr o ce d ures.  
1 6. 2.  
Et hic al C o n d uct of t he St u d y  
T his cli nical st u d y was d esi g ne d  a n d s hall be i m pl e me nte d, e x ec ute d , a n d re p orte d i n acc or da nce 
wit h t he I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble l ocal 
re g ulati o ns U S C F R 2 1, a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki. 
1 6. 3.  
I nf or me d C o nse nt 
Eli gi ble s u bjects ma y o nl y be i n cl u de d i n t he st u d y after pr o vi di n g ( wit nesse d, w here re q uir e d b y 
la w or re g ul ati o n), I R B/ E C-a p pr o ve d i nf or me d c o nse nt.  
If a p plica bl e, i n cases w h ere t he s u bject's re prese ntati ve(s) gi ves c o nse nt (if all o wed acc or di n g t o 
l ocal re q uir e me nts), t he s u bject m ust be i nf or me d a b o ut t he st u d y t o t he e xte nt p ossi ble gi ve n 
his/ her u n dersta n di n g. If t he s u bject is ca pa bl e, he/s he m ust i n dicate a gree me nt b y pers o nall y 
si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt d ocu me nt.  
I nf or me d c o ns e nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (e g, all 
pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or m e d c o nse nt m ust be 
d oc u me nte d i n t he s u bject s o urce d oc u me nts.  
W o me n of c hil d -beari n g p o te ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve 
u n k n o w n ris ks t o t he fet us if pre g n a nc y were t o occ ur d uri n g t he st u d y a n d a gree t hat t o partici pate , 
t he y m ust a d here t o t he c o ntrace pti o n re q uire me nts s pecifie d i n t his pr ot oc ol. 
A c o p y  of t he a p pr o ve d v ersi o n of all c o nse nt f or ms will be ke pt b y t he I n vesti gat or.  


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C o nfi de ntial  
1 7.  
D A T A H A N D LI N G A N D R E C O R D  K E E PI N G  
T he I n vesti gat or is r es p o nsi ble f or ass uri n g t hat t h e data (rec or de d o n C R Fs a n d e ntere d i nt o  t he 
e C R F) is c o m plete, acc urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y ma n ner. T he 
I n v esti gat or m ust certif y t hat t he data e ntere d are c o m plete a n d acc urate. 
After fi nal d ata bas e l oc k, t he In v esti gat or will recei ve c o pies of t he s u bject data f or arc hi vi n g at 
t he i n vesti gati o nal site. 
All d ata s h o ul d be rec or de d, ha n dle d , a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n, a n d v erific ati o n.  
1 7. 1.  
I ns pecti o n of Rec or ds 
T he In vesti gat or m ust mai ntai n s o urce d o c u me nts f or eac h s u bject i n t he st u d y, c o nsisti n g of 
case a n d visit n ot es ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y d ata, ele ctr ocar di o gra ms, a n d t he res ults of a n y ot h er tests or 
assess me nts. All i nf or mati o n o n C R Fs m ust be tracea ble t o t hes e s o urce d o c u me nts i n t he 
s u bject’s file. T he In vesti gat or m ust als o ke e p t he ori gi nal i nf or m e d c o nse nt f or m si g ne d b y t he 
s u bject (a si g ne d c o p y is gi ve n t o t he s u bject). 
T he In vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t h e data ca pt ure a n d/ or data e ntr y. A d diti o nal c hec ks of t h e c o nsiste nc y of t he 
s o urce dat a wit h t he C R Fs are perf or me d acc or di n g t o t he st u d y-s pecific m o nit ori n g pla n. N o 
i nf or mati o n i n s o urce d o c u me nts a b o ut t he i de ntit y of t he s u bj ects will be discl ose d. 
1 7. 2.  
Rete nti o n of Rec or ds  
T he Pri nci pal I n vesti gat or m ust mai ntai n all d oc u me ntati o n relati n g t o t he st u d y f or a peri o d of 2 
years after t he l ast mar keti n g a p plicati o n a p pr o val, or if n ot a p pr o ve d 2 years f oll o wi n g t he 
disc o nti n ua nce of t he t est article f or i n v esti gati o n. If it bec o mes necessar y f or Ki ni ksa  or t he 
Re g ulat or y A ut h orit y t o r e vie w a n y d o c u me ntati o n relati n g t o t he st u d y, t h e I n vesti gat or m ust 
per mit access t o s uc h rec or ds.  


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C o nfi de ntial  
1 8.  
P U B LI C A TI O N P O LI C Y  
P u blicati o n  o f t he st u d y res ults s hall be d o ne i n acc or da nce wit h, a n d are s u bject t o, t he 
p u blicati o n pr o visi o n i n t he cli nical trial a gree me nt g o ver ni n g t his st u d y . 


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7 3  of 1 0 9  
C o nfi de ntial  
1 9.  
LI S T O F R E F E R E N C E S  
Are ntz M, Yi m E, Klaff L, et al. C haracteristics a n d o utc o mes of 2 1 criticall y ill patie nts wit h 
C O VI D -1 9 i n W as hi n gt o n State. J A M A 2 0 2 0 ;3 2 3( 1 6): 1 6 1 2 -1 6 1 4 . 
B ur mester G R, Feist E, Slee ma n M A, et al. M a vrili m u ma b, a h u ma n m o n ocl o nal a nti b o d y 
tar geti n g G M-C S F rece pt or -α, i n s u bjects wit h r he u mat oi d art hritis: a ra n d o mize d, d o u ble -bli n d, 
place b o -c o ntr olle d, p has e I, first -i n-h u ma n st u d y. A n n R he u m Dis . 2 0 1 1; 7 0: 1 5 4 2 -1 5 4 9.  
Ca kar o va L, M ars h L M, Wil hel m J, et al. Macr o p ha ge t u m or necr osis fact or-α i n d uces e pit helial 
e x pressi o n of gra n ul oc yt e – macr o p ha ge c ol o n y -sti m ulati n g fact or: i m pact o n al ve olar e pit helial 
re pair. A m J R es p C rit C are M e d. 2 0 0 9; 1 8 0( 6): 5 2 1 -5 3 2.  
Ca o B, Wa n g Y, We n D, et al. A Trial of L o pi n a 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 gl J Me d 2 0 2 0;  3 8 2( 1 9): 1 7 8 7 -1 7 9 9 . 
Castella ni S, D’ Oria S, Dia na A, et al. G-c Sf a n d G M -c Sf M o dif y ne utr o p hil f u ncti o ns at 
c o nce ntr ati o ns f o u n d i n c ystic fi br osis. Sci R e p. 2 0 1 9 ;9( 1): 1 -1.  
Cli nical Trials. g o v [I nter n et]. Bet hes da ( M D): Nati o nal Li br ar y of Me dici ne ( U S). I de ntifier 
N C T 0 4 2 8 0 7 0 5, A da pti ve C O VI D -1 9 Treat me nt Trial ( A C T T); 2 0 2 0 Fe b 2 1 [cite d 2 0 2 0 Ma y 1]. 
htt ps://cli nicaltrials. g o v/ct 2/s h o w/ N C T 0 4 2 8 0 7 0 5?ter m = N C T 0 4 2 8 0 7 0 5 & dra w = 2 &ra n k = 1  
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m s er u m creati ni ne . Ne p hr o n 
1 9 7 6; 1 6: 3 1 -4 1.  
Cr otti C, Rai m o n d o M G , Becci oli ni A,  et al. S p otli g ht o n ma vrili m u ma b f or t he treat me nt of 
r he u mat oi d art hritis: e vi de nce t o dat e. Dr u g Des D e vel T her.2 0 1 7: 1 1: 2 1 1 -2 2 3.  
De L uca G, Ca valli G, Ca m p o c hiar o C, et al. G M -C S F bl oc ka de wit h ma vrili m u ma b i n se vere 
C O VI D -1 9 p ne u m o nia a n d s yste mic h y peri nfla m mati o n: a si n gle -ce ntre, pr os pecti ve c o h ort 
st u d y. La n cet R he u mat ol. 2 0 2 0; 2( 8):e 4 6 5-e 4 7 3. 
Fis her  CJ, D hai na ut J -F A, O pal S M, et al. Rec o m bi na nt h u ma n i nterle u ki n 1 rece pt or a nta g o nist 
i n t he treat me nt of patie nts wit h se psis s y n dr o me - res ults fr o m a ra n d o mize d, d o u ble-bli n d, 
place b o -c o ntr olle d trial. J A M A 1 9 9 4; 2 7 1( 2 3): 1 8 3 6 -1 8 4 3.  
Ha milt o n J A. G M -C S F i n i nfla m mati o n a n d a ut oi m m u nit y. Tre n ds I m m u n ol. 2 0 0 2;  2 3 (8 ): 4 0 3-
4 0 8 . 
Ha milt o n J A. C ol o n y -sti m ulati n g fact ors i n i nfla m mati o n a n d a ut oi m m u nit y. Nat Re v I m m u n ol. 
2 0 0 8; 8( 7): 5 3 3 -5 4 4.  
Ha milt o n J A. G M -C S F i n i nfla m mati o n. J E x p Me d. 2 0 2 0; 2 1 7 ( 1):e 2 0 1 9 0 9 4 5 . 
H ua n g C, Wa n g Y, Li X, et al. Cli nical feat ur es of patie nts i nfecte d wit h 2 0 1 9 n o vel c or o na vir us 
i n W u ha n, C hi na. La ncet 2 0 2 0; 3 9 5( 1 0 2 2 3): 4 9 7-5 0 6.  
H u ma ni ge n , I nc. H u ma ni ge n re p orts a d diti o nal a nal ysis of le nzil u ma b i n se vere a n d critical 
C O VI D -1 9 Patie nts . 1 6 J u ne 2 0 2 0 . htt ps:// w w w. h u ma ni ge n. c o m/ press/ H u ma ni ge n -Re p orts -
A d diti o nal -A nal ysis -of -Le nzil u ma b -i n-Se vere -a n d -Critica l-C O VI D -1 9 -Patie nts  
I nter nati o nal Se vere A c ute Res pirat or y a n d E mer gi n g I nfecti o ns C o ns orti u m (I S A RI C). C O VI D-
1 9 Re p ort: 2 7 A pril 2 0 2 0 . 


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7 4  of 1 0 9  
C o nfi de ntial  
htt ps:// me d ia.t g h n. or g/ m e diali brar y/ 2 0 2 0/ 0 5/I S A RI C _ Dat a _ Platf or m _ C O VI D-
1 9 _ Re p ort _ 2 7 A P R 2 0. p df  ( 1 Ma y 2 0 2 0) 
K o u pe n o va M. P ote ntial r ole of platelets i n C O VI D‐ 1 9: I m plicati o ns f or t hr o m b osis. Res Pract 
T hr o m b Hae m ost. 2 0 2 0 ;4( 5): 7 3 7 -7 4 0 . 
La n g F M, Lee K M, T eijar o J R, et al. G M-C S F -base d treat me nts i n C O VI D -1 9: rec o ncili n g 
o p p osi n g t hera pe utic a p pr oac hes. Nat Re v I m m u n ol. 2 0 2 0 ; 2 0( 8): 5 0 7-5 1 4 . 
Lia o M , Li u Y, Y ua n J , et al. Si n gle -cell la n dsca p e of br o nc h o al ve olar i m m u ne cells i n patie nts 
wit h C O VI D -1 9. Nat. M e d. 2 0 2 0; 2 6( 6): 8 4 2 -8 4 4.  
Li vi n gst o n L, B u c her K. J A M A I nf o gra p hic –  C or o na vir us disease  2 0 1 9 ( C O VI D -1 9) i n It al y. 
J A M A 2 0 2 0; 3 2 3( 1 4): 1 3 3 5. 
Me hta P, Mc A ule y D F, Br o w n M, et al. C O VI D-1 9: c o nsi der c yt o ki ne st or m s y n dr o m es a n d 
i m m u n os u p pressi o n. La n cet. 2 0 2 0; 3 9 5( 1 0 2 2 9): 1 0 3 3-1 0 3 4 . 
Miller G, Pillarisett y V G, S ha h A B, et al. E n d o ge n o us gra n ul oc yte-macr o p ha ge c ol o n y 
sti m ulati n g fact or o v ere x pressi o n i n vi v o res ults i n t he l o n gter m recr uit me nt of a disti nct 
de n dritic cell p o p ulati o n wit h e n ha nce d i m m u n osti m ulat or y f u ncti o n. J I m m u n o l 
2 0 0 2; 1 6 9( 6): 2 8 7 5 -2 8 8 5 . 
Mat ute -Bell o G, Lil es W C, Ra della F II, et al. M o d ulati o n of ne utr o p hil a p o pt osis b y gra n ul oc yte 
c ol o n y-sti m ulati n g fact or a n d gra n ul oc yte/ macr o p ha ge c ol o n y-sti m ulati n g fact or d uri n g t he 
c o urse of ac ute res pirat or y distress s y n dr o m e. Crit Care Me d. 2 0 0 0; 2 8 ( 1): 1– 7.  
N o vel C or o na vir us P ne u m o nia E mer ge nc y Res p o nse E pi de mi ol o g y Tea m. T he e pi de mi ol o gi cal 
c haracteristics of a n o ut brea k of 2 0 1 9 n o v el c or o n a vir us disease ( C O VI D -1 9) —  C hi na, 2 0 2 0. 
C hi na C D C W ee kl y 2 0 2 0; 2: 1 -1 0.  
Ra nieri V M, R u b e nfel d G D, T h o m ps o n B T, et al. Ac ute res pir at or y distress s y n dr o me: T h e 
Berli n D efi niti o n. J A M A 2 0 1 2; 3 0 7 ( 2 3): 2 5 2 6-3 3.  
Re ge n er o n. Re ge ner o n a n d S a n ofi pr o vi de U p dat e o n K e vzara ®  (saril u ma b) P hase 3 U S  T rial i n 
C O VI D -1 9 P atie nts . 2 J ul y 2 0 2 0. htt ps:// ne wsr o o m.re ge ner o n.c o m/ ne ws -releases/ ne ws-rel ease-
details/re ge ner o n -a n d -sa n ofi-pr o vi de -u p d ate -ke vz arar -saril u ma b-p h ase -3  
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 -4 1 7.  
R oc he Gr o u p. R oc h e pr o vi des a n u p date o n t he p h ase III C O V A C T A trial of  
Acte mra/ R o Act e mra i n h os pitalise d patie nts wit h se vere C O VI D -1 9 ass oci ate d p ne u m o nia .2 9 
J ul y 2 0 2 0. htt ps:// w w w.r oc he.c o m/i n vest ors/ u p dates/i n v -u p date -2 0 2 0 -0 7 -2 9. ht m  
R o ot R K,  Dale D C. Gra n ul oc yte c ol o n y -sti m ulati n g fact or a n d gra n ul oc yt e-macr o p ha ge c ol o n y -
sti m ulati n g fact or: c o m p aris o ns a n d p ote ntial f or use i n t he treat me nt of i nfecti o ns i n 
n o n ne utr o pe nic patie nts. J I nfect Dis. 1 9 9 9; 1 7 9: S 3 4 2 -S 3 5 2 . 
Sa ba S, S o o n g G, Gree n b er g S , et al. Bacterial sti m ulati o n of e pit helial G-C S F a n d G M -C S F 
e x pressi o n pr o m otes P M N s ur vi val i n C F air wa ys. A m J Res pir Cell M ol Bi ol 2 0 0 2; 2 7 :5 6 1 -5 6 7 . 
Sa m ps o n H A, M u ñ oz -F url o n g A, Ca m p b ell R L, et al. Sec o n d s y m p osi u m o n t he defi niti o n a n d 
ma na ge me nt of a na p h yla xis: s u m mar y re p ort --sec o n d Nati o nal I nstit ute of Aller g y a n d 


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7 5  of 1 0 9  
C o nfi de ntial  
I nfecti o us Dise ase/ F o o d Aller g y a n d A na p h yl a xis Net w or k s y m p osi u m. A n n E mer g Me d. 
2 0 0 6; 4 7( 4): 3 7 3 -3 8 0.  
S hi o mi A, Usi u T. Pi v otal roles of G M -C S F i n a ut oi m m u nit y a n d i nfl a m mati o n. Me diat ors of 
I nfla m mati o n, 2 0 1 5; 2 0 1 5: 5 6 8 5 4 3. 
Tatsi y O, M c D o nal d P P. P h ysi ol o gic al sti m uli i n d uce P A D 4 -d e pe n de nt, R O S -i n de pe n de nt 
N E T osis, wit h earl y a n d late e ve nts c o ntr olle d b y discrete si g nali n g pat h wa ys. Fr o nt Im m u n ol. 
2 0 1 8; 9: 2 0 3 6.  
Tra p nell B C , W hitsett J A. G M -C S F re g ulates p ul m o nar y s urfacta nt h o me ostasis a n d al ve olar 
macr o p ha ge -me diate d i n nate h ost defe ns e. A n n u Re v P h ysi ol . 2 0 0 2; 6 4 :7 7 5 -8 0 2 . 
W u Z, Mc G o o ga n J M. C haract eristics of a n d i m p orta nt less o ns fr o m t he C or o na vir us Diseas e 
2 0 1 9 ( C O VI D -2 0 1 9) o ut brea k i n C hi na: S u m mar y of a re p ort of 7 2, 3 1 4 cases fr o m t he C hi nese 
ce nter f or diseas e c o ntr ol a n d pre ve nti o n. J A M A 2 0 2 0 ;3 2 3( 1 3): 1 2 3 9 -1 2 4 2 . 
X u  X, Ha n M, Li T , et al. Effecti ve treat me nt of s e vere C O VI D -1 9 patie nts wit h t ociliz u ma b . 
Pr oc Natl Aca d Sci U S A. 2 0 2 0 ;1 1 7 ( 2 0): 1 0 9 7 0-1 0 9 7 5 Ya ma m ot o K, A h yi A N, Pe p per -
C u n ni n g ha m Z A, et al. R oles of l u n g e pit heli u m i n ne utr o p hil recr uit me nt d uri n g p n e u m oc occal 
p ne u m o nia. A m J R es p C ell M olec B i ol. 2 0 1 4;5 0( 2): 2 5 3 -2 6 2.  
Ya ma m ot o K, A h yi A, Pe p per -C u n ni n g ha m Z, et al. R oles of L u n g  E pit heli u m i n Ne utr o p hil 
Recr uit me nt d uri n g P ne u m oc occal P ne u m o nia. A m J Res pir Cell M ol Bi ol. 2 0 1 4; 5 0( 2): 2 5 3 –
2 6 2.  
Z h o u Y, F u B, Z he n g X, et al. Pat h o ge nic T cells a n d i nfla m mat or y m o n oc yt es i ncite 
i nfla m mat or y st or m i n se vere C O VI D-1 9 patie nts. Natl Sc i Re v. 2 0 2 0 ; 7( 6):9 9 8 -1 0 0 2 . 
 
 


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7 6  of 1 0 9  
C o nfi de ntial  
2 0.  
S U M M A R Y O F C H A N G E S  
2 0. 1.  
C h a n ges fr o m Gl o b al Pr ot oc ol Versi o n 5 ( A me n d me nt 4) t o Gl o b al 
Pr ot oc ol Versi o n 6 ( A me n d me nt 5 ) 
 
T he f oll o wi n g are c ha n ges t o t he K P L -3 0 1 -C 2 0 3 pr ot oc ol ( Gl o bal  versi o n 5 : 1 4J u n 2 0 2 1), w hic h 
s u m marizes maj or c ha n ges t o t he pr ot oc ol. A d diti o nal mi n or c ha n ges w ere als o ma de wit h 
res pect t o use of a b bre viati o ns, c orrecti o n of t y p os, re n u m beri n g of secti o ns ( w he n necessar y), 
a n d re visi n g/f or matti n g refere nces. T he ta ble of c o nte nts was u p date d.   
 
P r ot oc ol Secti o n  
( P a ge N u m ber1) 
M o dific ati o n  
R ati o n ale  
E mer ge nc y C o ntact 
I nf or mati o n ( p 4) 
U p date d Dr u g Safet y P h ysicia n fr o m 
 
 
A d mi nistrati ve 
u p date  
S y n o psis ( p 7 -8 ) 
a n d Secti o n 1 0. 2 
( p 48 ) 
Sec o n d ary E n d p oi nts:  
Sec o n dar y efficac y e n d p oi nts will be e xa mi ne d base d o n 
t he hierarc hical or der s pecifie d i n t he m ulti plicit y 
a dj ust me nt secti o n bel o w:  
C o h ort 2 ( Ve ntilate d S u bjects)  
•  
Ti me t o 1 -p oi nt cli nical i m pr o ve me nt b y Da y 2 9  
Defi ne d as ti me fr o m ra n d o mizati o n t o a 1 -p oi nt 
i m pr o ve me nt o n t he NI AI D 8-p oi nt or di nal scale, or 
disc har ge fr o m t he h os pital, w hic he ver occ urs first. 
S u bj ects w h o die bef ore Da y 2 9 will be ce ns ore d at 
Da y 3 0  3 5 . 
U n necessar y  te xt. 
 
 
 
Ce ns ori n g of ti me t o 
e ve nt e n d p oi nts 
re vise d t o i nc or p orate 
da y 2 9 visit wi n d o w 
( + 4 da ys) a n d 1 da y 
f or differe nce 
bet wee n 
ra n d o mizati o n a n d 
d osi n g  
S y n o psis ( p 8) a n d 
Secti o n 1 0. 3 ( p 4 8)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
                                                 
1 P a ge n u m ber f or t he trac ke d c ha n ge versi o n.  


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
7 7  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber1) 
M o dific ati o n  
R ati o n ale  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
S y n o psis ( p 1 0) a n d 
Secti o n 1 3. 2. 4 
( p 6 4) 
All efficac y a nal yses will be base d o n t he mI T T f or t he 
P hase 2 e n d p oi nts a n d base d o n t he I T T a nal ysis set f or 
t he P hase 3 e n d p oi nts. A nal yses base d o n ot her a nal ysis 
sets will be c o nsi dere d as se nsiti vit y a nal yses. All 
efficac y c o m paris o ns will be pri mar il y base d o n eac h of 
t he ma vrili m u ma b ar ms vers us t he place b o ar m. 
C o m paris o n bet wee n t he p o ole d ma vrili m u ma b ar m 
vers us place b o ar m will be s u p p orti ve . P hase 3, C o h ort 1 
pri mar y a n d sec o n dar y e n d p oi nts will be e xa mi ne d i n a 
hierarc hical or der as s pecifie d i n Secti o n 1 3. 4 . 
T here will be n o 
p o ole d 
ma v rili m u ma b ar m 
a nal ysis. 
T hir d se nte nce is i n 
t he s y n o psis a n d was 
a d de d here f or 
c o nsiste nc y.  
S y n o psis ( p 1 2) a n d 
Secti o n 1 3. 4 ( p 6 6)  
T he t w o -si de d t y pe I err or rate is 0. 2 f or eac h P hase 2 
c o h ort a n d 0. 0 5 f or eac h P hase 3 c o h ort. N o m ulti plicit y 
a dj ust me n t will be d o ne f or t he P hase 2 part a n dor  P hase 
3 C o h ort 2 ( n o f or mal testi n g will be d o ne as e nr oll me nt 
t o c o h ort 2 st o p pe d earl y). T y pe I err or rate f or eac h 
P hase 2 c o h ort is at a t w o -si de d al p ha val ue of 0. 2. 
M ulti plicit y a dj ust me nt f or P hase 3 C o h ort 1 will be d o ne 
t o g uara ntee str o n g c o ntr ol of t he o verall T y pe I err or rate 
at a t w o -si de d al p ha val ue of 0. 0 5 wit hi n eac h c o h ort . 
Si nce F or eac h e n d p oi nt, t he t w o test statistics f or t he t w o 
c o m paris o ns  d oses as y m pt oticall y f oll o w a bi variate 
n or mal distri b uti o n a n d are p ositi vel y c orrelate d d ue 
beca use t he y s hare  t o s hari n g a c o m m o n c o ntr ol ar m 
( place b o) i n t his trial.  C o n ve nti o nal H oc h ber g met h o d 
C ha n ge t o t he 
statistical a nal ysis f or 
m ulti plicit y 
a dj ust me nt d ue t o t he 
bi variate n or mal 
distri b uti o n of 
e n d p oi nts.   
 
 
N ote: Se nte nce i n 
gre y  a p pears o nl y i n 
Secti o n 1 4. 4 . 
 
 
 


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0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
7 8  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber1) 
M o dific ati o n  
R ati o n ale  
will be use d t o a dj ust f or m ulti plicit y i n t he a nal ysis of 
t he t w o d ose le vels a n d t he se q ue nce of efficac y 
e n d p oi nts . Details are pr o vi de d i n Secti o n 1 3. 4 .   
Se q ue ntial gate kee pi n g pr oce d ure will be use d t o c o n tr ol 
t he t y pe I err or rate. Statistical testi n g will be d o ne base d 
o n t he hierarc hical or der s pecifie d bel o w.  
 
 
 
 
 
 
 
 
 
 
 
T he ta ble was delete d 
beca use a nal ysis is n o 
l o n ger d o ne b y 
hierarc hical le vel  b y 
d ose . 
Secti o n 1 0 ( p 4 7)  
T he f oll o wi n g efficac y e n d p oi nts will be use d f or b ot h 
t he P hase 2 a n d P hase 3 parts of t he st u d y. E n d p oi nts will 
be e val uate d f or b ot h C o h orts 1 a n d 2, u nless ot her wise 
s pecifie d. P hase 3, C o h ort 1 pri mar y a n d sec o n dar y 
e n d p oi nts will be e xa mi ne d i n a hierarc hical or der as 
s pecifie d i n Secti o n 1 3. 4 . 
Se nte nce was delete d 
beca use a nal ysis is n o 
l o n ger d o ne b y 
hierarc hical le vel  b y 
d ose . 
Secti o n 1 1. 1 ( p 5 1)  
Sa m ples will be c ollecte d at Scree ni n g, Da y 1 ( pri or t o 
t he st u d y dr u g i nf usi o n a n d o nce it is c o m plete), a n d at 
Da ys 4 3, 7, 1 5 ± 2, 2 9 + 2  4, a n d at t he Disc har ge/ U N S 
visit.  
C orrecti o n t o Secti o n 
1 1. 1 t o ali g n wit h 
Sc he d ule of 
Acti vities . 


