Clinical trial NCT04439071
Conditions: Pneumonia COVID-19 Coronavirus
Sponsor: PTC Therapeutics
Start date: 2020-07-09; Completion date: 2022-07-20
Enrollment: 189 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, multicenter, 28-day study of adult participants hospitalized with COVID-19, with a safety follow-up telephone call at Day 60.

Detailed description:

Arms: arm 1: Participants will receive PTC299 at 200 milligrams (mg), administered orally, twice daily (BID) on Days 1 to 7, then at 50 mg administered orally, once daily (QD) on Days 8 to 14.

SOC will also be administered according to local, written policies or guidelines. arm 2: Participants will receive PTC299-matching placebo administered orally, BID on Days 1 to 7, then administered orally, QD on Days 8 to 14.

SOC will also be administered according to local, written policies or guidelines.
Interventions: intervention 1: PTC299 intervention 2: SOC intervention 3: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: As defined per local written policies or guidelines. intervention 3: Oral tablets

Protocol documents:
Prot_000.pdf: 
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
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C LI NI C A L P R O T O C O L  
E V A L U A TI O N O F T H E  E F FI C A C Y A N D S A F E T Y O F P T C 2 9 9 I N 
H O S PI T A LI Z E D S U B J E C T S WI T H C O VI D -1 9 ( FI T E 1 9)  
P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
0 2  J U N E  2 0 2 1  
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P T C T H E R A P E U TI C S, I N C.  
1 0 0 C O R P O R A T E C O U R T  
S O U T H P L AI N FI E L D, N J 0 7 0 8 0 U S A  
N otice of Pr o prietar y I nf or mati o n: T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n o w ne d b y or i n t he 
p oss essi o n/c o nt r ol of P T C T hera pe utics, I nc. E xce pt as ma y ot her wis e be per mitte d i n writi n g, b y acce pti n g or 
re vie wi n g t hes e materials, y o u a gree t hat t his i nf or mati o n s h o ul d n ot be dis cl os e d t o ot hers (e xce pt w here re q uire d b y 
a p plica ble la w) a n d s h o ul d n ot be us e d f or  u na ut h orize d p ur p os es. I n t he e ve nt of a n act ual or s us pecte d breac h of t his 
o bli gati o n, P T C T hera pe utics, I nc. s h o ul d be n otifie d pr o m ptl y .
N C T #: N C T 0 4 4 3 9 0 7 1


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P R O T O C O L I D E N TI FI E R S A N D S T U D Y P E R S O N N E L  
Pr oj ect C o d e  
P T C 2 9 9  
T h e r a p e utic Ar e a  
Vir ol o g y  
P T C T h e r a p e utics S u bst a nc e I d e ntifie r  
P T C 2 9 9  
N o n p r o priet ar y N a me  
E m v o d o dstat  
I N D N u m b er 
I N D 1 4 9 3 8 5 
E u d r a C T N u m b er  
2 0 2 0 -0 0 1 8 7 2 -1 3  
Pr ot oc ol N u m b er  
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Pr ot oc ol Ve rsi o n  
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Pr ot oc ol P h ase  
P hase 2/ 3  
Pr ot oc ol Title  
E val uati o n of t he effica c y a n d safet y of P T C 2 9 9 i n 
h os pitalize d s u bje cts wit h C O VI D -1 9  ( FI T E 1 9) 
P T C Cli nic al Le a d  
 
P T C M e dic al M o nit or  
 
P T C Bi ost atistici a n  
 
P T C St u d y M a n a ger  
 
 
 
 


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P T C T H E R A P E U TI C S P R O T O C O L A P P R O V A L SI G N A T U R E S  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
P T C T her a pe utics, I nc.  
 
D ate  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
P T C T her a pe utics, I nc.  
 
D ate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P T C T her a pe utics, I nc  
 
D ate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he e Si g nat ure pa g e  is l ocate d o n t h e last p a ge. 


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P RI N CI P A L I N V E S TI G A T O R A G R E E M E N T A N D SI G N A T U R E  
 
I ha ve r ea d t he pr ot oc ol d oc u me nt a n d, o n be half of m y i nstit uti o n, a gre e t o c o m pl y wit h t he pr ot oc ol 
a n d all a p plic a ble re g ulati o ns.  
 
 
 
 
Pri n ci p al I n vesti g at or  
 
D ate  
 
 
 
I nstit uti o n: 
 
A d dr ess:  
 
Cit y:  
 
State/ Pr o vi nc e:  
 
C o u ntr y:  
 
P h o ne:  
 
Fa x:  
 
E -mail:  
 
 
 
 
 


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S Y N O P SI S  
St u d y N u m ber  
P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
N a me of 
I n vesti g ati o nal  
Pr o d uct  
E m v o d o dstat ( P T C 2 9 9 ) 
St u d y Title  
E val uati o n of t h e effic ac y a n d saf et y of P T C 2 9 9 i n h os pitali ze d 
s u bjects wit h C O VI D-1 9  ( FI T E 1 9) 
Pr o p ose d I n dic ati o n  Treat me nt of C O VI D -1 9  
N u m ber of St u d y 
Sites  
A p pr o xi matel y 5 0  
P h ase of Tri al  
P hase 2/ 3  
St u d y O bjecti ves  
Pri m ary St u dy O bjectiv e  
T o e val u ate t he cli nic al effica c y of P T C 2 9 9 c o m p are d wit h plac e b o 
assesse d b y ti me t o r es pirat or y i m pr o ve m e nt  i n a d ult s u bjects 
h os pitali ze d wit h C O VI D -1 9.  
Sec o n d ary St u dy O bjecti ves  
•  T o e val u ate t he cli nic al effica c y of P T C 2 9 9 c o m p are d wit h 
place b o, as assesse d b y res pirat or y f u ncti o n, i m m u ne 
res p o nse, le n gt h of h os pit ali zati o n, a n d m ort alit y. 
•  T o e val u ate t he safet y of P T C 2 9 9 as assesse d b y 
dr u g -relat e d a d verse e v e nts. 
St u d y E n d p oi nts  
Pri m ary E n d p oi nt  
•  Ti me fr o m ra n d o mizati o n t o res pir at or y i m pr o ve m e nt, 
defi ne d as peri p heral o x y g e n sat urati o n ( S p O 2) ≥9 4 %  o n 
r o o m air, s ustai n e d u ntil disc har g e fr o m t he h os pital  or t he 
e n d of t he st u d y ( Da y  2 8) .  
Sec o n d ary E n d p oi nts  
•  T he pr o p orti o n of s u bj ects re q uiri n g i n vasi v e ve ntilati o n at 
a n y p oi nt d uri n g t he st u d y  
•  T he pr o p orti o n of s u bj ects re q uiri n g s u p ple m e ntal o x y ge n 
or n o n -i n vasi ve ve ntil ati o n at a n y p oi nt d uri n g t h e st u d y i n 
s u bjects w h o di d n ot re q uire s u p ple me ntal o x y ge n at 
baseli ne  
•  Ti me fr o m ra n d o mizati o n t o def er vesce n ce i n s u bj ects 
prese nti n g wit h f e ver at e nr oll me nt (te m p erat ur e of 
≥3 7. 6 ℃ a xilla, ≥3 8. 0℃ oral, or ≥3 8. 6° C t y m p a nic or 
rectal)  
•  Ti me fr o m ra n d o mizati o n t o res pir at or y rate 
≤2 4  breat hs/ mi n ut e o n r o o m air  
•  Ti me fr o m ra n d o mizati o n t o c o u g h r e p orte d as mil d or 
a bse nt ( o n a scale of se vere, m o derate, mil d, a bse nt, i n 
t h ose wit h c o u g h at e nr oll me nt rate d se v ere or m o d erate) 


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•  Ti me fr o m ra n d o mizati o n t o d ys p nea r e p orte d as mil d or 
a bse nt ( o n a scale of se vere, m o derate, mil d, a bse nt, i n 
t h ose wit h d ys p nea at e nr oll me nt rate d as se vere or 
m o derat e)  
•  Atte n uati o n of i m m u ne res p o nses as i n di cate d b y:  
− re d ucti o n i n c yt o ki ne l e vels, p ote ntiall y i n cl u di n g 
i nterl e u ki n (I L)-2, I L -6, I L -7, I L -1 7, gra n ul oc yt e -
c ol o n y sti m ulati n g fact or, i nt erfer o n -γ i n d u ci bl e pr ot ei n 
1 0, m o n oc yte c he m o attra cta nt pr otei n 1, ma cr o p ha ge 
i nfla m mat or y pr otei n 1-α, a n d t u m or n ecr osis fact or -α  
− re d ucti o n i n le v els of ac ut e p hase pr ot ei ns, p ote ntiall y 
i ncl u di n g f erriti n, C -reacti ve pr otei n, D-di mer, a n d 
car dia c tr o p o ni n   
− n or mali zati o n i n t h e c o m ple te bl o o d c o u nt 
− c ha n ges i n ot h er la b orat or y para met ers p ote ntiall y 
i ncl u di n g d ecre ases i n lactat e de h y dr o ge n ase, 
pr ot hr o m bi n ti me, a n d al b u mi n  
•  Re d ucti o n i n viral l oa d  
•  D urati o n of h os pitaliz ati o n meas ure d i n d a ys  
•  M ortalit y at Da y 2 8  
•  O verall safet y pr ofile c hara cterize d b y t y pe, fre q ue n c y, 
se verit y, ti mi n g, a n d rel ati o ns hi p t o st u d y treat me nt of a n y 
a d verse e ve nts ( A Es) or la b orat or y a b n or maliti es.  
St u d y P o p ul ati o n  
H os pitaliz e d a d ult s u bjects wit h c o nfir me d p ne u m o nia, dia g n ose d wit h 
C O VI D -1 9, a n d n ot re q uiri n g me c ha nic al ve ntil ati o n.  
F or t he p ur p oses of e nr oll m e nt of s u bje cts i nt o t he st u d y, “ h os pitalize d 
patie nts” will i ncl u d e  a n y C O VI D -1 9 patie nt eit h er a d mitt e d or u n der 
o bser vati o n i n t he h os pit al f or a c o nti n u o us peri o d of 2 4 h o urs or m ore 
w h o ot her wise f ulfills t he eli gi bilit y  criteria.   
S a m ple Size  
A t otal of 3 2 6 e v e nts i n t h e st u d y will pr o vi de m or e t ha n 8 0 % of 
p o wer t o dete ct a ha zar d rati o of 1. 3 8 at t w o -si de d t y pe I err or of 0. 0 5. 
A p pr o xi matel y 3 8 0 s u bjects, i n t ot al, will be nee d e d.  
1 9 0 ra n d o miz e d t o P T C 2 9 9 a n d 1 9 0 r a n d o mi ze d t o place b o. 
E nr oll m e nt will be halte d w he n a p pr o xi matel y 4 0 s u bjects ( 2 0 i n eac h 
ar m) ha ve b ee n e nr olle d a n d a n i nt eri m a nal ysis of s afet y data will be 
c o n d ucte d w he n t h ose 4 0 s u bjects ha ve rec ei ve d 1 4 da ys of treat me nt 
a n d 1 4 da ys of f oll o w -u p . E nr oll me nt will c o nti n ue if t here ar e n o 
safet y c o nc er ns.  
Met h o d ol o g y/ St u d y 
Desi g n  
T his is a ra n d o mize d,  d o u ble -bli n d, plac e b o -co ntr oll e d, m ultice nter 
2 8  -da y st u d y  wit h safet y f oll o w -u p b y tele p h o ne c all at Da y 6 0 .  


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S u bjects will b e ra n d o mize d 1: 1 t o P T C 2 9 9 tr eat me nt or plac e b o , wit h 
a p pr o xi matel y 1 9 0 s u bj ects i n eac h c o h ort. T he r a n d o mizati o n will be 
stratifi e d b y a ge ( ≤6 2 vs > 6 2), re m desi vir use ( yes vs n o) , a n d 
de xa met has o ne use ( yes vs n o) . All s u bjects will als o recei v e sta n dar d 
of care ( S O C) defi ne d per l ocal writt e n p oli cies or g ui deli n es. T he use 
of ster oi ds  (e xce pt de xa m et has o ne), se nsiti ve C Y P 2 D 6  s u bstrates, 
C Y P 2 C i n d ucers, I L-6 ne utralizi n g a nti b o dies, I L -6 r ece pt or 
i n hi bit ors, a n d a n y i n vesti gati o nal t hera py  ar e pr o hi bite d.  
F oll o wi n g eli gi bilit y scre e ni n g a n d e nr oll me nt, s u bj e cts will re cei v e 
oral ta blets c o ntai ni n g P T C 2 9 9 or matc h i n g place b o 2 0 0 m g t wice 
dail y ( m or ni n g a n d e v e ni n g) o n Da ys 1 t o 7 a n d 5 0 m g o nce dail y 
( m or ni n g) o n Da ys  8 t o 1 4.  
A p pr o xi matel y 4 0 s u bjects ( 2 0 i n eac h ar m) will be e nr olle d i niti all y, 
e nr oll m e nt will t he n h alt, a n d a n i nteri m a nal ysis will be perf or m e d t o 
assess safet y. N o f or mal statistic al testi n g will be perf or me d at t he first 
i nteri m a nal ysis . A n i n de pe n de nt data a n d safet y m o nit ori n g b oar d 
(D S M B ) will re vie w a vaila bl e data  f or t he 4 0 s u bje cts. E nr oll me nt will 
c o nti n ue if t her e are n o safet y c o nc er ns.  I n a d diti o n t o t he D S M B, a n 
i n de pe n de nt He patic A d vis or y Safet y C o m mittee ( H A C ) will als o 
re vie w dat a relate d t o li ver e ve nts .  
A  sec o n d i nteri m a nal ysis is pla n ne d t o assess f utilit y. It will be 
perf or me d  w he n 5 0 % of res pirat or y i m pr o v e me nt e v e nts ha ve be e n 
reac he d, ie, 1 6 3  e ve nts ha ve be e n o bser ve d ( a p pr o xi matel y  
1 9 0  s u bjects).  
T he u n bli n d e d  i nt eri m a nal yses will be c o n d ucte d b y a n i n de pe n d e nt 
statisti cia n a n d t he r es ults will b e o nl y s hare d wit h t h e cl osed  sessi o n 
of  t he D S M B . D S M B will ma ke t he g o - or n o -g o  re c o m me n dati o ns 
a n d t he re c o m m e n dati o ns will be c o m m u ni cat e d wit h t he st u d y te a m. 
T he st u d y te a m will  be ke pt bli n d e d  f or res ults rel ate d t o t he i nteri m 
a nal ys es.  
S u bjects will b e assesse d dail y w hile h os pit ali ze d. All s u bjects will 
u n der g o effic ac y, safet y, a n d la b or at or y assess me nts as s u m mariz e d i n  
Ta ble  3 . T here will be a f oll o w -u p tele p h o ne call at D a y 6 0 t o assess 
A Es, seri o us A Es, a n d deat hs.  
F or s u bjects w h o are disc har ge d fr o m t he h os pital pri or t o Da y 2 8:  
•  If S p O2 is < 9 4 %, S p O2 meas ure me nts will be ta ke n dail y 
u ntil Da y 2 8  
•  S u bject -re p orte d assess me nts f or c o u g h a n d d ys p ne a will 
c o nti n ue t o Da y 2 8  
•  N o ot her assess me nts will t a ke pl ace e x ce pt f or t h ose 
s pecifie d at Da y 1 4, 2 8 a n d Da y 6 0 i n t he pr ot o c ol.  
All s u bjects will u n der g o t h e assess me nts s pecifie d f or Da y 1 4 a n d 
Da y 2 8, a n d parti ci pate i n t h e Da y 6 0  tele p h o ne call, e ve n if t h e y are 
disc har ge d fr o m t he h os pit al pri or t o Da y 2 8.  


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Criteri a  
1.  S u bject  ( or l e gall y a ut h orize d re pr ese ntati ve) is willi n g a n d 
a ble t o pr o vi de i nf or me d c o nse nt a n d c o m pl y wit h all pr ot oc ol 
re q uire m e nts. 
2.  A grees t o t he c olle cti o n of nas o p har y n g eal s wa bs a n d ve n o us 
bl o o d a n d all ot her pr ot oc ol -s pecifie d pr o ce d ures. 
3.  Male or n o n -pr e g na nt fe male a d ult ≥1 8 y ears of a ge at ti me of 
e nr oll m e nt.  
4.  H os pitaliz e d a n d has l a b orat or y -c o nfir me d i nfecti o n wit h 
S A R S -C o V -2.  
5.  S y m pt o m o nset was ≤1 4  da ys pri or t o S cree ni n g . 
6.  Has S p O 2 < 9 4 % o n r o o m air  
7.  Has at least o n e of res pirat or y r ate > 2 4 br eat hs/ mi n ut e or 
c o u g h 
8.  L u n g i n v ol ve me nt as c o nfir m e d b y ra di o gra p hic i nfiltrates 
o bser ve d o n i ma gi n g (c hest X -ra y, C T sc a n, or a n e q ui vale nt 
test)  
9.  W o me n of c hil d be ari n g p ote ntial (as defi n e d i n (C T F G 2 0 1 4 )) 
m ust ha ve a n e gati ve pre g na n c y test at scre e ni n g a n d a gree t o 
a bsti ne nc e or t he use at le ast o ne of t h e f oll o wi n g hi g hl y 
effecti ve f or ms of c o ntr ace pti o n (wit h a fail ure rate of < 1 % per 
year w he n use d c o nsiste ntl y a n d c orr ectl y) . C o ntra ce pti o n or 
a bsti ne nc e m ust be c o nti n u e d  f or t he d urati o n of t h e st u d y 
f oll o wi n g disc har g e fr o m t h e h os pital, a n d f or u p t o 5 0 da ys 
after t h e last d ose of st u d y dr u g : 
•  c o m bi ne d ( estr o ge n a n d pr o gest o g e n c o nt ai ni n g) h or m o nal 
c o ntrac e pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:  
− oral  
− i ntra va gi nal 
− tra ns der mal 
•  pr o gest o ge n -o nl y h or m o n al c o ntrace pti o n ass oci ate d wit h 
i n hi biti o n of o v ulati o n: 
− oral  
− i njecta bl e 
− i m pla nta bl e 
•  i ntra ut eri ne d e vice 
•  i ntra ut eri ne h or m o ne-rel easi n g s yste m 
•  vasect o mize d p art ner  wit h c o nfir m e d az o os per mia  
All fe males will b e c o nsi dere d of c hil d b eari n g p ote ntial u nl ess 
t he y are p ost me n o pa usal (at l east 1 2 m o nt hs c o nsec uti ve 
a me n orr he a i n t h e a p pr o priate a g e gr o u p wit h o ut ot h er k n o w n 
or s us pecte d ca use) or ha v e bee n st erilize d s ur gi call y (e g, 
bilat eral t u bal li gati o n, h ystere ct o m y, bilateral o o p h orect o m y).  
1 0.  Me n se x uall y a cti v e wit h w o me n of c hil d be ari n g p ot e ntial w h o 
ha ve n ot ha d a vasect o m y m ust a gr ee t o u se a barri er met h o d 
of birt h c o ntr ol d uri n g t h e st u d y f oll o wi n g disc har ge fr o m t he 
h os pital a n d f or u p t o 5 0 da ys aft er t he l ast d ose of st u d y dr u g.  


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Criteri a  
1.  Re q uires me c ha ni cal ve ntil ati o n  
2.  C urre nt partici p ati o n i n a n y ot her inter v e nti o n al  st u d y  
3.  A la ni ne tr a nsa mi n ase/as part ate tra nsa mi nase l e vels ≥3 ti mes t h e 
u p per li mit of n or m al ( × U L N) or t ot al bilir u bi n ( T bili) ≥2 × U L N  
4.  L y m p h oc yt e c o u nt < 5 0 0 l y m p h oc ytes/ µ L or he m o gl o bi n 
< 1 1 . 0 g/ d L  
5.  Sta ge 4 se vere c hr o nic ki d n e y disease or r e q uiri n g di al ysis 
(ie, esti mat e d gl o m er ular filtrati o n rate < 3 0)  
6.  A n y ot her c o n diti o n, t hat i n t h e o pi ni o n of t he i n vesti gat or, 
ma y be c a use t o e xcl u de t h e s u bject fr o m t h e st u d y.  
7.  Use of ster oi ds  (e xce pt de x a met has o ne), se nsiti ve C Y P 2 D 6 
s u bstrates, C Y P 2 C i n d ucers, I L-6 ne utr ali zi n g a nti b o dies, I L -6 
rece pt or i n hi bit ors, or a n y i n vesti gati o n al t h era p y. 
8.  Pre g na nc y or breast fe e di n g.  
9.  A ntici pate d tr a nsfer t o a n ot h er h os pital w hic h is n ot a st u d y 
site wit hi n 7 2 h o urs. 
1 0.  K n o w n aller g y  t o P T C 2 9 9 or e x ci pi e nts  
P h ar m ac o ki netics  
At select sites, p har m ac o ki netics ( P K) will be assesse d after t he si n gl e 
d ose ( Da y 1) a n d re peat e d d osi n g Da y 7 a n d 1 4. Bl o o d sa m ples will b e 
c olle cte d o n Da ys 1 a n d 7 at pre-d ose ( 0), a n d 6  h o urs p ost -d ose a n d 
o n  Da y 1 4 at pre -d ose ( 0) a n d 4 h o urs p ost -d ose ( m or ni n g d ose o nl y).  
St u d y Tre at me nt  
P T C 2 9 9 or matc hi n g pla ce b o orall y a d mi nister e d ta blets at a d ose of 
2 0 0  m g t wice p er da y f or Da ys 1 t o 7 f oll o we d 5 0 m g orall y 
a d mi nist ere d o nc e dail y o n Da ys 8 t o 1 4.  
D ur ati o n of 
Tre at me nt  
S u bjects will r ecei ve tre at m e nt f or 1 4 da ys t h e n f oll o w -u p f or 1 4 da ys 
t o gi ve a t otal st u d y d urati o n of 2 8 da ys, wit h a safet y f oll o w-u p 
tele p h o n e call at Da y 6 0. 
S afet y M o nit ori n g  
S u bjects will b e m o nit ore d cl osel y f or A Es a n d la b o r at or y 
a b n or maliti es d uri n g t he st u d y. A n i n d e pe n de nt D S M B will m o nit or 
o n g oi n g res ults t o e ns ure s u bj ect well -bei n g a n d safet y as well as 
st u d y i nte grit y. T he D S M B will m a ke re c o m m e n dati o ns a b o ut earl y 
st u d y cl os ure or c ha n g es t o st u d y ar ms. A d diti o nall y,  an i n de pe n d e nt 
H A C  will o versee t he h e patic safet y of s u bj ects i n t h e st u d y. 
St atistic al Met h o ds  
T he pri m ar y e n d p oi nt is ti me fr o m ra n d o miz ati o n t o res pirat or y 
i m pr o ve m e nt, defi ne d as S p O 2 ≥9 4 % o n r o o m air  s ustai ne d u ntil 
disc har ge fr o m t he h os pit al or t he e n d of t he st u d y ( Da y 2 8) . 
Ka pla n -Meier pl ots of ti me t o res pir at or y i m pr o ve m e nt will b e 
prese nte d. Me di a n ti me t o res pir at or y i m pr o ve m e nt will be esti mate d 
via t he Ka pla n -Mei er pr o d uct li mit met h o d. A t w o -si de d 9 5 % 
c o nfi de nc e i nt er val ( CI)  f or t h e me dia n ti me t o res pir at or y 
i m pr o ve m e nt will be c o m p ute d f or P T C 2 9 9 a n d plac e b o  c o h orts base d 
o n a l o g -l o g tr a nsf or me d CI f or t he s ur vi v or f u n cti o n S(t). Ti me  t o 
res pirat or y i m pr o ve m e nt will be c o m p are d bet wee n treat m e nt gr o u ps 
usi n g stratifi e d l o g -ra n k test. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 0  of 6 2  
Hazar d rati o a n d c orres p o n di n g t w o -si de d 9 5 % CIs will be esti mate d 
usi n g a C o x pr o p orti o nal haz ar ds m o del, wit h treat m e nt ar m as a 
si n gle c o variat e, stratifie d b y t h e stratific ati o n f act ors. 
Res pirat or y i m pr o ve m e nt  rates at Da ys 7, 1 4, a n d 2 8 will als o be 
esti mate d usi n g Ka pl a n -Meier esti mates o n t he ti m e t o res pirat or y 
i m pr o ve m e nt c ur v e. Ass ociate d t w o -si de d 9 5 % CIs f or eac h tr eat me nt 
gr o u p a n d t he diff ere nce b et wee n t he 2  tr eat me nt gr o u ps will be 
calc ulat e d usi n g Gr ee n w o o d’s f or m ula f or varia n c e deri vati o n.  
S u bjects will b e ra n d o mize d 1: 1 t o P T C 2 9 9  or pl ace b o  (a p pr o xi matel y 
1 9 0 s u bjects i n e ac h c o h ort). T he ra n d o miz ati o n will be stratifie d b y 
a ge ( ≤6 2 vs > 6 2) , re m d esi vir use ( yes vs n o) , a n d de xa met h as o ne use 
( yes vs n o).  
T his is a gr o u p se q ue ntial d esi g n wit h 2 i nteri m a nal yses pla n ne d. T he 
first i nteri m a n al ysis will o nl y assess t he safet y a n d t he trial will n ot be 
st o p pe d f or f utilit y or s u peri orit y of effi cac y . It will be perf or me d after 
t he first 4 0 ra n d o miz e d s u bjects ha v e c o m plet e d Da y  2 8  or 
disc o nti n ue d d u e t o de at h , wit h dr e w  c o nse nt, or wer e l ost-t o-f oll o w-
u p .  
T he sec o n d i nteri m a nal ysis is t o assess f utilit y a n d will be perf or me d 
w he n 5 0 % of res pirat or y i m pr o ve me nt e ve nts ha ve b ee n rea c he d, 
ie, 1 6 3  e ve nts ha ve bee n o bser v e d ( a p pr o xi mat el y  1 9 0 s u bjects).  All 
s u bjects w h o ha ve c o m plete d t hr o u g h Da y 2 8, were disc har ge d wit h 
S p O 2 ≥9 4 % o n r o o m air , wit h dr e w  c o nse nt, die d , were l ost t o 
f oll o w-u p , or t o o k a n y C O VI D-1 9 resc ue t hera p y d uri n g t he st u d y will 
be i ncl u d e d i n t h e i nt eri m a nal ysis. S u bjects w h ose pri mar y e v e nt 
ca n n ot be d eter mi ne d at t he i nteri m c ut, ie, o n g oi n g s u bjects , will n ot 
be i ncl u d e d  i n t h e i nt eri m effica c y a nal ys is. S u bjects w h o die d , 
wit h dre w c o nse nt, were l ost t o f oll o w -u p, or t o o k a n y C O VI D -1 9 
resc ue t her a p y will be ce ns ore d at Da y 2 8. A stratifie d l o g -ra n k test 
will be perf or me d a n d t he haz ar d rati o (tre at m e nt vs place b o) will be 
c o m pare d wit h t he f utilit y b o u n dar y. T h e tr i al m a y b e st o p pe d f or 
f utilit y if t h e haz ar d rati o is less t ha n 1. 0 9 1. T h e f utilit y b o u n dar y is 
base d o n La n -De Mets beta s pe n di n g f u ncti o n ( n o n -bi n di n g o pti o n) 
wit h o verall bet a of 8 0 % . 
T he sa m pl e size was calc ul ate d b ase d o n t he pri mar y e n d p oi nt of ti me 
t o res pirat or y i m pr o ve me nt. It is a ntici pate d t h at t h e me dia n ti m e t o 
res pirat or y i m pr o ve m e nt f or t he plac e b o gr o u p is 1 1 da ys a n d P T C 2 9 9 
treat me nt will de crease it t o 8 da ys, a n i m pr o ve me nt of 3 -da ys. 
S u bjects will b e f oll o we d f or t he fi xe d a m o u nt of ti m e of 2 8 da ys fr o m 
ra n d o miz ati o n ( c orres p o n di n g t o t h e a ntici p ate d i m pr o ve me nt r ates of 
0. 8 2 9 a n d 0. 9 1 2 at Da y 2 8 f or pl ace b o  a n d P T C 2 9 9, res pecti v el y). 
A  t otal of 3 2 6 e v e nts will pr o vi de m or e t ha n 8 0 % of p o wer t o dete ct a 
hazar d rati o of 1. 3 8  at t w o-si de d t y pe I err or of 0. 0 5. A p pr o xi matel y 
3 8 0  s u bjects, i n t otal, will be n ee de d. 
De m o gra p hic a n d baseli ne c har act eristi cs, dis p ositi o n, a n d safet y will 
be s u m mari ze d descri pti vel y b y tre at m e nt gr o u p.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 1  of 6 2  
T A B L E O F C O N T E N T S  
P R O T O C O L I D E N TI FI E R S A N D S T U D Y P E R S O N N E L  ...........................................................2  
P T C T H E R A P E U TI C S P R O T O C O L A P P R O V A L SI G N A T U R E S ..............................................3  
P RI N CI P A L I N V E S TI G A T O R A G R E E M E N T A N D SI G N A T U R E ............................................4  
S Y N O P SI S  ......................................................................................................................................5  
T A B L E O F C O N T E N T S  ...............................................................................................................1 1  
LI S T O F T A B L E S  .........................................................................................................................1 4  
LI S T O F FI G U R E S  .......................................................................................................................1 4  
LI S T O F A B B R E V I A TI O N S A N D D E FI NI TI O N S O F T E R M S ................................................1 5  
1.  
I N T R O D U C TI O N ......................................................................................................1 7  
1. 1.  
St u d y Rati o nale  ...........................................................................................................1 8  
1. 2.  
Ris k/ Be nefit Assess me nt  ............................................................................................1 9  
2.  
S T U D Y O BJ E C TI V E A N D E N D P OI N T S  ................................................................2 0  
2. 1.  
O bjecti v es  ...................................................................................................................2 0  
2. 1. 1.  
Pri mar y O bjecti ve  .......................................................................................................2 0  
2. 1. 2.  
Sec o n dar y O bjecti ves  .................................................................................................2 0  
2. 1. 3.  
E x pl orat or y O bj ecti ves  ...............................................................................................2 0  
2. 2.  
E n d p oi nts  ....................................................................................................................2 0  
2. 2. 1.  
Pri mar y E n d p oi nt  ........................................................................................................2 0  
2. 2. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................2 0  
2. 2. 3.  
E x pl orat or y E n d p oi nts  ................................................................................................2 1  
3.  
S T U D Y D E SI G N  .......................................................................................................2 1  
3. 1.  
O verall Desi g n  ............................................................................................................2 1  
3. 2.  
J ustificati o n of D ose ...................................................................................................2 2  
3. 3.  
E n d of St u d y Defi niti o n  ..............................................................................................2 6  
4.  
S T U D Y P O P U L A TI O N  .............................................................................................2 6  
4. 1.  
O ver vie w  .....................................................................................................................2 6  
4. 2.  
I ncl usi o n Crit eria ........................................................................................................2 6  
4. 3.  
E xcl usi o n Criteri a  .......................................................................................................2 7  
4. 4.  
Scree n Fail ur es  ............................................................................................................2 8  
4. 5.  
Strate gi es f or Recr uit me nt a n d Ret e nti o n  ...................................................................2 8  
5.  
S T U D Y I N T E R V E N TI O N  ........................................................................................2 8  
5. 1.  
St u d y I nter ve nti o n(s) A d mi nistrati o n  .........................................................................2 8  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 2  of 6 2  
5. 1. 1.  
St u d y I nter ve nti o n Descri pti o n  ...................................................................................2 8  
5. 1. 2.  
D osi n g a n d A d mi nistrati o n  .........................................................................................2 8  
5. 2.  
Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  ............................................................2 8  
5. 2. 1.  
Acc o u nta bilit y  .............................................................................................................2 8  
5. 2. 2.  
F or m ul ati o n, A p pe ara nc e, Pac ka gi n g, a n d La b eli n g  ..................................................2 9  
5. 3.  
Meas ures t o Mi ni mi ze Bi as: Ra n d o mizati o n a n d Bli n di n g  ........................................2 9  
5. 3. 1.  
E mer ge n c y Pr oce d ure f or U n bli n di n g  ........................................................................2 9  
5. 4.  
St u d y I nter ve nti o n a n d C o m plia n ce  ...........................................................................2 9  
5. 5.  
C o nc o mit a nt T h era p y  .................................................................................................3 0  
6.  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ..................................................................3 0  
6. 1.  
Disc o nti n uati o n of St u d y I nter v e nti o n  ........................................................................3 0  
6. 1. 1.  
Disc o nti n uati o n d ue t o A b n or m al Li ver F u ncti o n  ......................................................3 1  
6. 1. 2.  
Disc o nti n uati o n d ue t o A b n or m al Bl o o d Test Res ults  ...............................................3 1  
6. 2.  
Partici p a nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ............................................3 2  
6. 3.  
L ost t o F oll o w -u p  .......................................................................................................3 2  
7.  
S T U D Y A S S E S S M E N T A N D P R O C E D U R E S  ........................................................3 3  
7. 1.  
Sc he d ule of E v e nts a n d St u d y Para meters  ..................................................................3 3  
7. 2.  
Effica c y Assess me nts  .................................................................................................3 6  
7. 3.  
P K a n d/ or Ot her Assess me nts  ....................................................................................3 7  
7. 4.  
Safet y Assess me nts  .....................................................................................................3 7  
7. 5.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  .............................................................3 7  
7. 5. 1.  
Defi niti o n of A d verse E ve nts  .....................................................................................3 7  
7. 5. 2.  
Defi niti o n of Seri o us A d verse E ve nts  ........................................................................3 9  
7. 5. 3.  
A d verse E ve nts of S peci al I nter est  .............................................................................4 0  
7. 5. 4.  
U ne x pecte d A d verse E v e nts  .......................................................................................4 0  
7. 5. 5.  
Eliciti n g A d verse E ve nt I nf or m ati o n  ..........................................................................4 0  
7. 5. 6.  
Rec or di n g N o n‑s eri o us A Es a n d S A Es  ......................................................................4 0  
7. 5. 7.  
Descri bi n g A d verse E ve nt Relati o ns hi p t o St u d y Dr u g  .............................................4 1  
7. 5. 8.  
Gra di n g of Se v erit y of A d verse E v e nt  ........................................................................4 1  
7. 5. 9.  
A d verse E ve nt Re p orti n g  ............................................................................................4 2  
7. 5. 1 0.  
Seri o us A d verse E ve nt Re p orti n g  ...............................................................................4 2  
7. 5. 1 1.  
Re p orti n g Pre g na n c y  ..................................................................................................4 3  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 3  of 6 2  
7. 5. 1 2.  
P T C T hera pe utics A d verse E ve nt Re p orti n g Re q uir e me nt  ........................................4 4  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................4 4  
8. 1.  
Statisti cal H y p ot h eses  .................................................................................................4 4  
8. 2.  
Sa m ple Siz e Deter mi nati o n  ........................................................................................4 4  
8. 3.  
P o p ulati o n f or A nal yses  ..............................................................................................4 5  
8. 4.  
Statisti cal A nal yses  .....................................................................................................4 5  
8. 4. 1.  
Ge ner al A p pr oac h  .......................................................................................................4 5  
8. 4. 2.  
A nal ysis of Pri mar y Effi cac y E n d p oi nts  ....................................................................4 5  
8. 4. 3.  
A nal ysis of Sec o n dar y Effi cac y E n d p oi nts  ................................................................4 6  
8. 4. 4.  
Safet y A nal yses  ..........................................................................................................4 7  
8. 4. 4. 1.  
S u bject Dis p ositi o n  .....................................................................................................4 7  
8. 4. 4. 2.  
Me dical Hist or y a n d Pri or Me dic ati o n  .......................................................................4 7  
8. 4. 4. 3.  
E xte nt of E x p os ure a n d Tre at m e nt C o m plia n ce  .........................................................4 7  
8. 4. 4. 4.  
A d verse E ve nts  ...........................................................................................................4 7  
8. 4. 4. 5.  
La b orat or y Par a meters  ................................................................................................4 7  
8. 4. 5.  
Baseli ne Descri pti v e Statistics  ....................................................................................4 7  
8. 4. 6.  
Pla n ne d I nteri m A nal yses  ...........................................................................................4 8  
8. 4. 7.  
S u b gr o u p A nal yses  .....................................................................................................4 8  
8. 4. 8.  
E x pl orat or y A nal yses  ..................................................................................................4 8  
9.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  ..................................................................................................4 8  
9. 1.  
Re g ulat or y, Et hi cal, a n d St u d y O versi g ht C o nsi derati o ns  .........................................4 8  
9. 1. 1.  
I nf or me d C o nse nt Pr ocess ..........................................................................................4 8  
9. 1. 2.  
St u d y Disc o nti n uati o n a n d Cl os ure  ............................................................................4 9  
9. 1. 3.  
C o nfi de nti alit y a n d Pri va c y  ........................................................................................4 9  
9. 1. 4.  
F ut ure use of St or e d S peci me ns a n d Data  ..................................................................4 9  
9. 1. 5.  
Safet y O versi g ht  .........................................................................................................5 0  
9. 1. 5. 1.  
Data a n d Safet y M o nit ori n g B o ar d  .............................................................................5 0  
9. 1. 5. 2.  
He patic A d vis or y Safet y C o m mitt ee  ..........................................................................5 1  
9. 1. 6.  
Cli nic al M o nit ori n g  ....................................................................................................5 1  
9. 1. 7.  
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol  ......................................................................5 2  
9. 1. 8.  
Data Ha n dli n g a n d Rec or d Kee pi n g  ...........................................................................5 2  
9. 1. 9.  
Pr ot oc ol De viati o ns  ....................................................................................................5 2  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 4  of 6 2  
9. 1. 1 0.  
P u blicati o n a n d Dat a S hari n g P oli c y  ..........................................................................5 3  
9. 2.  
Pr ot oc ol A me n d m e nt Hist or y  .....................................................................................5 4  
9. 2. 1.  
Versi o n 2. 0: 0 8 Ma y 2 0 2 0  ..........................................................................................5 4  
9. 2. 2.  
Versi o n 3. 0: 0 5 J u ne 2 0 2 0  ..........................................................................................5 6  
9. 2. 3.  
Versi o n 4. 0: 2 3 J ul y 2 0 2 0  ...........................................................................................5 7  
9. 2. 4.  
Versi o n 5. 0: 0 8 Oct o ber 2 0 2 0  .....................................................................................5 8  
9. 2. 5.  
Versi o n 6. 0: 1 8 Dece m b er 2 0 2 0  .................................................................................5 8  
9. 2. 6.  
Versi o n 7. 0: 0 2 J u ne 2 0 2 1  ..........................................................................................5 9  
1 0.  
R E F E R E N C E S  ...........................................................................................................6 0  
 
