Clinical trial NCT04565249
Conditions: Acute Respiratory Distress Syndrome SARS-CoV-2
Sponsor: Pliant Therapeutics, Inc.
Start date: 2020-10-22; Completion date: 2021-08-02
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluation of the safety, tolerability, and pharmacokinetics of PLN-74809 in participants with acute respiratory distress syndrome (ARDS) associated with at least severe COVID-19

Detailed description:
Approximately 36 participants will be enrolled sequentially into 3 cohorts. Within each cohort of 12 participants, 9 will be randomized to PLN-74809 and 3 will be randomized to placebo (3:1 ratio).

* In Part 1, approximately 12 participants will be randomized to Dose level 1 of PLN-74809 or placebo QD
* In Part 2, approximately 12 participants will be randomized to Dose level 2 of PLN-74809 or placebo QD
* In Part 3, approximately 12 participants will be randomized to Dose level 3 of PLN-74809 or placebo QD

Arms: arm 1: Dose Level 1 of PLN-74809 arm 2: Dose Level 2 of PLN-74809 arm 3: Dose Level 3 of PLN-74809
Interventions: intervention 1: PLN-74809 intervention 2: Placebo
Intervention descriptions: intervention 1: PLN-74809 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
PLN-74809-ARDS-204, 23 October 2020, Protocol Amendment 2 
Page 1 
PLIANT 
I K(I.AP( UlfLt. 
Study Title: 
Study Number: 
Study Phase: 
Product Name: 
IND Number: 
EudraCT Number: 
Indication: 
Sponsor: 
Sponsor Study 
Director: 
Document ID 
Original Protocol 
Amendment 1 
Amendment 2 
Clinical Trial Protocol 
PLN-74809-ARDS-204 
A randomized, double-blind. dose-ranging, placebo controlled, Phase 2a 
evaluation of the safety. tolerability, and pharmacokinetics of PLN-74809 
in paiticipants with acute respiratory distress syndrome (ARDS) associated 
with at least severe COVID-19 (INTEGRIS-ARDS) 
PLN-74809-ARDS-204 
2a 
PLN-74809-000 
150,181 
Not applicable 
Treannent of acute respiratory distress syndrome (ARDS) associated with 
at least severe COVID-19 
Pliant Therapeutics Inc. 
2 60 Littlefield A venue 
South San Francisco, CA 94080, USA 
Date 
24 June 2020 
31 July 2020 
23 October 2020 
Confidentiality Statement 
This document is the property of Pliant Therapeutics. The confidential inf01mation in this document 
may not be used, published or disclosed without the prior written consent of Pliant Therapeutics 
except to the extent required under applicable laws or regulations. 
Proprietaiy and Confidential 
Pliant TI1erapeutics, Inc. 






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7.  Cli nical dia g n osis of A R D S, as defi ne d b y Berli n criteria, i ncl u di n g:   
a. C hest i ma gi n g (ra di o gra p h y or C T sca n): bilateral o pacities n ot f ull y e x plai ne d b y 
eff usi o ns, l o bar/l u n g c olla pse, or n o d ules  
b.  Ori gi n of e de ma: res pirat or y fail ure n ot f ull y e x plai ne d b y car diac fail ure or fl ui d 
o verl oa d  
c. Ac ute h y p o xe mia defi ne d b y partial press ure of arterial o x y ge n ( Pa O 2)/ fracti o n of 
i ns pire d o x y ge n ( Fi O2): 
i. Mil d h y p o xe mia: 2 0 0 m m H g < Pa O
2/ Fi O2 ≤ 3 0 0 m m H g wit h p ositi ve 
e n d-e x pirat or y press ure ( P E E P) or c o nti n u o us p ositi ve air wa y press ure 
( C P A P) ≥ 5 c m H 2O 
ii. M o derate h y p o xe mia: 1 0 0 m m H g < Pa O
2/ Fi O2 ≤ 2 0 0 m m H g wit h 
P E E P ≥ 5 c m H 2O 
iii. Se vere h y p o xe mia: Pa O 2/ Fi O2 ≤ 1 0 0 m m H g wit h P E E P ≥ 5 c m H 2O 
N ote : If a relia ble esti mati o n of Fi O2 is n ot p ossi ble i n n o n-ve ntilate d partici pa nts, t h ose 
meeti n g i ncl usi o n Criteria 9 a n d 1 0 will be eli gi ble if all ot her criteria are met.  
8.  T he ra di ol o gical a n d h y p o xe mia i ncl usi o n criteria (i.e., 7a a n d 7c) m ust be met wit hi n t he 
sa me 2 4-h o ur peri o d. T he t i me of o nset of A R D S is defi ne d as t he ti me w he n t hese 
t w o criteria are met.  
9.  Recei vi n g s u p p ort f or ac ute l u n g i nj ur y/res pirat or y distress via s u p ple me ntal o x y ge n (e. g., 
hi g h fl o w nasal ca n n ula [ H F N C], face mas k [i.e., n o n -re breat her]), n o n-i n vasi ve ve ntilati o n, 
or via i nt u bati o n a n d mec ha nical ve ntilati o n.  
Me dical Hist or y a n d C o m or bi d C o n diti o ns  
1 0.  H os pitalize d wit h at least se vere C O VI D -1 9 
) 
a. P ositi ve testi n g b y sta n dar d re verse tra nscri pti o n p ol y merase c hai n reacti o n 
( R T-P C R) assa y ( or a n e q ui vale nt C O VI D -1 9 test a ut h orize d u n der E U A)  
b.  S y m pt o ms s u g gesti ve of se vere s yste mic ill ness wit h C O VI D -1 9, w hic h c o ul d 
i ncl u de a n y s y m pt o m of m o derate ill ness or s h ort ness of breat h at rest, or res pirat or y 
distress  
c. Cli nical si g ns i n dicati ve of se vere s yste mic ill ness wit h C O VI D -1 9, s uc h as 
res pirat or y rate ≥ 3 0 per mi n ute, heart rate ≥ 1 2 5 per mi n ute, o x y ge n sat urati o n 
( S p O2) ≤ 9 3 % o n r o o m air at sea le vel or Pa O2/ Fi O2 < 3 0 0 m m H g  
1 1.  Ser u m as partate a mi n otra nsferase ( A S T) c o nce ntrati o n ≤ 1 2 0 U/ L a n d ser u m a la ni ne 
a mi n otra nsferase ( A L T) c o nce ntrati o n ≤ 1 5 0 U/ L (a p pr o xi matel y 3 ×  U L N f or b ot h 
para meters)  
1 2.  Ser u m t otal bilir u bi n ≤ 1. 8 m g/ d L, i n t he a bse nce of Gil bert's s y n dr o me or he m ol ysis.  
1 3.  Platelet c o u nt ≥1 2 0, 0 0 0/ m m 3 
1 4.  Al b u mi n ≥ 3. 3 g/ d L  
1 5.  I nter nati o nal n or malized rati o (I N R) ≤1. 5 i n t he a bse nce of a ntic oa g ula nt t hera p y or ot her 
c oa g ul o pat hies  






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• Bi o mar kers: plas ma a n d ser u m sa m ples will be o btai ne d.  
  
St atistic al Met h o ds:  
T his is a safet y a n d P K st u d y, wit h e x pl orat or y e n d p oi nts; as s uc h, n o statistical h y p ot heses are 
b ei n g teste d.  
I n ge neral, data will be s u m marize d usi n g statistical s u m mar y met h o ds; gra p hic prese ntati o ns of 
data ma y als o be pre pare d.  
 


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T A B L E O F C O N T E N T S  
S Y N O P SI S  ................................................................................................................................. 2 
T A B L E O F C O N T E N T S  ........................................................................................................... 8 
LI S T O F I N -T E X T T A B L E S  .................................................................................................. 1 1 
LI S T O F I N -T E X T FI G U R E S ................................................................................................. 1 1 
LI S T O F A P P E N DI C E S  .......................................................................................................... 1 1 
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  .......................................... 1 2 
1  
I N T R O D U C TI O N ................................................................................................. 1 5 
1. 1  
Bac k gr o u n d ...................................................................................................... 1 5  
1. 2  
S u m mar y of Cli nical De vel o p me nt  ................................................................. 1 7 
1. 3  
Rati o nale f or St u d y  .......................................................................................... 1 8 
1. 4  
Be nefit -Ris k Assess me nt  ................................................................................. 1 9 
2  
S T U D Y O BJ E C TI V E S  .......................................................................................... 2 1 
2. 1  
Pri mar y O bjecti ve  ............................................................................................ 2 1 
2. 2  
Sec o n dar y O bjecti ve  ........................................................................................ 2 1 
2. 3  
E x pl orat or y O bjecti ves  .................................................................................... 2 1 
3  
I N V E S TI G A TI O N A L P L A N ................................................................................ 2 2 
3. 1  
O verall St u d y Desi g n a n d Pla n ........................................................................ 2 2  
3. 2  
Rati o nale f or St u d y Desi g n a n d C o ntr ol Gr o u p ............................................... 2 3  
3. 3  
St u d y D urati o n ................................................................................................. 2 4  
4  
S T U D Y P O P U L A TI O N A N D S E L E C TI O N  ........................................................ 2 5 
4. 1  
St u d y P o p ulati o n .............................................................................................. 2 5  
4. 1. 1  
I ncl usi o n Criteria ................................................................................. 2 5 
4. 1. 2  
E xcl usi o n Criteria  ................................................................................ 2 7 
5  
S T U D Y D R U G A N D A C C O U N T A BI LI T Y  ........................................................ 2 9 
5. 1  
Descri pti o n of St u d y Dr u g ............................................................................... 2 9  
5. 1. 1  
P L N - 7 4 8 0 9 ........................................................................................... 2 9 
5. 1. 2  
Place b o  ................................................................................................. 2 9 
5. 2  
Pac ka gi n g a n d La beli n g ................................................................................... 2 9  
5. 3  
St ora ge a n d Acc o u nta bilit y  .............................................................................. 2 9 
5. 4  
Treat me nt C o m plia nce  ..................................................................................... 2 9 
6  
S T U D Y T R E A T M E N T S  ....................................................................................... 3 0 
6. 1  
Descri pti o n of Treat me nts  ................................................................................ 3 0 
6. 2  
D ose M o dificati o ns a n d I nterr u pti o ns ............................................................. 3 0  
6. 3  
Selecti o n a n d Ti mi n g of D ose f or Eac h Partici pa nt ......................................... 3 0  
6. 4  
Met h o d of Assi g ni n g Partici pa nts t o Treat me nt Gr o u ps ................................. 3 0  
6. 5  
Bli n di n g............................................................................................................ 3 0  
6. 6  
C o nc o mita nt T hera p y....................................................................................... 3 1  


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6. 6. 1  
All o we d Me dicati o ns ........................................................................... 3 1  
6. 6. 2  
Disall o we d Me dicati o ns ....................................................................... 3 3 
6. 7  
Restricti o ns  ...................................................................................................... 3 4 
6. 7. 1  
Pri or T her a p y ....................................................................................... 3 4 
6. 7. 2  
Fl ui d a n d F o o d I nta ke .......................................................................... 3 4  
6. 7. 3  
Partici pa nt Acti vit y Restricti o ns  .......................................................... 3 4 
6. 7. 4  
C o ntrace pti o n ....................................................................................... 3 4  
7  
S T U D Y P R O C E D U R E S  ....................................................................................... 3 6 
7. 1  
I nf or me d C o nse nt............................................................................................. 3 6 
7. 2  
I ncl usi o n/ E xcl usi o n Criteria ............................................................................ 3 6 
7. 3  
De m o gra p hic I nf or mati o n  ................................................................................ 3 6 
7. 4  
Me dical Hist or y  ............................................................................................... 3 6 
7. 5  
Hei g ht a n d Wei g ht ........................................................................................... 3 6  
7. 6  
E x pl orat or y Efficac y Assess me nts  .................................................................. 3 7 
7. 6. 1  
 ............................................................................... 3 7 
7. 6. 2  
 ................................................. 3 7 
7. 6. 3  
 ................................... 3 7 
7. 7  
Pri or a n d C o nc o mita nt Me dicati o n Assess me nts  ............................................ 3 7 
7. 8  
P h ysical E xa mi nati o ns  ..................................................................................... 3 7 
7. 9  
Vital Si g ns  ........................................................................................................ 3 8 
7. 1 0  
 .......................................................................................... 3 8 
7. 1 1  
Cli ni cal La b orat or y Tests  ................................................................................. 3 8 
7. 1 1. 1  
La b orat or y Para meters  ......................................................................... 3 8 
7. 1 1. 2  
Sa m ple C ollecti o n, St ora ge, a n d S hi p pi n g .......................................... 4 0  
7. 1 2  
A d verse E ve nt Assess me nts  ............................................................................ 4 0 
7. 1 3  
P har mac o ki netic Assess me nts  ......................................................................... 4 0 
7. 1 4  
P har mac o d y na mic Assess me nts  ...................................................................... 4 1 
7. 1 5  
Dis pe nsi n g St u d y Dr u g  .................................................................................... 4 2 
7. 1 6  
Misse d Assess me nts ......................................................................................... 4 2 
7. 1 7  
A p pr o priate ness of Meas ure me nts  ................................................................... 4 2 
8  
A D V E R S E E V E N T S  ............................................................................................. 4 3 
8. 1  
Ti mi n g  .............................................................................................................. 4 3 
8. 2  
Defi niti o n of a n A d verse E ve nt ....................................................................... 4 3  
8. 3  
Se verit y of a n A d verse E ve nt .......................................................................... 4 4  
8. 4  
Ca usal Relati o ns hi p of a n A d verse E ve nt ........................................................ 4 4  
8. 5  
O utc o me ........................................................................................................... 4 5  
8. 6  
Pre g na nc y ......................................................................................................... 4 5  
8. 7  
Cli nical La b orat or y A d verse E ve nts  ................................................................ 4 5 