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
7 9  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber1) 
M o dific ati o n  
R ati o n ale  
Secti o n 1 2. 1. 5  
T a ble 4 ( p 5 3 -5 4)  
As s h o w n i n T a ble 4 bel o w:  
C ha n ge d Da y 2 9 wi n d o w fr o m ± 2 da ys t o + 4 da ys  
C ha n ge d Da y 6 0 wi n d o w fr o m t o ± 7 da ys + 1 4 da ys  
C ha n ge d Da y 9 0 wi n d o w ± 7 da ys t o + 1 4 da ys  
C orrecti o n t o Secti o n 
1 2. 1 t o ali g n wit h 
Sc he d ule of 
Acti vities . 
T a ble 4:  
Sc he d ule of L a b or at or y Assess me nts  
 


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 0  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber1) 
M o dific ati o n  
R ati o n ale  
 
Secti o n 1 3. 4 ( p 6 7)  
 Details f or m ulti plicit y a dj ust me nt will be pr o vi de d i n 
t he S A P. C o nsi deri n g t he h y p ot hesis testi n g of b ot h t he 
1 0 m g/ k g a n d t he 6 m g/ k g i n di vi d uall y vers us place b o f or 
eac h e n d p oi nt t o be a fa mil y, t he testi n g o n t he pri mar y 
e n d p oi nt a n d t he t hree or dere d sec o n dar y e n d p oi nts 
c orres p o n d t o Fa mil y 1, Fa mil y 2, Fa mil y 3, a n d Fa mil y 
4, res pecti vel y.  
T esti n g will be d o ne se q ue ntiall y ( Fa mil y 1, t he n 2, 3, 
a n d 4) base d o n t he f oll o wi n g decisi o n r ules ( p -val ues are 
all t w o -si de d):  
•  
If b ot h p-val ues i n a fa mil y are ≤ 0. 0 5, statisticall y 
si g nifica nt treat me nt effects f or t he e n d p oi nt ca n be 
clai me d f or b ot h d ose le vels, a n d testi n g ma y 
pr ocee d t o t he ne xt fa mil y t o test t h ose h y p ot heses 
at t w o-si de d si g nifica nce le vel of 0. 0 5.  
•  
If t he lar ger p-val ue is > 0. 0 5 a n d t he s maller p -
val ue is ≤ 0. 0 2 5, a statisticall y si g nifica nt treat me nt 
effect ca n be clai me d o nl y f or t he o ne d ose le vel 
c orres p o n di n g t o t he s maller p -val ue. Se q ue ntial 
testi n g st o ps here, a n d n o f urt her i nfere ntial testi n g 
ca n be d o ne. T he re mai ni n g data a nal yses will be 
pr o vi de d f or c o m plete ness ( wit h p val ues as 
n o mi nal) t o i nf or m t he disc ussi o n of be nefit -ris k.  
•  
If b ot h p-val ues i n t he fa mil y are > 0. 0 5, a 
statisticall y si g nifica nt treat me nt effect ca n n ot be 
clai me d f or eit her d ose le vel. Se q ue ntial testi n g 
st o ps here, a n d n o f urt her i nfere ntial testi n g ca n be 
d o ne. T he re mai ni n g data a nal yses wi ll be pr o vi de d 
f or c o m plete ness ( wit h p-val ues as n o mi nal) t o 
i nf or m t he disc ussi o n of be nefit-ris k. 
E x pla nati o n of t he 
ne w m ulti plicit y of 
a dj ust me nt sc he me 
w hic h uses e n d p oi nt 
gr o u pi n g b y fa mil y 
a n d se q ue ntial testi n g 
b y fa mil y.  


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
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2 0. 2.  
C h a n ges fr o m Br azil Pr ot oc ol Versi o n 4 ( A me n d me nt 3)  t o Gl o b al 
Pr ot oc ol Versi o n 5 ( A me n d me nt  4)  
 
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s u m marizes maj or c ha n ges t o t he pr ot oc ol. A d diti o nal mi n or c ha n ges w ere als o ma de wit h 
res pect t o use of a b bre viati o ns, c orrecti o n of t y p os, re n u m beri n g of secti o ns ( w he n necessar y), 
a n d re visi n g/f or matti n g refere nces . T he ta ble of c o nte nts was u p date d.  
 
P r ot oc ol Secti o n  
( P a ge N u m ber2) 
M o dific ati o n  
R ati o n ale  
S y n o psis + Secti o n 
6. 1 Over all St u dy 
Desi g n  ( pa ge 42 ) 
U p date d st u d y sc he matic t o reflect i ncrease i n sa m ple 
size i n P hase 3 C o h ort 1 fr o m 5 5 0 t o 6 0 0 s u bjects a n d 
cl os ure of e nr oll me nt i n P hase 3 C o h ort 2 (a p pr o xi matel y 
6 5  s u bjects e nr olle d at ti me of e nr oll me nt cl os ure) 
U p date d base d o n 
F D A fee d bac k  
S y n o psis + Secti o n 
6. 2 N u m ber of 
S u bjects ( pl a n ne d)  
( pa ge 4 3 ) 
N u m ber of s u bjects ( pl a n ne d):  
P hase 3:  A p pr o xi matel y 6 6 5  6 6 7  s u bj ects 
•  
C o h ort 1:  A p pr o xi matel y 6 0 0  5 5 0  n o n -ve ntilate d 
s u bj ects 
•  
C o h ort 2:  A p pr o xi matel y 1 1 7 ve ntilate d s u bjects  
(a p pr o xi matel y 6 5 s u bjects at ti me of e nr oll me nt 
cl os ure) 
Base d o n re vie w of t he P hase 2 C o h ort 2 res ults of t he 
pri mar y a n d sec o n dar y e n d p oi nts at da y 2 9, P hase 3 
C o h ort 2 is cl ose d t o f urt her e nr oll me nt, as t here was n o 
e vi de nce t hat ma vrili m u ma b pr o vi de d cli nical be nefit 
o ver place b o i n rece ntl y ve ntilate d patie nts.  
I ncrease d P hase 3 
C o h ort 1 t o 6 0 0 
s u bj ects base d o n 
P hase 2 C o h ort 1 
res ults of pri mar y 
e n d p oi nt. 
 
Decisi o n t o cl ose 
enr oll me nt i n P hase 3 
C o h ort 2 base d o n 
res ults of P hase 2 
C o h ort 2 res ults.  
S y n o psis + Secti o n 
1 3. 2. 4 Effic acy 
A n alysis ( pa ge 7 1 ) 
Efficac y A nal ysis:  
All efficac y a nal yses will be base d o n t he mI T T f or t he 
P hase 2 e n d p oi nts a n d base d o n t he I T T a nal ysis set f or 
t he P hase 3 e n d p oi nts. A nal yses base d o n ot her a nal ysis 
sets will be c o nsi dere d as se nsiti vit y a nal yses. All 
efficac y c o m paris o ns will be pri maril y base d o n eac h of 
t he ma vrili m u ma b ar ms vers us t he place b o ar m.  
C o m paris o n bet wee n t he p o ole d ma vril i m u ma b ar m 
vers us place b o ar m will be s u p p orti ve. P hase 3, C o h ort 1 
pri mar y a n d sec o n dar y e n d p oi nts will be e xa mi ne d i n a 
hierarc hical or der  as s pecifie d i n Secti o n 1 3. 4 . 
Pri m ary Effic acy E n d p oi nt:  
F or t he P hase 2 part of t he st u d y, t he Fis her’s e xact test 
will be perf or me d f or t he pri mar y efficac y e n d p oi nt f or 
U p date d t he pr o p ose d 
pri mar y a nal ysis f or 
pri mar y efficac y 
e n d p oi nt base d o n 
P hase 2 res ults.  
 
Re vise d sec o n dar y 
a n d ot her  efficac y 
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults 
                                                 
2 P a ge n u m ber f or t he trac ke d c ha n ge versi o n.  


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 2  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber2) 
M o dific ati o n  
R ati o n ale  
b ot h c o h orts. T he C oc hra n -Ma ntel -Hae nszel ( C M H) test 
a dj usti n g f or ra n d o mizati o n strata ( a uth orize d a p pr o ve d  
sta n dar d of care a nti viral t hera p y f or C O VI D-1 9 (e g, 
re m desi vir), a ge, a n d A R D S stat us) will be use d as 
s u p p orti ve a nal ysis of t he pri mar y efficac y e n d p oi nt f or 
C o h ort 1.  
F or b ot h c o h orts i n t he P hase 3 part of t he st u d y, t he 
C M H test a dj uste d b y ra n d o mizati o n strata will be use d 
t o test t he pri mar y efficac y e n d p oi nt f or p o ole d 
ma vrili m u ma b ar m vers us place b o ar m, as well as eac h 
ma vrili m u ma b d ose ar m vers us place b o. T he testi n g f or 
t he p o ole d ma vrili m u ma b ar m will be t he pri mar y 
a nal ysis . 
S y n o psis + Secti o n 
1 3. 2. 2 Str atifie d 
A n alysis ( pa ge 7 0 ) 
R a n d o miz ati o n Str at a:  
T here will be 3 stratificati o n fact ors f or ra n d o mizati o n:  
1. Use of a ut h orize d a p pr o ve d  sta n dar d of care 
a nti viral t hera p y f or C O VI D -1 9 (e g, re m desi vir): 
yes vs. n o  
C ha n ge d ‘a p pr o ve d’ 
t o ‘a ut h orize d’ f or 
clarit y.  
S y n o psis + Secti o n 
1 3. 2. 7 I nteri m 
A n alysis ( pa ge 7 2 ) 
I nteri m A n alysis 
T here is n o i nteri m a nal ysis pla n ne d f or t he P hase 2 or 
P hase 3 part of t he st u d y. I nstea d, t he S p o ns or will 
c o n d uct a pri mar y  a n d/ or fi nal efficac y a nal ysis (ie, 
re vie w of u n bli n de d st u d y res ults) w he n t he last s u bject 
i n eac h P hase a n d C o h ort c o m pletes t he Da y 2 9/Da y 9 0 
assess me nts. 
Clarifie d t he c o n d uct 
of t he pri mar y a n d/ or 
fi nal efficac y 
a nal ysis. 
Secti o n 1 3. 3. 2 
S a m ple Size 
Esti m ati o n P h ase 3  
( pa ge 7 3 ) 
S a m ple Size Esti m ati o n:  
P hase 3  
A p pr o xi matel y 6 6 5  6 6 7  s u bj ects will be ra n d o mize d t o 
t he P hase 3 part of t his st u d y. 
Sa m ple size f or C o h ort 1 ( n o n -ve ntilate d s u bjects) of t he 
P hase 3 part is deter mi ne d base d o n t he pri mar y efficac y 
e n d p oi nt of pr o p orti o n of s u bj ects ali ve a n d free of 
mec ha nical ve ntilati o n  at Da y 2 9  ( ma vrili m u ma b 6 m g/ k g 
vs place b o)  usi n g t he C hi s q uare. T he ass u m pti o ns use d 
f or t he calc ulati o n are a dj uste d base d o n t he res ults 
of P hase 2 p orti o n. A p pr o xi matel y 6 0 0  5 5 0  s u bjects 
will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. 
Ass u mi n g t he pr o p orti o ns f or t he acti ve ar m a n d place b o 
T he ass u m pti o ns f or 
t he pr o p orti o n of 
s u bj ects ali ve a n d 
free of ve ntilati o n 
were u p date d base d 
o n P hase 2 C o h ort 1 
res ults. P o wer 
esti mate was u p date d.  
 
Decisi o n t o cl ose 
e nr oll me nt  i n P hase 3 
C o h ort 2 base d o n 
res ults of P hase 2 
C o h ort 2 res ults.  


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 3  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber2) 
M o dific ati o n  
R ati o n ale  
ar m are 8 7. 5  8 6 % a n d 7 4 . 4 7 4 % res pecti vel y, 
a p pr o xi matel y 1 8 3  2 0 0 s u bjects per ar m are s ufficie nt t o 
ac hie ve at least  9 0 % p o wer f or t he treat me nt c o m paris o n 
of p o ole d ma vrili m u ma b ar ms vers us place b o a n d at least 
8 0 % p o wer f or t he c o m paris o n of eac h i n di vi d ual 
ma vrili m u ma b d ose ar m vers us place b o  t he t w o-si de d 
al p ha val ue is  si g nifica nce le vel of 0. 0 5 . 
Sa m ple size f or C o h ort 2 ( ve ntilate d s u bjects) of t he 
P hase 3 part is deter mi ne d base d o n t he m ortalit y rate at 
Da y 2 9  usi n g a Fis her’s e xact test. A p pr o xi matel y 1 1 7 
s u bj ects will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. 
Ass u mi n g t he m ortalit y rates f or t he acti ve ar m a n d 
place b o ar m are 4 0 % a n d 8 0 % res pecti vel y, 
a p pr o xi matel y 3 9 s u bj ects per ar m are re q uire d t o ac hie ve 
a 9 0 % p o wer f or a pair wise c o m paris o n vers us c o ntr ol 
w he n t he t w o -si de d al p ha val ue is 0. 0 2 5. H o we ver, base d 
o n re vie w of t he P hase 2 C o h ort 2 res ults of t he pri mar y 
a n d sec o n dar y e n d p oi nts at da y 2 9, P hase 3 C o h ort 2 is 
cl ose d t o f urt her e nr oll me nt (a p pr o xi matel y 6 5 s u bjects 
ra n d o mize d at t he ti me of e nr oll me nt cl os ure), as t here 
was n o e vi de nce t hat ma vrili m u ma b pr o vi de d cli nical 
be nefit o ver place b o i n rece ntl y ve ntilate d patie nts.  
S y n o psis + Secti o n 
1 3. 4 M ulti plicity 
A dj ust me nt  ( pa ge 
7 3 - 7 4 ) 
M ulti plicit y A dj ust me nt  
T he c o h orts wit hi n t he P hase 2 a n d P hase 3 st u d y parts 
will be a nal yze d se paratel y u nless ot her wise s pecifie d.  
N o m ulti plicit y a dj ust me nt will be d o ne f or t he P hase 2 
part. T y pe I err or rate f or eac h P hase 2 c o h ort is at a t w o -
si de d al p ha val ue of 0. 2. 
M ulti plicit y a dj ust me nt f or P hase 3 C o h ort 1 will be d o ne 
t o g uara ntee str o n g c o ntr ol of t he o verall T ype I err or at a 
t w o-si de d al p ha val ue of 0. 0 5 wit hi n eac h c o h ort f or t he 
c o m paris o ns of p o ole d ma vrili m u ma b ar ms vers us 
place b o  i n P hase 3 part. Details are pr o vi de d i n 
Secti o n  1 3. 4 . 
Se q ue ntial gate kee pi n g pr oce d ure will be use d t o c o ntr ol 
t he t y pe I err or rate. Statistical testi n g will be d o ne base d 
o n t he hierarc hical or der s pecifie d bel o w.   [ ne w ta ble] 
U p date d base d o n 
F D A fee d bac k . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 4  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber2) 
M o dific ati o n  
R ati o n ale  
Or der  E n d p oi nt   
C o m p aris o n  
1  
Pr o p orti o n of 
s u bj ects ali ve a n d 
free of mec ha nical 
ve ntilati o n at Da y 2 9  
ma vrili m u ma b 6 m g 
vs. place b o  
2  
M ortalit y rate at Da y 
2 9  
ma vrili m u ma b 6 m g 
vs. place b o  
3  
Ve ntilati o n free 
s ur vi val b y Da y 2 9 
ma vrili m u ma b 6 m g 
vs. place b o  
4  
M ortalit y rate at Da y 
2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
5  
Pr o p orti o n of 
s u bj ects ali ve a n d 
free of mec ha nical 
ve ntilati o n at Da y 2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
6  
Ve ntilati o n free 
s ur vi val b y Da y 2 9 
ma vrili m u ma b 1 0 m g 
vs. place b o  
7  
O verall s ur vi val b y  
Da y 2 9  
ma vrili m u ma b 6 m g 
vs. place b o  
8  
O verall s ur vi val b y 
Da y 2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
 
S y n o psis + Secti o n 
7. 2 Excl usi o n 
Criteri a  ( pa ge 4 7 ) 
a n d Secti o n 8. 2. 1 
Pr o hi bite d 
Me dic ati o ns  ( pa ge 
5 0 ) 
A d de d se nte nce t o e n d of e xcl usi o n criteri o n # 6 , sc he d ule 
of acti vities f o otn ote # 2 4  a n d t o Secti o n 8. 2. 1: 
“Me dicati o ns t hat bec o me sta n dar d of care f or C O VI D -
1 9 a n d/ or recei ve e mer ge nc y use a ut h orizati o n ma y be 
all o we d after disc ussi o n wit h t he me dical m o nit or.”  
T o all o w me dical 
m o nit or discreti o n 
re gar di n g 
c o nc o mita nt 
me dicati o ns relati ve 
t o C O VI D-1 9.  
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 5  of 1 0 9  
C o nfi de ntial  
2 0. 3.  
C h a n ges fr o m Gl o b al Pr ot oc ol Versi o n 3 ( A me n d me nt 2 ) t o Gl o b al 
Pr ot oc ol Versi o n 5 ( A me n d me nt 4)  
 
T he f oll o wi n g are c ha n ges t o t he K P L -3 0 1 -C 2 0 3 pr ot oc ol (gl o bal versi o n 3 : 1 5 Dec 2 0 2 0), w hi c h 
s u m marizes maj or c ha n ges t o t he pr ot oc ol. A d diti o nal mi n or c ha n ges w ere als o ma de wit h 
res pect t o use of a b bre viati o ns, c orrecti o n of t y p os, re n u m beri n g of secti o ns ( w he n necessar y), 
a n d re visi n g/f or matti n g refere nces . T he ta ble of c o nte nts was u p date d.   
 
N ote:  T here is n o Gl o b al Pr ot oc ol Versi o n 4.   
 
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
E mer ge nc y C o ntact 
I nf or mati o n 
C ha n ge d Dr u g Safet y P h ysicia n fr o m 
 
 
U p date d  
S y n o psis + Secti o n 
6. 1  Over all St u dy 
Desi g n  ( pa ge 4 4 ) 
U p date d st u d y sc h e matic t o reflect i ncrease i n sa m ple 
size i n P hase 3 C o h ort 1 fr o m 3 0 0 t o 6 0 0  s u bjects a n d 
cl os ure of e nr oll me nt i n P hase 3 C o h ort 2 (a p pr o xi matel y 
6 5 s u bjects e nr olle d at ti me of e nr oll me nt cl os ure)  
U p date d  base d o n 
P hase 2 res ults  
Secti o n 4 ( pa ge 3 9 -
4 1 ) 
R ati o n ale f or D ose a n d R o ute of A d mi nistr ati o n  
T he d ose rati o nale, a n d b y e xte nsi o n t he I V r o ute of 
a d mi nistrati o n f or C O VI D -1 9 s u bjects, is base d o n a 
c o m bi nati o n of data fr o m pri or safet y a n d efficac y 
e val uati o n of si n gle a n d m ulti ple d oses i n R A patie nts, 
a n d  t he assess me nt of ma vrili m u ma b l u n g distri b uti o n 
a n d p har mac o d y na mic effects i n mice, a n d res ults fr o m 
t he P hase 2 p orti o n ( C o h ort 1) of st u d y K P L-3 0 1 -C 2 0 3 . 
A n e xtra p olati o n of t hese fi n di n gs ta ke n t o get her wit h 
k n o w n pat h o p h ysi ol o g y of C O VI D -1 9, i n partic ular l u n g 
disease a n d h y peri nfla m mati o n, le d t o t he pr o p ose d d oses 
f or t his st u d y.  
[ …] 
T he effic ac y a n d s afet y res ults fr o m t he K P L -3 0 1 -
C 2 0 3, P h ase 2 C o h ort 1  s u bj ects, s u p p ort use of b ot h 
d oses of ma vrili m u ma b i n t he o n g oi n g P hase 3 st u d y. 
W hile ge nerall y t here are n o a p pare nt differe nces 
bet wee n t he t w o ma vrili m u ma b ar ms f or efficac y a n d 
safet y, gi ve n t he s mall n u m ber of pri mar y e ve nts of 
ve ntilati o n a n d/ or deat h a nal yze d t o date, t here are s o me 
differe nces bet wee n t he t w o d oses i n m ortalit y ( 1 0 m g/ k g 
is n u mericall y efficaci o us) or ve ntilati o n -free s ur vi val ( 6 
m g/ k g is n u mericall y m ore efficaci o us). O verall, b ot h t he 
1 0 m g/ k g a n d t he 6 m g/ k g a p pear well -t olerate d wit h n o 
M o difie d t he d ose 
rati o nale i n li g ht of 
t he P hase 2, C o h ort 1 
res ults. 
                                                 
3 P a ge n u m ber f or t he trac ke d c ha n ge versi o n.  


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 6  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
ne w i de ntifie d safet y ris ks i n t he C O VI D -1 9 st u d y 
p o p ulati o n. I n fact, seri o us i nfect i o ns (e. g., se ptic s h oc k, 
se psis) were s u bsta ntiall y l o wer i n b ot h ma vrili m u ma b 
d ose ar ms c o m pare d t o place b o, a n d t hr o m b osis e ve nts 
were o nl y re p orte d i n t he place b o ar m. T here were n o 
seri o us a d verse e ve nts relate d t o ma vrili m u ma b, n o d ose-
relate d a d verse e ve nts a n d n o i nf usi o n reacti o ns.  
I m p orta nt p ote ntial ris ks f or ma vrili m u ma b will c o nti n ue 
t o be m o nit ore d. T hese i ncl u de se vere h y perse nsiti vit y 
reacti o ns, i m m u ne c o m ple x disease, seri o us i nfecti o ns 
( viral, bacterial, a n d o p p ort u nistic i nfecti o ns), 
mali g na nc y, vacci ne i nteracti o ns, p ul m o nar y al ve olar 
pr otei n osis, re pr o d ucti ve t o xicit y a n d gra n ul oc ytic 
effects, i ncl u di n g ne utr o pe nia. Of n ote, t here is n o 
bi ol o gical rati o nale f or se veral of t hese p ote ntial ris ks i n 
t he setti n g of a si n gle d ose a d mi nistratio n. M ore 
i m p orta ntl y, n o ne of t hese p ote ntial ris ks ha ve bee n 
i de ntifie d i n t he R A de vel o p me nt pr o gra m t hr o u g h P hase 
2 b wit h a p pr o xi matel y 9 0 0 s u bj ect -years of e x p os ure. See 
I n vesti gat or’s Br oc h ure f or a d diti o nal details. 
Wit h re gar ds t o miti gati o n of t he a berra nt i m m u ne 
res p o nse i n t he setti n g of C O VI D-1 9, it is u nclear 
w het her bl oc ka de of G M -C S F i n t he l u n g is re q uire d i n 
a d diti o n t o a b oliti o n of si g nali n g i n t he peri p her y. St u dies 
wit h t he ma vrili m u ma b s urr o gate a nti -m o use G M -C S F -
R α a nta g o nistic a nti b o d y , C A M-3 0 0 3, were perf or me d t o 
i nterr o gate t he p ul m o nar y vs. peri p heral 
p har mac o d y na mics of asce n di n g si n gle a n d re peat d oses. 
Si n gle d oses of 3 -3 0 m g/ k g deli vere d i ntra -perit o neall y 
s h o we d n o p har mac o d y na mic effects i n t he l u n gs (as 
assesse d b y B A L F assa y) , des pite t he 3 m g/ k g d ose 
de m o nstrati n g c o m plete rece pt or occ u pa nc y ( R O) i n t he 
peri p her y. P har mac o d y na mic effects i n t he l u n gs, 
meas ure d b y I L -6 i n d ucti o n fr o m B A L cells ( 7 2 % ± 1 1 % 
i n hi biti o n), were see n o nl y f oll o wi n g re peat dail y d oses 
of 3 0 m g/ k g. I n c o ntrast, dail y a d mi nistrati o n of 3 m g/ k g 
di d n ot affect I L -6 i n d ucti o n of B A L cells. T his i n dicates 
t hat re peate d, ver y hi g h d oses ( ≥1 0 x re q uire d t o 
c o m pletel y bl oc k t he si g nali n g a xis i n t he peri p her y) are 
re q uire d f or t he a nti-G M -C S F -R α a nti b o d y t o ha v e a n 
i n hi bit or y effect o n al ve olar macr o p ha ges ( Ca m p bell J, 
2 0 1 6). Ca m p bell et al. als o i n dicate t hat si g nifica nt 
p har mac o d y na mic effects of t he a nti b o d y o n t he l u n g 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 7  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
cells c o ul d be o bser ve d after 5 dail y d oses of 3 0 m g/ k g 
C A M -3 0 0 3 ( 5 3 % ± 2 3 % i n hi biti o n). H o we ver, t he 
a ut h ors war ne d t hat P K st u dies usi n g B A L meas ure me nts 
t o q ua ntif y p orti o ni n g i n t he l u n g l u me n ma y 
u n deresti mate t he p orti o ni n g d ue t o dil uti o n wit h t he 
la va ge fl ui d. 
Of f urt her n ote, t hese st u dies were d o ne i n mice wit h o ut 
u n derl yi n g l u n g pat h ol o g y, a n d t he tra nslata bilit y of t hese 
st u dies i n n or mal mice t o h u ma ns wit h C O VI D-1 9 
p ne u m o nia is u nclear. Ne vert heless, t hese data s u g gest 
t hat a d ose hi g her t ha n t hat nee de d t o ac hie ve 1 0 0 % R O 
i n circ ulati o n ma y be re q uire d i n or der t o ac hie ve 
t hera pe utic c o nce ntrati o ns i n t he l u n g. I n c urre nt C O VI D-
1 9 s u bjects it is li kel y t hat t he i nfla m mat or y pr ocess 
afflicti n g t he l u n gs of se vere p ne u m o nia s u bjects wit h 
h y per -i nfla m mati o n ma y lea d t o a hi g her rati o of 
pe netrati o n t ha n t he o ne o bser ve d i n a ni mal st u d ies, t h us 
all o wi n g f or p ote ntiall y direct i n hi bit or y effects o n 
macr o p ha ges t hat ha ve alrea d y mi grate d i n t he l u n gs.  
T a ke n t o get her, a d ose of u p t o 1 0 m g/ k g (t he hi g hest 
teste d i n h u ma ns) ma y be re q uire d t o c o nfer si g nifica nt 
p har mac o d y na mic effects i n t h e l u n g t o i n hi bit c yt o ki ne 
st or m a n d pre ve nt f urt her l u n g da ma ge. S u p p orte d b y t he 
safet y data pr o vi de d b y t he P hase 1 st u d y, it w o ul d be 
reas o na ble t o a d mi nister a si n gle d ose of ma vrili m u ma b 
at le vels u p t o 1 0 m g/ k g i n a n atte m pt t o pr o vi de desire d 
p har m ac o d y na mics i n C O VI D -1 9 s u bjects, w here direct 
i n hi biti o n of G M-C S F i n t he l u n g ma y be a re q uire me nt. 
Preli mi nar y e nc o ura gi n g res ults fr o m ma vrili m u ma b a n d 
le nzil u ma b, t w o of t he dr u gs use d i n c o m passi o nate 
treat me nt pr ot oc ols t o ac hie ve t he G M-C S F bl oc ka d e, 
s u p p ort use of hi g her d oses t ha n o nes re q uire d t o ac hie ve 
1 0 0 % R O i n circ ulati o n, i n or der t o ac hie ve t hera pe utic 
dr u g le vels i n t he l u n g. H y p ot heticall y, a d ose of 3 m g/ k g 
ma y be s ufficie nt a n d reas o na ble t o be teste d, b ut o nl y if 
t he hi g her pr o p ose d doses i n t he st u d y, ie, 1 0 m g/ k g a n d 6 
m g/ k g, are f o u n d n ot t o be safe ( ver y cl ose safet y 
m o nit ori n g is pr o p ose d) f or t he tar get p o p ulati o n or if 
efficac y, if o bser ve d, is n ot a p pare ntl y d ose -de pe n de nt 
( decisi o n t o be dri ve n b y P hase 2 data). Gi ve n t he 
let halit y of p ul m o nar y c o m plicati o ns fr o m C O VI D-1 9, 
t he S p o ns or, wit h i n p ut fr o m C O VI D-1 9 treati n g 
p h ysicia ns, is pr o p osi n g t hat, i n P hase 2, hi g her d oses 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 8  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
( hi g her t ha n 3 m g/ k g, gi ve n t hat t his d ose is a p pare ntl y 
s ufficie nt t o c o m pletel y bl oc k t he si g nali n g a xis o nl y i n 
t he peri p her y) be teste d first. T he I V r o ute of 
a d mi nistrati o n is s u p p orte d b y P hase 1 safet y res ults fr o m 
t he S A D st u d y i n R A s u bjects ( B ur mester G R, 2 0 1 1). As 
a preca uti o n, t he I V i nf usi o n of ma vrili m u ma b i n t he 
C O VI D -1 9 P hase 2/ 3 st u d y will be a d mi nistere d at 
sl o wer rates t ha n t h ose a p plie d i n t he S A D st u d y. 
S y n o psis + Secti o n 
6. 2 N u m ber of 
S u bjects ( pl a n ne d)  
( pa ge 4 5 ) 
N u m ber of s u bjects ( pl a n ne d):  
P hase 3:  A p pr o xi matel y 6 6 5  4 1 7  s u bj ects 
•  
C o h ort 1:  A p pr o xi matel y 6 0 0  3 3 0  n o n -ve ntilate d 
s u bj ects 
•  
C o h ort 2:  A p pr o xi matel y 1 1 7 ve ntilate d s u bjects  
(a p pr o xi matel y 6 5 s u bjects at ti me of e nr oll me nt 
cl os ure) 
T he sa m ple size f or t he P hase 3 part of t he st u d y ma y b e 
m o difie d after re vie w of t he P hase 2 data. P hase 2 
s u bj ects will n ot be i ncl u de d i n t he a nal ysis of P hase 3 
res ults. Base d o n re vie w of t he P hase 2 C o h ort 2 res ults 
of t he pri mar y a n d sec o n dar y e n d p oi nts at da y 2 9, P hase 
3 C o h ort 2 is cl ose d t o f urt her e nr oll me nt, as t he re was n o 
e vi de nce t hat ma vrili m u ma b pr o vi de d cli nical be nefit 
o ver place b o i n rece ntl y ve ntilate d patie nts.  
I ncrease d P hase 3 
C o h ort 1  t o 6 0 0 
s u bj ects base d o n 
P hase 2 C o h ort 1 
res ults of pri mar y 
e n d p oi nt . 
 