LI S T O F  T A B L E S  
Ta ble  1:  
S u m mar y of P K a n d P D Para meters  ...........................................................................2 3  
Ta ble  2:  
S u m mar y of P T C 2 9 9 P har ma c o ki netics i n He alt h y V ol u nteers w he n 
A d mi nistere d wit h t he C a ps ule F or m ul ati o n ( ~ 2. 5 x of t he Bi oa v ail a bilit y of 
t he Ta blet F or m ulati o n) ( St u d y P T C 2 9 9-O N C -0 0 2 -H V)  ...........................................2 5  
Ta ble  3:  
Sc he d ule of E v e nts  .....................................................................................................3 3  
Ta ble 4:  
La b orat or y Par a meters t o be Assesse d  .......................................................................3 6  
Ta ble  5:  
Relati o ns hi p of St u d y Dr u g t o A d verse E ve nt Rel ati o ns hi p  ......................................4 1  
Ta ble  6:  
Gra di n g of A d verse E ve nt Se verit y Gra de  .................................................................4 2  
Ta ble  7:  
I n vesti gat or Site Re q uire m e nts f or Re p orti n g A d vers e E ve nts ..................................4 2  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
Plas ma D H O a n d P T C 2 9 9 C o nce ntrati o ns aft er a Si n gle Oral D ose of 
P T C 2 9 9  .......................................................................................................................2 3  
Fi g ure  2:  
P T C 2 9 9 I n hi bits D H O D H i n Patie nts wit h Ne ur ofi br o mat osis T y pe 2 
T u m ors  ........................................................................................................................2 4  
 
 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 5  of 6 2  
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 b br e vi ati o n or 
S p e ci ali z e d T er m  
E x pl a n ati o n  
A E  
A d v er s e e v e nt  
A E SI  
A d v er s e e v e nt of s p e ci al i nt er e st  
A L P  
Al k ali n e p h o s p h at a s e  
A L T  
Al a ni n e tr a n s a mi n a s e  
A M L  
A c ut e m y el oi d l e u k e mi a  
a P T T  
A cti v at e d p arti al t hr o m b o pl a sti n ti m e  
A R D S  
A c ut e r e s pir at or y di str e s s s y n dr o m e  
A S T  
A s p art at e tr a n s a mi n a s e 
A U C  
Ar e a u n d er t h e c ur v e  
A U C 0 -l a st 
Ar e a u n d er t h e c ur v e fr o m ti m e 0 t o l a st m e a s ur e m e nt 
B C R P  
Br e a st c a n c er r e si st a n c e pr ot ei n 
BI D  
T hr e e ti m e s p er d a y  
β H C G  
b et a h u m a n c h ori o ni c g o n a d otr o pi n  
C B C  
C o m pl et e bl o o d c o u nt  
CI  
C o nfi d e n c e i nt er v al  
C m a x  
m a xi m u m o b s er v e d c o n c e ntr ati o n  
C O VI D -1 9  
C or o n a vir u s di s e a s e 2 0 1 9  
C P K  
Cr e ati n e p h o s p h o ki n a s e  
C R F  
C a s e r e p ort f or m  
C R O  
C o ntr a ct R e s e ar c h Or g a ni z ati o n  
C R P  
C -r e a cti v e pr ot ei n 
D H O  
Di h y dr o or ot at e  
D H O D H  
Di h y dr o or ot at e d e h y dr o g e n a s e  
DI LI  
Dr u g -i n d u c e d li v er i nj ur y 
D S M B  
D at a a n d s af et y m o nit ori n g b o ar d  
E C  
Et hi c s c o m mitt e e  
e C R F  
El e ctr o ni c c a s e r e p ort f or m  
G C P  
G o o d L a b or at or y Pr a cti c e  
G -C S F  
Gr a n ul o c yt e -c ol o n y sti m ul ati n g f a ct or  
G G T  
G a m m a -gl ut a m yl tr a n s p e pti d a s e  
E D C  
El e ctr o ni c d at a c a pt ur e s y st e m  
H A C  
H e p ati c a d vi s or y s af et y c o m mitt e e  
H V  
H e alt h y v ol u nt e er  
I C F 
I nf or m e d c o n s e nt f or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni s ati o n  
I C U 
Int e n si v e c ar e u nit  
I L 
I nt erl e u ki n 
I N R 
I nt er n ati o n al n or m ali z e d r ati o 
I P-1 0  
I nt erf er o n g a m m a-i n d u c e d pr ot ei n 1 0 
I R B 
I n stit uti o n al R e vi e w B o ar d 
I T T 
I nt e nt-t o-tr e at 
L F T s  
Li v er f u n cti o n t e st s  
L D H  
L a ct at e d e h y dr o g e n a s e  
M C P  
M o n o c yt e c h e m o attr a ct a nt pr ot ei n  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
MI P  
M a cr o p h a g e i nfl a m m at or y pr ot ei n  
P D  
P h ar m a c o d y n a mi c s  
P K  
P h ar m a c o ki n eti c  
P T C  
P T C T h er a p e uti c s  
Q D  
O n c e d ail y  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 6  of 6 2  
A b br e vi ati o n or 
S p e ci ali z e d T er m  
E x pl a n ati o n  
R SI  
R ef er e n c e S af et y I nf or m ati o n  
R N A  
Ri b o n u cl ei c a ci d  
S A E  
S e v er e a d v er s e e v e nt  
S A P  
St ati sti c al a n al y si s pl a n  
S O C  
St a n d ar d of c ar e  
S O P  
St a n d ar d O p er ati n g Pr o c e d ur e  
S p O 2  
P eri p h er al o x y g e n s at ur ati o n  
t1/ 2  
H alf -lif e 
T bili  
T ot al bilir u bi n  
T E A E s  
Tr e at m e nt -e m er g e nt a d v er s e e v e nt s  
TI D  
T hr e e ti m e s p er d a y  
T m a x  
Ti m e t o C m a x  
T N F -α  
T u m or n e cr o si s f a ct or -al p h a  
U L N  
U p p er li mit s of n or m al  
V E G F  
V a s c ul ar e n d ot h eli al gr o wt h f a ct or  
W B C  
W hit e bl o o d c ell  
W O C B P  
W o m e n of c hil d b e ari n g p ot e nti al  
 
 
 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 7  of 6 2  
1.  
I N T R O D U C TI O N 
Si nce t he first patie nt wit h a p ne u m o nia of u n k n o w n ori gi n i n l ate De ce m ber 2 0 1 9 i n W u ha n 
Cit y, C hi na, a ne w c or o na vir us, desi g nate d S A R S -C o V -2, has res ulte d i n a r a pi dl y s prea di n g 
w orl d -wi de pa n de mic of res pirat or y ill ness ter m e d c or o na vir us disease 2 0 1 9 ( C O VI D-1 9). 
S A R S -C o V -2 is a p ositi ve se nse , ri b o n uclei c aci d ( R N A) vir us of z o o n otic ori gi n a n d is a 
me m ber of t he c or o na vir us fa mil y. D ue t o its n o velt y a n d t he a p p are nt lac k of p o p ul ati o n or 
gr o u p i m m u n it y, C O VI D-1 9 has bee n s prea di n g ra pi dl y i n ma n y c o u ntri es acr oss t he gl o be 
ca usi n g great har m t o h u ma n he alt h, ec o n o mic a cti vit y, a n d disr u pti n g t he s oci al fa bric o n ma n y 
le vels (W a n g 2 0 2 0a ). Si nce it was first descri be d i n N o ve m ber 2 0 1 9, C O VI D -1 9 has ra pi dl y 
s prea d acr oss t he gl o b e a n d milli o ns of pe o ple ha v e bec o me i nfecte d. 
All a ges are s usce pti bl e t o i nfe cti o n wit h S A R S -C o V -2 (C he n g 2 0 2 0 , Li 2 0 2 0 ). T h e cli nical 
feat ures of C O VI D-1 9 are varie d, r a n gi n g fr o m a n as y m pt o matic st ate t o ac ute res pirat or y 
distress s y n dr o me ( A R D S), m ulti -o r ga n d ysf u ncti o n, a n d deat h (C h e n 2 0 2 0a , H ua n g 2 0 2 0 , 
Li u  2 0 2 0a , W a n g 2 0 2 0 b ). Acc or di n g t o c urre nt a nal yses, a b o ut 8 0 % of t he c ases res ol ve wit h at 
h o me car e a n d s u p p orti n g t hera p y a n d 2 0 % r e q uire h os pitali zati o n of w hic h 2 5 % t o 3 0 % d e vel o p 
se vere res pirat or y c o m plicati o ns. T he o v erall fat alit y fr o m C O VI D -1 9 is esti mate d t o ra n ge fr o m 
1 % t o 5 % wit h a hi g h e r ris k of deat h i n t he el derl y a n d pers o ns wit h u n derl yi n g c o m or bi dities 
( 5 0 % t o 7 0 % of fatal cases) (C E B M 2 0 2 0 , C or o na vir us O ut brea k 2 0 2 0 ). 
C O VI D -1 9 ca n be br oa dl y di vi de d i nt o 3 sta g es (S hi 2 0 2 0 , Si d di qi 2 0 2 0 ): 
•  A n as y m pt o matic i n c u bati o n peri o d;  
•  N o n -se vere peri o d of earl y sta ge t y pifi e d b y ra pi d viral pr olif erati o n; 
•  Se vere res pirat or y s y m pt o m atic st a ge of t h e disease t y pifie d b y a rise i n i nfla m mat or y 
c yt o ki nes a n d t he i nfl ue nce of c o m or bi diti es o n dise ase pr o gressi o n a n d pr o g n osis.  
T he c o m m o n cli nic al feat ures of C O VI D -1 9 i ncl u de fe ver, c o u g h, s ore t hr oat, hea d ac he, f ati g u e, 
m yal gi a, a n d s h ort ness of breat h. I n a s u bset of patie nts, b y t he e n d of t h e first wee k, t he disease 
ca n pr o gress t o p ne u m o nia, res pirat or y fail ure, or ga n fail ure, a n d deat h. S A R S C o V -2 tar gets 
cili ate d cells t hat are s u bse q ue ntl y s he d. T he dise ase pr o gressi o n is als o ass ociat e d wit h e xtre me 
rise i n i nfl a m m at or y c yt o ki nes i n cl u di n g i nterl e u ki n (I L)-2, I L -7, I L -1 0, gra n ul o c yte -c ol o n y 
sti m ulati n g fa ct or ( G-C S F), i nterfer o n ga m ma -i n d uc e d pr otei n 1 0 (I P-1 0), m o n o c yte 
c he m oattra cta nt pr o tei n ( M C P) 1, ma cr o p ha ge i nfla m mat or y pr ot ei n ( MI P) 1 A, t u m or necr osis 
fact or al p ha ( T N F-α), a n d v asc ular e n d ot heli al gr o wt h fact or  ( V E G F) (C h e n 2 0 2 0a , 
H ua n g  2 0 2 0 ). B ot h I L-6 a n d I L -1 7 h a v e bee n i m plic ate d i n A R D S (Wa n g 2 0 2 0 b , X u 2 0 2 0 ). 
Le vels of I L -6 a p pear t o pla y a n i m p ort a nt r ol e i n C O VI D -1 9 disease se verit y as t here is str o n g 
e vi de nc e t hat I L -6 pea k le vels are ass oci ate d wit h se verit y of p ul m o nar y c o m pli cati o ns 
(R ussell  2 0 2 0 ). 
T he h y per -i n d u cti o n of pr o-i nfla m mat or y c yt o ki n es - als o referre d t o as a “c yt o ki ne st or m” or 
c yt o ki ne r ele ase s y n dr o me - is c o m m o n i n a c ute viral i nfecti o ns a n d ca n lea d t o tiss ue da ma ge 
a n d p ul m o nar y p at h ol o g y (Li u 2 0 2 0 b ). V E G F, w hi c h pla ys a r ole i n t he p at h o ge nesis of A R Ds, 
has als o bee n f o u n d t o b e i ncre ase d i n patie nts wit h C O VI D -1 9 (Li u 2 0 2 0 b ) T he vi ral l oa d of 
S A R S -C o V -2 detecte d i n t h e patie nt’s res pirat or y tra ct is p ositi v el y li n ke d t o l u n g disease 
se verit y (Li u 2 0 2 0 b ). 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 8  of 6 2  
P T C 2 9 9  (e m v o d o dstat) is a n orall y a vaila ble i n hi bit or of d i h y dr o or otat e de h y dr o ge nase 
(D H O D H ), a ke y e nz y me i n d e n o v o p yri mi di ne n u cle oti d e s y nt hesis. I n hi biti o n of D H O D H 
res ults i n t he d e pleti o n of p yri mi di n e n ucle oti des i n r a pi dl y di vi di n g c ells, l ea di n g t o a G 1/ S 
p hase cell c ycle arrest a n d s u bse q ue nt diff ere ntiati o n or cell d eat h. T heref ore, b y li miti n g h ost 
p yri mi di n e n ucl e oti d e le v els, P T C 2 9 9 ca n arr est viral R N A re plicati o n, re d u ce viral l oa d, a n d 
re d uce c yt o ki ne release. 
C o m p o u n ds t hat i n hi bit D H O D H e nz y me a cti vit y ha ve bee n s h o w n t o ha ve br oa d -s pe ctr u m 
a nti vir al a cti vit y  (L u cas -H o ura ni 2 0 1 5 , M u nier -L e h ma n n 2 0 1 5 , Le wis 2 0 1 6 , Die dric hs -M o hri n g 
2 0 1 8 , L olli 2 0 1 8 , S y kes 2 0 1 8 , C he n 2 0 1 9 , Mei -ji a o 2 0 1 9, Xi o n g 2 0 2 0 ). T his is d ue t o t h e ce ntral 
r ole of D H O D H  i n p yri mi di ne n ucle oti de  s y nt hesis a n d t he hi g h ne e d f or ne w p yri mi di ne 
n ucle oti de s y nt hesis i n viral  R N A  re plicati o n. T he D H O D H i n hi bit ors are parti c ularl y acti ve 
a gai nst R N A vir uses of b ot h p ositi v e a n d ne g ati ve stra n d ge n o me p olarit y a n d ha ve s h o w n 
effica c y a gai nst c or o na vir uses a n d a n u m ber of ot her res pirat or y R N A vir uses (H off ma n n 2 0 1 1 , 
Wa n g 2 0 1 1 , L uc as -H o ura ni 2 0 1 3 , Orti z -Ria n o 2 0 1 4 , C he u n g 2 0 1 7 , L ucas -H o ura ni 2 0 1 7 , 
L ut hra  2 0 1 8 , Ya n g 2 0 1 8 , C h e n 2 0 1 9 , Xi o n g 2 0 2 0 ). As D H O DH i n hi bit ors tar get a h ost pr otei n, 
t he y are e x pect e d t o retai n a nti viral acti vit y a gai nst all strai ns of S A R S-C o V -2  a n d mi ni mize t he 
e mer ge n ce of viral resista n ce . 
I n a d diti o n t o t heir p ote ntial a nti viral effects, D H O D H i n hi bit ors als o s u p press t he e x cessi ve 
i m m u ne r es p o nse c o m m o n t o viral i nfecti o ns w hic h res ults fr o m i ncr ease d c yt o ki ne e x pr essi o n 
(c yt o ki ne st or m) (Xi o n g 2 0 2 0 ). T his h y pera cti v e i m m u ne res p o nse res ults i n a n e xtre me 
i nfla m mat or y r es p o nse, res ulti n g i n p ul m o n ar y a n d m ulti-or g a n d ysf u ncti o n a n d da m a ge, 
ulti m atel y le a di n g t o m ulti ple or g a n fail ur e. I n t he l u n g, t he i nfl a m m at or y res p o nse ca n lea d t o 
fatal p n e u m o ni a, p ul m o n ar y i nfiltrati o n a n d d o w n-strea m fi br osis t h at c a n res ult i n t he ne e d f or 
ve ntil at or y s u p p ort. L u n g i nfla m mati o n is t h e lea di n g ca use of m ort alit y i n S A R S -C o V -2 
i nfecti o n. T her ef ore, P T C 2 9 9 ma y n ot o nl y aff ect vir al re plicati o n, b ut ca n pr o vi de pr otecti o n 
a gai nst t h e h y peri nfla m mat or y pr oc ess t hat u n der pi ns  vir us -relate d m ortalit y. 
Pre -cli ni cal d ata i n dicate P T C 2 9 9 i n hi bits a r a n ge of R N A vir uses a n d s u p presses h y per c yt o ki ne 
e x pressi o n. P T C 2 9 9 has bee n e xte nsi vel y e val u ate d i n 9 c o m plete d cli ni cal st u dies ; 5 were i n 
o nc ol o g y ( n = 1 3 4) a n d 4 were i n healt h y v o l u nteers (n = 1 6 9 ). A f urt her st u d y i n o nc ol o g y p ati e nts 
is o n g oi n g. Acr oss t hese st u dies, P T C 2 9 9 was ge ner all y well -t ol erat e d o ver a ra n g e of d osi n g 
re gi me ns. 
1. 1.  
St u d y R ati o n ale  
T he rati o nal e t o assess P T C 2 9 9 f or t he tre at m e nt of C O VI D -1 9 is base d o n e x peri me ntall y 
vali date d e vi de nce of P T C 2 9 9’s a bilit y t o t ar get t w o ke y as pects of C O VI D -1 9 pat h o ge nesis: 
1)  i n hi biti o n of D H O D H re d uces S A R S-C o V -2 re plicati o n (Xi o n g 2 0 2 0 ) a n d 2) P T C 2 9 9 i n hi bits 
e xcessi ve c yt o ki ne pr o d ucti o n ass oci ate d wit h viral i nfecti o ns (Xi o n g 2 0 2 0 ). 
P T C 2 9 9, si milar t o ot her D H O D H i n hi bit ors, de m o nstrates br oa d -s pectr u m a nti viral acti vit y i n 
vitr o i n hi bit i n g b ot h p ositi v e - a n d ne g ati v e -se nse R N A vir uses ( P T C 2 9 9-2 0 2 0 -0 0 7, 
P T C 2 9 9 -2 0 2 0 -0 0 9, a n d P T C 2 9 9 -2 0 2 0 -0 1 1). Im p orta ntl y , P T C 2 9 9 i n hi bits S A R S -C o V -2  i n cell 
c ult ure m o dels ( data o n file).  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 1 9  of 6 2  
D H O D H  i n hi bit ors als o atte n uate c yt o ki ne st or ms t h at ca n si g nific a ntl y c o ntri b ute t o p ul m o nar y 
pat h ol o g y, or ga n f ail ur e, a n d deat h i n vir al i nf ecti o ns, s pecific all y wit h S A R S -C o V -2 
(Y os hi ka wa 2 0 0 9 , Xi o n g 2 0 2 0 ). Le vels of I L-2, I L -7, I L -1 0, G -C S F , I P-1 0, M C P -1, MI P -1 A, 
a n d T N F were f o u n d t o be hi g h er i n C O VI D -1 9 pati e nts i n t he i nte nsi v e care u nit ( I C U) t ha n i n 
t h ose pati e nts  n ot i n t he I C U , i n di cati n g t hat t hese c yt o ki nes ma y b e s pecific mar k ers of se vere 
disease  (H ua n g 2 0 2 0 ). T he eff ect of P T C 2 9 9 o n c yt o ki ne pr o d ucti o n was assesse d usi n g 
Bi o M A P pr ofili n g ( Bi o See k, n o w part of E ur ofi ns) . P T C 2 9 9 was f o u n d t o be a p ote nt i n hi bit or 
of i m m u n o m o d ulat or y a n d i nfl a m m ati o n -relat e d pr o cesses . C o m pare d wit h v e hicle c o ntr ol, 
P T C 2 9 9 res ulte d i n:  
•  Decreases i n i m m u n o m o d ulat or y-ass oci ate d pr otei ns: C D 4 0, s ol u ble (s)I g G, sI L -1 7 A, 
sI L-1 7 F, sI L -6, sI L -2, sI L -1 0  
•  Decreases i n i nfla m mati o n -r elate d pr ot ei ns: M C P-1, I L -8, a n d s T N F -α  
•  Decreases i n tiss ue re m o deli n g pr otei ns: M M P -1  a n d s V E G F  
T he str o n g rati o nal e s u p p orti n g t h e de vel o p me nt of P T C 2 9 9 f or t he tre at m e nt of C O VI D -1 9 is 
base d o n t he f oll o wi n g reas o ns:  
•  P T C 2 9 9 is a n i n hi bit or of cell ul ar D H O D H e nz y me acti vit y.  
− D H O D H i n hi bit ors ha ve be e n s h o w n t o i n hi bit S A R S -C o V -2 re plicati o n  
(Xi o n g  2 0 2 0 ). 
•  P T C 2 9 9 has de m o nstrat e d i n hi biti o n of S A R S -C o V -2 re plic ati o n i n vitr o  
•  P T C 2 9 9 i n hi bits a h ost cell -pr otei n, a n d si milar t o ot her h ost -tar geti n g a nti virals, has 
br oa d a nti viral acti vit y.  
− H ost -tar geti n g a nti virals ha ve a d va nt a ges o ver dir ect vir us-acti n g a nti virals as 
t he y are n ot vir us-s pecific –  he nc e t he y ca n re mai n  effecti v e e ve n if t he vir us 
m utat es, t h us mi ni mizi n g t he e mer g e nce of vir al resista nce.  
•  P T C 2 9 9 i n hi bits c yt o ki ne st or ms d ue t o vir al i nf ecti o n t hat c a n ca use tiss ue da ma g e, 
p ne u m o nia, a n d or ga n fail ure.  
− P T C 2 9 9 re d uces le v els of I L -6 al o n g wit h ot her c yt o ki nes; el e vat e d le vels of I L -6 
are p ositi v el y ass oci ate d wit h se verit y of p ul m o nar y c o m pli cati o ns  
T o date, t here are n o s pecific t h era pe utic a ge nts f or C O VI D -1 9 a n d c urre ntl y treat me nt is 
s u p p orti ve a n d base d o n s y m pt o mat ol o g y (C he n 2 0 2 0 b , Ji n 2 0 2 0). A t hera pe utic a ge nt t hat 
tar gets b ot h viral r e pli cati o n a n d t he h y p er-rea cti v e i m m u ne res p o nse w o ul d offer a hi g hl y 
desira ble treat me nt f or C O VI D -1 9 ma na g e me nt.  
1. 2.  
Ris k/ Be nefit Assess me nt  
E xte nsi ve cli nical k n o wle d ge e xists f or P T C 2 9 9 as it has bee n e val uate d i n > 3 0 0 s u bje cts i n 
9  c o m plete d cli ni cal st u dies. I n ge neral, t hr o u g h o ut t his pri or cli nical e x perie nce, P T C 2 9 9 was 
well -t ol erat e d wit h mi ni m al a n d m a na ge a ble si d e-eff ects. St u d y P T C 2 9 9 -VI R -0 1 5 -C O V 1 9 will 
ha ve a d ata a n d safet y m o nit ori n g b oar d  (D S M B ) t hat will cl osel y m o nit or t h e safet y of p atie nts. 
I n a d diti o n, a n i n de p e n de nt H e patic A d vis or y S afet y C o m mittee ( H A C) will  r e vie w all m ar kers 
of  p ossi ble  li ver t o xicit y. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 0  of 6 2  
T he C O VI D -1 9 pa n de mic is a lar ge , ac ut e u n met me dical n ee d. T h e mec h a nis m of a cti o n of 
P T C 2 9 9 a n d t he f i n di n gs t hat it: a) has  br oa d -s pectr u m a nti viral acti vit y a n d i n hi bits 
S A R S -C o V -2  re plicati o n; b ) r e d uces c yt o ki ne st or ms; a n d c) is well-t oler ate d i n dicate t h ere is a 
p ositi ve be n efit/ris k pr ofil e f or e val u ati n g t he dr u g i n patie nts wit h C O VI D -1 9.  
2.  
S T U D Y O B J E C TI V E A N D E N D P OI N T S  
2. 1.  
O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti v e  
T he pri m ar y o bje cti ve of t he st u d y is t o e val u ate t he cli ni cal effica c y of P T C 2 9 9 c o m p are d wit h 
place b o assesse d b y ti me t o res pirat or y i m pro ve me nt  i n a d ult s u bj ects h os pit ali ze d wit h 
C O VI D -1 9 . 
2. 1. 2.  
Sec o n d ar y O bjecti ves  
Sec o n dar y o bje cti v es of t he st u d y are as f oll o ws:  
•  T o e val u ate t he cli nic al effica c y of P T C 2 9 9 c o m p are d wit h plac e b o , as assesse d b y 
res pirat or y f u ncti o n, i m m u ne res p o nse, l e n gt h of h os pitalizati o n, a n d m ortalit y.  
•  T o e val u ate t he safet y of P T C 2 9 9 as assesse d b y dr u g relat e d a d verse e v e nts.  
2. 1. 3.  
E x pl or at or y O bjecti ves  
T here ar e n o e x pl orat or y o bje cti v es i n t his st u d y.  
2. 2.  
E n d p oi nts  
2. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri m ar y e n d p oi nt is t he ti m e fr o m ra n d o mizati o n t o res pirat or y i m pr o ve me nt, defi ne d as 
peri p heral o x y ge n sat urati o n ( S p O 2) ≥9 4 % o n r o o m air  s ustai ne d u ntil disc har ge fr o m t he 
h os pital  or t h e e n d of t h e st u d y ( Da y 2 8). 
2. 2. 2.  
Sec o n d ar y E n d p oi nts  
Sec o n dar y e n d p oi nts of t he st u d y are as f oll o ws:  
•  T he pr o p orti o n of s u bj ects re q uiri n g i n vasi v e ve ntilati o n at a n y p oi nt d uri n g t he st u d y  
•  T he pr o p orti o n of s u bj ects re q uiri n g s u p ple m e ntal o x y ge n or n o n -i n vasi ve v e ntilati o n 
at a n y p oi nt d uri n g t h e st u d y i n s u bje cts w h o di d n ot re q uire s u p ple me nt al o x y ge n at 
baseli ne  
•  T i me fr o m ra n d o mizati o n t o def er vesce n ce i n s u bj ects prese nti n g wit h f e ver at 
e nr oll m e nt ( t e m perat ure of ≥3 7. 6℃ a xilla, ≥3 8. 0 ℃ oral, or ≥3 8. 6° C t y m pa ni c or 
rectal) 
•  Ti me fr o m ra n d o mizati o n t o res pir at or y rate ≤2 4 br e at hs/ mi n ute o n r o o m air  
•  Ti me fr o m ra n d o mizati o n t o c o u g h r e p orte d as mil d or a bse nt (o n a scale of se vere, 
m o derat e, mil d, a bse nt,  i n t h ose wit h c o u g h at e nr oll me nt rate d se vere or m o derate) 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 1  of 6 2  
•  Ti me fr o m ra n d o mizati o n t o d ys p nea r e p orte d as mil d or a bse nt ( o n a scale of se vere, 
m o derat e, mil d, a bse nt, i n t h ose wit h d ys p nea at e nr oll me nt rat e d as se vere or 
m o derat e)  
•  Atte n uati o n of i m m u ne res p o nses as i n di cate d b y:  
− re d ucti o n i n c yt o ki ne l e vels, p ote ntiall y i n cl u di n g i nt erle u ki n (I L)-2, I L -6, I L -7, 
I L-1 7, G -C S F, I P -1 0, M C P -1, MI P 1 -α, a n d T N F -α  
− re d ucti o n i n le v els of ac ut e p hase pr ot ei ns, p ote ntiall y i ncl u di n g f erriti n, 
C -reacti ve pr ot ei n, D-di mer, a n d car diac tr o p o ni n   
− n or mali zati o n i n t h e c o m plete bl o o d c o u nt  
− c ha n ges i n o t h er la b orat or y para met ers p ote ntiall y i n cl u di n g de creases i n lact ate 
de h y dr o ge nase, pr ot hr o m bi n ti me, al b u mi n  
•  Re d ucti o n i n viral l oa d  
•  D urati o n of h os pitaliz ati o n m eas ure d i n d a ys  
•  M ortalit y at Da y 2 8  
•  O verall safet y pr ofile c hara cterize d b y t y pe, fre q ue n c y, se verit y, ti mi n g, a n d 
relati o ns hi p t o st u d y tr eat me nt of a n y a d verse e v e nts ( A Es) or la b orat or y 
a b n or maliti es.  
2. 2. 3.  
E x pl or at or y E n d p oi nts  
T here ar e n o e x pl orat or y e n d p oi nts i n t his st u d y.  
3.  
S T U D Y D E SI G N  
3. 1.  
O ver all Desi g n  
T his is a ra n d o mize d, d o u ble -bli n d, plac e b o -c o ntr oll e d, m ultice nter 2 8 -da y st u d y , wit h a safet y 
f oll o w-u p tel e p h o ne c all at Da y 6 0 .  
T he st u d y p o p ulati o n is h os pit ali ze d a d ult s u bje cts wit h c o nfir me d p ne u m o nia, dia g n ose d wit h 
C O VI D -1 9, a n d n ot re q uiri n g me c ha nic al ve ntil ati o n.  F or t he p ur p oses of e nr oll m e nt of s u bje cts 
i nt o t he st u d y, “ h os pitaliz e d patie nts” will i ncl u de a n y C O VI D-1 9 patie nt eit her a d mitte d or 
u n der o bser vati o n i n t he h os pital f or a c o nti n u o us peri o d of 2 4 h o urs or m ore w h o ot her wise 
f ulfills t h e eli gibilit y  crit eria.   
S u bjects will b e ra n d o mize d 1: 1 t o P T C 2 9 9 tr eat me nt or plac e b o  usi n g a c e ntral r a n d o mi zati o n 
pr ocess , wit h a p pr o xi m atel y 1 9 0  s u bjects i n eac h c o h ort. T he ra n d o miz ati o n will be stratifi e d b y 
a ge ( ≤6 2  vs > 6 2) , re m d esi vir use ( yes vs n o ), a n d de xa met h as o ne use ( yes vs n o).  All s u bjects 
will als o re cei v e s ta n dar d of c are  ( S O C), defi ne d as t he S O C per l ocal writte n p olicies or 
g ui deli n es. T he use of ster oi ds  (e xce pt d e xa m et has o ne), se nsiti ve C Y P 2 D 6 s u bstrates, C Y P 2 C 
i n d ucers, I L-6 ne utralizi n g a nti b o di es , I L-6 r ec e pt or i n hi bit ors , a n d a n y i n vesti gati o nal t hera pi es 
are pr o hi bite d.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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P T C T her a pe utics - C o nfi de nti al  
P a ge 2 2  of 6 2  
F oll o wi n g eli gi bilit y scre e ni n g a n d e nr oll me nt, s u bj e cts will re cei v e oral t a blets c o ntai ni n g 
P T C 2 9 9 or matc h i n g pla ce b o 2 0 0 m g t wice dail y ( BI D) ( m or ni n g a n d e ve ni n g) o n Da ys 1 t o 7 
a nd 5 0 m g o nce d ail y ( Q D)  i n t h e m or ni n g o n Da ys 8 t o 1 4.  
A p pr o xi matel y 4 0 s u bjects ( 2 0 i n eac h ar m) will be e nr olle d i niti all y, e nr oll me nt will t h e n halt, 
a n d a n i nt eri m a nal ysis will be perf or m e d t o assess safet y. N o f or mal statistical testi n g will b e 
perf or me d at t he i nteri m  a nal ysis . A n i n de pe n de nt data safet y m o nit ori n g b oar d (D S M B ) a n d a n 
i n de pe n de nt H A C will re vi e w a vail a ble d ata  f or t he 4 0 s u bjects. E nr oll me nt will c o nti n u e if 
t here ar e n o safet y c o n cer ns.  
A sec o n d i nteri m a nal ysis is pla n ne d t o assess f utilit y. It will be p erf or me d w he n 5 0 % of 
res pirat or y i m pr o ve m e nt e ve nts ha ve be e n rea c he d, ie, 1 63  e ve nts ha v e bee n o bser ve d 
(a p pr o xi matel y 1 9 0 s u bj ects). 
S u bjects will b e assesse d dail y w hile h os pit ali ze d. All s u bjects will u n der g o effica c y, safe t y, a n d 
la b orat or y assess me nts as s u m mari ze d  i n T a ble  3 . T here will b e a f oll o w -u p tele p h o n e call at 
Da y 6 0 t o assess A Es, S A Es, a n d deat hs.  
F or s u bjects w h o are disc har ge d fr o m t he h os pital pri or t o Da y 2 8:  
•  If S p O2 is < 9 4 %, S p O 2 meas ure me nts will be ta ke n dail y u ntil Da y 2 8  
•  S u bject -re p orte d assess me nts f or c o u g h a n d d ys p ne a will c o nti n ue t o Da y 2 8 
•  N o ot her assess me nts will t a ke pl ace e x ce pt f or t h ose s pecifi e d at Da y 1 4, 2 8 a n d Da y 
6 0 i n t he pr ot o c ol.  
All s u bjects will u n der g o t h e assess me nts s pecifie d f or Da y 1 4 ( E n d of Treat me nt) a n d Da y  2 8 
( E n d of St u d y), a n d partici p ate i n t he Da y 6 0  t ele p h o ne call, e ve n if t he y ar e disc har g e d fr o m  t h e 
h os pital pri or t o Da y 2 8.   
3. 2.  
J ustific ati o n of D ose  
I n a precli nic al st u d y, m o n ke ys were gi ve n a si n gle oral 1 0 m g/ k g ca ps ule d ose of P T C 2 9 9. 
P las ma le v els of D H O, t he s u bstrate f or D H O D H, i ncrease d after d osi n g, pea k e d at 2 4 h o urs a n d 
t he n decr ease d (Fi g ure  1 ). T h e e x p os ure f or P T C 2 9 9 was 2 2. 5 µ g *hr/ m L. T he attai n me nt of t he  
pea k D H O c o nce ntrati o n  was  dela y e d rel ati v e t o t h e pea k c o nc e ntrati o n of P T C 2 9 9 ( 2 4 h o urs vs. 
2 h o urs) ( Ta ble  1 ). T h ese data s u g gest t hat a n e x p os ure of a p pr o xi m atel y 2 2. 5 µ g *hr/ m L  will 
res ult i n si g nifica nt D H O D H i n hi biti o n. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 3  of 6 2  
Fi g ur e  1 : 
Pl a s m a D H O a n d P T C 2 9 9 C o n c e ntr ati o n s aft er a Si n gl e Or al D o s e of P T C 2 9 9  
0
5 0
1 0 0
1 5 0
2 0 0
0
1
2
3
4
0
1
2
3
P l a s m a D H O  ( g/ m L )
H o u r s
P T C 2 9 9 P l a s m a C o n c e n t r a ti o n  ( g/ m L )
D H O
P T C 2 9 9
 
A b br e vi ati o n s : D H O, di h y dr o or ot at e 
T a bl e  1 : 
S u m m ar y of P K a n d P D P ar a m et er s  
 