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Plia nt T hera pe utics, I nc.  
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
A A G  
al p ha- 1 aci d gl yc o pr otei n  
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase  
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  
A U C 0- 2 4 
area u n der t he plas ma c o nce ntrati o n- ti me c ur ve fr o m ti me zer o t o 2 4 
h o urs  
 
 
B A L F  
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 O VI D -1 9  
c or o na vir us disease  
C P A P  
c o nti n u o us p ositi ve air wa y press ure  
C R O  
c o ntract researc h or ga nizati o n  
C T  
c o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
 
 
D DI  
dr u g- dr u g i nteracti o n  
 
 
D S M B  
Data Safet y M o nit ori n g B oar d  
 
 
e C R F  
electr o nic case re p ort f or m  
E C L S  
e xtrac or p oreal life s u p p ort 
E C M O  
e xtrac or p oreal me m bra ne o x y ge nati o n 
E D C  
electr o nic data ca pt ure  
E o T  
e n d of treat me nt 
E T  
earl y ter mi nati o n 
E U A  
E mer ge nc y Use A ut h orizati o n ( b y t he F D A) 


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F A C T T  
Fl ui ds a n d Cat heters Treat me nt Trial  
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
Fi O 2 
fracti o n of i ns pire d o x y ge n 
F S H  
f ollicle-sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practice  
G D P R  
Ge neral Data Pr otecti o n Re g ulati o n  
H F N C  
hi g h fl o w nasal ca n n ula 
H F O V  
hi g h -fre q ue nc y oscillat or y ve ntilati o n 
HI P A A  
Healt h I nf or mati o n P orta bilit y a n d Acc o u nta bilit y Act 
I C5 0, I C8 0 
5 0 %, 8 0 % i n hi bit or y c o nce ntrati o n  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce 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 L 
i nterle u ki n 
I N R 
i nter nati o nal n or malize d rati o 
I P F 
i di o pat hic p ul m o nar y fi br osis 
I R B 
i nstit uti o nal re vie w b oar d 
L A P  
late nc y-ass ociate d pe pti de  
M A T E 1  
m ulti dr u g t o xi n e xtr usi o n tra ns p orter 1  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M E R S  
Mi d dle East Res pirat or y S y n dr o me  
N E  
nas oe nteric  
N G  
nas o gastric  
 
 
 
 
 
 
Pa C O 2 
partial press ure of arterial car b o n di o xi de  
Pa O 2 
partial press ure of arterial o x y ge n  


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P D  
p har mac o d y na mics(s) 
P E E P  
p ositi ve e n d- e x pirat or y press ure  
PI P E D A  
Pers o n nel I nf or mati o n Pr otecti o n a n d Electr o nic D oc u me nts Act  
P K  
p har mac o ki netic(s) 
P P B  
plas ma -pr otei n bi n di n g  
P S C  
pri mar y scler osi n g c h ola n gitis  
Q D  
o nce dail y 
 
 
R E B  
researc h et hics b oar d 
R T -P C R  
re verse tra nscri pti o n p ol y merase c hai n reacti o n 
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  
Se vere Ac ute Res pirat or y S y n dr o me  
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 M A  
s m o ot h m uscle a nti b o d y 
S M A D  
fa mil y of pr otei ns si milar t o t he ge ne pr o d ucts of t he Dr os o p hila ge ne 
' m ot hers a gai nst deca pe nta ple gic' (M a d ) a n d t he C. ele g a ns  ge ne S m a  
 
 
S p O 2 
o x y ge n sat urati o n  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T G F -β  
tra nsf or mi n g gr o wt h fact or-beta  
U L N  
u p per li mit of n or mal  
W H O  
W orl d Healt h Or ga nizati o n 
 


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1  
I N T R O D U C TI O N 
1. 1  
B ac k gr o u n d 
Dise ase B ac k gr o u n d 
Plia nt T hera pe utics, I nc. ( Plia nt) is de vel o pi n g P L N - 7 4 8 0 9-0 0 0 ( hereafter referre d t o as 
P L N - 7 4 8 0 9) f or t he treat ment of ac ute res pirat or y distress s y n dr o me ( A R D S) ass ociate d wit h 
at least se vere c or o na vir us disease ( C O VI D -1 9). A R D S is a maj or ca use of m ortalit y i n 
patie nts i nfecte d wit h 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), 
w hic h ca uses C O VI D - 1 9. I nfecti o n b y S A R S- C o V-2 ca n ca use a ra n ge of s y m pt o ms fr o m 
mil d fe ver a n d c o u g h t o se vere res pirat or y ill ness, i ncl u di n g A R D S, res pirat or y fail ure a n d 
deat h. A R D S is c haracterize d b y persiste nt p ul m o nar y e de ma w hic h is a res ult of i m paire d 
fl ui d a n d i o n tra ns p ort i n t he al ve olar s pace. 
I n a rece nt st u d y of 2 0 1 patie nts wit h c o nfir me d C O VI D-1 9 p ne u m o nia h os pitalize d at 
Ji n yi nta n H os pital i n W u ha n ( C hi na), ris k fact ors ass ociate d wit h t he de vel o p me nt of A R D S 
a n d pr o gressi o n fr o m A R D S t o deat h i ncl u de d ol der a ge, ne utr o p hilia, a n d or ga n a n d 
c oa g ulati o n d ysf u ncti o n (
). I n t his st u d y, t he me dia n a ge of patie nts was 5 1 years 
a n d 6 3. 7 % patie nts were me n. Ei g ht y-f o ur patie nts ( 4 1. 8 %) we nt o n t o de vel o p A R D S, a n d 
of t h ose 8 4 patie nts, 4 4 ( 5 2. 4 %) die d.  
I n a n o bser vati o nal data base i ncl u di n g 8 9 1 0 patie nts fr o m 1 6 9 h os pitals i n Asia, E ur o pe, a n d 
N ort h A merica, t he relati o ns hi p bet wee n car di o vasc ular disease a n d i n - h os pital deat h a m o n g 
h os pitalize d patie nts wit h C O VI D -1 9 was e val uate d.  T his i n vesti gati o n c o nfir me d pre vi o us 
re p orts of t he i n de pe n de nt relati o ns hi p of ol der a ge, u n derl yi n g car di o vasc ular disease 
(c or o nar y arter y disease, heart fail ure, a n d car diac arr h yt h mias), c urre nt s m o ki n g, a n d 
c hr o nic o bstr ucti ve p ul m o nar y disease wit h deat h d ue t o C O VI D- 1 9 (
). Alt h o u g h 
t he m ortalit y rate i n patie nts wit h A R D S a n d C O VI D- 1 9 was n ot re p orte d i n t his a nal ysis, 
ol der a ge a n d c o m or bi dities c o nti n ue t o be str o n gl y ass ociate d wit h i ncrease d ris k of deat h.  
Av ail a ble A R D S/ C O VI D - 1 9 T her a pies 
Vari o us s u p p orti ve t hera pies ha ve bee n f o u n d t o re d uce m ortalit y i n patie nts wit h A R D S; 
h o we ver, m ortalit y re mai ns hi g h at 2 0 % t o 4 0 % (
 
). Effecti ve s u p p orti ve t hera pies are l u n g- pr otecti ve mec ha nical ve ntilati o n a n d 
a fl ui d c o nser vati ve strate g y, al o n gsi de ne ur o m usc ular bl oc ka de a n d pr o ne p ositi o ni n g i n 
m o re se vere cases. L u n g- pr otecti ve ve ntilati o n, usi n g a ti dal v ol u me of 6 m L per k g of 
pre dicte d b o d y wei g ht a n d a platea u air wa y press ure of < 3 0 c m H 2O, has ha d a maj or effect 
i n re d uci n g m ortalit y fr o m A R D S. Ne ur o m usc ular bl oc ka de a n d pr o ne p ositi o ni n g ha ve 
f urt her re d uce d m ortalit y i n m ore se verel y h y p o xe mic A R D S patie nts; pr o ba bl y b y e xte n di n g 
t he t hera pe utic effects of l u n g pr otecti ve ve ntilati o n. I n a d diti o n, fl ui d-c o nser vati ve t hera p y 
has i ncrease d ve ntilat or -free da ys.  


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 1 6  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
H o we ver, n o effecti ve p har mac ol o gical t hera pies ha ve bee n f o u n d t o i m pr o ve cli nical 
o utc o me i n A R D S (
). T he lac k of a vaila bilit y of dr u gs t o treat 
A R D S re mai ns a si g nifica nt me dical c halle n ge. Ma n y l ar ge m ultice nter cli nical trials wit h 
vari o us dr u g t hera pies, i ncl u di n g gl uc oc ortic oi ds ( met h yl pre d nis ol o ne), nitric o xi de, 
s urfacta nt, β2-a g o nists, stati ns (si m vastati n a n d r os u vastati n), a nti o xi da nts, ket oc o naz ole, 
lis of ylli ne, o me ga 3 s u p ple me ntati o n, acti vate d pr otei n C, li p os o mal pr osta gla n di n, 
gra n ul oc yte- macr o p ha ge sti m ulati n g fact or, si velestat, a n d fact or VIIai, ha ve faile d t o s h o w 
a n y clear be nefit.  
O ne p har mac ol o gical i nter ve nti o n has bee n all o we d u n der E mer ge nc y Use A ut h orizati o n 
( E U A) b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A): re m desi vir, f or treat me nt of s us pecte d 
or la b orat or y c o nfir me d C O VI D- 1 9 i n a d ults a n d c hil dre n h os pitalize d wit h se vere disease. 
P at h o p hysi ol o gy of A R D S 
A R D S is c haracterize d b y persiste nt p ul m o nar y e de ma, w hic h is a res ult of i m paire d fl ui d 
a n d i o n tra ns p ort i n t he al ve olar s pace. Tra nsf or mi n g gr o wt h fact or beta ( T G F- β) is a 
pl uri p ote nt c yt o ki ne wit h esta blis he d r oles i n A R D S a n d p ul m o nar y fi br osis (
 
). T G F-β le vels are si g nifica ntl y i ncrease d i n l u n g tiss ue a n d 
br o nc h oal ve olar la va ge fl ui d ( B A L F) fr o m A R D S patie nts a n d T G F -β is i m plicate d i n earl y 
l u n g i nj ur y as well as pr o m oti o n of t he fi br o pr oliferati ve p hase of A R D S (
 
). T hr o m bi n as well as i nterle u ki n (I L)-1 β, earl y me diat ors of ac ute l u n g i nj ur y, 
acti vate T G F -β i n a n α vβ 6 i nte gri n-s pecific ma n ner, pr o m oti n g e pit helial da ma ge, al ve olar 
lea k a n d c olla ge n s y nt hesis a n d fi br osis (
).  
I nte gri n αvβ 6, e x presse d o n l u n g e pit helial cells, bi n ds t o t he ar gi ni ne-gl yci ne -as partate 
se q ue nce of late nc y-ass ociate d pe pti de ( L A P) a n d u p o n sti m ulati o n b y a variet y of si g nals 
(e. g. pr otei nase-acti vate d rece pt or -1 a n d l ys o p h os p hati dic aci d) releases T G F -β fr o m t he 
late nt c o m ple x a n d i nitiates T G F-β dri ve n pr ocesses (
). I n t he l u n g, αvβ 6 is t he 
ke y re g ulat or of T G F- β acti vit y (
). I n healt h y l u n gs, αvβ 6 is e x presse d at l o w 
le vels a n d pri maril y f u ncti o ns t o s u p press al ve olar macr o p ha ge activati o n. I n l u n g i nj ur y i n 
mice a n d h u ma ns, t he e x pressi o n of α vβ 6 o n e pit helial cells a n d acti vati o n of T G F -β is 
dra maticall y i ncrease d a n d T G F -β dri ve n tiss ue i nj ur y a n d re pair effects d o mi nate w hile a nti -
i nfla m mat or y effects are o verc o me b y ot her pr o-i nfla m mat or y me diat ors. I n a d ults, αvβ 6 
e x pressi o n is li mite d t o e pit helial cells a n d is e x presse d at l o w le vels i n healt h y tiss ues, 
s u g gesti n g t hat p har mac ol o gical i n hi biti o n of α vβ 6 ma y pr o vi de a tiss ue-tar gete d a n d 
p ote ntiall y safer a p pr oac h f or T G F- β i n hi biti o n. 
Si milarl y, i nte gri n α vβ 1 is e x presse d b y l u n g fi br o blasts a n d, li ke αvβ 6 o n e pit helial cells, 
re g ulates T G F-β acti vit y t hr o u g h bi n di n g t o L A P a n d release of acti ve T G F -β (
). 
P har mac ol o gical i n hi biti o n of α vβ 1 atte n uates fi br osis i n t he ble o m yci n m o use m o del of 
p ul m o nar y fi br osis (
), i m plicati n g αvβ 1 i n T G F-β - dri ve n l u n g i nj ur y. I n A R D S a 
s u bset of patie nts de vel o p fi br otic disease t hat res ults i n re d uce d l u n g f u ncti o n after rec o ver y 
fr o m ac ute i nj ur y, i ncl u di n g a p pr o xi matel y 3 0 % of Mi d dle East Res pirat or y S y n dr o me 
( M E R S) a n d Se vere Ac ute Res pirat or y S y n dr o me ( S A R S) s ur vi v ors (
). W hile it 
is t o o earl y t o k n o w t he l o n g ter m i m pact of C O VI D- 1 9 A R D S o n l u n g healt h a n d f u ncti o n 


