Decisi o n t o cl ose 
e nr oll me nt i n P hase 3  
C o h ort 2  base d o n 
res ults of P hase 2 
C o h ort 2 res ults.  
S y n o psis + Secti o n 
1 0. 2 Sec o n d ary 
Effic acy E n d p oi nts  
( pa ge 5 6 -5 7 ) 
S ec o n dar y efficac y e n d p oi nts will be e xa mi ne d base d o n 
t he hierarc hical or der as s pecifie d bel o w  i n t he 
m ulti plicit y a dj ust me nt secti o n  ( Secti o n 1 3. 4 ). 
C o h ort 1 ( n o n -ve ntilate d s u bj ects) : 
1.  
 
[de m ote d t o Ot her Efficac y E n d p oi nt]  
 
 
 
 
 
2.  
 
[ de m oted t o Ot her Efficac y E n d p oi nt]  
 
 
 
Re vise d a n d 
re or dere d sec o n dar y 
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults.  S pecifie d 
t hat statistical 
e xa mi nati o n  t o be 
perf or me d as per t he 
m ulti plicit y 
a dj ust me nt secti o n . 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
8 9  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
 
  
1.  M ortalit y rate a t Da y 2 9 
2.  Ve ntilati o n free s ur vi val ( Ti me t o ve ntilati o n or 
deat h) b y Da y 2 9  [ pr o m ote d fr o m Ot her Efficac y 
E n d p oi nts]  
Defi ne d as ti me fr o m ra n d o mizati o n t o 
ve ntilati o n or deat h; s u bjects still ali ve will be 
ce ns ore d at Da y 2 9  
3.  O verall s ur vi val b y Da y 2 9  [ pr o m ote d fr o m 
Ot her Efficac y E n d p oi nts]  
Defi ne d as ti me fr o m ra n d o mizati o n t o deat h; 
s u bj ects still ali ve will be ce ns ore d at Da y 2 9 
S y n o psis + Secti o n 
1 0. 3 Ot her Effic acy 
E n d p oi nts  ( pa ge 
5 7 ) 
Ot her Effic acy E n d p oi nts : 
C o h ort 1:  
3.  
 
 
[ de m ote d fr o m Sec o n dar y E n d p oi nts]  
 
 
 
 
 
4.  
 
 [ de m ote d fr o m Sec o n dar y E n d p oi nts] 
 
 
 
 
 
 
 
Re vise d a n d 
re or dere d ot her  
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults 
S y n o psis + Secti o n 
1 0. 3 Ot her Effic acy 
E n d p oi nts  ( pa ge 
5 8 ) 
 
 
 
  
 
 
Re vise d a n d 
re or dere d ot her  
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 0  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
 
 
 
 
 
 
 
 
 
 
 
 
S y n o psis + Secti o n 
1 0. 3 Ot her 
E n d p oi nts  (pa ge 
5 8 ) 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
[re mai n der of e n d p oi nts  u nc ha n ge d]  
Re vise d a n d 
re or dere d ot her  
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults. 
 
 
 
 
 
S y n o psis +  Secti o n 
1 3. 1 A n a lysis Sets 
( pa ge 7 2 ) 
A n alysis Sets:  
I nte nt-t o-Treat (I T T) A nal ysis Set:  
All ra n d o mize d s u bjects w h o meet eli gi bilit y criteria  will 
be i ncl u de d i n t he I T T a nal ysis set.  
M o difie d I T T ( mI T T) A nal ysis Set:  
All ra n d o mize d s u bjects w h o meet eli gi bilit y criteria a n d 
recei ved  st u d y dr u g will be i ncl u de d i n t he mI T T a nal ysis 
set.  
U p date t o a nal ysis set 
defi niti o ns  
S y n o psis +  Secti o n 
1 3. 2. 2 Str atifie d 
A n alysis  ( pa ge 7 2 ) 
R a n d o miz ati o n Str at a:  
T here will be 3 stratificati o n fact ors f or ra n d o mizati o n: 
1. Use of a ut h orize d a p pr o ve d  sta n dar d of care 
a ntiretr o viral  a nti viral  t hera p y f or C O VI D-1 9  (e g, 
re m desi vir): yes vs. n o   
C ha n ge d 
‘a ntiretr o viral ’ t o 
‘a nti viral ’ t o be 
i ncl usi ve a n d 
clarifie d t hat a nti viral 
t hera p y is s pecific t o 
C O VI D -1 9 .  Als o 
c ha n ge d ‘a p pr o ve d’ 
t o ‘a ut h orize d’ f or 


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 1  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
clarit y.  
S y n o psis +  Secti o n 
1 3. 2. 4 Effic acy 
A n alysis ( pa ge 7 3 -
7 4 ) 
Efficac y A nal ysis :  
All efficac y a nal yses will be base d o n t he mI T T f or t he 
P hase 2 e n d p oi nts a n d base d o n t he  I T T a nal ysis set f or 
t he P hase 3 e n d p oi nts. A nal yses base d o n ot her a nal ysis 
sets will be c o nsi dere d as se nsiti vit y a nal yses. All 
efficac y c o m paris o ns will be pri maril y base d o n eac h of 
t he ma vrili m u ma b ar ms vers us t he place b o ar m.  
C o m paris o n bet wee n t he  p o ole d ma vrili m u ma b ar m 
vers us place b o ar m will be s u p p orti ve. P hase 3, C o h ort 1 
pri mar y a n d sec o n dar y e n d p oi nts will be e xa mi ne d i n a 
hierarc hical or der  as s pecifie d i n Secti o n 1 3. 4 . 
Pri m ary Effic acy E n d p oi nt:  
F or t he P hase 2 part of t he st u d y, t he Fis her’s e xact test 
will be perf or me d f or t he pri mar y efficac y e n d p oi nt f or 
b ot h c o h orts. T he C oc hra n -Ma ntel -Hae nszel ( C M H) test 
a dj usti n g f or ra n d o mizati o n strata ( a ut h orize d a p pr o ve d  
sta n dar d of care a ntiretr o viral  a nti viral t hera p y f or 
C O VI D -1 9 (e g, re m desi vir) , a ge, a n d A R D S stat us) will 
be use d as s u p p orti ve a nal ysis of t he pri mar y efficac y 
e n d p oi nt f or C o h ort 1.  
F or b ot h c o h orts i n t he P hase 3 part of t he st u d y, t he 
C M H test a dj uste d b y ra n d o mizati o n strata will be use d 
t o test t he pri mar y efficac y e n d p oi nt f or b ot h c o h orts . 
T he n u m ber of s u bjects a n d perce nta ges will be 
s u m marize d b y treat me nt. T he 8 0 % (f or P hase 2) a n d 
9 5 %  (for P hase 2 a n d 3) c o nfi de nce i nter vals will als o be 
pr o vi de d as a p pr o priate.  
Sec o n d ary a n d Ot her Effic acy E n d p oi nts:  
Ti me t o ve ntilati o n or deat h,  V e ntilati o n  free s ur vi val, 
o verall s ur vi val , 
, 
ti me t o cli nical i m pr o ve me nt, a n d all ot her ti me t o e ve nt 
e n d p oi nts will be a nal yze d usi n g l o g -ra n k test stratifie d 
b y ra n d o mizati o n strata. T he hazar d rati o f or 
ma vrili m u ma b vs. place b o a n d t he c orres p o n di n g Wal d 
8 0 % (f or P hase 2) a n d 9 5 % (f or P hase  2 a n d  3) CI will be 
calc ulate d base d o n a C o x pr o p orti o nal -hazar ds m o del 
wit h treat me nt as c o variate, stratifie d b y ra n d o mizati o n 
strata. 
U p date d t he pr o p ose d 
pri mar y a nal ysis f or 
pri mar y efficac y 
e n d p oi nt base d o n 
P hase 2 res ults.  
 
Re vise d sec o n dar y 
a n d ot her  efficac y 
e n d p oi nts  base d o n 
P hase 2, C o h ort 1 
res ults 


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 2  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
S y n o psis + Secti o n 
1 3. 2. 7 I nteri m 
A n alysis ( pa ge 7 4 -
7 5 ) 
I nteri m A n alysis 
T here is n o i nteri m a nal ysis pla n ne d f or t he P hase 2 or 
P hase 3  part of t he st u d y. I nstea d , t he S p o ns or will 
c o n d uct a pri mar y  a n d/ or fi nal  efficac y a nal ysis (ie, 
re vie w of u n bli n de d st u d y res ults) w he n t he last s u bject 
i n eac h P hase a n d C o h ort c o m pletes t he Da y 2 9 /Da y 9 0  
assess me nts. 
F or t he P hase 3 part of t he st u d y, o ne i nteri m a nal ysis f or 
eac h c o h ort will be perf or me d w he n 5 0 % of t he s u bj ects 
are ra n d o mize d a n d ha ve bee n f oll o we d u p f or 2 9 da ys. 
T he D M C will re vie w t he u n bli n de d i nteri m a nal ysis 
res ults a n d pr o vi de t he S p o ns or wit h a rec o m me n dati o n 
base d o n t he pre -s pecifie d earl y st o p pi n g r ule bel o w f or 
o ver w hel mi n g efficac y. T here is n o f utilit y a nal ysis 
pla n ne d. H o we ver, t he D M C ma y rec o m me n d st o p pi n g 
t he trial d ue t o safet y c o ncer ns. 
T he O’ Brie n -Fle mi n g st o p pi n g b o u n dar y base d o n t he 
La n -De Mets al p ha s pe n di n g f u ncti o n will be a p plie d at 
t he i nteri m a n d fi nal a nal yses. If t he i nf or mati o n fracti o n 
at t he i nteri m a nal ysis is 5 0 %, t he t w o -si de d si g nifica nce 
le vels at t he i nteri m a n d fi nal a nal yses will be gi ve n b y 
α 1= 0. 0 0 3 0 a n d α 2= 0. 0 4 9 0. T he si g nifica nce le vels will be 
calc ulate d base d o n t he act ual i nf or mati o n fracti o n at t he 
i nteri m a nal ysis. 
Eli mi nat e d t he 
i nteri m a nal ysis f or 
P hase 3 d ue t o ra pi d 
e nr oll me nt 
Secti o n 1 3. 3. 2 
S a m ple Size 
Esti m ati o n P h ase 3  
( pa ge 7 5 -7 6 ) 
S a m ple Size Esti m ati o n:  
P hase 3  
A p pr o xi matel y 6 6 5  4 1 7  s u bj ects will be ra n d o mize d t o 
t he P hase 3 part of t his st u d y. 
Sa m ple size f or C o h ort 1 ( n o n -ve ntilate d s u bjects) of t he 
P hase 3 part is deter mi ne d base d o n t he pri mar y efficac y 
e n d p oi nt of pr o p orti o n of s u bj ects ali ve a n d free of 
mec ha nical ve ntilati o n  at Da y 2 9  ( ma vrili m u ma b 6 m g/ k g 
vs place b o)  usi n g t he C hi s q uare  Fis her’s e xact  test. T he 
ass u m pti o ns use d f or t he calc ulati o n are a dj uste d 
base d o n t he res ults of P hase 2 p orti o n. 
A p pr o xi matel y 6 0 0  3 0 0  s u bj ects will be ra n d o mize d wit h 
a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he pr o p orti o ns f or t he 
acti ve ar m a n d place b o ar m  are 8 7. 5  9 5 % a n d 7 4 . 4 7 5 % 
res pecti vel y, a p pr o xi matel y 1 0 0  2 0 0 s u bjects per ar m are 
s ufficie nt t o ac hie ve at least 9 0 % p o wer f or a pair wise 
T he ass u m pti o ns f or 
t he pr o p orti o n of 
s u bj ects ali ve a n d 
free of ve ntilati o n 
were u p date d base d 
o n P hase 2  C o h ort 1  
res ults. P o wer 
esti mate was u p date d . 
 
Decisi o n t o cl ose 
e nr oll me nt i n P hase 3 
C o h ort 2 base d o n 
res ults of P hase 2 
C o h ort 2 res ults.  


ma vrili m u ma b ( K P L -3 0 1)  
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Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 3  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
c o m paris o n vers us c o ntr ol w he n  t he treat me nt 
c o m paris o n at t he t w o-si de d al p ha val ue is  si g nifica nce 
le vel of 0. 0 5  0. 0 2 5 . 
Sa m ple size f or C o h ort 2 ( ve ntilate d s u bjects) of t he 
P hase 3 part is deter mi ne d base d o n t he m ortalit y rate at 
Da y 2 9  usi n g a Fis her’s e xact test. A p pr o xi matel y 1 1 7 
s u bj ects will be ra n d o mize d wit h a 1: 1: 1 all ocati o n rati o. 
Ass u mi n g t he m ortalit y rates f or t he acti ve ar m a n d 
place b o ar m are 4 0 % a n d 8 0 % res pecti vel y, 
a p pr o xi matel y 3 9 s u bj ects per ar m are re q uire d t o ac hie ve 
a 9 0 % p o wer f or a pair wise c o m paris o n vers us c o ntr ol 
w he n t he t w o -si de d al p ha val ue is 0. 0 2 5. H o we ver, base d 
o n re vie w of t he P hase 2 C o h ort 2 res ults of t he pri mar y 
a n d sec o n dar y e n d p oi nts at da y 2 9, P hase 3 C o h ort 2 is 
cl ose d t o f urt her e nr oll me nt (a p pr o xi matel y 6 5 s u bjects 
ra n d o mize d at t he ti me of e nr oll me nt cl os ure), as t here 
was n o e vi de nce t hat ma vrili m u ma b pr o vi de d cli nical 
be nefit o ver place b o i n rece ntl y ve ntilate d patie nts.  
Sa m ple size f or t he P hase 3 part of t he st u d y ma y be 
m o difie d after re vie w of t he P hase 2 data.  
S y n o psis + Secti o n 
1 3. 4 M ulti plicity 
A dj ust me nt  ( pa ge 
7 6 -7 7 ) 
M ulti plicit y A dj ust me nt  
T he c o h orts wit hi n t he P hase 2 a n d P hase 3 st u d y parts 
will be a nal yze d se paratel y u nless ot her wise s pecifie d.  
N o m ulti plicit y a dj ust me nt will be d o ne  f or t he P hase 2 
part. T y pe I err or rate f or eac h P hase 2 c o h ort is at a t w o -
si de d al p ha val ue of 0. 2. 
T here are t hree s o urces of m ulti plicit y i n t he P hase 3 part 
of t his trial:  
•  
A nal ysis of t he pri mar y/sec o n dar y e n d p oi nts  
•  
A nal ysis of t he d ose -place b o c o m p aris o ns  
•  
A nal ysis of treat me nt effects at t he i nteri m 
a n d t he fi nal a nal yses   
M ulti plicit y a dj ust me nt  f or P hase 3 C o h ort 1 will be d o ne 
t o g uara ntee str o n g c o ntr ol of t he o verall T y pe I err or rate 
wit h res pect t o all t hree s o urces of m ulti plicit y  at a t w o-
si de d al p ha val ue of 0. 0 5 wit hi n eac h c o h ort . Details are 
pr o vi de d i n Secti o n  1 3. 4 .   
T o a d dress m ulti plicit y i n d uce d b y t he first t w o s o urces 
of m ulti plicit y i n t his trial, na mel y, m ulti plicit y i n d uce d 
b y t he a nal ysis of t he pri mar y/sec o n dar y e n d p oi nts a n d  
U p date d base d o n t he 
pr o p ose d a nal ysis f or 
p o ole d 
ma vrili m u ma b ar m 
vers us place b o.  


ma vrili m u ma b ( K P L -3 0 1)  
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Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 4  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
m ulti plicit y i n d u ce d b y t he a nal ysis of t he d ose -place b o 
c o m paris o ns, a gate kee pi n g pr oce d ure i n c o nj u ncti o n 
wit h tr u ncate d H oc h ber g met h o d will be a p plie d. T his 
gate kee pi n g pr oce d ure is deri ve d usi n g t he mi xt ure 
met h o d ol o g y ori gi nall y pr o p ose d i n D mitrie n k o a n d 
T a m ha ne a n d later e n ha nce d i n K or dza k hia et al. 
( D mitrie n k o A, 2 0 1 3; K or dza k hia G a n d D mitrie n k o A, 
2 0 1 8).  
T o acc o u nt f or t he t hir d s o urce of m ulti plicit y (a nal ysis of 
treat me nt effects at t he i nteri m a nal ysis a n d fi nal 
a nal ysis), t he af ore me nti o ne d O’ Brie n -Fle mi n g  st o p pi n g 
b o u n dar y will be use d t o deter mi ne t he o verall t y pe I 
err or rate at eac h i nteri m a n d fi nal a nal ysis, a n d t he 
m ulti plicit y a dj ust me nt f or m ulti -sta ge cli nical trials 
defi ne d i n K or dza k hia, D mitrie n k o a n d Is hi da will be 
a p plie d ( K or dza k hia G a n d Br ec he n mac her  T, 2 0 1 8; 
Je n nis o n C, 2 0 0 0). 
Se q ue ntial gate kee pi n g pr oce d ure will be use d t o c o ntr ol 
t he t y pe I err or rate. Statistical testi n g will be d o ne base d 
o n t he hierarc hical or der s pecifie d bel o w.  
Or der  E n d p oi nt  
C o m p aris o n  
1  
Pr o p orti o n of s u bj ects  
ali ve a n d free of 
mec ha nical ve ntilati o n 
at Da y 2 9  
ma vrili m u ma b 6 m g vs. 
place b o  
2  
M ortalit y rate at Da y 
2 9  
ma vrili m u ma b 6 m g vs. 
place b o  
3  
Ve ntilati o n free 
s ur vi val b y Da y 2 9 
ma vrili m u ma b 6 m g vs. 
place b o  
4  
M ortalit y rate at Da y 
2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
5  
Pr o p orti o n of s u bj ects 
ali ve a n d free of 
mec ha nical ve ntilati o n 
at Da y 2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
6  
Ve ntilati o n free 
s ur vi val b y Da y 2 9 
ma vrili m u ma b 1 0 m g 
vs. place b o  
7  
O verall s ur vi val b y 
Da y 2 9  
ma vrili m u ma b 6 m g vs. 
place b o  
8  
O verall s ur vi val b y 
Da y 2 9  
ma vrili m u ma b 1 0 m g 
vs. place b o  
 


ma vrili m u ma b ( K P L -3 0 1)  
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Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 5  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
S y n o psis + Secti o n 
7. 2 Excl usi o n 
Criteri a  ( pa ge 4 9 ) 
a n d Secti o n 8. 2. 1 
Pr o hi bite d 
Me dic ati o ns  ( pa ge 
5 2 ) 
A d de d se nte nce t o e n d of e xcl usi o n criteri o n # 6 , sc he d ule 
of acti vities f o ot n ote # 2 4 a n d als o t o Secti o n 8. 2. 1: 
“Me dicati o ns t hat bec o me sta n dar d of care f or C O VI D -
1 9 a n d/ or recei ve e mer ge nc y use a ut h orizati o n ma y be 
all o we d after disc ussi o n wit h t he me dic al m o nit or.” 
T o all o w me dical 
m o nit or discreti o n 
re gar di n g 
c o nc o mita nt 
me dicati o ns relati ve 
t o C O VI D-1 9.  
T a ble 2:  Sc he d ule 
of Acti vities  ( pa ges 
1 7 -2 1 ) + Secti o n 
1 0. 4. 2 Res pir at ory 
P ar a meters ( pa ge 
5 9 ) 
1.  C ha n ge d t he acce pta ble visit wi n d o w s f or t he Da y 2 9 
visit  fr o m ± 2 t o + 4 a n d  f or t he Da y 6 0 a n d Da y 9 0 - 
visit s fr o m ± 7 da ys t o + 1 4 da ys  
2.  A d de d a f o ot n ote ( # 1 0) t o Ra n d o mizati o n a n d St u d y 
Dr u g A d mi nistrati o n, “ T he NI AI D sc ore s h o ul d be 
rec or de d at t he ti me of ra n d o mizati o n f or all eli gi ble 
s u bj ects. F or s ubjects i n C o h ort 1 o nl y, als o rec or d 1) 
eit her Pa O 2 ( m m H g) if a vaila ble or S p O 2 ( %) a n d 2) 
Fi O 2 ( %) f or s u bjects o n assisti ve ve ntilati o n or 
L/ mi n of o x y ge n f or s u bjects n ot o n assisti ve 
ve ntilati o n (e g, si m ple mas k/ca n n ula). I nitiati o n of 
st u d y dr u g a d mi nistrati o n s h o ul d occ ur wit hi n 2 4 
h o urs of ra n d o mizati o n ” [re n u m bere d all s u bse q ue nt 
f o ot n otes] 
3.  M o difie d f o ot n ote # 1 1 (f or mer f o ot n ote # 1 0): “If t he 
s u bj ect re mai ns h os pitalize d after Da y 8 t hese 
assess me nts s h o ul d be c ollecte d dail y u ntil t he da y of 
disc ha r ge (ie, Da ys 9-1 4, 1 6 -2 1, 2 3 -2 8 or after Da y 
2 9). O n Da y 1, assess me nts s h o ul d be c ollecte d at t he 
ti me cl osest t o a n d pri or t o t he i nitiati o n of st u d y dr u g 
a d mi nistrati o n. Dail y c ollecti o n g ui deli nes  after Da y 
1 : c ollect assess me nt i n t he m or ni n g at a p pr o xi matel y 
t he sa me ti me eac h da y a n d cl osest t o t he c ollecti o n 
of t he NI AI D sc ore assess me nt , e xce pt f or res pirat or y 
para meters (see f o ot n ote # 1 6)  
4.  Re vise d t he Assess me nt of S ur vi val t o o nl y re q uire at 
st u d y visits be gi n ni n g at D a y 1 5 
5.  A d de d  “t o h o me” t o f o ot n ote 1 3. 
6.  Re vise d te xt t o f o ot n ote # 1 6 : “Dail y val ues base d o n 
t he hi g hest dail y Fi O 2, i ncl u di n g Pa O2, Fi O2, S p O2 
a n d o x y ge n re q uire me nt . calc ulate d P t o F rati o (if 
act ual val ues are n ot a vaila ble a n d t he rati o is 
a vaila ble), O t her A B G ( arterial bl o o d  gas es) 
para meters if a vaila ble a n d res pirat or y rate (if s u bject 
1.  S hifte d acce pta ble 
visit wi n d o w s t o 
e ns ure f oll o w -u p  
2.  A d de d c ollecti o n 
of ke y para meters 
at t he ti me of 
ra n d o mizati o n a n d 
clarifie d t he ti mi n g 
of ra n d o mizati o n 
relati ve t o 
i nitiati o n of st u d y 
dr u g 
a d mi nistrati o n 
3.  Clarif y data 
c ollecti o n 
re q uire me nts 
4.  S ur vi val 
i nf or mati o n is o nl y 
re q uire d p ost-
disc har ge  
5.  Clarifie d t hat a 
NI AI D sc ore of 7 
or 8 is re q uire d f or 
s u bj ects w h o are  
disc har ge d t o h o me  
6.  Clarifie d c ollecti o n 
of  res pirat or y 
para meters  ( n ote:  
res pirat or y rate is 
c ollecte d as part of 
vital si g ns ) 