P T C 2 9 9  
D H O  
A U C 0 -l a st ( µ g*hr/ m L)  
2 2. 5  
7 1. 4  
C m a x  ( µ g/ m L) 
2. 5 1  
2. 4 8  
T m a x  ( hr p o st-d o s e)  
2  
2 4  
H alf -lif e ( hr) 
3 3  
1 0  
A b br e vi ati o n s : A U C, ar e a u n d er t h e c ur v e: D H O, di h y dr o or ot at e 
Cli nic al D at a  
T he a bilit y of P T C 2 9 9 t o i n hi bit D H O D H i n h u ma ns was e xa mi ne d i n t he P hase 2 cli nical st u d y 
P T C 2 9 9 -O N C -0 0 7 -N F 2 ( St u d y 0 0 7). St u d y 0 0 7 e val uate d P T C 2 9 9 m o n ot hera p y i n a d ult 
patie nts wit h ne ur ofi br o mat osis t y p e 2  ( N F 2). P T C 2 9 9 was a d mi nister e d at a d ose of 1 0 0 m g 
ca ps ule BI D  (c orres p o n di n g t o  2 5 0 m g BI D of t he t a blet  f or m ulati o n).  
T he ser u m l e vels of D H O  were bel o w t he l o wer li mit of q ua ntificati o n pri or t o d osi n g a n d w ere 
si g nifica ntl y ele vate d at eit h er 8 or 1 6 wee ks  (Fi g ure  2 A ), c o nsiste nt wit h i n hi biti o n of D H O D H 
b y  P T C 2 9 9. T he el e vati o n of D H O le vels  (a b o ut 1. 7 µg/ m L ) aft er P T C 2 9 9 t her a p y is si milar if 
n ot great er t o t h at o bser ve d i n a patie nt wit h Mi ll er s y n dr o me ( 0. 5 3 7 µ g/ m L)  (D ul e y 2 0 1 6 ). 
Miller s y n dr o me is ca use d  b y  a m utati o n i n t he D H O D H  ge ne res ulti n g i n a deficie nc y i n 
D H O D H e nz y me acti vit y, w hic h le a ds t o  el e vat e d ser u m D H O le vels (D ule y 2 0 1 6 ).  
T he acti vit y of P T C 2 9 9 as a D H O D H i n hi bit or was als o teste d b y assessi n g  t he effect o n t he 
pr o d ucti o n of t h e c yt o ki ne vasc ul ar e n d ot h eli al gr o wt h fact or (V E G F ). V E G F l e vels are k n o w n 
t o be a b n or m all y ele vate d i n N F 2  patie nts (Pl ot ki n 2 0 0 9 ). D H O D H i n hi bit ors ha ve be e n s h o w n 
t o s u p press V E G F e x pr essi o n (Die dric hs -M o hri n g 2 0 1 8 ). As s h o w n i n  
Fi g ure  2 B , ser u m V E G F l e vels were ele vate d pri or t o d osi n g b ut were n or maliz e d  after 8 we e ks 
of treat me nt t o le v els si milar t o t h ose re p orte d f or h e alt h y s u bje cts (Rai m o n d o 2 0 0 1 , K ut 2 0 0 7 ), 
a statisticall y si g nifica nt re d ucti o n .  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 4  of 6 2  
T he P T C 2 9 9 -de pe n d e nt c h a n ges i n D H O a n d V E G F le vels str o n gl y i n dic ate t he dr u g dire ctl y 
i n hi bits D H O D H i n t hese pati e nts a n d elicits a p pr o priate p h ar ma c o d y na mi c c ha n g es.  
T h e re d ucti o n of V E G F le vels  was ass ociate d wit h a plas ma c o n ce ntr ati o n of P T C 2 9 9 4  -h o urs 
p ost d ose of 1. 9 µ g / m L, w hic h  is k n o w n t o be cl ose t o Cma x . 
Fi g ur e  2 : 
P T C 2 9 9 I n hi bit s D H O D H i n P ati e nt s wit h N e ur ofi br o m at o si s T y p e 2 T u m or s  
 
L e g e n d : ( A) D H O s a m pl e s fr o m a t ot al of 4 p ati e nt s pr e- a n d p o st -d o si n g wit h P T C 2 9 9 d o si n g. ( B) V E G F pl a s m a 
l e v el s f or 1 1 p ati e nt s pr e- a n d p o st -P T C 2 9 9 d o si n g.  
S o ur c e : P a n el A ( D H): P T C 2 9 9-1 7 0 3 0  
Pre dicti o n b ase d o n i n vitr o S A R S -C o V -2 d at a  
A c o nce ntrati o n of 2 5 0 n M P T C 2 9 9 ( 1 1 7 n g/ m L) re d uce d S A R S -C o V -2 viral tit er b y 3 -l o gs i n 
me dia wit h 5 % ser u m ( P T C 2 9 9 -2 0 -0 1 2). T o mai ntai n le vels 1 0 -f ol d a b o ve t his c o nce ntr ati o n, or 
1 1 7 0 n g/ m L, f or 2 4 h o urs w o ul d res ult i n a n A U C 0 -2 4 h of 2 8. 1 µ g *hr/ m L . T his is a b o v e t he tar get 
le vel r e q uire d f or D H O D H i n hi biti o n of 2 2. 5 µ g*hr/ m L.  
D ose Re gi m e n Re q uire d t o  Re ac h A U C  S h o w n t o I n hi b it D H O D H 
Cli nic al St u d y P T C 2 9 9 -O N C -0 0 2 -H V e val uat e d t he P K a n d safet y of i ncreasi n g d oses of t he 
ca ps ule f or m ulati o n of P T C 2 9 9 i n he alt h y v ol u nteers ( N = 3 2; n = 2 4 recei v e d P T C 2 9 9 a n d n = 8 
recei v e d plac e b o).  
St u d y 0 0 2 ha d 2 sta ges; i n St a ge 1, d oses ra n ge d fr o m 0. 3 t o 1. 2 m g/ k g BI D, a n d i n Sta ge 2, a 
1. 6 m g/ k g d ose was a d mi nistere d TI D (Ta ble  2 ). Pati e nts recei ve d t h e ca ps ule f or m ulati o n of 
P T C 2 9 9 f or 7 da ys i n b ot h sta ges. T h e 1. 2 m g/ k g ca ps ule f or m ulati o n s h o ul d ha v e si milar 
e x p os ure t o t he  a b o ut 2 0 0 m g of t he ta blet f or m ulati o n base d o n relati ve bi oa vaila bilit y; t he 
ta blet f or m ul ati o n h as a p pr o xi matel y 4 0 % r elati ve bi oa vail a bilit y c o m pare d wit h t he c a ps ule. F or 
refere nce, Ta bl e  2  prese nts t h e a p pr o xi mat e d ose of t he ta bl et f or m ulati o n, w hic h will be use d i n 
P T C 2 9 9 -VI R -0 1 5 -C O V 1 9, f or eac h d ose of t he ca ps ule f or m ul ati o n a d mi nistere d i n St u d y 0 0 2.  
T he e x p os ure o bser ve d f oll o wi n g t he 1. 2 m g/ k g  BI D d ose at Da y 1 was 1 8 µ g *hr/ m L a n d at 
Da y  7 was 3 2. 9 µ g *hr/ m L  (Ta bl e  2 ). T he Da y 1 e x p os ure is si milar t o t he e x p os ure of 
2 2. 5  µ g *hr/ m L o bser ve d after a b o ut 2 4 h o urs i n t he r hes us m o n ke y e x peri me nt t hat de m o nstrat e d 
D H O D H i n hi biti o n. T h e C ma x  of P T C 2 9 9 was 2. 1 1 µ g/ m L, w hic h is si mil ar t o t h at ass oci ate d 
wit h D H O D H i n hi biti o n (ie, 1. 9 µ g/ m L) see n i n p ati e nts i n St u d y 0 0 7.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 5  of 6 2  
Ba s ed o n t he bi ol o gic al data o utli ne d a b o v e, t he P T C 2 9 9 e x p os ure after d osi n g at 1. 2 m g/ k g BI D 
w o ul d res ult i n si g nifica nt re d ucti o n of D H O D H e nz y me acti vit y i n t h e cli nic.  
N o seri o us a d verse e ve nts were re p orte d i n St u d y 0 0 2.  
T a bl e  2 : 
S u m m ar y of P T C 2 9 9 P h ar m a c o ki n eti c s i n H e alt h y V ol u nt e er s w h e n A d mi ni st er e d 
wit h t h e C a p s ul e F or m ul ati o n ( ~ 2. 5 x of t h e Bi o a v ail a bilit y of t h e T a bl et 
F or m ul ati o n) ( St u d y P T C 2 9 9 -O N C -0 0 2 -H V)  
A b br e vi ati o n s : A U C0 -4 , ar e a u n d er t h e c o n c e ntr ati o n c ur v e fr o m h o ur 0 t o 4; Cm a x , m a xi m al c o n c e ntr ati o n; 
T 1/ 2 , h alf -lif e; Tm a x , ti m e t o m a xi m al c o n c e ntr ati o n 
a  St u d y 0 0 2 o nl y a d mi ni st er e d t h e c a p s ul e f or m ul ati o n of P T C 2 9 9. T h e v al u e s f or t h e t a bl et r e pr e s e nt t h e 
a p pr o xi m at e d o s e of t h e t a bl et f or m ul ati o n f or r ef er e n c e. T h e d o s e c al c ul ati o n s a s s u m e a b o ut a 7 0 k g b o d y w ei g ht.  
N ot e: T h e v al u e s i n b ol d s h o w t h e d o s e  t h at r e s ult s i n e x p o s ur e s t h at ar e si mil ar t o t h o s e m e a s ur e d i n 
St u d y  P T C 2 9 9 -O N C -0 0 7 -N F 2.  
Pr o p ose d d osi n g re gi m e n  
S u bjects will b e d ose d f or a t otal of 1 4 da ys a n d f oll o we d f or a n a d diti o nal 1 4 d a ys wit h o ut 
d osi n g. S u bjects will r ecei ve oral ta bl ets c o nt ai ni n g P T C 2 9 9 or matc h e d pla ce b o 2 0 0 m g BI D 
( m or ni n g a n d e v e ni n g) o n D a ys 1 t o 7 a n d 5 0 m g Q D o n Da ys 8 t o 1 4.  S u bjects 
will  s u bse q ue ntl y b e  f oll o we d fr o m Da y 1 5 t o 2 8, a n d t here will be a tele p h o n e call at Da y 6 0 t o 
assess A Es, S A Es, a n d deat hs .  
T he d osi n g re gi me n t a kes i nt o c o nsi derati o n t he t y pi cal pr o gressi o n of t h e disease i n cl u di n g t he 
disease c har acteristics i n p ati e nts w h o are h os pit ali ze d wit h C O VI D -1 9. T he d osi n g of 2 0 0 m g 
BI D f or t he first 7 da ys will r aise t h e e x p os ure of t he dr u g q uic kl y t o ac c o m m o date t he n ee d f or 
ra pi d o nset of P T C 2 9 9 a cti vit y. T h e d osi n g of 5 0 m g Q D f or t he sec o n d 7 da ys will pre ve nt t he  
e x p os ure fr o m s u bsta nti all y d ecreasi n g. I m p orta ntl y, cli ni cal e vi de n ce i n di cat es t hat t his d osi n g 
re gi me n s h o ul d b e well t olerate d. 
T he d os i n g re gi me n is base d o n e xte nsi ve cli nical, safet y, a n d cli ni cal p har mac ol o g y e x perie nc e 
wit h t he c a ps ule f or m ulati o n of P T C 2 9 9, w hic h was use d i n t he pri or s oli d t u m or cli nical st u dies. 
T he res ults fr o m cli nical st u d y P T C 2 9 9 -O N C -0 0 2 -H V ( St u d y 0 0 2) i n dicat e t hat 2 0 0 m g BI D 
d osi n g w o ul d raise t he e x p os ure of P T C 2 9 9 wit hi n 7 da ys t o t he a ntici pat e d t hera p e uti c ra n ge  
( 2 3 t o 3 3 µ g *h r/ m L). 
A p pr o xi m at e C orr e s p o n di n g D o s e a  
D o s e 
Fr e q u e n c y  
D a y  
P T C 2 9 9  
T a bl et ( m g)  
C a p s ul e ( m g/ k g)  
T m a x  
( h) 
T 1/ 2  
( h) 
C m a x  
( µ g/ m L) 
A U C 0 -4  
( µ g*hr/ m L)  
5 0  
0. 3  
BI D  
1  
4. 0  
N A  
0. 2 8  
4. 3 1  
1 2 5  
0. 6  
3. 0  
0. 7 1  
1 0. 1  
2 0 0  
1. 2  
3. 5  
1. 1 4  
1 8. 0  
2 8 0  
1. 6  
TI D  
3. 0  
1. 6 7  
3 7. 1  
5 0  
0. 3  
BI D  
7  
3. 5  
1 6 4  
0. 5 1  
8. 4 4  
1 2 5  
0. 6  
4. 0  
2 1 0  
1. 1 1  
1 8. 6  
2 0 0  
1. 2  
4. 0  
2 2 8  
2. 1 1  
3 2. 9  
2 8 0  
1. 6  
TI D  
3. 0  
2 2 5  
3. 5 3  
7 8. 6  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 6  of 6 2  
P T C 2 9 9 2 0 0 m g t a blet BI D f or 7 d ays is e x pecte d t o be t oler at e d i n p ati e nts.  
T he e x pe cte d e x p os ure fr o m t he pr o p ose d d osi n g r e gi me n is e x p ect e d t o be well -t ol erat e d, as t he 
c o m para ble e x p os ure i n St u d y 0 0 2 di d n ot c a use  S A Es. T he C ma x  aft er gi vi n g t he 2 0 0 m g ta bl et 
BI D f or 7 da ys is a ntici p ate d t o be a b o ut 2. 1 1 µ g/ m L a n d is n ot e x pe cte d t o ca use a n y saf et y 
c o ncer n, as si milar plas ma c o n ce ntr ati o ns were o bser ve d i n t he p ati e nts w h o were treate d wit h 
P T C 2 9 9 ca ps ule f or > 4 0 da ys.  
Safet y e ve nts wit h re gar d t o i ncre ases i n P T C 2 9 9 le v els d ue t o sat ur ati o n of eli mi nati o n are 
u nli kel y as eli mi nati o n of t h e dr u g will n ot be sat urat e d wit h 7 da ys of 2 0 0 m g t a blet BI D d osi n g 
f oll o we d b y 7 da ys of 5 0 m g t a blet Q D d osi n g. T his is s u p p orte d b y res ults fr o m St u d y 0 0 2 i n 
w hic h relati ve d ose li nearit y was o bser ve d fr o m 0. 3 m g/ k g t o 1. 2 m g/ k g BI D d oses of P T C 2 9 9 
ca ps ules (e q ui v ale n t t o 2 0 0 m g BI D ta blets). It is als o s u p p orte d b y t he o n g oi n g A M L 
o pe n -la bel, n o n-ra n d o mize d, p hase 1 b st u d y, P T C 2 9 9-H E M -0 0 1 -L E U i n w hic h t he st ea d y stat e 
was reac he d at a p pr o xi m atel y Da y 1 5 aft er a d mi nistr ati o n of a n 8 0 m g Q D l oa di n g d ose of t h e 
ta blet f or m ul ati o n of P T C 2 9 9 f or 7 d a ys f oll o we d b y a 4 0 m g Q D mai nt e na nc e d ose. 
3. 3.  
E n d of St u d y Defi niti o n  
T he st u d y will e n d w he n t he last s u bje ct has c o m plet e d t he fi n al assess me nt. 
4.  
S T U D Y P O P U L A TI O N  
4. 1.  
O ver vi e w  
T he st u d y p o p ulati o n is h os pit ali ze d a d ult s u bje cts wit h  c o nfir me d p ne u m o nia, dia g n ose d wit h 
C O VI D -1 9, a n d n ot re q uiri n g me c ha nic al ve ntil ati o n. A p pr o xi matel y 3 8 0 s u bjects will be 
ra n d o miz e d: 1 9 0 s u bje cts t o pl ace b o  a n d 1 9 0 s u bj ects t o P T C 2 9 9. 
4. 2.  
I ncl usi o n Criteri a 
Bef ore e nr oll me nt i n t h e st u d y, s u bjects m ust f ul fil all of t he f oll o wi n g criteria: 
1.  S u bject ( or l e gall y a ut h orize d re pr ese ntati ve) is willi n g a n d a ble t o pr o vi de i nf or me d 
c o nse nt a n d c o m pl y wit h all pr ot oc ol re q uire m e nts . 
2.  A grees t o t he c olle cti o n of nas o p har y n g eal s wa bs a n d ve n o us bl o o d a n d all ot her 
pr o t oc ol-s pecifie d pr oc e d ures. 
3.  Male or n o n -pre g na nt fe male a d ult ≥1 8 y ears of a ge at ti me of e nr oll m e nt.  
4.  H os pitaliz e d a n d has l a b orat or y -c o nfir me d i nfecti o n wit h S A R S -C o V -2.  
5.  S y m pt o m o nset was ≤1 4  da ys pri or t o S cree ni n g  
6.  Has S p O 2 < 9 4 % o n r o o m air  
7.  Has at least o n e of res pirat or y r ate > 2 4 br eat hs/ mi n ut e or c o u g h  
8.  L u n g i n v ol ve me nt as c o nfir m e d b y ra di o gra p hic i nfiltrates o bser ve d o n i ma gi n g (c hest 
X -ra y, C T sca n, or a n e q ui v ale nt test )  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 2 7  of 6 2  
9.  W o me n of c hil d be ari n g p ote ntial (as defi n e d i n (C T F G 2 0 1 4 )) m ust ha ve a ne gati ve 
pre g na nc y t est at scre e ni n g a n d a gree t o a bsti n e nce or t he use at least o n e of t he 
f oll o wi n g hi g hl y effecti ve f or ms of c o ntrac e pti o n  (wit h  a fail ure r ate of < 1 % p er year 
w he n use d c o nsiste ntl y a n d c orrectl y). C o ntr ace pti o n or a bsti ne nc e m ust be c o nti n ue d  f or 
t he d urati o n of t he st u d y f oll o wi n g disc h ar ge fr o m t h e hos pital , a n d f or u p t o 5 0  da ys 
after t h e last d ose of st u d y dr u g : 
•  c o m bi ne d ( estr o ge n a n d pr o gest o g e n c o nt ai ni n g) h or m o nal c o ntrac e pti o n ass oci ate d 
wit h i n hi biti o n of o v ul ati o n:  
− oral  
− i ntra va gi nal 
− tra ns der mal 
•  pr o gest o ge n -o nl y h or m o n al c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ul ati o n:  
− oral  
− i njecta bl e 
− i m pla nta bl e 
•  i ntra ut eri ne d e vice 
•  i ntra ut eri ne h or m o ne-rel easi n g s yste m 
•  vasect o mize d p art ner  wit h c o nfir m e d az o os per mia  
All fe males will b e c o nsi dere d of c hil d b eari n g p ote ntial u nl ess t he y are p ost me n o pa usal 
(at le ast 1 2 m o nt hs c o nse c uti v e a me n orr h ea i n t he a p pr o priate a ge gr o u p wit h o ut ot her 
k n o w n or s us pecte d ca use) or ha ve b ee n sterili ze d s ur gicall y (e g , bilat eral t u b al li gati o n, 
h ysterect o m y, bil ateral o o p h orect o m y).  
1 0.  Me n se x uall y a cti v e wit h w o me n of c hil d be ari n g p ot e ntial w h o ha ve n ot h a d a vasect o m y 
m ust a gree t o use a barri er met h o d of birt h c o ntr ol d uri n g t he st u d y f oll o wi n g disc har g e 
fr o m t he h os pit al a n d f or u p t o 5 0 da ys after t he l ast d ose of st u d y dr u g.  
4. 3.  
E xcl us i o n Criteri a 
S u bjects will n ot be per mitte d t o e nr oll i n t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
1.  Re q uires me c ha ni cal ve ntil ati o n  
2.  C urre nt partici p ati o n i n a n y ot her i nter v e nti o n al st u d y. 
3.  A la ni ne tr a nsa mi n ase/as part ate tra nsa mi nase l e vels ( A L T/ A S T) ≥3 ti mes t he u p p er li mit 
of n or mal  (× U L N)  or t ot al bilir u bi n ( T bili) ≥2 × U L N . 
4.  L y m p h oc yt e c o u nt < 5 0 0 l y m p h oc ytes/ µ L  or he m o gl o bi n < 1 1 . 0 g/ d L  
5.  Sta ge 4 se vere c hr o nic ki d n e y disease or r e q uiri n g di al ysis (ie, esti mate d gl o mer ul ar 
filtrati o n rate < 3 0) 
6.  A n y ot her c o n diti o n, t hat i n t h e o pi ni o n of t he i n vesti gat or, m a y be c a use t o e xcl u de t h e 
s u bject fr o m t he st u d y. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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V 7 . 0 
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7.  Use of ster oi ds  (e xce pt de x a met has o ne), se nsiti ve C Y P 2 D 6 s u bstrates, C Y P 2 C i n d ucers,  
I L-6 ne utralizi n g a nti b o dies, I L -6 re ce pt or i n hi bit ors , or a ny i n vesti g ati o n al t h era p y . 
8.  Pre g na nc y or breast fe e di n g.  
9.  A ntici pate d tr a nsfer t o a n ot h er h os pital w hic h is n ot a st u d y site wit hi n 7 2 h o urs.  
1 0.  K n o w n aller g y t o P T C 2 9 9  or e x ci pi e nts . 
4. 4.  
Scree n F ail ures  
A n y s u bject t hat d oes n ot m eet i ncl usi o n or e x cl usi o n criteri a wit hi n t he d efi ne d scre e ni n g 
wi n d o w pri or t o ra n d o mi zati o n, will b e c o nsi dere d a scree n fail ure. Scree ni n g a n d ra n d o miz ati o n 
s h o ul d occ ur wit hi n a 1-da y peri o d. Scree n fail ures will be c a pt ure d i n t he electr o nic d ata ca pt ur e 
s yste m ( E D C). Scree n fail ures  ca n b e rescre e ne d after c o ns ultati o n wit h t h e Me dic al M o nit or.  
4. 5.  
Str ate gies f or Recr uit m e nt a n d Rete nti o n  
S u bjects will b e recr uite d via e xisti n g p o p ulati o ns wit h C O VI D -1 9  at i de ntifie d i n v esti gati o nal 
sites. 
5.  
S T U D Y I N T E R V E N TI O N  
5. 1.  
St u d y I nter ve nti o n(s) A d mi nistr ati o n 
5. 1. 1.  
St u d y Inter ve nti o n D escri pti o n  
P T C 2 9 9 or matc hi n g pla ce b o t a blets f or oral a d mi nistrati o n will be pr o vi de d i n t he 5 0 m g d osa g e 
stre n gt h. 
5. 1. 2.  
D osi n g a n d A d mi nistr ati o n  
P T C 2 9 9 or matc hi n g pla ce b o oral ta bl e ts will b e a d mi nister e d at a d ose of 2 0 0 m g BI D ( m or ni n g 
a n d e ve ni n g  at a p pr o xi mat el y 1 2 -h o ur i nter vals ) o n Da ys 1 t o 7 f oll o we d b y 5 0 m g Q D (i n t he 
m or ni n g)  o n Da ys 8 t o 1 4.  It is re c o m m e n de d t hat P T C 2 9 9 be a d mi nister e d wit h f o o d.  
Ta blets will be a d mi nistere d i n t he h os pital; s h o ul d a s u bject be disc har ge d pri or t o Da y 1 4 , 
ta blets will be dis pe nse d t o t a ke at h o me.  
5. 2.  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Ac c o u nt a bilit y  
5. 2. 1.  
Acc o u nt a bilit y  
St u d y pers o n nel m ust e ns ure t hat all st u d y dr u g s u p plies are k e pt i n a sec ure l o c ke d ar ea with 
access li mit e d t o a ut h orize d p ers o n nel. St u d y dr u g  m ust n ot be use d o utsi de t he c o nte xt of t his 
pr ot oc ol. U n der n o circ u mst a nces s h o ul d t he i n vesti g at or or site p ers o n nel s u p pl y st u d y dr u g t o 
ot her i n vesti gat ors or cli ni cs or all o w st u d y dr u g t o b e use d ot her t h a n as directe d b y t his 
pr ot oc ol.  
T he i n vesti gat or is res p o nsi ble f or kee pi n g ac c urat e r ec or ds of t he cli ni cal s u p plies recei ve d fr o m 
P T C or desi g nee, t h e a m o u nt dis pe nse d t o a n d ret ur n e d b y t he s u bje cts, a n d t h e a m o u nt 
re mai ni n g at t he c o ncl usi o n of t he trial. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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V 7 . 0 
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P a ge 2 9  of 6 2  
U se d a n d u n use d cli ni cal s u p plies m ust be ret ur ne d t o P T C T hera pe utics ( P T C)  or its desi g nee 
after t h e st u d y is c o m plet e d. If t he Sta n d ar d O perati n g Pr oce d ure ( S O P) at a n y site st ates t hat t he 
dr u g ca n n ot  be r et ur ne d a n d m ust be dis p ose d of o nsite, P T C m ust r e vie w t h e S O P of t hat site 
pri or t o a n y fi n al dis p ositi o n d o ne b y sit e. Rec or ds d oc u me nti n g t he d ate of st u d y  me di cati o n 
destr ucti o n or s hi p pi n g, a n d a m o u nt destr o y e d or s hi p pe d s h o ul d be  ke pt.  
5. 2. 2.  
F or m ul ati o n, A p pe ar a nce, P ac k a gi n g, a n d L a beli n g  
P T C 2 9 9 a n d mat c hi n g pl ace b o ta blets f or oral a d mi nistrati o n will be pr o vi de d i n 5 0 m g d osa ge 
stre n gt h. 
Ta blets will be p ac ka ge d i n b ottles f or distri b uti o n t o i n vesti gati o nal sites.  
P T C 2 9 9 a n d mat c hi n g pl ace b o ta blets m ust be st ore d per t he l a bel ed st ora ge c o n diti o ns.  
5. 3.  
Me as ures t o Mi ni mi ze Bi as: R a n d o miz ati o n a n d Bli n di n g  
T he st u d y is perf or m e d i n a d o u ble -bli n d f as hi o n. T h e I n vesti gat or a n d st u d y staff (i ncl u di n g 
pr ocessi n g la b pers o n nel), t he s u bje cts, a n d t h e s p o ns or’s staff will re mai n bli n d e d t o t h e 
treat me nt u ntil st u d y cl os ure. T h e i n vesti g ati o n al dr u g a n d its matc hi n g plac e b o are 
i n disti n g uis ha ble a n d will be p ac ka ge d i n t he sa me wa y. 
T he ra n d o mizati o n c o de will be k e pt stri ctl y c o nfi de ntial. F urt h er det ails ar e pr o vi de d i n t he 
P har mac y Ma n ua l. 
S u bjects will b e ra n d o mize d 1: 1 t o eit her P T C 2 9 9  or place b o usi n g a ce ntral ra n d o miz ati o n 
pr ocess . T he ra n d o mizati o n will b e stratifie d b y a ge ( ≤6 2 vs > 6 2) , re m desi vir use ( y es vs n o ), 
a n d de xa m et has o ne use ( yes vs n o).  
5. 3. 1.  
E mer ge nc y P r oce d ure f or U n bli n di n g  
T he I n vesti g at or a n d t he st u d y staff m ust r e mai n bli n de d t o t he s u bj ect's tre at me nt assi g n me nt, 
e ve n if t h e s u bject ref uses t o partici p ate i n a n y st u d y pr oce d ures or e x peri e nces a n A E. T he 
i de ntit y of t he st u d y dr u g ma y be r e veal e d o nl y if t he s u bject e xp erie n ces a me dical e m er ge nc y 
w h ose ma na ge m e nt w o ul d be i m pr o ve d b y t h e k n o wle d ge of t h e bli n d e d treat me nt assi g n me nt.  
T he occ urr e nce of a n y c o de bre a k d uri n g t h e st u d y m ust be cl earl y j ustifi e d a n d e x pl ai ne d b y t he 
I n vesti gat or. B ef ore u n bli n di n g, e ver y att e m pt m ust be ma de b y t he I n vesti gat or t o disc uss t he 
i nte n de d c o de brea k wit h P T C. I n all cases, t h e s p o ns or m ust be i nf or me d as s o o n as p ossi ble 
bef ore or after t he c o d e brea k.  
A n y c o de brea k m ust b e d oc u me nte d i n a det ail e d re p ort wit h t he d ate a n d ti m e of t he c o de bre a k 
a n d si g ne d b y t he I n v esti gat or. T his re p ort is t o be attac he d t o t he s o urc e d oc u me nts a n d t he d ate 
a n d ti m e of c o de br ea k will b e d oc u m e nte d i n t he e C R F.  
5. 4.  
St u d y I nter ve nti o n a n d C o m pli a nce  
C o m plia n ce will be c alc ulate d as descri be d i n Se cti o n 8. 4. 4. 3 . 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 0  of 6 2  
5. 5.  
C o nc o mit a nt T her a p y  
All s u bjects i n b ot h c o h orts will rec ei ve S O C, acc or di n g t o writt e n l oc al g ui d eli n es a n d practices.  
C o nc o mit a nt use of ster oi ds  (e xce pt d e xa m et has o ne), se nsiti ve C Y P 2 D 6 s u bstrates, C Y P 2 C 
i n d ucers, I L-6 ne utralizi n g a nti b o di es,  I L-6 rec e pt or i n hi bit ors , or a n y i n vesti g ati o n al t h era p y  
will n ot be p er mitte d.  
Ca uti o n s h o ul d be use d i n t he c o nc o mita nt a d mi nistr ati o n of bre ast ca nc er resista n ce pr ot ei n 
(B C R P ) s u bstrate dr u gs as i ntesti n al B C R P i n hi biti o n b y P T C 2 9 9 f oll o wi n g a 2 0 0 m g BI D d ose 
of P T C 2 9 9 ca n n ot be  e xcl u d e d ; g ui da n ce s h o ul d be s o u g ht fr o m t he st u d y Me dical M o nit or i n 
eac h c ase . 
A n atte m pt will b e ma d e t o rec or d all me di cati o ns ta ke n b y s u bjects 3 0 da ys pri or t o t he first 
d ose of st u d y dr u g a n d t hr o u g h Da y 2 8 . 
All c o nc o mita nt me dicati o ns ( prescri pti o n a n d o ver t he c o u nter), vita mi n a n d mi neral 
s u p ple me nts, a n d h er bs ta ke n d uri n g t he st u d y will b e d oc u me nte d o n t h e c o nc o mita nt 
me dic ati o n ele ctr o nic case re p ort f or m (e C R F). I nf or mati o n r ec or de d will i n cl u de start a n d st o p 
dates, d ose a n d r o ut e of a d mi ni strati o n, a n d i n dicati o n. 
6.  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  
6. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
S u bjects will  r ecei ve st u d y tr eat m e nt u ntil tr eat me nt disc o nti n uati o n f or o ne of t he reas o ns liste d 
bel o w. H o we ver , s u bjects m a y disc o nti n ue st u d y tre at me nt or wit h dra w t h eir c o nse nt t o 
partici pat e i n t h e st u d y at a n y ti m e wit h o ut pr ej u di ce.  
T he f oll o wi n g c o n diti o ns re q uire s u bj ect disc o nti n uati o n fr o m all st u d y tr eat me nt:  
1.  At t heir o w n re q uest or at t h e re q uest of t h e ir l e gall y a ut h oriz e d re prese nt ati v e 
2.  If a s u bject e x perie n ces a n A E t h at is de e me d r elate d t o treat me nt wit h P T C 2 9 9 a n d i n 
t he In vesti g at or’s or t he S p o ns or’s me di cal j u d g me nt c o nti n uati o n of tr eat me nt w o ul d be 
detri m e ntal t o t h e s u bject  
3.  At t he s pecific re q uest of a re g ul at or y a g e nc y f or t er mi nati o n of tre at m e nt of a n 
i n di vi d ual s u bject or all s u bjects u n der t he pr ot o c ol 
4.  S u bject partici pati o n i n a n ot her cli nic al st u d y usi n g a n i n vesti gati o nal a ge nt or 
i n vesti gati o nal me dical de vic e 
5.  Ref usal of se x uall y acti ve fertil e s u bjects (e xcl u di n g s u bjects w h o ha ve be e n sterilize d) t o 
use me dic all y acce pte d m et h o ds of c o ntr ace pti o n  
6.  If a s u bject b ec o mes pre g n a nt 
7.  Si g nifica nt n o nc o m plia n ce wit h t he pr ot oc ol i n t h e o pi ni o n of t he i n vesti g at or or t h e 
s p o ns or 
8.  Di sease pr o gressi o n necessitati n g (i n t he o pi ni o n of t he i n vesti g at or) disc o nti n uati o n of 
st u d y treat me nt 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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P T C T her a pe utics - C o nfi de nti al  
P a ge 3 1  of 6 2  
S u bject s w h o disc o nti n u e st u d y tre at m e nt will be tre ate d at t he discreti o n of t he i n v esti gat or, 
i ncl u di n g, as a p pr o priate, a n y m e dic ati o ns .  
6. 1. 1.  
Disc o nti n u a ti o n d ue t o A b n or m al Li ver F u ncti o n  
S e veral s pecific meas ures will b e u n dert a ke n t o i de ntif y t he ris k of he p at ot o xicit y i n s u bje cts a n d 
ma na ge hi g h dr u g e x p os ure. T o a v oi d he pat ot o xi cit y, P T C has i m ple me nt e d a c o m pre he nsi ve 
m o nit ori n g of li ver f u n cti o n tests (L F Ts ), i ncl u di n g A L T, A S T, t otal bilir u bi n (T bili ), a n d 
al kali ne p h os p hat ase ( A L P ). D uri n g h os pitali zati o n, t he L F Ts  will b e m o nit ore d dail y d uri n g  
treat me nt a n d at Da y 2 8 . A n  H A C will c o m pr e he nsi vel y m o nit or all he patic a b n or maliti es a n d 
c o nti n uall y e v al uate he patic saf et y d uri n g t he st u d y.  
C o nsiste nt wit h  t h e F o o d a n d Dr u g A d mi nistrati o n Dr u g I n d uce d Li v er I nj ur y ( DI LI ) g ui da n ce  
(F D A 2 0 0 9 ), s u bjects will b e cl osel y m o nit or e d f or a n y of t he f oll o wi n g: 
•  A n y ser u m A L T or A S T Gra de ≥3 ( > 5 × U L N), re gar dless of baseli ne   
•  T bili ( > 2 × U L N), w het h er or n ot ser u m A L T or A S T val ues are ele vate d; if s uc h a n 
ele vati o n oc c urs, direct bilir u bi n  will b e me as ure d  
If a n y of t he a b o v e c o n diti o ns are m et, t h e f oll o wi n g ste ps will be t a ke n: 
•  Te m p oraril y s t o p d osi n g st u d y dr u g a n d r etest A L T, A S T, a n d T bili wit hi n 7 2 h o urs 
t o c o nfir m c ha n ges. S u bje cts wit h Gra de 3 li ver f u ncti o n a b n or m alities will be 
m o nit ore d u ntil t hese val ues ret ur n t o t he baseli ne.  
•  N otif y t he s p o ns or a n d me dical m o nit or (see als o Se cti o n 7. 5. 3  a n d Se cti o n  7. 5. 1 0 ) 
•  Res u me d osi n g wit h st u d y dr u g if t he retesti n g d o es n ot c o nfir m t he m a g nit u d e of t he 
a b n or malit y(i es) , after disc ussi o n wit h t he m e dic al m o nit or. 
•  E val uate A L T, A S T, T bili, a n d A L P dail y , u ntil st a ble or res ol ve d. 
•  C o nsi der f urt her w or k -u p i n c o ns ultati o n wit h t he m e dical m o nit or.  
Per ma ne nt d isc o nti n u ati o n of st u d y dr u g f or a b n or m al li v er f u ncti o n s h o ul d be c o nsi d ere d b y t he 
i n vesti gat or w he n a s u bje ct me ets o ne of t h e c o n diti o ns o utli ne d a b o v e or if t h e i n vesti gat or 
belie v es t hat it is i n b est i nt erest of t he s u bject.  Aft er eac h a b n or mal li ver f u ncti o n e v e nt t h at 
meets t h e criteria f or disc o nti n u ati o n , t he H A C will meet t o assess t he se verit y a n d ca usalit y of 
t he e ve nt a n d ge n erate a case r e p ort.  
6. 1. 2.  
Disc o nti n u ati o n d ue t o A b n or m al Bl o o d Test Res ults  
S u bjects will b e m o nit ore d f or a n e mia a n d l o w l y m p h oc yte c o u nt. If eit her of the f oll o wi n g 
occ urs:  
•  L y m p h oc yt e c o u nt < 5 0 0 l y m p h oc ytes/µ L  
•  He m o gl o bi n < 1 1 . 0 g/ d L ( 1 1 0  g/ L)  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 2  of 6 2  
T he n t he f oll o wi n g ste ps will be t a ke n: 
•  Te m p oraril y s t o p d osi n g st u d y dr u g a n d r etest l y m p h oc yte c o u nt a n d he m o gl o bi n 
wit hi n 7 2  h o urs t o c o nfir m c ha n g es.  
•  Res u me d osi n g wit h st u d y dr u g if t he retesti n g d o es n ot c o nfir m t he m a g nit u d e of t he 
a b n or malit y(i es).  
•  N otif y t he m e dic al m o nit or if t he ret esti n g c o nfir ms a b n or maliti es.  
P er ma ne nt d isc o nti n u ati o n of st u d y dr u g f or a b n or m al bl o o d  t est res ults s h o ul d be c o nsi dere d b y 
t he i n vesti gat or w he n a s u bject meets o ne of t he c o n diti o ns o utli ne d a b o v e or if t h e i n vesti gat or 
belie v es t hat it is i n b est i nt erest of t he s u bject.  
6. 2.  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  
I n all c ases of s u bject wit h dra wal or disc o nti n uati o n , t he reas o n f or wit h dr a wal m ust be r ec or de d 
i n t he e C R F a n d i n t he s u bj ect’s m e dic al rec or ds.  If t he reas o n is n ot k n o w n, t he s u bj ect m ust be 
f oll o we d t o est a blis h w het h er t he re as o n was d ue t o a n A E, a n d, if s o, t his m ust b e re p ort e d i n 
acc or da n ce wit h t h e pr oce d ur es i n S ecti o n 7. 5. 9 . 
All s u bjects will u n der g o assess me nts u ntil Da y 2 8 u nless t he y die, are l ost t o f oll o w -u p or 
wit h dra w c o nse nt. F or s u bjects w h o are disc har ge d fr o m t he h os pit al pri or t o Da y 2 8:  
•  If S p O2 is <9 4 %, S p O 2 meas ure me nts will be ta ke n dail y u ntil Da y 2 8  
•  S u bject -re p orte d assess me nts f or c o u g h a n d d ys p ne a will c o nti n ue t o Da y 2 8 
•  N o ot her assess me nts will t a ke pl ace e x ce pt f or t h ose s pecifi e d at Da y 1 4, 2 8 a n d Da y 
6 0 i n t he pr ot o c ol.  
T he in vesti gat or will m a ke e ver y eff ort t o c o nta ct s u bjects l ost t o f oll o w -u p. S u bje ct s w h o ha ve 
a n o n g oi n g A E at t he ti me of st u d y c o m pl eti o n will be f oll o we d u ntil t h e e ve nt res ol ves, or u ntil 
t he S p o ns or a n d t he I n vesti gat or a gree t h at f urt h er f oll o w-u p is n ot me dicall y ne cessar y.  
6. 3.  
L ost t o F oll o w -u p  
A su bject is c o nsi der e d l ost t o f oll o w -u p if t h e he or s he  lea ves t h e h os pital a n d d oes n ot 
c o m plete t h e st u d y a n d atte m pts t o c o nt act t he s u bje ct are u ns uc cessf ul. Eff orts m ust be ma de o n 
t he part of t he sit e t o av oi d a n y s u bject bei n g l ost t o f oll o w -u p d uri n g t he st u d y. B ef ore a n y 
s u bject is c o nsi d ere d l ost t o f oll o w -u p, a mi ni m u m of 2 d oc u me nt e d tele p h o ne c o ntact atte m pts 
a n d 1 certifie d letter wit hi n a wee k of t h e m ost re ce nt pla n ne d st u d y assess me nt m ust be se n t i n 
eff orts t o c o nt act t he s u bject. After bei n g c o nsi der e d l ost t o f oll o w -u p, a s u bj ect’s stat us ma y be 
c ha n ge d if t he s u bje ct ma k es c o nta ct at a l ater ti m e pr o vi de d t he trial is o n g oi n g.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 3  of 6 2  
7.  
S T U D Y A S S E S S M E N T A N D P R O C E D U R E S  
7. 1.  
Sc he d ule of E ve nts a n d St u d y P ar a meters  
T a bl e  3 : 
S c h e d ul e of E v e nt s  
A s s e s s m e nt/ A cti vit y  
S cr e e ni n g  
D a y 
1  
Tr e at m e nt P eri o d  
F oll o w -u p  
N ot e s  
D a y s 
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y 1 4/  
E O T  
D a y s 
1 5 -2 7  
D a y 2 8/  
E O S  
D a y 
6 0  ± 3  
S cr e e ni n g a n d D a y 1 s h o ul d o c c ur wit hi n a 
1 -d a y p eri o d; w h er e t h e y o c c ur o n t h e s a m e 
d a y, a s s e s s m e nt s n e e d n ot b e r e p e at e d. 
S u bj e ct s r e m ai ni n g i n h o s pit al will u n d er g o 
t h e a s s e s s m e nt s s p e cifi e d. All s u bj e ct s will 
u n d er g o t h e a s s e s s m e n t s s p e cifi e d f or 
D a y  1 4, D a y 2 8, a n d D a y 6 0 e v e n if t h e y ar e 
di s c h ar g e d fr o m t h e h o s pit al pri or t o 
D a y  2 8.  
I nf or m e d c o n s e nt 
X  
 