P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
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Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
4  
S T U D Y P O P U L A TI O N A N D S E L E C TI O N  
4. 1  
St u d y P o p ul ati o n  
Partici pa nts wit h A R D S ass ociate d wit h at least se vere C O VI D - 1 9 w h o meet wit h t he 
f oll o wi n g eli gi bilit y criteria ma y be e nr olle d. 
Treat me nt wit h i n vesti gati o nal C O VI D - 1 9 t hera pies a vaila ble u n der E U A b y t he F D A a n d/ or 
off-la bel use of a n y ot her dr u gs, de vices, or i nter ve nti o ns t hat mi g ht be use d t o ma na ge 
C O VI D - 1 9 ma y be all o we d, pe n di n g re vie w a n d a p pr o val b y t he Me dical M o nit or a n d 
S p o ns or St u d y Direct or. 
4. 1. 1  
I ncl usi o n Criteri a 
Eac h partici pa nt m ust meet al l t he f oll o wi n g criteria t o be e nr olle d i n t he st u d y. 
Ge neral a n d A d mi nistrati ve  
1.  A ges 1 8 years a n d ol der. 
2.  A ble t o pr o vi de c o nse nt eit her o n t heir o w n be half or t hr o u g h a le gall y a ut h orize d 
re prese ntati ve. 
3.  Fe male partici pa nts of c hil d beari n g p ote ntial ( o v ul ati n g or pre me n o pa usal a n d n ot 
s ur gicall y sterile) a n d male partici pa nts wit h se x ual part ners of c hil d beari n g p ote ntial 
m ust a gree t o use hi g hl y effecti ve met h o ds of birt h c o ntr ol d uri n g t heir partici pati o n i n 
t he st u d y a n d f or 3 0 da ys f or fe male partici pa nts a n d 9 0 da ys f or male partici pa nts a n d 
fe male part ners of male partici pa nts after t he last a d mi nistrati o n of st u d y dr u g. Hi g hl y 
effecti ve met h o ds of birt h c o ntr ol are defi ne d as t h ose wit h 9 9 % or greater efficac y (see 
Secti o n  6. 7. 4 ). 
4.  Fe male partici pa nts of n o nc hil d beari n g p ote ntial m ust be eit her s ur gicall y sterile ( defi ne d 
as h ysterect o m y, bilateral t u bal li gati o n, sal pi n gect o m y a n d/ or bilateral o o p h orect o m y at 
least 6 m o nt hs pri or t o scree ni n g) or p ost me n o pa usal ( defi ne d as 1 2 m o nt hs of 
s p o nta ne o us a me n orr hea wit h o ut a n alter nati ve me dical ca use or 6 m o nt hs of 
s p o nta ne o us a me n orr hea wit h ser u m f ollicle-sti m ulati n g h or m o ne [ F S H] le vels 
> 4 0 mI U/ m L)  
5.   A gree t o a bstai n fr o m s per m or e g g d o nati o n t hr o u g h 9 0 da ys or 3 0 da ys, res pecti vel y, 
after a d mi nistrati o n of t he last d ose of st u d y dr u g.  
6.   
 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
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Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
A R D S Dia g n osis  
7.  Cli nical dia g n osi s of A R D S, as defi ne d b y Berli n criteria (refer t o A p pe n di x 2 ), 
i ncl u di n g:  
a. C hest i ma gi n g (ra di o gra p h y or C T sca n) : bilateral o pacities n ot f ull y e x plai ne d b y 
eff usi o ns, l o bar/l u n g c olla pse, or n o d ules 
b.  Ori gi n of e de ma: res pirat or y fail ure n ot f ull y e x plai ne d b y car diac fail ure or fl ui d 
o verl oa d 
c. Ac ute h y p o xe mia defi ne d b y p artial press ure of arterial o x y ge n ( Pa O 2)/ fracti o n 
of i ns pire d o x y ge n ( Fi O 2): 
i. Mil d h y p o xe mia: 2 0 0 m m H g < Pa O
2/ Fi O2 ≤ 3 0 0 m m H g wit h 
p ositi ve e n d-e x pirat or y press ure ( P E E P) or c o nti n u o us p ositi ve air wa y 
press ure ( C P A P) ≥ 5 c m H 2O 
ii. M o derate h y p o xe mia: 1 0 0 m m H g < Pa O
2/ Fi O2 ≤ 2 0 0 m m H g wit h 
P E E P ≥5 c m H 2O 
iii. Se vere h y p o xe mia: Pa O 2/ Fi O2 ≤ 1 0 0 m m H g wit h P E E P ≥ 5 c m H 2O 
N ote : If a relia ble esti mati o n of Fi O2 is n ot p ossi ble i n n o n- ve ntilate d partici pa nts, t h ose 
meeti n g i ncl usi o n Criteria 9 a n d 1 0 will be eli gi ble if all ot her criteria are met.  
8.  T he ra di ol o gical a n d h y p o xe mia i ncl usi o n criter ia (i.e., 7a a n d 7c) m ust be met wit hi n t he 
sa me 2 4- h o ur peri o d. T he ti me of o nset of A R D S is defi ne d as t he ti me w he n t hese 
t w o criteria are met. 
9.  Recei vi n g s u p p ort f or ac ute l u n g i nj ur y/res pirat or y distress via s u p ple me ntal o x y ge n 
(e. g., hi g h fl o w nasal ca n n ula [ H F N C], face mas k [i.e., n o n-re breat her]), n o n-i n vasi ve 
ve ntilati o n, or via i nt u bati o n a n d mec ha nical ve ntilati o n.  
Me dical Hist or y a n d C o m or bi d C o n diti o ns 
1 0.  H os pitalize d wit h at least se vere C O VI D - 1 9 (
) 
a. P ositi ve testi n g b y sta n dar d re ve rse tra nscri pti o n p ol y merase c hai n reacti o n 
( R T-P C R) assa y ( or a n e q ui vale nt C O VI D - 1 9 test a ut h orize d u n der E U A) 
b.  S y m pt o ms s u g gesti ve of se vere s yste mic ill ness wit h C O VI D - 1 9, w hic h c o ul d 
i ncl u de a n y s y m pt o m of m o derate ill ness or s h ort ness of breat h at rest, or 
res pirat or y distress  
c. Cli nical si g ns i n dicati ve of se vere s yste mic ill ness wit h C O VI D - 1 9, s uc h as 
res pirat or y rate ≥ 3 0 per mi n ute, heart rate ≥ 1 2 5 per mi n ute, o x y ge n sat urati o n 
( S p O2) ≤ 9 3 % o n r o o m air at sea le vel or Pa O2/ Fi O2 < 3 0 0 m m H g 
1 1.  Ser u m as partate a mi n otra nsferase ( A S T) c o nce ntrati o n ≤ 1 2 0 U/ L a n d ser u m ala ni ne 
a mi n otra nsferase ( A L T) c o nce ntrati o n ≤ 1 5 0 U/ L (a p pr o xi matel y 3 × U L N f or b ot h 
para meters)  
1 2.  Ser u m t otal bilir u bi n ≤ 1. 8 m g/ d L, i n t he a bse nce of Gil bert's s y n dr o me or he m ol ysis  


















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Plia nt T hera pe utics, I nc.  
 
- 
Oral h or m o nal c o ntrace pti ves wit h less t ha n 1 year of use i n c o nj u ncti o n wit h 
c o n d o m 
• Se x ual part ner wit h s ur gical sterilizati o n (e. g., vasect o m y, t u bal li gati o n, h ysterect o m y 
a n d/ or bilateral o o p h orect o m y)  
Fe male partici pa nts w h o are usi n g h or m o nal c o ntrace pti ves m ust ha ve bee n usi n g t he 
h or m o nal c o ntrace pti ve f or at least 1 2  wee ks  bef ore scree ni n g. Partici pa nts m ust a gree t o 
a bstai n fr o m s per m or e g g d o nati o n f or at least 9 0  da ys or 3 0 da ys, res pecti vel y, after 
a d mi nistrati o n of t he last d ose of st u d y dr u g. 








P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 3 9  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
T a ble  2.  
L a b or at or y Tests, as Liste d, or per L oc al St a n d ar ds 
He m at ol o g y  
Ser u m C he mistr y  
- 
He mat ocrit ( Hct)  
- 
He m o gl o bi n ( H g b)  
- 
Mea n c or p usc ular he m o gl o bi n ( M C H)  
- 
Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n ( M C H C)  
- 
Mea n c or p usc ular v ol u me ( M C V)  
- 
Platelet c o u nt  
- 
Re d bl o o d cell ( R B C) c o u nt  
- 
W hite bl o o d cell ( W B C) c o u nt wit h 
differe ntial  
- 
Ala ni ne a mi n otra nsferase ( A L T)  
- 
Al b u mi n ( A L B)  
- 
Al kali n e p h os p hatase ( A L P)  
- 
Al p ha - 1-aci d-gl uc o pr otei n ( A A G)  
- 
A m ylase (refle x li pase if a m ylase 
≥1. 5  × U L N)  
- 
As partate a mi n otra nsferase ( A S T)  
- 
Bilir u bi n (t otal a n d direct)  
- 
Bl o o d urea nitr o ge n ( B U N)  
- 
Calci u m ( Ca)  
- 
C hl ori de ( Cl)  
- 
Creati ni ne  
- 
Creati ne ki nase ( C K)  
- 
Ga m ma -gl uta m yl tra nsferase ( G G T)  
- 
Gl o b uli n  
- 
Gl uc ose  
- 
Lactate de h y dr o ge nase ( L D H)  
- 
P h os p h or us ( P)  
- 
P otassi u m ( K)  
- 
S o di u m ( Na)  
- 
T otal pr otei n  
- 
T otal c h olester ol  
- 
Tri gl yceri des  
- 
Tr o p o ni ns  
- 
Uric aci d  
C o a g ul ati o n  
- 
I nter nati o nal n or malize d rati o (I N R) 
Uri n al ysis  
- 
A p peara nce  
- 
Bilir u bi n  
- 
C ol or  
- 
Gl uc ose  
- 
Ket o nes  
- 
Micr osc o pic e xa mi nati o n of se di me nt  
- 
Nitrite  
- 
Occ ult bl o o d  
- 
p H  
- 
Pr otei n  
- 
S pecific gra vit y  
- 
Ur o bili n o ge n  
Ot her  
Scree ni n g O nl y  
- 
Ser u m h u ma n c h ori o nic g o na d otr o pi n 
( h C G) (fe males) 
- 
F ollicle -sti m ulati n g h or m o ne ( F S H) –  
t o c o nfir m p ost me n o pa usal stat us 
- 
He patitis A I g M a nti b o d y ( H A V -I g M 
A b)  
- 
He patitis B s urface a nti ge n ( H bs A g)  
- 
He patitis C vir us a nti b o d y ( H C V A b)  
- 
H u ma n i m m u n o deficie nc y vir us ( HI V)  
- 
S A R S - C o V-2 P C R ( or C O VI D -1 9 tests 
a ut h orize d u n der E U A)  
- 
Uri ne dr u g scree n, i ncl u di n g, b ut n ot 
li mite d t o: 
o  a m p heta mi nes  
o  bar bit urates  
o  be nz o diaze pi nes  
o  c ocai ne  
o  met ha d o ne  
o  p he nc ycli di ne  
o  o piates  
 