ma vrili m u ma b ( K P L -3 0 1)  
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0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 6  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber3) 
M o dific ati o n  
R ati o n ale  
is n ot mec ha nicall y ve ntilate d) s h o ul d be rec or de d. I n 
a d diti o n, resc ue t hera p y (e g, Fl o na n), a n d ot her 
s u p p orti ve meas ures (e g, i ncl u di n g pr o nati o n, 
ne ur o m usc ular bl oc ka de, trac he ost o m y, E C M O, 
vas o press or or i n otr o pic t hera p y, i n hale d nitric o xi de 
or ot her s) s h o ul d be rec or de d. 
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 7  of 1 0 9  
C o nfi de ntial  
2 0. 4.  
C h a n ges fr o m Gl o b al Pr ot oc ol Versi o n 2 ( A me n d me nt 1)  t o Gl o b al 
Pr ot oc ol Versi o n 3 ( A me n d me nt 2)  
T he f oll o wi n g are c ha n ges t o t he K P L -3 0 1 -C 2 0 3 pr ot oc ol ( versi o n 2 :  1 3 A u g  2 0 2 0), w hic h s u m marize s 
maj or c ha n ges t o t he pr ot oc ol.  A d diti o nal mi n or c ha n ges were als o ma de wit h res pect t o use of 
a b bre viati o ns, c orrecti o n of t y p os, re n u m beri n g of secti o ns ( w he n necessar y), a n d re visi n g/f or matti n g 
refere nces.   
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
S y n o psis  
St u d y ce nter(s):  A p pr o xi matel y 5 0 st u d y ce nters are 
pla n ne d i n t he U nite d States, E M E A, Lati n A merica, a n d 
Africa a n d A ustralia 
U p date t o pla n ne d 
c o u ntries 
S y n o psis  
St u die d peri o d ( ye ars):  
Esti mate d  D d ate first s u bject e nr olle d:  T B D  J ul y 2 0 2 0 
Esti mate d date last s u bject c o m plete d: T B D  
U p date d i nf or mati o n 
o n st u d y peri o d  
S y n o psis + Secti o n 
5. 2  Sec o n d ary 
O bjectives  
( pa ge 35 ) 
C ha n ge d sec o n dar y o bjecti ves t o:  
“ T o assess t he i m pact of treat me nt o n cli nical stat us  ti me 
t o ret ur n t o r o o m air, c ha n ges i n nee d f or i n vasi ve 
ve ntilati o n or critical care o ver ti me , m ortalit y, 
res pirat or y para meters, a n d safet y of a si n gle I V d ose of 
ma vrili m u ma b ( 1 0 m g/ k g or 6 m g/ k g) relati ve t o pla ce b o 
i n a d ult s u bjects h os pitalize d wit h se vere C O VI D-1 9 
p ne u m o nia a n d h y per -i nfla m mati o n.” 
Si m plificati o n  
S y n o psis + Secti o n 
5. 3  Ot her O bjective  
( pa ge 35 ) 
“ E x pl orat or y o bjecti ve” re na me d “ o t her o bjecti ves” 
Ali g n wit h c ha n ge t o 
e n d p oi nt secti o n 
w here a n d 
“e x pl orat or y 
e n d p oi nts” i nt o 
“ ot her e n d p oi nts” 
were mer ge d a n d 
re na me d “ ot her 
e n d p oi nts” 
S y n o psis  
Met h o d ol o g y - re vise d descri pti o n of t he patie nt 
p o p ulati o n t o:    
“ …s u bjects w h o ha ve teste d p ositi ve f or t he se vere ac ute 
res pirat or y s y n dr o me c or o na vir us 2 ( S A R S-C o V -2) wit h 
x -ra y/c o m p ute d t o m o gra p h y ( C T) e vi de nce of bilateral 
p ne u m o nia a n d acti ve or rece nt si g ns of 
h y peri nfla m mati o n (fe ver a n d/or  cli nical la b orat or y 
res ults i n dicati ve of h y per -i nfla m mati o n). 
Ali g n wit h re visi o ns 
t o I ncl usi o n Criteri o n 
# 7  ( Fe ver) 
S y n o psis  
Met h o d ol o g y -re vise d state me nt o n ra n d o mizati o n t o:   
“F oll o wi n g Scree ni n g, e nr olle d s u bjects i n eac h c o h ort 
will be ra n d o mize d 1: 1: 1 t o recei ve ma vrili m u ma b 
1 0  m g/ k g or 6  m g/ k g, or place b o as a si n gle I V i nf usi o n 
( Da y 1) i n a d diti o n t o sta n dar d of care as per i nstit uti o nal 
pr ot oc ol a n d at t he discreti o n of t h e i n vesti gat or 
Clarifie d t hat st u d y 
d r u g is i n 
c o m bi nati o n wit h 
sta n dar d of care 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 8  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
( pr o vi de d t hat t he me dicati o n/t hera p y is n ot e x plicitl y 
pr o hi bite d per pr ot oc ol)  as a si n gle I V i nf usi o n ( D a y 1) .” 
S y n o psis + Secti o n 
6. 1 Over all St u dy 
Desi g n  ( pa ge 3 6) 
C ha n ge d t he ti mi n g of t he P hase 2 pri mar y efficac y a n d 
safety a n al yses: 
O nce t he last s u bject i n P hase 2 c o m pletes Da y 1 5  2 9 , 
pri mar y efficac y a n d safet y a nal yses of t he P hase 2 data 
will be c o n d ucte d b y t he S p o ns or.  
Ali g ns wit h t he 
c ha n ge i n t he pri mar y 
efficac y a nal ysis  
S y n o psis + Secti o n 
6. 1 Over all St u dy 
Desi g n  ( pa ge 3 7) 
Re vise t he descri pti o n of t he S R C i n de pe n de nt p h ysicia n:  
“ A Safet y Re vie w C o m mittee ( S R C) i ncl u di n g safet y 
p h ysicia ns fr o m t he S p o ns or, t he S p o ns or’s c o ntract 
researc h or ga nizati o n ( CR O), a n d  at least 1 me dical 
e x pert i n C O VI D -1 9 treat me nt  2 p h ysicia ns fr o m t he 
S p o ns or, 1 p h ysicia n fr o m t he S p o ns or’s c o ntract 
researc h or ga nizati o n ( C R O), a n d 1 i n de pe n de nt 
p h ysicia n w h o is a n e x pert i n critical care me dici ne, 
p ul m o nar y dis or ders, i nfect i o us diseases a n d/ or C O VI D-
1 9 treat me nt ( S R C C hair pers o n)  will meet peri o dicall y t o 
re vie w A Es/seri o us A Es ( S A Es), reas o ns f or st u d y 
disc o nti n uati o ns, a n d ke y cli nical a n d la b orat or y 
assess me nts. 
Clarif y t he 
q ualificati o ns of t he 
i n de pe n de nt 
p h ysicia n  
S y n o psis + Secti o n 
1 0. 1. 1 C o h ort 1 
( N o n-ve ntil ate d 
S u bjects)  ( pa ge 4 9) 
C ha n ge d pri mar y efficac y e n d p oi nt of C o h ort 1 t o:  
“ Pr o p orti o n of s u bj ects ali ve a n d free of mec ha nical 
ve ntilati o n wit h o ut res pirat or y fail ure  at Da y 2 9 1 5 ., 
w here res pirat or y fail ure  Mec ha nical ve ntilati o n is 
defi ne d as  t he nee d f or hi g h fl o w o x y ge n ( H F O), n o n-
i n vasi ve ve ntilati o n ( NI V), i n vasi ve mec ha nical 
ve ntilati o n (I M V), or e xtrac or p oreal me m bra ne 
o x y ge nati o n ( E C M O).”  
Mec ha nical ve ntilati o n Res pirat or y fail ure  stat us will be 
e val uate d base d o n t he Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Diseases ( NI AI D) cli nical o utc o me 8-p oi nt 
or di nal scale. S u bjects w h ose cli nical o utc o me meets  has 
met NI AI D cate g ories sc ore of 2 or 3  will be c o nsi dere d 
as usi n g  mec ha nical ve ntilati o n ha vi n g res pirat or y fail ure .  
Pri mar y e n d p oi nt 
f oc uses o n 
mec ha nical 
ve ntilati o n a n d deat h 
i n or der t o si m plif y 
assess me nt of be nefit 
a n d a v oi d a n y 
c o nf usi o n fr o m t he 
differe nces i n 
practice(s) of n o n -
i n vasi ve ve ntilati o n. 
T he d urati o n of 
o bser vati o n is p us he d 
t o Da y 2 9 t o all o w 
f or s ufficie nt ti me t o 
assess t he ne w 
pri mar y e n d p oi nt  
S y n o psis + Secti o n 
1 0. 1. 2 C o h ort 2 
( Ve ntil ate d 
S u bjects)  ( Pa ge 4 9) 
C ha n ge d t he pri mar y efficac y e n d p oi nt of C o h ort 2 t o:  
“ T he pri mar y efficac y e n d p oi nt is m ortalit y rate at Da y 
2 9 1 5 , defi ne d as t he pr o p orti o n of s u bjects w h o ha ve 
die d b y Da y 2 9 1 5 .” 
T he d urati o n of 
o bser vati o n is p us he d 
t o Da y 2 9 t o all o w 
f or s ufficie nt ti me t o 
assess t he ne w 
pri mar y e n d p oi nt a n d 
matc h C o h ort 1  
S y n o psis + Secti o n 
1 0. 2 Sec o n d ary 
Ke y s S ec o n dar y efficac y e n d p oi nts will be e xa mi ne d 
base d o n t he hierarc hical or der as s pecifie d bel o w:  
Re vise d a n d 
re or dere d sec o n dar y 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
9 9  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
Effic acy E n d p oi nts  
( pa ge 4 9 -5 0 ) 
C o h ort 1 ( n o n -ve ntilate d s u bj ects)  
1.  Ti me t o 2 -p oi nt cli nical i m pr o ve me nt b y Da y 1 5  
2 9 [ pr o m ote d t o 1 st sec o n d ary e n d p oi nt]  
Defi ne d as ti me fr o m ra n d o mizati o n t o a 2 -p oi nt 
i m pr o ve me nt o n t he NI AI D 8-p oi nt or di nal scale, 
or disc har ge fr o m t he h os pital, w hic he ver c o mes 
first. S u bjects w h o die bef ore Da y 1 5  2 9  will be 
ce ns ore d at Da y 1 5  3 0 . 
2.  Ti me t o ret ur n t o r o o m air or disc har ge b y Da y 
1 5 a n d Da y 2 9  [de m ote d t o 2 n d sec o n d ary 
e n d p oi nt]  
Defi ne d as ti me fr o m t he date of ra n d o mizati o n 
t o t he start of  a peri o d of 2 4 h o urs w hile  
breat hi n g r o o m air ( NI AI D scalesc ore ≥ 5), or 
disc har ge fr o m t he h os pital, w hic he ver occ urs 
first. S u bjects w h o die bef ore Da y 1 5 / Da y 2 9 
will be ce ns ore d at Da y 1 5 /  Da y 2 9  3 0 .  
3.  M ortalit y rate at Da y 2 9  
C o h ort 2 ( ve ntilate d s u bjects)  
1.  Ti me t o 1 -p oi nt cli nical i m pr o ve me nt b y Da y 2 9  
1 5  
Defi ne d as ti me fr o m ra n d o mizati o n t o a 1 -p oi nt 
i m pr o ve me nt o n t he NI AI D 8-p oi nt or di nal scale, 
or disc har ge fr o m t he h os pital, w hic he ver c o mes 
first. S u bjects w h o die bef ore Da y 1 5  2 9 will be 
ce ns ore d at Da y 1 5  3 0  
2.  M ortalit y rate at Da y 2 9  
3.  Ti me t o ret ur n t o r o o m air b y Da y 2 9  
Defi ne d as ti me fr o m t he date of ra n d o mizati o n t o 
t he start of a peri o d of 2 4 h o urs w hile breat hi n g 
r o o m air ( NI AI D scale ≥ 5), or disc har ge fr o m t he 
h os pital, w hic he ver occ urs first. S u bjects w h o die 
bef ore Da y 2 9 will be ce ns ore d at Da y 2 9  
e n d p oi nts 
S y n o psis + Secti o n 
1 0. 3 Ot her 
E n d p oi nts  ( pa ge 50  
t o 51 ) 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
C o m bi ne d “ ot her 
sec o n dar y e n d p oi nts” 
a n d “e x pl orat or y 
e n d p oi nts” i nt o 
“ ot her e n d p oi nts”, 
re or dere d, a n d 
re m o ve d s o me 
e n d p oi nts; (f or clarit y 
t he fi nal versi o n 3 
te xt is s h o w n) 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 0  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 1  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
2 8.  
 
 
. 
S y n o psis +  Secti o n  
1 3. 2. 4. 1  Pri m ary 
Effic acy E n d p oi nt  
( pa ge 66 ) 
Pri mar y e n d p oi nt a nal ysis m o difie d:  
F or t he P hase 2 part of t he st u d y, t he Fis her’s e xact test 
will be perf or me d f or t he pri mar y efficac y e n d p oi nt f or 
b ot h c o h orts. T he C M H test a dj usti n g f or ra n d o mizati o n 
strata (sta n dar d of care a ntiretr oviral t hera p y, a ge, a n d 
A R D S stat us) will be use d as s u p p orti ve a nal ysis of t he 
pri mar y efficac y e n d p oi nt f or C o h ort 1. 
F or t he P hase 3 part of t he st u d y, t he C oc hra n -Ma ntel -
Hae nszel ( C M H ) test a dj uste d b y t he ra n d o mizati o n strata 
(sta n dar d of care a ntiretr o viral t hera p y, a ge, a n d A R D S 
stat us) will be use d t o test t he pri mar y efficac y e n d p oi nt 
f or b ot h c C o h ort s 1 ( n o n -ve ntilate d s u bjects). Fis her’s 
e xact test will be perf or me d f or C o h ort 2 ( ve ntilate d 
s u bj ects). 
Clarificati o n a n d 
a d diti o n of 
s u p p orti ve a nal ysis i n 
P hase 2. 
Si m plificati o n f or 
P hase 3  
S y n o psi s + 
1 3. 2. 4. 2  Sec o n d ary 
a n d Ot her Effic acy 
E n d p oi nts  
( Pa ge 66 -6 7 ) 
1 3. 2. 4. 2   Sec o n d ar y a n d Ot her Effic ac y E n d p oi nts  
Ti me t o ve ntilati o n or deat h, ve ntilati o n -free s ur vi val, 
ti me t o cli nical 
i m pr o ve me nt, a n d all ot her ti me t o e ve nt e n d p oi nts will 
be a nal yze d usi n g l o g -ra n k test stratifie d b y t he 
ra n d o mizati o n strata. T hese ti me t o e ve nt e n d p oi nts will 
be s u m marize d wit h t he 2 5t h, 5 0t h ( me dia n), a n d 7 5t h 
perce ntiles usi n g t he  Ka pla n -Meier met h o d. T he 8 0 % (f or 
P hase 2) a n d 9 5 % (f or P hase 3) c o nfi de nce i nter val ( CI) 
f or t he perce ntiles will be calc ulate d usi n g a l o g-l o g 
tra nsf or mati o n. T he perce nta ge of s u bjects wit h e ve nts 
a n d its 8 0 % (f or P hase 2) a n d 9 5 % (f or P hase 3) CI will  
be calc ulate d at Da y 4, 8 , 1 5, 2 2 a n d Da y 2 9 1 5  si nce 
ra n d o mizati o n as a p pr o priate , usi n g Gree n w o o d’s 
f or m ula wit h a l o g-l o g tra nsf or mati o n. 
T he hazar d rati o f or ma vrili m u ma b vs. place b o a n d t he 
c orres p o n di n g Wal d 8 0 % (f or P hase 2) a n d 9 5 % (f or 
P hase 3) CI  will be calc ulate d base d o n a C o x 
pr o p orti o nal -hazar ds m o del wit h treat me nt as c o variate, 
stratifie d b y ra n d o mizati o n strata. 
M ortalit y rate a n d a A ll ot her bi nar y e n d p oi nts i n b ot h 
c o h orts f or P hase 2  a n d i n C o h ort 2 ( ve ntilate d s u bjects) 
o nl y f or P hase 3  will be pri maril y a nal yze d usi n g t he 
Fis her’s e xact test. T he C M H test a dj usti n g f or 
ra n d o mizati o n strata (sta n dar d of care a ntiretr o viral 
t hera p y, a ge, a n d A R D S stat us) will be use d as s u p p orti ve 
a nal ysis f F or C o h ort 1 ( n o n -ve ntilate d s u bjects).  i n P hase 
3 t he y will be a nal yze d usi n g a C M H test a dj uste d b y t he 
ra n d o mizati o n strata.  
Clarificati o n of t he 
tests use d f or 
sec o n dar y a n d ot her 
e n d p oi nts 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 2  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
F or t he P hase 3 part of t he st u d y, t he C M H test a dj uste d 
b y ra n d o mizati o n strata will be use d t o test all bi nar y 
sec o n dar y a n d ot her efficac y e n d p oi nt f or b ot h c o h orts. 
S y n o psis + Secti o n 
1 3. 2. 6 Ot her 
A n alyses  ( pa ge 6 7 ) 
Ot her A n alys es 
P har mac o ki netic para meters of ma vrili m u ma b will be 
s u m marize d. 
 
 
 T he pres e nce of a nti -dr u g a nti b o dies 
( A D As) will be e x pl ore d. Para meters of mec ha nical 
ve ntilati o n, res pirat or y stat us, Se q ue ntial Or ga n Fail ure 
Assess me nt  ( S O F A)/ q uic k S O F A, a n d healt h care 
res o urce utilizati o n (e g, da ys a n d/ or le n gt h i n 
h os pital/I C U/ o x y ge n use) will be s u m marize d.  
E x pl orati o n of t he 
ass ociati o n bet wee n 
ser u m i nfla m mat or y 
bi o mar kers a n d 
assess me nts of 
cli nical res p o nses 
will n ot be 
perf or m e d.  
S y n o psis + Secti o n 
1 3. 2. 7  I nteri m 
A n alysis  ( pa ge 6 7 ) 
I nteri m A n alysis 
T here is n o i nteri m a nal ysis pla n ne d f or t he P hase 2 part 
of t he st u d y. I nstea d , t he S p o ns or will c o n d uct a pri mar y 
efficac y a nal ysis (ie, re vie w of u n bli n de d st u d y res ults) 
w he n t he last s u bject i n P hase 2 c o m pletes t he Da y 2 9 1 5  
assess me nts. 
F or t he P hase 3 st u d y part, o ne i nteri m a nal ysis f or eac h 
c o h ort will be d o ne w he n 5 0 % of t he  s u bjects are 
ra n d o mize d a n d ha ve bee n f oll o we d u p f or 2 9 1 5  da ys. 
T he D M C will re vie w t he u n bli n de d i nteri m a nal ysis 
res ults a n d pr o vi de t he S p o ns or wit h a rec o m me n dati o n 
base d o n t he pre-s pecifie d earl y st o p pi n g r ule bel o w f or 
o ver w hel mi n g efficac y  t he sta n dar d al p ha s pe n di n g 
a p pr oac h.   
I nteri m a nal ysis 
c ha n ge d t o reflect 
c ha n ges t o pri mar y 
e n d p oi nt 
 
S y n o psis + 
t hr o u g h o ut 
pr ot oc ol  
N u m ber of s u bjects ( pla n ne d):  
P hase 2:  A p pr o xi matel y 1 5 6  1 7 1 s u bj ects 
•  C o h ort 1:  A p pr o xi matel y 1 0 5  1 2 0 n o n -ve ntilate d 
s u bj ects 
•  C o h ort 2:  A p pr o xi matel y 5 1 ve ntilate d s u bj ects  
Sa m ple size f or P hase 
2 re vise d as per t he 
c ha n ge of pri mar y 
e n d p oi nt 
S y n o psis + Secti o n 
1 3. 3. 1  S a m ple Size 
Esti m ati o n  ( pa ge 
6 8 ) 
P hase 2 sa m ple size:  
Sa m ple size esti mati o n f or C o h ort 1 ( n o n -ve ntila te d 
s u bj ects) i n P hase 2 is base d o n t he pri mar y efficac y 
e n d p oi nt of pr o p orti o n of s u bj ects ali ve a n d free of 
mec ha nical ve ntilati o n  wit h o ut res pirat or y fail ure  at Da y 
2 9 1 5 , usi n g a Fis her’s e xact test. 
A p pr o xi matel y 1 2 0 1 0 5  s u bj ects will be ra n d o mize d wit h 
a 1: 1: 1 all ocati o n rati o. Ass u mi n g t he pr o p orti o ns of 
s u bj ects ali ve a n d free of mec ha nical ve ntilati o n wit h o ut 
res pirat or y fail ure at Da y 2 9 1 5  isare 9 5 0 % a n d 7 6 5 % f or 
t he acti ve treat me nt ar m a n d place b o ar m, res pecti vel y, 
4 0  3 5  s u bjects per ar m will ac hie ve a mi ni m u m 8 0 % 
p o wer f or a pair wise c o m paris o n vers us c o ntr ol w he n t he 
Re vise d sa m ple size 
esti mati o ns 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 3  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
t w o-si de d al p ha val ue is 0. 2 0, after acc o u nti n g f or 1 5 % 
dr o p o ut . 
P hase 3 sa m ple size:  
Sa m ple size f or C o h ort 1 ( n o n -ve ntilate d s u bjects) of t he 
P ha se 3 part is deter mi ne d base d o n t he pri mar y efficac y 
e n d p oi nt of pr o p orti o n of s u bj ects ali ve a n d free of 
mec ha nical ve ntilati o n  wit h o ut res pirat or y fail ure  at Da y 
1 5  2 9  usi n g a Fis her’s e xact test C M H test . 
A p pr o xi matel y 3 0 0 s u bjects will be ra n d o mize d wit h a 
1: 1: 1 all ocati o n rati o. Ass u mi n g t he pr o p orti o ns f or t he 
acti ve ar m a n d place b o ar m are 9 0  9 5 % a n d 7 0  7 5 % 
res pecti vel y, a p pr o xi matel y 1 0 0 s u bjects per ar m are 
re q uire d s ufficie nt t o ac hie ve at least 9 0 % p o wer f or a 
pair wise c o m paris o n vers us c o ntr ol w he n t he t w o -si de d 
al p ha val ue is 0. 0 2 5.  
S y n o psis + Secti o n 
7. 1 S u bject 
I ncl usi o n Criteri a 
( pa ge 40 ) 
C ha n ge d i ncl usi o n criteri o n # 7:  
7.  At least o ne of t he f oll o wi n g, wit hi n 7 da ys pri or 
t o ra n d o mizati o n:  
•  
Ferriti n > 5 0 0 n g/ m L  
•  
C R P > 5 m g/ d L  
•  
D -di mer > 1, 0 0 0 n g/ m L  
•  
L D H > 2 5 0 U/ L  
•  
Fe ver , i ncl u di n g a n y of t he f oll o wi n g: 
− (aA  meas ure d te m perat ure of at least 
1 0 0. 4° F [ 3 8° C] ) 
− If n o te m perat ure meas ure d ( C D C 
criteria): 
▪ 
a self -re p orte d hist or y of feeli n g 
fe veris h w he n a t her m o meter is n ot 
a vaila ble, or t he ill pers o n has ta ke n 
me dicati o n t hat w o ul d l o wer t he 
meas ure d te m perat ure (e g, 
a nti p yretics, c ortic oster oi ds)  
▪ 
a n a p peara nce of a fl us he d face, 
glass y e yes, or c hills if it is n ot 
feasi ble t o t o uc h t he pers o n 
Si m plificati o n  
S y n o psis + Secti o n 
7. 2  S u bject 
Excl usi o n Criteri a  
( pa ge 41 ) 
M o difie d e xcl usi o n criteri o n # 5 , f o urt h b ullet: 
•  
He m o d y na mic i nsta bilit y wit h press or re q uire me nts 
of n ore pi ne p hri ne  at a d ose of > 0. 5 mc g/ k g/ mi n or 
e q ui vale nt (t otal if m ulti ple press ors use d) f or m ore 
t ha n 1 2 h o urs c o nti n u o usl y, m y ocar dial i nfarcti o n, 
str o ke, he m o d y na mic i nsta bilit y,  a n d/ or car di o ge nic 
se ptic s h oc k wit hi n 3 0 da ys pri or t o ra n d o mizati o n. 
All o w s u bj ect s o n 
l o w d ose press ors 
use d o utsi de of s h oc k 
sit uati o ns t o 
partici pate i n t he 
st u d y 


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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
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C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
S y n o psis + Secti o n 
7. 2  S u bject 
Excl usi o n Criteri a  
( pa ge 42 ) 
A d de d e xcl usi o n criteri o n # 1 7:  
K n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n 
(re gar dless of i m m u n ol o gical stat us), k n o w n he patitis B 
vir us s urface a nti ge n p ositi vit y a n d/ or a nti -he patitis C 
vir us p ositi vit y  
E xcl usi o n of s u bjects 
wit h ot her viral 
i nfecti o ns 
T a ble 2. Sc he d ule 
of Activities  ( pa ges 
1 6 -1 9 ) + T a ble 4 
Sc he d ule of 
L a b or at ory 
Assess me nts  ( pa ges 
5 5 -5 6 ) 
1.  A d de d f o ot n ote 2 t o Da y 1 5 , 2 2 , a n d 2 9. 
2.  Clarifie d t hat t he S A R S -C o V -2 test is o pti o nal at 
Da ys 1 -8, 1 5, 2 2,  2 9 a n d Date of Disc har ge/ U N S 
visit . 
3.  Re m o ve d t he p h ysical e xa m at Da y 1 5 . 
4.  Re m o ve d C hest X -ra y or C T sca n at Da y 2 9 a n d 
re q uire d c hest x-ra y ( n ot a C T sca n) at Date of 
Disc har ge/ U N S visit . 
5.  F or para meters c ollecte d dail y, s witc h t o si n gle 
c ollecti o n i nstea d of c ollecti o n of hi g hest a n d l o west 
val ues. T o t his e n d, a d de d f o ot n ote 1 0 : If t he s u bject 
re mai ns h os pitalize d after Da y 8 t hese assess me nts 
s h o uld be c ollecte d dail y u ntil t he da y of disc har ge 
(ie, Da ys 9-1 4, 1 6 -2 1, 2 2 -2 8 or after Da y 2 9) . Dail y 
c ollecti o n g ui deli nes:  c ollect assess me nt i n t he 
m or ni n g at a p pr o xi matel y t he sa me ti me eac h da y a n d 
cl osest t o t he c ollecti o n of t he NI AI D sc ore 
assess me nt . 
6.  F or NI AI D at disc har ge, a d de d f o ot n ote 1 3 : T he 
NI AI D at disc har ge s h o ul d reflect stat us i m me diatel y 
p ost -disc har ge (ie, eit her 7 or 8) . 
 