 
 
 
 
 
 
 
 
M e di c al hi st or y  
X  
 
 
 
 
 
 
 
 
 
W H O or di n al s c al e 
a s s e s s m e nt  
X  
 
 
 
 
 
 
 
 
(W H O 2 0 2 0 ) 
Pr e g n a n c y t e st  
X  
 
 
 
 
 
 
X  
X  
W O C B P o nl y. Pr e g n a n c y t e st c a n b e s er u m 
β H C G or uri n e.  T h e D a y 6 0 t e st s h o ul d b e 
t a k e n at h o m e a n d s elf-r e p ort e d d uri n g 
t el e p h o n e c o nt a ct. 
Vit al si g n s  
X  
X  
X  
X  
X  
X  
X  
X  
 
Vit al si g n s will i n cl u d e o x y g e n s at ur ati o n d ail y 
f or pri m ar y e n d p oi nt a s s e s s m e nt i n a d diti o n, 
t e m p er at ur e, r e s pir at or y r at e, a n d bl o o d 
pr e s s ur e will al s o b e a s s e s s e d . 
C o u g h a n d d y s p n e a 
a s s e s s m e nt s  
X  
X  
X  
X  
X  
X  
X  
X  
 
C o u g h a n d d y s p n e a ar e a s s e s s e d d ail y o n a 
p ati e nt r e p ort e d s c al e of s e v er e, m o d er at e, 
mil d, or a b s e nt.  
B o d y w ei g ht a n d h ei g ht  
X  
 
 
 
 
 
 
 
 
 
P h y si c al e x a mi n ati o n  
X  
X  
X  
X  
X  
X  
 
X  
 
F ull p h y si c al e x a mi n ati o n (i n cl u di n g a mi ni m u m 
of g e n er al a p p e ar a n c e, h e a d, e y e s, e ar s, n o s e, 
m o ut h, t hr o at, h e art, t h yr oi d, c h e st a n d l u n g s, 
a b d o m e n, e xtr e miti e s, n e ur o m u s c ul ar s y st e m, 
s ki n, a n d l y m p h n o d e s) will b e c o m pl et e d 
d uri n g s cr e e ni n g; at all ot h er ti m e p oi nt s t h e 
e x a mi n ati o n will b e t ar g et e d.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 4  of 6 2  
A s s e s s m e nt/ A cti vit y  
S cr e e ni n g  
D a y 
1  
Tr e at m e nt P eri o d  
F oll o w -u p  
N ot e s  
D a y s 
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y 1 4/  
E O T  
D a y s 
1 5 -2 7  
D a y 2 8/  
E O S  
D a y 
6 0  ± 3  
S cr e e ni n g a n d D a y 1 s h o ul d o c c ur wit hi n a 
1 -d a y p eri o d; w h er e t h e y o c c ur o n t h e s a m e 
d a y, a s s e s s m e nt s n e e d n ot b e r e p e at e d. 
S u bj e ct s r e m ai ni n g i n h o s pit al will u n d er g o 
t h e a s s e s s m e nt s s p e cifi e d. All s u bj e ct s will 
u n d er g o t h e a s s e s s m e n t s s p e cifi e d f or 
D a y  1 4, D a y 2 8, a n d D a y 6 0 e v e n if t h e y ar e 
di s c h ar g e d fr o m t h e h o s pit al pri or t o 
D a y  2 8.  
C h e st X -r a y  
X  
 
 
 
 
X  
 
 
 
X -ra y t a k e n wit hi n 2 4 h o ur s pri or t o S cr e e ni n g 
will b e a c c e pt e d.  C T s c a n will b e a c c e pt e d i n 
pl a c e of t h e X -ra y if t a k e n wit h 4 8 h o ur s pri or t o 
S cr e e ni n g . 
N a s o p h ar y n g e al s w a b  
 
X  
X  
X  
 
X  
 
X  
 
N a s o p h ar y n g e al s w a b will b e t a k e n o n D a y s 1, 
2, 4, 7, 1 4, a n d 2 8.  
H e m at ol o g y, 
c o a g ul ati o n, a n d cli ni c al 
c h e mi str y a s s e s s m e nt  
X  
X  
X  
X  
X  
X  
 
X  
 
A s s e s s m e nt s t a k e n wit hi n 2 4 h o ur s pri or t o  
S cr e e ni n g will b e a c c e pt e d.  
Uri n al y si s  
X  
X  
X  
X  
X  
X  
 
 
 
 
C o n c o mit a nt m e di c ati o n s  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
St u d y dr u g 
a d mi ni str ati o n  
 
X  
X  
X  
X  
X  
 
 
 
St u d y dr u g will b e a d mi ni st er e d or all y at 
2 0 0  m g BI D o n D a y s 1 t o 7 f oll o w e d b y 5 0 m g 
Q D o n D a y s 8 t o 1 4. S h o ul d a s u bj e ct b e 
di s c h ar g e d pri or t o D a y 1 4, t a bl et s will b e 
di s p e n s e d t o t a k e at h o m e  a n d c o m pli a n c e will 
b e r e c or d e d at D a y  1 4 . 
Bl o o d dr a w f or P K  
 
X  
 
X  
 
X  
 
 
 
O n D a y s 1  a n d  7 , bl o o d s a m pl e s f or P K 
a s s e s s m e nt will b e c oll e ct e d pr e -d o s e  ( 0) a n d 
at 6  h o ur s p o st -d o s e a n d o n D a y 1 4 at pr e -
d o s e ( 0) a n d 4 h o ur s p o st -d o s e ( m or ni n g d o s e 
o nl y) . A n a d h o c P K a s s e s s m e nt  will b e 
p erf or m e d i n t h e c a s e of h e p at ot o xi cit y  ( s e e 
al s o S e cti o n 7. 3 ). 
Bl o o d dr a w f or c yt o ki n e 
a s s e s s m e nt  
 
X  
X  
X  
 
X  
 
X  
 
 
Bl o o d dr a w f or a c ut e 
p h a s e pr ot ei n 
a s s e s s m e nt  
 
X  
X  
X  
 
X  
 
X  
 
 
A nti b o d y tit er 
a s s e s s m e nt  
 
X  
 
 
 
 
 
X  
 
 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 5  of 6 2  
A s s e s s m e nt/ A cti vit y  
S cr e e ni n g  
D a y 
1  
Tr e at m e nt P eri o d  
F oll o w -u p  
N ot e s  
D a y s 
2 -6  
D a y 
7  
D a y s 
8 -1 3  
D a y 1 4/  
E O T  
D a y s 
1 5 -2 7  
D a y 2 8/  
E O S  
D a y 
6 0  ± 3  
S cr e e ni n g a n d D a y 1 s h o ul d o c c ur wit hi n a 
1 -d a y p eri o d; w h er e t h e y o c c ur o n t h e s a m e 
d a y, a s s e s s m e nt s n e e d n ot b e r e p e at e d. 
S u bj e ct s r e m ai ni n g i n h o s pit al will u n d er g o 
t h e a s s e s s m e nt s s p e cifi e d. All s u bj e ct s will 
u n d er g o t h e a s s e s s m e n t s s p e cifi e d f or 
D a y  1 4, D a y 2 8, a n d D a y 6 0 e v e n if t h e y ar e 
di s c h ar g e d fr o m t h e h o s pit al pri or t o 
D a y  2 8.  
A d v er s e e v e nt s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
At D a y 6 0, t h e vi sit will b e a t el e p h o n e c all t o 
r e c or d A E s, S A E s, a n d d e at h s f or all s u bj e ct s 
e x c e pt t h o s e w h o di e or ar e l o st t o f oll o w -u p  or 
wit h dr a w c o n s e nt . 
A b br e vi ati o n s:  β H C G, b et a h u m a n c h ori o ni c g o n a d otr o pi n; BI D, t wi c e d ail y; E O S, e n d of st u d y; E O T, e n d of tr e at m e nt; P K, p h ar m a c o ki n eti c; Q D, o n c e d ail y , 
W H O, W orl d H e alt h Or g a ni z ati o n; W O C B P, w o m e n of c hil d b e ari n g  p ot e nti al . 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 6  of 6 2  
7. 2.  
Effic ac y Assess me nts  
All assess me nts will be i n li n e wit h t h e site’s C O VI D -1 9 assess me nt g ui deli n es.  
Fe ver ( b o d y te m p erat ure), r es pirat or y r ate, a n d S p O2 will be m o nit ore d r e g ularl y t hr o u g h o ut 
eac h da y d uri n g h os pitalizati o n. If a s u bj ect h as recei ve d a n a nti p yretic, assess me nt of fe v er 
s h o ul d occ ur ≥4 h o urs aft er a d mi nistrati o n of t he a nti p yretic. 
C o u g h se verit y a n d d ys p ne a will b e assesse d dail y vi a s u bject -r e p orte d scales as se vere, 
m o derat e, mil d, or a bse nt. 
F or s u bjects w h o are disc har ge d fr o m t he h os pital pri or t o Da y 2 8:  
•  If S p O2 is < 9 4 %, S p O 2 meas ure me nts will be ta ke n dail y u ntil Da y 2 8  
•  Patie nt -r e p orte d assess me nts f or c o u g h a n d d ys p nea will c o nti n ue t o Da y 2 8 
•  N o ot her assess me nts will t a ke pl ace e x ce pt f or t h ose s pecifi e d at Da y 1 4, 2 8 a n d Da y 
6 0 i n t he pr ot o c ol.  
F or a n y s u bje cts w h o are tr a nsferre d t o t h e I nte nsi v e Care U nit d uri n g t he st u d y, assess me nts per 
pr ot oc ol s h o ul d be p erf or me d w here v er reas o na bl y practi ca bl e.  
C ollecti o n of bl o o d, ser u m a n d nas o p har y n ge al s wa bs f or assess me nt of c yt o ki ne le vels, ac ute 
p hase pr otei ns, c o m plete bl o o d  c o u nt, ot her la b orat or y para meters, a n d viral l oa d will be 
perf or me d b y q ualifi e d a n d trai ne d pers o n nel d uri n g h os pitali zati o n, or aft er disc har ge at a 
me dic al fa cilit y as a gre e d b y t he me di cal m o nit or. L a b orat or y par a met ers assesse d will i ncl u de, 
b ut n ot  be li mite d t o, t h ose i n T a ble 4 . 
T a bl e 4 : 
L a b or at or y P ar a m et er s t o b e A s s e s s e d  
L a b or at or y A s s e s s m e nt s  
P ar a m et er s  
N a s o p h ar y n g e al  s w a b  
R P P a  
H e m at ol o g y  
C B C c o u nt wit h W B C diff er e nti al  
Cli ni c al C h e mi str y  
C o m pr e h e n si v e m et a b oli c p a n el t o i n cl u d e:  
•  
A S T  
•  
A L T  
•  
G G T  
•  
L D H  
•  
A L P  
•  
T bili  (dir e ct a n d i n dir e ct bilir u bi n , if a p pr o p ri at eb )  
•  
C P K  
•  
T ot al pr ot ei n  
•  
Al b u mi n  
C o a g ul ati o n  
a P T T  
P T/ I N R 
Uri n al y si s  
Bl o o d  
Bilir u bi n  
Gl u c o s e  
K et o n e s  
p H  
Pr ot ei n  
Pr e g n a n c y  ( W O C B P o nl y) 
Uri n e or S er u m β H C G [ R efl e cti v e fr o m C h e mi str y S a m pl e]  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 3 7  of 6 2  
L a b or at or y A s s e s s m e nt s  
P ar a m et er s  
Ot h er s  
C yt o ki n e s a  
A nti b o d y tit er s a  
A c ut e p h a s e pr ot ei n s  
•  
F erriti n  
•  
C R P  
•  
D -di m er  
C ar di a c tr o p o ni n  
A b br e vi ati o n s:  A L P, al k ali n e p h o s p h at a s e; A L T, al a ni n e a mi n otr a n sf er a s e; a P T T, a cti v at e d p arti al t hr o m b o pl a sti n 
ti m e; A S T, a s p art at e a mi n otr a n sf er a s e; β H C G, b et a h u m a n c h ori o ni c g o n a d otr o pi n ; C B C,  c o m pl et e bl o o d c o u nt; 
C R P, C -r e a cti v e pr ot ei n; C P K, cr e ati ni n e p h o s p h o ki na s e; G G T, g a m m a -gl ut a m yl tr a n s p e pti d a s e; I N R, int er n ati o n al 
n or m ali z e d r ati o; L D H, l a ct at e d e h y dr o g e n a s e; P T, pr ot hr o m bi n ti m e ; R P P,  r e s pir at or y p at h o g e n p a n el; T bili, t ot al 
bilir u bi n; W B C, w hit e bl o o d c ell; W O C B P, w o m e n of c hil d b e ari n g p ot e nti al.  
a  T o b e a n al y z e d at a c e ntr al l a b or at or y.  
b  Dir e ct a n d i n dir e ct bilir u bi n will b e m e a s ur e d if p art of t h e l o c al l a b or at or y u s u al a s s e s s m e nt  p a n el . In t h e c a s e of 
T bili > 2 x U L N  dir e ct bilir u bi n m u st b e a s s e s s e d ( S e cti o n  6. 1. 1 ).  
All la b orat or y para meters  s h o ul d be assesse d pri or t o d osi n g o n Da y 1.  
7. 3.  
P K a n d/ or Ot her Assess me nts  
A t select sites, P K will be assesse d aft er t he si n gl e d ose ( Da y 1) a n d re peat e d d osi n g Da y 7 a n d 
1 4. Bl o o d sa m ples will be c olle cte d o n Da ys 1  a n d 7  at pre-d ose ( 0), a n d 6 h o u rs p ost-d ose  a n d 
o n Da y 1 4 at pre -d ose ( 0) a n d 4 h o urs p ost -d ose  ( m or ni n g d ose o nl y). Plas ma c o nce ntrati o ns of 
P T C 2 9 9 a n d O -des met h yl P T C 2 9 9  will be e val u ate d f or a t le ast 1 2 e val ua ble p ati e nts w h o 
recei v e P T C 2 9 9. A nal yses will ta ke pl ace at a ce ntr al la b orat or y.  
F or t h ose s u bje cts disc har g e d fr o m t h e h os pital pri or t o Da y 7, P K sa m pli n g s h o ul d be o bt ai ne d 
o n t he last d a y of h os pitaliz ati o n, if p ossi ble. F or s u bjects disc h ar ge d pri or t o Da y  1 4, P K 
sa m ples o n Da y 1 4 s h o ul d be c olle cte d pre -d ose a n d at 4 h o urs p ost -d ose.  
A n a d h oc P K assess me nt will als o be p erf or me d i n t he case of he pat ot o xicit y , r e gar dl ess of 
w het her t he s u bj ect h as u n der g o ne ot her P K assess me nts . 
7. 4.  
S afet y Assess me nts  
S u bjects will b e m o nit ore d cl osel y f or A Es a n d la b or at or y a b n or m alities , i n cl u di n g assess me nt 
of vital si g ns,  d uri n g t he st u d y.  
F or A Es a n d la b or at or y a b n or malities, t h e i n vesti gat o r s h o ul d use his/ her j u d g m e nt i n 
deter mi ni n g w het h er t he e v e nt or a b n or malit y is cli ni call y si g nific a nt, w het h er dia g n osti c 
e val uati o n is warra nte d, a n d w het h er p ote ntial i nt err u pti o n of st u d y dr u g t her a p y is a p pr o pri ate. 
I n ge neral, life-t hreat e ni n g ( Gra de 4) or se v ere ( Gra d e 3) A E or la b orat or y a b n or malities s h o ul d 
be c o nsi dere d cli nicall y si g nifi ca nt, alt h o u g h r ec urre nt or persiste nt m o derate e ve nts ( Gra d e 2) 
ma y als o be c o nsi dere d cli ni call y si g nifi ca nt i n certai n circ u mst a nces. Refer e nce s h o ul d b e ma d e  
t o t he C T C A E Versi o n 5. 0 f or gr a di n g t h e se verit y of A Es a n d la b orat or y a b n or maliti es. 
7. 5.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
7. 5. 1.  
Defi niti o n of A d verse E ve nts  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n 
h u m a ns, w het her or n ot it is c o nsi d ere d rel ate d t o t he dr u g. A n A E ca n t heref ore b e a n y 


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u nfa v ora ble a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m, or 
disease i n a st u d y s u bj ect w h o is a d mi nist ere d st u d y dr u g i n t his st u d y.  
F or t his p r ot o c ol, u nt o war d me di cal o cc urre nc es t hat s h o ul d be re p orte d as A Es i ncl u de t he 
f oll o wi n g: 
•  All A Es d uri n g t he c o urse of treat me nt wit h st u d y dr u g a d mi nistr ati o n  
•  All A Es res ulti n g fr o m me di cati o n mis use, a b use, wit h dra wal, or o ver d ose, of st u d y 
dr u g  
•  All A E s res ulti n g fr o m me di cati o n err ors s uc h as dis pe nsi n g or a d mi nistrati o n err or 
o utsi de of w hat is descri be d i n t he pr ot oc ol  
•  A p pare ntl y u nrelat e d ill nesses, i ncl u di n g w orse ni n g of a pree xisti n g ill ness  
•  W orse ni n g of s y m pt o ms relat e d t o C O VI D -1 9  
•  I nj ur y or accide nts. N ote t hat if a me dical c o n diti o n is k n o w n t o ha ve ca use d t h e 
i nj ur y or ac ci de nt (a fall sec o n dar y t o diz zi ness), t he me dic al c o n diti o n ( dizzi ness) 
a n d t he a cci d e nt (fall) s h o ul d be re p orte d as 2 se par ate A Es. T he o ut c o me of t he 
acci d e nt ( hi p fra ct ur e se c o n dar y t o t he fall) s h o ul d b e rec or de d i n s o urce d oc u m e nts.  
•  A b n or malities i n p h ysi ol o gical testi n g or p h ysical e x a mi nati o n fi n di n gs t hat r e q uire 
cli ni cal i nter v e nti o n or f urt h er i n vesti gati o n ( be y o n d or deri n g a re p eat [c o nfir mat or y] 
test) 
•  La b orat or y a b n or malities t hat r e q uire cli nical i nt er ve nti o n or f urt her i n vesti g ati o n 
( be y o n d or deri n g a re p eat [ c o nfir m at or y] t est) u nless t he y are ass ociate d wit h a n 
alrea d y r e p orte d cli ni cal e ve nt. La b orat or y a b n or m alities ass oci ate d wit h a cli ni cal 
e ve nt s h o ul d be ca pt ur e d i n t he s o urc e d oc u m e nts. L a b orat or y a b n or malities n ot 
re q uiri n g cli ni cal i nter ve nti o n or f urt h er i n vesti gati o n will be c a pt ure d as part of 
o verall la b orat or y m o nit ori n g a n d s h o ul d n ot be re p orte d as A Es.  
•  A pree xisti n g c o n diti o n ( e g, aller gic r hi ni tis) m ust be n ote d o n t he a p pr o priate C R F 
f or scree ni n g b ut s h o ul d n ot be re p ort e d as a n A E u nless t he c o n diti o n w orse ns, or 
e pis o des i ncre ase i n fre q ue n c y d uri n g t h e A E re p orti n g peri o d. Dia g n osti c a n d 
t hera pe utic n o n-i n vasi ve a n d i n vasi ve pr o ce d ures, s u c h as s ur ger y, s h o ul d n ot be 
re p orte d as A Es. H o we ver, t he m e dic al c o n diti o n f or w hic h t he pr oc e d ure was 
perf or me d s h o ul d be r e p orte d if it m eets t h e defi niti o n of a n A E. F or e x a m pl e, a n 
ac ute a p pe n di citis t hat oc c urs d uri n g t he treat me nt wit h st u d y dr u g s h o ul d be re p orte d 
as t he A E a n d t h e res ulti n g a p pe n de ct o m y s h o ul d b e rec or de d i n t he s o urce 
d oc u me nts a n d e C R F. If a s ur gical pr oce d ure was pl a n ne d pri or t o e ntr y i nt o t he 
st u d y, a n d t he s ur ger y is n ot p erf or me d be ca use of a w orse ni n g of a baseli n e 
c o n diti o n, t his s h o ul d n ot be r e p orte d as a n A E. N ote t hat, as descri be d i n 
Secti o n  7. 5. 2  a n y h os pitalizati o n oc c urri n g as t he c o nse q ue nce of a n A E d uri n g t he 
st u d y peri o d s h o ul d be re p orte d as a n S A E.  
Eac h A E is t o b e cl assifie d as seri o us or n o n -seri o us b y t he i n vesti gat or usi n g me di cal a n d 
scie ntific j u d g me nt. 


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7. 5. 2.  
Defi niti o n of S eri o us  A d verse E ve nts  
A n S A E is a n u nt o war d me dic al occ urr e nce or effect ass ociate d wit h t he use of a st u d y dr u g at 
a n y d ose, re gar dl ess of w het her it is c o nsi d ere d t o b e relat e d t o t h e st u d y dr u g, w hic h res ults i n 
o ne of t he f oll o wi n g:  
•  D eat h. T his i n cl u des all deat hs o n treat me nt or wit hi n 3 0 da ys after l ast st u d y dr u g 
a d mi nistr ati o n, i ncl u di n g deat hs d ue t o disease pr o gr essi o n. A n y deat h occ urri n g later 
t ha n 3 0 da ys f oll o wi n g t he l ast d ose nee d n ot be re p orte d as a n S A E u nless it is a 
res ult of a n e v e nt t h at start e d wit hi n t he peri o d c o ver e d b y t he o n-st u d y defi niti o n. 
T he re p ort e d A E s h o ul d be t he e ve nt t hat ca use d t h e deat h. I n a d diti o n, a n y A E 
res ulti n g i n d eat h t hat o cc urs s u bse q ue ntl y t o t he A E re p orti n g peri o d a n d t h at t he 
i n vesti gat or assesses as p ossi bl y relat e d t o t he st u d y dr u g s h o ul d als o be re p ort e d as 
seri o us. 
•  A  life-t hre ate ni n g c o n diti o n. T his ref ers t o a n e v e nt i n w hic h t he s u bje ct was at ris k of 
deat h at t he ti m e of t he e v e nt. It d o es n ot i ncl u de a n e ve nt t h at, ha d it oc c urre d i n a 
m ore se vere f or m, h y p ot heticall y mi g ht ha v e ca use d deat h.  
•  H os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitaliz ati o n (e x cl u di n g h os pitalizati o ns 
f or a d mi nistr ati o n of t he st u d y dr u g, pr oce d ur es re q uire d b y t he st u d y pr ot oc ol, or 
treat me nt-r elat e d dia g n ostic pr oc e d ures; ot h er pla n n e d h os pitalizati o ns; or 
h os pitali zati o ns relate d o nl y t o pr o gressi o n of diseas e). P r o gressi o n of disease 
res ulti n g i n tra nsfer t o I C U, m ec ha ni cal v e ntilati o n, or ot her me dicall y i m p orta nt 
e ve nt (at t he discreti o n of t he i n v esti gat or)  w o ul d be c o nsi dere d  S A Es. Treat me nts i n 
t he e m er ge nc y r o o m f or pr oce d ures s uc h as h y drati o n t hat d o n ot r e q uire a d mitti n g 
t he s u bject t o t h e h os pital a n d o bser vati o nal d ur ati o ns i n t he e m er ge nc y r o o m f or less 
t ha n 2 4 h o urs d o n ot fall i nt o t his cate g or y. 
•  P ersiste nt or si g nif i ca nt disa bilit y or i n ca pacit y or s u bsta ntial disr u pti o n of t he a bilit y 
t o c o n d uct n or mal life f u ncti o ns. 
•  A n y ot her me di call y i m p orta nt e v e nt t h at t h e i n vesti gat or or t he s p o ns or j u d ges t o b e 
seri o us or w hic h is defi ne d as seri o us b y t he re g ul at or y a ge nc y i n t he l o cal c o u ntr y. 
T hese are A Es t h at mi g ht n ot be i m me diatel y life -t hr eate ni n g or res ult i n deat h or 
h os pitali zati o n b ut mi g ht j e o par di ze t he s u bj ect or mi g ht re q uir e i nt er ve nti o n t o 
pre ve nt o ne of t he ot h er o utc o m es liste d a b o ve. Me di cal j u d g me nt s h o u l d b e 
e xercise d i n deci di n g w het her a n A E is seri o us base d o n a b o ve defi niti o n. E xa m ples 
of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer g e n c y r o o m or at h o me f or aller gi c 
br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n , 
or de vel o p m e nt of dr u g de pe n d e nc y or dr u g a b use.  
•  A pre g na nc y res ulti n g i n s p o nta n e o us a b orti o n, still birt h, ne o natal d eat h, or 
c o n ge nit al a n o mal y (i ncl u di n g t hat i n a n a b orte d fet us).  
N ote t hat a n y S A Es occ urri n g at a n y ti me u p t o Da y 6 0  s h o ul d be re p orte d t o t he s p o ns or if t h e 
i n vesti gat or bec o mes a ware of t h e m. 


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A d verse E ve nts of S peci al I nterest  
E ve nts t hat ma y b e i n di cati ve of he pat ot o xi cit y  (i ncl u di n g t he l o wer le vel Me d D R A ter m of 
h e pat ot o xicit y  or dr u g -i n d uce d h e pat ot o xicit y) ar e c onsi dere d a d verse e v e nts of s peci al i nterest 
( A E SIs) a n d will be re p ort e d o n a n e x pe dite d b asis. T hese i ncl u de: 
•  A L T i ncre ase Gra d e ≥3 ( > 5 × U L N)  
•  A S T i ncrease Gra de ≥3 ( > 5 × U L N)  
•  T bili  i ncre ase > 2 × U L N 
•  A L P ≥ 2 × U L N  
All i nsta nc es meeti n g t h e a b o ve criteria s h o ul d be r e p orte d wit hi n 2 4 h o urs  t o t he P T C 
T hera pe utics P har m ac o vi gila nc e De part me nt o n t he S A E f or m. If t he e ve nt is c o nsi dere d 
n o n -seri o us b y t he i n vesti gat or t he n t h e S A E f or m a n d A E C R F pa ge s h o ul d b e mar k e d as 
n o n -seri o us. Me dicall y si g nifi ca nt li ver e v e nts t hat are c o nsi dere d S A Es a n d c o nsist of mar ke d 
ele vati o ns of L F Ts a n d / or pr e -s pecifi e d A Es ma y als o be i ncl u de d i n e x pe dite d re p orti n g.  
7. 5. 4.  
U ne x pecte d A d verse E ve nts  
T he I n vesti g at or’s Br oc h ure  c o ntai ns t h e Refer e nce Safet y I nf or mati o n ( R SI) w hic h will be use d 
f or assessi n g e x pecte d ness. If a n e v e nt is n ot liste d i n t he R SI, it s h o ul d be c o nsi dere d 
u ne x pect e d or if t h e A E occ urs at a greater se verit y, s pecificit y or fre q ue n c y, it s h o ul d b e 
c o nsi dere d u ne x p ect e d.  
A n y he patic a b n or malities/ he pat ot o xi cit y ( h y p er bilir u bi ne mi a, as part ate a mi n otr a nsferase 
i ncrease, ala ni ne a mi n otra nsfer ase i ncr ease) of Gra d e ≥4 will b e c o nsi der e d u ne x pecte d.  
7. 5. 5.  
Eliciti n g A d verse E ve nt Inf or m ati o n  
T he i n vesti gat or is t o re p ort all dire ctl y o bser ve d A Es a n d all A Es s p o nta ne o usl y r e p orte d b y t he 
st u d y s u bject/ p are nt(s)/le gal g uar dia n/le g all y acc e pta ble re prese ntati ve. I n a d diti o n, e ac h st u d y 
s u bject/ p are nt(s)/le gal g u ar dia n/le g all y acc e pta ble re prese ntati ve will be q uesti o ne d a b o ut A Es at  
eac h sc he d ule d cli nic visit after st u d y dr u g a d mi nistr ati o n or d uri n g a n y tele p h o ne c o ntact wit h 
t he s u bject/ par e nt(s)/le g al g uar dia n/le gall y a cce pta bl e re prese nt ati ve. T he t y p e of q uesti o n as ke d 
s h o ul d be o pe n-e n de d, f or e x a m pl e, “ H o w h ave y o u bee n fe eli n g ? ” or a si milar t y pe of q uer y.  
7. 5. 6.  
Rec or di n g N o n ‑seri o us A Es a n d S A Es  
All A Es ( b ot h seri o us a n d n o n -seri o us) t hat occ ur i n s u bjects d uri n g t h e A E re p orti n g peri o d 
m ust be rec or d e d, w het her or n ot t he e v e nt is c o nsi d ere d dr u g  rel ate d. I n a d diti o n, a n y k n o w n 
u nt o war d e ve nt t hat o cc urs s u bse q ue nt l y t o t he A E r e p orti n g peri o d t hat t he i n vesti g at or assesses 
as p ossi bl y relat e d t o t h e i n vesti gati o nal dr u g/ pr o d u ct s h o ul d als o be re c or de d as a n A E.  
All A Es are t o be r ec or de d i n t he s o urce d o c u me nts a n d o n t he e C R F us i n g c o n cise m e dic al 
ter mi n ol o g y; w he ne v er p ossi ble, t er ms c o ntai ne d i n t he Me dical Dicti o nar y f or Re g ul at or y 
Acti vities ( Me d D R A) s h o ul d be e m pl o y e d. I n a d diti o n, t he f oll o wi n g i nf or mati o n s h o ul d be 
rec or de d: 
•  I n dicati o n of w het her t he e ve nt is seri o us or n on -seri o us (see Secti o n 7. 5. 2 ) 
•  Relati o ns hi p t o st u d y dr u g (see Se cti o n  7. 5. 7 ) 


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•  Se verit y of t h e e ve nt (see Secti o n  7. 5. 8 ) 
•  O nset date  
•  Res ol uti o n date, or date of deat h  
•  Acti o n ta k e n  
•  O utc o me of t h e e ve nt  
Classificati o n of t h e e ve nt as seri o us or n o n -seri o us deter mi nes t he r e p orti n g pr oc e d ures t o be 
f oll o we d. 
7. 5. 7.  
Descri bi n g A d verse E ve nt R el ati o ns hi p t o S t u d y D r u g 
T he i n vesti gat or s h o ul d pr o vi de a n assess me nt of t he relati o ns hi p of t he A E t o t he st u d y dr u g, 
ie, w het her t here is a reas o na bl e p ossi bilit y t hat t he st u d y dr u g ca use d t h e A E, usi n g t he 
c o nsi derati o ns o utli n e d i n  T a ble  5 . 
T a bl e  5 : 
R el ati o n s hi p of St u d y Dr u g t o A d v er s e E v e nt R el ati o n s hi p  
 
D e s cri pti o n  
Pr o b a bl e  
A cli ni c al e v e nt i n w hi c h a r el ati o n s hi p t o t h e st u d y dr u g s e e m s pr o b a bl e b e c a u s e of s u c h 
f a ct or s a s c o n si st e n c y wit h k n o w n eff e ct s of t h e dr u g; a cl e ar t e m p or al a s s o ci ati o n wit h 
t h e u s e of t h e dr u g; i m pr o v e m e nt u p o n wit h dr a w al of t h e dr u g; r e c urr e n c e u p o n 
r e-c h all e n g e wit h t h e dr u g; l a c k of alt er n ati v e e x pl a n ati o n s f or t h e e v e nt.  
P o s si bl e  
A cli ni c al e v e nt o c c urri n g c oi n ci d e nt wit h a d mi ni str ati o n of t h e st u d y dr u g a n d w hi c h m a y 
or m a y n ot b e e x pl ai n e d b y c o n c urr e nt di s e a s e or ot h er dr u g s or c h e mi c al s. I nf or m ati o n 
o n dr u g wit h dr a w al or r e -c h all e n g e m a y b e l a c ki n g.  
U nli k el y  
A cli ni c al e v e nt w it h a t e m p or al r el ati o n s hi p t o t h e st u d y dr u g e x p o s ur e t h at d o e s n ot 
pr e cl u d e c a u s alit y b ut f or w hi c h t h er e i s a cl e ar alt er n at e c a u s e t h at i s m or e li k el y t o h a v e 
c a u s e d t h e a d v er s e e v e nt t h a n st u d y dr u g. S u c h alt er n ati v e s i n cl u d e a c o n c o mit a ntl y 
a d mi ni st e r e d dr u g, t h e s u bj e ct’ s di s e a s e st at e, ot h er m e di c al c o n diti o n s, or 
e n vir o n m e nt al f a ct or s.  
U nr el at e d  
A cli ni c al e v e nt, f or w hi c h a r el ati o n s hi p t o t h e st u d y dr u g s e e m s i m pr o b a bl e b e c a u s e of 
f a ct or s s u c h a s i n c o n si st e n c y wit h k n o w n eff e ct s of t h e st u d y dr u g, l a c k of a t e m p or al 
a s s o ci ati o n wit h st u d y dr u g a d mi ni str ati o n, l a c k of a s s o ci ati o n of t h e e v e nt wit h st u d y 
dr u g wit h dr a w al or r e -c h all e n g e, a n d/ or pr e s e n c e of alt er n ati v e e x pl a n ati o n s f or t h e 
e v e nt. Alt er n ati v e e x pl a n ati o n s mi g ht i n cl u d e a k n o w n r el at i o n s hi p of t h e a d v er s e e v e nt 
t o a c o n c o mit a nt dr u g, m e di c al hi st or y of a si mil ar e v e nt, t h e s u bj e ct’ s di s e a s e st at e, 
ot h er m e di c al c o n diti o n s, or e n vir o n m e nt al f a ct or s.  
7. 5. 8.  
Gr a di n g of S e verit y of A d verse E v e nt  
T he se verit y of A E will b e gra de d usi n g t h e C o m m o n Ter mi n ol o g y Crit eria f or A d verse E v e nts 
( C T C A E) Versi o n 5. 0 (refer t o t h e st u d y ma n u al). F or eac h e pis o de, t he hi g hest se verit y gra de 
attai ne d s h o ul d be r e p orte d.  
If a C T C A E criteri o n d o es n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves: Gra d e 1 
( mil d), Gra de 2 ( m o derat e), Gr a de 3 (se ver e), Gr a de 4 (life-t hr eat e ni n g), or Gr a de 5 (fatal) t o 
descri be t h e ma xi m u m i nte nsit y of t he A E. F or p ur p oses of c o nsiste nc y wit h t h e C T C A E, t h ese 
i nte nsit y gr a des are d efi ne d i n Ta bl e  6 . 