P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 4 1  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
7. 1 4  
P h ar m ac o d y n a mic Assess me nts  
Plas ma a n d ser u m bi o mar ker sa m ples will be o btai ne d as detaile d i n t he Sc he d ule of E ve nts 
(A p pe n di x 1 ).  
T he st u d y will test, i n a n e x pl orat or y ma n ner, a pa nel of bi o mar kers wit h p ote ntial t o assess 
dr u g effects. A ta ble of ke y e x pl orat or y bi o mar kers of i nterest a n d e vi de nce f or t heir 
pr o g n ostic or p har mac o d y na mic val ue is prese nte d i n Ta ble  3.  
I nf or mati o n o n t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g of bi o mar ker sa m ples will be 
pr o vi de d i n a la b orat or y ma n ual.  
T a ble  3.  
Ke y E x pl or at or y Bi o m ar kers of I nterest a n d E vi de nce f or T heir 
Pr o g n ostic or P h ar m ac o d y n a mic V al ue  
C ate g or y  
Bi o m ar ker  
E vi de nce of Pr o g n ostic or P h ar m ac o d y n a mic V al ue 
( Refere nce) 
E pit helial 
Da ma ge  
Rece pt or f or a d va nce d 
gl ycati o n e n d -pr o d ucts 
( R A G E) 
Hi g her le vels i ncrease o d ds of A R D S dia g n osis i n at ris k 
patie nts (
) a n d pre dict m ortalit y i n A R D S 
patie nts wit h hi g h -ti dal v ol u me ve ntilati o n (
) 
Kre bs v o n de n L u n ge n -
6 
( K L-6)  
Hi g her le vels i n patie nts wit h A R D S t ha n ve ntilate d a n d 
healt h y c o ntr ols a n d, wit hi n A R D S patie nts, hi g her le vels i n 
n o n -s ur vi v ors t ha n s ur vi v ors (
) 
S urfacta nt pr otei n D  
( S P-D)  
Hi g her baseli ne le vels of S P -D were ass ociate d wit h w orse 
o utc o mes a n d i ncrease d m ortalit y i n A R D S (
) 
Fi bri n ol ysis  
Plas mi n o ge n acti vat or 
i n hi bit or 1 ( P AI-1)  
Hi g her baseli ne le vels of P AI -1 i n A R D S patie nts a n d 
pre dict or of m ortalit y (
) 
D- di mer  
Hi g her le vels of   D-di mer ma y pre dict i n -h os pital m ortalit y 
i n C O VI D-1 9 patie nts (
) 
I nfla m mati o n 
I nterle u ki n 6 (I L-6)  
Hi g her baseli ne le vels of I L -6 pre dict m ore se vere C O VI D -
1 9 a n d a si g nifica nt decrease i n I L -6 was o bser ve d i n 
rec o veri n g patie nts (
). Hi g her le vels were o bser ve d 
i n patie nts w h o die d vers us t h ose w h o were disc har ge d 
(
). 
I nterle u ki n 8 (I L-8)  
Hi g her le vels are a pre dict or of m ortal it y i n patie nts wit h 
A R D S (
) 
C- reacti ve pr otei n 
( C R P) 
Hi g her le vels o bser ve d i n patie nts wit h se vere C O VI D -1 9 
(
) a n d i n patie nts w h o die d vers us t h ose w h o 
were disc har ge d (
) 
Fi br osis  
Pr o C 3 ( T y pe III 
c olla ge n s y nt hesis 
ne oe pit o pe)  
Hi g her le vels of relate d N -ter mi nal pe pti de f or t y pe III 
pr oc olla ge n were o bser ve d i n ser u m of patie nts wit h bi o ps y -
c o nfir me d fi br o pr oliferati ve A R D S (
) 
  
 




P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
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Plia nt T hera pe utics, I nc.  
 
8  
A D V E R S E E V E N T S  
8. 1  
Ti mi n g  
I n t his st u d y, A Es will be c ollecte d fr o m t he ti me t he partici pa nt si g ns t he I C F u ntil t he Da y 
2 8 st u d y visit. 
8. 2  
Defi niti o n of a n A d verse E ve nt  
A n A E is a n y e ve nt, si de effect, or ot her u nt o war d me dical occ urre nce t hat occ urs i n 
c o nj u ncti o n wit h t he use of a st u d y dr u g i n h u ma ns, w het her or n ot c o nsi dere d t o ha ve a 
ca usal relati o ns hi p t o t his treat me nt. A n A E ca n, t heref ore, be a n y u nfa v ora ble a n d 
u ni nte n de d si g n (t hat c o ul d i ncl u de a cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a st u d y dr u g, w het her or n ot 
c o nsi dere d relate d t o t he st u d y dr u g. E ve nts meeti n g t he defi niti o n of a n A E i ncl u de:  
• E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n. 
• Ne w c o n diti o ns detecte d or dia g n ose d after st u d y dr u g a d mi nistrati o n e ve n t h o u g h it ma y 
ha ve bee n prese nt pri or t o t he start of t he st u d y. 
• Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nteracti o n.  
• Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y dr u g or 
a c o nc o mita nt me dicati o n ( o ver d ose per se will n ot be re p orte d as a n A E/ S A E). E ve nts 
t hat d o n ot meet t he defi niti o n of a n A E i ncl u de: 
- 
Me dical or s ur gical pr oce d ure (e. g., e n d osc o p y, a p pe n dect o m y); t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E.  
- 
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (e. g., s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
- 
A ntici pate d da y -t o-da y fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.  
• If t here is e vi de nce of a n A E t hr o u g h re p ort or o bser vati o n, t he I n vesti gat or or desi g nee 
will e val uate f urt her a n d rec or d t he f oll o wi n g i nf or mati o n:  
- 
Ti me of o nset a n d res ol uti o n  
- 
Se verit y  
- 
Ca usalit y/relati o n  t o st u d y treat me nt 
- 
Acti o n ta ke n re gar di n g st u d y dr u g 
- 
O utc o me 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 4 4  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
8. 3  
Se verit y of a n A d verse E ve nt  
Gra di n g t he se verit y of A Es will use t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E) gra di n g s yste m, versi o n 5. 0 (
), as descri be d bel o w. T he cli nical 
si g nifica nce of t he A E is deter mi ne d b y t he I n vesti gat or. T he I n vesti gat or is e nc o ura ge d t o 
c o ns ult wit h t he Me dical M o nit or. F or A Es or la b orat or y a b n or malities n ot liste d i n t he 
C T C A E gra di n g s yste m, please use t he gra di n g scale as descri be d bel o w.  
Gra de 1 a 
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d 
Gra de 2 a 
M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -
a p pr o priate i nstr u me ntal A D L b 
Gra de 3 a 
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care A D L c 
Gra de 4 a 
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d 
Gra de 5 a 
Deat h relate d t o A E  
a. A se mi -c ol o n i n dicates ‘ or’ wit hi n t he descri pti o n of t he gra de.  
b.  I nstr u me ntal acti vities of dail y li vi n g ( A D L) refer t o pre pari n g meals, s h o p pi n g f or gr oceries or 
cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y, etc. 
c. Self -care A D L refer t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g 
me dicati o ns, a n d n ot be dri d de n.  
 
8. 4  
C a us al Rel ati o ns hi p of a n A d verse E ve nt 
T he I n vesti gat or will assess t he relati o ns hi p bet wee n st u d y dr u g a n d t he occ urre nce of eac h 
A E. T he I n vesti gat or’s assess me nt of t he relati o ns hi p of eac h A E t o st u d y dr u g will be 
rec or de d i n t he s o urce d oc u me nts a n d o n t he e C R F. Alter nati ve ca uses, s uc h as me dical 
hist or y, c o nc o mita nt t he ra p y, or ot her ris k fact ors, a n d t he te m p oral relati o ns hi p of t he e ve nt 
t o t he st u d y dr u g s h o ul d be c o nsi dere d a n d i n vesti gate d, if a p pr o priate. T he relati o ns hi p or 
ass ociati o n of t he A E t o a st u d y dr u g ( P L N- 7 4 8 0 9 or place b o) s h o ul d be assesse d usi n g 
cli nical j u d g me nt a n d t he f oll o wi n g c o nsi derati o ns:  
N o:  
E vi de nce e xists t hat t he a d verse e ve nt has a n eti ol o g y ot her t ha n t he st u d y 
dr u g. F or S A Es, a n alter nati ve ca usalit y m ust be pr o vi de d (e. g., pree xisti n g 
c o n diti o n, u n derl yi n g disease, i nterc urre nt ill ness, or c o nc o mita nt 
me dicati o n).  
Yes:  A te m p oral relati o ns hi p e xists bet wee n t he A E o nset a n d a d mi nistrati o n of 
t he st u d y dr u g t hat ca n n ot be rea dil y e x plai ne d b y t he partici pa nt’s cli nical 
state or c o nc o mita nt t hera pies. F urt her m ore, t he A E a p pears wit h s o me 
de gree of certai nt y t o be relate d, base d o n t he k n o w n t hera pe utic a n d 
p har mac ol o gic acti o ns or A E pr ofile of t he st u d y dr u g. I n case of cessati o n 




P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 4 6  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
T he I n vesti gat or s h o ul d e xercise his/ her me dical a n d scie ntific j u d g me nt i n deci di n g w het her 
a n a b n or mal la b orat or y fi n di n g or ot her a b n or mal assess me nt is cli nicall y si g nifica nt. 
Us uall y, t he a b n or malit y s h o ul d be ass ociate d wit h a cli nicall y e vi de nt si g n or s y m pt o m or 
be li kel y t o res ult i n a n e vi de nt si g n or s y m pt o m i n t he near ter m t o be c o nsi dere d cli nicall y 
si g nifica nt. A cli nicall y si g nifica nt la b orat or y a b n or malit y i n t he a bse nce of cli nical 
s y m pt o ms ma y je o par dize t he partici pa nt a n d ma y re q uire i nter ve nti o n t o pre vent i m me diate 
c o nse q ue nces. F or e xa m ple, a mar ke dl y l o w ser u m gl uc ose c o nce ntrati o n ma y n ot be 
acc o m pa nie d b y c o ma or c o n v ulsi o ns yet be of a ma g nit u de t o re q uire gl uc ose a d mi nistrati o n 
t o pre ve nt s uc h se q uelae. 
8. 8  
Seri o us A d verse E ve nts  
8. 8. 1  
Defi niti o n of Seri o us A dverse Eve nts  
A n S A E is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:  
• Is life-t hreate ni n g 
• Res ults i n deat h  
• Re q uires i n patie nt h os pitalizati o n (i.e., a d missi o n, o ver ni g ht sta y) or pr ol o n gs e xisti n g 
h os pitalizati o n  
• Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
• Is a c o n ge nital a n o mal y/ birt h defect 
A n A E is c o nsi dere d life-t hreate ni n g if, i n t he o pi ni o n of eit her t he I n vesti gat or or t he 
S p o ns or, its occ urre nce places t he partici pa nt at i m me diate ris k of deat h. It d oes n ot i ncl u de 
a n A E t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h. 
I m p orta nt me dical e ve nts t hat are n ot o ne of t he a b o ve ma y be c o nsi dere d t o be S A Es b y t he 
I n vesti gat or w he n, base d u p o n a p pr o priate me dical j u d ge me nt, t he y are c o nsi dere d t o be 
cli nicall y si g nifica nt a n d ma y je o par dize t he partici pa nt or w he n me dical or s ur gical 
i nter ve nti o n ma y be re q uire d t o pre ve nt o ne of t he o utc o mes liste d a b o ve. ( E xa m ples of s uc h 
e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt at a n e mer ge nc y r o o m or 
at h o me, bl o o d d yscrasias, c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.) 
8. 8. 2  
Re p orti n g Seri o us A dverse Eve nts  
T o meet t he re q uire me nts f or e x pe dite d re p orti n g of S A Es t hat meet s pecifi c re q uire me nts t o 
a p plica ble re g ulat or y a ut h orities a n d i nstit uti o nal re vie w b oar ds (I R Bs)/ i n de pe n de nt et hics 
c o m mittees (I E Cs)/ researc h et hics b oar ds ( R E Bs), all S A Es m ust be re p orte d t o t he S p o ns or 
wit hi n 2 4 h o urs fr o m t he ti me site pers o n nel first bec o me a ware of t he e ve nt. T his ma y 
i nitiall y be ac hie ve d b y tele p h o ne or b y c o m pleti n g a n S A E re p ort f or m a n d e maili n g t he 
f or m t o t he e mail a d dress, as pr o vi de d o n t he f or m.  