 
 
8.  
, he mat ol o g y/c oa g ulati o n/c he mistr y/ 
li ver pr ofile, a n d P K sa m pli n g s witc he d fr o m Da y 4 
t o Da y 3, a n d 
 sa m pli n g s witc he d fr o m 
Da y 8 t o Da y 7 t o c oi nci de wit h ot her bl o o d sa m pli n g 
ti mi n g.  
9.  Re m o ve d li pi d pa nel at Da ys 7, 1 5, a n d 2 9 . 
1 0.  Re m o v e d P K sa m pli n g at Scree ni n g ( u n necessar y 
si nce pre-d ose P K is perf or me d at Da y 1) . 
1 1.  C ha n ge d f o ot n ote 1 t o: T here is n o Da y 0. Scree ni n g 
acti vities ca n occ ur fr o m u p t o -3 a n d -1 da ys pri or 
t obef ore e nr oll me nt  st u d y dr u g a d mi nistrati o n, e xce pt 
f or C O VI D-1 9 testi n g , w hic h ma y occ ur wit hi n 1 4 
da ys bef ore e nr oll me nt (see f o ot n ote # 4), scree ni n g 
la bs (see f o ot n ote # 1 7) a n d c hest x-ra y or C T sca n 
(see f o ot n ote # 6). S u bject eli gi bilit y s h o ul d be 
c o nfir me d at Da y 1 pri or t o st u d y dr u g 
a d mi nistrati o n. 
Si m plif y a n d re d uce 
t he n u m ber of 
pr oc e d ures, clarif y 
s o me f o ot n otes, a d d 
f o ot n otes f or 
clarificati o n . 


ma vrili m u ma b ( K P L -3 0 1)  
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0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 5  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
1 2.  C ha n ge d f o ot n ote 2 t o: F or h os pitalize d s u bjects, t his 
visit will i ncl u de acti vities liste d. F or s u bjects 
disc har ge d bef ore Da y 1 5 2 9 , t he Da y 1 5, 2 2, a n d 
2 9 t his visit s will be c o n d ucte d b y p h o ne a n d will n ot 
i ncl u de a n y la b orat or y tests, vital si g ns, or b o d y 
te m perat ure. F or s u bjects w h o re mai n h os pitalize d 
after Da y 2 9, t he sa me assess me nt s s h o ul d be 
c o m plete d o n a wee kl y basis.  
1 3.  C ha n ge d f o ot n ote 3  t o: S u bjects disc har ge d bef ore 
Da y 2 9 (earl y ter mi nati o n) s h o ul d At t he ti me of 
disc har ge , c o m plete O N L Y  t he Date of Disc har ge / 
U N S visit assess me nts o n t heir t he disc har ge date (ie, 
st u d y da y assess me nts are n ot re q uire d). If a s u bject 
is disc har ge d a n d t he I n vesti gat or j u d ges t hat is it n ot 
safe f or t he s u bject t o ret ur n t o t he site, or t he s u bject 
is n ot willi n g t o ret ur n t o t he site, t he re q uire d visits 
( Da ys 1 5, 2 2, 2 9, 6 0 a n d 9 0) t hat occ ur t hereafter 
ma y be d o ne b y p h o ne call f oll o w -u p a n d la b tests 
will n ot be perf or me d.  
1 4.  A d de d ne w f o ot n ote 7:  T he disc har ge X -ra y ca n be 
d o ne wit hi n 7 2 h o urs of disc ha r ge. 
1 5.  C ha n ge d f o ot n ote 1 5 : Res pirat or y f u ncti o n 
para meters will be rec or de d dail y u ntil t he date of 
Disc har ge/ U N S. Dail y Best a n d w orst  val ues  base d o n 
t he hi g hest dail y Fi O 2, i ncl u di n g f or Pa O 2, Fi O2, 
S p O 2, calc ulate d P t o F rati o (if act ual val ues are n ot 
a vaila ble a n d t he rati o is a vaila ble), ot her A B G 
(arterial bl o o d gases) para meters if a vaila ble a n d 
res pirat or y rate (if s u bject is n ot mec ha nicall y 
ve ntilate d) s h o ul d be rec or de d. I n a d diti o n, resc ue 
t hera p y use d (e g, Fl ola n), a n d ot her s u p p orti ve 
meas ure s (e g, pr o nati o n, ne ur o m usc ular bl oc ka de, 
trac he ost o m y, E C M O, vas o press or or i n otr o pic 
t hera p y, i n hale d nitric o xi de or ot her) s h o ul d als o be 
rec or de d.  
1 6.  S plit f or mer f o ot n ote 1 4 i nt o 2 se parate f o ot n otes ( 1 6 
a n d 1 7) f or clarit y. 
1 7.  A d de d t o f o ot n ote 1 9: 
 
 
 
 
 
 
  
1 8.  A d de d  t o f o ot n ote 2 0 : N o p har mac o ki netic sa m ples 
are re q uire d after Da y 2 9 .  


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 6  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
1 9.  A d d ne w f o ot n ote 2 2:  C ollect a bl o o d sa m ple f or 
c yt o ki ne assess me nt if a seri o us i nf usi o n reacti o n 
occ urs, or a s u bject e x perie nces ne w s y m pt o ms or 
w orse ni n g of s y m pt o ms of c yt o ki ne release s y n dr o me 
(e g, malaise, na usea a n d v o miti n g, diarr hea). 
2 0.  C ha n ge d f o ot n ote 2 3 : “ Pr o hi bite d me dicati o ns 
i ncl u de a n y cell-de pleti n g bi ol o gical t hera pies (e g, 
a nti -C D 2 0) wit hi n 1 2 m o nt hs pri or t o Scree ni n g; or 
p re vi o us treat me nt wit h n o n-cell -de pleti n g bi ol o gical 
t hera pies (s uc h as a nti-T N F, a na ki nra, a nti -I L-6 
rece pt or [e g, t ociliz u ma b], or a batace pt) wit hi n 8 
wee ks ( or 5 half -li ves, w hic he ver is l o n ger) pri or t o 
Scree ni n g; treat me nt wit h al k ylati n g a ge nts wit hi n 1 2 
wee ks pri or t o Scree ni n g; recei pt of li ve (atte n uate d) 
vacci ne wit hi n t he 4 wee ks pri or t o Scree ni n g, 
treat me nt wit h c ycl os p ori ne A, azat hi o pri ne, 
c ycl o p h os p ha mi de, m yc o p he n olate m ofetil ( M M F ), 
or ot her i m m u n os u p pressa nt (e xce pt f or 
c ortic oster oi ds) wit hi n 4 wee ks of Scree ni n g. 
C o nc o mita nt me dicati o ns t o trac k i ncl u de 
a nti p yretics, a nti -i nfecti ves relate d t o C O VI D-1 9, a n d 
c ortic oster oi ds. Ot her c o nc o mita nt me dicati o ns 
rec or de d at Baseli ne Da y 1 a n d ma xi m u m d ose.”  
Secti o n 7. 3. 1 
Tre at me nt St o p pi n g 
Criteri a  ( Pa ge 42 ) 
S h o ul d a m o derate reacti o n occ ur d uri n g i nf usi o n of t he 
st u d y dr u g, t he i nf usi o n will be st o p pe d a n d restarte d at 
t he I n vesti gat or’s discreti o n after t he e ve nts ha ve 
res ol ve d. S h o ul d a se vere reacti o n occ ur, t he i nf usi o n will 
be per ma ne ntl y disc o nti n ue d, b ut s u bjects will c o nti n ue 
t heir partici pati o n i n t he st u d y. S uc h se vere reacti o ns 
i ncl u de, b ut are n ot li mite d t o, urticaria, h y perse nsiti vit y, 
h y p ote nsi o n, bra d ycar dia, h y p o xia, ge neralize d ras h, or a 
c ha n ge i n me ntal stat us.  If f o ur ( 4) ca usall y relate d 
se vere reacti o ns wit h 2 4-h o ur of d osi n g occ ur, st u d y 
e nr oll me nt will be pa use d u ntil t he D M C ca n re vie w t he 
cases a n d deter mi ne if t here is a n a d verse dr u g -relate d 
safet y si g nal.  Details re gar di n g st u d y dr u g d osi n g are 
pr o vi de d i n Secti o n  9. 5 . 
Clarifie d a n d defi ne d 
se vere reacti o n 
criteri o n 
Secti o n 8. 1. 2  
Descri pti o n  ( pa ge 
4 4)  
Ma vrili m u ma b is a sterile, clear t o o palesce nt, c ol orless 
t o sli g htl y br o w n-yell o w li q ui d, free fr o m visi ble 
particles a n d is f or m ulate d 
 
 
 
 
 
 
 
 
 
 
 


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0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 7  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
Secti o n 8. 1. 3 D ose 
a n d A d mi nistr ati o n 
( pa ge 4 4) 
S u bj ects will recei ve a si n gle I V i nf usi o n of eit her 1 0 
m g/ k g or 6 m g/ k g ma vrili m u ma b or place b o o ver 
a p pr o xi matel y 6 0 mi n utes. T here is n o b o d y wei g ht li mit, 
tT he ma xi m u m d ose ma y n ot e xcee d 1 0 0 0 m g, w hic h 
was a p pr o xi matel y t he ma xi m u m d ose a d mi nistere d i n 
t he P hase 1 st u d y wit h I V i nf usi o n. D osi n g will be based 
o n b o d y wei g ht o btai ne d at Scree ni n g. A d diti o nal details 
re gar di n g ma vrili m u ma b d osi n g are pr o vi de d i n 
Secti o n  9. 5 . 
Re m o ve d 
u n necessar y 
i nf or mati o n. 
Secti o n 8. 4. 2 
Tre at me nt Bli n di n g  
( pa ge 46 ) 
If t he I n vesti gat or deci des t hat u n bli n di n g t he s u bj ect is 
esse ntial f or t heir cli nical ma na ge me nt, t he n t he s u bject 
ma y be e mer ge ntl y u n bli n de d , eit her bef ore or after a 
disc ussi o n bet wee n t he S p o ns or’s safet y p h ysicia n or 
desi g nee a n d t he Pri nci pal I n ves ti gat or. 
Clarifie d t he 
e mer ge nc y 
u n bli n di n g pr oce d ure  
Secti o n 1 0. 4. 1  
Mec h a nic al 
Ve ntil ati o n 
P ar a meters  ( pa ge 
5 1)  
Mec ha nical ve ntilati o n meas ures f or eac h s u bject will be 
rec or de d dail y u ntil t he date of Disc har ge/ U N S. 
Ve ntilati o n  a n d t y pe, o x y ge nati o n m o de a n d ass ociate d 
meas ures will be c ollecte d  i ncl u di n g.  T his will i ncl u de 
nee d f or hi g h fl o w o x y ge n  ( H F O), n o n -i n vasi ve 
ve ntilati o n ( NI V ), i n vasi ve mec ha nical ve ntilati o n (I M V), 
or E C M O  a n d will be rec or de d dail y u ntil t he date of 
Disc har ge / U N S. 
Clarif icati o ns 
re gar di ng c ollecti o n 
of mec ha nical 
ve ntilati o n meas ures  
Secti o n 1 0. 4. 2 
Res pir at ory 
P ar a meters  ( pa ge 
5 1)  
Res pirat or y f u ncti o n para meters will be rec or de d dail y 
u ntil t he date of Disc har ge / U N S. Best a n d w ors t Dail y 
val ues f or Pa O 2, Fi O 2, S p O 2, or i n n o n-ve ntilate d 
patie nt s t he dail y o x y ge n nee d ( m ost pre vale nt dail y 
re gi me n re p orte d as liters/ mi n) t o calc ulate re p orte d P t o 
F rati o (if act ual val ues are n ot a vaila ble a n d t he rati o is 
a vaila ble), ot her A B G (arterial bl o o d gases) para meters if 
a vaila ble a n d res pirat or y rate (if s u bject is n ot 
mec ha nicall y ve ntilate d) s h o ul d be rec or de d.  
C ha n ge t o si n gle 
dail y c ollecti o n base d 
o n cli nical site 
feed bac k.  
Secti o n 1 2. 1. 3  
P hysic al 
Ex a mi n ati o n  ( pa ge 
5 4)  
A p h ysical e xa mi nati o n of eac h s u bject will be c o n d ucte d 
at Scree ni n g, Da y 1 5, a n d at t he Disc har ge/ U N S visit. 
Hei g ht a n d wei g ht will be c ollecte d at Scree ni n g o nl y.  
Ali g n wit h re visi o ns 
t o t he Sc he d ule of 
Acti vities.   
Secti o n 1 2. 1. 4 
Electr oc ar di o gr a m, 
a n d C hest X -r ay or 
C T Sc a n  ( pa ge 5 4) 
A n E C G wil l be o btai ne d at Scree ni n g a n d at t he 
Disc har ge/ U N S visit. A c hest x -ra y or c hest C T sca n will 
be o btai ne d at Scree ni n g . a n d o n Da y 2 9, or at t he T he 
c hest x -ra y will be re peate d at t he Disc har ge / U N S visit  if 
t he s u bject is disc har ge d pri or t o Da y 2 9. 
Ali g n wit h re visi o ns 
t o t he Sc he d ule of 
Acti vities .   
Secti o n 1 2. 1. 5 
L a b or at ory 
Assess me nts  ( pa ge 
5 4)  
All safet y la b orat or y para meters i n t he st u d y will be 
c o n d ucte d at Scree ni n g ( Da y -3 t o Da y -1  as per Ta ble  2 ) 
wit h a d diti o nal p ost -d ose ti me p oi nts n ote d i n T a ble  4 .  
S u bj ects w h o are disc har ge d or d isc o nti n ue bef ore Da y 
2 9  s h o ul d c o m plete t he Disc har ge/ U N S visit (t he st u d y 
da y assess me nts are n ot re q uire d) . 
T a ble 2 pr o vi des 
detail o n t he 
per missi ble visit 
wi n d o ws f or safet y 
la b orat or y testi n g at 
Scree ni n g .  Clarif y 


ma vrili m u ma b ( K P L -3 0 1)  
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Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 8  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
la b assess me nts at t he 
ti me of disc har ge.  
Secti o n 1 2. 2. 1. 2 
A dverse Dr u g 
Re acti o n  ( pa ge 5 7 ) 
1 2. 2. 1. 2.  
A d verse Dr u g Re acti o n  
A n a d verse dr u g reacti o n is defi ne d as, “ A res p o nse t o a 
me dici nal pr o d uct w hic h is n o xi o us a n d u ni nte n de d [ DI R 
2 0 0 1/ 8 3/ E C Art 1( 1 1)]. Res p o nse i n t his c o nte xt me a ns 
t hat a ca usal relati o ns hi p bet wee n a me dici nal pr o d uct 
a n d a n A E is at least a reas o na ble p ossi bilit y ” (see A n ne x 
I V, I C H-E 2 A G ui deli ne).  
I nf or mati o n a b o ut a d verse dr u g reacti o ns f or t he 
i n vesti gati o nal dr u g ca n be f o u n d i n t he I n vesti gat or’s 
Br oc h ure.  
A d de d defi niti o n of 
a d verse dr u g 
reacti o ns 
Secti o n 1 2. 2. 1. 3 
A dverse Eve nts of 
S peci al I nterest  
( pa ge 5 8 ) 
Ac ute a n d Del a ye d H y perse nsiti v it y Re acti o ns: 
Bi ol o gic t hera pies are k n o w n t o be ass ociate d wit h a n 
i ncrease d ris k of i m me diate a n d dela ye d h y perse nsiti vit y 
reacti o ns as well as a na p h yla xis. A na p h yla xis is defi ne d 
bel o w usi n g Sa m ps o n’s criteria ( Sa m ps o n H A, 2 0 0 6).  
A na p h yla xis a n d se vere h y perse nsiti v it y reacti o ns are 
re q uire d t o be re p orte d wit hi n 2 4 h o urs of k n o wle d ge of 
t he e ve nt. 
A d de d T a ble 5:  Cli nical Criteria f or Dia g n osi n g 
A na p h yla xis  ( pa ge 5 8) 
A d de d a na p h yla xis 
defi niti o n  
Secti o n 1 2. 2. 1. 3 
A dverse Eve nts of 
S peci al I nterest  
( pa ge 5 9 ) 
W orse ni n g of C yt o ki ne Rele ase S y n dr o me  
T here is li mite d e x perie nce wit h ma vrili m u ma b or ot her 
a nti -G M -C S F a ge nts i n patie nts wit h C O VI D -1 9. I n t he 
e x pa n de d access pr ot oc ol c o n d ucte d b y Italia n 
i n vesti gat ors wit h ma vrili m u ma b ( De L uca  G,  2 0 2 0), all 
e xce pt for o ne of t he s u bjects treate d wit h ma vrili m u ma b 
e x perie nce d a decrease i n C R P a n d I L -6. Gi ve n t he 
li mite d e x perie nce, i n t his st u d y [ w orse ni n g of] c yt o ki ne 
release s y n dr o me ( C R S) will be assesse d as a n A E SI a n d 
s h o ul d be re p orte d wit hi n 2 4 h o urs of k n o wled ge of t he 
e ve nt .  If a s us pecte d C R S occ urs, e g, s y m pt o ms s uc h as 
malaise, na usea a n d v o miti n g, diarr hea, u nsc he d ule d 
bl o o d sa m ple kits s h o ul d be c ollecte d, w hic h will i ncl u de 
serial c yt o ki nes a n d i nfla m mat or y bi o mar kers. T hese 
sa m ples s h o ul d be i m me diatel y s hi p pe d t o t he ce ntral 
la b orat or y a n d t he st u d y site s h o ul d c ollect l ocal a vaila ble 
c yt o ki nes a n d i nfla m mat or y bi o mar kers i n parallel.  
A d de d C R S as a n 
A E SI per re g ulat or y 
a ut h orit y re q uest  
Secti o n 1 2. 3  
Rel ati o ns hi p t o 
St u dy Dr u g  ( pa ge 
6 0 ) 
Rel ati o ns hi p t o St u d y Dr u g 
A n I n vesti gat or w h o is q ualifie d i n me dici ne m ust ma ke 
t he deter mi nati o n of relati o ns hi p t o t he i n vesti gati o nal 
pr o d uct f or eac h A E ( U nrelate d  N ot Relate d, U nli kel y 
Relate d, P ossi bl y Relate d or Pr o ba bl y  Defi nitel y 
Relate d ).  T he I n vesti gat or s h o ul d deci de w het her, i n his 
or her me dical j u d g me nt, t here is a reas o na ble p ossi bilit y 
Clarifie d defi niti o n of 
A d verse E ve nt  t o 
ali g n  wit h e C R F data 
c ollecti o n 


ma vrili m u ma b ( K P L -3 0 1)  
 Ki ni ksa P har mace uticals, Lt d  
Cli nical St u d y Pr ot oc ol:  K P L -3 0 1 -C 2 0 3  
 
0 8  N o v 2 0 2 1  
 
Gl o bal Versi o n 6  ( A me n d me nt 5 ) 
1 0 9  of 1 0 9  
C o nfi de ntial  
P r ot oc ol Secti o n  
( P a ge N u m ber) 
M o dific ati o n  
R ati o n ale  
t hat t he e ve nt ma y ha ve bee n ca use d b y t he 
i n vesti gati o nal pr o d uct. If n o vali d reas o n e xists f or 
s u g gesti n g a relati o ns hi p, t he n t he A E s h o ul d be 
classifie d as “N ot u n relate d.”  If t here is a n y vali d reas o n, 
e ve n if u n deter mi ne d, f or s us pecti n g a p ossi ble ca use -
a n d -effect relati o ns hi p bet wee n t he i n vesti gati o nal 
pr o d uct a n d t he occ urre nce of t he A E, t he n t he A E s h o ul d 
be c o nsi dere d “relate d.”  
If t he relati o ns hi p bet wee n t he S A E a n d t he 
i n vesti gati o nal pr o d uct is deter mi ne d t o be “ p ossi ble” or 
“ pr o ba ble” “ P ossi bl y” or “ Defi nitel y” relate d , t he e ve nt 
will be c o nsi dere d relate d t o t he i n vesti gati o nal pr o d uct 
f or t he p ur p oses of e x pe dite d re g ulat ory re p orti n g.  
Secti o n 1 2. 4 
Rec or di n g of 
A dverse Eve nts  
( pa ge 6 1 ) 
5. Acti o n ta ke n re gar di n g wit h st u d y treat me nt.  
All A Es m ust be treate d a p pr o priatel y.  T his st u d y 
i ncl u des a si n gle IV d ose a d mi nistrati o n. N o d ose 
a dj ust me nt is a ntici pate d. Acti o ns ma y i ncl u de:  
Treat me nt ma y i ncl u de o ne or m ore of t he f oll o wi n g : 
•  
D ose n ot c ha n ge d  N ot a p plica ble  
•  
D ose te m p oraril y i nterr u pte d b ut later 
c o m plete d 
•  
D ose i nterr u pte d a n d n ot c o m plete d  
Clarif y st u d y dr u g 
relate d acti o ns gi ve n 
si n gle I V d ose 
a d mi nistrati o n 
Secti o n 1 2. 5  
Re p orti n g Seri o us 
A dverse Eve nts  
( pa ges 6 2) 
T o e ns ure s u bject safet y, e ver y S A E, re gar dless of 
ca usalit y, occ urri n g after t he s u bject has pr o vi de d 
i nf or me d c o nse nt a n d u ntil t he last st u d y visit m ust be 
re p orte d t o t he S p o ns or or desi g nee, wit hi n 2 4 h o urs of 
lear ni n g of its occ urre nce. A d diti o nall y, I n vesti gat or 
re p orti n g of S A Es t o I R B/ E C a n d ot her Re g ulat or y 
Healt h A ut h orities ma y be re q uire d per l ocal r ules a n d 
re g ulati o ns. F or t he p ur p ose of deter mi ni n g t he 
e x pecte d ness of Seri o us S us pecte d A d verse Reacti o ns i n 
o n g oi n g st u dies c o n d ucte d b y Ki ni ks a, t he f oll o wi n g 
Seri o us S us pecte d A d verse Reacti o n is c o nsi dere d a n 
e x pecte d reacti o n : P ne u m o nia .   
[ …] A d de d se nte nce: T he sta n dar d ti meli nes f or S U S A R 
re p orti n g as per I C H E 2 A will be f oll o we d.  
I de ntificati o n of 
p ne u m o nia as a n 
e x pecte d reacti o n.  
 
 
 
 
 
 
A d de d state me nt 
re gar di n g S U S A R 
re p orti n g as per I C H 
E 2 A  
 


Si g nat ure Pa ge f or RI M- C LI N- 0 0 0 2 8 7 v 5. 0
Si g nat ure Pa ge f or RI M- C LI N- 0 0 0 2 8 7 v 5. 0
A p pr o val


 
 
 
Statistical Analysis Plan 
 
 
A Phase 2/3, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of mavrilimumab (KPL-301) treatment in adult 
subjects hospitalized with severe COVID-19 pneumonia and hyper-
inflammation 
 
Phase 3 Part of the Study 
 
 
Sponsor: 
 
Kiniksa Pharmaceuticals, Ltd. 
Hamilton, Bermuda 
 
 
 
 
Study Drug: 
Mavrilimumab (KPL-301) 
Protocol Number: 
KPL-301-C203  
Version: 
2.0  
Date:  
14 December 2021 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is the property of Kiniksa Pharmaceuticals, Ltd. and contains proprietary 
and confidential information to be held in strict confidence and not disclosed to any third party, without prior 
written consent of Kiniksa Pharmaceuticals, Ltd. Persons within your organization to whom any information 
herein is disclosed is on a need-to-know basis solely to carry out the purpose of this document, and be 
informed that such information is confidential and shall not be further disclosed by them without prior written 
consent from Kiniksa Pharmaceuticals, Ltd.  Documentation, data, and all other information generated during 
the clinical study is proprietary and confidential information of Kiniksa Pharmaceuticals, Ltd. and shall not be 
disclosed to any third party, without prior written consent of Kiniksa Pharmaceuticals, Ltd. 
 


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History of Changes 
 
Version Number 
Version Date 
Notes 
1.0 
November 9, 2021 
Final, submitted to the FDA. 
2.0 
December 13, 2021 Amendment, to be submitted to the FDA. 
 