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T a bl e  6 : 
Gr a di n g of A d v er s e E v e nt S e v erit y Gr a d e  
 
A dj e cti v e  
D e s cri pti o n  
Gr a d e 1  
Mil d  
Si g n or s y m pt o m i s pr e s e nt, b ut it i s e a sil y t ol er at e d, i s n ot e x p e ct e d t o 
h a v e a cli ni c all y si g nifi c a nt eff e ct o n t h e s u bj e ct’ s o v er all h e alt h a n d 
w ell -b ei n g, d o e s n ot i nt erf er e wit h t h e s u bj e ct’ s u s u al f u n cti o n, a n d i s 
n ot li k el y t o r e q uir e m e di c al att e n ti o n  
Gr a d e 2  
M o d er at e  
Si g n or s y m pt o m c a u s e s i nt erf er e n c e wit h u s u al a cti vit y or aff e ct s 
cli ni c al st at u s, a n d m a y r e q uir e m e di c al i nt er v e nti o n  
Gr a d e 3  
S e v er e  
Si g n or s y m pt o m i s i n c a p a cit ati n g or si g nifi c a ntl y aff e ct s cli ni c al st at u s 
a n d li k el y r e q uir e s m e di c al i nt er v e nti o n a n d/ or cl o s e f oll o w -u p  
Gr a d e 4  
Lif e -t hr e at e ni n g  
Si g n or s y m pt o m r e s ult s i n a p ot e nti al t hr e at t o lif e  
Gr a d e 5  
F at al  
Si g n or s y m pt o m r e s ult s i n d e at h  
7. 5. 9.  
A d verse E ve nt Re p orti n g  
In vesti gat or site re p orti n g re q uir e me nts f or A Es are s u m mari ze d i n  Ta bl e  7 . 
T a bl e  7 : 
I n v e sti g at or Sit e R e q uir e m e nt s f or R e p orti n g A d v er s e E v e nt s 
E v e nt  
R e c or d e d o n t h e e C R F  
R e p ort e d o n t h e S A E R e p ort F or m t o 
P T C P h ar m a c o vi gil a n c e Wit hi n 
2 4  H o ur s of A w ar e n e s s  
S eri o u s A E  
All  
All  
N o n -S eri o u s A E  
All  
N o n e  
E x p o s ur e t o t h e st u d y 
dr u g d uri n g pr e g n a n c y or 
br e a stf e e di n g, a n d 
o c c u p ati o n al e x p o s ur e  
All (r e g ar dl e s s of w h et h er 
a s s o ci at e d wit h a n A E), e x c e pt 
o c c u p ati o n al e x p o s ur e  
E x p o s ur e d uri n g pr e g n a n c y, e x p o s ur e 
vi a br e a stf e e di n g, o c c u p ati o n al e x p o s ur e 
(r e g ar dl e s s of w h et h er a s s o ci at e d wit h 
a n A E)  
A b br e vi ati o n s: A E, a d v er s e e v e nt; e C R F, el e ctr o ni c c a s e r e p ort f or m; S A E, s eri o u s a d v er s e e v e nt 
All A Es s h o ul d be f oll o we d u p b y t h e i n vesti gat or u ntil t h e y are r es ol ve d, or t he i n vesti g at or 
assesses t he m as c hr o nic or st a ble. T h e i n vesti gat or s h o ul d c o nsi der pr ot o c ol g ui d eli n es a n d use 
his/ her discreti o n i n or d eri n g  a d diti o nal tests as ne cessar y t o m o nit or t h e res ol uti o n of s uc h 
e ve nts. I n t he e ve nt of a d diti o n al i n v esti gati o ns, t he P T C T hera pe utics P har m ac o vi gila nc e 
De part me nt or desi g nee s h o ul d be i nf or m e d via e -mail or fa x. A s u bject wit h dra w n fr o m t he 
st u d y beca use of a n A E m ust be f oll o we d b y t he i n v esti gat or u ntil cli nical rec o ver y is c o m pl ete 
a n d la b orat or y res ults ha ve r et ur ne d t o n or mal, or u ntil pr o gressi o n has be e n sta biliz e d. 
F oll o w -u p m a y nee d t o c o nti n ue after t he s u bj ect h as disc o nti n ue d fr o m t he st u d y,  a n d a d diti o nal 
i n vesti gati o ns ma y b e re q uest e d b y t he m e dic al m o nit ori n g te a m. 
T he first da y of A E r e p orti n g will c oi n ci de wit h t he date of si g ni n g of I nf or me d C o nse nt.  
7. 5. 1 0.  
Seri o us A d verse E ve nt R e p orti n g  
All S A Es s h o ul d be re p orte d vi a t he “S A E R e p ort F or m ” t o P T C T h era pe utics wit hi n 2 4 h o urs of 
bec o mi n g a ware of t he e ve nt(s). I n a d diti o n, t he A E p orti o n of t he e C R F m ust als o be c o m pl ete d  
i n E D C. 
T he S A E re p ort f or m s h o ul d b e si g ne d b y t h e i n vesti gat or; h o we ver, if t he i n vesti gat or is u na bl e 
t o si g n at t h e time of t h e e ve nt or wit hi n 2 4 h o urs, t h e f or m s h o ul d be si g ne d b y t he cli ni cal staff 
me m ber r e p orti n g t he S A E (e g, t he st u d y c o or di nat or). T he S A E re p ort f or m m ust be fa xe d or 
e-maile d t o t he P T C T h era pe utics P har ma c o vi gila nc e De part m e nt or desi g ne e a n d t o t he sit e 
I nstit uti o n al Re vie w B oar d/ Et hi cs C o m mitte e I R B/ E C (if re q uire d b y l ocal re g ulati o ns) wit hi n 
2 4 h o urs.  


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F oll o w -u p i nf or mati o n t o t h e S A E s h o ul d be cl earl y d oc u me nt e d wit h  “ F oll o w -u p” b o x c hec k e d 
a n d t he f oll o w -u p n u m ber i n t he S A E Re p ort F or m c o m plet e d a n d fa x e d or e-maile d t o t he sa me 
part y. All f oll o w -u p S A E re p ort f or ms f or t he e v e nt m ust be si g ne d b y t h e i n vesti gat or. A n y 
s o urce d oc u me nts (e g, pr o gress n otes, n urses’ n otes, la b orator y a n d dia g n ostic test res ults, 
disc har ge s u m m aries) pr o vi de d t o t he s p o ns or s h o ul d be re dacte d s o t hat t he s u bje ct’s na m e, 
a d dress, a n d ot her pers o nal i de ntit y i nf or mati o n are o bsc ure d. O nl y t he s u bje ct’s st u d y n u m ber 
a n d i nitials ar e t o be pr o vi de d (i n re gi o ns w here t he pr o visi o n of s uc h i nf or mati o n is per mitte d). 
T he i nf or m ati o n i n t he A E p orti o n of t he e C R F a n d t he S A E re p ort f or m(s) m ust m atc h or be 
rec o ncile d. W her e t he sa me data ar e c ollecte d, t he i nf or mati o n o n t he S A E Re p ort F or m m ust be 
c o m plete d i n a c o nsiste nt ma n ner.   
I n t he rare e ve nt t h at t h e i n vesti gat or d o es n ot bec o m e a ware of t he o cc urre n ce of a n S A E 
i m me diat el y (f or e xa m ple, if a s u bje ct i niti all y se e ks treat me nt else w here), t h e i n vesti gat or is t o 
re p ort t he e ve nt wit hin 2 4 h o urs after lear ni n g of it a n d t o d oc u me nt his/ her first a ware ness of t he 
A E.  
T he P T C T her a pe utics P har mac o vi gil a nce De p art m e nt c o nta ct i nf or mati o n f or re p orti n g S A Es is 
pr o vi de d bel o w. T his i nf or mati o n is als o pr o vi de d i n t he St u d y Ma n ual a n d i n t h e S A E re p ort 
f or m. 
P T C T her a pe utics S afet y D e p art me nt  
Atte nti o n: P h ar m ac o vi gil a nc e  
E -m ail:
F acsi mil e: 
 
7. 5. 1 1.  
Re p orti n g Pre g n a nc y  
P T C T hera pe utics s h o ul d be n otifi e d i n t h e e ve nt t hat a fe m ale s u bj ect i n t he st u d y, or a f e male 
part ner of a male s u bject i n t he st u d y, b ec o m es pre g na nt o n -st u d y or wit hi n 5 0 d a ys of t he l ast 
a d mi nistr ati o n of st u d y dr u g m ust be re p orte d o n a n electr o nic f or m “I n vesti g ati o n al a n d 
Mar kete d Pr o d ucts Pre g na n c y Re p ort F or m” (se e st u d y ma n ual f or details).  
T his m ust be d o ne w het her or n ot a n A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he 
pre g na nc y. T h e i nf or mati o n s u b mitte d s h o ul d i ncl u d e t he a ntici pat e d date of birt h or pre g n a nc y 
ter mi n ati o n. 
Writt e n c o nse nt is re q uire d pri or t o c ollecti n g  a n d r e p orti n g a n y i nf or mati o n o n a fe male p art ner 
of a mal e s u bject i n t h e st u d y.  
If p ossi ble, t he i n v esti gat or s h o ul d f oll o w t h e s u bject, or t he pre g na nt fe male part ner of a mal e 
s u bject, u ntil c o m pleti o n of t h e pre g na nc y a n d n otif y t he me dical m o nit or o f t he o utc o me wit hi n 
5 da ys or as s pecifie d b el o w. T he i n v esti gat or will pr o vi de t his i nf or mati o n wit h ‘ F oll o w -u p”  
b o x c hec k e d a n d t he f oll o w -u p n u m b er c o m plete d o n t he Pre g na nc y R e p ort F or m (see t he st u d y 
ma n ual f or d etails).  
If t he o utc o me of t h e pre g na nc y meets t he criteria f or i m me diat e cl assificati o n as a n S A E 
(ie, pret er m t er mi nati o n, electi ve a b orti o n , i ntra uteri ne deat h,  or ot her) , t he i n vesti g at or s h o ul d 
f oll o w t he pr oc e d ures f or re p orti n g S A Es, ie, r e p ort t he e ve nt t o t he P T C T hera pe utics Safet y 
D e part me nt or desi g nee a n d f oll o w -u p b y s u b missi o n of a p pr o priat e A E e C R Fs 
(see Secti o n  7. 5. 1 0 ). 


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7. 5. 1 2.  
P T C T her a pe utics A d verse E ve nt Re p orti n g Re q uire me nt  
As t he s p o ns or of t he st u d y, P T C T hera pe utics is res p o nsi ble f or re p orti n g certai n safet y 
i nf or mati o n, partic ul arl y A E SIs,  S A Es a n d s u bject d eat hs rel ate d t o parti ci pati o n i n t he st u d y, t o 
eac h i n v esti gat or i n a n e x p e dit e d ma n n er. If n otificati o n of a n A E re q uiri n g e x pe dite d re p orti n g 
t o i n vesti g at ors is rec ei ve d, P T C T hera pe utics or its desi g nate d r e prese ntati ve will c o ntact ea c h 
i n vesti gati o nal site p arti ci pati n g i n t his st u d y b y e-m ail, fa x, a n d/ or o ver ni g ht mail s uc h t h at t h e 
i n vesti gat or can pr o m ptl y n otif y t h e site I R B/ E C per t heir l o cal r e q uire m e nts. T he i nitial 
e x pe dit e d safet y re p ort will b e pr o vi de d as re q uire d acc or di n g t o l oc al re g ul ati o ns (e g, wit hi n 
1 5  da ys) after t h e earliest date P T C T h era pe utics or a n a ge nt of P T C T h era pe utics (e g, a site 
m o nit or) be c o mes a ware of a n A E. T his a war e ness date is t h e dat e t he re g ulat or y r e p orti n g cl oc k 
be gi ns , a n d t he d ate is c o nsi dere d Da y 0.  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
A statistic al a n al ysis pla n ( S A P) will be pr e pare d a n d a p pr o ve d pri or t o t he first u n bli n de d 
i nteri m a nal ysis t o pr o vi de a m ore detaile d descri pti o n of t he nat ur e of t he a n al yses a n d t h e 
ma n ner i n w hi c h res ults will be c o m p iled. T he S A P will i ncl u de details of t he statisti cal m o dels 
t o be use d a n d t h e test st atistics t o be e m pl o ye d. 
8. 1.  
St atistic al H y p ot heses  
T he n ull h y p ot hesis f or t he pri mar y effica c y c o m p aris o n is t hat t he distri b uti o n of ti me t o 
res pirat or y i m pr o ve m e nt i n h os pitalize d s u bje cts wit h C O VI D-1 9 is t he  sa me bet wee n t he 
2  gr o u ps of P T C 2 9 9 a n d place b o . T he alter nati ve h y p ot hes is is t hat t he distri b uti o n of ti m e t o 
res pirat or y i m pr o ve m e nt bet we e n t he 2 treat me nt gr o u ps is n ot t he sa me. R eje cti n g t he n ull 
h y p ot hesis wit h s h orte ne d ti m e t o res pir at or y i m pr o v e me nt i n t he P T C 2 9 9, f or t he i nte nt-t o-treat 
(I T T) p o p ulati o n, will be c o nsi d ere d a s ucc essf ul de m o nstrati o n of effic ac y.  
8. 2.  
S a m ple Size Deter mi n ati o n  
T his is a gr o u p se q ue ntial d esi g n wit h 2 i nteri m a nal yses pla n ne d. T he first i nt eri m a n al ysis will 
o nl y assess t he safet y a n d t he trial will n ot be st o p p e d f or f utilit y or s u peri orit y  of effic ac y . It 
will be perf or me d after t he first 4 0 ra n d o mize d s u bj e cts ha ve c o m plete d Da y 2 8  or  disc o nti n ue d 
d ue t o deat h , wit h dr e w  c o nse nt, or were l ost-t o-f oll o w-u p .  
T he sec o n d i nteri m a nal ysis is t o assess f utilit y a n d will be perf or me d w he n 5 0 % of res pirat or y 
i m pr o ve m e nt e v e nts ha ve be e n rea c he d, ie, 1 6 3  e ve nts ha ve bee n o b ser v e d (a p pr o x i m atel y 
1 9 0  s u bjects). La n -De Mets beta s pe n di n g f u n cti o n ( n o n -bi n di n g o pti o n) is use d t o de fi n e t he 
b o u n dar y f or t he 2n d i nteri m f utilit y a nal ysis a n d t h e fi nal a n al ysis t o e ns ure t he o verall beta of 
8 0 % . T he sa m pl e size was calc ul ate d t o refl ect t he pri mar y e n d p oi nt of ti me fr o m ra n d o mizati o n 
t o res pirat or y i m pr o ve me nt, w hic h is defi ne d  as t he ti me fr o m r a n d o mi zati o n  t o res pirat or y 
i m pr o ve m e nt (S p O 2  ≥9 4 % i n r o o m air) , s ustai n e d u ntil disc h ar ge fr o m t he h os pit al  or t he e n d of 
t he st u d y ( D a y 2 8). Me dia n ti m e t o res pirat or y i m pr o ve me nt was n ot r ea dil y a vaila bl e fr o m t h e 
liter at ure. B ase d o n  ver y li mite d dat a, it is a nti ci pate d t hat t h e me dia n ti me t o res pirat or y 
i m pr o ve m e nt f or t h e plac e b o gr o u p is 1 1  da ys a n d P T C 2 9 9 treat me nt will d ecrease it t o 8  d a ys , 
a n i m pr o ve me nt of 3 -d a ys . S u bjects will be f oll o we d f or t he fi xe d a m o u nt of ti m e of 2 8 da ys 
fr o m ra n d o mi zati o n (c orres p o n di n g t o t he a ntici pat e d i m pr o ve m e nt rates of  0. 8 2 9  a n d 0.9 1 2  at 
Da y 2 8 f or place b o  a n d P T C 2 9 9, res pecti vel y ). A  t ot al of 3 2 6 e ve nts will pr o vi d e m ore t ha n 8 0 % 


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of p o w er t o dete ct a ha zar d  rati o of 1. 3 8  at t w o -si de d t y pe I err or of 0. 0 5. A p pr o xi matel y 
3 8 0  s u bjects, i n t otal, will be n ee de d. 
8. 3.  
P o p ul ati o n f or A n al yses  
I nte nt-t o-tre at (I T T) p o p ul ati o n: will i ncl u de all ra n d o mize d s u bj ects. T h e I T T p o p ulati o n will 
be use d i n all effi cac y a n al ysis a n d s u b je cts will b e gr o u pe d base d o n t he ar m t he y are 
ra n d o miz e d t o. I n t h e e ve nt t hat a s u bject rec ei ve d tr eat m e nt i n t he ar m differe nt fr o m t h e o ne t o 
w hic h he/s he was ra n d o mize d, t h e s u bject’s effic ac y data will be a n al yze d “as ra n d o mize d. ”  
S afet y p o p ul ati o n : will i ncl u de all r a n d o mi ze d s u bj ects w h o recei ve d at least o n e  d ose of st u d y 
dr u g . I n t he e ve nt t hat a s u bject rec ei ve d treat me nt i n t he ar m differe nt fr o m t he o n e t o w hic h 
he/s he was ra n d o mi ze d, t he s u bject’s safet y dat a will be a nal y ze d “as tr eat e d.” T h e  Safet y 
A nal ysis p o p ulati o n will be use d i n t he st atistical a nal yses f or safet y.   
P K  p o p ul ati o n:  will i ncl u de  safet y p o p ulati o n s u bje cts w h o ha d at l east o ne P K pr ofil e 
assess me nt.  
8. 4.  
St atistic al A n al yses  
8. 4. 1.  
Ge ner al A p pr o ac h  
F or c o nti n u o us varia bles, me dia n, m ea n, sta n dar d d e viati o n, mi ni m u m, m a xi m u m, a n d t h e 
n u m ber of s u bjects wit h n o n -missi n g data will be pr o vi de d f or ea c h treat me nt gr o u p . F or 
cate g orical varia bles, t he n u m ber ( per ce nt) of s u bj ects i n eac h c ate g or y will be pr o vi d e d.  
8. 4. 2.  
A n al ysis of P ri m ar y E ffic a c y E n d p oi nts  
T he pri m ar y e n d p oi nt is ti me fr o m ra n d o miz ati o n t o res pirat or y i m pr o ve m e nt, defi n e d as S p O 2 
≥9 4 % o n r o o m air  s ustai ne d u n til disc h ar ge fr o m t h e h os pital or t h e e n d of t h e st u d y ( Da y 2 8) . 
All h os pitalize d s u bj ects will be f oll o we d f ull y t o Da y 2 8 wit h effic ac y m eas ure me nts ta ke n 
dail y u nl ess t he y die, are l ost t o f oll o w -u p, or wit h dr a w c o nse nt. F or s u bj ects w h o are disc har ge d  
fr o m t he h os pit al pri or t o Da y 2 8 wit h o ut ac hie vi n g r es pirat or y i m pr o ve m e nt, S p O 2 
meas ure m e nts will b e ta ke n d ail y u ntil Da y 2 8 . All meas ure m e nts rec or de d will be use d f or 
effica c y a nal ysis.  
S u bjects w h o ac hi e ve d S p O 2 ≥9 4 % o n r o o m air a n d s ustai ne d t his t o Da y 2 8 or disc har ge 
wit h o ut ta ki n g a n y C O VI D -1 9 resc ue t hera py  d uri n g t he st u d y will b e c o nsi der e d as ac hi e vi n g 
t he res pirat or y i m pr o v e me nt e ve nt a n d t he e ve nt d ate will be t h e first date of ac hie vi n g S p O 2 
≥9 4 %. S u bjects will be c e ns o re d at Da y 2 8 if a n y of t he f oll o wi n g a p pl y : 
•  ra n d o miz e d b ut ha d n o f oll o w-u p  
•  t o o k a n y C O VI D -1 9 resc ue t hera py  d uri n g t he st u d y  
•  l ost t o f oll o w-u p pri or t o Da y 2 8  
•  die d pri or t o Da y 2 8  
•  wit h dr e w  c o nse nt pri or t o Da y 2 8  
•  ha d f ull f oll o w -u p wit h o ut a c hie vi n g  s ustai ne d S p O 2 ≥9 4 %.  


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Resc ue t her a p y is defi ne d as a n y a d diti o nal me dicati o n , e xcl usi ve of S O C, use d t o tr eat a 
w orse ni n g of C O VI D -1 9 s y m pt o ms a n d rec or de d as resc ue t her a p y o n t he e C R F.  
Ka pla n -Meier pl ots of ti me t o res pir at or y i m pr o ve m e nt will b e prese n t e d. Me dia n ti me t o 
res pirat or y i m pr o ve m e nt will be esti mat e d via t he K a pla n -Mei er  pr o d uct li mit met h o d. A  tw o -
si de d 9 5 % c o nfi de n ce i nter val ( CI ) f or t he m e dia n ti me t o res pir at or y i m pr o ve me nt will be 
c o m p ute d f or P T C 2 9 9  a n d pla ce b o c o h orts  base d o n a l o g -l o g tr a nsf or me d CI f or t he s ur vi v or 
f u ncti o n S(t). Ti me t o res pirat or y i m pr o ve me nt  will be c o m par e d bet wee n treat me nt gr o u ps 
usi n g stratifi e d l o g -ra n k test. 
Hazar d rati o a n d c orres p o n di n g t w o -si de d 9 5 % CIs will be esti mate d usi n g a C o x pr o p orti o nal 
hazar ds m o del, wit h tr eat m e nt ar m as a si n gl e c o vari ate, stratifi e d b y t he stratifi cati o n fact ors.  
Res pirat or y i m pr o ve m e nt  rates at D a ys 7 , 1 4, a n d 2 8 will als o be esti m ate d usi n g Ka pla n -Meier  
esti mates o n t he ti m e t o res pir at or y i m pr o v e me nt c ur ve. Ass ociate d t w o-si de d 9 5 % CIs f or ea c h 
treat me nt gr o u p a n d t he differe nc e bet we e n t he 2  tre at me nt gr o u ps will be cal c ulat e d usi n g 
Gree n w o o d’s f or m ul a f or varia n ce deri vati o n.  
8. 4. 3.  
A n al ysis of S ec o n d ar y E ffic ac y E n d p oi nts  
Si milar t o t he pri mar y e n d p oi nt, Ka pla n -Meier esti m ate, m e dia n a n d rate at D a ys 7, 1 4 , a n d 2 8 
will be prese nte d f or ti me fr o m r a n d o mi zati o n t o def er vesce nce (i n s u bjects prese nti n g wit h 
fe ver at e nr oll me nt), ti me fr o m ra n d o mizati o n t o r es pirat or y rate ≤2 4 br eat hs/ mi n ute o n r o o m air , 
ti me fr o m ra n d o mizati o n t o c o u g h re p orte d as mil d or a bse nt (i n t h ose wit h c o u g h at e nr oll me nt 
rate d se ver e or m o derate), a n d ti m e fr o m ra n d o miz ati o n t o d ys p nea re p orte d as mil d or a bse nt 
( o n a scale of se ver e, m o der ate, mil d, a bse nt, i n t h ose wit h d ys p nea at enr oll me nt  rate d as se vere 
or m o derat e) .  
T he pr o p orti o n of s u bj ects re q uiri n g i n vasi v e ve ntilati o n at a n y p oi nt d uri n g t he st u d y , s u bj ects 
re q uiri n g s u p ple me nt al o x y ge n or n o n-i n v asi ve ve ntilati o n at a n y p oi nt i n t he st u d y i n s u bj ects 
wit h o ut s u p ple m e ntal o x y ge n or n o n-i n v asi ve ve ntilati o n at b aseli n e, s u bjects wit h n or malizati o n 
of  t he c o m plet e bl o o d c o u nt, a n d t he n u m ber of s u bj ects w h o die d at t he e n d of t he st u d y will be 
s u m mariz e d b y fre q ue nc y a n d perc e nt.  
T he f oll o wi n g se c o n dar y e n d p oi nt s will be s u m mari ze d descri pti vel y 
•  Re d ucti o n i n c yt o ki ne l e vels, p ot e ntiall y i ncl u di n g I L -2, I L -6, I L -7, I L -1 7, G -C S F, 
I P-1 0, M C P 1, MI P 1 -α, a n d T N F -α,  
•  Re d ucti o n i n le v els of ac ute p hase pr ot ei ns, p ote ntiall y i ncl u di n g ferriti n a n d 
C -reacti ve pr ot ei n, D -di mer, a n d car diac tr o p o ni n,  
•  C ha n ges i n ot her la b orat or y para m eters i n cl u di n g lactate d e h y dr o ge nase, pr ot hr o m bi n 
ti me, al b u mi n,  
•  Re d ucti o n i n viral l oa d, a n d  
•  D urati o n of h os pitaliz ati o n meas ure d i n d a ys   


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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8. 4. 4.  
S afet y A n al yses  
8. 4. 4. 1.  
S u bject Dis p ositi o n  
T he dis p ositi o n of s u bj ects, i n cl u di n g t he n u m b er of s u bjects scree n e d, t he n u m ber of 
ra n d o miz e d s u bjects, t he n u m ber of r a n d o mi ze d s u bj ects w h o recei ve d at least 1 d ose of st u d y 
dr u g, a n d t he n u m b er of s u bjects w h o pre mat urel y disc o nti n ue st u d y dr u g , as well as t he r eas o n 
f or t he pre m at ure ter mi n ati o n, will be ta b ul ate d.  
8. 4. 4. 2.  
Me dic al Hist ory a n d Pri or Me dic ati o n  
Me dical hist or y a n d pri or me dic ati o n i nf or mati o n will be s u m m ariz e d.  
8. 4. 4. 3.  
E xte nt  of E x p os ure a n d Tre at m e nt C o m pli a nce  
T he e xt e nt of e x p os ure t o st u d y me di cati o n is defi n e d as t he last d ose d ate mi n us t he first d ose 
date + 1 da y. C o m pli a nce will be assesse d i n ter ms of t he perc e nta ge of dr u g act u all y ta ke n 
relati ve t o t he a m o u nt t h at s h o ul d ha ve b ee n t a ke n d uri n g t he st u d y. E x p os ure a n d c o m plia nc e 
will be s u m m ari z e d descri pti vel y.  
8. 4. 4. 4.  
A dverse Eve nts  
S u m mar y i nf or m ati o n (t he n u m b er a n d perc e nt of s u bjects b y tr eat me nt) will be ta b ulate d f or:  
•  Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es)  
•  Treat me nt -r elat e d A Es 
•  T E A Es b y se verit y  
•  S A Es  
•  A Es lea di n g t o disc o nti n u ati o n  
•  A E SIs  
S u m ma ries will be prese nte d b y tre at m e nt gr o u p a n d cate g orize d b y Me d D R A S yste m Or ga n 
Class a n d Preferre d Ter m. T he fr e q ue ncies of A Es dis pla ye d will b e t he cr u de rat es t hat 
re prese nt t h e n u m ber of s u bje cts e x perie nci n g A Es di vi de d b y t h e t ot al n u m b er of s u bjects. 
8. 4. 4. 5.  
L a b or at ory P ar a m eters  
C ha n ges i n cli nic al l a b orat or y t ests fr o m baseli ne (l ast meas ure m e nt pri or t o first d ose) a n d 
la b orat or y mar ke d a b n or maliti es usi n g pre-defi n e d a b n or malit y criteri a will b e descri pti vel y 
s u m mariz e d. 
8. 4. 5.  
B aseli ne D escri pti v e S t atistics 
De m o gra p hic a n d baseli ne c har act eristi cs of s u bjects (i ncl u di n g or di nal sc al e sc ore (W H O 2 0 2 0 ) 
will be s u m m ariz e d descri pti vel y b y mea ns a n d st a n dar d de viati o ns f or c o nti n u o us varia bl es, a n d 
fre q ue nc y distri b uti o n f or cate g orical vari a bles. S u m maries will be perf or me d base d o n all 
ra n d o miz e d s u bjects. 


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8. 4. 6.  
Pl a n ne d Interi m A n al yses  
T w o i nteri m a nal yses are pla n n e d. T he first  i nt eri m a nal ysis will be c o n d uct e d w he n 
a p pr o xi matel y 4 0 r a n d o mi ze d s u bjects ( 2 0 i n ea c h ar m) ha ve re cei ve d 1 4 d a ys of treat me nt a n d 
c o m plete d 1 4 da ys of f oll o w -u p  or disc o nti n ue d d u e t o deat h , wit h dr e w  c o nse nt, or were 
l ost-t o-f oll o w-u p . N o f or mal statistic al t esti n g will b e perf or me d at t he first i nt eri m a nal ysis . A n 
i n de pe n de nt dat a safet y m o nit ori n g b o ar d will r e vie w t he safet y data. E nr oll me nt will c o nti n u e if 
t here ar e n o safet y c o n cer ns. A sec o n d i nt eri m a nal ysis will be c o n d ucte d f or f utilit y . It will be 
perf or me d w he n 5 0 % of res pirat or y i m pr o v e me nt e v e nts ha ve be e n reac h e d, ie , 1 6 3  e ve nts ha v e 
bee n o bser ve d ( a p pr o xi mat el y  1 9 0 s u bje cts). Res pirat or y i m pr o ve me nt is defi ne d as S p O 2≥ 9 4 % 
i n r o o m air u ntil disc har ge fr o m t he h os pital or t h e e n d of st u d y  ( Da y 2 8). All s u bjects w h o ha ve 
c o m plete d t hr o u g h D a y 2 8 , were  disc har ge d wit h S p O 2 ≥9 4 % o n r o o m air , wit h dr e w c o nse nt, 
die d, were l ost t o f oll o w -u p, or t o o k a n y C O VI D -1 9 resc ue t her a py  d uri n g t he st u d y  will be 
i ncl u de d i n t he i nteri m a n al ysis . S u bjects w h ose pri mar y e ve nt ca n n ot be det er mi n e d at t he 
i nteri m c ut, ie, o n g oi n g s u bj ects , will n ot be i ncl u de d  i n t he i nteri m effi cac y a n al ysis. S u bjects 
w h o die d , wit h dre w c o nse nt, were l ost t o f oll o w-u p, or t o o k a n y C O VI D -1 9  resc ue t hera p y will 
be ce ns ore d at Da y 2 8. A stratifi e d l o g -ra n k test will be perf or me d a n d t he ha zar d rati o 
(treat me nt vs pl ace b o) will be c o m pare d wit h t he f utilit y b o u n dar y. T he trial ma y be st o p pe d f or 
f utilit y if t h e haz ar d rati o is less t ha n 1. 0 9 1. T h e f utilit y b ou n dar y is base d o n La n -De Mets bet a 
s pe n di n g f u ncti o n ( n o n-bi n di n g o pti o n) wit h o ver all beta of 8 0 % .  
T he u n bli n d e d i nt eri m a nal yses will be c o n d ucte d b y a n i n de pe n d e nt statisti cia n a n d t he res ults 
will be o nl y s har e d wit h t h e cl ose d sessi o n of t he D S M B. D S M B will ma ke t he g o - or n o -g o 
rec o m m e n dati o ns a n d o nl y t h e rec o m me n dati o ns will be c o m m u nic ate d wit h t he st u d y tea m. T he 
st u d y tea m will be k e pt bli n de d f or res ults relat e d t o t he i nt eri m a nal yses.  
8. 4. 7.  
S u b gr o u p  A n al yses  
S u b gr o u p a nal yses of t he pri mar y e n d p oi nt b y  baseli ne disease ris k fa ct ors  will be e x pl ore d as 
dee me d a p pr o priate. I n s uc h a nal yses,  a n u n-stratifie d l o g-ra n k test a n d t he h azar d rati o will be 
esti mate d usi n g t h e u nstratifie d C o x pr o p orti o nal h az ar ds m o del.  
8. 4. 8.  
E x pl or at or y A n al yses  
N ot a p plic a ble.  
9.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
9. 1.  
Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns  
9. 1. 1.  
I nf or me d C o nse nt P r ocess 
B y si g ni n g t he pr ot o c ol, t h e i n vesti gat or ass ures t hat i nf or me d c o nse nt will b e o btai ne d fr o m 
eac h s u bje ct  or l e gall y a ut h ori ze d re pr ese ntati ve  pri or t o st u d y e ntr y a n d t hat t he i nf or me d 
c o nse nt will b e o btai ne d i n acc or da n ce wit h c urre nt r e g ulati o ns.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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T he i n vesti gat or or q u alifie d re prese ntati ve  will gi ve eac h s u bje ct or l e gall y a ut h ori ze d 
re prese ntati ve f ull an d a d e q uat e ver bal a n d writte n i nf or mati o n r e gar di n g t he o bje cti v es a n d 
pr oce d ures of t he st u d y a n d t he p ossi ble ris ks i n v ol v e d. A n i nf or me d c o nse nt d oc u me nt will b e 
pr o vi de d t o e ac h s u bje ct or le g all y a ut h ori ze d re pr ese ntati ve  i n a la n g u a ge i n w hic h t he su bje ct is 
fl ue nt, or tr a nslat e d, acc or di n g t o l o cal r e g ulati o ns. T his i nf or mati o n m ust be pr o vi de d t o t he 
s u bject or l e gall y a ut h orize d re pr ese ntati ve  pri or t o u n derta ki n g a n y st u d y rel ate d pr oc e d ure. 
A de q uate ti me s h o ul d b e pr o vi de d f or t h e s u bject or le g all y a ut h orize d re pr ese ntati ve  t o rea d t he 
i nf or me d c o nse nt, t o u n derst a n d t he ris ks a n d be n efits of partici p ati n g i n t he st u d y, a n d t o as k 
a n y q uesti o ns t hat t he s u bj ect ma y ha ve a b o ut t h e st u d y. T he s u bject or le g all y a ut h oriz e d 
re prese ntati ve s h o ul d b e a ble t o as k a d diti o nal q uesti o ns as a n d w he n nee de d d uri n g t he c o n d uct 
of t he st u d y. T he s u bj ect  or le gall y a ut h orize d r e pres e ntati ve ’s si g nat ur e o n t he i nf or me d c o nse nt 
f or m s h o ul d be o btai ne d at t he i n vesti gat or site i n t he prese nce of t h e i n vesti gat or or a q u alifie d 
re prese ntati ve (e g, s u b i n v esti gat or).  
Eac h s u bje ct will be gi v e n a c o p y of t h e si g ne d c o ns e nt/asse nt f or m. T he ori gi nal si g ne d 
i nf or me d c o nse nt f or ms will b e retai ne d b y t h e i n vesti gat or wit h t he st u d y r ec or ds. 
9. 1. 2.  
St u d y D isc o nti n u ati o n a n d C l os ure 
P T C T hera pe utics reser ves t h e ri g ht t o disc o nti n ue t h e st u d y pri or t o i n cl usi o n of t h e i nt e n de d 
n u m ber of s u bjects. T he i n v esti gat or, after c o ns ultati o n wit h t he m e dic al m o nit or, reser ves t h e 
ri g ht t o disc o nti n ue t he st u d y at t he i n vesti g at or sit e f or safet y reas o ns at a n y ti me. 
After a decisi o n t o t er mi nate t h e st u d y, i n vesti gat ors m ust c o nta ct all s u bje cts w h o are c o nti n ui n g 
t heir partici pati o n i n t h e st u d y a n d m ust d o s o wit hi n a ti m e peri o d set b y P T C T her a pe uti cs. As 
direct e d b y P T C T her a pe uti cs, all st u d y mat erials m ust be c oll ect e d,  a n d all el ectr o nic data e ntr y 
f or ms c o m plete d t o t he greatest e xte nt p ossi bl e. 
9. 1. 3.  
C o nfi de nti alit y a n d P ri v ac y  
Researc h rec or ds will be c olle cte d a n d st ore d i n a ma n ner t hat pr otects t he c o nfi d e nti alit y of 
s u bject i nf or mati o n. T he n a mes a n d i d e ntities of all r esearc h s u bje cts will b e ke pt i n strict 
c o nfi de nc e a n d will n ot a p pe ar o n e C R Fs, pa per C R Fs, or ot her re c or ds pr o vi de d t o or retai n e d 
b y P T C T hera pe utics ( or its a ut h oriz e d desi g ne e). T h e na mes a n d i de ntiti es of t he s u bjects nee d 
n ot be di v ul g e d; h o we ver, t he rec or ds m ust n e vert h el ess be i ns pecte d. T his will b e acc o m plis he d 
b y bla n ki n g o ut t he s u bje ct’s na m e a n d re pl aci n g t he na me wit h t he s u bje ct’s st u d y i de ntifi cati o n 
n u m ber o n a n y re c or d pr o vi de d t o or r etai ne d b y P T C T hera pe utics. T h e i nf or me d c o nse nt f or m 
m ust i ncl u d e a p pr o pri ate st ate m e nts e x pl ai ni n g t hese re q uire m e nts.  
B y si g ni n g t his pr ot oc ol, t he i n vesti g at or affir ms t o P T C T hera p e uti cs t hat t he i n vesti gat or will 
mai nt ai n, i n c o nfi de n ce, i nf or m ati o n f ur nis he d b y P T C T hera p e uti cs a n d will di v ul ge s uc h 
i nf or mati o n t o t h e I R B/I E C u n d er a n a p pr o pri ate u n d ersta n di n g of c o nfi de ntialit y wit h s uc h 
b oar d.  
9. 1. 4.  
F ut ure use of S t ore d S peci me ns a n d D at a  
As part of t he c urre nt st u d y  bl o o d, ser u m, uri n e, a n d nas o p har y n geal s wa bs wi ll b e c ollect e d.  
Sa m ple pr oc essi n g will be p erf or me d b y a la b orat or y u n der t he dir ecti o n of t he s p o ns or. 
Pr ocessi n g, a nal ysis, a n d st ora g e will b e perf or me d at a sec ure la b orat or y f acilit y t o pr ote ct t h e 
vali dit y of t he d ata a n d mai ntai n s u bj ect pri vac y.  