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 4 7  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
I nitial n otificati o n of a n S A E b y tele p h o ne m ust be c o nfir me d i n writi n g wit hi n 2 4 h o urs 
fr o m t he ti me t he site pers o n nel first bec o me a ware of t he e ve nt usi n g t he S A E re p ort f or m as 
descri be d a b o ve. As f urt her i nf or mati o n re gar di n g t he S A E bec o mes a vaila ble, s uc h 
f oll o w- u p i nf or mati o n s h o ul d be d oc u me nte d o n a ne w S A E re p ort f or m, mar ke d as a 
f oll o w- u p re p ort, sca n ne d, a n d e maile d t o t he a d dress pr o vi de d. 
Wit h dra wal fr o m t he st u d y i n t he e ve nt of a n S A E a n d t he t hera pe utic meas ures t hat are 
ta ke n s hall be at t he discreti o n of t he I n vesti gat or. A f ull e x pla nati o n f or t he disc o nti n uati o n 
fr o m t he st u d y s h o ul d be ma de i n t he e C R F. 
T he re p orti n g of a n y S A Es t o a p plica ble re g ulat or y a ut h orities will be t he res p o nsi bilit y of 
t he S p o ns or i n c o m plia nce wit h a p plica ble c o u ntr y re g ulati o ns. All S A Es m ust be re p orte d t o 
t he I R B/I E C/ R E B b y t he I n vesti gat or i n acc or da nce wit h rele va nt re g ulati o ns. 


























P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 6 0  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
1 3  Q U A LI T Y C O N T R O L A N D A S S U R A N C E  
D uri n g t he st u d y, t he S p o ns or a n d/ or re prese ntati ves of t he S p o ns or ma y visit t he site t o 
c o n d uct a n a u dit of t he st u d y. T he p ur p ose of t his visit will be t o deter mi ne t he I n vesti gat or’s 
a d here nce t o t he pr ot oc ol, a p plica ble re g ulati o ns, a n d t he S p o ns or’s pr oce d ures, i n a d diti o n 
t o assessi n g t he acc urac y of t he st u d y data. Pri or t o i nitiati n g t his a u dit, t he I n vesti gat or will 
be c o ntacte d b y t he S p o ns or t o arra n ge a c o n ve nie nt ti me f or t his visit. T he I n vesti gat or a n d 
staff are e x pecte d t o c o o perate wit h t he a u dit ors a n d t o all o w access t o all partici pa nt rec or ds 
s u p p orti n g t he e C R Fs a n d ot her st u d y-relate d d oc u me nts. 
At s o me p oi nt d uri n g t he de vel o p me nt pr o gra m f or t he st u d y dr u g, a re g ulat or y a ut h orit y 
ma y visit t he I n vesti gat or t o c o n d uct a n i ns pecti o n of t he st u d y a n d t he site. T he I n vesti gat or 
a n d staff are e x pecte d t o c o o perate wit h t he i ns pect ors a n d t o all o w access t o a ll s o urce 
d oc u me nts s u p p orti n g t he e C R Fs a n d ot her st u d y relate d d oc u me nts. T he I n vesti gat or m ust 
i m me diatel y n otif y t he S p o ns or w he n c o ntacte d b y a n y re g ulat or y a ut h orit y f or p ur p oses of 
c o n d ucti n g a n i ns pecti o n.  


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 6 1  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
1 4  A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
1 4. 1  
I nstit uti o n al Re vie w B o ar d, I n de pe n de nt Et hics C o m mittee A p pr o v al, or 
Rese arc h Et hics B o ar d A p pr o v al  
T he I n vesti gat or m ust i nf or m a n d o btai n a p pr o val fr o m t he I R B/I E C/ R E B f or t he c o n d uct of 
t he st u d y at na me d sites, f or t he pr ot oc ol, f or t he partici pa nt I C F a n d a n y other writte n 
i nf or mati o n t hat will be pr o vi de d t o t he partici pa nts, a n d a n y a d vertise me nts t hat will be 
use d. Writte n a p pr o val m ust be o btai ne d pri or t o recr uit me nt of partici pa nts i nt o t he st u d y 
a n d s hi p me nt of i n vesti gati o nal a ge nt.  
Pr o p ose d a me n d me nts t o  t he pr ot oc ol a n d af ore me nti o ne d d oc u me nts m ust be disc usse d 
a m o n g t he S p o ns or a n d c o ntract researc h or ga nizati o n ( C R O) pers o n nel, s u b mitte d t o t he 
I R B/I E C/ R E B f or a p pr o val, a n d t he n s u b mitte d t o re g ulat or y a ut h orities f or a p pr o val pri or t o 
i m ple me ntati o n. A me n d me nts ma y be i m ple me nte d o nl y after a c o p y of t he l ocal 
I R B/I E C/ R E B a p pr o val letter has bee n tra ns mitte d t o t he S p o ns or. A me n d me nts t hat are 
i nte n de d t o eli mi nate a n a p pare nt i m me diate hazar d t o partici pa nts ma y be i m ple me nte d pri or 
t o recei vi n g S p o ns or or I R B/I E C/ R E B a p pr o val. H o we ver, i n t his case, a p pr o val m ust be 
o btai ne d as s o o n as p ossi ble after i m ple me ntati o n.  
T he I n vesti gat or will be res p o nsi ble f or re p orti n g pr ot oc ol de viati o ns t o t he I R B/I E C/ R E B as 
re q uire d b y l ocal re q uire me nts. T he I n vesti gat or will be res p o nsi ble f or e ns uri n g t hat a n 
a n n ual u p date is se nt t o t he I R B/I E C/ R E B t o facilitate c o nti n ui n g re vie w of t he trial (if 
nee de d) a n d t hat t he I R B/I E C/ R E B is i nf or me d a b o ut t he e n d of t he st u d y. C o pies of t he 
u p date, s u bse q ue nt a p pr o vals, a n d fi nal letter m ust be se nt t o t he S p o ns or.  
1 4. 2  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he c urre nt versi o n of t he Declarati o n of 
Helsi n ki, c o ncer ni n g me dical researc h i n h u ma ns. T he st u d y will be c o n d ucte d i n a d here nce 
t o t he st u d y pr ot oc ol a n d G o o d Cli nical Practice ( G C P), as defi ne d i n Title 21 of t he U S 
C o de of Fe deral Re g ulati o ns ( C F R) Parts  5 0, 5 4 5 6, 3 1 2 a n d Part 1 1 a n d i n I nter nati o nal 
C o nfere nce o n Har m o nisati o n (I C H) E 6: G ui deli ne f or G o o d Cli nical Practice C o ns oli date d 
G ui deli nes (I C H -G C P), a n d a p plica ble re g ulat or y re q uire me nts.  
1 4. 3  
P artic i p a nt I nf or m ati o n a n d C o nse nt 
It is t he I n vesti gat or’s res p o nsi bilit y t o o btai n writte n i nf or me d c o nse nt fr o m t he partici pa nt, 
or t he partici pa nt's le gall y a ut h orize d re prese ntati ve, after a de q uate e x pla nati o n of t he 
o bjecti ves, met h o ds, a ntici pate d be nefi ts, a n d p ote ntial hazar ds of t he st u d y a n d bef ore a n y 
st u d y pr oce d ures c o m me nce.  
T he partici pa nt, or t he partici pa nt's le gall y a ut h orize d re prese ntati ve, s h o ul d be gi ve n a c o p y 
of t he I R B/I E C/ R E B -a p pr o ve d I C F i n his/ her nati ve la n g ua ge. T he i nf or me d c o nsent pr ocess 
s h o ul d be rec or de d i n t he s o urce d oc u me ntati o n. T he ori gi nal c o p y of t he si g ne d a n d date d 
I C F m ust be retai ne d i n t he i nstit uti o n’s rec or ds a n d be a vaila ble f or i ns pecti o n b y 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
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Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
re prese ntati ves of t he S p o ns or or re prese ntati ves fr o m re g ulat or y a ge ncies. T he partici pa nt, 
or t he partici pa nt's le gall y a ut h orize d re prese ntati ve, will be gi ve n a c o p y of t he si g ne d I C F. 
T he partici pa nt, or t he partici pa nt's le gall y a ut h orize d re prese ntati ve, will be i nf or me d t hat 
he/s he ca n freel y wit h dra w c o nse nt a n d st o p partici pati o n i n t he st u d y at a n y ti me wit h n o 
prej u dice t o f urt her treat me nt. It is t he partici pa nt’s, or t he partici pa nt's le gall y a ut h orize d 
re prese ntati ve res p o nsi bilit y t o c o m m u nicate t his decisi o n t o t he I n vesti gat or. 
1 4. 4  
P artici p a nt C o nfi de nti alit y  
T h e I n vesti gat or m ust e ns ure t hat t he partici pa nt’s pri vac y is mai ntai ne d. O n t he e C R F a n d 
ot her d oc u me nts t hat are s u b mitte d t o t he S p o ns or, partici pa nts will be i de ntifie d b y a 
partici pa nt st u d y n u m ber o nl y. D oc u me nts t hat are n ot s u b mitte d t o t he S p o ns or (e. g., si g ne d 
I C F) s h o ul d be ke pt i n a strictl y c o nfi de ntial file b y t he I n vesti gat or.  
T he I n vesti gat or s hall per mit a ut h orize d re prese ntati ves of t he S p o ns or, re g ulat or y a ge ncies, 
a n d I R Bs/I E Cs/ R E Bs t o re vie w t he p orti o n of t he partici pa nt’s me dical rec or d t hat is directl y 
relate d t o t he st u d y. As part of t he re q uire d c o nte nt of i nf or me d c o nse nt, t he partici pa nt m ust 
be i nf or me d t hat his/ her rec or ds will be re vie we d i n t his ma n ner.  
A p plica ble data pri vac y la ws a n d re g ulati o ns m ust be a d here d t o. T he I n ves ti gat or a n d t he 
S p o ns or are res p o nsi ble f or e ns uri n g t hat se nsiti ve i nf or mati o n is ha n dle d i n acc or da nce wit h 
l ocal re q uire me nts (e. g., Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act [ HI P A A], 
Pers o n nel I nf or mati o n Pr otecti o n a n d Electr o nic D oc u me nts A ct [ PI P E D A], Ge neral Data 
Pr otecti o n Re g ulati o n [ G D P R]). A p pr o priate c o nse nt a n d a ut h orizati o ns f or use a n d 
discl os ure a n d/ or tra nsfer (if a p plica ble) of pr otecte d i nf or mati o n m ust be o btai ne d.  
1 4. 5  
St u d y M o nit ori n g  
T he I n vesti gat or m ust all o w t he St u d y M o nit or s t o peri o dicall y re vie w, at m ut uall y 
c o n ve nie nt ti mes, d uri n g t he st u d y a n d after t he st u d y has bee n c o m plete d, all e C R Fs a n d 
office, h os pital, a n d la b orat or y rec or ds t hat s u p p ort t he partici pati o n of eac h partici pa nt i n t he 
st u d y (s o urce data). T he e C R Fs a n d ot her d oc u me ntati o n t hat s u p p ort t he st u d y m ust be ke pt 
u p- t o-date b y t he I n vesti gat or a n d t he researc h staff at t he i n vesti gati ve site. T hese st u d y 
materials m ust be a vaila ble f or re vie w b y t he St u d y M o nit or a n d/ or ot her q ualifie d 
re prese ntati ves of t he S p o ns or, at eac h m o nit ori n g visit. 
It is t he m o nit or’s res p o nsi bilit y t o i ns pect t he e C R Fs at re g ular i nter vals t hr o u g h o ut t he trial 
t o verif y a d here nce t o t he pr ot oc ol; t he c o m plete ness, acc urac y a n d c o nsiste nc y of t he data; 
a n d a d here nce t o G C P g ui de li nes. 
T he I n vesti gat or a grees t o c o o perate wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d 
d uri n g t he c o urse of t hese m o nit ori n g visits are res ol ve d.  




P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3  Oct o ber  2 0 2 0, Pr ot oc ol A me n d me nt 2  
 Pa ge 6 4  
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
1 4. 9  
Fi n a nci al Discl os ure  
F i na ncial Discl os ure state me nts will be ha n dle d i n a se parate a gree me nt a part fr o m t he 
pr ot oc ol, ke pt o n file, a n d s u b mitte d as a p plica ble wit h a n y s u bse q ue nt lice nse a p plicati o n.   
1 4. 1 0  
P u blic ati o n a n d Discl os ure P olic y  
T he data ge nerate d i n t his cli nical st u d y are t he e xcl usi ve pr o pert y of t he S p o ns or a n d are 
c o nfi de ntial. A n y p u blicati o n of t he res ults of t his st u d y m ust be a ut h orize d b y t he S p o ns or. 
T he S p o ns or will ha ve t he o p p ort u nit y t o re vie w a n y p u blicati o ns t hat arise fr o m t he 
I n vesti gat ors bef ore s u b missi o n f or p u blicati o n. A n y s uc h re vie w a n d a p pr o val of 
p u blicati o ns relate d t o t he st u d y s hall be ma de p urs ua nt t o t he pr ocess a gree d bet wee n t he 
parties i n t he site’s cli nical trial a gree me nt wit h S p o ns or. A ut h ors hi p o n a n y p u blicati o n of 
t he res ults fr o m t his st u d y will be base d o n c o ntri b uti o ns t o st u d y desi g n, data ac q uisiti o n a n d 
a nal ysis, a n d i nter pretati o n of res ults.  