The following changes are madeper FDA feedback on 
SAP V1.0:  
1) As per FDA guidance, the ITT definition was 
reverted back to the original definition to clarify 
unequivocally that all randomized subjects will be 
in the ITT analysis set. 
2) For binary endpoints, specified the CMH test 
stratified by randomization strata as the main 
method for the 95% CI. Removed the 95% CI 
based on normal approximation. 
3) Added sensitivity analysis using multiple 
imputation methods to handle missing data in 
binary endpoints. 
4) Added details for tipping point analysis and 
reference. 
 
The definition of NIAID at randomization and Day 1 
NIAID are further clarified via some editorial changes. 
 
 
 
 


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Table of Contents 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Objectives .....................................................................................................................6 
1.1.1. 
Primary Objective .........................................................................................................6 
1.1.2. 
Secondary Objectives ...................................................................................................6 
1.1.3. 
Other Objective .............................................................................................................6 
1.2. 
Study Design .................................................................................................................6 
1.3. 
NIAID Scale .................................................................................................................7 
1.4. 
Sample Size Justification ..............................................................................................7 
2. 
ENDPOINTS ................................................................................................................8 
2.1. 
Primary Efficacy Endpoint ...........................................................................................8 
2.2. 
Secondary Efficacy Endpoints ......................................................................................8 
2.3. 
Other Efficacy Endpoints .............................................................................................8 
2.4. 
Safety Endpoints .........................................................................................................10 
3. 
ANALYSIS SETS ......................................................................................................11 
3.1. 
Intent-to-Treat (ITT) Analysis Set ..............................................................................11 
3.2. 
Safety Analysis Set .....................................................................................................11 
3.3. 
Per-Protocol (PP) Analysis Set ...................................................................................11 
3.4. 
Day 90 Analysis Set ....................................................................................................11 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................11 
4.1. 
Randomization, Stratification, and Blinding ..............................................................11 
4.2. 
Data Analysis General Information and Definition ....................................................12 
4.2.1. 
Study Drug ..................................................................................................................12 
4.2.2. 
Day 1 ...........................................................................................................................12 
4.2.3. 
Baseline Values ..........................................................................................................12 
4.2.4. 
Last Contact ................................................................................................................13 
4.2.5. 
Calculation Using Dates .............................................................................................13 
4.2.6. 
Duration Derivation ....................................................................................................13 
4.3. 
Windowing of Visits ...................................................................................................13 
4.4. 
Methods for Handling Missing Data ..........................................................................13 
4.5. 
Protocol Deviations ....................................................................................................13 
4.6. 
Data Cut-off Date .......................................................................................................14 
5. 
STATISTICAL METHODOLOGY ...........................................................................15 


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5.1. 
Study Population .........................................................................................................15 
5.2. 
Subject Disposition .....................................................................................................15 
5.3. 
Demographics and Baseline Disease Characteristics and History .............................15 
5.3.1. 
Demographics .............................................................................................................15 
5.3.2. 
Baseline Disease Characteristics ................................................................................16 
5.3.3. 
SOFA and qSOFA ......................................................................................................17 
5.4. 
Medical History ..........................................................................................................18 
5.5. 
Prior and Concomitant Medications ...........................................................................18 
5.6. 
Study Treatments and Extent of Exposure .................................................................18 
5.7. 
Efficacy Analysis ........................................................................................................18 
5.7.1. 
Multiplicity Adjustment..............................................................................................18 
5.7.2. 
NIAID Scale and Missing Data Imputation for Binary Endpoints .............................19 
5.7.3. 
Censoring Rules for Time to Event Endpoints ...........................................................20 
5.7.4. 
Analysis of Primary Efficacy Endpoint ......................................................................21 
5.7.5. 
Analysis of Secondary and Other Efficacy Endpoints ...............................................22 
5.7.6. 
Subgroup analysis .......................................................................................................23 
5.8. 
Safety Analysis ...........................................................................................................23 
5.8.1. 
Adverse Events ...........................................................................................................23 
5.8.2. 
Clinical Laboratory Parameters ..................................................................................24 
5.8.3. 
Vital Signs ..................................................................................................................25 
5.8.4. 
Electrocardiogram (ECG) ...........................................................................................25 
5.8.5. 
Physical Examination .................................................................................................25 
5.8.6. 
Chest Imaging .............................................................................................................25 
6. 
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL ......................25 
7. 
REFERENCE .............................................................................................................26 
8. 
APPENDICES ............................................................................................................26 
8.1. 
Handling of Missing Safety Data ...............................................................................26 
8.1.1. 
Adverse Event Date Imputation ..................................................................................26 
8.1.2. 
Concomitant Medication Date Imputation .................................................................27 
 
 
 


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List of Abbreviations  
 
2019-nCoV  
2019 novel coronavirus  
AE  
Adverse event  
AESI  
Adverse event of special interest  
ALT  
Alanine aminotransferase  
ARDS  
Acute respiratory distress syndrome  
AST  
Aspartate aminotransferase  
ATC 
Anatomic-therapeutic-chemical 
BiPAP  
Bi-level positive airway pressure  
CMH  
Cochran-Mantel-Haenszel  
COVID-19  
Corona Virus Disease 2019  
CPAP  
Continuous positive airway pressure  
CRF  
Case report form  
CRP  
C-reactive protein  
CT  
Computerized tomography  
ECG  
Electrocardiogram  
ECMO  
Extracorporeal membrane oxygenation  
EDC 
Electronic Data Capture 
eCRF  
Electronic case report form  
FiO2  
Fraction of inspired oxygen  
ICU  
Intensive care unit  
IL  
Interleukin  
IMV 
Invasive mechanical ventilation 
IRT 
Interactive Response Technology 
LDH  
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS  
Middle East respiratory syndrome  
ITT  
Modified intent-to-treat  
NIAID 
National Institute of Allergy and Infectious Diseases 
PaO2  
Partial pressure of oxygen  
PCR  
Polymerase chain reaction  
PD 
Pharmacodynamics 
PEEP  
Positive end-expiratory pressure  
PK  
Pharmacokinetics  
PT 
Preferred term 
qSOFA 
Quick sequential organ failure assessment  
SAP 
Statistical analysis plan 
SOC 
System organ class 
SOFA  
Sequential Organ Failure Assessment Score  
TEAE 
Treatment-emergent adverse event  
 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical analyses and data presentation to be 
performed for the Phase 3 part of the study KPL-301-C203 by Cohort. The efficacy endpoints are 
based on protocol amendment 6.0 dated November 8, 2021; while the data collection and visits might 
reflect previous versions of the protocol depending on the reconsent date. Selected outputs supporting 
efficacy of pooling Phase 2 and Phase 3 parts of the study by Cohort are covered under this SAP. 
It contains definitions of analysis populations, derived variables, and statistical methods for the 
analyses of efficacy and safety. It is to ensure that the data listings, summary tables, and figures 
which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
The SAP will be finalized and approved prior to the clinical database lock (DBL) for the primary 
analyses when the last subject in Cohort 1 completes Day 29. A follow-up analysis will be conducted 
at the end of a 90-day safety follow-up period for all subjects. Cohort 1 and 2 will be analyzed 
separately.  The database locks might be combined for the two cohorts as appropriate.   
Analyses of pharmacokinetics (PK), Pharmacodynamics (PD), other biomarkers, and health care 
resource utilization are outside the scope of this SAP and will be addressed separately.  
 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the clinical efficacy of a single intravenous (IV) 
dose of mavrilimumab (10 mg/kg or 6 mg/kg) relative to placebo in adult subjects hospitalized with 
severe Corona Virus Disease 2019 (COVID-19) pneumonia and hyper-inflammation to reduce 
progression to respiratory failure or death.  
 
1.1.2. 
Secondary Objectives 
The secondary objectives of this study are to assess impact of treatment on clinical status, mortality, 
and safety of a single IV dose of mavrilimumab (10 mg/kg or 6 mg/kg) relative to placebo in adult 
subjects hospitalized with severe COVID-19 pneumonia and hyper-inflammation.  
 
1.1.3. 
Other Objective 
 
 
. 
 
1.2. 
Study Design 
This is a prospective, Phase 2/3, interventional, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy and safety of mavrilimumab (KPL-301) treatment in adult subjects 
hospitalized with severe COVID-19 pneumonia and hyper-inflammation.  
Screening activities will be performed up to 3 days prior to randomization. The study main follow-up 
period for efficacy will conclude on study Day 29, and subjects will be further followed for 
AEs/SAEs, concomitant medications, mortality, and clinical improvement (National Institute of 


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Allergy and Infectious Diseases (NIAID) scale) through study Day 90. The schedule of activities is 
presented in Table 2 of the protocol. 
The Phase 3 part of the study will enroll approximately 600 subjects in Cohort 1 (581 subjects at time 
of enrollment closure) and 117 subjects in Cohort 2 (63 subjects at time of enrollment closure). Each 
cohort will randomize subjects in a 1:1:1 allocation ratio to receive a single IV infusion of 
mavrilimumab (10 mg/kg or 6 mg/kg) or placebo. Cohort 1 will include non-intubated hospitalized 
subjects who require supplemental oxygen to maintain SpO2 ≥ 92%, i.e., “non-ventilated” subjects. 
Cohort 2 will include hospitalized subjects for whom mechanical ventilation was recently initiated 
(within 48 hours prior to randomization), i.e., “ventilated” subjects.  
 
1.3. 
NIAID Scale 
Subject clinical status will be assessed daily using the 8-point NIAID scale, which is the basis for 
assessment of primary and secondary endpoints for Cohort 1 and Cohort 2.  
1. Death  
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO)  
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices  
4. Hospitalized, requiring supplemental oxygen  
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 
related or otherwise)  
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care  
7. Not hospitalized, limitation on activities and/or requiring home oxygen  
8. Not hospitalized, no limitations on activities  
 
1.4. 
Sample Size Justification  
Sample sizes were calculated separately for each cohort based on their primary endpoint and other 
assumptions.  Subjects will be randomized with a 1:1:1 allocation ratio within each cohort.  
Sample size estimation for Cohort 1 (non-ventilated subjects) in Phase 3 is based on the primary 
efficacy endpoint proportion of subjects alive and free of mechanical ventilation at Day 29, using a 
Chi square test. The assumptions used for the calculation are adjusted based on the results of Phase 2 
portion. Assuming the proportions of subjects alive and free of ventilation at Day 29 are 87.5% and 
74.4% for the active treatment arm and placebo arm, respectively, approximately 200 subjects per 
arm will achieve a minimum 90% power for the treatment comparison at the two-sided alpha value of 
0.05. A total of 600 subjects will be randomized. At the time of the enrollment closure, 581 subjects 
were randomized. 
Sample size for Cohort 2 (ventilated subjects) in Phase 3 is based on the primary efficacy endpoint 
mortality rate at Day 29, using a Fisher’s exact test.  Approximately 117 subjects will be randomized 
with a 1:1:1 allocation ratio.  Assuming the mortality rates at Day 29 are 40% and 95% for the active 
treatment arm and placebo arm, respectively, 39 subjects per arm will achieve 90% power for the 
treatment comparison when the two-sided alpha value is 0.05.  Sixty-three subjects were randomized 
at the time of enrollment closure. 


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2. 
ENDPOINTS 
The primary, secondary, and other efficacy endpoints are defined in this section and summarized by 
assessment day in Table 1Table 1 . 
2.1. 
Primary Efficacy Endpoint 
Cohort 1 (Non-ventilated Subjects) 
The primary efficacy endpoint for cohort 1 is proportion of subjects alive and free of mechanical 
ventilation at Day 29.  Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or 
extracorporeal membrane oxygenation (ECMO).  Subjects whose clinical outcome meets NIAID 
(defined in Section 1.3) score 2 will be considered as using mechanical ventilation.  
Cohort 2 (Ventilated Subjects) 
The primary efficacy endpoint for cohort 2 is mortality rate at Day 29, defined as the proportion of 
subjects who die by Day 29. 
2.2. 
Secondary Efficacy Endpoints 
Cohort 1 (Non-ventilated Subjects) 
1. Mortality rate at Day 29 
2. Ventilation-free survival (Time to ventilation or death) by Day 29  
3. Overall survival by Day 29 
Defined as time from randomization to death; subjects still alive will be censored at Day 29 
Cohort 2 (Ventilated Subjects) 
1. Time to 1-point clinical improvement by Day 29 
Defined as time from randomization to a 1-point improvement on the NIAID 8-point ordinal 
scale, or discharge from the hospital, whichever comes first. Subjects who die before Day 29 
will be censored at Day 35.  
2.3. 
Other Efficacy Endpoints 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 


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3. 
ANALYSIS SETS 
3.1. 
Intent-to-Treat (ITT) Analysis Set  
All randomized subjects will be included in the ITT analysis set.  All efficacy analyses of the study 
will be based on the ITT analysis set.  All ITT analyses will be based on the randomized treatment.   
3.2. 
Safety Analysis Set  
All randomized subjects who receive study drug will be included in the safety analysis set. Safety 
analyses will be based on the actual treatment received. 
3.3. 
Per-Protocol (PP) Analysis Set  
All ITT subjects without protocol deviations deemed to impact efficacy or ethical conduct will be 
included in the PP analysis set and will be determined before the database lock. The primary and 
secondary efficacy endpoints will be further analyzed based on the PP set. 
3.4. 
Day 90 Analysis Set  
All ITT subjects who were randomized at least 90 days prior to the data cutoff date for the first 
database lock. Selected Day 90 efficacy endpoints, e.g., mortality will be analyzed based on Day 90 
set and the randomized treatment. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
Analyses described in this SAP will be conducted separately for each of the two cohorts. Treatment 
comparison will be primarily between each of the KPL-301 treatment arms (10 mg/kg, 6 mg/kg) vs 
placebo. Comparisons between the pooled KPL-301 treatment arms vs placebo will also be provided.  
Summary statistics for continuous variables will include n (non-missing observations), mean, 
standard deviation, minimum, median, and maximum. Summary statistics for categorical variables 
will be presented in terms of frequencies and percentages based on the analysis set unless otherwise 
specified. In by-visit summary tables, only scheduled visits/timepoints will be summarized.  
Time to event data will be summarized using the Kaplan-Meier (KM) method, which will include the 
estimated median, 25th percentiles, 75th percentiles, and their 95% confidence interval (CI).  The CIs 
will be calculated using a log-log transformation. The event-free probability and its 95% CI will be 
calculated at days 4, 8, 15, 22, 29, 60 and 90 as appropriate using Greenwood’s formula with a log-
log transformation.   
The 95% confidence interval (CI) of the difference in the proportion (KPL-301 – placebo) will be 
primary based on Cochran Mantel-Haenszel (CMH) test stratified by the randomization strata for 
binary (proportion or rate) endpoints.  
All relevant subject data will be listed by cohort, treatment, subject and visit/time point including both 
scheduled and unscheduled visits. 
Analyses of selected Day 90 efficacy endpoints will be conducted in the Day 90 analysis set in the 
Day 29 database lock.  All Day 90 efficacy endpoints will be analyzed based on the ITT analysis set 
at the Day 90 database lock. 
4.1. 
Randomization, Stratification, and Blinding 
An Interactive Web Response System (IWRS) will be used for assignment of the subject 
identification number at enrollment, randomization to a treatment arm (10 mg/kg KPL-301, 6 mg/kg 
KPL-301 or placebo), and assignment of blinded investigational product. 


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The randomization is stratified by the three following characteristics for subjects in Cohort 1 and by 
the first two following characteristics for subjects in Cohort 2: 
1. Use of approved standard of care antiretroviral therapy: yes vs. no  
2. Age: <65 vs. ≥ 65 years  
3. Acute respiratory distress syndrome (ARDS) status: normal – mild (> 200 PaO2/FiO2) vs. 
moderate-severe (≤ 200 PaO2/FiO2). If PaO2 is unavailable, use SpO2/FiO2: normal–mild 
(>235) vs. moderate-severe (≤235)    
There should be no overlap of subject populations between the two cohorts since Cohort 1 baseline 
NIAID should be 3 or 4 and Cohort 2 baseline NIAID should be 2. In case of subjects being 
erroneously randomized under the incorrect cohort, the subjects will be analyzed in the correct cohort 
defined by the baseline NIAID scale. Subjects with baseline NIAID ≥ 5 will be included in Cohort 1 
for the ITT and safety populations but excluded from Cohort 1 in the per-protocol analyses. 
If subjects were randomized based on incorrect baseline information for use of approved standard of 
care antiretroviral therapy and age, then the correct strata will be used for stratified analysis rather 
than the incorrect strata in the IRT.  
For ARDS status, data collected in IRT will be used since actual ARDS status at randomization was 
not collected in EDC. For Cohort 1 subjects who were incorrectly randomized under Cohort 2, the 
actual ARDS status derived from baseline information in EDC will be used, since the randomization 
for Cohort 2 is not stratified by ARDS status in the IRT.   
If fewer than 5 subjects are in a stratification group of all three (or two for cohort 2) factors, that 
group will be pooled with another stratification group. If the same situation occurs, strata for the 
second factor will be pooled. If the same situation still exists, the analysis will be done without 
stratification.  
For stratified analyses, if there is no event for both arms of comparison, or all responses are the same 
within a stratification group, that group will be pooled with another stratification group per the order 
of the stratification factors listed previously. This principal will be analogously applied to subgroup 
analyses. 
4.2. 
Data Analysis General Information and Definition  
4.2.1. 
Study Drug 
Study drug or study treatment refers to 10 mg/kg KPL-301 (mavrilimumab), 6 mg/kg KPL-301 
(mavrilimumab) or placebo.   
4.2.2. 
Day 1  
Day 1 is defined as the day of the study treatment after randomization.    
For subjects without dosing, Day 1 is defined as the randomization date in the analysis of efficacy 
while endpoints points are defined by study day, like Day 29, Day 90 endpoints. 
 
4.2.3. 
Baseline Values 
Baseline is defined as the last non-missing value obtained prior to the start of study treatment. The 
baseline NIAID is defined separately in Section 5.7.2.  
The change from baseline values will be derived for each subject as the post-baseline evaluation 
minus the baseline evaluation. 


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4.2.4. 
Last Contact 
Last contact or last date known alive is defined as the last non-imputed date of any subject record 
prior to or on the data cut-off date in the clinical database. 
4.2.5. 
Calculation Using Dates 
Calculations using dates will adhere to the following conventions: 
Study day for a date of interest (TARGET DATE) is calculated as 
STUDY DAY = TARGET DATE – Date of Day 1 + 1 if TARGET DATE is on or after Day 1; 
STUDY DAY = TARGET DATE – Date of Day 1 otherwise. 
Day X in this document refer to the study day X, where X can be 4, 8, 15, 22, 29, 60, 90, etc.   
4.2.6. 
Duration Derivation 
Unless otherwise specified for a specific panel or variable, duration variables will be derived 
according to the following rules. Duration variables expressed in units greater than day will be 
rounded to 1 decimal place. 
Duration (in days) = [end date – start date +1] 
Duration (in weeks) = [end date – start date +1] / 7 
Duration (in months) = [end date – start date +1] / 30.4375 
 
4.3. 
Windowing of Visits 
Data will be summarized by eCRF scheduled visits and allowed visit windows. When there are 
multiple assessments for a scheduled visit, the first non-missing value will be used. No additional 
windowing will be considered.  
Due to changes of visit windows across protocol versions, the minimum window that can cover 
windows in all protocol versions will be used in the analysis of the efficacy endpoints:  the window is 
(-2 days, + 2 days) for Day 15 endpoints, (-2 days, + 4 days) for Day 29 endpoints, (-7 days, +14 
days) for Day 90 endpoints. 
4.4. 
Methods for Handling Missing Data 
For efficacy data, missing NIAID scale and survival status at target days will be handled per 
Section 5.7.2. 
For safety data, refer to Section 8.1  for detailed date imputation guidelines. 
 
4.5. 
Protocol Deviations 
The study team will have a blinded review of protocol deviations to determine their classification 
(important, not important) periodically.  Prior to the database lock, the study team will assess impact 
of all important protocol deviations on efficacy and whether they should be excluded from per-
protocol analysis set.  
The number of important protocol deviations, the number of subjects with at least one important 
protocol deviation, and the number of subjects with at least one important protocol deviation 
with/without a potential impact on efficacy will be summarized by treatment group. The protocol 


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deviation criterion types will also be summarized, with reference to an evaluability document that will 
be signed off prior to database lock.  
All protocol deviations will be presented in by-subject listings, and subjects with protocol deviations 
that lead to exclusion from the per-protocol analysis set will be flagged.  
 
4.6. 
Data Cut-off Date 
Two DBLs are planned for Phase 3 Cohort 1:  
• For the first DBL, unless otherwise specified, all analyses will be conducted based upon data 
through Day 29 for each subject instead of a fixed data cut-off date: 
o For Day 29 efficacy endpoints, a + 4-day window is allowed.  
o For Day 90 efficacy data, mortality rate will be produced.  
o Selected TEAE tables may be produced for a subgroup of subjects (for selected sites 
and randomization date) with complete TEAE data through Day 90.  
o Laboratory endpoints will only be analyzed for baseline values. 
• For the second DBL, all analyses will be updated based on the complete study data. Data 
throughout Day 29 are expected to remain the same as the first DBL. 
Only one DBL is planned for Phase 3 Cohort 2. All data through study completion/early 
discontinuation will be included. 
 
 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
Study Population 
A summary of analysis sets by treatment will be presented along with percentages relative to the ITT 
Analysis Set.  
• ITT Analysis Set 
• Safety Analysis Set 
• Per-protocol Analysis Set 
• Day 90 Analysis Set 
A listing will be provided to describe when informed consent was obtained and if the subject meets 
all inclusion/exclusion criteria. Reasons of subjects’ exclusion from safety, or PP analysis sets will 
also be listed. 
5.2. 
Subject Disposition  
The number and percentage of subjects will be tabulated for the ITT analysis set by treatment:  
• Subjects who are ongoing  
• Subjects who completed the study 
• Subjects who ended study early 
Reasons for early study discontinuation will be summarized with the following categories: 
• Adverse event 
• Lost to follow-up 
• Death 
• Physician decision 
• Site terminated by sponsor 
• Study terminated by sponsor 
• Technical problem 
• Withdrawal by subject 
• Other 
A listing will be presented to describe whether the subject is on study, completed the study, date of 
completion or early withdrawal, and the reason for early study discontinuation.  
 
5.3. 
Demographics and Baseline Disease Characteristics and History 
5.3.1. 
Demographics 
Demographic and other baseline characteristics will be summarized for each treatment group and 
overall based on the ITT analysis set. They will also be presented in by-subject listings. For 
categorical variables, missing category will be added when at least 1 subject does not have value. 
Demographic descriptive statistics will be provided for the following: 
• Age  


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• Weight (kg) 
• Height (cm)  
• Body mass index (BMI) (kg/m2) 
Demographic frequency tabulations will be presented for: 
• Age (< 65 years or ≥ 65 years)  
• Sex (Male or Female) 
• Childbearing potential of female (Yes or No) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Stated, Unknown) 
5.3.2. 
Baseline Disease Characteristics 
Baseline characteristics frequency tabulations will be summarized by the CRF categories, which are 
detailed below:  
• Randomization strata from IWRS:  use of approved standard antiretroviral therapy (Yes or 
No), age (< 65 years or ≥ 65 years), ARDS status (normal – mild or moderate-severe, for 
cohort 1 only)  
• Actual randomization strata based on the baseline information 
• Covid-19 symptom history findings (fever, fatigue, cough (productive), cough (non-
productive), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, headache, 
diarrhea, nausea, vomiting, pneumonia, loss of taste, loss of smell, other) 
• Tuberculosis (negative, positive, indeterminate) 
• NIAID 8-point ordinal scale 
• Receiving invasive ventilation  
− No 
− Yes (mode of ventilation at time of highest FiO2 requirement) 
• Receiving non-invasive ventilation OR high flow nasal cannula? 
− No 
− Yes (mode of ventilation) 
• Receiving supplemental oxygen  
− No 
− Yes (delivery method) 
− Other 
 
• Required any other oxygen delivery methods since last assessment 
o No 
o Yes (modalities) 
o Unknown 
• P/F ratio (PaO2/FiO2), conversion from S/F ratio (SpO2/FiO2) if PaO2 is unavailable (Brown 
et al Chest, 2016; OpenCriticalCare.org, n.d.)  
• Currently requiring or since last assessment has required prone positioning  


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• Currently requiring or since last assessment has required neuromuscular blockade 
• Currently requiring or since last assessment has required pulmonary vasodilators  
• Currently have or since last assessment had tracheostomy 
• Currently requiring or since last assessment has required ECMO 
• Currently requiring or since last assessment has required vasopressor support 
• Currently requiring or since last assessment has required renal replacement therapy 
• SARS-CoV-2 (RT-PCR) (negative, positive, indeterminate) 
• Anti-2019-nCoV (negative, positive, or not test/missing)  
Continuous variables collected on respiratory and clinical assessment eCRF page will be summarized 
descriptively as appropriate. 
5.3.3. 
SOFA and qSOFA 
Sequential Organ Failure Assessment Score (SOFA) at baseline will be summarized for Cohort 2. 
• Descriptive statistics will be provided for the following: 
− PaO2 (mmHg) 
− FiO2 (%) 
− P/F Ratio 
− SOFA Score 
• Frequency tabulations will be presented for: 
− assessment performed (No (in ICU, Other) or Yes) 
− on mechanical ventilation (No or Yes) 
− platelets (x 10^3/uL) (≥ 150, 100-149, 50-99, 20-49, or <20) 
− Glasgow coma scale (15, 13-14, 10-12, 6-9, or <6) 
− bilirubin (mg/dl (umol/L)) (<1.2 (<20)), 1.2 - 1.9 (20 - 32), 2.0 - 5.9 (33 - 101), 6.0 - 
11.9 (102 - 204), or ≥12.0(≥204)) 
− mean arterial pressure OR administration of vasoactive agents required (Blood 
pressure stable without need for pressor support, MAP less than 70 mmHg, (Dopamine 
<=5 mcg/kg/min or Dobutamine), (Dopamine >5 mcg/kg/min, Epinephrine <=0.1 
mcg/kg/min, or nor Epinephrine <=0.1 mcg/kg/min), or (Dopamine >15 mcg/kg/min, 
Epinephrine >0.1 mcg/kg/min, or nor Epinephrine >0.1 mcg/kg/min)) 
− creatinine (mg/dL) (umol/L) (or urine output) (<1.2 (<110)), 1.2 - 1.9 (110 - 170), 2.0 - 
3.4 (171 - 299), 3.5 - 4.9 (300 - 440), or 5.0 mL/day<=UOP<500 mL/day (>440))  
Quick Sequential Organ Failure Assessment (qSOFA) at baseline will be tabulated for Cohort 1: 
− qSOFA Score  
− assessment performed (No (Invasive/noninvasive ventilation, Other) or Yes) 
− respiration rate >=22 breaths/min (No or Yes) 
− change in mental status (Glasgow score less than 15) (No or Yes) 


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− systolic blood pressure less than or equal to 100 mm/Hg (No or Yes) 
By subject SOFA and qSOFA will be listed. 
5.4. 
Medical History 
Medical history data will be summarized by system organ class (SOC) and preferred term (PT) per 
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 based on the safety analysis 
set. Subjects with multiple events coded to the same SOC or PT will only be counted once in the 
summary for that category. 
All medical history data will be listed. 
5.5. 
Prior and Concomitant Medications 
Prior medications are defined as those taken before the date of the study drug.  Concomitant 
medications are defined as any non-study medication taken during the study i.e., on or after the date 
of the study drug and within 90 days of the study drug treatment.  
The number and percentage of subjects taking prior and concomitant medications will be tabulated 
separately by anatomical-therapeutic-chemical (ATC) level 2 and preferred drug name by treatment 
for the safety analysis set. A subject taking the same medication multiple times is counted only once 
under that preferred drug name. The summary will be sorted in the alphabetic order of ATC classes 
and preferred terms. 
Prior and concomitant medications will be listed with flag. 
Medications are coded using the World Health Organization (WHO) Drug dictionary B3 enhanced, 
version Mar 2020. 
5.6. 
Study Treatments and Extent of Exposure 
Study drug exposure will be summarized descriptively by treatment for the safety analysis set: 
• Duration of infusion (minutes) 
• Received the full injection volume (Yes or No) 
• Infusion interrupted (Yes or No) 
− Reasons for infusion interruption (Adverse event, Technical Issue, Other) 
• Infusion resumed (Yes or No) 
The study drug administration details including the administration date and time will be presented in a 
by-subject listing.  
5.7. 
Efficacy Analysis 
All efficacy endpoints will be analyzed for the ITT analysis set.  The primary and secondary 
endpoints will also be performed for the Per-protocol analysis set. Treatment comparisons will be for 
each KPL-301 arm vs placebo 
5.7.1. 
Multiplicity Adjustment 
Multiplicity adjustment for Phase 3 Cohort 1 will be done to guarantee strong control of the overall 
Type I error rate at a two-sided alpha value of 0.05.  For each endpoint, the test statistics for the two 
comparisons asymptotically follow a bivariate normal distribution and are positively correlated due to 
sharing a common control arm (placebo). Thus, the conventional Hochberg method will be used to 
adjust for multiplicity in the analysis of the two dose levels and the sequence of efficacy endpoints. 
Below are the details.  