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Sa m ples will o nl y be use d f or t h e p ur p oses descri be d i n t his pr ot oc ol. La b or at ori es c o ntracte d t o 
perf or m t he a nal ysis o n be half of t he s p o ns or will n ot retai n ri g hts t o t he sa m ples be y o n d t h ose 
necessar y t o perf or m t he s pecifie d a nal ysis a n d will n ot tra n sfer or sell t h ose sa m ples. T he 
s p o ns or will n ot sell t h e sa m pl es t o a t hir d part y.  
Sa m ples will b e st ore d u ntil t h e c o m pleti o n of t he st u d y ( defi ne d as s u b missi o n of t h e cli nical 
st u d y re p ort t o t h e a p pr o pri ate re g ulat or y a ge ncies). At t he e n d of t h e st or a ge peri o d, sa m pl es 
will be destr o y e d. Sa m pl es ma y be st ore d l o n ger if a healt h a ut h orit y ( or me dici nal pr o d uct 
a p pr o val a g e nc y) has acti ve q u esti o ns a b o ut t he st u d y. I n t his s pecial cir c u msta nc e, t he sa m ples 
will be st ore d u ntil t he q uesti o ns ha ve bee n a d e q uatel y a d dresse d.  
N o s u bject -i de ntif yi n g i nf or mati o n (e g, i niti als, dat e of birt h, g o ver n m e nt i d e ntif yi n g n u m ber) 
will be ass oci ate d wit h a n y of t he bi ol o gic sa m pl es. All sa m ples will be si n gl e c o de d. T he 
s p o ns or will ta ke ste ps t o e ns ure t hat data are pr ot ect e d acc or di n gl y, a n d c o nfi de ntialit y is 
mai nt ai ne d as far as p ossi ble. Data fr o m s u bjects e nr olle d i n t his st u d y ma y b e a nal yze d 
w orl d -wi de , re gar dless of l oc ati o n of c oll ecti o n. 
T he s p o ns or a n d its re prese ntati ves a n d a ge nts ma y s hare c o de d d ata wit h  p ers o ns a n d 
or ga nizati o ns i n v ol v e d i n t h e c o n d uct or o v ersi g ht of t his researc h. T hese i ncl u de:  
•  C o ntract R esearc h Or ga ni zati o ns ( C R Os ) retai ne d b y t he s p o ns or 
•  I E Cs or I R Bs t hat ha ve r es p o nsi bilit y f or t his resear c h st u d y 
•  Nati o nal r e g ulat or y a ut h orities or  e q ui val e nt g o ver n me nt a g e nci es  
At t he e n d of t h e a nal ysis, res ults ma y be pr ese nte d i n a fi nal r e p ort w hic h c a n i ncl u de part or all 
of t he c o de d d ata, i n listi n g or s u m mar y f or m at. Ot her p u blicati o n (e g, i n peer -re vie we d 
scie ntific j o ur n als) or p u bli c prese ntati o n of t h e st u d y res ults will o nl y i ncl u d e s u m maries of t he 
p o p ulati o n i n t he st u d y, a n d n o i de ntifi e d i n di vi d ual res ults will be discl ose d.  
Gi ve n t he rese arc h nat ur e of t he la b orat or y a nal ysis, it will n ot be p ossi ble t o ret ur n i n di vi d u al 
data t o s u bj ects. T h e res ults t h at ma y b e ge ner ate d ar e n ot c urre ntl y a ntici pate d t o ha ve cli nical 
rele va n ce t o t he patie nts or t h eir fa mil y me m b ers. T h eref ore, t h ese res ults will n ot be discl ose d 
t o t he patie nts or t heir p h ysi cia ns. 
9. 1. 5.  
S afet y O versi g ht  
9. 1. 5. 1.  
D at a a n d S afety M o nit ori n g B o ar d  
E xter nal o versi g ht f or t his tri al will be pr o vi de d b y a D S M B. T he pri mar y res p o nsi bilit y of t h e 
D S M B is t o pr otect t he saf et y a n d welfare of s u bje cts partici p ati n g i n t his cli ni cal trial a n d t o 
e ns ure t he i nte grit y of t he cli ni cal trial.  T o m ai nt ai n t he bli n di n g a n d i nt e grit y of t he st u d y, 
pr oce d ures will b e i m ple me nte d t o e ns ure t he D S M B a n d i n de pe n d e nt statisti cia n ha v e s ole 
access t o u n bli n de d safet y data.  
S pecific all y, f or t his st u d y, t he D S M B will be r es p o nsi ble f or:  
•  E xa mi ni n g ac c u m ul ate d safet y dat a, P K, a n d c o m pli a nce data i n or der t o ma k e 
rec o m m e n dati o ns c o ncer ni n g c o nti n u ati o n, ter mi nati o n, or m o dific ati o n of t he trial 
base d o n t he safet y of t he i nter ve nti o ns u n der s t u d y 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
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P a ge 5 1  of 6 2  
•  Re vie wi n g m aj or st u d y desi g n m o difi cati o ns pr o p ose d b y P T C T hera p e uti cs or t he 
i n vesti gat ors pri or t o i m ple me nt ati o n of t h ose m o difi cati o ns 
•  Re vie wi n g t h e ge ner al pr o gress of t he st u d y as re g ar ds accr ual, pr ot oc ol vi olati o ns, 
a n d st u d y c o n d uct  
T he D S M B  will re vie w t h e i nt eri m P K ( Da y 1 a n d 7) a n d safet y data w he n a p pr o xi mat el y 
4 0  s u bjects ha ve r ecei v e d 1 4 da ys of st u d y tre at m e nt. T he D S M B ma y re vie w t h e safet y data at 
ot her ti mes as warra nte d b y e mer gi n g res ults. Base d o n re vie w of t he safet y dat a, t he D S M B ca n 
rec o m m e n d c o nti n uati o n of t he st u d y u nc h a n ge d, st u d y i nterr u pti o n, st u d y ter mi nati o n, 
m o dific ati o n of t he trial, or alter a ti o n. F ull det ails of t he D S M B pr oce d ures, i ncl u di n g pri m ar y 
res p o nsi bilities, will b e d oc u m e nte d i n a D S M B C harter. 
9. 1. 5. 2.  
He p at i c A dvis ory S afet y C o m mittee  
A H A C c o m prise d of he pat ol o gists e x perie n ce d in t h e m o nit ori n g a n d i d e ntificati o n  of DI LI  wil l 
o versee t h e h e patic safet y of s u bj ects e nr olle d i n t he st u d y. T he H A C will me et re g ularl y t o 
assess t he se verit y a n d ca usalit y of all he pat ot o xi cit y e ve nts . F ull details of t he H A C pr oce d ures 
will be d oc u me nt e d i n t h e H A C C harter.  
9. 1. 6.  
Cli nic al M o nit o ri n g  
I n acc or da nc e wit h 2 1 C o de of Fe d eral R e g ulati o ns Part 3 1 2. 5 6 a n d/ or rele va nt  I nter nati o nal 
C o u ncil f or Har m o nisati o n  (I C H) g ui d eli nes, P T C T hera pe utics or a desi g ne e will p eri o di call y 
i ns pect all e C R Fs, st u d y d oc u m e nts, researc h f aciliti es, a n d cli nical la b orat or y facilities 
ass ociate d wit h t his st u d y at m ut u all y c o n ve nie nt ti m es, bef ore, d uri n g, a n d after c o m pleti o n of 
t he st u d y. As re q uire d b y a p plic a ble re g ulati o ns ( Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors), 
t he m o nit ori n g visits pr o vi de P T C T h era pe utics wit h the o p p ort u nit y t o e v al uate t h e pr o gress of 
t he st u d y; verif y t he acc ura c y a n d c o m plete ness of d ata i n t he e C R Fs; e ns ure t hat all pr ot oc ol 
re q uire m e nts, rel e va nt re g ulati o ns, a n d i n vesti gat or’s o bli gati o ns are bei n g f ulfille d; a n d res ol ve 
a n y i nc o nsiste n cie s i n t he st u d y rec or ds. T his i ncl u d es i ns pecti o n of all d o c u me nts a n d rec or ds 
re q uire d t o b e mai ntai ne d b y t he i n vesti g at or, i n cl u di n g b ut n ot li mit e d t o m e dic al re c or ds 
( office, cli ni c, or h os pital) f or t he s u bje cts i n t his st u d y. T he na m es a n d i de ntities of all r esearc h 
s u bjects will b e ke pt i n strict c o nfi d e nce a n d will n ot a p pear o n e C R Fs or ot her r ec or ds pr o vi de d 
t o or retai ne d b y P T C T h era pe utics. T he i n vesti g at or/i nstit uti o n g uar a nte es direct acc ess t o 
s o urce d oc u me nts b y P T C T hera pe utics a n d a p pr o pri ate re g ulat or y a ut h orities. 
It is i m p ort a nt t h at t h e i n vesti gat or a n d rele v a nt i nstit uti o nal p ers o n nel ar e a vaila bl e d uri n g t h e 
m o nit ori n g visits a n d p ossi ble a u dits or i ns pe cti o ns a n d t hat s ufficie nt ti m e is de v ot e d t o t he 
pr ocess.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 2  of 6 2  
9. 1. 7.  
Q u alit y A ss ur a nce a n d Q u alit y C o ntr ol  
T o e ns ure c o m plia n ce wit h G o o d Cli nical  Practice ( G C P) a n d all a p plica ble re g ul at or y 
re q uire m e nts, P T C, P T C’s re prese nt ati ves, a r e g ulat or y a ut h orit y or a n d I nstit uti o nal Re vi e w 
b oar d ma y c o n d u ct a q ualit y ass ura nce a u dit. Re as o ns f or q uali t y ass ura nc e a u dit ma y i n cl u de 
b ut are n ot li mite d t o  ra n d o m selecti o n, ge o gra p hic pr o xi mit y, s us pecte d G C P vi olati o n, hi g h 
e nr olli n g site, a n d r ec urri n g pr ot o c ol de viati o ns. T he p ur p ose of a S p o ns or a u dit or i ns pecti o n is 
t o s yste maticall y a n d i n de pe n de ntl y e x a mi n e all st u d y relat e d acti vities a n d d oc u me nts t o 
deter mi ne w het h er t hese a cti viti es were c o n d ucte d, a n d data were re c or de d, a n al yz e d, a n d 
acc uratel y re p orte d a cc or di n g t o t he pr ot oc ol, G o o d Cli nic al Practic e g ui deli nes of t he I C H, a n d 
a n y a p pli ca bl e re g ulat or y re q uir e me nts. T he i n v esti g at or s h o ul d c o nt act t he S p o ns or i m m e diatel y 
if c o nta cte d b y a re g ulat or y a ge n c y a b o ut a n i ns pecti o n. 
9. 1. 8.  
D at a H a n dli n g a n d R ec or d K ee pi n g 
T o e na bl e e val uati o ns a n d/ or a u dits fr o m re g ul at or y a ut h orities or P T C T her a pe utics, t he 
i n vesti gat or a gre es t o kee p a cc urate a n d c o m pl ete r e c or ds, i ncl u di n g t he i d e ntit y of all 
partici pati n g s u bjects (s ufficie nt i nf or mati o n t o li n k e C R Fs a n d cli ni c rec or ds/s o urc e 
d oc u me nts), all ori gi nal si g n e d i nf or me d c o nse nt f or ms, electr o nic c o pies (ie, C D -R O M, U S B, 
etc.) or pa p er c o pies of t h e dat a t hat ha ve b ee n c a pt ure d i n t he E D C f or eac h s u bje ct (e C R Fs), 
a n d detaile d r ec or ds of st u d y dr u g dis p ositi o n. All re c or ds a n d d oc u me nts pertai ni n g t o t he st u d y 
will be m ai nt ai ne d b y t he i n v esti gat or u ntil n otifi cati o n is recei v e d fr o m P T C T h era pe utics t hat 
t he rec or ds n o l o n g er nee d t o b e ret ai ne d. 
T he i n vesti gat or m ust o btai n writt e n per missi o n fr o m P T C T hera p e uti cs bef ore dis p osi n g of a n y 
rec or ds. T he i n v esti gat or will pr o m ptl y n otif y P T C T hera pe utics i n t h e e ve nt of acci de nt al l oss 
or destr ucti o n of a n y st u d y rec or ds. If t he i n vesti g at or rel ocates, retires, or f or a n y reas o n 
wit h dra ws fr o m t he st u d y, t h e st u d y rec or ds ma y b e tra nsferre d t o a n a cce pta bl e desi g ne e, s uc h 
as a n ot her i n v esti gat or, a n ot her i nstit uti o n, or t o P T C T hera pe utics as a p plica ble.  
9. 1. 9.  
Pr ot oc ol D e vi ati o ns  
A pr ot oc ol de vi ati o n is defi ne d as a n y i nte nti o nal or u ni nte nti o nal c ha n ge t o, or n o nc o m plia nc e 
wit h, t he a p pr o v e d pr ot oc ol pr oce d ures or re q uire m e nts. De viati o ns m a y res ult fr o m t he acti o n or 
i nacti o n of t he s u bj ect, i n vesti g at or, or site st aff. E xa m ples of de vi ati o ns i n cl u de, b ut are n ot 
li mite d t o: 
•  Fail ure t o a d here t o st u d y e xcl usi o n a n d i ncl usi o n criteria  
•  Fail ure t o c o m pl y wit h dis pe nsi n g or d osi n g re q uire me nts  
•  Use of me dica ti o ns t hat are s pecific all y pr o hi bit e d i n t he pr ot oc ol 
•  Misse d or o ut -of -wi n d o w visits  
•  Dr u g d osi n g n ot a d mi nist ere d wit hi n t he ti m e fra me s pecifie d i n t he pr ot oc ol  
•  Fail ure t o a d here t o test re q uire m e nts, i ncl u di n g vital si g ns, la b orat or y t ests, p h ysical 
e xa mi n ati o ns, P K bl o o d dra ws, me di cal hist or y, etc. - eit her tests n ot d o ne, i nc orrect 
tests d o ne, or n ot d o ne wit hi n t h e ti me fra me s pecifie d i n t he pr ot o c ol 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 3  of 6 2  
•  Pr oce d u ral de viati o ns s uc h as i nc orrect st ora ge of st u d y dr u g, fail ure t o u p dat e t he 
inf or me d c o nse nt f or m  (I C F) w he n ne w ris ks bec o m e k n o w n, or fail ure t o o btai n 
I R B/I E C a p pr o vals f or t he pr ot o c ol a n d I C F re visi o ns  
Maj or  de viati o ns are a n y de viati o ns t hat i m p act  s u bj ect eli gi bilit y (ie, pr ot oc ol 
i ncl usi o n/ e xcl usi o n vi olati o ns), s u bject safet y or a s u bject’s a bilit y t o c o nti n ue i n t he cli nical 
trial. 
At t he o utset of t he st u d y, a pr o cess f or defi ni n g a n d ha n dli n g pr ot o c ol de viati o ns will be 
esta blis he d wit h t he C R O. T his will i n cl u de d eter mi ni n g w hic h de vi ati o ns will be desi g n ate d 
maj or ; t h us, re q uiri n g i m m e diate n otificati o n t o t he me dic al m o nit or a n d t he s p o ns or. 
Pr os pecti ve de viati o ns (e g, pr ot oc ol wai vers) are pr o hi bite d p er P T C p oli c y.  
T he i n vesti gat or is res p o nsi ble f or s eei n g t hat a n y k n o w n pr ot oc ol de vi ati o ns ar e rec or de d as 
a gree d.  
9. 1. 1 0.  
P u blic ati o n a n d D at a S h ari n g P olic y  
T he i nf or m ati o n d e vel o pe d d uri n g t he c o n d uct of t his cli nic al st u d y is c o nsi d ere d c o nfi de nti al b y 
P T C T hera pe utics. T his i nf or mati o n m a y be di scl ose d as dee me d n ecessar y b y 
P T C  T hera pe utics.  
P T C T hera pe utics i nte n ds t hat t he data fr o m t his st u d y will be prese nte d a n d p u blis he d. T he 
P T C  T hera pe utics staff u n d er t he dir ecti o n of t he P T C T hera pe utics C hi ef Me dical Officer or 
desi g nee i n c oll a b orati o n wit h t he i n vesti g at or will b e res p o nsi ble f or writi n g prese ntati o ns a n d 
ma n uscri pts f or p u blicati o n. I n vesti gat ors will n ot be all o we d t o p u blis h or prese nt t he data fr o m 
t his st u d y wit h o ut pri or a gree me nt wit h P T C T her a p e utics. 
T he i n vesti gat or is o bli ge d t o pr o vi de t he s p o ns or wit h c o m pl ete test res ults a n d all data d eri ve d 
b y t he i n vesti gat or fr o m t he st u d y. D uri n g t he st u d y, o nl y t he s p o ns or ma y m a ke st u d y 
i nf or mati o n a vaila ble t o ot her st u d y I n vesti g at ors or t o re g ulat or y a ge n cies, e xc e pt as re q uired b y 
la w or re g ulati o n. E x ce pt as ot h er wise all o wa ble i n t he C li ni cal S t u d y S ite A gree me nt, a n y 
p u blic discl os ure (i ncl u di n g p u blicl y accessi bl e we bsites) rel ate d t o t he pr ot oc ol or st u d y res ults, 
ot her t ha n st u d y r ecr uit me nt mat erials a n d/ or a d v ertise me nt s, is t he s ol e res p o nsi bilit y of t h e 
sp o ns or.  
T he s p o ns or ma y p u blis h a n y d ata a n d i nf or mati o n fr o m t he st u d y (i n cl u di n g d ata a n d 
i nf or mati o n ge ner ate d b y t h e i n vesti gat or) wit h o ut t h e c o nse nt of t h e I n vesti g at or. Ma n uscri pt 
a ut h ors hi p f or a n y pe er -re vie wed p u blic ati o n will a p pr o priatel y refl ect c o ntri b uti o ns t o t he 
pr o d ucti o n a n d r e vie w of t he d o c u me nt. All p u blicati o ns a n d prese ntati o ns m ust be pre p are d i n 
acc or da n ce wit h t his secti o n a n d t he Cli ni cal St u d y Site A gree me nt. I n t he e ve nt of a n y 
discre pa nc y b et wee n t h e pr ot oc ol a n d t h e Cli nical St u d y Site A gree m e nt, t h e Cli nical St u d y Site 
A gree me nt will pre v ail.  
Data fr o m all sit es partici pati n g i n t h e st u d y will b e p o ole d a n d a n al yz e d b y t he s p o ns or or t he 
s p o ns or’s desi g nee. T he first p u blicati o n of t he stu d y res ults s hall be ma de i n c o nj u n cti o n wit h 
t he res ults fr o m ot her st u d y sit es as a m ultice nter p u blicati o n. If a m ultice nter p u bli cati o n is n ot 
f ort hc o mi n g wit hi n 2 4 m o nt hs of c o m pl eti o n of t he st u d y at all sit es, t he I n vesti gat or ma y 
p u blis h or prese nt  t h e res ults ge n erate d at his or her site. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 4  of 6 2  
T he i n vesti gat or will pr o vi d e t he s p o ns or wit h a c o p y of a n y pr o p ose d p u blic ati o n or 
prese ntati o n f or re vie w a n d c o m m e nt at le ast 6 0 da ys pri or t o s uc h prese ntati o n or s u b missi o n 
f or p u blicati o n. T h e s p o ns or s hall i nf or m t he i n vesti gat or i n writi n g of a n y c h a n ges or deleti o ns 
i n s uc h prese ntati o n or p u blicati o n re q uir e d t o pr ot ect t he s p o ns or’s c o nfi de ntial a n d pr o priet ar y 
tec h ni cal i nf or mati o n a n d t o a d dress i nac c urat e dat a or i na p pr o priate i nter pret ati o ns i n t he 
c o nte xt of a n y p o ole d m ultice nter res ults. At t h e e x pirati o n of s uc h 6 0 -da y p eri o d, t he 
i n vesti gat or ma y pr o cee d wit h t he prese ntati o n or s u b missi o n f or p u blic ati o n u nless t he s p o ns or 
has n otifie d t he i nstit uti o n or t he i n vesti g at or i n writi n g t hat s uc h pr o p ose d p u blicati o n or 
prese ntati o n discl oses t h e s p o ns or’s c o nfi de ntial a n d pr o prietar y tec h nical i nf or mati o n. F urt her, 
u p o n t he re q uest of t he s p o ns or, t he i n v esti gat or will dela y t h e p u bli cati o n or prese ntati o n f or a n 
a d diti o n al 9 0 da ys t o p er mit t he s p o ns or t o t a ke nec essar y acti o ns t o pr ot ect its i nt ell ect ual 
pr o pert y i nt erests.  
9. 2.  
Pr ot oc ol A me n d me nt Hist or y  
V e rsi o n 1. 0: 1 7 A pril 2 0 2 0  
9. 2. 1.  
Versi o n 2. 0: 0 8  M a y 2 0 2 0   
O ver all re as o n f or Versi o n 2. 0:  T he o v erall reas o n f or Versi o n 2. 0 of t he pr ot oc ol was t o 
i nc or p orat e Healt h A ut h orit y fe e d bac k . 
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 2/ U p d at e  
R e a s o n/ R ati o n al e  
1  
Pr ot o c ol  
T h e pr ot o c ol w a s u p d at e d t hr o u g h o ut t o r e pl a c e t h e 
S O C c o m p ari s o n ar m wit h pl a c e b o c o ntr ol. T h e v er si o n 
n u m b er a n d d at e w er e u p d at e d t hr o u g h o ut. 
E dit ori al a n d a d mi ni str ati v e r e vi si o n s ( e g, t y p o gr a p hi c al 
err or, p u n ct u ati o n, t e n s e s, a b br e vi ati o n s) w er e 
i n c or p or at e d t o pr o vi d e cl arit y. T h e s y n o p si s a n d 
s c h e d ul e of e v e nt s w er e  u p d at e d t o b e c o n si st e nt wit h 
c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
2  
S e cti o n 1  
U p d at e d wit h l at e st s pr e a d of di s e a s e.  
U p d at e  
3  
S e cti o n 1. 1  
N e w n o n cli ni c al d at a w er e a d d e d  
U p d at e  
4  
S e cti o n 2. 1. 1  
T h e pri m ar y o bj e cti v e w a s u p d at e d t o b e t h e ti m e t o 
r e s pir at or y i m pr o v e m e nt. 
U p d at e  
5  
S e cti o n  2. 2. 1  
T h e pri m ar y e n d p oi nt w a s u p d at e d, c o n si st e nt wit h t h e 
n e w pri m ar y o bj e cti v e . 
U p d at e  
6  
S e cti o n 2. 2. 2  
F or t h o s e s e c o n d ar y e n d p oi nt s r e c or di n g ti m e t o 
i m pr o v e m e nt, it w a s cl arifi e d t h at t h e ti m e st art s at 
r a n d o mi z ati o n. Cl arifi c ati o n w a s a d d e d o n t h e c o u g h 
s e v erit y s c al e. D -di m er a n d c ar di a c tr o p o ni n w er e 
s p e cifi e d i n t h e li st of p ot e nti al a c ut e p h a s e pr ot e i n s t o 
b e a s s e s s e d.  
Cl arifi c ati o n  
7  
S e cti o n 3. 1  
T h e st u d y d e si g n w a s u p d at e d t o r efl e ct t h e c h a n g e t o a 
pl a c e b o -c o ntr oll e d, d o u bl e bli n d st u d y  a n d t o i n cl u d e 
str atifi c ati o n b y re m d e si vir, pr o hi biti o n of s e n siti v e 
C Y P 2 D 6 s u b str at e s a n d i n v e sti g ati o n al t h er a pi e s,  a n 
i n cr e a s e d s a m pl e si z e, a n d t h e a d diti o n of t h e D a y 6 0 
s af et y t el e p h o n e c all.  
U p d at e  
8  
S e cti o n 3. 2  
A d diti o n al cli ni c al e x p eri e n c e w a s a d d e d t o t h e d o s e 
j u stifi c ati o n. 
U p d at e  
9  
S e cti o n 4. 1  
T h e st u d y p o p ul ati o n si z e w a s i n cr e a s e d.  
U p d at e  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 5  of 6 2  
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 2/ U p d at e  
R e a s o n/ R ati o n al e  
1 0  
S e cti o n 4. 2  
I n cl u si o n crit eri o n # 1 w a s a m e n d e d t o S u bj e ct ( or  l e g all y 
a ut h ori z e d r e pr e s e nt ati v e) i s willi n g a n d a bl e t o pr o vi d e 
i nf or m e d c o n s e nt a n d c o m pl y wit h all pr ot o c ol 
r e q uir e m e nt s 
“ Or e q ui v al e nt t e st” w a s a d d e d t o c h e st X -r a y or C T 
s c a n i n I n cl u si o n  crit eri o n # 9.  
U p t o 5 0 d a y s aft er l a st d o s e w a s a d d e d t o I n cl u si o n 
crit eri o n # 1 0  
Cl arifi c ati o n  
1 1  
S e cti o n 4. 3  
E x cl u si o n crit eri o n # 3 w a s c h a n g e d t o e x cl u d e s u bj e ct s 
wit h ≥3 × U L N A L T or A S T or ≥2 × U L N T bili.  
E x cl u si o n  crit eri o n # 4 w a s a d d e d t o e x cl u d e s u bj e ct s 
wit h l o w l y m p h o c yt e c o u nt or h e m o gl o bi n l e v el s.  
S e n siti v e C Y P 2 D 6 s u b str at e s a n d a n y i n v e sti g ati o n al 
t h er a p y w er e a d d e d t o pr o hi bit e d m e di ci n e s i n E x cl u si o n 
crit eri o n # 7.  
E x ci pi e nt s w er e i n cl u d e d i n E x cl u si o n crit eri o n # 1 0.  
U p d at e  
1 2  
S e cti o n 5. 1. 2  
A r e c o m m e n d ati o n t o t a k e P T C 2 9 9 wit h f o o d w a s 
a d d e d.  
U p d at e  
1 3  
S e cti o n 5. 3  
T h e s e cti o n w a s u p d at e d t o r efl e ct t h e c h a n g e i n st u d y 
d e si g n fr o m o p e n -l a b el t o d o u bl e bli n d a n d t o i n cl u d e 
t h e e m er g e n c y u n bli n di n g pr o c e d ur e.  
U p d at e  
1 4  
S e cti o n 5. 5  
S e n siti v e C Y P 2 D 6 s u b str at e s a n d i n v e sti g ati o n al 
t h er a pi e s w er e a d d e d t o t h e pr o hi bit e d c o n c o mit a nt 
m e di c ati o n.  
U p d at e  
1 5  
S e cti o n 6. 1  
Cl arifi c ati o n w a s a d d e d ar o u n d tr e at m e nt of s u bj e ct s 
aft er di s c o nti n u ati o n.  
Cl arifi c ati o n  
1 6  
S e cti o n 6. 1. 2  
St o p pi n g r ul e s w er e a d d e d f or l o w l y m p h o c yt e c o u nt s 
a n d l o w h e m o gl o bi n l e v el s.  
U p d at e  
1 7  
S e cti o n 7. 1  
A s af et y t el e p h o n e c all at D a y 6 0 w a s a d d e d a n d 
cl arifi c ati o n w a s a d d e d ar o u n d S cr e e ni n g a n d D a y  1 
o c c urri n g o n t h e s a m e d a y or 1 d a y a p art.  
U p d at e a n d 
cl arifi c ati o n  
1 8  
S e cti o n 7. 2  
D -di m er a n d c ar di a c tr o p o ni n w er e s p e cifi e d i n t h e li st of 
p ot e nti al l a b or at or y p ar a m et er s t o b e a s s e s s e d  
Cl arifi c ati o n  
1 9  
S e cti o n 7. 3  
T h e s e cti o n w a s u p d at e d t o s p e cif y t h at P K 
a s s e s s m e nt s will b e at s el e ct sit e s . Cl arifi c ati o n ar o u n d 
P K a s s e s s m e nt s f oll o wi n g di s c h ar g e fr o m t h e h o s pit al 
w a s a d d e d.  
U p d at e  
2 0  
S e cti o n 7. 4  
Cl arifi c ati o n w a s a d d e d t h at vit al si g n s ar e p art of s af et y 
a s s e s s m e nt s . 
Cl arifi c ati o n  
2 1  
S e cti o n 7. 5. 1  
E C G s w er e r e m o v e d  
U p d at e  
2 2  
S e cti o n 7. 5. 2  
U p d at e d t o ali g n wit h t h e n e w D a y 6 0 s af et y t el e p h o n e 
c all.  
U p d at e  
2 3  
S e cti o n 7. 5. 1 0  T e xt c o n c er ni n g  t h e S A E f or m w a s u p d at e d.  
U p d at e  
2 4  
S e cti o n 7. 5. 1 1  T e xt c o n c er ni n g t h e pr e g n a n c y f or m w a s u p d at e d.  
U p d at e  
2 5  
S e cti o n 8  
U p d at e s w er e m a d e t hr o u g h o ut c o n si st e nt wit h t h e 
u p d at e d e n d p oi nt s a n d a d diti o n of pl a c e b o, i n cl u di n g a n  
i n cr e a s e d s a m pl e si z e.  
U p d at e  
2 6  
S e cti o n 9. 1. 5  
F urt h er d et ail s of t h e D S M B w er e a d d e d.  
Cl arifi c ati o n  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 6  of 6 2  
9. 2. 2.  
Versi o n 3. 0: 0 5  J u ne 2 0 2 0  
O ver all re as o n f or Versi o n 3. 0: T he o v erall reas o n f or Versi o n 3. 0 of t he pr ot oc ol was t o 
i nc or p orat e fee d ba c k fr o m t h e F D A. 
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 3 / U p d at e 
R e a s o n/ R ati o n al e  
1  
Pr ot o c ol  
T h e v er si o n n u m b er a n d d at e w er e u p d at e d t hr o u g h o ut.  
E dit ori al a n d a d mi ni str ati v e r e vi si o n s ( e g, t y p o gr a p hi c al 
err or, p u n ct u ati o n, t e n s e s, a b br e vi ati o n s) w er e 
i n c or p or at e d t o pr o vi d e cl arit y. T h e s y n o p si s a n d 
s c h e d ul e of e v e nt s w er e  u p d at e d t o b e c o n si st e nt wit h 
c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
2  
S e cti o n s  1. 2  
a n d  6. 1. 1  
A n i n d e p e n d e nt H e p ati c A d vi s or y S af et y C o m mitt e e will 
m o nit or h e p ati c s af et y t hr o u g h o ut t h e st u d y a n d t h e 
pr ot o c ol w a s a m e n d e d a c c or di n gl y.  
U p d at e  
3  
S e cti o n s  
2. 2. 1 , 8. 2 , a n d 
8. 4. 2  
T h e pri m ar y e n d p oi nt w a s a m e n d e d t o t h e ti m e fr o m 
r a n d o mi z ati o n t o r e s pir at or y i m pr o v e m e nt, d efi n e d a s 
p eri p h er al o x y g e n s at ur ati o n ( S p O 2 ) ≥9 4 % o n r o o m air 
s u st ai n e d u ntil di s c h ar g e fr o m t h e h o s pit al or t h e e n d of 
t h e st u d y ( D a y 2 8) 
U p d at e  
4  
S e cti o n 3. 1  
T h e st u d y d e si g n w a s a m e n d e d t o r efl e ct c h a n g e s 
m a d e el s e w h er e, n a m el y e x cl u si o n of C Y P 2 C i n d u c er s , 
i n cl u si o n of t h e H A C, a n d a d diti o n of t h e i nt eri m a n al y si s 
f or f utilit y.  
U p d at e  
5  
S e cti o n s  4. 3  
a n d 5. 5  
C Y P 2 C i n d u c er s w er e a d d e d t o t h e e x cl u d e d t h er a pi e s 
i n e x cl u si o n crit eri o n # 7. 
U p d at e  
6  
S e cti o n 7. 1  
T h e s c h e d ul e of e v e nt s w a s u p d at e d t o i n cl u d e W H O 
or di n al s c al e a s s e s s m e nt at b a s eli n e,  dr u g c o m pli a n c e 
c h e c k o n D a y 1 4, a d diti o n al P K a s s e s s m e nt o n D a y 2 8 
a n d i n t h e c a s e of h e p at ot o xi cit y, a n d t o cl arif y w hi c h  
s u bj e ct s m u st att e n d  t h e D a y 6 0 t el e p h o n e c all.  
U p d at e a n d 
cl arifi c ati o n  
7  
S e cti o n 7. 2  
A nti b o d y tit er s w er e a d d e d t o t h e li st of l a b or at or y 
p ar a m et er s  
Cl arifi c ati o n  
8  
S e cti o n 7. 3  
A d diti o n al P K a s s e s s m e nt s o n D a y 2 8 a n d i n t h e c a s e 
of h e p at ot o xi cit y w er e a d d e d.  
U p d at e  
9  
S e cti o n 7. 5. 3  
A s e cti o n w a s a d d e d t o d efi n e a d v er s e e v e nt s of s p e ci al 
i nt er e st ( A E SI s).  
U p d at e  
1 0  
S e cti o n 7. 5. 1 2  A E SI s w er e a d d e d t o t h e e v e nt s t o b e r e p ort e d i n a n 
e x p e dit e d m a n n er.  
U p d at e  
1 1  
S e cti o n 8  
T h e st ati sti c al c o n si d er ati o n s s e cti o n s  w er e  u p d at e d t o 
i n cl u d e t h e u p d at e d pri m ar y e n d p oi nt, d et ail s of t h e  
s e c o n d i nt eri m a n al y si s f or  f utilit y, t h e r e s ulti n g s a m pl e 
si z e c h a n g e s , a n d t o i n cl u d e A E SI s . 
U p d at e  
1 2  
S e cti o n 8. 4. 5  
B a s eli n e cl a s sifi c ati o n o n t h e W H O or di n al s c al e w a s 
s p e cifi e d  
U p d at e  
1 3  
S e cti o n 
9. 1. 5. 2  
S e cti o n a d d e d t o d e s cri b e t h e H A C  
U p d at e  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 7  of 6 2  
9. 2. 3.  
Versi o n 4. 0: 2 3  J ul y 2 0 2 0  
O ver all re as o n f or Versi o n 4. 0:  T he o v erall reas o n f or Versi o n 4. 0 of t he pr ot oc ol was t o 
i nc or p orat e fee d ba c k fr o m Healt h A ut h orities . 
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 4 / U p d at e 
R e a s o n/ R ati o n al e  
1  
Pr ot o c ol  
T h e v er si o n n u m b er a n d d at e w er e u p d at e d t hr o u g h o ut.  
E dit ori al a n d a d mi ni str ati v e r e vi si o n s ( e g, t y p o gr a p hi c al 
err or, p u n ct u ati o n, t e n s e s, a b br e vi ati o n s) w er e 
i n c or p or at e d t o pr o vi d e cl arit y. T h e s y n o p si s a n d 
s c h e d ul e of e v e nt s w er e  u p d at e d t o b e c o n si st e nt wit h 
c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
2  
S y n o p si s  
T h e n u m b er of sit e s w a s i n cr e a s e d t o a p pr o xi m at el y 4 0  
U p d at e  
3  
S e cti o n 3. 1  
A d efi niti o n of h o s pit ali z ati o n w a s a d d e d.  
Cl arifi c ati o n  
4  
S e cti o n 3. 1  
a n d 4. 1  
A n err or i n t h e n u m b er of st u d y s u bj e ct s w a s c orr e ct e d  
Cl arifi c ati o n  
5  
S e cti o n s 3. 1 , 
5. 3 , a n d 8. 4. 7  
St r atifi c ati o n f a ct or s w er e a m e n d e d t o r e m o v e 
h y dr o x y c hl or o q ui n e a n d a d d d e x a m et h a s o n e.  
U p d at e  
6  
S e cti o n s 3. 1 , 
6. 2 , a n d 7. 2   
Cl arifi c ati o n w a s a d d e d r e g ar di n g o n g oi n g a s s e s s m e nt 
of s u bj e ct s di s c h ar g e d fr o m t h e h o s pit al b ef or e D a y 2 8.  
Cl arifi c ati o n  
7  
S e cti o n s  4. 2  
a n d  7. 2  
I n cl u si o n Crit eri o n # 5 w a s m o difi e d t o s p e cif y S cr e e ni n g 
n ot e nr oll m e nt  a n d I n cl u si o n Crit eri o n # 7 w a s m o difi e d 
f or u s e of a nti p yr eti c s.  
Cl arifi c ati o n  
8  
S e cti o n 4. 3  
E x cl u si o n Crit eri o n # 2 w a s a m e n d e d t o cl arif y t h at 
p arti ci p ati o n i n i nt er v e nti o n al st u di e s i s n ot p er mitt e d 
a n d E x cl u si o n Crit eri o n # 7 w a s a m e n d e d t o p er mit u s e  
of d e x a m et h a s o n e  
Cl arifi c ati o n a n d 
u p d at e  
9  
S e cti o n 5. 3  
T e xt r e g ar di n g t h e r a n d o mi z ati o n c o d e w a s r e m o v e d 
a n d r ef er e n c e w a s m a d e t o t h e P h ar m a c y M a n u al.  
Cl arifi c ati o n  
1 0  
S e cti o n 5. 5  
C o n c o mit a nt d e x a m et h a s o n e u s e w a s p er mitt e d a n d a 
c a uti o n ar y n ot e w a s a d d e d r e g ar di n g B C R P s u b str at e s.  
U p d at e  
1 1  
S e cti o n 6. 2  
Err o n e o u s t e xt r e g ar di n g r e pl a c e m e nt of dr o p o ut s w a s 
r e m o v e d. 
Cl arifi c ati o n  
1 2  
S e cti o n 7. 1  
A pr e g n a n c y t e st w a s a d d e d at D a y 6 0 a n d t h e 
n a s o p h ar y n g e al s w a b at S cr e e ni n g w a s r e m o v e d. 
Cl arifi c ati o n w a s a d d e d t h at C T s c a n s w o ul d b e 
a c c e pt a bl e i n t h e pl a c e of X -r a y s if t a k e n wit hi n 4 8 h o ur s 
b ef or e S cr e e ni n g a n d t h at l a b or at or y a s s e s s m e nt s 
t a k e n u p t o 2 4 h o ur s b ef or e S cr e e ni n g ar e a c c e pt a bl e.  
U p d at e a n d 
cl arifi c ati o n  
1 3  
S e cti o n 8. 4  
St ati sti c al m et h o d s w er e u p d at e d t o r efl e ct c h a n g e s 
el s e w h er e i n t h e pr ot o c ol  a n d f or cl arit y .  
U p d at e  
1 4  
S e cti o n 8. 4. 6  
T e xt r e g ar di n g r e c o m m e n d ati o n s fr o m t h e D S M B w a s 
cl arifi e d.  
Cl arifi c ati o n  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 8  of 6 2  
9. 2. 4.  
Versi o n 5. 0: 0 8  Oct o ber  2 0 2 0  
O ver all re as o n f or Versi o n 5. 0:  T he o v erall reas o n f or Versi o n 5 . 0 of t he pr ot oc ol was t o 
i nc or p orat e fee d ba c k fr o m st u d y sit es. 
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 5 / U p d at e 
R e a s o n/ R ati o n al e  
1  
Pr ot o c ol  
T h e v er si o n n u m b er a n d d at e w er e u p d at e d t hr o u g h o ut.  
E dit ori al a n d a d mi ni str ati v e r e vi si o n s ( e g, t y p o gr a p hi c al 
err or, p u n ct u ati o n, t e n s e s, a b br e vi ati o n s) w er e 
i n c or p or at e d t o pr o vi d e cl arit y. T h e s y n o p si s w a s  
u p d at e d t o b e c o n si st e nt wit h c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
2  
S e ct i o n 2. 2. 2  
a n d 8. 4. 3   
Cl arifi c ati o n w a s a d d e d t h at t h e s e c o n d ar y e n d p oi nt of 
ti m e fr o m r a n d o mi z ati o n t o d ef er v e s c e n c e a p pli e s o nl y 
t o s u bj e ct s wit h f e v er at e nr oll m e nt. 
Cl arifi c ati o n  
3  
S e cti o n 4. 2  
I n cl u si o n Crit eri o n # 7 , r e q uiri n g s u bj e ct s t o pr e s e nt wit h 
f e v er, w a s r e m o v e d. 
U p d at e  
4  
S e cti o n  4. 3  
E x cl u si o n Crit eri o n # 4 w a s m o difi e d t o e x cl u d e s u bj e ct s 
wit h l y m p h o c yt e c o u nt < 5 0 0  l y m p h o c yt e s/μ L  a n d a n y 
s u bj e ct wit h h e m o gl o bi n < 1 1 . 0 g/ d L  
U p d at e  
5  
S e cti o n 6. 1  
T h e t e xt w a s u p d at e d t o cl arif y t h at s u bj e ct s w o ul d b e 
di s c o nti n u e d fr o m st u d y tr e at m e nt, n ot t h e st u d y, i n c a s e 
of di s e a s e pr o gr e s si o n.  
Cl arifi c ati o n  
6  
S e cti o n  6. 1. 2  
L e v el s of l y m p h o c yt e s a n d h e m o gl o bi n i n di c ati n g 
a n e mi a or l o w l y m p h o c yt e c o u nt w er e r e d u c e d t o 
< 5 0 0  l y m p h o c yt e s/μ L a n d 1 1 g/ d L, r e s p e cti v el y.  
U p d at e  
9. 2. 5.  
Versi o n 6. 0: 1 8  Dece m ber  2 0 2 0  
O ver all re as o n f or Versi o n 6. 0:  T he o v erall reas o n f or Versi o n 6. 0 of t he pr ot oc ol was t o 
i nc or p orat e fee d ba c k fr o m st u d y sit es a n d Healt h A ut h oriti es . 
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 6 / U p d at e 
R e a s o n/ R ati o n al e  
1  
Pr ot o c ol  
T h e v er si o n n u m b er a n d d at e w er e u p d at e d t hr o u g h o ut.  
E dit ori al a n d a d mi ni str ati v e r e vi si o n s ( e g, t y p o gr a p hi c al 
err or, p u n ct u ati o n, t e n s e s, a b br e vi ati o n s) w er e 
i n c or p or at e d t o pr o vi d e cl arit y. T h e s y n o p si s w a s  
u p d at e d t o b e c o n si st e nt wit h c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
2  
S e cti o n  4. 2   
I n I n cl u si o n C rit eri o n # 5, t h e wi n d o w f or s y m pt o m o n s et 
pri or t o S cr e e ni n g w a s c h a n g e d fr o m 7 t o 1 0 d a y s.  
I n I n cl u si o n C rit eri o n # 9 t h e c o ntr a c e pti on  r e q uir e m e nt s 
a n d d efi niti o n of W O C B P w er e u p d at e d i n li n e wit h t h e 
CI T G g ui d eli n e s . 
U p d at e  
3  
S e cti o n  6. 1. 1  
a n d 
S e cti o n  6. 1. 2   
T e xt w a s a m e n d e d t o cl arif y  t h e di sti n cti o n b et w e e n 
t e m p or aril y st o p pi n g st u d y dr u g a n d p er m a n e nt 
di s c o nti n u ati o n , a n d t o e n s ur e n otifi c ati o n of t h e 
m e di c al m o nit or  i n c a s e of a b n or m al L F T s . 
Cl arifi c ati o n  
4  
S e cti o n  7. 1   
A wi n d o w of ± 3 d a y s w a s a d d e d t o t h e D a y 6 0 
t el e p h o n e c all. 
A pr e g n a n c y t e st w a s a d d e d at D a y 2 8 . 
C yt o ki n e a n d a c ut e p h a s e pr ot ei n bl o o d dr a w s w er e 
s e p ar at e d o nt o 2 diff er e nt r o w s f or cl arit y.  
F urt h er d efi niti o n of t h e p h y si c al e x a mi n ati o n w a s  
a d d e d.  
U p d at e  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 5 9  of 6 2  
It e m 
N o.  
Pr ot o c ol 
S e cti o n  
V er si o n 6 / U p d at e 
R e a s o n/ R ati o n al e  
5  
S e cti o n  7. 2   
T e xt w a s a m e n d e d t o cl arif y t h at t h e l a b or at or y 
a s s e s s m e nt s s h o ul d i n cl u d e all p ar a m et er s , w hi c h 
a n al y s e s o c c ur at a c e ntr al l a b or at or y , t o cl arif y 
a s s e s s m e nt of dir e ct a n d i n dir e ct bilir u bi n, a n d t h at all 
l a b or at or y p ar a m et er s s h o ul d b e a s s e s s e d at b a s eli n e.  
Cl arifi c ati o n  
6  
S e cti o n  7. 3   
T e xt w a s a d d e d t o c o nfir m t h at a n al y s e s will b e at 
c e ntr al l a b or at or y.  
Cl arifi c ati o n  
7  
S e cti o n  7. 5. 2  
Cl arifi c ati o n w a s a d d e d t h at tr a n sf er t o I C U, m e c h a ni c al 
v e ntil ati o n , or a n ot h er m e di c all y i m p ort a nt e v e nt ( at t h e 
di s cr eti o n of t h e i n v e sti g at or) a s a r e s ult of di s e a s e 
pr o gr e s si o n w o ul d b e cl a s sifi e d a s a n S A E.  
U p d at e  
8  
S e cti o n  8. 2  
a n d 
S e cti o n  8. 4. 6  
T e xt w a s a m e n d e d t o cl arif y t h at t h e fir st i nt eri m 
a n al y si s w o ul d b e aft er t h e fir st 4 0 s u bj e ct s r e a c h e d 
D a y 2 8 or di e d, wit h dr e w c o n s e nt, or w er e l o st t o f oll o w -
u p  a n d t o cl arif y t h o s e s u bj e ct s w h o w o ul d b e c e n s or e d.  
Cl arifi c ati o n  
9  
S e cti o n  8. 4. 2   
T e xt w a s a m e n d e d t o cl arif y t h at s u bj e ct s w o ul d b e 
f oll o w e d u nl e s s t h e y or di e d, wit h dr e w c o n s e nt, or w er e 
l o st t o f oll o w-u p ; t o cl arif y a c hi e v e m e nt of t h e pri m ar y 
e n d p oi nt;  a n d t o cl arif y t h o s e s u bj e ct s w h o w o ul d b e 
c e n s or e d . 
Cl arifi c ati o n  
1 0  
S e cti o n  8. 4. 3  
A s s e s s m e nt of o v er all s ur vi v al h a d b e e n err o n e o u sl y 
i n cl u d e d a n d w a s r e m o v e d.  
U p d at e  
1 1  
S e cti o n  8. 4. 4. 5   T h e b a s eli n e l a b or at or y a s s e s s m e nt w a s cl arifi e d a s 
b ei n g pri or t o fir st d o s e.  
Cl arifi c ati o n  
9. 2. 6.  
Versi o n 7 . 0: 0 2  J u ne 2 0 2 1   
O ver all re as o n f or Versi o n 7 . 0: T he o v erall reas o n f or Versi o n 7 . 0 of t he pr ot oc ol was t o 
i nc or p orat e fee d ba c k fr o m st u d y sit es a n d Healt h A ut h oriti es.  
Pr ot o c ol 
S e cti o n  
V er si o n 7 / U p d at e 
R e a s o n/ R ati o n al e  
Pr ot o c ol  
T h e n e w n o n pr o pri et ar y n a m e w a s a d d e d. T h e v er si o n n u m b er 
a n d d at e w er e u p d at e d t hr o u g h o ut.  E dit ori al a n d a d mi ni str ati v e 
r e vi si o n s ( e g, t y p o gr a p hi c al err or, p u n ct u ati o n, t e n s e s, 
a b br e vi ati o n s) w er e i n c or p or at e d t o pr o vi d e cl arit y. T h e 
s y n o p si s a n d S c h e d ul e of E v e nt s w er e u p d at e d t o b e c o n si st e nt 
wit h c h a n g e s i n t h e pr ot o c ol.  
U p d at e  
S y n o p si s  
T h e n u m b er of sit e s w a s i n cr e a s e d t o a p pr o xi m at el y 5 0 . 
U p d at e  
S e cti o n  4. 2   
I n cl u si o n crit eri o n # 5 w a s c h a n g e d t o all o w s y m pt o m o n s et ≤1 4 
d a y s.  
U p d at e  
S e cti o n  6. 1. 1   
T h e t e xt w a s a m e n d e d t o cl arif y t h at L F T m o nit ori n g i s d ail y 
d uri n g h o s pit ali z ati o n.  
Cl arifi c ati o n  
S e cti o n  7. 2   
D et ail s of w h at a s s e s s m e nt s t a k e pl a c e s h o ul d a s u bj e ct b e 
tr a n sf err e d t o t h e I C U w er e cl arifi e d.  
Cl arifi c ati o n  
S e cti o n  7. 3   
T h e P K a s s e s s m e nt s w er e r e d u c e d t o gi v e s p ar c e P K s a m pli n g.  U p d at e  
S e cti o n  7. 5. 4   
H e p ati c a b n or m aliti e s of Gr a d e ≥4 will b e c o n si d er e d 
u n e x p e ct e d a d v er s e e v e nt s.  
U p d at e  
S e cti o n  8. 4. 2   
R e s c u e t h er a p y w a s d efi n e d . 
U p d at e  
 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 6 0  of 6 2  
1 0.  
R E F E R E N C E S  
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2 0 1 9 N o vel C or o na vir us i n W u h a n, C hi na. La ncet 2 0 2 0; 3 9 5( 1 0 2 2 3): 4 9 7 -5 0 6.  
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( Sta n dar d V ersi o n). Mil Me d Res 2 0 2 0; 7( 1): 4. 