P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 2 , Pr ot oc ol A me n d me nt 2 
Pa ge 7 1  
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
 
 
Da y 7: pre d ose, 3 h o urs ( ± 6 0 mi n), a n d 2 4 h o urs ( ± 6 0 mi n) p ost d ose  
 
Da y 1 4: pre d ose f or partici pa nts o n st u d y dr u g  
If t he partici pa nt is n o l o n ger bei n g treate d wit h st u d y dr u g, disc o nti n ues t he st u d y earl y, or is n ot treate d wit h st u d y dr u g o n Da y 1 4, a si n gle plas ma sa m ple 
f or P K s h o ul d be ta ke n at t he Da y 1 4/ E o T/ E T Visit if p ossi ble. Act ual P K sa m ple c ollecti o n ti me a n d d osi n g ti me will be rec orde d.  
  
j 
F or partici pa nts o n he m o dial ysis, t he st u d y dr u g will be a d mi nistere d after t he partici pa nt has c o m plete d t he he m o dial ysis.  
 
 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 , Pr ot oc ol A me n d me nt 2 
 Pa ge 7 2   
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
A P P E N DI X 2. 
B E R LI N D E FI NI TI O N O F A R D S  
 
A R D S  
Ti mi n g  
Wit hi n 1 wee k of a k n o w n cli nical i ns ult or ne w or w orse ni n g res pirat or y 
s y m pt o ms 
C hest i ma gi n g a 
Bilateral o pacities – n ot f ull y e x plai ne d b y eff usi o ns, l o bar/l u n g c olla pse, or 
n o d ules  
Ori gi n of e de ma  
Res pirat or y fail ure n ot f ull y e x plai ne d b y car diac fail ure or fl ui d o verl oa d  
Nee d o bjecti ve assess me nt (e. g., ec h ocar di o gra p h y) t o e xcl u de h y dr ostatic 
e de ma if n o ris k fact or prese nt  
O x y ge nati o n b 
 
Mil d  
2 0 0 m m H g < Pa O 2/ Fi O2 ≤ 3 0 0 m m H g wit h P E E P or C P A P ≥5 c m H 2O c 
 
M o derate  
1 0 0 m m H g < Pa O 2/ Fi O2 ≤ 2 0 0 m m H g wit h P E E P ≥5 c m H 2O 
 
Se vere  
Pa O 2/ Fi O2 ≤ 1 0 0 m m H g wit h P E E P ≥ 5 c m H 2O 
C P A P = c o nti n u o us p ositi ve air wa y press ure; Fi O 2 = fracti o n of i ns pire d o x y ge n; Pa O 2 = partial press ure of 
arterial o x y ge n; P E E P = p ositi ve e n d -e x pirat or y press ure.  
a 
C hest ra di o gra p h or C T sca n  
b 
If altit u de is hi g her t ha n 1 0 0 0 m, t he c orrecti o n fact or s h o ul d be calc ulate d as foll o ws:  
[ Pa O2/ Fi O2 × ( bar o metric press ure/ 7 6 0)]  
c 
T his ma y be deli vere d n o ni n vasi vel y i n t he mil d A R D S gr o u p  
S o urce: 
 
 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 , Pr ot oc ol A me n d me nt 2 
 Pa ge 7 3   
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
A P P E N DI X 3. 
V E N TI L A TI O N P R O T O C O L A N D F L UI D M A N A G E M E N T 
P R O T O C O L  
M ay be m o difie d per l oc al i nstit uti o n al st a n d ar ds 
A R D S Ve ntil ati o n Pr ot oc ol (
) 
L o w ti dal v ol u me ve ntilati o n i n patie nts wit h ac ute res pirat or y distress s y n dr o me  
I nitial Ve ntilat or Setti n gs 
Calc ulate pre dicte d b o d y wei g ht ( P B W) 
Male = 5 0 + 2. 3 [ hei g ht (i nc hes) – 6 0] or 5 0 + 0. 9 1 [ hei g ht (c m) – 1 5 2. 4] 
Fe male = 4 5. 5 + 2. 3 [ hei g ht (i nc hes) – 6 0] or 4 5. 5 0. 9 1 [ hei g ht (c m) – 1 5 2. 4] 
Set m o de t o v ol u me assista nt -c o ntr ol 
Set i nitial ti dal v ol u me t o 6 m L/ k g P B W  
Set i nitial ve ntilat or rate ≤ 3 5 breat hs/ mi n t o matc h baseli ne mi n ute ve ntilati o n  
S u bse q ue nt ti dal v ol u me a dj ust me nt 
Platea u press ure g oal: P plat ≤ 3 0 c m H 2O 
C hec k i ns pirat or y platea u press ure wit h 0. 5 sec o n d i ns pirat or y pa use at least e ver y 4 h o urs 
a n d after eac h c ha n ge i n P E E P or ti dal v ol u me 
If P plat > 3 0 c m H 2O, decrease ti dal v ol u me i n 1 m L/ k g P D W ste ps t o 5 or if 
necessar y t o 4 m L/ k g P W B  
If P plat < 2 5 c m H2O a n d ti dal v ol u me < 6 m L/ k g, i ncrease ti dal v ol u me b y 1 m L/ k g 
P B W u ntil P plat > 2 5 c m H 2O or t i dal v ol u me = 6 m L/ k g 
If breat h stac ki n g ( A ut o P E E P) or se vere d ys p nea occ urs, ti dal v ol u me ma y be 
i ncrease d t o 7 or 8 m L/ k g P D W if P plat re mai ns ≤ 3 0 c m H2O 
Arterial O x y ge nati o n a n d P E E P 
O x y ge nati o n g oal: Pa O 2 5 5 t o 8 0 m m H g or S p O2 8 8 % t o 9 5 % 
Use t hese Fi O 2/ P E E P c o m bi nati o ns t o ac hie ve o x y ge nati o n g oal: 
Fi O 2 
0. 3  
0. 4  
0. 5  
0. 6  
0. 7  
0. 8  
0. 9  
1. 0  
P E E P 
5 
5 t o 8  
8 t o 1 0  
1 0  
1 0 t o 1 4  
1 4  
1 4 t o 1 8  
1 8 t o 2 4  
P E E P s h o ul d be a p plie d starti n g wit h t he mi ni m u m val ue f or a gi ve n Fi O 2 
P plat: platea u press ure. Pa O 2: arterial o x y ge n te nsi o n. S p O2: o x y he m o gl o bi n sat urati o n. P E E P: p ositi ve e n d-
e x pirat or y press ure. Fi O 2: fracti o n of i ns pire d o x y ge n. 
A da pte d fr o m 
. 


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 , Pr ot oc ol A me n d me nt 2 
 Pa ge 7 4   
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
Fl ui d M a n a ge me nt Pr ot oc ol: F A C T T -Lite (
) 
Ce ntr al Ve n o us 
Press u re 
( Rec o m me n de d) 
P ul m o n ar y 
Arter y 
Occl usi o n 
Press u re 
( O pti o n al) 
Me a n Arteri al Press ure ≥ 6 0 m m H g  
a n d Off V as o press ors ≥ 1 2 h o urs  
Uri ne o ut p ut < 0. 5 m L/ k g/ h  
Uri ne o ut p ut ≥ 0. 5  m L/ k g/ h  
> 8  
> 1 2  
F ur ose mi de a; reassess i n 1 h 
F ur ose mi de a; reassess i n 4 h 
4 – 8 
8 – 1 2  
Gi ve fl ui d b ol us; reassess i n 1 h  
F ur ose mi de a; reassess i n 4 h 
< 4  
< 8  
Gi ve fl ui d b ol us; reassess i n 1 h  N o i nter ve nti o n; reassess i n 4 h  
 
Rec o m me n de d f ur ose mi de d osi n g = be gi n wit h 2 0 m g b ol us or 3 m g/ h i nf usi o n or last k n o w n effecti ve 
d ose. D o u ble eac h s u bse q ue nt d ose u ntil g oal ac hie ve d ( oli g uria re versal or i ntra vasc ular press ure ta r get) or 
ma xi m u m i nf usi o n rate of 2 4 m g/ h or 1 6 0 m g b ol us reac he d. D o n ot e xcee d 6 2 0 m g/ d. Als o, if patie nt has 
heart fail ure, c o nsi der treat me nt wit h d o b uta mi ne.  
 
I nitiate t his pr ot oc ol wit hi n 4 h o urs of ra n d o mizati o n i n e nr olle d partici pa nts a n d c o nti n ue 
u ntil u nassiste d breat hi n g or st u d y Da y 1 4, w hic he ver occ urs first. 
Pr ot oc ol Meta -r ules: 
1.  Disc o nti n ue mai nte na nce fl ui ds  
2.  C o nti n ue me dicati o ns a n d n utriti o n 
3.  Ma na ge electr ol ytes a n d bl o o d pr o d ucts per us ual practice  
4.  F or s h oc k, use a n y c o m bi nati o n of fl ui d b ol uses (rec o m me n de d fl ui d b ol us = 1 5 m L/ k g 
cr ystall oi d [r o u n d t o nearest 2 5 0 m L] or 1 u nit pac ke d re d cells or 2 5 g al b u mi n) a n d 
vas o press or(s) t o ac hie ve mea n arterial press ure ≥ 6 0 m m H g as fast as p ossi ble. Wea n 
vas o press ors as q uic kl y as t olerate d be gi n ni n g 4 h o urs after bl o o d press ure has sta bilize d  
5.  Wit h h ol d di uretic t hera p y i n re nal fail ure ( defi ne d as dial ysis de pe n de nce, oli g uria wit h 
ser u m creati ni ne > 3 m g/ d L, or oli g uria wit h ser u m creati ni ne 0 – 3 wit h ur i nar y i n dices 
i n dicati ve of ac ute ki d ne y i nj ur y) a n d u ntil 1 2 h o urs after last fl ui d b ol us or vas o press or 
gi ve n 
 
Please refer t o t he f oll o wi n g ta ble f or t he F A C T T C o nser vati ve Fl ui d Ma na ge me nt Pr ot oc ol.  


P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 , Pr ot oc ol A me n d me nt 2 
 Pa ge 7 5   
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
S u p ple me nt al T a ble: Fl ui d a n d C at heter Tre at me nt Tri al ( F A C T T) C o nser v ati ve a n d 
Li ber al Fl ui d M a n a ge me nt Pr ot oc ols (
) 
Me as ure d i ntr a v asc ul ar 
press ure ( m m H g)  
M A P 
< 6 0  m m H g 
or a nee d f or 
a n y 
v as o press or  
M A P ≥ 6 0 m m H g wit h o ut v as o press ors  
(e xce pt d o p a mi ne ≤ 5 μ g/ k g/ mi n)  
C V P  
P A O P 
A ver a ge uri n ar y o ut p ut 
< 0. 5  m L/ k g/ h  
A ver a ge uri n ar y o ut p ut 
≥ 0. 5  m L/ k g/ h  
C o nser v ati ve  
Li ber al  
C o nser v ati ve  
Li ber al  
I neffecti ve 
Circ ul ati o n §  
Effecti ve 
Circ ul ati o n #  
I neffecti ve 
Circ ul ati o n §  
Effecti ve 
Circ ul ati o n #  
Ra n ge 1  
vas o press or 
fl ui d b ol us 
K V O I V  
D o b uta mi ne  
F ur ose mi de  
K V O I V  
F ur ose mi de  
K V O I V  
D o b uta mi ne  
F ur ose mi de  
K V O I V  
F ur ose mi de  
> 1 3  
> 1 8  
> 1 8  
> 2 4  
Ra n ge 2  
K V O I V  
D o b uta mi ne  
K V O I V  
F ur ose mi de  
K V O I V  
D o b uta mi ne  
K V O I V  
F ur ose mi de  
9 -1 3  
1 5 -1 8  
1 3 -1 8  
1 9 -2 4  
Ra n ge 3  
fl ui d b ol us 
vas o press or  
Fl ui d b ol us  
Fl ui d b ol us  
Fl ui d b ol us  
Li beral  
K V O I V  
4- 8 
1 0 -1 4  
8- 1 2  
1 4 -1 8  
C o nser vati ve  
F ur ose mi de  
Ra n ge 4  
Fl ui d b ol us  
Fl ui d b ol us  
Fl ui d b ol us  
Li beral  
Fl ui d b ol us  
< 4  
< 1 0  
< 8  
< 1 4  
C o nser vati ve  
K V O I V  
C V P = ce ntral ve n o us press ure; I V = i ntra ve n o us; K V O = kee p vei n o pe n; P A O P = p ul m o nar y arter y occl usi o n 
press ure  
§ I neffecti ve circ ulati o n: Car diac i n de x < 2. 5 L/ mi n/ m 2 or c ol d, m ottle d s ki n wit h ca pillar y -refilli n g ti me 
> 2 sec o n ds 
# Effecti ve circ ulati o n: Car diac i n de x ≥ 2. 5 L/ mi n/ m 2 or a bse nce of criteria f or i neffecti ve circ ulati o n  








P L N- 7 4 8 0 9 -A R D S -2 0 4, 2 3 Oct o ber 2 0 2 0 , Pr ot oc ol A me n d me nt 2 
 Pa ge 7 9   
 
Pr o prietar y a n d C o nfi de ntial  
 
Plia nt T hera pe utics, I nc.  
A P P E N DI X 7. 
I N V E S TI G A T O R SI G N A T U R E 
St u d y Title:  
A ra n d o mize d, d o u ble -bli n d, d ose -ra n gi n g, place b o-c o ntr olle d, P hase 2a 
e val uati o n of t he safet y, t olera bilit y, a n d p har mac o ki netics of P L N -
7 4 8 0 9 i n partici pa nts wit h ac ute res pirat or y distress s y n dr o me ( A R D S) 
ass ociate d wit h at least se v ere C O VI D -1 9 (I N T E G RI S -A R D S)  
St u d y N u m ber:  
P L N -7 4 8 0 9 -A R D S -2 0 4  
Fi nal Date:  
2 3 Oct o ber 2 0 2 0  
 
 
 
 
I ha ve rea d t he pr ot oc ol descri be d a b o ve. I a gree t o c o m pl y wit h all a p plica ble re g ulati o ns 
a n d t o c o n d uct t he st u d y as descri be d i n t he pr ot oc ol.  
 