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Considering the hypothesis testing of both the 10 mg/kg and the 6 mg/kg individually versus placebo 
for each endpoint to be a family, the testing on the primary endpoint and the three ordered secondary 
endpoints correspond to Family 1, Family 2, Family 3, and Family 4, respectively.  
Testing will be done sequentially (Family 1, then 2, 3, and 4) based on the following decision rules 
(p-values are all two-sided):  
• If both p-values in a family are ≤ 0.05, statistically significant treatment effects for the 
endpoint can be claimed for both dose levels, and testing may proceed to the next family to 
test those hypotheses at two-sided significance level of 0.05.  
• If the larger p-value is > 0.05 and the smaller p-value is ≤ 0.025, a statistically significant 
treatment effect can be claimed only for the one dose level corresponding to the smaller p-
value. Sequential testing stops here, and no further inferential testing can be done. The 
remaining data analyses will be provided for completeness (with p values as nominal) to 
inform the discussion of benefit-risk.  
• If both p-values in the family are > 0.05, a statistically significant treatment effect cannot be 
claimed for either dose level. Sequential testing stops here, and no further inferential testing 
can be done. The remaining data analyses will be provided for completeness (with p values as 
nominal) to inform the discussion of benefit-risk.  
No multiplicity adjustment will be done for Phase 3 Cohort 2. No formal testing will be conducted as 
enrollment for this cohort stopped early.  
5.7.2. 
NIAID Scale and Missing Data Imputation for Binary Endpoints 
NIAID scores at randomization should be derived from the last NIAID assessment prior to 
randomization. When not able to be derived, the screening NIAID will be used unless missing, in 
which case the (first) score from Day 1 will be used.  
Baseline NIAID scores should be derived from the last NIAID assessment prior to dosing. 
When two or more NIAID scores are collected on the same study day, the lowest score will be used, 
except at the date of discharge, in which the highest NIAID score will be used. When the derived 
NIAID at randomization happens to be from Day 1, then the Day 1 NIAID should be the lowest score 
on or after the NIAID at randomization time. 
For endpoints where the event of interest is favorable, like proportion of subjects alive and free of 
ventilation, and proportion of subjects with 1-point/2-point clinical improvement, the following 
imputation rule of NIAID scale will be adopted: 
• When the NIAID assessment is missing at the target day (Day 15, 29, etc.), the NIAID score 
closest to and within the window of the target day will be used.  In case of ties with equal 
number of days on either side of target day, the value before the target day will be used. The 
window is (-2 days, +2 days) for Day 15 endpoints, (-2 days, +4 days) for Day 29 endpoints, 
and (-7 days, +14 days) for Day 90 endpoints. 
• When no NIAID assessment is available within the window of the target day, the primary 
treatment comparison will be based on a combination of responder imputation and non-
responder imputation. The rules taking into consideration of missing data are mostly related to 
subjects being improved and discharged from the hospital. 
− Discharged subjects will be considered as having had the event (responders). 
− Subjects who are still in the hospital will be considered as not having had the event 
(non-responders). 
− Subjects who died will be considered as not having had the event for all subsequent 
target days after discontinuation (non-responders).  


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− Subjects who terminated study before the target day, if the NIAID met the endpoint 
criteria as of last assessment before the study termination, they will be considered as 
having had the event for all subsequent target days after discontinuation (responders).  
− Subjects without any post randomization assessment will be considered non-
responders. 
 
In calculation of the mortality rate, a subject with the last known alive date on or after the target day 
is considered alive. If the last known alive date is before the target day but within their visit window, 
the subject is considered alive at the target day. Subjects terminated the study early will be considered 
alive since all subjects in the study are hospitalized and early termination other than due to death 
mostly happens to subjects improved or discharged. 
Sensitivity analyses may be conducted to assess missing data assumptions for the primary endpoint 
and the mortality rate at Day 29. Two methods might be considered: 
1) Multiple imputation approach with a covariate of discharge status at last assessment, adjusting 
for randomization strata. 
2) Tipping point analyses. The goal is to explore the plausibility of missing data assumptions 
under which the conclusions change, i.e., under which there is no longer evidence of efficacy. 
We plan to extend tipping points for binary data (Yan et al., 2009) to binary data with stratification.  
Let 𝑛1𝑚 and 𝑛0𝑚 be the number of missing values in the treatment and placebo arms respectively. 
When there is no stratification, the responders (Let 𝑟1𝑚 and 𝑟0𝑚 to denote the numbers) among the 
𝑛1𝑚 and 𝑛0𝑚subjects can range from 0 to 𝑛1𝑚 and 𝑛0𝑚, respectively, by adding 1 responder at a time.  
A heat map plot can be drawn for assessment.  
In our study when stratification exists, multiple imputation might be needed in extending Yan et al’s 
approach.  Repeat the following algorithm for each combination of  𝑟1𝑚 and 𝑟0𝑚, where  𝑟1𝑚 = 0, …, 
𝑛1𝑚 and 𝑟01𝑚 = 0, …, 𝑛0𝑚, 1), and draw a heat map plot using data obtained. 
1) Randomly select 𝑟1𝑚 and 𝑟0𝑚 subjects as responders and the rest as the non-responders. 
2) Include the responders from step 1) in the observed responders without missing data, calculate 
the approximately normally distributed CMH test statistic instead of the usual Chi-square 
distributed CMH test statistic.  
3) Repeat Step 1 and Step 2 a fixed number of times, e.g. 200. The statistics obtained are passed 
to PROC MIANALYZE to perform a combined CMH test to obtain a p-value. 
 
5.7.3. 
Censoring Rules for Time to Event Endpoints  
NIAID scores collected within visit windows (described in Section 4.3) of the target days will be used 
for time to event analysis by the corresponding target day. The last assessments referred to in this 
section include those occur after the target day but within the protocol-defined visit window. For 
example, if a subject has not had 2-point clinical improvement by Day 29 visit, which occurs on Day 
30, the subject will be censored at Day 30 instead of Day 22 (the last assessment before Day 29).  
For favorable time to event endpoints, death before the target date Day X (X=15, 29, or 90) will be 
censored at Day 19 for X = 15, and Day 35 for X = 29 unless otherwise specified. Details are below. 
• Time to ventilation or death (Ventilation free survival) by Day 29 
Defined as time (in days) from randomization to the date of death or start date of using 
mechanical ventilation (NIAID ≤ 2) by Day 29 for Cohort 1.  All subjects who have never had 


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NIAID ≤ 2 by Day 29 will be censored at the last assessment date of NIAID 8-point ordinal 
scale. 
 
• 
 
 
 
 
 
 
• Overall survival by Day X (X=29, or 
) 
Defined as time (in days) from the randomization date to the date of death by Day X.  All 
survival subjects will be censored at last date known alive on/before Day X. 
 
• 
 
 
 
 
 
 
 
• Time to K-point clinical improvement by Day X (K=1, or , X=
, or 29) 
Defined as time (in days) from randomization to the date of a K-point improvement on the 
NIAID 8-point ordinal scale, or discharge from the hospital, whichever occurs first, by Day X.  
Alive subjects who do not have K-point improvement nor discharge from the hospital will be 
censored at the date of the last NIAID 8-point ordinal scale assessment on/before Day X. 
Dead subjects will be censored at Day 19 for Day 
endpoint and at Day 35 for Day 29 
endpoint. 
 
• 
 
 
 
 
 
 
 
 
 
 
 
  
 
5.7.4. 
Analysis of Primary Efficacy Endpoint 
The proportion of subjects alive and free of ventilation at Day 29 for Cohort 1, and the proportion of 
subjects who die (mortality rate) by Day 29 for Cohort 2 will be analyzed by the CMH test adjusted 
for the actual randomization strata (Cohort 1: standard of care antiretroviral therapy, age, and ARDS 
status; Cohort 2: standard of care antiretroviral therapy and age).  The 95% confidence interval (CI) 
will be calculated using the Clopper-Pearson exact method. Number of subjects and percentages will 
be summarized by treatment.  
The CMH method addresses the global null hypothesis of no difference between treatments. Hence, it 
corresponds to the risk difference being 0, the risk ratio being 1, and the odds ratio being 1. The CMH 


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p-value is the same across odds ratio/risk ratio/risk difference. In addition to CMH p-value, the 
stratified risk difference, stratified relative risk, and the stratified odds ratio and their 95% confidence 
interval (CI) will be provided in our analyses.  
Analysis of the primary efficacy endpoint based on the per-protocol population will be conducted 
following the same methods. 
5.7.5. 
Analysis of Secondary and Other Efficacy Endpoints 
5.7.5.1. 
Time to event endpoints 
For all time to event endpoints, the primary treatment comparison between the active treatment and 
the placebo (10 mg/kg mavrilimumab vs. placebo, and 6 mg/kg mavrilimumab vs. placebo) will be 
based on log-rank test stratified by the actual randomization strata.  
The Kaplan-Meier (KM) method will be used to estimate the survival distribution function for all the 
time to event endpoints. The 25th, 50th (median), 75th percentiles and their two-sided 95% 
confidence interval (CI) will be estimated. In addition, the probability of favorable outcome (event 
rates, or event-free rates depending on the endpoints) at Day 4, 8, 15, 22, 29, 60, and 90 will be 
calculated as appropriate, along with their standard errors using Greenwood’s formula (Klein, 2003) 
stratified by the actual randomization strata. Corresponding Kaplan-Meier plot will be produced. In 
case of favorable outcomes, the plot will be based on 1 - KM estimate. 
The hazard ratio for (10 mg/kg mavrilimumab vs. placebo) or (6 mg/kg mavrilimumab vs. placebo) 
and the corresponding Wald 95% CI will be calculated based on a Cox proportional-hazards model 
with treatment as covariates, stratified by the actual randomization strata. 
5.7.5.2. 
Binary (rate or proportion) endpoints 
The primary treatment comparison for all binary endpoints will be based on the CMH test adjusted by 
actual randomization strata. Number of subjects and percentages will be summarized by treatment. 
The stratified risk difference, stratified relative risk, and the stratified odds ratio and their 95% CIs 
along with the CMH p-value will be provided in these analyses. 
The event rates (or event-free) from the corresponding time to event analysis can serve as supportive 
analyses. For example, proportion of subjects with K-point clinical improvement can be estimated 
from time to K-point clinical improvement; mortality rate can be estimated from the overall survival. 
No formal testing will be conducted. 
 
5.7.5.3. 
Endpoints to be summarized descriptively  
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will be used to 
summarize the following endpoints. No imputation will be done unless otherwise specified. 
• 
 
 
 
 
 
 
 
 
 
 
 
  


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5.7.6. 
Subgroup analysis 
Subgroup analyses will be conducted for each of the randomization stratum for the primary efficacy 
endpoint and secondary endpoints.   
 
 
5.8. 
Safety Analysis 
The safety endpoints will be tabulated by treatment based on the Safety Analysis Set. All safety data 
including those collected during the safety follow-up will be listed by subject. 
5.8.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product. An AE does not necessarily have a causal relationship 
with this treatment. An AE will be defined as treatment-related if its relationship to the study drug is 
reported as Possibly Related or Definitely Related by Investigator. 
An AE is considered treatment-emergent adverse event (TEAE) if the AE begins on/after and within 
90 days of the study drug administration. If the date of AE onset is missing or coincides with the date 
of the study drug administration and AE time is not captured, AE will be considered treatment 
emergent. 
All AEs will be coded using MedDRA version 23.0. A subject experiencing multiple AEs under the 
same preferred term (PT) or same system organ class (SOC) will be counted only once for that PT or 
SOC by maximum severity. If a subject experience the same AE more than once with more than one 
causal relationship to study drug, the strongest causal relationship to study drug will be given 
precedence. Any missing severity, causality, or outcome will not be imputed and classified as 
‘Missing’. Detailed imputation rules for missing AE dates are in Section 8.1.1.  
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and requires close monitoring and rapid communication 
by the investigator to the sponsor. An AESI may be serious or non-serious.  


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The number of subjects with at least one TEAE will be tabulated. The following tables summarize 
incidences of various aspects of TEAEs, treatment-emergent serious AEs (TESAEs), and treatment-
emergent AESIs (TEAESIs):  
• Overview of TEAEs (summary of all the subsequent items) 
• TEAEs by SOC and PT 
• TEAEs by PT 
• TEAEs by maximum severity (mild, moderate, or severe) 
• Drug related TEAEs (related or not related) by SOC and PT 
• TESAEs by SOC and PT 
• Drug related TESAEs by SOC and PT 
• TESAEs by PT 
• TEAESIs by SOC and PT 
• TEAEs leading to dose interruption by SOC and PT 
• TEAEs leading to death by SOC and PT  
All information pertaining to adverse events will be listed by subject, detailing verbatim term given 
by the investigator, preferred term, system organ class, start date, stop date, severity, outcome, action 
taken and drug relatedness.  
Separate listings will be created for Serious TEAEs, and TEAESI, and death. 
Additionally, non-serious TEAEs by SOC and PT will be tabulated. 
5.8.2. 
Clinical Laboratory Parameters 
The following laboratory tests are performed at the Study Site/Clinic laboratories and recorded on the 
eCRF: 
• Screening for tuberculosis  
• Pregnancy 
• SARS-CoV-2 test with RT-PCR  
• Hematology: complete blood count + differential  
• Chemistry: electrolytes, blood urea nitrogen, glucose, and CR  
• Liver profile: AST, ALT, Alb, AlkP, Tbili, Dbili  
• Lipid panel: Cholesterol, total; high-density lipoprotein (HDL) cholesterol; low-density 
lipoprotein (LDL) cholesterol (calculation); triglycerides; very low-density lipoprotein 
(VLDL) cholesterol (calculation)  
• Urinalysis  
• 
  
The following tests are performed by the central lab: 
• Respiratory Viral Panel 
• Anti-mavrilimumab Antibody 


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• 
  
Continuous laboratory data (
, anti-mavrilimumab antibody, hematology, coagulation, 
chemistry, liver profile, and lipid panel) will be examined for trends using descriptive statistics of 
actual values and changes from baseline over time by treatment for the safety analysis set.   
Shift tables will be produced for hematology and chemistry. 
All laboratory results will be presented in by-subject listings.  
5.8.3. 
Vital Signs 
Vital signs include temperature, respiratory rate, systolic blood pressure/ diastolic blood pressure, and 
heart rate. Body weight and height will be reported in Body Measurements eCRF. 
Actual values of vital signs (including weight) and changes from baseline will be summarized using 
descriptive statistics by visit.  
All vital signs data will be listed. 
5.8.4. 
Electrocardiogram (ECG) 
All ECG data will be listed. 
5.8.5. 
Physical Examination 
All physical examination data will be listed. 
5.8.6. 
Chest Imaging 
Chest imaging data will be listed. 
6. 
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL 
• The following other efficacy endpoints are out of scope for this SAP, and will be reported 
separately 
o 
 
 
 
 
 
 
 
• All randomized subjects will be included in the ITT analysis set.  
• Summary of Remdesivir and Corticosteroids Before Day 29 are added  
• For favorable Day 29 endpoints, death will be censored at Day 35 instead of Day 30 as 
specified in the protocol 
• The main analyses for the first database lock of Cohort 1 will not use a fixed data cut-off date. 
Subject level Day 29 dates will be used instead. 
o Efficacy endpoints based on Day 29 will consider data through Day 29 window. 
o Non-efficacy parameters that involve data after Day 29 by definition, e.g., TEAE, CM, 
will only include data through Day 29 in the first database lock. 
o Lab summary tables will only include baseline; and lab shift tables will not be 
provided since only baseline lab data will be cleaned in the first DBL. 


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7. 
REFERENCE 
Brown SM, Grissom CK, Moss M, Rice TW, Schoenfeld D, Hou PC, Thompson BT, Brower RG; 
NIH/NHLBI PETAL Network Collaborators. Nonlinear Imputation of Pao2/Fio2 from Spo2/Fio2 
Among Patients with Acute Respiratory Distress Syndrome. Chest. 2016 Aug;150(2):307-13. doi: 
10.1016/j.chest.2016.01.003. Epub 2016 Jan 19. 
 
Klein JP, Moeschberger ML. Survival analysis technique for censored and truncated data 
(second edition). Springer-Verlag; 2003.  
 
OpenCriticalCare.org, n.d. https://opencriticalcare.org/imputed-pao2-calculator/. 
 
Yan X, Lee S, Li N. Missing Data Handling Methods In Medical Device Clinical Trials. Journal of 
Biopharmaceutical Statistics, 19: 1085–1098, 2009. 
8. 
APPENDICES 
8.1. 
Handling of Missing Safety Data 
No imputation will be made for completely missing date unless otherwise specified. General 
imputation rules mentioned below apply to partially missing or impossible dates: 
• If the stop date is not missing, and the imputed start date is after the stop date, the start date 
will be imputed by the stop date 
• If the start date is not missing, and the imputed stop date is before the start date, then the 
imputed stop date will be equal to the start date 
• Any imputed dates need to be logical. For example, last dose date should not be later than 
death date. 
When imputation rules in subsequent sections contradicts the general rule, always follow the general 
rule.  
8.1.1. 
Adverse Event Date Imputation 
Follow the general rule specified in Section 8.1. 
Incomplete Start Date: 
Missing day, month, and year 
No imputation will be made; the corresponding AE will be included.  
Missing day and month 
• If the year is the same as the year of the first dose date, then impute day and month as the day 
and month of the first dose 
• If the year is prior to the year of the first dose date, then impute day and month as 31 Dec 
• If the year is after the year of the first dose date, then impute day and month as 01 Jan. 
Missing day only 


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• If the month and year are the same as those of the first dose date, then impute day as the day 
of the first dose date 
• If either the year of partial date is before the year of the first dose date, or the years are the 
same, but the month of partial date is before the month of the first dose date then impute day 
as last day of the month 
• If either the year of partial date is after the year of the first dose date, or the years are the 
same, but the month of partial date is after the month of the first dose date, then impute day as 
first day of the month.  
Incomplete Stop Date: 
Missing day, month, and year 
• No imputation will be made. 
Missing day and month 
• If the year is the same as the year of the last dose date, then impute day and month as the day 
and month of the last dose date 
• If the year is prior to the year of the last dose date, then impute day and month as 31 Dec 
• If the year is after the year of last dose date, then impute day and month as 01 Jan. 
Missing day only 
• If the month and year are the same as those of the last dose date, then impute day as the day of 
the last dose date 
• If either the year of partial date is not the same as the year of the last dose date, or the years 
are the same, but the month of partial date is not the same as the month of the last dose date, 
then impute day as last day of the month.  
8.1.2. 
Concomitant Medication Date Imputation 
Follow the general rules specified in Section 8.1 and Section 8.1.1. 
 






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Table of Contents 
LIST OF ABBREVIATIONS  .........................................................................................................4 
1. 
INTRODUCTION ........................................................................................................5 
1.1. 
Objectives .....................................................................................................................5 
1.1.1. 
Primary Objective .........................................................................................................5 
1.1.2. 
Secondary Objectives ...................................................................................................5 
1.1.3. 
Other Objective .............................................................................................................5 
1.2. 
Study Design .................................................................................................................5 
1.3. 
NIAID Scale .................................................................................................................6 
1.4. 
Sample Size Justification ..............................................................................................6 
2. 
ENDPOINTS ................................................................................................................7 
2.1. 
Primary Efficacy Endpoint ...........................................................................................7 
2.2. 
Secondary Efficacy Endpoints ......................................................................................7 
2.3. 
Other Efficacy Endpoints .............................................................................................8 
2.4. 
Safety Endpoints ...........................................................................................................9 
3. 
ANALYSIS SETS ......................................................................................................10 
3.1. 
Modified Intent-to-Treat (mITT) Analysis Set ...........................................................10 
3.2. 
Safety Analysis Set .....................................................................................................10 
3.3. 
Per-Protocol (PP) Analysis Set ...................................................................................10 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................10 
4.1. 
Randomization, Stratification, and Blinding ..............................................................10 
4.2. 
Data Analysis General Information and Definition ....................................................11 
4.2.1. 
Study Drug ..................................................................................................................11 
4.2.2. 
Day 1 ...........................................................................................................................11 
4.2.3. 
Baseline Values ..........................................................................................................11 
4.2.4. 
Last Contact ................................................................................................................11 
4.2.5. 
Calculation Using Dates .............................................................................................11 
4.2.6. 
Duration Derivation ....................................................................................................12 
4.3. 
Windowing of Visits ...................................................................................................12 
4.4. 
Methods for Handling Missing Data ..........................................................................12 
4.5. 
Protocol Deviations ....................................................................................................12 
5. 
STATISTICAL METHODOLOGY ...........................................................................13 
5.1. 
Study Population .........................................................................................................13 
5.2. 
Subject Disposition .....................................................................................................13 


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5.3. 
Demographics and Baseline Disease Characteristics and History .............................13 
5.3.1. 
Demographics .............................................................................................................13 
5.3.2. 
Baseline Disease Characteristics ................................................................................14 
5.3.3. 
SOFA and qSOFA ......................................................................................................15 
5.4. 
Medical History ..........................................................................................................16 
5.5. 
Prior and Concomitant Medications ...........................................................................16 
5.6. 
Study Treatments and Extent of Exposure .................................................................16 
5.7. 
Efficacy Analysis ........................................................................................................16 
5.7.1. 
Multiplicity Adjustment..............................................................................................17 
5.7.2. 
NIAID Scale and Missing Data Imputation for Binary Endpoints .............................17 
5.7.3. 
Censoring Rules for Time to Event Endpoints ...........................................................17 
5.7.4. 
Analysis of Primary Efficacy Endpoint ......................................................................18 
5.7.5. 
Analysis of Secondary and Other Efficacy Endpoints ...............................................19 
5.7.6. 
Subgroup analysis .......................................................................................................20 
5.8. 
Safety Analysis ...........................................................................................................20 
5.8.1. 
Adverse Events ...........................................................................................................20 
5.8.2. 
Clinical Laboratory Parameters ..................................................................................21 
5.8.3. 
Vital Signs ..................................................................................................................22 
5.8.4. 
Electrocardiogram (ECG) ...........................................................................................22 
5.8.5. 
Physical Examination .................................................................................................22 
5.8.6. 
Chest Imaging .............................................................................................................22 
6. 
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL ......................22 
7. 
REFERENCE .............................................................................................................23 
8. 
APPENDICES ............................................................................................................23 
8.1. 
Handling of Missing Safety Data ...............................................................................23 
8.1.1. 
Adverse Event Date Imputation ..................................................................................23 
8.1.2. 
Concomitant Medication Date Imputation .................................................................24 
 
 
 


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List of Abbreviations  
 
2019-nCoV  
2019 novel coronavirus  
AE  
Adverse event  
AESI  
Adverse event of special interest  
ALT  
Alanine aminotransferase  
ARDS  
Acute respiratory distress syndrome  
AST  
Aspartate aminotransferase  
ATC 
Anatomic-therapeutic-chemical 
BiPAP  
Bi-level positive airway pressure  
CMH  
Cochran-Mantel-Haenszel  
COVID-19  
Corona Virus Disease 2019  
CPAP  
Continuous positive airway pressure  
CRF  
Case report form  
CRP  
C-reactive protein  
CT  
Computerized tomography  
ECG  
Electrocardiogram  
ECMO  
Extracorporeal membrane oxygenation  
eCRF  
Electronic case report form  
FiO2  
Fraction of inspired oxygen  
ICU  
Intensive care unit  
IL  
Interleukin  
IMV 
Invasive mechanical ventilation 
IWRS  
Interactive web-based response system  
LDH  
Lactate dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS  
Middle East respiratory syndrome  
mITT  
Modified intent-to-treat  
NIAID 
National Institute of Allergy and Infectious Diseases 
PaO2  
Partial pressure of oxygen  
PCR  
Polymerase chain reaction  
PD 
Pharmacodynamics 
PEEP  
Positive end-expiratory pressure  
PK  
Pharmacokinetics  
PT 
Preferred term 
qSOFA 
Quick sequential organ failure assessment  
SAP 
Statistical analysis plan 
SOC 
System organ class 
SOFA  
Sequential Organ Failure Assessment Score  
TEAE 
Treatment-emergent adverse event  
 
 
 




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Allergy and Infectious Diseases (NIAID) scale) through study Day 90. The schedule of activities is 
presented in Table 2 of the protocol. 
The Phase 2 part of the study will enroll approximately 171 subjects (120 in Cohort 1 and 51 in 
Cohort 2). Each cohort will randomize subjects in a 1:1:1 allocation ratio to receive a single IV 
infusion of mavrilimumab (10 mg/kg or 6 mg/kg) or placebo. Cohort 1 will include non-intubated 
hospitalized subjects who require supplemental oxygen to maintain SpO2 ≥ 92%, i.e., “non-
ventilated” subjects. Cohort 2 will include hospitalized subjects for whom mechanical ventilation was 
recently initiated (within 48 hours prior to randomization), i.e., “ventilated” subjects.  
 