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 6 1  of 6 2  
K ut C, Mac Ga b h a n n F a n d P o pel A S. W here  Is Ve gf i n t he B o d y? A Meta-A nal ysis of Ve gf 
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Ml 3 9 0: A H u ma n D h o d h I n hi bit or T h at I n d uc es Differe nti a ti o n i n Ac ute M yel oi d Le u k e mi a. 
A C S Me d C he m Lett 2 0 1 6; 7( 1 2): 1 1 1 2 -1 1 1 7.  
Li Q, G ua n X, W u P, W a n g X, Z h o u L, T o n g Y, et al. Earl y Tra ns missi o n D y na mics i n W u h a n, 
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2 0 2 0 b; 6 3( 3): 3 6 4 -3 7 4.  
L olli M L, Sai nas S, Pi p pi o ne A C, Gi or gis M, B osc hi D a n d D osi o F. Use of H u ma n 
Di h y dr o or otate De h y dr o g e nase ( H d h o d h) I n hi bit ors i n A ut oi m m u n e Disease s a n d Ne w 
Pers pecti ves i n C a ncer T hera p y. Re ce nt Pat A ntic a n cer Dr u g Disc o v 2 0 1 8; 1 3( 1): 8 6 -1 0 5.  
L ucas -H o ura ni M, Da uz o n ne D, J or da P, C o usi n G, L u pa n A, Hel y nc k O, et al. I n hi biti o n of 
P yri mi di ne Bi os y nt hesis Pat h wa y S u p presses Viral Gr o wt h t hr o u g h I n nate I m m u nit y. P L o S 
Pat h o g 2 0 1 3; 9( 1 0):e 1 0 0 3 6 7 8.  
L ucas -H o ura ni M, Da uz o n ne D, M u nier -L e h ma n n H, K hiar S, Nis ole S, Dair o u J, et al. Ori gi nal 
C he mic al Seri es of P yri mi di n e Bi os y nt hesis I n hi bit ors T hat B o ost t he A nti viral I nterfer o n 
Res p o nse. A nti micr o b A ge nts C he m ot h er 2 0 1 7; 6 1( 1 0).  
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L ut hra P,  Nai d o o J, Piet zsc h C A, De S, K ha d ka S, A na nt pa d m a M, et al. I n hi biti n g P yri mi di ne 
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of Select e d I m p d h a n d D h o d h I n hi bit ors a gai nst F o ot a n d M o ut h Disease Vir us. Bi o me dici n e & 
P har mac ot h era p y 2 0 1 9; 1 1 8: 1 0 9 3 0 5.  
M u nier -Le h m a n n H, L ucas -H o ura ni M, G uill o u S, H el y n c k O, Za n g hi G, N oel A, et al. Ori gi nal 
2 -( 3-Al k o x y -1 h -P yraz ol -1 -Yl) P yri mi di ne Deri vati ves as I n hi bit ors of H u ma n Di h y dr o or otate 
De h y dr o ge nase ( D h o d h). J Me d C he m 2 0 1 5; 5 8( 2): 8 6 0 -8 7 7.  
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Me d 2 0 0 9; 3 6 1( 4): 3 5 8 -3 6 7.  


P T C 2 9 9 -VI R -0 1 5 -C O V 1 9  
Cli nic al Pr ot oc ol  
V 7 . 0 
P T C T her a pe utics - C o nfi de nti al  
P a ge 6 2  of 6 2  
Rai m o n d o F, Azzar o M P, Pal u m b o G A, Ba g nat o S, Sta g n o F, Gi ust olisi G M, et al. Ele v ate d 
Vasc ular E n d ot h eli al Gr o wt h Fact or ( Ve gf) Ser u m L e vels i n I di o p at hi c M yel ofi br osis. L e u ke mi a 
2 0 0 1; 1 5( 6): 9 7 6 -9 8 0.  
R ussell B, M oss  C, Ge or ge G, Sa nta ol all a A, C o pe A, Pa pa S, et al. Ass ociati o ns bet wee n 
I m m u ne-S u p pressi ve a n d Sti m ul ati n g Dr u gs a n d N o vel C o vi d -1 9 — a S yste matic Re vie w of 
C urre nt E vi d e nce. eca nc er me dicalscie n ce 2 0 2 0; 1 4: 1 0 2 2.  
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o n I m m u ne Res p o nses. Cell Deat h Diff er 2 0 2 0.  
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D h o d h, a Rate -Li miti n g E n z y me i n < E m > De N o v o </ E m > P yri mi di ne Bi os y nt hesis, Are Br oa d -
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I nfecti o n i n S usce pti ble a n d R esista nt Tra ns ge nic Mi ce E x pressi n g H u ma n A n gi ote nsi n-
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SAP_001.pdf: 
V3.0 
PTC Therapeutics - Confidential 
Page 1 of 35 
STATISTICAL ANALYSIS PLAN 
EVALUATION OF THE EFFICACY AND SAFETY OF PTC299 IN 
HOSPITALIZED SUBJECTS WITH COVID-19 (FITE19) 
PTC299-VIR-015-COV19 
19AUG2022 
VERSION 3.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc.  Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes.  In the event of an actual or suspected breach of 
this obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #: NCT04439071


PTC299-VIR-015-COV19 
Statistical Analysis Plan 
V3.0 
PTC Therapeutics - Confidential 
Page 2 of 35 
APPROVAL SIGNATURE PAGE 
 
Protocol Title: 
EVALUATION OF THE EFFICACY AND SAFETY OF 
PTC299 IN HOSPITALIZED SUBJECTS WITH COVID-19 
(FITE19) 
SAP Version and Date 
Final version 3.0, 19 August 2022 
Protocol Number: 
PTC299-VIR-015-COV19 
Phase: 
2/3 
SAP Author 
 
 
                                                       Date  
 
PTC Therapeutics, Inc. 
Signature Statement 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
The eSignature page is located on the last page. 
 
 


PTC299-VIR-015-COV19 
Statistical Analysis Plan 
V3.0 
PTC Therapeutics - Confidential 
Page 3 of 35 
REVISION HISTORY 
Date 
Version 
Description 
Author 
22FEB2021 
1.0 
Initial version 
 
21JUL2021 
2.0 
Revised per protocol version 7.0 
- 
Section 3.2: study population was changed to subjects 
with symptom onset ≤14 days 
- 
Section 4.9.1:  Added definition of rescue therapies 
- 
Section 4.9.1.1: Added two additional sensitivity analyses 
- 
Section 4.9.2.2: Added handling of transformation of viral 
load/cytokine/protein data. 
- 
Appendix 6.3: Added the details of handling of 
laboratory/viral load/cytokine/protein data 
 
19AUG2022 
3.0 
Added subgroup analysis in section 4.11 
- 
Days from symptom to randomization less than or equal 
to 5 days (yes vs no) 
 
 
 
 


PTC299-VIR-015-COV19 
Statistical Analysis Plan 
V3.0 
PTC Therapeutics - Confidential 
Page 4 of 35 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BID 
Twice a day 
BLQ 
Below the limit of quantitation 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
CTCAE 
Common terminology criteria for adverse event 
DSMB 
Data and safety monitoring board 
G-CSF 
Granulocyte-colony stimulating factor 
eCRF 
Electronic case report form 
HAC 
Hepatic advisory safety committee 
IL 
Interleukin 
IP-10 
Interferon gamma-induced protein 10 
ITT 
Intent-to-treat 
KM 
Kaplan-Meier 
LLOQ 
Lower limit of quantitation 
MCP 
Monocyte chemoattractant protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
PK 
Pharmacokinetic 
PTC 
PTC Therapeutics 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SOC 
Standard of care 
SpO2 
Peripheral oxygen saturation 
Tbili 
Total bilirubin 
T2RI 
Time to respiratory improvement 
TEAE 
Treatment-emergent adverse event 
TNF-α 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantitation 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 


PTC299-VIR-015-COV19 
Statistical Analysis Plan 
V3.0 
PTC Therapeutics - Confidential 
Page 5 of 35 
TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
REVISION HISTORY.....................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
2.1. 
Study Objectives ...........................................................................................................9 
2.1.1. 
Primary Objective .........................................................................................................9 
2.1.2. 
Secondary Objectives ...................................................................................................9 
2.1.3. 
Exploratory Objectives .................................................................................................9 
2.2. 
Study Endpoints ............................................................................................................9 
2.2.1. 
Primary Endpoints ........................................................................................................9 
2.2.2. 
Secondary Endpoints ....................................................................................................9 
2.2.3. 
Exploratory Endpoints ................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Overall Design ............................................................................................................11 
3.2. 
Study Population .........................................................................................................12 
3.3. 
Study Treatment ..........................................................................................................12 
3.4. 
Study Assessments and Procedures ............................................................................12 
3.5. 
Stratification, Randomization, and Blinding ..............................................................13 
3.6. 
Sample Size Determination ........................................................................................13 
3.7. 
Interim Analyses .........................................................................................................14 
3.8. 
Data and Safety Monitoring Board (DSMB) and Hepatic Advisory Safety 
Committee (HAC) ......................................................................................................14 
4. 
STATISTICAL CONSIDERATIONS .......................................................................15 
4.1. 
General Methods and Reporting Conventions ............................................................15 
4.2. 
Analysis Populations ..................................................................................................15 
4.2.1. 
Intent-to-Treat (ITT) Population .................................................................................15 
4.2.2. 
Safety Population ........................................................................................................15 
4.2.3. 
Pharmacokinetic (PK) Population ..............................................................................15 
4.3. 
Subject Disposition .....................................................................................................15 


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4.4. 
Protocol Deviations ....................................................................................................16 
4.5. 
Demographic and Baseline Characteristics ................................................................17 
4.5.1. 
Demographics .............................................................................................................17 
4.5.2. 
Baseline Characteristics ..............................................................................................17 
4.6. 
Medical History ..........................................................................................................18 
4.7. 
Prior/Concomitant/Post Medications/Procedures .......................................................18 
4.7.1. 
COVID-19 Standard of Care Medications..................................................................19 
4.7.2. 
COVID-19 Procedures ................................................................................................19 
4.7.3. 
Other Prior/Concomitant/Post Medications ................................................................19 
4.8. 
Study Drug Exposure ..................................................................................................19 
4.8.1. 
Treatment Duration .....................................................................................................19 
4.8.2. 
Treatment Compliance ................................................................................................20 
4.9. 
Efficacy Analysis ........................................................................................................20 
4.9.1. 
Primary Efficacy Analysis ..........................................................................................20 
4.9.1.1. 
Sensitivity Analysis for Primary Endpoint .................................................................21 
4.9.2. 
Secondary Efficacy Analyses .....................................................................................21 
4.9.2.1. 
Respiratory Functions .................................................................................................21 
4.9.2.2. 
Immune Response .......................................................................................................23 
4.9.2.3. 
Reduction in Viral Load .............................................................................................24 
4.9.2.4. 
Duration of Hospitalization ........................................................................................24 
4.10. 
Safety Analysis ...........................................................................................................24 
4.10.1. 
Adverse Events ...........................................................................................................24 
4.10.2. 
Death ...........................................................................................................................25 
4.10.3. 
Adverse Events of Special Interest (AESI).................................................................25 
4.10.4. 
Clinical Laboratory Evaluations .................................................................................26 
4.10.4.1. 
Liver Related Laboratory Parameters .........................................................................26 
4.10.5. 
Vital Signs ..................................................................................................................26 
4.10.6. 
Physical Examination .................................................................................................27 
4.11. 
Subgroup Analysis ......................................................................................................27 
4.12. 
Pharmacokinetic Analysis ..........................................................................................27 
5. 
CHANGES TO THE PLANNED STATISTICAL ANALYSIS IN THE 
PROTOCOL ...............................................................................................................28 
6. 
APPENDICES ............................................................................................................29 


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6.1. 
General Data Presentation ..........................................................................................29 
6.2. 
Handling of Dates .......................................................................................................29 
6.2.1. 
Calculation Using Dates .............................................................................................30 
6.2.2. 
Missing Date Imputation ............................................................................................31 
6.2.2.1. 
Imputation of Adverse Events/Medication Start Dates ..............................................31 
6.2.2.2. 
Imputation of Adverse Events/Medication Stop Dates ..............................................31 
6.3. 
Handling of Laboratory/Viral Load/Cytokine/Protein Data .......................................32 
7. 
REFERENCES ...........................................................................................................35 
LIST OF TABLES 
Table 1: 
Liver Function Test Result Categories .......................................................................26 
Table 2: 
Schedule of Events and Study Parameters ..................................................................33 
 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the analysis method for PTC’s protocol “Evaluation 
of the efficacy and safety of PTC299 in hospitalized subjects with COVID-19 (FITE19)”; 
Protocol Version 7.0 was issued on 02 June 2021. It contains definitions of analysis populations, 
derived variables, data handling rules, format of data presentation and statistical methods for the 
analysis of efficacy and safety.  
This SAP provides a comprehensive and detailed description of the strategy, rationale, and 
statistical techniques to evaluate the necessary efficacy and safety endpoints. The purpose of this 
SAP is to ensure the credibility of the study findings by pre-specified statistical approaches to the 
study data prior to the database lock. The PK analyses will be addressed separately and not 
included in this SAP 
The SAP will be finalized and approved prior to the data base lock. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of PTC299 compared with 
placebo assessed by time to respiratory improvement in adult subjects hospitalized with 
COVID-19 
2.1.2. 
Secondary Objectives 
• To evaluate the clinical efficacy of PTC299 compared with placebo, as assessed by 
respiratory function, immune response, length of hospitalization, and mortality. 
• To evaluate the safety of PTC299 as assessed by drug related adverse events.  
2.1.3. 
Exploratory Objectives 
There are no exploratory objectives in this study. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint is the time from randomization to respiratory improvement, defined as 
peripheral oxygen saturation (SpO2) ≥94% on room air sustained until discharge from the 
hospital or the end of the study (Day 28). 
2.2.2. 
Secondary Endpoints 
• The proportion of subjects requiring invasive ventilation at any point during the study 
• The proportion of subjects requiring supplemental oxygen or non-invasive ventilation 
at any point during the study in subjects who did not require supplemental oxygen at 
baseline 
• Time from randomization to defervescence in subjects presenting with fever at 
enrollment (temperature of ≥37.6℃ axilla, ≥38.0℃ oral, or ≥38.6°C tympanic or 
rectal) 
• Time from randomization to respiratory rate ≤24 breaths/minute on room air 
• Time from randomization to cough reported as mild or absent (on a scale of severe, 
moderate, mild, absent, in those with cough at enrollment rated severe or moderate) 
• Time from randomization to dyspnea reported as mild or absent (on a scale of severe, 
moderate, mild, absent, in those with dyspnea at enrollment rated as severe or 
moderate) 


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• Attenuation of immune responses as indicated by: 
− reduction in cytokine levels, potentially including interleukin (IL)-2, IL-6, IL-7, 
IL-17, G-CSF, IP-10, MCP-1, MIP1-α, and TNF-α 
− reduction in levels of acute phase proteins, potentially including ferritin, 
C-reactive protein, D-dimer, and cardiac troponin  
− normalization in the complete blood count 
− changes in other laboratory parameters potentially including decreases in lactate 
dehydrogenase, prothrombin time, albumin 
• Reduction in viral load  
• Duration of hospitalization measured in days 
• Mortality at Day 28 
• Overall safety profile characterized by type, frequency, severity, timing, and 
relationship to study treatment of any adverse events (AEs) or laboratory 
abnormalities. 
2.2.3. 
Exploratory Endpoints 
There are no exploratory endpoints in this study. 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, multicenter, Phase 2/3, 28-day study 
with safety follow-up by telephone call at Day 60. The study is designed to evaluate the efficacy 
and safety of PTC299 as compared with placebo in hospitalized adult subjects with confirmed 
pneumonia, diagnosed with COVID-19, and not requiring mechanical ventilation. All subjects 
regardless of receiving PTC299 or placebo, will also receive standard of care as defined per local 
written policies or guidelines. Eligible subjects will be equally (1:1) randomized to one of the 
two following treatment arms: 
Arm A - Subjects in arm A will receive PTC299 200mg twice a day (BID) (morning and evening 
at approximately 12-hour intervals) on Days 1 to 7 followed by 50 mg QD (in the morning) on 
Days 8 to 14. Subjects will be followed up to Day 28 with a safety follow-up phone call at 
Day 60. 
Arm B - Subjects in arm B will receive the matching placebo BID (morning and evening at 
approximately 12-hour intervals) on Days 1 to 7 followed by the matching placebo QD 
(in the morning) on Days 8 to 14. Subjects will be followed up to Day 28 with a safety follow-up 
phone call at Day 60. 
Randomization will be stratified by the following three stratification factors: 
• Age (≤62 vs >62) 
• Remdesivir use (yes vs no) 
• Dexamethasone use (yes vs no) 
The study is expected to enroll approximately 380 subjects with two planned interim analyses. 
The first interim analysis is planned when approximately 40 randomized subjects 
(20 in each arm) have been enrolled and followed to Day 28 or discontinued due to death, or 
withdrawal consent, or lost-to-follow-up to assess the safety of the study drug. The 2nd interim 
analysis is planned when approximately 163 events have been observed (approximately 
190 subjects have been followed up to 28 days) to assess the futility of the study.  
An independent data and safety monitoring board (DSMB) will review available interim analyses 
data. After the first 40 subjects (20 in each arm) are enrolled, enrollment will then be temporarily 
halted, and an interim analysis will be performed to assess safety. The enrollment will continue if 
there are no safety concerns. During the 2nd interim analysis, the DSMB will make go- or no-go 
recommendation based on the futility and the recommendation will be communicated to the 
study team. In addition to the scheduled data review meetings for the 1st and 2nd interim 
analyses, the DSMB may request ad hoc reports and/or meetings. 
In addition to the DSMB, an independent Hepatic Advisory Safety Committee (HAC) will also 
review each case related to liver toxicity in an ongoing basis. 


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3.2. 
Study Population 
The study will enroll male and female subjects aged ≥18 years, who are hospitalized and infected 
with a new coronavirus, SARS-Co-V-2, resulting in coronavirus disease 2019 (COVID 2019). 
Subjects are required to have had symptom onset ≤14 days prior to enrollment; had SpO2 <94% 
on room air; had at least one of respiratory rate >24 breaths/minute or cough; and had confirmed 
lung involvement by radiographic imaging. Women of childbearing potential (WOCBP) or men 
who are sexually active with WOCBP must be willing to use birth control methods as detailed in 
the protocol for up to 50 days after the last dose of study drug, and all subjects have to 
understand and be willing to sign a written informed consent and agree to adhere to the study 
visit schedule and other protocol procedures. The inclusion and exclusion criteria are detailed in 
protocol Section 4.  
3.3. 
Study Treatment 
PTC299 tablets with dosage strengths of 50 mg and matching placebo will be provided. Eligible 
subjects will receive PTC299 200 mg (or matching placebo) orally BID (morning and evening at 
approximately 12-hour intervals) on Days 1 to 7 followed by PTC299 50 mg (or matching 
placebo) QD (in the morning) on Days 8 to 14. Subjects will be followed up to Day 28 with a 
safety follow-up phone call at Day 60. 
3.4. 
Study Assessments and Procedures 
Subjects will be assessed daily while hospitalized. All subjects will undergo efficacy, safety, and 
laboratory assessments as summarized in Table 2. There will be a follow-up telephone call at 
Day 60 to assess AEs, serious AEs, and deaths.  
 For subjects who are discharged from the hospital prior to Day 28:  
• If SpO2 is <94%, SpO2 measurements will be taken daily until Day 28  
• Subject-reported assessments for cough and dyspnea will continue to Day 28  
• No other assessments will take place except for those specified at Day 14, Day 28 and 
Day 60 in the protocol  
A follow-up telephone call at Day 60 will be performed to assess AEs, serious AEs, and deaths. 
The Day 60 pregnancy test will be taken at home and self-reported during the telephone contact. 
All subjects will undergo the assessments specified for Day 14 and Day 28 (End of Study), and 
participate in the Day 60 telephone call, even if they are discharged from the hospital prior to 
Day 28.  


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3.5. 
Stratification, Randomization, and Blinding 
Randomization will occur at each subject’s baseline (screening) visit using an Interactive 
Response Technology (IRT) system. Assignment to treatment groups is determined by a 
computer-generated random sequence.  Randomization will be stratified by the following three 
stratification factors: 
• Age (≤62 vs >62) 
• Remdesivir use (yes vs no) 
• Dexamethasone use (yes vs no) 
This is a double-blind study. PTC personnel who are directly involved in the conduct of the 
study will remain blinded until the final database lock. Dummy treatment codes will be used for 
programming and review before final database lock. 
The unblinded interim analyses will be conducted by an independent statistician and the results 
will be only shared in the closed session of the DSMB. The study team will be kept blinded for 
results related to the interim analyses. 
3.6. 
Sample Size Determination 
This is a group sequential design with 2 interim analyses planned. The first interim analysis 
will only assess the safety and the trial will not be stopped for futility or superiority of efficacy. 
It will be performed after the first 40 randomized subjects have completed Day 28 or 
discontinued due to death, or withdrawal consent, or lost-to-follow-up. The second interim 
analysis is to assess futility and will be performed when 50% of respiratory improvement events 
have been reached, ie, 163 events have been observed (approximately 190 subjects). 
Lan-DeMets beta spending function (non-binding option) is used to define the boundary for the 
2nd interim futility analysis and the final analysis to ensure the overall beta of 80%. 
The sample size was calculated to reflect the primary endpoint of time from randomization to 
respiratory improvement, which is defined as the time from randomization to respiratory 
improvement (SpO2 ≥94% in room air), sustained until discharge from the hospital or the end of 
the study (Day 28). Median time to respiratory improvement was not readily available from the 
literature. Based on very limited data, it is anticipated that the median time to respiratory 
improvement for the placebo group is 11 days and PTC299 treatment will decrease it to 8 days, 
an improvement of 3 days. Subjects will be followed for the fixed amount of time of 28 days 
from randomization (corresponding to the anticipated improvement rates of 0.829 and 0.912 at 
Day 28 for placebo and PTC299, respectively). A total of 326 events will provide more than 80% 
of power to detect a hazard ratio of 1.38 at two-sided type I error of 0.05. Approximately 
380 subjects, in total, will be needed. 


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3.7. 
Interim Analyses 
Two interim analyses are planned. The first interim analysis will be conducted when 
40 randomized subjects (approximately 20 in treatment arm and 20 in placebo arm) have 
received 14 days of treatment and completed 14 days of follow-up or discontinued due to death, 
withdrew consent, or were lost-to-follow-up. No formal statistical testing will be performed at 
the first interim analysis. An independent data safety monitoring board will review the safety 
data. Enrollment will continue if there are no safety concerns. 
The second interim analysis will be conducted for futility. It will be performed when 50% of 
respiratory improvement events have been reached, ie, 163 events have been observed 
(approximately 190 subjects). Respiratory improvement is defined as SpO2≥ 94% in room air 
until discharge from the hospital or the end of study (Day 28). All subjects who have completed 
through Day 28, were discharged with SpO2 ≥94% on room air, withdrew consent, died, were 
lost to follow-up, or took any COVID-19 rescue therapy during the study will be included in the 
interim analysis. Subjects whose primary event cannot be determined at the interim cut, 
i.e., ongoing subjects, will not be included in the interim efficacy analysis. Subjects who died, 
withdrew consent, were lost to follow-up, or took any COVID-19 rescue therapy will be 
censored at Day 28. The detailed censoring rules for the primary endpoint are described in 
Section 4.9.1. 
A stratified log-rank test will be performed, and the hazard ratio (treatment vs placebo) will be 
compared with the futility boundary. The trial may be stopped for futility if the hazard ratio is 
less than 1.091. The futility boundary is based on Lan-DeMets beta spending function 
(non-binding option) with overall beta of 80%.  
The unblinded interim analyses will be conducted by an independent statistician and the results 
will be only shared with the closed session of the DSMB. DSMB will make the go- or no-go 
recommendation and only the recommendation will be communicated to the study team. The 
study team will be kept blinded for results related to the interim analyses.  
For the first and second interim analyses, all safety analyses will be based on safety population 
and all efficacy analyses will be based on ITT population. 
3.8. 
Data and Safety Monitoring Board (DSMB) and Hepatic Advisory Safety 
Committee (HAC) 
An external DSMB is established in this study. The DSMB will review the interim analyses data 
and results and make the go- or no-go recommendation. The recommendation will be 
communicated to the study team. The composition and responsibilities of DSMB are detailed in 
the DSMB Charter. 
A HAC is also established in the trial. The HAC will review safety data with respect to the liver 
related toxicities on an ongoing case by case basis. HAC will also provide recommendations to 
the DSMB. Additional information can be obtained in the HAC charter. 