 
Si g ne d:  
 
 
Date:    
 
 
Na me:     
  
  
  
  
  
 
 
Affiliati o n:   
  
  
  
  
  
 
 
Site N u m ber:      
  
  
  
  
 

SAP_001.pdf: 




 
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Page 3 of 25 
 
 
 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION ................................................................................................................. 7 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 7 
2.1 
OBJECTIVES ....................................................................................................................... 7 
2.1.1 Primary Objective ......................................................................................................... 7 
2.1.2 Secondary Objectives (analysis not described in this SAP) ......................................... 7 
2.1.3 Exploratory Objectives ................................................................................................. 7 
2.2 
ENDPOINTS ........................................................................................................................ 7 
2.2.1 Primary Endpoint ......................................................................................................... 7 
2.2.2 Secondary Endpoints .................................................................................................... 8 
2.2.3 Exploratory Efficacy Endpoints.................................................................................... 8 
3. 
INVESTIGATIONAL PLAN ............................................................................................... 8 
3.1 
STUDY DESIGN .................................................................................................................. 8 
3.2 
TREATMENT ...................................................................................................................... 9 
3.2.1 Randomization scheme and treatment arm assignment ............................................. 10 
3.2.2 Blinding ...................................................................................................................... 10 
3.2.3 Dosing schedule .......................................................................................................... 10 
3.2.4 Subject compliance ..................................................................................................... 10 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ........................................... 11 
4.1 
DATA QUALITY ASSURANCE ........................................................................................... 11 
4.2 
ANALYSIS SETS ............................................................................................................... 12 
4.3 
ASSESSMENT WINDOWS .................................................................................................. 12 
4.4 
HANDLING OF DROPOUTS OR MISSING DATA .................................................................. 12 
4.5 
MULTIPLE COMPARISONS ................................................................................................ 12 
4.6 
DATA DERIVATIONS AND TRANSFORMATIONS ................................................................ 12 
5. 
STUDY SUBJECTS ............................................................................................................ 13 
5.1 
DISPOSITION OF SUBJECTS .............................................................................................. 13 
5.2 
PROTOCOL DEVIATIONS .................................................................................................. 13 
5.3 
DEMOGRAPHIC CHARACTERISTICS .................................................................................. 13 
5.4 
BASELINE CHARACTERISTICS .......................................................................................... 13 
5.5 
MEDICAL HISTORY .......................................................................................................... 13 
5.6 
CONCOMITANT MEDICATIONS/THERAPIES ...................................................................... 13 
5.6.1 Medications ................................................................................................................ 13 
5.6.2 Non‐ drug therapy  ..................................................................................................... 13 
6. 
EFFICACY ANALYSES .................................................................................................... 13 


 
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6.1 
PHARMACOKINETIC ENDPOINTS AND ANALYSIS ............................................................. 13 
6.2 
EXPLORATORY EFFICACY ENDPOINTS AND ANALYSIS .................................................... 14 
6.2.1 Efficacy ....................................................................................................................... 14 
6.2.2 Pharmacodynamics .................................................................................................... 14 
7. 
SAFETY ANALYSIS .......................................................................................................... 15 
7.1 
EXTENT OF EXPOSURE..................................................................................................... 15 
7.2 
ADVERSE EVENTS ........................................................................................................... 15 
7.2.1 Treatment-Emergent Adverse Events ......................................................................... 15 
7.2.2 Adverse Event Severity ............................................................................................... 15 
7.2.3 Adverse Event Relationship to Study Drug................................................................. 16 
7.2.4 Serious Adverse Events ............................................................................................... 16 
7.2.5 Adverse Event Summaries .......................................................................................... 17 
7.3 
CLINICAL LABORATORY ASSESSMENTS .......................................................................... 18 
7.4 
VITAL SIGNS ................................................................................................................... 19 
7.5 
ELECTROCARDIOGRAM ................................................................................................... 19 
8. 
INTERIM ANALYSES ....................................................................................................... 19 
9. 
DATA SAFETY MONITORING BOARD ....................................................................... 19 
10. 
SAMPLE SIZE AND POWER CALCULATIONS ...................................................... 19 
11. 
REFERENCES ................................................................................................................. 20 
12. 
APPENDIX ....................................................................................................................... 21 
12.1 APPENDIX A: SCHEDULE OF EVENTS ............................................................................... 21 
12.2 
 .................... 24 
12.3 
 
 
 ................ 25 
 


 
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Page 5 of 25 
LIST OF ABBREVIATIONS  
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse events 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
ATC 
Anatomical, therapeutic, and chemical 
COVID-19 
Coronavirus disease 
CS 
Clinically significant 
CTCAE 
Common terminology criteria for adverse events 
 
 
DSMB 
Data safety and monitoring board 
 
 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EoT 
End of treatment 
ET 
Early termination 
EUA 
Emergency use authorization (by the FDA) 
FDA 
Food and drug administration 
FiO2 
Fraction of inspired oxygen 
ICF 
Informed consent form 
ICU 
Intensive care unit 
MAP 
Mean arterial pressure 
MedDRA 
Medical dictionary for regulatory activities 
NCS 
Not clinically significant 
NE 
Nasoenteric 
NG 
Nasogastric 
 
 
PaO2 
Partial pressure of arterial oxygen 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
QD 
Once daily 


 
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Abbreviation or Term 
Definition/Explanation 
 
 
RTSM 
Randomization & trial supply management 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
 
 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent severe adverse event 
WHO 
World health organization 
 
 




 
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Page 8 of 25 
2.2.2 
Secondary Endpoints 
2.2.2.1 
Secondary Pharmacokinetic (PK) Endpoints 
The secondary PK endpoints are the plasma PLN-74809 concentrations (total and unbound 
concentrations, as appropriate) at each sampling timepoint by dose and visit. 
2.2.3 
Exploratory Efficacy Endpoints 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a Phase 2a, multicenter, randomized, double-blind, dose-ranging, placebo-controlled, study 
to evaluate the safety, tolerability, and PK of treatment with PLN-74809 for at least 7 and up to 14 
days in participants with ARDS associated with at least severe COVID-19. The study will include 
an up to 3-day screening period, a 7- to 14-day (or day of hospital discharge, whichever one is 
sooner) treatment period, and a 90-day follow-up period. 
Approximately 36 participants will be enrolled sequentially into 3 cohorts. Within each cohort of 
12 participants, 9 will be randomized to PLN-74809 and 3 will be randomized to placebo (3:1 
ratio). 
 In Part 1, approximately 12 participants will be randomized to 40 mg PLN-74809 or 
placebo QD (Cohort 1). 
 In Part 2, approximately 12 participants will be randomized to 80 mg PLN-74809 or 
placebo QD (Cohort 2). 
 In Part 3, approximately 12 participants will be randomized to 160 mg PLN-74809 or 
placebo QD (Cohort 3). 
A data safety monitoring board (DSMB) will be established to assess participant safety at 
predetermined intervals during the study, and as needed. 
 
 


 
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Commencement of Part 2 and Part 3 will occur only following favorable DSMB review of the 
previous study part. The 160 mg cohort will only be dosed following favorable DSMB review of 
the 80 mg cohort (see Figure 1: Study Schematic). 
Figure 1: Study Schematic 
 
Successful treatment of ARDS associated with COVID-19 will likely require co-administration of 
drugs with complementary mechanisms of action targeting different components of the disease, 
such as antiviral compounds to control viral replication (e.g., remdesivir) combined with drugs 
with the potential to address the pathophysiology of ARDS, in addition to respiratory support 
measures. Therefore, treatment with investigational COVID-19 therapies available under 
Emergency Use Authorization (EUA) by the FDA may be allowed, pending review and approval 
by the Medical Monitor and Sponsor Study Director. Key considerations for allowing co-
administration of PLN-74809 with investigational COVID-19 therapies under EUA will include 
the potential for drug interactions and adverse drug reactions. Treatment with off-label use of any 
other drugs, devices, or interventions that might be used to manage COVID-19 may also be 
allowed, pending review and approval by the Medical Monitor and Sponsor Study Director. 
Each participant will participate in the study for up to approximately 107 days, including 
screening, treatment, and post-treatment follow-up. The end of study is defined as the last 
visit of the last randomized participant.  
See Appendix A for the Schedule of Assessments out to the 90-day follow-up.  
3.2 
Treatment 
The following treatments will be administered for each part of the study: 
 Part 1: 40 mg of PLN-74809 or matching placebo QD 
 Part 2: 80 mg of PLN-74809 or matching placebo QD 
 Part 3: 160 mg of PLN-74809 or matching placebo QD 
 
 
 
 


 
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3.2.1 
Randomization scheme and treatment arm assignment 
Within each part, participants will be randomized in a 3:1 manner to PLN-74809 or placebo. There 
will be no other stratification. A central randomization system, Medidata Rave Randomization & 
Trial Supply Management (RTSM)®, will be used for this study. 
Participants who are randomized and never receive study drug will not be replaced. 
3.2.2 
Blinding 
The PLN-74809 and placebo tablets will be identical in appearance and will be packaged 
identically to ensure that the participant, Investigator and clinical site staff are unaware of the 
treatment assignments, hence blinded. 
After the last participant enrolled in each study part completes the end of treatment or early 
termination visit (whichever applies), selected Sponsor representatives with no direct interactions 
with clinical sites will subsequently be unblinded to allow for a more comprehensive review and 
assessment of the safety and PK data by the DSMB before proceeding to subsequent parts of the 
study. 
In case a medical emergency requires knowledge of a participant’s treatment assignment, the 
Principle Investigator and designated Sub-Investigator(s) at each site, as well as 
Safety and 
Medical Monitors, will have rights to automatically obtain a participant’s treatment assignment 
through Medidata Rave RTSM®, thereby breaking the blind. 
3.2.3 
Dosing schedule 
All doses of study drug will be taken at the investigative site. 
 
 
 
 
 
 
 
3.2.4 
Participant compliance 
The Investigator may withdraw a participant from the study or discontinue study drug for any 
of the following reasons: 
 Noncompliance with protocol procedures, including those relating to administration of 
study drug 
 Occurrence of a serious adverse event (SAE) or intolerable adverse event (AE) 
 Occurrence of a clinically significant change in a laboratory parameter 
 
 
 
 
 
 
 
 
 
 
 


 
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 Termination of the study by the Sponsor or Investigator 
 The participant requests to be discontinued from the study 
Participants who discontinue study drug (regardless of reason) will be asked to remain in the study 
to complete all remaining assessments until hospital discharge or Day 28, whichever is sooner, 
unless they withdraw consent or are lost to follow-up. If this is not feasible, the participant will be 
assessed for an early termination visit. All assessments that are required at the last study visit, as 
shown in Appendix A, should be completed for any participant who is withdrawn from the study 
or prematurely discontinues study drug and does not agree to complete all remaining assessments. 
 