1.3. 
NIAID Scale 
Subject clinical status will be assessed daily using the 8-point NIAID scale, which is the basis for 
assessment of primary and secondary endpoints for Cohort 1 and Cohort 2.  
1. Death  
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation 
(ECMO)  
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices  
4. Hospitalized, requiring supplemental oxygen  
5. Hospitalized, not requiring supplemental oxygen – requiring ongoing medical care (COVID-19 
related or otherwise)  
6. Hospitalized, not requiring supplemental oxygen – no longer requires ongoing medical care  
7. Not hospitalized, limitation on activities and/or requiring home oxygen  
8. Not hospitalized, no limitations on activities  
 
1.4. 
Sample Size Justification  
Sample sizes were calculated separately for each cohort and phase of the study based on their primary 
endpoint and other assumptions. Key elements for Phase 2 sample size are summarized below with 
type I error of 0.20 and power of 80%. 
Cohort KPL-301  Placebo  Sample Size  Primary Endpoint  
1  
95%  
75%  
120  
D29 Proportion of subjects alive and free of ventilation 
2  
40%  
80%  
51  
D29 Mortality rate  
Approximately 171 subjects will be randomized to the Phase 2 part of this study.  
Sample size estimation for Cohort 1 (non-ventilated subjects) in Phase 2 is based on the primary 
efficacy endpoint proportion of subjects alive and free of mechanical ventilation at Day 29, using a 
Fisher’s exact test.  
Approximately 120 subjects will be randomized with a 1:1:1 allocation ratio.  Assuming the 
proportions of subjects alive and free of ventilation at Day 29 are 95% and 75% for the active 
treatment arm and placebo arm, respectively, 40 subjects per arm will achieve a minimum 80% power 
for a pairwise comparison versus control when the two-sided alpha value is 0.20.  


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Sample size for Cohort 2 (ventilated subjects) in Phase 2 is based on the primary efficacy endpoint 
mortality rate at Day 29, using a Fisher’s exact test.  Approximately 51 subjects will be randomized 
with a 1:1:1 allocation ratio.  Assuming the mortality rates at Day 29 are 40% and 80% for the active 
treatment arm and placebo arm, respectively, 17 subjects per arm will achieve 80% power for a 
pairwise comparison versus control when the two-sided alpha value is 0.20.   
 
2. 
ENDPOINTS 
The primary, secondary, and other efficacy endpoints are defined in this section and summarized by 
assessment day in Table 1 . 
2.1. 
Primary Efficacy Endpoint 
Cohort 1 (Non-ventilated Subjects) 
The primary efficacy endpoint for cohort 1 is proportion of subjects alive and free of mechanical 
ventilation at Day 29.  Mechanical ventilation is defined as invasive mechanical ventilation (IMV) or 
extracorporeal membrane oxygenation (ECMO).  Subjects whose clinical outcome meets NIAID 
(defined in Section 1.3) score 2 will be considered as using mechanical ventilation.  
Cohort 2 (Ventilated Subjects) 
The primary efficacy endpoint for cohort 2 is mortality rate at Day 29, defined as the proportion of 
subjects who die by Day 29. 
 
2.2. 
Secondary Efficacy Endpoints 
Cohort 1 (Non-ventilated Subjects) 
1. Time to 2-point clinical improvement by Day 29 
Defined as time from randomization to a 2-point improvement on the NIAID 8-point ordinal 
scale, or discharge from the hospital, whichever comes first. Subjects who die before Day 29 
will be censored at Day 30. 
2. Time to return to room air or discharge by Day 29 
Defined as time from randomization to breathing room air (NIAID scale ≥ 5), or discharge 
from the hospital, whichever occurs first. Subjects who die before Day 29 will be censored at 
Day 30.  
3. Mortality rate at Day 29 
Cohort 2 (Ventilated Subjects) 
1. Time to 1-point clinical improvement by Day 29 
Defined as time from randomization to a 1-point improvement on the NIAID 8-point ordinal 
scale, or discharge from the hospital, whichever comes first. Subjects who die before Day 29 
will be censored at Day 30.  
 






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3. 
ANALYSIS SETS 
3.1. 
Modified Intent-to-Treat (mITT) Analysis Set  
All randomized subjects who receive study drug will be included in the mITT analysis set.  All 
efficacy analyses of the study will be based on the mITT analysis set.  All mITT analyses will be 
based on the randomized treatment.   
 
3.2. 
Safety Analysis Set  
All randomized subjects who receive study drug will be included in the safety analysis set. Safety 
analyses will be based on the actual treatment received. 
 
3.3. 
Per-Protocol (PP) Analysis Set  
All mITT subjects without protocol deviations deemed to impact efficacy will be included in the PP 
analysis set and will be determined before the database lock. The primary and secondary efficacy 
endpoints will be further analyzed based on the PP set. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
Analyses described in this SAP will be conducted separately for each of the two cohorts. 
Summary statistics for continuous variables will include n (non-missing observations), mean, 
standard deviation, minimum, median, and maximum. Summary statistics for categorical variables 
will be presented in terms of frequencies and percentages based on the analysis set unless otherwise 
specified. In by-visit summary tables, only scheduled visits/timepoints will be summarized.  
Time to event data will be summarized using the Kaplan-Meier (KM) method, which will include the 
estimated median, 25th percentiles, 75th percentiles, and their 80% confidence interval (CI).  The CIs 
will be calculated using a log-log transformation. The event-free probability and its 80% CI will be 
calculated at days 4, 8, 15, 22, 29, 60 and 90 as appropriate using Greenwood’s formula with a log-
log transformation.  
The 80% confidence interval (CI) of the difference in the proportion (KPL-301 – placebo) will be 
primary based on normal approximation when comparing treatment for binary (proportion or rate) 
endpoints.  
All relevant subject data will be listed by cohort, treatment, subject and visit/time point including both 
scheduled and unscheduled visits. 
 
4.1. 
Randomization, Stratification, and Blinding 
An Interactive Web Response System (IWRS) will be used for assignment of the subject 
identification number at enrollment, randomization to a treatment arm (10 mg/kg KPL-301, 6 mg/kg 
KPL-301 or placebo), and assignment of blinded investigational product. 
The randomization is stratified by three characteristics of the subjects in Cohort 1 and by the first two 
characteristics for Cohort 2. 
1. Use of approved standard of care antiretroviral therapy: yes vs. no  
2. Age: <65 vs. ≥ 65 years  


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3. Acute respiratory distress syndrome (ARDS) status: normal – mild (> 200 PaO2/FiO2) vs. 
moderate-severe (≤ 200 PaO2/FiO2). If PaO2 is unavailable, use SpO2/FiO2: normal–mild 
(>235 mmHg) vs. moderate-severe (≤235 mmHg)    
There should be no overlap of subject populations between the two cohorts since Cohort 1 baseline 
NIAID should be 3 or 4 and Cohort 2 baseline NIAID should be 2. In case of subjects being 
erroneously randomized under the incorrect cohort, the subjects will be analyzed in the correct cohort 
defined by the baseline NIAID scale. Subjects with baseline NIAID ≥ 5 will be included in Cohort 1 
for analyses based on mITT and safety populations but excluded from per protocol analyses. 
If subjects were randomized based on incorrect baseline information (strata), then the correct strata 
will be used for stratified analysis rather than the incorrect strata recorded at randomization.  
If fewer than 5 subjects are in a stratification group of all three (or two for cohort 2) factors, that 
group will be pooled with another stratification group. If the same situation occurs, strata for the 
second factor will be pooled. If the same situation still exists, the analysis will be done without 
stratification.  
For stratified analyses, if there is no event for both arms of comparison, or all responses are the same 
within a stratification group, that group will be pooled with another stratification group per the order 
of the stratification factors listed previously. This principal will be analogously applied to subgroups, 
but only to those subgroups for which lack of events/responses require it. 
 
4.2. 
Data Analysis General Information and Definition  
4.2.1. 
Study Drug 
Study drug or study treatment refers to 10 mg/kg KPL-301 (mavrilimumab), 6 mg/kg KPL-301 
(mavrilimumab) or placebo.   
4.2.2. 
Day 1  
Day 1 is defined as the day of the study treatment after randomization.    
4.2.3. 
Baseline Values 
Baseline is defined as the last non-missing value obtained prior to the start of study treatment. The 
baseline NIAID is defined separately in Section 5.7.2.  
The change from baseline values will be derived for each subject as the post-baseline evaluation 
minus the baseline evaluation. 
4.2.4. 
Last Contact 
Last contact or last date known alive is defined as the last non-imputed date of any subject record 
prior to or on the data cut-off date in the clinical database. 
4.2.5. 
Calculation Using Dates 
Calculations using dates will adhere to the following conventions: 
Study day for a date of interest (TARGET DATE) is calculated as 
STUDY DAY = TARGET DATE – Date of Day 1 + 1 if TARGET DATE is on or after Day 1; 
STUDY DAY = TARGET DATE – Date of Day 1 otherwise. 
Day X in this document refer to the study day X, where X can be 4, 8, 15, 22, 29, 60, 90, etc.   


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4.2.6. 
Duration Derivation 
Unless otherwise specified for a specific panel or variable, duration variables will be derived 
according to the following rules. Duration variables expressed in units greater than day will be 
rounded to 1 decimal place. 
Duration (in days) = [end date – start date +1] 
Duration (in weeks) = [end date – start date +1] / 7 
Duration (in months) = [end date – start date +1] / 30.4375 
 
4.3. 
Windowing of Visits 
Data will be summarized by eCRF visits without windowing. 
 
4.4. 
Methods for Handling Missing Data 
For efficacy data, a survival sweep will be conducted before the database lock to minimize the 
amount of missing survival status data.  Missing NIAID scale and survival status at target days will 
handled per Section 5.7.2. 
For safety data, refer to Section 8.1  for detailed date imputation guidelines. 
 
4.5. 
Protocol Deviations 
All protocol deviations will be entered into database by site staff. The study team will have a blinded 
review of protocol deviations to determine their classification (important, not important) periodically.  
Prior to the database lock, the study team will assess impact of all important protocol deviations on 
efficacy and whether they should be excluded from the per-protocol analysis set.  
The number of important protocol deviations, the number of subjects with at least one important 
protocol deviation, and the number of subjects with at least one important protocol deviation 
with/without a potential impact on efficacy will be summarized by treatment group. The protocol 
deviation criteria types will also be summarized, with reference to an evaluability document that will 
be signed off prior to database lock.  
All protocol deviations will be presented in by-subject listings, and subjects with protocol deviations 
that lead to exclusion from the per-protocol analysis set will be flagged.  
 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
Study Population 
A summary of analysis sets by treatment will be presented along with percentages relative to the 
mITT Analysis Set.  
• All Screened 
• Randomized 
• mITT Analysis Set 
• Safety Analysis Set 
• Per-protocol Analysis Set 
A listing will be provided to describe when informed consent was obtained and if the subject meets 
all inclusion/exclusion criteria. Reasons of subjects’ exclusion from safety, mITT or PP analysis sets 
will also be listed. 
 
5.2. 
Subject Disposition  
The number and percentage of subjects will be tabulated for the mITT analysis set by treatment:  
• Subjects who are ongoing  
• Subjects who completed the study 
• Subjects who ended study early 
Reasons for early study discontinuation will be summarized with the following categories: 
• Adverse event 
• Lost to follow-up 
• Death 
• Physician decision 
• Site terminated by sponsor 
• Study terminated by sponsor 
• Technical problem 
• Withdrawal by subject 
• Other 
A listing will be presented to describe whether the subject is on study, completed the study, date of 
completion or early withdrawal, and the reason for early study discontinuation.  
 
5.3. 
Demographics and Baseline Disease Characteristics and History 
5.3.1. 
Demographics 
Demographic and other baseline characteristics will be summarized for each treatment group and 
overall based on the mITT analysis set. They will also be presented in by-subject listings. For 
categorical variables, missing category will be added when at least 1 subject does not have value. 


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Demographic descriptive statistics will be provided for the following: 
• Age  
• Weight (kg) 
• Height (cm)  
• Body mass index (BMI) (kg/m2) 
Demographic frequency tabulations will be presented for: 
• Age (< 65 years or ≥ 65 years)  
• Sex (Male or Female) 
• Childbearing potential of female (Yes or No) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or Other Pacific Islander, White, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Stated, Unknown) 
5.3.2. 
Baseline Disease Characteristics 
Baseline characteristics frequency tabulations will be summarized by the CRF categories, which are 
detailed below:  
• Randomization strata from IWRS:  use of approved standard antiretroviral therapy (Yes or 
No), age (< 65 years or ≥ 65 years), ARDS status (normal – mild or moderate-severe, for 
cohort 1 only)  
• Actual randomization strata based on the baseline information 
• Covid-19 symptom history findings (fever, fatigue, cough (productive), cough (non-
productive), anorexia, malaise, muscle pain, sore throat, dyspnea, nasal congestion, headache, 
diarrhea, nausea, vomiting, pneumonia, loss of taste, loss of smell, other) 
• Tuberculosis (negative, positive, indeterminate) 
• NIAID 8-point ordinal scale 
• Receiving invasive ventilation  
− No 
− Yes (mode of ventilation at time of highest FiO2 requirement) 
• Receiving non-invasive ventilation OR high flow nasal cannula? 
− No 
− Yes (mode of ventilation) 
• Receiving supplemental oxygen  
− No 
− Yes (delivery method) 
− Other 
• Required any other oxygen delivery methods since last assessment 
o No 
o Yes (modalities) 
o Unknown 


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• Currently requiring or since last assessment has required prone positioning  
• Currently requiring or since last assessment has required neuromuscular blockade 
• Currently requiring or since last assessment has required pulmonary vasodilators  
• Currently have or since last assessment had tracheostomy 
• Currently requiring or since last assessment has required ECMO 
• Currently requiring or since last assessment has required vasopressor support 
• Currently requiring or since last assessment has required renal replacement therapy 
• SARS-CoV-2 (RT-PCR) (negative, positive, indeterminate) 
• Anti-2019-nCoV (negative, positive or not test/missing)  
Continuous variables collected on respiratory and clinical assessment eCRF page will be summarized 
descriptively as appropriate. 
5.3.3. 
SOFA and qSOFA 
Sequential Organ Failure Assessment Score (SOFA) at baseline will be summarized for Cohort 2. 
• Descriptive statistics will be provided for the following: 
− PaO2 (mmHg) 
− FiO2 (%) 
− P/F Ratio 
− SOFA Score 
• Frequency tabulations will be presented for: 
− assessment performed (No (in ICU, Other) or Yes) 
− on mechanical ventilation (No or Yes) 
− platelets (x 10^3/uL) (≥ 150, 100-149, 50-99, 20-49, or <20) 
− Glasgow coma scale (15, 13-14, 10-12, 6-9, or <6) 
− bilirubin (mg/dl (umol/L)) (<1.2 (<20)), 1.2 - 1.9 (20 - 32), 2.0 - 5.9 (33 - 101), 6.0 - 
11.9 (102 - 204), or ≥12.0(≥204)) 
− mean arterial pressure OR administration of vasoactive agents required (Blood 
pressure stable without need for pressor support, MAP less than 70 mmHg, (Dopamine 
<=5 mcg/kg/min or Dobutamine), (Dopamine >5 mcg/kg/min, Epinephrine <=0.1 
mcg/kg/min, or nor Epinephrine <=0.1 mcg/kg/min), or (Dopamine >15 mcg/kg/min, 
Epinephrine >0.1 mcg/kg/min, or nor Epinephrine >0.1 mcg/kg/min)) 
− creatinine (mg/dL) (umol/L) (or urine output) (<1.2 (<110)), 1.2 - 1.9 (110 - 170), 2.0 - 
3.4 (171 - 299), 3.5 - 4.9 (300 - 440), or 5.0 mL/day<=UOP<500 mL/day (>440))  
Quick Sequential Organ Failure Assessment (qSOFA) at baseline will be tabulated for Cohort 1: 
− qSOFA Score  
− assessment performed (No (Invasive/noninvasive ventilation, Other) or Yes) 
− respiration rate >=22 breaths/min (No or Yes) 


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− change in mental status (glascow score less than 15) (No or Yes) 
− systolic blood pressure less than or equal to 100 mm/Hg (No or Yes) 
By subject SOFA and qSOFA will be listed. 
5.4. 
Medical History 
Medical history data will be summarized by system organ class (SOC) and preferred term (PT) per 
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 based on the safety analysis 
set. Subjects with multiple events coded to the same SOC or PT will only be counted once in the 
summary for that category. 
All medical history data will be listed. 
 
5.5. 
Prior and Concomitant Medications 
Prior medications are defined as those taken before the date of the study drug.  Concomitant 
medications are defined as any non-study medication taken during the study i.e. on or after the date of 
the study drug and within 90 days of the study drug treatment.  
The number and percentage of subjects taking prior and concomitant medications will be tabulated 
separately by anatomical-therapeutic-chemical (ATC) level 2 and preferred drug name by treatment 
for the safety analysis set. A subject taking the same medication multiple times is counted only once 
under that preferred drug name. The summary will be sorted in the alphabetic order of ATC classes 
and preferred terms. 
Prior and concomitant medications will be listed with flag. 
Medications are coded using the World Health Organization (WHO) Drug dictionary B3 enhanced, 
version Mar 2020. 
 
5.6. 
Study Treatments and Extent of Exposure 
Study drug exposure will be summarized descriptively by treatment for the safety analysis set: 
• Duration of infusion (minutes) 
• Received the full injection volume (Yes or No) 
• Infusion interrupted (Yes or No) 
− Reasons for infusion interruption (Adverse event, Technical Issue, Other) 
• Infusion resumed (Yes or No) 
The study drug administration details including the administration date and time will be presented in a 
by-subject listing.  
 
5.7. 
Efficacy Analysis 
All efficacy endpoints will be analyzed for the mITT analysis set.  The primary and secondary 
endpoints will also be performed for the Per-protocol analysis set. Treatment comparisons will be for 
each KPL301 arm vs placebo.  


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5.7.1. 
Multiplicity Adjustment 
No multiplicity adjustment will be applied for the Phase 2 part of the study.  
 
5.7.2. 
NIAID Scale and Missing Data Imputation for Binary Endpoints 
When two or more NIAID scores are collected on the same study day, the lowest score will be used, 
except at the date of discharge, in which the highest NIAID score will be used. 
 
Baseline NIAID scores are derived from Day 1 or screening assessment: 
• If screening and day 1 are the same day, and screening assessment is available, then the 
screening NIAID will be used as baseline. 
• If screening and day 1 are not on the same day, or screening NIAID assessment is missing, the 
score from Day 1 will be used as baseline.  
 
For endpoints where the event of interest is favorable, like proportion of subjects alive and free of 
ventilation, and proportion of subjects with 1-point/2-point clinical improvement, the following 
imputation rule of NIAID scale will be adopted: 
• When the NIAID assessment is missing at the target day (Day 15, 29, etc.), the NIAID score 
closest to and within 2 days of the target day will be used.  In case of ties with equal number 
of days on either side of target day, the value before the target day will be used. 
• When no NIAID assessment is available within 3 days of the target day, the primary treatment 
comparison will be based on a combination of responder imputation and non-responder 
imputation: 
− Discharged subjects will be considered as having had the event (responders). 
− Subjects who are still in the hospital will be considered as not having had the event 
(non-responders). 
− Subjects who terminate the study early including death will be considered as not 
having had the event for all subsequent target days after discontinuation (non-
responders). 
In calculation of the mortality rate, a subject with the last known alive date on or after the target day 
is considered alive. If the last known alive date is before the target day but within 2 days of the visit 
window, the subject is considered alive at the target day. Since survival sweep will be conducted for 
each database lock, minimum missing mortality status is expected. 
 
5.7.3. 
Censoring Rules for Time to Event Endpoints  
Since scheduled visits allow windows (2-day for Day 15 and Day 29, and 7-day for Day 60 and 90), 
NIAID scores collected within visit windows of the the target days will be used for time to event 
analysis by the corresponding target day. The last assessments referred to in this section include those 
occur after the target day but within the protocol-defined visit window, in which cases the date of the 
target day instead of the actual day will be used for calculation of time. For example, if a subject has 
not had 2-point clinical improvement by Day 29 visit, which occurrs on Day 30, the subject will be 
censored at Day 29 instead of Day 30 or Day 22 (the assessment before Day 29).  
• Time to ventilation or death by Day 29 
Defined as time (in days) from randomization to the date of death or start date of using 
mechanical ventilation (NIAID ≤ 2) by Day 29 for Cohort 1.  All subjects who have never had 








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An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and requires close monitoring and rapid communication 
by the investigator to the sponsor. An AESI may be serious or non-serious.  
The number of subjects with at least one TEAE will be tabulated. The following tables summarize 
incidences of various aspects of TEAEs, treatment-emergent serious AEs (TESAEs), and treatment-
emergent AESIs (TEAESIs):  
• Overview of TEAEs (summary of all the subsequent items) 
• TEAEs by SOC and PT 
• TEAEs by PT 
• TEAEs by maximum severity (mild, moderate, or severe) 
• Drug related TEAEs (related or not related) by SOC and PT 
• TESAEs by SOC and PT 
• Drug related TESAEs by SOC and PT 
• TESAEs by PT 
• TEAESIs by SOC and PT 
• TEAEs leading to dose interruption by SOC and PT 
• TEAEs leading to death by SOC and PT  
All information pertaining to adverse events will be listed by subject, detailing verbatim term given 
by the investigator, preferred term, system organ class, start date, stop date, severity, outcome, action 
taken and drug relatedness.  
Separate listings will be created for Serious TEAEs, and TEAESI, and death. 
Additionally, non-serious TEAEs by SOC and PT will be tabulated. 
 
5.8.2. 
Clinical Laboratory Parameters 
The following laboratory analyses are performed at the Study Site/Clinic laboratories and recorded on 
the eCRF: 
• Screening for tuberculosis  
• Pregnancy 
• SARS-CoV-2 test with RT-PCR  
• Hematology: complete blood count + differential  
• Chemistry: electrolytes, blood urea nitrogen, glucose, and CR  
• Liver profile: AST, ALT, Alb, AlkP, Tbili, Dbili  
• Lipid panel: Cholesterol, total; high-density lipoprotein (HDL) cholesterol; low-density 
lipoprotein (LDL) cholesterol (calculation); triglycerides; very low-density lipoprotein 
(VLDL) cholesterol (calculation)  
• Urinalysis  
• 
  


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The following tests are performed by the central lab: 
• 
 
 
 
 
  
Continuous laboratory data (
, hematology, coagulation, 
chemistry, liver profile, lipid panel, urinalysis) will be examined for trends using descriptive statistics 
of actual values and changes from baseline over time by treatment for the safety analysis set.  
Urinalysis will be summarized categorically.  
Shift tables will be produced for hematology and chemistry. 
All laboratory results will be presented in by-subject listings.  
 
5.8.3. 
Vital Signs 
Vital signs include temperature, respiratory rate, systolic blood pressure/ diastolic blood pressure, and 
heart rate. Body weight and height will be reported in Body Measurements eCRF. 
Actual values of vital signs (including weight) and changes from baseline will be summarized using 
descriptive statistics by visit.  
All vital signs data will be listed. 
 
5.8.4. 
Electrocardiogram (ECG) 
All ECG data will be listed. 
 
5.8.5. 
Physical Examination 
All physical examination data will be listed. 
 
5.8.6. 
Chest Imaging 
Chest imaging data will be listed. 
 
6. 
CHANGES TO PLANNED ANALYSES FROM THE PROTOCOL 
• The SAP is for Phase 2 only and a separate SAP will be developed for the Phase 3 part of the 
study 
• The following other efficacy endpoints are out of scope for this SAP, and will be reported 
separately 
o 
 
 




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• If either the year of partial date is before the year of the first dose date, or the years are the 
same, but the month of partial date is before the month of the first dose date then impute day 
as last day of the month 
• If either the year of partial date is after the year of the first dose date, or the years are the 
same, but the month of partial date is after the month of the first dose date, then impute day as 
first day of the month.  
Incomplete Stop Date: 
Missing day, month, and year 
• No imputation will be made. 
Missing day and month 
• If the year is the same as the year of the last dose date, then impute day and month as the day 
and month of the last dose date 
• If the year is prior to the year of the last dose date, then impute day and month as 31 Dec 
• If the year is after the year of last dose date, then impute day and month as 01 Jan. 
Missing day only 
• If the month and year are the same as those of the last dose date, then impute day as the day of 
the last dose date 
• If either the year of partial date is not the same as the year of the last dose date, or the years 
are the same, but the month of partial date is not the same as the month of the last dose date, 
then impute day as last day of the month.  
8.1.2. 
Concomitant Medication Date Imputation 
Follow the general rules specified in Section 8.1 and Section 8.1.1.