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4. 
STATISTICAL CONSIDERATIONS 
4.1. 
General Methods and Reporting Conventions 
Data will be summarized by treatment groups. Categorical variables will be summarized by 
frequency distributions (number and percentage of subjects). A missing category will be created 
for subjects with missing information. If no subjects in a category for a categorical variable, the 
category will be presented with zero count. Continuous variables will be summarized by 
descriptive statistics (such as number of subjects, mean, standard deviations, median, minimum, 
maximum, and number of missing if any). All tests of hypotheses will be considered nominally 
statistically significant if the 2-sided p-value is less than 0.05 or a pre-specified significance 
level.  
Statistical analyses will be performed using the Statistical Analysis System (SAS) version 9.4 or 
higher. 
4.2. 
Analysis Populations 
4.2.1. 
Intent-to-Treat (ITT) Population 
ITT population will include all randomized subjects. The ITT population will be used in all 
efficacy analyses and subjects will be grouped based on the arm they are randomized to. If a 
subject receives treatment different from the one to which he/she was randomized, the subject’s 
efficacy data will be analyzed “as randomized.”  
4.2.2. 
Safety Population 
Safety population will include all randomized subjects who received at least one dose of study 
drug. If a subject receives treatment different from the one to which he/she was randomized, the 
subject’s safety data will be analyzed “as treated.” The Safety Analysis population will be used 
in the statistical analyses for safety. 
4.2.3. 
Pharmacokinetic (PK) Population 
PK population will include all safety population subjects who had at least one PK profile 
assessment. 
4.3. 
Subject Disposition 
A summary of subject disposition (analysis population allocation, treated, early treatment 
discontinued, the primary reason for treatment discontinuation, completed the study, 
discontinued the study, and the reason for study discontinuation) will be presented by treatment 
groups and overall using frequency and percentage. 


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The reasons for treatment discontinuations will be summarized based on the following 
categories: 
• Withdrew Consent 
• Disease Progression 
• Adverse Event 
• Protocol Deviation 
• Investigator/Sponsor Decision 
• Lost to Follow up 
• Death 
• Other 
The reasons of study discontinuations will be summarized based on the following categories: 
• Study Completed 
• Adverse Event 
• Lost to Follow up 
• Investigator/Sponsor Decision 
• Withdrawal of Consent 
• Death 
• Other  
A separate summary of the number of subjects screened screen failure and reasons for screen 
failure will be provided as well. 
A by-subject data listing of treatment/study completion information including the reason for 
study withdrawal, if applicable, as well as a by-subject data listing for subjects with reasons for 
screening failure will be presented. 
4.4. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff.  Significant deviations are any deviations that 
impact subject eligibility (i.e., protocol inclusion/exclusion violations), subject safety, subject 
efficacy or a subject’s ability to continue in the clinical trial. 
Protocol deviations will be defined and handled by CRO and reviewed by PTC. Protocol 
deviations will be finalized and documented prior to the database lock. 
All protocol deviations will be presented in a data listing. 


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4.5. 
Demographic and Baseline Characteristics 
The demographics and baseline characteristics will be summarized in the ITT population. 
4.5.1. 
Demographics 
The following demographics will be summarized by treatment arms and overall 
• Age (years): as reported in the screen visit 
• Gender 
• Race  
• Ethnicity 
• Height (cm) 
• Weight(kg) 
• Body Mass Index (BMI) (kg/m2): weight (kg)/(height in m)2 
• BMI categories (underweight (<18.5), normal (18.5 - 24.9), overweight (25.0 - 29.9), 
obesity (≥30) 
• Smoking history (smoker, non-smoker, former smoker) 
• Years of smoking (years) 
• Average packs smoked per week 
4.5.2. 
Baseline Characteristics 
The following baseline characteristics will be summarized by treatment arms and overall.  
Stratification factors: 
• Age (≤62 vs >62) 
• Dexamethasone use (yes vs no) 
• Remdesivir use (yes vs no) 
Baseline disease risk factors: 
• Chronic kidney disease (yes vs no) 
• COPD/asthma (yes vs no) 
• Immunocompromised (yes vs no) 
• Type 2 diabetes (yes vs no) 
• Heart disease (yes vs no) 
• Sickle cell disease (yes vs no) 
• Obesity (yes vs no) 
• Hypertension (yes vs no) 


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Baseline disease characteristics: 
• WHO ordinal scale for clinical improvement 
• Received any of COVID-19 treatment as SOC (yes vs no) 
• Time from symptom onset to randomization 
• Time from COVID-19 diagnosis to randomization 
• COVID-19 initial symptoms 
4.6. 
Medical History 
All medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). The MedDRA version will be indicated in the footnote of the relevant tables and 
listings based on the version used in the clinical data. A summary of medical and surgical history 
will be presented by MedDRA system and organ class and preferred term (PT).  
Medical history will be presented in by-subject listings as well. 
4.7. 
Prior/Concomitant/Post Medications/Procedures 
Prior medications/procedures are defined as non-study medications/procedures that were 
initiated prior to the start of study treatment. Concomitant medications/procedures are defined as 
non-study medications/procedures that were initiated before the first dose of study drug and 
continued during the study treatment or initiated on/after the first dose date but before the end of 
study treatment. Post medication/procedures are defined as non-study medications/procedures 
that were initiated after the last dose of study treatment up to Day 28 or medications/procedures 
initiated prior to the last study treatment and continued after the last dose. It is possible that some 
medications/procedures can be counted in more than 1 category. A medication/procedure flag 
will be created for each medication/procedure to indicate the type of the medication/procedure 
(ie, prior or concomitant or post). Medications with missing start or end dates will be categorized 
as either prior or concomitant or post or all unless there is evidence contradictory. For example, 
if the start date of a medication/procedure is missing and the end date is prior to the first study 
treatment date, the medication/procedure will be considered as prior. If the end date is after the 
first study treatment date or is missing or the medication/procedure is ongoing, the 
medication/procedure will be considered concomitant or post. 
All non-study drugs and therapies will be coded by Anatomical Therapeutic Chemical (ATC) 
code and PT using the World Health Organization Drug Dictionary (WHODD). All procedures 
will be coded by the MedDRA. The WHODD and MedDRA versions will be indicated in the 
footnote of the relevant tables and listings based on the versions used in the clinical data. 


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4.7.1. 
COVID-19 Standard of Care Medications 
All prior/concomitant COVID-19 standard of care medications will be categorized as:  
• COVID-19 medications initiated and ended prior to the first study treatment 
• COVID-19 medications initiated prior to the first study treatment and continued 
during the study 
• COVID-19 medications initiated after the first study treatment as part of SOC but not 
as rescue medications 
• COVID-19 medications initiated after the first study treatment as rescue medications 
COVID-19 standard of care medications will be summarized with subject counts and percentages 
by the above medication categories, WHO ATC level 3, and PT and by treatment groups.  
4.7.2. 
COVID-19 Procedures 
Number and percent of the subjects who undergo COVID-19 procedures (i.e., CT scan, x-ray, 
and other) as well as the results (normal and abnormal) will be summarized by study visit, and 
treatment groups. Subjects requires mechanical ventilation during the study will be summarized 
by treatment groups. 
4.7.3. 
Other Prior/Concomitant/Post Medications 
Prior medications other than medications used for COVID-19 will be summarized with subject 
counts and percentages by WHO ATC level 3 and PT and by treatment groups and overall. 
Concomitant medications other than medications used for COVID-19 will be summarized with 
subject counts and percentages by WHO ATC level 3 and PT and by treatment groups and 
overall. 
Post medications other than medications used for COVID-19 will be summarized with subject 
counts and percentages by WHO ATC level 3 and PT and by treatment groups and overall. 
All prior concomitant and post medications/procedures including medications/procedures used 
for COVID-19 will be listed.  
4.8. 
Study Drug Exposure 
Treatment duration, and treatment compliance will be summarized by treatment groups and 
overall. 
4.8.1. 
Treatment Duration 
Treatment duration (days) is defined as the date of last study dose - the date of first study 
dose +1. For subjects who are still on treatment at a data cut-off (extraction) date, the last dose 
date is the last dosing date on or prior to the data cut-off date.  


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4.8.2. 
Treatment Compliance 
Treatment compliance is defined as [total cumulative dose received/total cumulative dose 
prescribed]x100%, where the total cumulative dose received is defined as the sum of all doses 
taken in mg during the treatment period and the total cumulative dose prescribed is defined as the 
sum of all doses prescribed. For example, if a subject completed 14 days of treatment, the total 
cumulative dose prescribed is calculated as 200 (mg) x 2 (BID) x first 7 (days) +50 (mg) x 
1(QD) x second 7 (days)=3150 (mg) 
Study drug exposure will also be presented in by-subject listings. 
4.9. 
Efficacy Analysis 
Efficacy analyses will be based on the ITT population. The null hypothesis for primary efficacy 
comparison is that the distribution of time to respiratory improvement (T2RI) between the two 
treatment groups is the same. The alternative hypothesis is that the distribution of T2RI between 
the two treatment groups is not the same. Rejecting the null hypothesis with shortened T2RI in 
PTC299 as compared with the placebo arm in the ITT population will be considered a successful 
demonstration of efficacy. 
All statistical tests will be 2-sided at the significance level of 0.05. The corresponding p-values 
and 2-sided 95% CIs for intended point estimates will be reported. 
4.9.1. 
Primary Efficacy Analysis 
The primary endpoint is the time from randomization to respiratory improvement (T2RI), 
defined as SpO2 ≥94% on room air sustained until discharge from the hospital or the end of the 
study (Day 28). 
All hospitalized subjects will be followed fully to Day 28 with efficacy measurements taken 
daily unless they die, are lost to follow-up, or withdraw consent. For subjects who are discharged 
from the hospital prior to Day 28 without achieving respiratory improvement, SpO2 
measurements will be taken daily until Day 28. All measurements recorded will be used for 
efficacy analysis. 
Subjects who achieved SpO2 ≥94% and sustained to Day 28 or discharge without taking any 
COVID-19 rescue therapy during the study will be considered as achieving respiratory 
improvement event and the event date will be the first date of achieving SpO2 ≥94%. For all 
other subjects i.e., a). randomized but had no follow-up; b). initiated any COVID-19 rescue 
therapy during the study, where a rescue therapy is defined as any additional medication, 
exclusive of SOC, used to treat worsening of COVID-19 symptoms and recorded as rescue 
therapy on the eCRF; c). lost follow-up prior to Day 28 d). died prior to Day 28; e). withdrawn 
consent prior to Day 28; f). had full follow-up without achieving sustained SpO2 ≥94%, will be 
censored at Day 28. 
Kaplan-Meier (KM) plots of time to respiratory improvement will be presented. Median time to 
respiratory improvement will be estimated via the Kaplan-Meier product limit method. 
A two-sided 95% confidence interval (CI) for the median time to respiratory improvement will 
be computed for PTC299 and placebo cohorts based on a log-log transformed CI for the survivor 
function S(t). Time to respiratory improvement will be compared between treatment groups 
using stratified log-rank test by randomization strata. 


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Hazard ratio and corresponding two-sided 95% CIs will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors. 
Respiratory improvement rates at Days 7, 14, and 28 will also be estimated using KM estimates 
on the time to respiratory improvement curve. Associated two-sided 95% CIs for each treatment 
group and the difference between the 2 treatment groups will be calculated using Greenwood’s 
formula for variance derivation. 
4.9.1.1. 
Sensitivity Analysis for Primary Endpoint 
 Three sensitivity analyses will be performed for the primary endpoint as follows: 
• Randomized subjects without any follow-up will be censored at the randomization 
date. 
• Subjects will not be censored by rescue therapy in the primary analysis. 
• An additional variable of time from symptom onset to randomization (≤7 days versus 
>7 days) will be added in the primary analysis model.  
4.9.2. 
Secondary Efficacy Analyses 
4.9.2.1. 
Respiratory Functions 
The proportion of subjects requiring invasive ventilation at any point during the study  
Number and the percentage of subjects requiring invasive ventilation during the study will be 
summarized by treatment groups. Cochran Mantel-Haenszel test will be used to compare the 
treatment difference. 
A by-subject listing will also be provided for subjects requiring invasive ventilation. 
The proportion of subjects requiring supplemental oxygen or non-invasive ventilation at 
any point during the study in subjects who did not require supplemental oxygen at baseline 
Number and the percentage of subjects requiring supplemental oxygen or noninvasive ventilation 
during the study in subjects who did not require supplemental oxygen at baseline will be 
summarized by treatment groups. Cochran Mantel-Haenszel test will be used to compare the 
treatment difference. 
A by-subject listing will also be provided for subjects requiring supplemental oxygen or 
non-invasive ventilation. 
Time from randomization to defervescence 
Time from randomization to defervescence will be analyzed in subjects who had fever 
(body temperature of ≥37.6℃ axilla, ≥38.0℃ oral, or ≥38.6°C tympanic or rectal) at baseline. 
Defervescence is defined as body temperature of <37.6℃ axilla, <38.0℃ oral, or <38.6°C 
tympanic or rectal without taking any antipyretic treatment and sustained until discharge or 
Day 28. Time from randomization to the first defervescence event will be analyzed using KM 
method by treatment groups in subjects who had fever at baseline. A summary table of the 
number of events, the number of censors, and KM estimates (25th, 50th, 75th percentile of time 
to defervescence along with the 95% CI), and the defervescence rate at Day 7, Day 14, and 
Day 28 will be provided.  


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Hazard ratio and corresponding two-sided 95% CIs will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors. 
A KM plot by treatment groups will be provided for time from randomization to defervescence 
and a by-subject listing will also be provided. 
Time from randomization to respiratory rate ≤24 breaths/minute on room air 
Respiratory rate ≤24 breaths/minute on room air and sustained until discharge or Day 28 will be 
considered as achieving the respiratory rate normalization event. Time from randomization to the 
first date of achieving normalization of respiratory rate will be analyzed using KM method by 
treatment groups. A summary table of the number of events, the number of censors, and KM 
estimates (25th, 50th, 75th percentile of time to normalization of respiratory rate along with the 
95% CI), and the rate of normalization of respiratory rate at Day 7, Day 14, and Day 28 will be 
provided.  
Hazard ratio and corresponding two-sided 95% CIs will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors. 
A KM plot by treatment groups will be provided for time from randomization to respiratory rate 
normalization and a by-subject listing will also be provided. 
Time from randomization to cough reported as mild or absent (on a scale of severe, 
moderate, mild, absent, in those with cough at enrollment rated as severe or moderate) 
Time from randomization to cough relief will only be analyzed in subjects with cough 
self-reported as severe or moderate at baseline on a scale of severe, moderate, mild, or absent. 
Cough relief event is defined as subjects with cough self-reported as severe or moderate at 
baseline and reported as mild or absent during the study and sustained until discharge or Day 28. 
Time from randomization to the first date of achieving cough relief event will be analyzed using 
KM method by treatment groups. A summary table of the number of events, the number of 
censors, and KM estimates (25th, 50th, 75th percentile of time to cough relief along with the 
95% CI), and the cough relief rate at Day 7, Day 14, and Day 28 will be provided.  
Hazard ratio and corresponding two-sided 95% CIs will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors. 
A KM plot by treatment groups will be provided for time from randomization to cough relief and 
a by-subject listing will also be provided. 
Time from randomization to dyspnea reported as mild or absent (on a scale of severe, 
moderate, mild, absent, in those with dyspnea at enrollment rated as severe or moderate) 
Time from randomization to dyspnea relief will only be analyzed in subjects with dyspnea 
self-reported as severe or moderate at baseline on a scale of severe, moderate, mild, or absent. 
Dyspnea relief event is defined as subjects with dyspnea self-reported as severe or moderate at 
baseline and reported as mild or absent during the study and sustained until discharge or Day 28. 
Time from randomization to the first date of achieving dyspnea relief event will be analyzed 
using KM method by treatment groups. A summary table of the number of events, the number of 
censors, and KM estimates (25th, 50th, 75th percentile of time to dyspnea relief along with the 
95% CI), and the dyspnea relief rate at Day 7, Day 14, and Day 28 will be provided.  


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Hazard ratio and corresponding two-sided 95% CIs will be estimated using a Cox proportional 
hazards model, with treatment arm as a single covariate, stratified by the stratification factors. 
A KM plot by treatment groups will be provided for time from randomization to dyspnea relief 
and a by-subject listing will also be provided. 
4.9.2.2. 
Immune Response 
For viral load, cytokine, and protein data, descriptive summaries and analyses will be performed 
on logarithm base 10 transformed data and a value of 1 will be added to the original value before 
the transformation. Plasma concentration values that are below the limit of quantitation (BLQ) 
will be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated 
one-half the value of the lower limit of quantitation (LLOQ). The conventions are detailed in 
Section 6.3 . 
Reduction in cytokine levels, potentially including interleukin (IL)-2, IL-6, IL-7, IL-17, 
granulocyte-colony stimulating factor (GSF), interferon-γ inducible protein 10, monocyte 
chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis 
factor-α 
Descriptive statistics will be provided for each inflammatory cytokine such as IL-2, IL-6, IL-7, 
IL-17, GSF etc.at baseline, at each study visit post baseline for actual values and changes from 
baseline by treatment groups. Unless otherwise specified, only scheduled visits will be included 
in the summary tables. In the event of repeated values for a test at a visit, the last non-missing 
value at that visit will be used. 
A by-subject listing will also be provided for cytokine data. 
Reduction in levels of acute phase proteins, potentially including ferritin, C-reactive 
protein, D-dimer, and cardiac troponin  
Descriptive statistics will be provided for each acute phase protein at baseline, at each study visit 
post baseline for actual values and changes from baseline by treatment groups. Unless otherwise 
specified, only scheduled visits will be included in the summary tables. In the event of repeated 
values for a test at a visit, the last non-missing value at that visit will be used. 
A by-subject listing will also be provided for acute phase protein data. 
Normalization in the complete blood count 
Normalization of complete blood count is defined as all blood components such as WBC, RBC, 
HGB, HT, HCV, HCH, HCHC, and platelets return to the lab normal range post baseline during 
the study for subjects who had out of the normal range value of any of the blood component at 
baseline.  
Number and percentage of subject achieving normalization of complete blood count in subjects 
with abnormal complete blood count at baseline will be summarized by treatment groups. 


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Changes in other laboratory parameters potentially including decreases in lactate 
dehydrogenase, prothrombin time, and albumin 
Descriptive statistics will be provided for each laboratory parameter at baseline, at each study 
visit post baseline for actual values and changes from baseline by treatment groups. Unless 
otherwise specified, only scheduled visits will be included in the summary tables. In the event of 
repeated values for a test at a visit, the last non-missing value at that visit will be used. 
A by-subject listing will also be provided for laboratory data. 
4.9.2.3. 
Reduction in Viral Load  
Descriptive statistics will be provided for subjects’ viral load at baseline, at each study visit post 
baseline for actual values and changes from baseline by treatment groups. Unless otherwise 
specified, only scheduled visits will be included in the summary tables. In the event of repeated 
values for a test at a visit, the last non-missing value at that visit will be used. 
A by-subject listing will also be provided for the viral load data. 
4.9.2.4. 
Duration of Hospitalization 
Duration of hospitalization is defined as the sum of the days stayed in hospital. Descriptive 
statistics (such as mean, standard deviation, median, minimum, and maximum) of duration of 
hospitalization will be provided by treatment groups. 
A by-subject listing will also be provided. 
4.10. 
Safety Analysis 
All safety analyses will be performed on the safety population. Summary tables will be provided 
by treatment groups. 
4.10.1. 
Adverse Events 
All adverse events (AEs) will be coded using the MedDRA. The MedDRA version will be 
indicated in the footnote of relevant AE tables based on the current version used in the clinical 
data. 
AEs will be analyzed in terms of treatment-emergent adverse events (TEAEs), which are defined 
as any AEs that occurring on or after the first study treatment through 30 days after the last dose, 
or any AEs occurring before the first study treatment but worsening during the treatment through 
30 days after the last dose. 
A treatment related TEAE is defined as TEAE that is suspected (possibly or probably related) by 
the investigator to be related to the study treatment. The severity/intensity of AEs will be graded 
1 to 5 according to the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. For AEs not described in CTCAE criteria, the intensity 
will be assessed by the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 3), 
life threatening (Grade 4), and fatal (Grade 5).  


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An overview of TEAE summary by treatment groups table will be provided with following 
information: 
• The number of subjects with at least one TEAE 
• The number of subjects with at least one treatment related TEAE 
• The number of subjects with at least one Grade 3 or Grade 4 TEAE 
• The number of subjects with a Grade 5 TEAE (Fatal) 
• The number of subjects with at least one SAE 
The number of subjects with at least one TEAE leading to treatment discontinuation. 
All TEAEs will be summarized by MedDRA system organ class (SOC), and PT. If a subject 
experiences multiple AEs under the same SOC, the subject will be only counted once for the 
SOC with the greatest severity. Similarly, if a subject experiences multiple AEs under the same 
PT and SOC, the subject will be counted only once for the PT with the greatest severity. 
The table will be sorted by the descending order of the frequency of SOC then by the descending 
order of the frequency of PT under SOC based on the PTC299 column. 
In addition, the following summary tables will be provided: 
• All TEAE by descending frequency of PT  
• All TEAE by maximum severity under each SOC and PT  
• SAE by SOC and PT 
• Treatment related TEAE by SOC and PT 
• TEAE leading to treatment discontinuation by SOC and PT  
All TEAEs will be presented in a by-subject listing. Listings for non-treatment-emergent AEs, 
DLTs, SAEs, TEAEs leading to treatment discontinuation, TEAEs leading to dose 
reduction/interruption, and TEAEs leading to death will also be provided. 
4.10.2. 
Death 
The number and the percentage of deaths at Day 28 and Day 60, respectively, will be 
summarized by treatment groups.  
All deaths will be presented in a by-subject listing. 
4.10.3. 
Adverse Events of Special Interest (AESI) 
Adverse events that may be indicative of hepatotoxicity (including the lower level MedDRA 
term of hepatotoxicity or drug-induced hepatotoxicity) are considered adverse events of special 
interest (AESIs). These include: 
• ALT increase Grade ≥3 (>5×ULN) 
• AST increase Grade ≥3 (>5×ULN) 
• Tbili increase >2×ULN 
• ALP≥2×ULN  


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The number and the percentage of subjects experiencing AESIs will be summarized by each 
criterion and overall, and by treatment groups. 
4.10.4. 
Clinical Laboratory Evaluations 
Laboratory values will be presented in standard units. If any assessment is performed at both 
local and central laboratories, the value from central laboratory will be used in the analysis. 
In the event of repeated values for a test at a visit from same laboratory, the last non-missing 
value at that visit will be used 
Descriptive statistics will be provided for each clinical laboratory parameter at baseline, at each 
study visit post baseline for actual values and changes from baseline by treatment groups. Unless 
otherwise specified, only scheduled visits will be included in the summary tables.  
Clinical laboratory values will be graded according to NCI CTCAE version 5.0 for applicable 
tests. A summary table of the worst CTC grade post baseline during the treatment period of 
laboratory data will be provided by treatment groups. For the worst CTC grade tables, 
unscheduled laboratory values will be considered as well. 
A by-subject listing will also be provided for laboratory data. Laboratory values that are outside 
the normal range will also be flagged in the data listings. Any out-of-range values that are 
identified by the investigator as being clinically significant will also be shown in a listing. 
4.10.4.1. Liver Related Laboratory Parameters 
The liver function related parameters will be assessed and summarized. The potential Hy’s law 
cases (as serum ALT or AST >3xULN and total bilirubin >2xULN) will be evaluated and 
summarized based on the criteria listed in Table 1: 
Table 1: 
Liver Function Test Result Categories 
Parameter 
Criteria 
ALT 
>3ULN and <=5ULN 
>5ULN and <=8ULN 
>8ULN 
AST 
>3ULN and <=5ULN 
>5ULN and <=8ULN 
>8ULN 
Total Bilirubin 
>2ULN 
>3ULN 
Total Bilirubin>2ULN and ALT 
>3ULN and <=5ULN 
>5ULN and <=8ULN 
>8ULN 
Total Bilirubin>2ULN and AST 
>3ULN and <=5ULN 
>5ULN and <=8ULN 
>8ULN 
4.10.5. 
Vital Signs 
Vital sign parameters will be summarized for both actual and change from baseline values by 
study visit, by treatment groups. 
Vital signs will also be listed. 


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4.10.6. 
Physical Examination 
Physical examination results will be presented in a by-subject listing.  
4.11. 
Subgroup Analysis 
To evaluate treatment effect in a more homogeneous population, the primary endpoint will be 
explored within the following subgroups as deemed appropriate: 
• Age (≤62 vs >62) 
• Remdesivir use (yes vs no) 
• Dexamethasone use (yes vs no) 
• Chronic kidney disease (yes vs no) 
• COPD/asthma (yes vs no) 
• Immunocompromised (yes vs no) 
• Type 2 diabetes (yes vs no) 
• Heart disease (yes vs no) 
• Sickle cell disease (yes vs no) 
• Obesity (yes vs no) 
• Hypertension (yes vs no) 
• Days from symptom to randomization less than or equal to 5 days (yes vs no) 
If any of the subgroup levels has less than 10% of subjects the subgroup analysis will not be 
performed.  
The treatment effect in the subgroup analysis will be evaluated by an un-stratified log-rank test 
and the hazard ratio will be estimated using the unstratified Cox proportional hazards model. 
The subgroup analysis will be performed in ITT population in each subgroup. 
4.12. 
Pharmacokinetic Analysis 
PK analyses will be discussed in a separate SAP. 


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5. 
CHANGES TO THE PLANNED STATISTICAL ANALYSIS IN THE 
PROTOCOL 
There is no change relative to the planned statistical analyses in the protocol amendment. 


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6. 
APPENDICES 
6.1. 
General Data Presentation 
Common data presentation conventions to be used in this study are as following: 
• Data from all study centers will be combined for analysis. 
• All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value. 
• All percentages will be rounded to one decimal place. The number and percentage of 
values will be presented in the form XX (XX.X%), where the percentage is in the 
parentheses. 
• Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified.  
• The day of the first dose of study drug will be defined as Day 1.  
• In general, unless otherwise specified, baseline value will be defined as the last non-
missing value before the first dose of study drug is administrated for safety 
parameters. (The date of baseline assessment can be on or before the date of first dose 
of study drug). For randomized subjects who did not receive any of the study drug, 
the baseline is defined as the last non-missing value before or on the date of 
randomization.  
• To summarize efficacy/safety data by visit, the post-baseline results will be 
summarized by the scheduled visit as appropriate 
• All analysis and summary tables will have the analysis population sample size for 
each cohort in the column heading (i.e., number of subjects). 
• All listings will be sorted in order of treatment group, study center, subject, and date 
of procedure or event. 
6.2. 
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates. 
• Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, 
imaging (chest X-ray, CT scan, or an equivalent test), etc.  They should be present 
whenever data for a protocol-specified procedure is present and should only be 
missing when a procedure is not done in the database.  Procedure dates will not be 
imputed. 


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• Log Dates are dates recorded in the case report form (eCRF) data logs. Specifically, 
they are the start and end dates for AEs and concomitant medications/procedures. 
They should not be missing unless an event or medication is marked as ongoing in the 
database.  Otherwise, incomplete log dates will be imputed according to the rules in 
Section 6.2.2.2 of this SAP.  However, in listings, log dates will be shown as recorded 
without imputation. 
• Milestone Dates are dates of protocol milestones such as enrollment date, study drug 
start date, study termination, etc.  They should not be missing if the milestone occurs 
for a subject. They will not be imputed. 
• Outcome Dates are dates corresponding to study endpoints such as the first date of 
achieving the primary or secondary endpoints, disease progression, etc. They may be 
subject to endpoint-specific censoring rules if the outcome event, for instance, did not 
occur; otherwise, they are not subject to imputation. 
• Special Dates cannot be classified in any of the above categories and they include, for 
example, the date of birth.  They may be subject to variable-specific censoring and 
imputation rules. 
6.2.1. 
Calculation Using Dates 
Calculations using dates will adhere to the following conventions:  
• Relative study day is calculated as: 
− Assessment Date - First Dose Date +1, if the assessment date is done on or after 
the first dose date 
− Assessment Date - First Dose Date, if the assessment date is done prior to the first 
dose date. 
− Date of first dose is defined as Study Day 1.  
• Intervals that are presented in weeks will be transformed from days (as calculated 
above) to weeks by using (without truncation) the following conversion formula: 
• WEEKS=DAYS/7 
• Intervals that are presented in months will be transformed from days (as calculated 
above) to months by using (without truncation) the following conversion formula: 
• MONTHS=DAYS/30.4167 
• Intervals that are presented in years will be transformed from days (as calculated 
above) to years by using (without truncation) the following conversion formula: 
− YEARS=DAYS/365.25 


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6.2.2. 
Missing Date Imputation 
6.2.2.1. 
Imputation of Adverse Events/Medication Start Dates 
• Missing day only 
− If the month and year are the same as the year and month of the first study 
treatment date, then the first dosing date will be assigned to the missing field. 
− If the partial date (year and month) is prior to the first study treatment date 
(year and month), then the last day of the month will be assigned to the missing 
field. 
− If the partial date (year and months) is after the first study treatment date 
(year and month), then the first day of the month will be assigned to the missing 
field. 
• Missing month only 
− The day will be treated as missing and both month and day will be imputed 
according to the imputation’s rules for missing day and month. 
• Missing day and month 
− If the year is the same as the year of the first dosing date, then the first dosing date 
will be assigned to the missing field.  
− If the year is prior to the year of the first dosing date, then December 31 will be 
assigned to the missing field.  
− If the year is after the year of the first dosing date, then January 1st will be 
assigned to the missing field.  
• Missing year  
− No Imputation will be done. 
− The AE will be considered as TEAE if the end date is missing or after the first 
dosing date. 
− The medication will be considered as both prior and concomitant if the end date is 
missing or after the first dosing date. 
If the stop date is non-missing and the imputed start date is after the stop date, the start date will 
be imputed by stop date. 
6.2.2.2. 
Imputation of Adverse Events/Medication Stop Dates 
• Missing day only 
− If the month and year are the same as the year and month of the last study 
treatment date, then the last dosing date will be assigned to the missing field. 
− If the partial date (year and month) is prior to the last study treatment date 
(year and month), then the last day of the month will be assigned to the missing 
field. 


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− If the partial date (year and months) is after the last study treatment date 
(year and month), then the first day of the month will be assigned to the missing 
field. 
• Missing month only 
− The day will be treated as missing and both month and day will be imputed 
according to the imputations rules for missing day and month. 
• Missing day and month 
− If the year is the same as the year of the last dosing date, then the last dosing date 
will be assigned to the missing field.  
− If the year is prior to the year of the last dosing date, then December 31 will be 
assigned to the missing field.  
− If the year is after the year of the last dosing date, then January 1st will be 
assigned to the missing field.  
• Missing year 
− No Imputation will be done. 
− If both start and stop date of an AE are missing, the AE will be considered as 
TEAE 
− If both start and stop date of a medication are missing, the medication will be 
considered as both prior and concomitant medication. 
If the start date is non-missing and the imputed stop date is before the start date, the stop date 
will be imputed by start date. 
6.3. 
Handling of Laboratory/Viral Load/Cytokine/Protein Data 
In the continuous laboratory, viral load, cytokine, and acute phase protein data, if the value is 
less than the LLOQ or above the upper limit of quantitation (ULOQ), it will be imputed as 
following: 
• A ½ value of the LLOQ will be used for calculation of descriptive statistics if the data 
is reported in the form of “<x”. For example, if the value is reported as <3, the value 
will be reported as 1.5. 
• A 2 times ULOQ value will be used for calculation of descriptive statistics if the data 
is reported in the form of “>x”. For example, if the value is reported as >3, the value 
will be reported as 6. 
• The limit of quantitation will be used for calculation of descriptive statistics if the 
data is reported in the form of “≥x” or “≤x”, where x is considered as the limit of 
quantitation. 


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Table 2: 
Schedule of Events and Study Parameters 
Assessment/Activity 
Screening 
Day 
1 
Treatment Period 
Follow-up 
Notes 
Days 
2-6 
Day 
7 
Days 
8-13 
Day 
14/EOT 
Days 
15-27 
Day 
28/EOS 
Day 
60 ±3 
Screening and Day 1 should occur within a 
1-day period; where they occur on the same 
day, assessments need not be repeated. 
Subjects remaining in hospital will undergo 
the assessments specified. All subjects will 
undergo the assessments specified for 
Day 14, Day 28, and Day 60 even if they are 
discharged from the hospital prior to 
Day 28. 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
WHO ordinal scale 
assessment 
X 
 
 
 
 
 
 
 
 
(WHO 2020) 
Pregnancy test 
X 
 
 
 
 
 
 
X 
X 
WOCBP only. Pregnancy test can be serum 
βHCG or urine. The Day 60 test should be 
taken at home and self-reported during 
telephone contact. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs will include oxygen saturation daily 
for primary endpoint assessment in addition, 
temperature, respiratory rate, and blood 
pressure will also be assessed. 
Cough and dyspnea 
assessments 
X 
X 
X 
X 
X 
X 
X 
X 
 
Cough and dyspnea are assessed daily on a 
patient reported scale of severe, moderate, 
mild, or absent.  
Body weight and height 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
 
X 
 
Full physical examination (including a minimum 
of general appearance, head, eyes, ears, nose, 
mouth, throat, heart, thyroid, chest and lungs, 
abdomen, extremities, neuromuscular system, 
skin, and lymph nodes) will be completed 
during screening; at all other timepoints the 
examination will be targeted. 
Chest X-ray  
X 
 
 
 
 
X 
 
 
 
X-ray taken within 24 hours prior to Screening 
will be accepted. CT scan will be accepted in 
place of the X-ray if taken with 48 hours prior to 
Screening. 
Nasopharyngeal swab 
 
X 
X 
X 
 
X 
 
X 
 
Nasopharyngeal swab will be taken on Days 1, 
2, 4, 7, 14, and 28. 
Hematology, 
coagulation, and clinical 
chemistry assessment 
X 
X 
X 
X 
X 
X 
 
X 
 
Assessments taken within 24 hours prior to 
Screening will be accepted. 


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Assessment/Activity 
Screening 
Day 
1 
Treatment Period 
Follow-up 
Notes 
Days 
2-6 
Day 
7 
Days 
8-13 
Day 
14/EOT 
Days 
15-27 
Day 
28/EOS 
Day 
60 ±3 
Screening and Day 1 should occur within a 
1-day period; where they occur on the same 
day, assessments need not be repeated. 
Subjects remaining in hospital will undergo 
the assessments specified. All subjects will 
undergo the assessments specified for 
Day 14, Day 28, and Day 60 even if they are 
discharged from the hospital prior to 
Day 28. 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
administration 
 
X 
X 
X 
X 
X 
 
 
 
Study drug will be administered orally at 
200 mg BID on Days 1 to 7 followed by 50 mg 
QD on Days 8 to 14. Should a subject be 
discharged prior to Day 14, tablets will be 
dispensed to take at home and compliance will 
be recorded at Day 14. 
Blood draw for PK 
 
X 
 
X 
 
X 
 
 
 
On Days 1 and 7, blood samples for PK 
assessment will be collected predose (0) and 
at 6 hours post-dose and on Day 14 at pre-
dose (0) and 4 hours post-dose(morning dose 
only). An ad hoc PK assessment will be 
performed in the case of hepatotoxicity (see 
also protocol section 7.3). 
Blood draw for cytokine 
assessment 
 
X 
X 
X 
 
X 
 
X 
 
 
Blood draw for acute 
phase protein 
assessment 
 
X 
X 
X 
 
X 
 
X 
 
 
Antibody titer 
assessment 
 
X 
 
 
 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
At Day 60, the visit will be a telephone call to 
record AEs, SAEs, and deaths for all subjects 
except those who die or are lost to follow-up or 
withdraw consent. 
Abbreviations: βHCG, beta human chorionic gonadotropin; BID, twice daily; EOS, end of study; EOT, end of treatment; PK, pharmacokinetic; QD, once daily, 
WHO, World Health Organization; WOCBP, women of childbearing potential. 


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7. 
REFERENCES 
WHO. WHO R&D Blueprint novel Coronavirus: COVID-19 Therapeutic Trial Synopsis.  2020.