 
 
 
 
 
4. GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
With the availability of COVID-19 vaccines beginning in the fourth quarter of 2020, as well as the 
increased and successful measures taken to contain the virus, a dramatic decrease in the number 
of patients with ARDS associated with severe and critical COVID-19 was observed. Given the 
current and predicted decline in potential study participants, the study was terminated by the 
Sponsor. No statistical hypotheses will be tested. Unless otherwise specified, continuous data will 
be summarized using descriptive statistics (n, mean, standard deviation (SD), median, minimum, 
and maximum). Categorical variables will be summarized showing the number and percentage of 
participants within each category. All tabulations will be based on pooled data across centers.  
Analyses will be performed using SAS for Windows statistical software, version 9.4 or higher 
(SAS, Cary, NC), except where other software may be deemed more appropriate. 
 will perform all efficacy and safety analyses described in this SAP. 
 will 
perform pharmacokinetic analysis. Pharmacodynamic analysis will be performed by 
 
. 
Participant data will be listed, sorted by treatment arm, cohort, investigative center, and participant 
number. When applicable, listings will be additionally sorted by visit and assessment date/time. 
4.1 
Data Quality Assurance 
Once all the source verification is complete, all queries are resolved, and the database has been 
updated appropriately, the database will be locked and made available to 
Biostatistics for final 
analysis. 
Data may be pulled by 
 Biostatistics for DSMB analysis at a time when source verification and 
query resolution is ongoing. 
All SAS programs used to create analysis data sets, tables, and listings are double programmed. 


 
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The SAS outputs will be compared and the programs will be updated until the outputs match. 
4.2 
Analysis Sets 
The following analysis sets will be defined for this study: 
Safety Set: The Safety Set will consist of all randomized participants who receive at least 1 dose 
of study drug.  
PK Concentration Set: all randomized participants who receive at least 1 dose of study drug and 
have any measurable PLN-74809 concentration data. 
4.3 
Assessment Windows 
All data will be included in the analysis based on the visit recorded in the database. 
4.4 
Handling of Dropouts or Missing Data 
Missing data on demographic, baseline information and safety will be treated as missing; no 
method for imputation is planned.  
Details of any missing data imputation will be specified in the analysis methods for each of the 
exploratory efficacy endpoints. 
4.5 
Multiple Comparisons 
No hypotheses are being tested. 
4.6 
Data Derivations and Transformations 
The following derivations will be used in this study: 
Study day:  
 Date of assessment – date of study drug administration + 1 for assessments done on or after 
date of study drug administration 
 Date of assessment – date of study drug administration for assessments done before date 
of study drug administration 
Baseline value: the last non-missing value prior to study drug administration. 
Shift from baseline: current value – baseline value. Although generally reserved for quantitative 
variables, it is also applied to some numeric ordinals 
 
 
 
 
 
  
 
 


 
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5. STUDY PARTICIPANTS 
5.1 
Disposition of Participants 
A table of frequency counts and percentages of all participants in the Safety and PK Concentration 
sets will be provided. Participant disposition including study completion status and reasons for 
early termination (if applicable) will be tabulated by treatment arm and overall.  A by participant 
listing will be provided. 
5.2 
Protocol Deviations 
A listing of all protocol deviations will be provided. 
5.3 
Demographic Characteristics 
Descriptive statistics will be used to summarize the demographic characteristics (age, sex, race, 
ethnicity, height, weight) for the participants in the Safety Set.  A by participant listing will be 
provided. 
5.4 
Baseline Characteristics 
Descriptive statistics will be used to summarize the baseline characteristics 
 
 for the participants in the Safety Set. 
5.5 
Medical History 
All medical conditions and surgical procedures will be classified by system organ class (SOC) and 
preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) version 
23.0. The number and percent of participants with each medical condition and surgical procedure 
will be presented for each SOC and PT for the Safety Set. A listing will also be provided. 
5.6 
Concomitant Medications/Therapies 
5.6.1 
Medications 
Concomitant medications/therapies collected will be coded using the March 2021 B3 WHO-Drug 
Dictionary. A listing of medications will also be provided. 
5.6.2 
Non‐ drug therapy  
Non‐ drug therapies (e.g., ice pack, intubation, tracheostomy, ECMO) will be coded using 
MedDRA (version 23.0). A listing of non-drug therapy will be provided. 
6. EFFICACY ANALYSES 
The PK analyses will be performed using the PK Concentration set. All other exploratory efficacy 
summaries will be conducted using the Safety Set. 
6.1 
Pharmacokinetic Endpoints and Analysis 
Blood samples for determination of plasma levels of PLN-74809 will be obtained at the following 
timepoints: 




 
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7. SAFETY ANALYSIS 
Safety assessments will include assessment of AEs, laboratory parameters, vital signs, and 
. All safety summaries (or analyses if applicable) will be conducted using the 
Safety Set. No formal hypothesis testing will be performed to compare differences between 
treatment arms. 
7.1 
Extent of Exposure 
The number of tablets received, the occurrence of dose interruption, the duration of interruption, 
and total amounts of PLN-74809 in mg will be tabulated. 
7.2 
Adverse Events 
An AE is any event, side effect, or other untoward medical occurrence that occurs in conjunction 
with the use of a study drug in humans, whether or not considered to have a causal relationship to 
this treatment. An AE can, therefore, be any unfavorable and unintended sign (that could include 
a clinically significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a study drug, whether or not considered related to the study drug. 
AEs will be coded using the MedDRA (version 23.0) and collected from the time the participant 
signs the informed consent form (ICF) until Day 28. 
7.2.1 
Treatment-Emergent Adverse Events  
A TEAEs is defined as an AE that emerged or worsened in severity after the first administration 
of study drug.  
7.2.2 
Adverse Event Severity 
Grading the severity of AEs will use the Common Terminology Criteria for Adverse Events 
(CTCAE) grading system, version 5.0 (
), as described below. The clinical significance 
of the AE is determined by the Investigator. The Investigator is encouraged to consult with the 
Medical Monitor.  
For AEs or laboratory abnormalities not listed in the CTCAE grading system, please use the 
grading scale as described below. 
Table 1: Adverse Event Severity Grading Terminology 
CTCAE 
Grade 
Common 
Terminology 
Descriptiona  
Grade 1 
Mild  
asymptomatic or mild symptoms; clinical or  diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate 
minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADLb 


 
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CTCAE 
Grade 
Common 
Terminology 
Descriptiona  
Grade 3 
Severe 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADLc 
Grade 4 
Life-threatening 
Life-threatening consequences; urgent intervention 
indicated 
Grade 5 
Death 
Death related to AE 
a A semi-colon indicates ‘or’ within the description of the grade. 
b Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
c Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
7.2.3 
Adverse Event Relationship to Study Drug 
The Investigator will assess the relationship between study drug and the occurrence of each AE. 
The Investigator’s assessment of the relationship of each AE to study drug will be recorded in the 
source documents and on the eCRF. Alternative causes, such as medical history, concomitant 
therapy, or other risk factors, and the temporal relationship of the event to the study drug should 
be considered and investigated, if appropriate. The relationship or association of the AE to a study 
drug (PLN-74809 or placebo) should be assessed using clinical judgment and the following 
considerations: 
No:  
Evidence exists that the adverse event has an etiology other than the study drug. For 
SAEs, an alternative causality must be provided (e.g., preexisting condition, 
underlying disease, intercurrent illness, or concomitant medication).  
Yes:  A temporal relationship exists between the AE onset and administration of the study 
drug that cannot be readily explained by the participant’s clinical state or concomitant 
therapies. Furthermore, the AE appears with some degree of certainty to be related, 
based on the known therapeutic and pharmacologic actions or AE profile of the study 
drug. In case of cessation or reduction of the dose, the AE abates or resolves and 
reappears upon re-challenge. 
The relationship to study procedures (such as venipuncture) should be assessed using the following 
considerations: 
No:  
Evidence exists that the AE has an etiology other than the study procedure. 
Yes:  The AE occurred as a result of protocol-mandated procedures 
The relationships will be summarized using “Yes” or “No” for “Related to Investigational Product” 
and “Related to Trial Procedure”. 
7.2.4 
Serious Adverse Events 
A SAE is defined as an AE that meets at least one of the following serious criteria:  


 
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 Is life-threatening 
 Results in death 
 Requires inpatient hospitalization (i.e., admission, overnight stay) or prolongs existing 
hospitalization  
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect  
An AE is considered life-threatening if, in the opinion of either the Investigator or the Sponsor, its 
occurrence places the participant at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.  
Important medical events that are not one of the preceding may be considered to be SAEs by the 
Investigator when, based upon appropriate medical judgement, they are considered to be clinically 
significant and may jeopardize the participant or when medical or surgical intervention may be 
required to prevent one of the outcomes listed above. (Examples of such events include allergic 
bronchospasm requiring intensive treatment at an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse.) 
7.2.5 
Adverse Event Summaries 
All AEs (serious and non-serious) occurring after study drug administration and by Day 28 of the 
study, regardless of relationship to study drug, will be included and classified by SOC and PT 
using MedDRA.  
For TEAEs, the following will be summarized and presented for the Safety Set. 
i. 
An overall summary of TEAEs, which includes:   
a. the number and percentage of participants experiencing a TEAE 
b. the number and percentage of participants experiencing a TEAE by strongest 
relationship to investigational product 
c. the number and percentage of participants experiencing a TEAE by strongest 
relationship to trial procedure 
d. the number and percentage of participants experiencing a TEAE by greatest 
severity  
e. the number and percentage of participants experiencing a TEAE with NCI CTCAE 
version 5.0 Grade 3 or higher 
f. the number and percentage of participants experiencing a treatment emergent 
serious adverse event (TESAE) 
g. the number and percentage of participants experiencing a TESAE by strongest 
relationship to investigational product 
h. the number and percentage of participants experiencing a TESAE by strongest 
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i. the number and percentage of participants experiencing a TEAE leading to death 
j. the number and percentage of participants experiencing a TEAE which leads to a 
premature withdrawal 
ii. 
the number and percentage of participants experiencing a TEAE by SOC and PT 
iii. 
the number and percentage of participants experiencing a TEAE by SOC, PT and the 
strongest relationship to investigational product 
iv. 
the number and percentage of participants experiencing a TEAE by SOC, PT and the 
strongest relationship to trial procedure 
v. 
the number and percentage of participants experiencing a TESAE by SOC, PT and the 
strongest relationship to trial procedure  
In the overall summary of TEAEs table (i), besides tabulating the number and percentage of 
participants, the total number of TEAE episodes will also be provided. If a participant has repeated 
episodes of a particular TEAE, all episodes will be counted in the summary table. 
In the remaining summary tables, the incidence of TEAEs will be calculated by dividing the 
number of participants who have experienced the event by the total number of participants in the 
Safety Set.  Thus, the incidence of TEAEs is shown in terms of the total number of participants 
and not in terms of the total number of episodes.  If a participant has repeated episodes of a 
particular TEAE, only the most severe episode, or the episode with the strongest causal 
relationship, will be counted in the summary tables.  
A participant with more than one type of TEAE in a particular SOC or PT will be counted only 
once in the total of participants experiencing TEAEs in that particular SOC or PT.  
All occurrences of all AEs and SAEs will be listed for each participant, grouped by treatment arm.  
The listing will contain the following information: treatment arm, verbatim term, SOC, PT, 
severity, related to investigational product, related to trial procedure, date and day of onset, date 
and day of resolution, action taken with regard to study drug, treatment given to treat the adverse 
event, the outcome, whether the event was an SAE, SAE criteria (if applicable), whether it led to 
study withdrawal, and whether it is a TEAE.  Listings will be sorted by treatment arm, participant 
identification number, onset date, SOC, and PT. If the onset date is completely missing, then these 
events will be presented first. If the onset date is missing a month or a day, then these events will 
be presented before any complete dates. 
7.3 
Clinical Laboratory Assessments 
Clinical laboratory tests will be obtained at the time points presented in Appendix A. The incidence 
of treatment-emergent laboratory abnormalities will be summarized by severity and treatment 
group. Continuous clinical laboratory values will be summarized by presenting descriptive 
statistics of raw data and change from baseline values at each time point for each treatment arm.  
Laboratory parameter results from unscheduled visits will be excluded from table summaries but 
will be included in data listings.  When there are repeat measurements for a given visit, only the 
last measurement will be used in the table summaries.   
Listings will include flags for values outside of the reference ranges, and clinical significance if a 
laboratory result is deemed abnormal, if available. The biomarker analysis is described separately 


 
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in Section 6.2.2. 
7.4 
Vital Signs 
Descriptive summaries of the vital signs (both raw and change from baseline values) including 
weight, temperature, systolic and diastolic blood pressure, and heart rate will be prepared for each 
study treatment by visit.   
Unscheduled visits will be excluded from the summaries but will be included in the data listings.  
7.5 
 
 
 
 
 
 
 
 
 
  
 
8. INTERIM ANALYSES 
No interim analysis is planned. 
9. DATA SAFETY MONITORING BOARD 
A DSMB will be established to assess participant safety at predetermined intervals during the 
study, and as needed. The DSMB will formally assess and review all available safety and PK data 
and will issue recommendations pertaining to the conduct of the study and the dose escalation from 
Part 1 to Part 2 and from Part 2 to Part 3. Further details will be provided in the DSMB Charter. 
Due to the early termination of the study, the DSMB meetings did not occur.  
 
 
 
10. SAMPLE SIZE AND POWER CALCULATIONS 
 
 
. 


 
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11. REFERENCES 
 
 
 
 
 
 
 
 
 






 
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12.2 
Appendix B: