EXPEDITE: A 16-Week, Multicenter, Open-label Study of Remodulin Induction Followed by Orenitram Optimization in Subjects With Pulmonary Arterial Hypertension
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Sponsor: United Therapeutics

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
C O N FI D E N TI A L A N D P R O P RI E T A R Y, U NI T E D T H E R A P E U TI C S C O R P O R A TI O N  
All c o nte nt c o ntai ne d herei n is c o nfi de ntial a n d pr o prietar y i nf or mati o n of U nite d T hera pe utics 
C or p orati o n a n d s hall n ot be discl ose d i n w h ole or i n part e xce pt as per mitte d b y a si g ne d c o ntract wit h 
U nite d T hera pe utics C or p orati o n. © 2 0 1 9 U nite d T hera pe utics C or p orati o n  
 
P a ge 1 
 
E X P E DI T E: A 1 6 -Wee k, M ulti ce nter, O pe n -la bel St u d y of 
Re m o d uli n I n d ucti o n F oll o we d b y Ore nitr a m O pti miz ati o n i n 
S u bjects wit h P ul m o n ar y Arteri al H y perte nsi o n  
I N D N u m ber 6 7, 5 6 1  
Pr ot oc ol T D E -P H -4 0 2  
C O N FI D E N TI A L  
U NI T E D T H E R A P E U TI C S C O R P O R A TI O N  
Ori gi nal Pr ot oc ol Date:  2 2  Fe br u ar y 2 0 1 8  
A me n d me nt 1  
0 9 A pril 2 0 1 8  
A me n d me nt 2  
2 3 A u g ust 2 0 1 8  
A me n d me nt 3  
2 4 J u ne 2 0 1 9  
 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 
I N V E S TI G A T O R’ S A G R E E M E N T  
I h a ve r ea d t he attac he d pr ot oc ol e ntitle d “E X P E DI T E: A 1 6- Wee k, M ultice nter, O p e n -la b el 
St u d y of Re m o d uli n I n d u cti o n F oll o we d b y Ore nitra m O pti mizati o n i n S u bjects wit h 
P ul m o nar y Arterial H y perte nsi o n ,” A me n d me nt 3 date d 2 4 J u ne 2 0 1 9 a n d a gree t o a bi de b y 
all pr o visi o ns set f ort h t herei n. 
I a gree t o c o m pl y wit h t he I nter n ati o nal C o u ncil f or Har m o nisati o n (I C H) G ui deli ne f or G o o d 
Cli nical Practice a n d a p plica ble F o o d a n d Dr u g A d mi nistrati o n re g ulati o ns/ g ui deli nes set 
f ort h i n 2 1 C o de of Fe der al Re g ulati o ns Parts 5 0, 5 4, 5 6, a n d 3 1 2 a n d a n y l ocal re g ulati o ns 
per c o u ntr y. 
I a gree t o e ns ur e t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot be use d 
f or a n y p ur p os e ot her t ha n t he e val uati o n or c o n d u ct of t he cli nical i n vesti g ati o n wit h o ut t he 
pri or writte n c o nse nt of U nite d T hera p e utics C or p.  
I als o ha ve r ea d t he c urr e nt Cli nical I n vesti gat ors’ Br oc h ures f or Re m o d uli n (tre pr osti nil) 
I njecti o n a n d Or e nitra m (tre pr osti nil) E xte n de d Release Ta bl ets a n d ac k n o wle d ge t hat re vi e w 
of t he i nf or mati o n c o ntai ne d i n t he Cli nical I n v esti gat ors’ Br oc h ures is a re q uire me nt f or 
I n v esti gat ors bef ore usi n g Re m o d uli n a n d Ore nitra m i n a cli nical st u d y. 
T his pr ot oc ol has bee n r ecei ve d f or i nf or mati o n o nl y a n d m ust n ot be i m ple me nte d bef ore all 
necessar y re g ul at or y a ge nc y a n d Et hics C o m mittee/I nstit uti o nal Re vie w B oar d a p pr o v al 
d oc u me nts ha ve bee n o bt ai ne d.  
 
 
 
 
Si g nat ure of Pri nci pal I n vesti gat or  
 
Date  
 
 
 
 
 
 
Pri nte d Na me of Pri nci pal I n vesti gat or  
 
 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 
P R O T O C O L S Y N O P SI S  
Title  
E X P E DI T E: A 1 6 -Wee k, M ultice nter, O pe n -la bel St u d y of 
Re m o d uli n I n d ucti o n F oll o we d b y Ore nitra m O pti mizati o n i n 
S u bjects wit h P ul m o nar y Arterial H y p erte nsi o n  
St u d y P h ase  
4  
I n dic ati o n 
P ul m o nar y arterial h y perte nsi o n ( P A H)  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t he st u d y is t o e val ua te t he d ose of 
Ore nitra m ®  (tre pr osti nil) E xte n de d Releas e T a blets ac hie ve d at 
1 6 wee k s after i n d ucti o n t hera p y wit h Re m o d uli n ®  (tre pr osti nil) 
I njecti o n i n P A H patie nts.  T he pri mar y e n d p oi nt is: 
T he perce nta g e of s u bjects ac hie vi n g a n Ore nitra m d ose of 4 m g  
3 ti mes dail y ( TI D) ( or a t otal dail y d ose of 1 2 m g) or hi g her at 
Wee k 1 6 ( or a d os e of 0. 0 5 7 m g/ k g TI D [ or a t otal dail y d ose of 
0. 1 7 1 m g/ k g] or greater f or s u bjects < 7 0 k g). 
Sec o n d ar y O bjecti ve(s)  
T o assess t he effect of Ore nitra m treat me nt at 1 6 wee k s after 
i n d ucti o n t hera p y wit h Re m o d uli n o n t he f oll o wi n g: 
1.  Cli nical res p o nse :  
•  6- Mi n ute W al k D ista nce ( 6 M W D) 
•  B or g d ys p nea sc ore 
•  W orl d Healt h Or ga nizati o n ( W H O ) F u ncti o nal 
Classificati o n ( F C ) 
•  Ser u m N- ter mi nal pro- brai n natri uretic pe pti de 
(N T - pr o B N P) 
•  Ec h ocar di o gra m 
•  P A H s y m pt o m sc ore 
•  H ealt h-relate d q ualit y of life (e m P Hasis - 1 0) 
•  Treat me nt Satisfacti o n Q uesti o n nair e f or M e dicati o n 
( T S Q M) sc ores 
•  P erce nta g e of s u bjects t h at i m pr o ve i n eac h of t he 
f oll o wi n g i n di vi d ual 4 cli nical para m eters at Wee k 1 6 
( 6 M W D, N T- pr o B N P, W H O F C, ri g ht atrial area) t o a 
l o wer ris k strat u m, as defi ne d b y t he 2 0 1 5 E ur o pea n 
S ociet y of Car di ol o g y g ui deli nes, c o m pare d t o Baseli ne 
•  P erce nta g e of s u bjects t h at meet eac h  of t he f oll o wi n g 
4 i n di vi d ual cli nical para meters at Wee k 1 6 i n t he l o w 
ris k cate g or y, as defi ne d b y 2 0 1 5 E ur o pea n S ociet y of 
Car di ol o g y g ui deli nes: 6 M W D > 4 4 0 meters, ser u m 
N T - pr o B N P < 3 0 0 n g/ L, W H O F C I or II, a n d ri g ht atrial 
area < 1 8 c m 2 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 
 
•  P erce nta g e of s u bjects t h at eit her ac hie ve a n Ore nitra m 
d ose of 4 m g TI D ( or a t otal dail y d ose of 1 2 m g) or 
hi g her at Wee k 1 6 ( or a d ose of 0. 0 5 7 m g/ k g TI D [ or a 
t otal dail y d ose of 0. 1 7 1 m g/ k g] or greater f or s u bjects 
< 7 0  k g) or t he p erce nta g e of s u bjects t hat ac hie ve a n 
Ore nitra m d ose ≥2  m g TI D a n d < 4 m g TI D ( or a t otal 
dail y d ose ≥6 m g a n d < 1 2  m g) at Wee k 1 6, wit h at least 
2 of t he f oll o wi n g 3 cli nical para meters at Wee k 1 6: 
6 M W D i ncrease b y ≥1 0 % or ≥3 0 meters fr o m Baseli ne , 
ser u m N T- pr o B N P re d ucti o n > 3 0 % fr o m Baseli ne, or 
W H O F C I or II  
•  T he perce nta g e of s u bjects t hat s uccessf ull y tra nsiti o ne d 
t o Ore nitra m at a n y d os e a n d were mai ntai ne d o n 
t hera p y at Wee k 1 6 
2.  Safet y a n d t olera bilit y  
•  A d verse e ve nts   
•  A E  B ot hers o me S ur ve y 
•  Cli nical la b orat or y para meters  
•  Vital si g ns  
E x pl or at or y O bjecti ves  
O pti o nal e val uati o n of p har mac o g e n o mics ( g e n etic/ri b o n ucleic 
aci d [R N A ]) a n d bi o mar ker testi n g (s pecifi c tar g ets t o be 
deter mi ne d) at Baseli ne , t he Tra nsiti o n Visit, a n d Wee k 1 6.  
St u d y Desi g n  
1 6 -wee k, m ultice nter, o p e n -la bel, u nc o ntr olle d st u d y i n s u bjects 
wit h P A H  
S a m ple Size  
A p pr o xi ma tel y 3 0 e val ua ble s u bjects  will be e nr olle d  
S u m m ar y of S u bject  
Eli gi bilit y Criteri a  
Eli gi ble s u bjects m ust be a ge d 1 8  t o 7 5  years , ha v e a c o nfir me d 
dia g n osis of W H O Gr o u p 1 p ul m o nar y h y perte nsi o n b y ri g ht 
heart cat heterizati o n, ha v e W H O F C II or III s y m pt o ms at 
Baseli ne , a n d ha v e a Bas eli ne 6 M W D of > 2 5 0 meters.   S u bjects 
w h o are eit her n ot recei vi n g P A H- tar gete d t h era p y or are 
c urre ntl y bei n g treate d wit h 1 or 2 F o o d a n d Dr u g 
A d mi nistrati o n ( F D A )-a p pr o ve d oral t hera pies c o nsisti n g of a n 
e n d ot heli n rece pt or a nta g o nist ( E R A) a n d/ or eit her a 
p h os p h o diesterase t y pe- 5 i n hi bit or ( P D E 5-I) or a s ol u ble 
g ua n ylate c y clase (s G C) sti m ulat or f or ≥4 5 da ys, a n d o n a sta ble 
d ose f or ≥3 0 da ys pri or t o t he Baseli ne Visit .  S u bjects w h o 
ha ve recei ve d a pr ostac y cli n -class t hera p y wit hi n 2 8 da ys of 
Baseli ne a n d t h ose wit h a Re gistr y t o E val uate Earl y a n d L o n g-
Ter m P A H Diseas e Ma n a ge me nt  (R E V E A L ) 2. 0 ris k sc ore of 
1 0 or  great er are i neli gi ble  f or t his st u d y.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 
Dr u g D os a ge  
a n d F or m ul ati o n 
Re m o d uli n will be pr o vi de d i n vial stre n gt hs of 1 m g/ m L, 
2. 5 m g/ m L, 5 m g/ m L, a n d 1 0 m g/ m L.  S u bjects will be i nitiate d 
o n s u bc uta ne o us ( S C) or i ntra ve n o us (I V) Re m o d uli n at 2 
n g/ k g/ mi n i n t he i n patie nt or o ut patie nt setti n g  a n d s h o ul d be 
o pti mize d o n Re m o d uli n t hera p y p ri or t o tra nsiti o n t o 
Ore nitra m;  a d ose s h o ul d be ac hie v e d t hat i m pr o v es t he 
s y m pt o ms of P A H w hile mi ni mizi n g e xcessi ve p har mac ol o gic 
effects of Re m o d uli n.  T here is n o ma xi m u m Re m o d uli n d ose 
d uri n g t he st u d y. 
 
S u bjects ma y tra nsiti o n at Wee ks 2, 4, or 8 if t he y ha ve 
ac hie ve d a mi ni m u m Re m o d uli n d ose of 2 0 n g/ k g/ mi n a n d t he 
I n v esti gat or dee ms t he s u bject s uita ble f or tra nsiti o n.  All 
s u bjects still o n Re m o d uli n at Wee k 8 s h o ul d tra nsiti o n t o 
Ore nitra m  re gar dl ess of t heir Re m o d uli n d ose u nless t he 
I n v esti gat or dee ms t he m u ns uita ble f or tra nsiti o n t o Ore nitra m 
d ue t o si g nifica nt si g ns or s y m pt o ms of P A H or a n y ot her 
seri o us safet y c o ncer ns.  
 
Ore nitra m will be pr o vi d e d i n t he e xte n de d- releas e ta blet 
stren gt hs of 0. 1 2 5 m g, 0. 2 5 m g, 1 m g, 2. 5 m g, a n d 5 m g. 
S u bjects will be i nstr ucte d t o ta ke t he a p pr o priate n u m ber of 
0. 1 2 5 m g, 0. 2 5 m g, 1 m g, 2. 5 m g, a n d 5 m g ta blets base d u p o n 
t heir Re m o d uli n d ose a n d t he tra nsiti o n sc he d ule c h ose n b y 
t heir healt hcare pr o vid er .  T here is n o ma xi m u m Ore nitra m d ose 
d uri n g t he st u d y.  
C o ntr ol Gr o u p  
N o ne  
R o ute of  
A d mi nistr ati o n  
Re m o d uli n: S C or I V  
Ore nitra m: oral  
Pr oce d ures  
St u dy Visit Sc he d ule  
•  S u bjects will be assesse d at Scree ni n g, Baseli ne, 
Wee ks  2, 4, 8, 1 2, a n d 1 6.  S u bjects will als o ret ur n t o t he 
st u d y site 7 t o 1 4 da ys after be gi n ni n g tra nsiti o n t o 
Ore nitra m (ie, P ost Tra nsiti o n Visit).  
•  S u bjects wi ll be assesse d d uri n g Scree ni n g a n d Baseli ne 
t o deter mi ne eli gi bilit y f or t he st u d y.  
•  At Baseli ne, s u bjects will be i nitiate d o n S C or I V 
Re m o d uli n at 2 n g/ k g/ mi n.  
•  S u bjects s h o ul d be o pti mize d o n Re m o d uli n t hera p y pri or 
t o tra nsiti o n t o Ore nitra m; a d ose s h o ul d be ac hi e v e d t hat 
i m pr o ves t he s y m pt o ms of P A H w hile mi ni mizi n g 
e xcessi ve p h ar mac ol o gic eff ects of Re m o d uli n . 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 
•  S u bjects ma y tra nsiti o n at Wee ks 2, 4 , or 8  if t he y ha ve 
ac hie ve d a mi ni m u m Re m o d uli n d ose of 2 0 n g/ k g/ mi n 
a n d t he I n vesti gat or d ee ms t he s u bject s uita ble f or 
tra nsiti o n.  
•  Tra nsiti o n ma y be re v ers e d or st o p pe d if t he I n v esti gat or 
feels it is necessar y f or s u bject safet y.   
•  S u bjects will tra nsiti o n fr o m Re m o d uli n t o Orenitra m  
o ver t he c o urse of 1 t o 2 1 da ys i n a n i n patie nt or 
o ut patie nt setti n g .   
•  F oll o wi n g tra nsiti o n, Ore nitra m titrati o n s h o ul d c o nti n ue 
t hr o u g h Wee k 1 6 t o reac h t he ma xi m u m t olerate d d ose.  
 
Effic acy Assess me nts : Ore nitra m d ose ac hie ve d, e xercise 
ca pacit y ( 6 M W D a n d B or g d ys p nea sc ore), W H O F C, 
N T - pr o B N P, healt h-relat e d q ualit y of life (e m P Hasis- 1 0), 
T S Q M sc ores , P A H s y m pt o m sc ore, ec h o car di o gra ms 
 
S afety a n d T oler a bility Assess me nts : A d verse e ve nts, cli nical 
la b orat or y e v al uati o ns, vital si g ns 
 
O pti o n al Assess me nts: P har mac o g e n o mic ( ge n etic/ R N A ) a n d 
bi o mar ker testi n g  
St atistic al C o nsi der ati o ns  A p pr o xi matel y 3 0 e val ua ble s u bjects were set f or feasi bilit y a n d 
t o e ns ure a reas o n a ble dataset t o e val uate t he Ore nitra m d ose 
ac hie ve d, a n d t he cli nical res p o nse , safet y, a n d t ol era bilit y of 
Ore nitra m  after i n d ucti o n t hera p y wit h Re m o d uli n.  N o f or mal 
sa m ple size c o m p utati o n was perf or me d wit h res pect t o t he 
st u d y e n d p oi nts. 
S p o ns or  
U nite d T hera p e utics C or p.  
5 5 T W Ale xa n d er Dri ve 
Researc h Tria n gle Par k, N C 2 7 7 0 9 
U nite d States of A merica  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 8 
T A B L E O F C O N T E N T S  
LI S T O F C O N T A C T S F O R S T U D Y  .................................................................................... 2 
I N V E S TI G A T O R’ S A G R E E M E N T ..................................................................................... 3 
P R O T O C O L S Y N O P SI S  ....................................................................................................... 4 
T A B L E O F C O N T E N T S  ........................................................................................................ 8 
T a ble of I n- Te xt T a bles  ........................................................................................................ 1 1 
LI S T O F A B B R E VI A TI O N S  .............................................................................................. 1 2 
1  B A C K G R O U N D A N D R A TI O N A L E  .......................................................................... 1 4 
1. 1  
D E FI NI TI O N O F C LI NI C A L P R O B L E M  ............................................................. 1 4 
1. 2  
T R E P R O S TI NI L B A C K G R O U N D  ......................................................................... 1 5 
1. 2. 1  
Ge ner al P h ar m ac ol o g y .......................................................................................... 1 5  
1. 2. 2  
Ge ner al T o xic ol o g y ................................................................................................ 1 6  
1. 2. 3  
Cl i nic al P h ar m ac ol o g y .......................................................................................... 1 7 
1. 3  
R A TI O N A L E F O R D E V E L O P M E N T O F S T U D Y D R U G I N 
DI S E A S E/ C O N DI TI O N  ............................................................................................ 1 9 
1. 4  
C LI NI C A L H Y P O T H E SI S  ....................................................................................... 2 1 
2  O B J E C TI V E S  ................................................................................................................. 2 1 
2. 1  
P RI M A R Y O B J E C TI V E  .......................................................................................... 2 1 
2. 2  
S E C O N D A R Y O B J E C TI V E S  .................................................................................. 2 1 
2. 3  
E X P L O R A T O R Y O B J E C TI V E S  ............................................................................ 2 1 
3  E X P E RI M E N T A L P L A N  .............................................................................................. 2 1 
3. 1  
S T U D Y D E SI G N  ........................................................................................................ 2 1 
3. 2  
O V E R A L L S C H E D U L E O F TI M E S A N D E V E N T S  ............................................ 2 2 
3. 3  
C LI NI C A L A S S E S S M E N T S  .................................................................................... 2 6 
3. 3. 1  
Effic ac y  ................................................................................................................... 2 6 
3. 3. 1. 1  
D ose of St u d y Dr u g  ............................................................................................ 2 6 
3. 3. 1. 2  
P ul m o n ar y Arteri al H y perte nsi o n S y m pt o m Sc ore ........................................ 2 6 
3. 3. 1. 3  
W H O F u ncti o n al Cl assific ati o n  ........................................................................ 2 7 
3. 3. 1. 4  
6- Mi n ute W al k Test  ........................................................................................... 2 7 
3. 3. 1. 5  
B or g D ys p ne a Sc ore ........................................................................................... 2 9  
3. 3. 1. 6  
P atie nt -re p orte d O utc o mes  ............................................................................... 2 9 
3. 3. 1. 7  
Ser u m N -Ter mi n al Pr o -br ai n N atri uretic P e pti de  ......................................... 2 9 
3. 3. 1. 8  
Ec h oc ar di o gr a ms ............................................................................................... 3 0  
3. 3. 1. 9  
De m o gr a p hics, Me dic al Hist or y, P A H Hist or y, C o nc o mit a nt 
Me dic ati o ns, Pri or P A H Me dic ati o ns, P h ysic al E x a mi n ati o n ....................... 3 0  
3. 3. 2  
S afet y  ...................................................................................................................... 3 1 
3. 3. 2. 1  
A d verse E ve nts a n d t he A E B ot hers o me S ur ve y  ............................................ 3 1 
3. 3. 2. 2  
Cli nic al L a b or at or y E v al u ati o ns ...................................................................... 3 2  
3. 3. 2. 3  
Uri ne Pre g n a nc y Tests  ....................................................................................... 3 2 
3. 3. 2. 4  
Vit al Si g ns  ........................................................................................................... 3 2 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 9 
3. 3. 2. 5  
Peri o dic C o nt act wit h St u d y S u bjects  .............................................................. 3 2 
3. 3. 3  
Ot her Testi n g  ......................................................................................................... 3 3 
3. 3. 3. 1  
P h ar m ac o ge n o mic ( Ge netic/ R N A) a n d Bi o m ar ker Testi n g ( O pti o n al)  ........ 3 3 
3. 3. 3. 2  
He m o d y n a mics  ................................................................................................... 3 3 
3. 4  
N U M B E R O F C E N T E R S  .......................................................................................... 3 3 
3. 5  
N U M B E R O F S U B J E C T S  ........................................................................................ 3 4 
3. 6  
E S TI M A T E D S T U D Y D U R A TI O N  ......................................................................... 3 4 
4  S U B J E C T E LI GI BI LI T Y  .............................................................................................. 3 4 
4. 1  
I N C L U SI O N C RI T E RI A .......................................................................................... 3 4 
4. 2  
E X C L U SI O N C RI T E RI A  ......................................................................................... 3 6 
4. 3  
P R E S C RI B E D T H E R A P Y  ........................................................................................ 3 7 
4. 3. 1  
C o nc o mit a nt Me dic ati o ns ..................................................................................... 3 7  
4. 3. 2  
Ot her Tre at m e nts  .................................................................................................. 3 7 
5  S U B J E C T E N R O L L M E N T  ........................................................................................... 3 8 
5. 1  
T R E A T M E N T A S SI G N M E N T  ................................................................................ 3 8 
5. 2  
R A N D O MI Z A TI O N  .................................................................................................. 3 8 
5. 3  
B LI N DI N G  .................................................................................................................. 3 8 
6  D R U G S A N D D O SI N G ( O R T R E A T M E N T P R O C E D U R E S)  ................................. 3 8 
6. 1  
D R U G D O S A G E, A D MI NI S T R A TI O N A N D S C H E D U L E  ................................. 3 8 
6. 2  
A C C E S S T O B LI N D E D T R E A T M E N T A S SI G N M E N T  ..................................... 4 0 
6. 3  
C O M P LI A N C E  .......................................................................................................... 4 0 
7  E X P E RI M E N T A L P R O C E D U R E S  ............................................................................. 4 1 
7. 1  
S C R E E NI N G ( D A Y S - 2 8 T O - 1) .............................................................................. 4 2 
7. 1. 1  
Re -scree ni n g of S u bjects ....................................................................................... 4 3 
7. 2  
B A S E LI N E ( D A Y S - 1 4 T O - 1) .................................................................................. 4 3 
7. 3  
T R E A T M E N T P H A S E  .............................................................................................. 4 4 
7. 3. 1  
Wee k 2 ( D a y 1 5 [ ± 3 D a ys]) ................................................................................... 4 4  
7. 3. 2  
Wee k 4 ( D a y 2 9 [ ± 5 D a ys]) ................................................................................... 4 5  
7. 3. 3  
Wee k 8 ( D a y 5 7 [ ± 5 D a ys]) ................................................................................... 4 5  
7. 3. 4  
Tr a nsiti o n Visit ( Wee k 2, 4, or 8) ......................................................................... 4 6  
7. 3. 5  
P ost Tr a nsiti o n Visit ( 7 t o 1 4 d a ys after Tr a nsiti o n Visit) ................................. 4 8  
7. 3. 6  
Wee k 1 2 ( D a y 8 5 [ ± 5 D a ys]) ................................................................................. 4 8  
7. 3. 7  
Wee k 1 6/ E arl y St u d y Wit h dr a w al ( D a y 1 1 3 [ ± 7 D a ys]) .................................... 4 9
 
8  S T U D Y T E R MI N A TI O N  ............................................................................................... 5 0 
8. 1  
C RI T E RI A F O R S U B J E C T WI T H D R A W A L  ....................................................... 5 0 
8. 2  
C RI T E RI A F O R T E R MI N A TI N G T H E S T U D Y  .................................................. 5 0 
8. 3  
C RI T E RI A F O R DI S C O N TI N UI N G T H E SI T E  ................................................... 5 1 
9  A D V E R S E E V E N T R E P O R TI N G  ................................................................................ 5 1 
9. 1  
D E FI NI TI O N S  ........................................................................................................... 5 1 
9. 1. 1  
A d verse E ve nt  ........................................................................................................ 5 1 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 0 
9. 1. 2  
Seri o us A d verse E ve n t .......................................................................................... 5 2 
9. 2  
D O C U M E N T A TI O N O F A D V E R S E E V E N T S  ..................................................... 5 3 
9. 3  
R E P O R TI N G R E S P O N SI BI LI TI E S O F T H E I N V E S TI G A T O R  ....................... 5 4 
9. 4  
S A F E T Y R E P O R T S  .................................................................................................. 5 4 
9. 5  
P R E G N A N C Y  ............................................................................................................ 5 4 
1 0  S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................... 5 5 
1 0. 1  D A T A P R O C E S SI N G  ................................................................................................ 5 5 
1 0. 1. 1  
E D C  ......................................................................................................................... 5 5 
1 0. 2  S A M P L E SI Z E  ........................................................................................................... 5 5 
1 0. 3  A N A L Y SI S P L A N  ...................................................................................................... 5 6 
1 0. 3. 1  
Pri m ar y E n d p oi nt  .................................................................................................. 5 6 
1 0. 3. 1. 1  
Effic ac y E n d p oi nt ............................................................................................... 5 6 
1 0. 3. 2  
Sec o n d ar y E n d p oi nts  ............................................................................................. 5 6 
1 0. 3. 2. 1  
S afet y E n d p oi nts  ................................................................................................ 5 6 
1 0. 3. 2. 2  
Effic ac y E n d p oi nts  ............................................................................................. 5 6 
1 0. 3. 3  
S afet y A n al yses ...................................................................................................... 5 7  
1 0. 4  I N T E RI M A N A L Y SI S ............................................................................................... 5 8 
1 0. 5  O T H E R A N A L Y S E S  ................................................................................................. 5 8 
1 0. 6  D A T A LI S TI N G S A N D S U M M A RI E S  ................................................................... 5 8 
1 1  P A C K A GI N G A N D F O R M U L A TI O N  ........................................................................ 5 8 
1 1. 1  C O N T E N T S O F S T U D Y D R U G  .............................................................................. 5 8 
1 1. 2  L A B E LI N G  ................................................................................................................. 5 9 
1 1. 3  S T O R A G E A N D H A N D LI N G O F C LI NI C A L S T U D Y M A T E RI A L  ................. 5 9 
1 1. 4  S U P P L Y A N D R E T U R N O F C LI NI C A L S T U D Y M A T E RI A L  .......................... 5 9 
1 1. 5  D R U G A C C O U N T A BI LI T Y  .................................................................................... 6 0 
1 2  R E G U L A T O R Y A N D E T HI C A L O B LI G A TI O N  ...................................................... 6 0 
1 2. 1  U S F D A O R A P P LI C A B L E R E G U L A T O R Y R E Q UI R E M E N T S  ...................... 6 0 
1 2. 2  I N F O R M E D C O N S E N T R E Q UI R E M E N T S ......................................................... 6 1 
1 2. 3  I N D E P E N D E N T E T HI C S C O M MI T T E E/I N S TI T U TI O N A L R E VI E W 
B O A R D  ....................................................................................................................... 6 1 
1 2. 4  P R E S T U D Y D O C U M E N T A TI O N R E Q UI R E M E N T S ......................................... 6 2 
1 2. 5  S U B J E C T C O N FI D E N TI A LI T Y  ............................................................................. 6 2 
1 3  A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S  ................................................. 6 2 
1 3. 1  P R O T O C O L A M E N D M E N T S A N D S T U D Y T E R MI N A TI O N  .......................... 6 2 
1 3. 2  S T U D Y D O C U M E N T A TI O N A N D S T O R A G E  .................................................... 6 3 
1 3. 3  S T U D Y M O NI T O RI N G A N D D A T A C O L L E C TI O N  .......................................... 6 3 
1 3. 4  E T HI C A L C O N D U C T O F T H E S T U D Y  ................................................................ 6 4 
1 4  R E F E R E N C E S  ................................................................................................................ 6 5 
1 5  A P P E N DI C E S  ................................................................................................................. 6 7 
A p pe n di x A.  
6- Mi n ute W al k Test a n d B or g D ys p ne a Sc ore ..................................... 6 7  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 1 
A p pe n di x B.  
W orl d He alt h Or g a niz ati o n F u ncti o n al Cl assific ati o n f or 
P ul m o n ar y H y perte nsti o n  ......................................................................................... 7 0 
A p pe n di x C.  
G ui deli nes a n d Defi niti o ns f or Rec o r di n g A d verse E ve nts  ................. 7 1 
A p pe n di x D.  
Cli nic al L a b or at or y P ar a meters ............................................................ 7 5  
A p pe n di x E.  
A E B ot hers o m e S ur ve y  ........................................................................... 7 6 
A p pe n di x F.  
C oc kcr oft -G a ult E q u ati o n a n d C hil d -P u g h Sc ore  ............................... 7 7 
A p pe n di x G.  
Tre at m e nt S atisf acti o n Q uesti o n n aire f or Me dic ati o n ( T S Q M) 
( Versi o n 1. 4) ................................................................................................................ 7 8 
A p pe n di x H.  
e m P H asis - 1 0 Q uesti o n n aire ................................................................... 8 1 
A p pe n di x I.  Tr a nsiti o n Sc he d ule E x a m ples  ..................................................................... 8 2 
A p pe n di x J.  
R E V E A L 2. 0 Ris k Sc ore  ....................................................................... 1 0 2 
 
T a ble of I n- T e xt T a bles 
Ta ble 3 - 1 
O verall Sc he d ule of Ti me a n d E ve nts  ............................................................. 2 2 
Ta ble 3 - 2 
P ul m o nar y Arterial H y perte nsi o n S y m pt o ms ................................................. 2 6  
Ta ble 9 - 1 
A d verse E v e nts Attri b uta ble t o t he Pr o gressi o n of Disease............................ 5 2  
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 2 
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
6 M W D  
6 -M i n ute W al k D ista nce 
6 M W T  
6 -M i n ute W al k T est 
A E  
A d verse e ve nt  
BI D  
T wice dail y  
C ma x  
Ma xi mal dr u g c o nce ntrati o n  
C Y P  
C yt oc hr o me P 4 5 0  e nz y me 
E C H O  
Ec h ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
E R A  
E n d ot heli n rece pt or a nta g o nist  
F C  
F u ncti o nal C lassificati o n 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G D S  
Gl o bal Dr u g Safet y  
HI V  
H u ma n i m m u n o deficie nc y vir us  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntra ve n o us(l y) 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N T -pr o B N P  
N -T er mi nal pr o-brai n  natri uretic pe pti de  
P A H  
P ul m o nar y arterial h y perte nsi o n  
P A W P  
P ul m o nar y arter y we d ge press ure  
P K  
P har mac o ki netic(s)  
P D E 5 -I 
P h os p h o diesterase t y pe -5 i n hi bit or  
P V R  
P ul m o nar y vasc ular resista nce  
R E V E A L  
Re gistr y t o E val uate Earl y a n d L o n g -Ter m P A H Disease Ma na ge me nt  
R H C  
Ri g ht heart cat heterizati o n  
R N A  
Ri b o n ucleic aci d  
S A E  
Seri o us a d verse e ve nt  
R V  
Ri g ht ve ntric ular  
S C  
S u bc uta ne o us (l y) 
S D  
Sta n dar d de viati o n  
s G C 
S ol u ble g ua n ylate c yclase  
S R  
S ustai ne d release  
T D D  
T otal dail y d ose  
TI D  
3  ti mes dail y 
T S Q M  
Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n  
U S  
U nite d States  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 3 
U S PI  
U nite d States Prescri bi n g I nf or mati o n  
W H O  
W orl d Healt h Or ga nizati o n  
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 4 
1  
B A C K G R O U N D  A N D R A TI O N A L E  
1. 1  
D E FI NI TI O N  O F C LI NI C A L P R O B L E M  
P ul m o nar y arterial h y perte nsi o n ( P A H), w hic h is defi ne d as a n ele v ati o n i n p ul m o nar y arteri al 
press ure a n d p ul m o nar y vasc ular r esista nce ( P V R), is a se vere he m o d y na mic a b n or malit y 
ass ociate d wit h a v a riet y of diseases a n d s y n dr o mes.  Ele vati o ns i n P V R ca use a n i ncrease i n 
ri g ht ve ntric ular ( R V) aft erl oa d, i m pairi n g R V f u n cti o n a n d ulti matel y lea di n g t o pr o gressi ve 
li miti n g s y m pt o ms a n d deat h.  
Ore nitra m ®  was a p pr o ve d b y t he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) i n 2 0 1 3 
f or P A H ( W orl d Healt h Or ga nizati o n [ W H O] Gr o u p 1) t o i m pr o ve e xercise ca pacit y.  
Ore nitra m d osi n g is i n di vi d ualize d t o effect a n d t olera bilit y, t h us it is i m p orta nt t o ac hie ve 
o pti mal tre pr osti nil d oses as q uic kl y as p ossi ble.  Hi g her d oses of tre pr osti nil c orrelate wit h 
i m pr o ve d e xer cise ca pacit y, a n d t here are d ata t o s u g gest t hat Re m o d uli n®  d oses of 
≥4 0 n g/ k g/ mi n ma y i m pr o ve l o n g-ter m s ur vi val ( Si m o n nea u 2 0 0 2, Hire mat h 2 0 1 0, Ta ps o n 
2 0 1 3, Ji n g 2 0 1 3, Be nza 2 0 1 1). 
C o m mercial data, as w ell as a nec d ot al re p orts fr o m healt h care pr o vi ders, s u g gest t hat a d verse 
e ve nts ( A Es) are a c o m m o n ca use of Ore nitra m disc o nti n uati o n earl y o n i n t he c o urse of 
treat me nt.  T his is reflecte d b y t he me dia n t otal dail y d ose ( T D D) of Ore n itra m at 6 m o nt hs of 
7. 5 m g ( Balas u bra ma nia n 2 0 1 7).  Res ults fr o m a rece nt cli nical st u d y s u g gest P A H patie nts 
pre vi o usl y recei vi n g Re m o d uli n ma y t olerate si g nifica ntl y hi g her d oses of Ore nitra m as 
c o m pare d t o patie nts wit h o ut pri or Re m o d uli n e x p os ure ( C ha ki nala 2 0 1 7) .  A d diti o nall y, 
se veral o p e n-la bel a n d c o ntr olle d st u dies ha ve de m o nstrate d t he safet y a n d efficac y of 
a g gressi ve Re m o d uli n titrati o n ( Sit b o n 2 0 0 7, Ha nse n 2 0 1 4, Gr ü ni g 2 0 1 6).  
T he E X P E DI T E  st u d y will e val uate t he Ore nitra m d oses t hat P A H  patie nts ac hie ve after 
tre pr osti nil i n d ucti o n usi n g a s h ort-ter m c o urse of Re m o d uli n.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 5 
1. 2  
T R E P R O S TI NI L  B A C K G R O U N D  
1. 2. 1  
Ge ner al P h ar m ac ol o g y 
Tre pr osti nil, [[( 1 R, 2 R, 3a S, 9a S) 2, 3, 3a, 4, 9, 9a- he x a h y dr o- 2- h y dr o x y- 1- [( 3 S)- 3- h y dr o x y o ct yl]-
1 H be nz [f]i n de n- 5- yl] o x y]acetic aci d, is a c h e micall y sta ble tric yclic a n al o g ue of 
pr ostac ycli n.  T he p h ar m ac ol o g y of tre pr osti nil has bee n e xte nsi vel y c haracterize d i n well-
esta blis he d m o dels, all c o nfir mi n g t he s uita bilit y of t he dr u g t o treat P A H f oll o wi n g t he 
pare nteral (as tr e pr osti nil s o di u m), i n hale d (as tre pr osti nil s o di u m), or oral (as tre pr osti nil 
di ola mi ne) r o utes of a d mi nistrati o n.  A detaile d descri pti o n of precli nical a n d cli nical 
i nf or mati o n of tre pr osti nil f or i njecti o n is pr o vi de d i n t he Re m o d uli n I n vesti gat or’s Br oc h ure. 
T he maj or p har m ac ol o gi cal acti o ns of tre pr osti nil are direct vas o dilati o n of p ul m o nar y a n d 
s yste mic arterial v asc ular be ds a n d i n hi biti o n of platelet a g gre gati o n.  I n vitr o, tre pr osti nil 
i n d uce d c o nce ntrati o n- d e pe n de nt rela x ati o n of ra b bit-is olate d prec o ntracte d mese nteric 
arteries, a n d i n hi biti o n of a de n osi ne di p h os p hate-i n d uce d platelet a g gre g ati o n i n h u ma n a n d 
rat platelet-ri c h plas ma.  I n a ni mals, t he vas o dilat or y effects of tre pr osti nil re d uce ri g ht a n d 
left ve ntric ular afterl oa d, t here b y i ncreasi n g car diac o ut p ut a n d str o ke v ol u me.  Pr ostac ycli ns 
l o wer p ul m o nar y arter y press ure, i ncreas e car diac o ut p ut wit h out affecti n g t he heart rate, 
i m pr o ve s yste mic o x y ge n tra ns p ort, as well as p ossi bl y re versi n g p ul m o nar y arter y 
re m o deli n g.  T her e is als o i ncreasi n g e vi d e nce t h at t he a bilit y t o bl oc k t he pr oliferati o n of 
p ul m o nar y arter y s m o ot h m uscle cells ma y c o ntri b ute, al o n g wit h vas o dilati o n, t o t he 
t hera pe utic eff ects of pr ostac ycli ns i n t he treat me nt of P A H.  T he mec h a nis m of acti o n is 
t heref or e li kel y t o be m ultifact orial. 
Tre pr osti nil di ola mi ne ( U T -1 5 C s ustai ne d releas e [ S R]),  herei nafter  referre d t o as oral 
tre prosti nil , was selecte d fr o m a seri es of tre pr osti nil salts base d o n critical p h ysic oc he mical 
c haracteristics ( e g , s ol u bilit y, h y gr osc o picit y, melti n g p oi nt) wit h a g oal of deli veri n g 
tre pr osti nil b y t he oral r o ute as a n S R d osa ge f or m.  I n s ol uti o n, b ot h tre pr osti nil s o di u m a n d 
tre pr osti nil di ola mi ne are disass ociate d fr o m t heir res pecti ve s alt c o u nter-i o ns a n d e xist as t he 
freel y i o nize d f or m of tr e pr osti nil.  As a res ult, t he bi ol o gicall y acti ve  f or m prese nt i n t he 
bl o o dstrea m is i de ntical , irres pecti ve of t he c o u nt er-i o n use d i n t he f or m ulati o n.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 6 
A d diti o nal n o ncli nical st u dies ha ve s h o w n t hat t h e o bser ve d p h ar mac ol o gical pr ofile of oral 
tre pr osti nil reflects t he acti vit y of t he pare nt m olec ule, tre pr osti nil, a n d t hat t he c o ntri b uti o n t o 
t hat pr ofile of a n y k n o w n meta b olite t hat w o ul d be f or me d i n vi v o w o ul d be mi ni mal.  
1. 2. 2  
Ge ner al  T o xic ol o g y 
Oral tre pr osti nil is a n o vel salt f or m of Re m o d uli n (tre pr osti nil) I njecti o n a n d T y vas o ®  
(tre pr osti nil) I n halati o n S ol uti o n, w hic h are a p pr o ve d i n t he U nite d States ( U S) t o treat 
s u bjects wit h P A H.  I n a d diti o n t o t he n o ncli nical st u dies c o n d ucte d wit h oral tre pr osti nil, a n 
e xte nsi ve a m o u nt of p har mac ol o g y, p har mac o ki netic ( P K), a n d t o xic ol o g y i nf or mati o n o n 
tre pr osti nil s o di u m is a vaila ble fr o m Re m o d uli n a n d T y vas o de vel o p me nt. 
D uri n g t he de vel o p me nt of Re m o d uli n, tre pr osti nil s o di u m was a d mi nistere d s u bc uta ne o usl y 
(S C ) a n d/ or i ntra ve n o usl y (I V) i n ac ute t o xicit y st u dies, re peat- d ose t o xicit y st u dies, 
re pr o d ucti ve t o xicit y st u dies, a n d ge n ot o xicit y st u dies, a n d has a w ell-defi n e d cli nical safet y 
pr ofile.  Tre pr osti nil s o di u m was a d mi nistere d via c o nti n u o us i nf usi o n t o rats a n d d o gs i n 
t o xicit y stu dies f or u p t o 6 m o nt hs, w hic h s u p p orte d t he safet y of c hr o ni c a d mi nistrati o n of 
Re m o d uli n t o s u bjects.  
I n a d diti o n t o t he e xte nsi ve t o xic ol o g y data wit h tre pr osti nil s o di u m, t he t o xicit y a n d 
t o xic o ki netic pr ofiles of oral tre pr osti nil ha ve b ee n e val uate d i n ac ute a n d re peat- d ose or al 
t o xicit y st u dies of u p t o 1 3 wee ks d urati o n i n r o de nts a n d u p t o 9 m o nt hs d urati o n i n d o gs.  
Oral tre pr osti nil has als o bee n e v al uate d i n re pr o d ucti ve de vel o p me ntal t o xicit y st u dies i n 
pre g na nt r ats a n d ra b bits a n d i n a n i n vi v o rat micr o n ucle us assa y.  
N o ncli nical data r e veal n o s pecial hazar d f or h u m a ns base d o n c o n v e nti o nal st u dies of safet y 
p har mac ol o g y, r e peat- d ose t o xicit y, a n d ge n ot o xicit y.  A c o m pre he nsi v e d escri pti o n of oral 
tre pr osti nil, i ncl u di n g t he p har mac ol o g y, t o xic ol o g y, a n d cli nical st u dies c o m plete d t o date, 
ma y be f o u n d i n t he c urr e nt Ore nitra m I n v esti gat or’s Br oc h ure. 
Se g me nt I, II, a n d III st u dies ha ve bee n c o m plete d i n rats, a n d a Se g me nt II st u d y has b ee n 
c o m plete d i n ra b bits.  N o a d verse effects f or fetal  via bilit y/ gr o wt h a n d fetal de vel o p me nt 
(terat o ge ni cit y) wer e see n i n rats at or bel o w 2 0 m g/ k g/ da y or i n ra b bits at or bel o w 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 7 
0. 5 m g/ k g/ da y.  At hi g h d oses, terat o ge nic effects of oral tre pr osti nil were o bser ve d i n ra b bits.  
Fi n di n gs i ncl u de d i ncrease d fet al i nci de n ce of e xt er nal, s oft tiss ue, a n d s keletal 
malf or mati o ns.   I nitial pare nt ge nerati o n fe mal e rats recei vi n g 1 0 m g/ k g/ da y ha d decreas e d 
f o o d c o ns u m pti o n a n d b o d y wei g hts d uri n g gestati o n, i ncreas e d d urati o n of gestati o n, sli g ht 
decreases i n t he via b ilit y a n d n u m ber of p u ps p er litter, a n d p u ps wit h decrease d mea n 
ne o natal b o d y wei g hts. 
A 6 - m o nt h car ci n o ge nicit y st u d y i n mice wit h oral tre pr osti nil a d mi nistere d at dail y oral d oses 
of 3, 7. 5, a n d 1 5 m g/ k g i n fe males a n d 5, 1 0, a n d 2 0 m g/ k g i n males f or 2 6 wee ks di d n ot 
de m o nstrate i ncr eases i n t he i nci de nce of ne o plastic lesi o ns.   A 2- year rat carci n o ge nicit y 
st u d y de m o nstrate d t hat dail y a d mi nistrati o n of oral tre pr osti nil d oes n ot ha ve carci n o ge nic 
p ote ntial. 
A G o o d La b or at or y Practices, car di o vasc ular, safet y p har mac ol o g y st u d y t o e val uate 
di ola mi ne effects , i n de pe n de nt of tre pr osti nil, o n car di o vasc ular f u ncti o n i n tele metere d d o gs 
was c o n d ucte d.  Data s u p p ort t hat oral a d mi nistrati o n of di ola mi ne at d oses u p t o 
2 m g/ k g/ d ose t wice dail y ( BI D; 4 m g/ k g/ da y) t o male bea gle d o gs w as n ot ass ociate d wit h 
a n y defi niti ve c ha n g es i n arterial pr ess ure, h eart rate , or electr ocar di o gra m para meters.   I n 
a d diti o n, n o a b n or mal cli nical si g ns were n ote d i n t he a ni mals d ose d wit h t he ve hicle or wit h 
a n y of t he d oses o f di ola mi ne. 
1. 2. 3  
Cli nic al P h ar m ac ol o g y 
T he m ost fre q ue nt A Es ass ociate d wit h Re m o d uli n i n cli nical st u dies of s u bjects wit h P A H 
were relate d t o t he p h ar m ac ol o gical pr o p erties of Re m o d uli n a n d were g e n erall y n ot seri o us.  
T hese pr ostac ycli n -r elate d A Es i ncl u de d diarr h ea, hea dac he, a n d n a usea.  Re m o d uli n has n ot 
bee n ass oci ate d wit h a n y si g nifica nt c ha n ges i n la b orat or y para meters or e n d- or ga n t o xicit y.  
T he safet y pr ofile n ote d i n a n o pe n-la b el e xte nsi o n st u d y, wit h m uc h l o n ger d urati o ns of 
e x p os ure a n d a lar g er, m ore di verse s u bj ect p o p ul ati o n, was c o nsiste nt wit h t he pr ofile n o te d 
i n t he c o ntr olle d st u dies.  T o date, o ver 2 0, 0 0 0 p atie nts ha ve bee n e x p ose d t o Re m o d uli n.  
T his n u m ber i ncl u des s u bjects w h o ha ve recei ve d si n gle a d mi nistrati o n t o s u bjects recei vi n g 
c o nti n u o us i nf usi o n f or greater t ha n 1 5 years.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 8 
Oral tre pr osti nil has bee n a d mi nistere d t o a p pr o xi matel y 2 3 4 4 s u bjects i n P hase 1 t o 3 cli nical 
st u dies.  Oral tre pr osti nil d oses of u p t o 3 m g BI D ha ve bee n a d mi nistere d t o healt h y 
v ol u nteers, a n d s u bjects wit h P A H ha ve recei ve d u p t o 2 7. 5 m g 3 ti mes dail y ( TI D)  i n a n 
o pe n-la bel e xt e nsi o n st u d y.  T he a vera ge e x p os ure is a p pr o xi matel y 2 years; t he l o n gest 
e x p os ure is a p pr o xi mat el y 8 years. 
T he a bs ol ute bi oa vaila bilit y of t he oral tre pr osti nil 1 m g ta blet is 1 7. 6 %.  F oll o wi n g 
a d mi nistrati o n, tre pr osti nil di ola mi ne is wi del y distri b ute d.  Tre pr osti nil is a p pr o xi matel y 
9 6 % pr otei n b o u n d, wit h n o effect o n warfari n or di g o xi n dis place me nt.  P har mac o ki netic 
data (area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve) i n dicat e t hat Da y 1 P K data are 
pre dicti v e of D a y 1 3, a n d li nearit y was o bser v e d i n plas ma e x p os ure c o m pari n g 1- m g a n d 
2- m g d oses i n healt h y v ol u nteers.  F o o d, p artic ularl y a hi g h fat, hi g h cal ori e meal, has bee n 
o bser ve d t o i ncr ease a bs or pti o n a n d pr ol o n g t he s yste mic e x p os ure t o tre pr osti nil, 
c o ntri b uti n g t o t he desire d P K pr ofile.  C o nsiste nt wit h  i n vitr o st u dies, cli nical st u dies 
assessi n g t he i m pact of i n d ucti o n a n d i n hi biti o n of t he c yt oc hr o m e P 4 5 0 e nz y me ( C Y P) 2 C 8 
a n d C Y P 2 C 9 meta b olic pat h wa ys o n oral tre pr osti nil i n dicate t hat C Y P 2 C 8 a p pears t o b e of 
maj or i m p orta nce a n d C Y P 2 C 9 of mi n or i m p orta nce t o i n vi v o meta b olis m of oral 
tre pr osti nil i n h u ma ns. 
T o date, t he maj orit y of oral tre pr osti nil st u dies ha ve bee n c o n d ucte d wit h BI D d osi n g.  I n a n 
atte m pt t o u n dersta n d t he P K of TI D d osi n g, a st u d y was c o n d uct e d i n healt h y v ol u nteers.  I n 
t his o pe n-la bel, si n gle-ce nter st u d y, 1 9 healt h y s u bjects recei ve d 0. 5 m g TI D f or 7 da ys.  
Ni netee n s u bjects ( 1 0 fe males a n d 9 males) wit h a mea n a g e of 3 5. 2 years (ra n ge: 2 0 t o 
5 4 years) wer e e nr olle d.  O n  Da y 1 , t he mea n ma xi mal dr u g c o nce ntrati o n ( Cma x ) ± sta n dar d 
de viati o n ( S D) of  tre pr osti nil was 0. 5 7 4 ± 0. 2 2 n g/ m L, w hic h occ urre d at a me dia n ti me of 
4 h o urs (ra n g e: 2 t o 6 h o urs).  I n c o m paris o n, t he Da y 8 mea n C ma x  ( ± S D) was 
0. 6 1 5 ± 0. 3 2 n g/ m L a n d occ urr e d at a m e dia n ti me of 4 h o urs (ra n ge: 1 t o 6 h o urs). 
O n Da y 7, t he mea n C ma x  ( ± S D) was 0. 8 1 0 ± 0. 4 9 1 n g/ m L a n d occ urre d at a me dia n ti me of 
1 4 h o urs (ra n g e: 6 t o 2 0 h o urs) f oll o wi n g t he m or ni n g d ose.  T his i n dicate d t ha t ma xi m u m 
c o nce ntr ati o n d uri n g a dail y i nter val at stea d y state occ urs after t he e ve ni n g ( or t hir d) d ose of 
t he da y.  Mea n tr o u g h pl as ma c o nce ntrati o ns pri or t o t he m or ni n g d ose o n Da ys 5, 6, 7, a n d 8 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 9 
were 0. 0 4 9, 0. 0 4 9, 0. 0 5 0, a n d 0. 0 5 3 n g/ m L, res pecti vel y.  Mea n tr o u g h c o n ce ntrati o ns pri or 
t o t he e ve ni n g d ose o n D a ys 4, 5, 6, a n d 7 were 0. 4 8 7, 0. 3 9 6, 0. 4 3 7, a n d 0. 3 5 3 n g/ m L, 
res pecti vel y. 
Si xtee n A Es occ urre d i n 7 s u bjects a n d pri maril y i ncl u de d k n o w n pr ostac ycli n class effect-
relate d A Es (e g, hea dac h e, diarr h ea, a n d j a w pai n). 
A c o m pre he nsi v e descri pti o n of oral tre pr osti nil, i ncl u di n g t he p har mac ol o g y, t o xic ol o g y, a n d 
cli nical st u dies c o m plete d t o  date ca n b e f o u n d i n t he c urre nt Ore nitra m I n vesti gat or’s 
Br oc h ure.  
1. 3  
R A TI O N A L E F O R D E V E L O P M E N T O F S T U D Y D R U G I N 
DI S E A S E/ C O N DI TI O N  
Ore n itra m has d e m o nstrate d  cli nical i m pr o ve me nts i n e xercise ca pacit y aft er 1 2 wee ks of 
t hera p y i n s u bjects wit h W H O Gr o u p I p ul m o nar y h y perte nsi o n (Ji n g 2 0 1 3).  It is titrate d b y 
0. 2 5 or 0. 5 m g BI D  or 0. 1 2 5 m g TI D e ver y 3 t o 4 da ys, as t olerate d ( Ore nitra m U nite d States 
Prescri bi n g I nf or m ati o n [ U S PI ], 2 0 1 7).  T h us, t h e ma xi m u m d oses of Ore nitra m t hat ca n be 
reac h e d are a p pr o xi matel y 1 a n d 3 m g TI D at 1 a n d 3 m o nt hs, res pecti vel y, w hic h i n practice 
is rarel y ac hie ve d, ofte n beca use p r osta n oi d si de effects li mit a g gressi ve d ose titrati o n. 
C o m mercial data de m o nstrate t he me dia n T D D of Ore nitra m at 6 m o nt hs is 7. 5 m g 
( Balas u bra ma ni a n 2 0 1 7).  Res ults fr o m Ore nitra m cli nical st u dies s h o w t hat A Es  acc o u nte d 
f or a p pr o xi matel y 5 0 % of all disc o nti n uati o ns of st u d y dr u g (Ji n g 2 0 1 3, Ta ps o n 2 0 1 2, 
Ta ps o n 2 0 1 3).  A nec d otal re p orts fr o m p h ysicia ns a n d n urses s u g gest t hat A Es  lea di n g t o 
dr u g disc o nti n uati o n occ ur earl y after starti n g treat me nt, a n d t hat na usea a n d v o miti n g are t he 
m ost c o m m o n  reas o ns f or dr u g disc o nti n uati o n. 
Res ults fr o m a rece nt cli nical st u d y s u g gest P A H patie nts pre vi o usl y e x p os e d t o Re m o d uli n 
a p pear t o t olerate si g nifica ntl y hi g her d oses of Ore nitra m as c o m pare d t o patie nts wit h o ut 
pri or Re m o d uli n e x p os ure ( C ha ki nala 2 0 1 7 ).  T he mea n T D D of Ore nitra m ac hie ve d i n t he 
pi v otal cli nical st u dies was  a p pr o xi matel y 6 m g at 1 2 t o 1 6 wee ks a n d 8 m g at 1 year, 
c o m pare d wit h 4 0 m g at 2 4 wee ks i n t he Re m o d uli n t o Ore nitra m tra nsiti o n st u d y (Ji n g 2 0 1 3, 
Ta ps o n 2 0 1 2, Ta ps o n 2 0 1 3, Ore nitr a m Pac k a ge I nsert, C ha ki nala 2 0 1 7).  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 0 
A g gressi ve Re m o d uli n titrati o n ca n be w ell-t olerate d as de m o nstrate d i n m ulti ple pr os pecti ve 
st u dies, wit h d oses ra n gi n g fr o m 2 3 t o 1 3 9 n g/ k g/ mi n at 1 2 wee ks ( Sit b o n 2 0 0 7, Ha nse n 
2 0 1 4, Gr ü ni g 2 0 1 6).  T his is a p pr o xi matel y e q ui vale nt t o Ore nitra m 4 t o 2 3 m g TI D ( T D D of 
1 2 t o 7 0 m g) i n a 7 0- k g patie nt ( Ore nitra m U S PI, 2 0 1 7).  I n c o ntrast, c o m mercial data s u g g est 
t he me dia n T D D of Ore nitra m at 3 m o nt hs is 4. 5 m g ( 6. 3 8 m g i n tra nsiti o n patie nts a n d 
4. 1 3 m g i n de n o v o patie nts ta ki n g it TI D) ( B alas u bra ma nia n 2 0 1 7). 
I n st u dies t hat ha v e i n vesti gate d a g gressi ve Re m o d uli n titrati o n, hi g h d oses were ofte n 
ac hie ve d i n a s h ort ti mefr a me.   I n 1 st u d y, patie nts ac hie ve d a mea n d os e of 5 2 n g/ k g/ mi n b y 
Wee k 6 ( Sit b o n 2 0 0 7).  T his is a p pr o xi matel y e q ui vale nt t o a n Ore nitra m T D D of 2 6 m g i n a 
7 0- k g patie nt ( Or e nitra m U S PI, 2 0 1 7).  I n a n ot her st u d y, patie nts ac hie ve d a me dia n d ose of 
1 7. 2 n g/ k g/ mi n b y Wee k 4 ( Gr ü ni g 2 0 1 6).  T his is a p pr o xi matel y e q ui vale nt t o a n Ore nitra m 
T D D of 8. 7 m g i n a 7 0- k g patie nt ( Ore nitra m U S PI, 2 0 1 7).  
Ac hie vi n g hi g h d oses of Ore nitra m is a g oal of ma n y cli nicia ns, as t here is e vi de nce 
s u g gesti n g t hat i ncrease d e x p os ure a n d d urati o n of treat me nt is ass ociate d wit h i m pr o ve d 
treat me nt effect.  P ost- h o c a nal ysis of F RE E D O M - M data s u g gests t hat t he le n gt h of ti me a 
patie nt s pe n ds o n a T D D greater t ha n 8 m g c orrelates t o a hi g her c o m bi ne d 6- Mi n ute W al k 
D ista nce ( 6 M W D) a n d B or g d ys p nea sc ore effect.   I n a d diti o n, f or e ver y 1-m g i ncrease i n 
c u m ulati ve dail y d ose, t here is a p pr o xi mat el y 2 0 % i ncrease d o d ds of ac hi e vi n g a mea ni n gf ul 
res p o nse t o t her a p y, w hic h was defi ne d as a ≥2 3- m eter c ha n g e fr o m B as eli ne i n 6 M W D 
( K u mar 2 0 1 3). 
T here als o a p pears t o be a d ose-r es p o nse relati o ns hi p f or Re m o d uli n.  I n 1 retr os pecti ve 
re vie w, r es ults s u g gest t hat a t hres h ol d d ose ma y b e ass ociate d wit h i m pr o ve d s ur vi val.  I n 
t his re vie w, t he Re m o d uli n d ose was a statisticall y si g nifica nt o n -treat me nt pre dict or of 
s ur vi val.  D oses ≥4 0 n g/ k g/ mi n res ulte d i n si g nifica ntl y i m pr o ve d l o n g-ter m s ur vi val, a n d 
e ver y 1 0- n g/ k g/ mi n i ncre me ntal d ose i ncrease als o si g nifica ntl y i m pr o ve d l o n g-ter m s ur vi val 
( Be nza 2 0 1 1). 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 1 
1. 4  
C LI NI C A L  H Y P O T H E SI S  
T he h y p ot hesis of t his st u d y is t hat tre pr osti nil i n d ucti o n usi n g a s h ort- ter m c o urse of 
Re m o d uli n pri or t o i nitiati n g Ore nitra m will i m pr o ve t olera bilit y a n d all o w s u bjects wit h 
P A H t o ac hie ve hi g her d ail y d oses of Ore nitra m at 1 6 wee k s c o m pare d t o patie nts i nitiati n g 
Ore nitra m  de n o v o.  
2  
O B J E C TI V E S  
2. 1  
P RI M A R Y  O B J E C TI V E  
T he pri mar y o bjecti ve of t he st u d y is t o e val ua te t he d ose of Ore nitra m (tre pr osti nil) E xte n de d 
Release ta blets ac hie ve d at 1 6 wee k s after i n d ucti o n t hera p y wit h Re m o d uli n ( tre pr osti nil) 
I njecti o n i n P A H s u bjects.  
2. 2  
S E C O N D A R Y  O B J E C TI V E S  
T he sec o n d ar y o bjecti ve of t he st u d y is t o assess t he effect of treat me nt wit h Ore nitra m 
(tre pr osti nil) E xte n de d R elease ta bl ets at 1 6 wee ks after i n d ucti o n t hera p y wit h Re m o d uli n 
(tre pr osti nil) I njecti o n o n cli nical res p o nse, s afet y, a n d t olera bilit y. 
2. 3  
E X P L O R A T O R Y  O B J E C TI V E S  
E x pl orat or y o bjecti ves of t his st u d y are e val uati o n of p har mac o ge n o mics ( g e netic/ri b o n ucleic 
aci d [R N A ] testi n g) a n d e val uati o n of bi o mar k ers (s pecific tar gets t o be deter mi ne d) at 
Baseli ne , t he Tra nsiti o n Visit, a n d Wee k 1 6.  
3  
E X P E RI M E N T A L  P L A N  
3. 1  
S T U D Y  D E SI G N  
T he st u d y is a 1 6- wee k, o p e n-la bel, m ultice nter, u nc o ntr olle d st u d y i n s u bjects wit h P A H.  
T he f oll o wi n g st u d y visits will occ ur d uri n g t he 1 6 -wee k st u d y at t he f oll o wi n g ti me p oi nts:  
•  Scree ni n g  
•  Baseli ne  
•  Wee k 2 ( Da y 1 5 [ ± 3 d a ys ]), Wee k 4 ( D a y 2 9 [± 5 da ys]), Wee k 8 ( Da y 5 7 [ ± 5 da ys]), 
Wee k  1 2 ( Da y 8 5 [± 5 d a ys] ), a n d Wee k 1 6/ Earl y St u d y Wit h dra wal ( Da y 1 1 3 
[± 7 da ys]) 
•  Tra nsiti o n Visit ma y occ ur at Wee ks 2, 4 , or 8 if t he s u bject has ac hie ve d a mi ni m u m 
Re m o d uli n d ose of 2 0 n g/ k g/ mi n a n d t he I n vesti gat or dee ms t he s u bject s uit a ble f or 
tra nsiti o n.  Tra nsiti o n ma y be re verse d or st o p p e d if necessar y d ue t o si g nifica nt si g ns 
or s y m pt o ms of P A H or d ue t o seri o us safet y c o n cer ns.  
•  P ost Tra nsiti o n Visit ( 7 t o 1 4 da ys after t he Tra nsiti o n Visit ) 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 2 
3. 2  
 O V E R A L L  S C H E D U L E O F TI M E S A N D E V E N T S  
T a ble 3- 1 
O ver all Sc he d ule of Ti me a n d E ve nts  
St u d y Visit/ Wee k  
Scree ni n g a B aseli ne a, b 
Tre at me nt P h ase  
Wee k 2 s 
Wee k 4
s, v 
Wee k 8
s 
P ost Tr a nsiti o n 
Visit v 
Wee k 1 2  
Wee k  1 6/  
E arl y St u d y 
Wit h dr a w al
c 
D a y  
- 2 8 t o - 1 
- 1 4 t o - 1 
1 5 ( ± 3 d a ys) 
2 9 ( ± 5 d a ys) 5 7 ( ± 5 d a ys)  7 t o 1 4 d a ys after 
Tr a nsiti o n Visit v 8 5 ( ± 5 d a ys) 1 1 3 ( ± 7 d a ys)  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
I ncl usi o n a n d e xcl usi o n criteria 
assess me nt 
X 
X 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
P A H hist or y d 
X  
 
 
 
 
 
 
 
T S Q M e 
 
X  
-------------X s------------- 
 
 
X  
e m P Hasis -1 0 q uesti o n naire e 
 
X  
-------------X s------------- 
 
 
X  
P A H s y m pt o m sc ore  
 
X  
-------------X s------------- 
 
 
X  
W H O F C  
X  
X  
X  
X  
X  
X  
X  
X  
S wa n -Ga nz ri g ht heart 
cat heterizati o n f 
X 
 
 
 
 
 
 
 
Me dical hist or y  
X  
X  
 
 
 
 
 
 
Pri or P A H me dicati o ns g 
X  
X  
 
 
 
 
 
 
C o nc o mita nt me dicati o ns g, h 
X  
X  
X  
X  
X  
X  
X  
X  
P h ysical e xa mi nati o n i 
X  
 
-------------X s------------- 
 
 
X  
Vital si g ns j 
X  
X  
X  
X  
X  
X  
X  
X  
C D 4 c o u nt (f or s u bjects wit h 
h u ma n i m m u n o deficie nc y 
vir us)  
X 
 
 
 
 
 
 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 3 
St u d y Visit/ Wee k  
Scree ni n g a B aseli ne a, b 
Tre at me nt P h ase  
Wee k 2 s 
Wee k 4
s, v 
Wee k 8
s 
P ost Tr a nsiti o n 
Visit v 
Wee k 1 2  
Wee k  1 6/  
E arl y St u d y 
Wit h dr a w al
c 
D a y  
- 2 8 t o - 1 
- 1 4 t o - 1 
1 5 ( ± 3 d a ys) 
2 9 ( ± 5 d a ys) 5 7 ( ± 5 d a ys)  7 t o 1 4 d a ys after 
Tr a nsiti o n Visit v 8 5 ( ± 5 d a ys) 1 1 3 ( ± 7 d a ys)  
Cli nical la b orat or y para meters 
(ser u m c he mistr y a n d 
he mat ol o g y)  
X 
X 
-------------X s------------- 
 
 
X 
Uri ne pre g na nc y test k 
X  
X  
X s 
X  
X  
 
X  
X  
Ec h ocar di o gra m  
 
X  
-------------X s------------- 
 
 
X  
Ser u m N T -pr o B N P l 
X  
X  
-------------X s------------- 
 
 
X  
Bl o o d sa m ple f or 
p har mac o ge n o mics 
( ge netic/ R N A)m  
 
X 
 
 
 
 
 
 
Bl o o d sa m ple f or bi o mar ker 
e val uati o n ( o pti o nal) m  
 
X 
-------------X s------------- 
 
 
X 
6 M W T f oll o we d b y heart -rate 
rec o ver y ( 1 mi n ute) a n d B or g 
d ys p nea sc ore n 
X 
X 
X o, p 
X o, p 
X o, p 
X p 
X p 
X p 
St u d y dr u g  d osi n g q 
 
X r,t 
X r,t 
X r,t 
X r,t 
X r,t 
X r,t 
X r,t 
Rec or di n g of a d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
A E  B ot hers o me S ur ve y  
 
X  
-------------X s------------- 
 
 
X  
Peri o dic patie nt c o ntact u 
 
X  
X  
X  
X  
X  
X  
 
Dr u g acc o u nta bilit y w  
 
 
X  
X  
X  
X  
X  
X  
6 M W D , 6- Mi n ute W al k D ista nce; 6 M W T, 6- Mi n ute W al k T est; E C H O, ec h ocar di o gra m; e C R F , electr o nic case re p ort f or m; F C , Fu ncti o nal C lassificati o n; I V, 
i ntra ve n o us(l y); N T -pr o B N P , N-ter mi nal pr o-brai n  natri uretic pe pti de; P A H , p ul m o nar y arterial h y perte nsi o n; R H C, ri g ht heart cat h eterizati o n; R N A , ri b o n ucleic aci d; 
S C, s u bc uta ne o us(l y); T S Q M, Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n ; W H O , W orl d Healt h Or ga nizati o n  
a Scree ni n g a n d B aseli ne assess me nts ca n be c o n d ucte d u p t o 2 8 a n d 1 4 da ys pri or t o starti n g t he Re m o d uli n i nf usi o n, res pecti vel y. Scree ni n g m ust occ ur pri or t o B aseli ne 
assess me nts t o c o nfir m eli gi bilit y. S u bjects wit h s h ort -ter m m usc ul os keletal c o n diti o ns (e g, s prai ne d a n kle) ca n be re-scree ne d s o t hat assess me nts are n’t i m pacte d b y 
u n us u al or e xte n uati n g circ u msta nces (refer t o Secti o n 7. 1. 1 ). 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 4 
b F oll o wi n g c o m pleti o n of Baseli ne assess me nts, s u bjects will be i nitiate d o n  Re m o d uli n at 2 n g/ k g/ mi n S C or I V i n a n i n patie nt or o ut patie nt setti n g.   I V Re m o d uli n ma y  
be a d mi nistere d t hr o u g h a n i n d welli n g ce ntral ve n o us cat heter  or  a peri p herall y i nserte d cat heter , as cli nicall y i n dicate d .  F or s u bjects recei vi n g I V Re m o d uli n t hr o u g h a 
ce ntral ve n o us cat heter, it is rec o m me n de d t hat t he ce ntral ve n o us cat heter be retai ne d f or at least 2 8  da ys after t he tra nsiti o n fr o m Re m o d uli n.  
c T he assess me nts of Wee k 1 6 / Earl y St u d y Wit h dra wal Visit ca n occ ur o ver 5 da ys s o t hat assess me nts ca n ta ke place o n se parate da ys  if nee de d.  All assess me nts s h o ul d 
be c o n d ucte d pri or t o  wit h dra wi n g fr o m t he st u d y, pri or t o disc o nti n uati o n of Ore nitra m or Re m o d uli n, a n d as cl ose as p ossi ble t o t he last d ose ta k e n b y  t he s u bject. 
d T he s u bject’s P A H dia g n osis date, past ( n o nc urre nt) P A H me dicati o ns, P A H eti ol o g y, a n d W H O F C will be rec or de d.  
e T hese patie nt -re p orte d o utc o mes s h o ul d be c o m plete d b y s u bjects pri or t o ot her assess me nts a n d bef ore i m parti n g ne ws re gar di n g  stat us of t heir disease.  S u bjects s h o ul d 
be all o we d t o c o m plete t he q uesti o n naires at t heir o w n pace , a n d wit h mi ni mal  hel p fr o m ot hers.  
f O pti o nal: R H C d oes n ot nee d t o be c o n d ucte d if t he patie nt has a n R H C wit hi n 1 8 0 da ys of Baseli ne  wit h a car diac i n de x ≥2. 0  L/ mi n/ m 2 wit h n o c ha n ges i n P A H 
me dicati o n re gi me n si nce t he R H C.   If an R H C is perf or me d at Scree ni n g, val ues s h o ul d be o btai ne d f or mea n ri g ht atrial press ure ( m R A P) a n d p ul m o nar y vasc ular 
resista nce ( P V R) t o calc ulate t he Scree ni n g R E V E A L 2. 0 ris k sc ore. 
g T he s u bject’s pri or P A H me dicati o ns a n d c o nc o mita nt me dicati o ns s h o ul d be rec or de d o n t he e C R F.  
h T he I n vesti gat or will rec or d t he s u bject’s c o nc o mita nt me dicati o ns a n d rec or d w het her t he c o nc o mita nt me dicati o n was use d t o treat a n a d verse e ve nt (i ncl u di n g w het her 
pr osta n oi d a d verse e ve nt or n ot).  F or t his st u d y, pr osta n oi d a d verse e ve nts i ncl u de hea dac he, diarr hea, fl us hi n g, na usea, ja w pai n, e xtre mit y pai n, a n d v o miti n g.   
i A f ull p h ysical e xa mi nati o n is a n e val uati o n of ge neral a p peara nce; me ntal e xa mi nati o n; hea d, ear, e yes, n ose, a n d t hr oat e xa mi nati o ns; a n d e xa mi nati o n of der mat ol o gic, 
car di o vasc ular, res pirat or y, gastr oi ntesti nal, m usc ul os keletal, a n d ne ur ol o gic b o d y s yste ms . 
j Vital si g ns i ncl u de bl o o d press ure, heart rate, res pirati o n rate, hei g ht, a n d wei g ht.  Vital si g ns m ust be c ollecte d after 5 mi n utes of rest w hile seate d.  N o ot her 
meas ure me nts or pr oce d ures s h o ul d occ ur d uri n g t he 5 mi n utes  of rest .  Vital si g ns will be c ollecte d pri or t o or at least 3 0 mi n utes after t he 6 M W T.  
k Uri ne pre g na nc y test s will be c o n d ucte d o n all fe male s u bjects of c hil d beari n g p ote ntial.   A ne gati ve uri ne pre g na nc y test is re q uire d of all fe male s u bjects of c hil d beari n g 
p ote ntial t o be eli gi ble f or t he st u d y a n d  re mai n e nr olle d as a s u bject. 
l Bl o o d sa m ples f or N T -pr o B N P m ust be dra w n pri or t o c o n d ucti n g t he 6 M W T a n d will occ ur at t he Scree ni n g Visit, Baseli ne Visit ( pri or t o Re m o d uli n i nitiati o n) , t he 
Tra nsiti o n Visit ( pri or t o Ore nitra m i nitiati o n) , a n d t he Wee k 1 6 / Earl y St u d y Wit h dra wal visit. 
m  W here l ocal re g ulati o ns all o w, t he s u bject’s bl o o d sa m ple will be c ollecte d f or p har mac o ge n o mic ( ge netic/ R N A ) a n d bi o mar ker a nal ys is f or t h ose s u bjects w h o c o nse nt t o 
t he o pti o nal testi n g. 
n T he s u bject s h o ul d rest (seate d) f or 1 0 mi n utes bef ore eac h 6 M W T.   If t he 6 M W T is c o n d ucte d usi n g s u p ple me ntal o x y ge n at Baseli ne, t he n all s u bse q ue nt 6 M W Ts 
d uri n g t he st u d y s h o ul d be c o n d ucte d wit h s u p ple me ntal o x y ge n.  Si milarl y, if t he B aseli ne assess me nt is c o n d ucte d wit h o ut s u p ple me ntal o x y ge n, t he n s u bse q ue nt 
assess me nts s h o ul d als o be c o n d ucte d wit h o ut o x y ge n.  All eff orts s h o ul d be ma de t o kee p t he s u p ple me ntal o x y ge n fl o w rate c o nsiste nt d uri n g t he 6 M W T.  T he 
s u p ple me ntal o x y ge n fl o w rate m ust be rec or de d at e ver y 6 M W T, if a p plica ble.  T he B or g d ys p nea sc ore  a n d  heart  rate rec o ver y ( 1 mi n ute) s h o ul d ta ke place 
i m me diatel y f oll o wi n g t he 6 M W T. 
o At t he Tra nsiti o n Visit, 6 M W T s h o ul d occ ur wit h t he s u bject still o n Re m o d uli n t hera p y , bef ore i nitiati n g t he tra nsiti o n t o Ore nitra m.  
p W he n  t he s u bject is recei vi n g Ore nitra m, t he 6 M W T s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he s u bject’s m ost rece nt d ose. 
q St u d y dr u g refers t o b ot h Re m o d uli n a n d Ore nitra m. 
r If t he I n vesti gat or dee ms a s u bject u ns uita ble f or tra nsiti o n t o Ore nitra m d ue t o si g nifica nt si g ns a n d s y m pt o ms of P A H or a n y ot her seri o us safet y c o ncer ns, t he s u bject 
ma y re mai n o n Re m o d uli n f or t he d urati o n of t he st u d y.  T he I n vesti gat or ma y re verse, or st o p t he tra nsiti o n t o Ore nitra m d ue t o c o ncer ns of s u bject safet y.  
s I n a d diti o n t o t he sc he d ule d assess me nts, a d diti o nal testi n g will be perf or me d at t he Tra nsiti o n Visit as i n dicate d.  S u bjects ma y tra nsiti o n at Wee ks 2, 4 , or 8 if t he y ha ve 
ac hie ve d a mi ni m u m Re m o d uli n d ose of 2 0 n g/ k g/ mi n a n d t he I n vesti gat or dee ms t he s u bject s uita ble f or tra nsiti o n .  Tra nsiti o n ma y be re verse d or st o p pe d f or s u bject 
safet y. 
t S u bjects s h o ul d be o pti mize d o n Re m o d uli n t hera p y pri or t o tra nsiti o n t o Ore nitra m ; a d ose s h o ul d be ac hie ve d t hat i m pr o ves t he s y m pt o ms of P A H w hile mi ni mizi n g 
e xcessi ve p har mac ol o gic effects of Re m o d uli n.  Tra nsiti o n fr o m Re m o d uli n t o Ore nitra m will occ ur o ver t he c o urse of 1 t o 2 1 da ys.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 5 
u T he st u d y site will c o ntact s u bjects dail y d uri n g t he first 2 wee ks of t he st u d y, dail y d uri n g t he tra nsiti o n peri o d (ie, w hile t he s u bject is o n b ot h Re m o d uli n a n d 
Ore nitra m), a n d t wice wee kl y  f or t he first 2 wee ks after tra nsiti o ni n g (ie, w hile t he s u bject is o n Ore nitra m a n d n o l o n ger o n Re m o d uli n).  At all ot her ti me p oi nts d uri n g 
t he st u d y, s u bjects will be c o ntacte d o nce wee kl y. 
v T he P ost Tra nsiti o n Visit occ urs 7 t o 1 4 da ys after tra nsiti o n fr o m Re m o d uli n t o Ore nitra m is i nitiate d.  If t he Tra nsiti on Visit occ urs at Wee k 2, t he Wee k 4 visit ca n be 
s u bstit ute d f or t he P ost Tra nsiti o n Visit (ie, a n e xtra visit is n ot necessar y). 
w   St u d y site or p har mac y pers o n nel s h o ul d assess dr u g ret ur ne d a n d d osi n g i nf or mati o n t o c o nfir m dr u g acc o u nta bilit y.   See Se cti o n 1 1. 5 . 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 6 
3. 3  
C LI NI C A L  A S S E S S M E N T S  
S u bjects will recei ve dr u g i n a n o ut patie nt setti n g , a n d cli nical la b orat or y tests will be 
c ollecte d fr o m s u bjects at t he st u d y sites d uri n g st u d y visits.  Refer t o Ta ble 3- 1  f or t he 
sc he d ules of st u d y assess me nts.  Data will be c ollecte d fr o m t he I n v esti gat or or st u d y site 
staff e nteri n g t he s u bject’s data fr o m t he st u d y visits i nt o a n electr o nic data ca pt ure ( E D C) 
s yste m. 
3. 3. 1  
Effic ac y  
3. 3. 1. 1  
D ose  of St u d y Dr u g  
At all st u d y visits t hat occ ur w hile t he s u bject is o n st u d y dr u g, t he In vesti gat or will rec or d t h e 
d ose of Re m o d uli n a n d/ or Ore nitra m t hat t he p atie nt is ta ki n g.  F or Ore nitra m, all 3 d oses 
ta ke n i n 1 da y s h o ul d be rec or d e d i n di vi d uall y (ie, m or ni n g, mi d da y, a n d e ve ni n g). 
3. 3. 1. 2  
P ul m o n ar y  Arteri al H y perte nsi o n S y m pt o m  Sc ore  
T he In vesti gat or will ass ess t he s u bject’s P A H s y m pt o m sc ore at ti me p oi nts  liste d i n  
Ta ble 3- 1.  P A H s y m pt o ms i ncl u de fati g ue, d ys p nea, l o wer e xtre mit y e d e ma, dizzi ness, 
s y nc o pe, c hest p ai n, a n d ort h o p nea.  S y m pt o ms s h o ul d be sc ore d ( gra d es 0 t o 3) as liste d i n 
Ta ble 3- 2 . 
T a ble 3- 2 
P ul m o n ar y Arteri al H y perte nsi o n S y m pt o ms  
S y m pt o m  
Gr a de  
0 
1 
2 
3 
Fati g ue 
N o fati g ue 
e x perie nce d o utsi de 
of da y- t o-da y li vi n g 
o ver t he past 
4  wee k s 
A vera ge fati g ue o ver 
t he past 4 wee ks 
c o nsi dere d mil d 
A vera ge fati g ue o ver 
t he past 4 wee ks 
c o nsi dere d m o derate 
A vera ge fati g ue o ver 
t he past 4 wee ks 
c o nsi dere d se vere 
D ys p nea 
N o d ys p nea or 
d ys p nea prese nt 
o nl y wit h hea v y 
e xerti o n o ver t he 
past 4  wee ks  
A vera ge d ys p nea o ver 
t he past 4  wee ks 
c o nsi dere d mil d 
A vera ge d ys p nea 
o ver t he past 4 wee ks 
c o nsi dere d m o derate 
A vera ge d ys p nea 
o ver t he past 4 wee ks 
c o nsi dere d se vere 
L o wer 
e xtre mit y 
e de ma 
N o e de ma 
e x perie nce d o ver 
t he past 4 wee ks  
A vera ge e de ma o ver 
t he past 4 wee ks 
c o nsi dere d mil d 
A vera ge e de ma o ver 
t he past 4 wee ks 
c o nsi dere d m o derate 
A vera ge e de ma o ver 
t he past 4 wee ks 
c o nsi dere d se vere 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 7 
S y m pt o m  
Gr a de  
0 
1 
2 
3 
Dizzi ness  
N o dizzi ness 
e x perie nce d o ver 
t he past 4 wee ks  
A vera ge dizzi ness 
o ver t he past 4 wee ks 
c o nsi dere d mil d 
A vera ge dizzi nes s 
o ver t he past 4 wee ks 
c o nsi dere d m o derate 
A vera ge dizzi ness 
o ver t he past 4 wee ks 
c o nsi dere d se vere 
S y nc o pe 
N o s y nc o pe 
e pis o des 
e x perie nce d  o ver 
t he past 4 wee ks  
I nfre q ue nt s y nc o pe 
o ver t he past 4 wee ks 
( 1 e pis o de) 
S o me w hat fre q ue nt 
s y nc o pe e pis o des 
o ver t he past 4 wee ks 
( 2 t o 3  e pis o des) 
Ofte n o ver t he past 
4 wee ks 
( > 4 e pis o des) 
C hest pai n  
N o c hest pai n 
e x perie nce d o ver 
t he past 4 wee ks  
I nfre q ue nt a n d 
a vera ge se verit y  c hest 
pai n o ver t he past 
4 wee ks c o nsi dere d 
mil d  
S o me w hat fre q ue nt 
or a vera ge se verit y 
c hest pai n o ver t he 
past 4  wee ks 
c o nsi dere d m o derate  
Ofte n or  a vera ge 
se verit y o ver t he past 
4 wee ks c o nsi dere d 
se vere 
Ort h o p nea 
N o ort h o p nea 
e x perie nce d o ver 
t he past 4  wee ks  
A vera ge ort h o p nea 
o ver t he past 4 wee ks 
c o nsi dere d mil d 
A vera ge ort h o p nea 
o ver t he past 4 wee ks 
c o nsi dere d m o derate 
A vera ge ort h o p nea 
o ver t he past 4 wee ks 
c o nsi dere d se vere 
 
3. 3. 1. 3  
W H O F u ncti o n al Cl assific ati o n  
W H O F u n cti o nal Classificati o n ( F C ) f or p ul m o nar y h y perte nsi o n (A p p e n di x B ) will be 
assesse d f or s u bj ects at t he ti me p oi nts liste d i n Ta ble 3- 1 . 
3. 3. 1. 4  
6- M i n ute W al k Test 
T he 6 - Mi n ute Wal k T est ( 6 M W T) is t o e val uat e e xercise ca pacit y ass ociat e d wit h carr yi n g 
o ut acti vities of dail y li vi n g.  All 6 M W Ts will be c o n d ucte d b y q ualifie d, trai ne d pers o n nel i n 
a desi g nate d 6 M W T ar ea, w hic h meets t he re q uire me nts descri be d i n A p pe n di x A  ( America n 
T h oracic S oci et y  2 0 0 2, H olla n d 2 0 1 4).  T he s u bj ect s h o ul d rest (seate d) f or at least 
1 0 mi n utes bef ore e v er y 6 M W T.   T he 6 M W T i nstr ucti o ns i n A p pe n di x A a p pl y t o t he 
practice wal k, t he w al ks c o n d ucte d d uri n g t he ti m e p oi nts liste d i n  Ta ble 3- 1, a n d a n y re p eat 
6 M W T c o n d ucte d f or t he st u d y. 
3. 3. 1. 4. 1  
Pr actice 6 -Mi n ute W alk Test  
All s u bjects m ust ha ve a d oc u me nte d 6 M W T c o n d ucte d at t he st u d y site o n t he c o urse f or use 
d uri n g t he st u d y.  If n o pre vi o us 6 M W T has b ee n c o n d ucte d at t he st u d y sit e, a practice 
6 M W T m ust be c o n d ucte d at least 1 da y pri or t o t he Baseli ne 6 M W T f or a p plica b le s u bjects. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 8 
3. 3. 1. 4. 2  
B aseli ne 6 -Mi n ute W alk Test  
T he Baseli ne 6 M W T m ust be c o n d ucte d pri or t o i nitiati o n of st u d y dr u g.  T he Baseli ne 
6 M W T m ust be c o n d ucte d n o s o o ner t ha n 1 da y f oll o wi n g t he practice 6 M W T, f or a p plica ble 
s u bjects. 
T he Baseli ne 6 M W T m ust be c o n d ucte d free of a n y u n us ual or e xte n uati n g circ u msta nces 
(e g, i nterc urre nt ill ness ot her t ha n t hat u n der st u d y, a n kle or k nee s prai ns, u n us ual pai n 
affecti n g t he l o wer li m bs, res pirat or y i nfecti o n, et c).  If t here is a n y u n us u al or e xte n uati n g 
circ u msta nce at Baseli ne, t he visit s h o ul d be p ost p o ne d s o t hat t here is a d e q uate ti me f or t he 
rec o ver y of t he s u bject.  If t he 2 8- da y Scree ni n g wi n d o w is e xcee d e d b y t he s u bject’s 
rec o ver y, t he s u bject ca n be re-s cree ne d at a later ti me w he n t he u n us ual or e xte n uati n g 
circ u msta nce is a de q uat el y res ol ve d , s o as t o n ot i m pact t he res ults of t he Baseli ne 6 M W T. 
N O T E: T he Baseli ne 6 M W T ( n ot t he practice 6 M W T) will be t he criteri o n t o assess t he 
s u bject’s eli gi bilit y t o partici pate i n t he st u d y. 
3. 3. 1. 4. 3  
Tre at me nt 6 -Mi n ute W al k Tests  
6- Mi n ute W al k T ests will be c o n d ucte d at  t he ti me p oi nts liste d i n Ta ble 3- 1 .  At t he 
Tra nsiti o n Visit, t he 6 M W T s h o ul d occ ur wit h t he s u bject still o n Re m o d uli n t hera p y, bef ore 
i nitiati n g t he tra nsiti o n t o Ore nitra m.  At t he ti me p oi nts after t he Tra nsiti o n Visit, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he s u bject’s m ost rece nt d ose of Ore nitra m . 
Pri or t o t he start of e ver y 6 M W T, t he s u bject s h o ul d rest (seate d) f or at least 1 0  mi n utes.   
B or g d ys p nea sc ori n g a n d heart r ate rec o ver y ( 1 mi n ute) s h o ul d ta ke place i m me diatel y 
f oll o wi n g t he 6 M W T. 
If t he 6 M W T is c o n d u cte d usi n g s u p ple me ntal o x y ge n at Baseli ne, t he n all s u bse q ue nt 
6 M W Ts d uri n g t he st u d y s h o ul d be c o n d ucte d wit h s u p ple me ntal o x y ge n.  Si milarl y, if t he 
Baseli ne assess me nt is c o n d ucte d wit h o ut s u p ple me ntal o x y ge n, t he n s u bs e q ue nt assess me nts 
s h o ul d als o be c o n d ucte d wit h o ut o x y ge n.  All eff orts s h o ul d be ma de t o kee p t he 
s u p ple me ntal o x y ge n fl o w rate c o nsiste nt d uri n g t he 6 M W T.  A n y c h a n ges i n o x y ge n t hera p y 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 2 9 
a d mi nistrati o n bet wee n st u d y visits s h o ul d be n ote d i n t he electr o nic case re p ort f or m (e C R F).  
T he s u p ple me ntal o x y ge n fl o w rate m ust be rec or de d at e ver y 6 M W T , if a p plica ble. 
I n a d diti o n, s u bjects recei vi n g p ul m o nar y re ha bilitati o n pri or t o st u d y e ntr y s h o ul d c o nti n ue 
o n t he sa me sc he d ul e u p t o a n d i ncl u di n g Wee k 1 6 .  S u bjects utilizi n g a wal ker or ca ne f or 
sta bilit y m ust als o use a walker or ca n e at e v er y 6 M W T d uri n g t he st u d y. 
3. 3. 1. 5  
B or g D ys p ne a Sc ore 
T he B or g d ys p nea s c ore is a 1 0- p oi nt scale rati n g t he ma xi m u m le vel of d ys p nea a s u bject 
e x perie n ces d uri n g t he 6 M W T ( A p pe n di x A ).  T h e B or g d ys p nea sc ore will be assesse d 
i m me diatel y f oll o wi n g e ver y 6 M W T at ti me p oi nts liste d i n Ta ble 3- 1 . 
3. 3. 1. 6  
P atie nt -re p orte d  Outc o mes  
T he patie nt -r e p orte d o utc o mes s h o ul d be c o m plete d b y t he s u bjects pri or t o ot her assess me nts 
a n d bef or e i m parti n g ne ws re gar di n g t he stat us of t heir disease.  S u bjects s h o ul d be all o we d t o 
c o m plete t he q uesti o n naires at t heir o w n p ace , a n d wit h mi ni mal  hel p fr o m ot hers.   
T he s u bject s h o ul d be i nf or me d of t he p ur p os e a n d i m p orta nce of c o m pleti n g t he 
q uesti o n naires acc or di n g t o t he g ui deli nes f or sta n dar dize d a d mi nistrati o n.  T he q uesti o ns 
s h o ul d be c o m plete d i n a q uiet place wit h o ut i nfl ue nce fr o m ot hers.  Ot hers s h o ul d n ot hel p a 
s u bject a ns wer, i nter pret, or re p hr ase t he q u esti o ns f or t he s u bject u nless a bs ol utel y necessar y . 
Res p o nses t o t he e m P Hasis - 1 0©  ( P H A U K) q uesti o n naire (A p p e n di x H ) a n d t he T S Q M  
(A p pe n di x G ) f or effecti ve ness, si de effects, c o n v e nie nce, a n d gl o bal satisfacti o n will be 
c ollecte d b y st u d y site staff at st u d y visits liste d i n Ta ble 3- 1. 
3. 3. 1. 7  
Ser u m N -Ter mi n al Pr o -br ai n  N atri uretic P e pti de  
Ser u m N- ter mi nal pr o-br ai n  natri uretic pe pti de ( N T-pr o B N P) c o nce ntrati o n is a bi o mar ker 
ass ociate d wit h c h a n ges i n ri g ht heart m or p h ol o g y a n d f u ncti o n ( Fijal k o ws ka 2 0 0 6).  
N T - pr o B N P will be dra w n at ti me p oi nts liste d i n  Ta ble 3- 1.  Sa m ples m ust be dra w n pri or t o 
c o n d ucti n g t he 6 M W T, a n d wil l occ ur at t he Scree ni n g Visit, t he Baseli ne Visit ( pri or t o 
Re m o d uli n i nitiati o n), t he Tra nsiti o n  Visit ( pri or t o Ore nitra m i nitiati o n ), a n d t he Wee k 1 6/ 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 0 
Earl y St u d y Wit h dra wal Visit.  Ser u m N T - pr o B N P will be assesse d b y a ce ntral cli nical 
la b orat or y. 
3. 3. 1. 8  
Ec h oc ar di o gr a ms 
Ec h ocar di o gra m ( E C H O) e xa mi nati o ns as assess e d b y ce ntral rea d er will be c o n d ucte d at t he 
ti me p oi nts liste d i n Ta ble 3- 1 .  Ec h o car di o gra ms will be u pl oa de d a n d st ore d i n a ce ntral 
re p osit or y a n d e v al uate d b y a n i n de pe n de nt ce ntral rea der.  Se veral ec h o car di o gra p hic 
para meters ma y be c ollecte d, i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g: ri g ht atrial area, 
tric us pi d a n n ular plane s yst olic e xc ursi o n, R V strai n, R V/left ve ntric ular rati o at diast ole, 
Ecce ntri cit y I n d e x, strai n i ma gi n g or s pec kle-trac ki n g; R V M y ocar dial Perf or ma nce I n de x or 
Tei i n de x; P ul m o nar y Arter y Accelerati o n Ti me a n d prese nce/ti mi n g of N otc hi n g; a n d car diac 
o ut p ut b y left ve ntric ular o utfl o w tract dia meter a n d ti me -vel ocit y i nte gral of a ortic fl o w  b y 
p ulse- wa ve D o p pler . 
All meas ure me nts will be ma de i n acc or d a nce wit h t he A merica n S oci et y of 
Ec h ocar di o gra p h y g ui deli nes.  See t he E C H O trai ni n g ma n ual f or a d diti o n al i nf or mati o n 
re gar di n g all met h o d ol o gies a n d meas ures.  A ce ntral rea der will be utilize d t o assess t he 
ec h ocar di o gra p hi c data.  Ec h ocar di o gra m i ma ges will be st ore d f or ce ntral rea der access.  
3. 3. 1. 9  
De m o gr a p hics, Me dic al Hist or y, P A H Hist or y, C o nc o mit a nt Me dic ati o ns, 
Pri or P A H Me dic ati o ns , P h ysic al E x a mi n ati o n 
T he s u bject’s de m o gr a p hics ( birt h date, se x, race, a n d et h nicit y), me dical hist or y , P A H 
hist or y ( P A H dia g n osis date, past [ n o nc urre nt] P A H me dicati o ns, P A H eti ol o g y, a n d W H O 
F C) , a n d c o n c o mita nt a n d prior P A H me dicati o ns will be rec or d e d as liste d i n  Ta ble 3- 1. 
T he I n vesti gat or will rec or d t he s u bject’s c o n c o mita nt me dicati o ns at ti me p oi nts liste d i n  
Ta ble 3- 1, a n d rec or d w h et her t he c o n c o mita nt me dicati o n was use d t o treat a n A E , i ncl u di n g 
w het her t he A E was a pr osta n oi d A E .  F or t his st u d y, pr osta n oi d A Es  i ncl u de hea d ac he, 
diarr hea, na usea, fl us hi n g, ja w pai n, e xtre mit y pai n, a n d v o miti n g. 
Si g nifica nt past or prese nt ill nesses, c urre nt prescri pti o n a n d n o n prescri pti o n me dicati o ns 
(i ncl u di n g vita mi ns, her bal pr o d ucts), a n d a hist or y of aller gies or i di os y ncratic res p o ns es t o 
dr u gs s h o ul d be n ote d i n t he e C R F, as re q uire d.  A n y si g nifica nt c ha n ges t o t he s u bject’s 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 1 
me dical c o n diti o n, p h ysical e xa mi nati o n, a n d c o n c o mita nt me dicati o ns m ust be d oc u me nte d 
d uri n g t he st u d y. 
A f ull p h ysical e xa mi nati o n will be c o n d ucte d at S cree ni n g, t he Tra nsiti o n  Visit , a n d t he 
Wee k 1 6/ Earl y Wit h dra wal Visit .  A f ull p h ysical e xa mi nati o n is a n e val u ati o n of ge neral 
a p pear a nce; me ntal e xa mi nati o n; hea d, ear, e yes, n ose, a n d t hr oat e x a mi nati o ns; a n d 
e xa mi nati o n of der m at ol o gic, car di o vas c ular, res pirat or y, gastr oi ntesti nal, m usc ul os keletal, 
a n d ne ur ol o gic b o d y s yst e ms. 
3. 3. 2  
S afet y  
3. 3. 2. 1  
A d verse  E ve nts  a n d t he A E  B ot hers o me S ur ve y  
A d verse e ve nts will be ca pt ure d fr o m  w he n t he s u bject si g ns t he i nf or me d c o nse nt f or m ( I C F) 
u ntil t he s u bject c o m pletes t he st u d y or is wit h dra w n fr o m t he st u d y.  A d verse e ve nts s h o ul d 
be f oll o we d u ntil eit her r es ol uti o n ( or ret ur n t o n or mal or B aseli ne val u es), u ntil t he y are 
j u d ge d b y t he I n vesti gat or t o n o l o n ger be cli nicall y si g nifica nt, or f or at least 4 wee ks  if t he 
A E  e xte n ds be y o n d t he fi nal st u d y visit ( Wee k 1 6).  All seri o us a d vers e e ve nts (S A Es ) t hat 
occ ur d uri n g t he st u d y will be f oll o we d u ntil res ol uti o n, deat h, or t he s u bject is l ost t o 
f oll o w- u p, e ve n if t he y ar e o n g oi n g m ore t ha n 4 w ee ks  aft er c o m pleti o n of t he fi nal st u d y 
visit.  
T he In vesti gat or will a d mi nister t he A E  B ot hers o me S ur ve y (A p pe n di x E ) at ti me p oi nts 
liste d in Ta ble 3- 1  t o c ollect i nf or mati o n a b o ut pr osta n oi d-relate d effects e x perie nce d b y t he 
s u bject. T his q uesti o n naire ma y be us e d t o g ui de A E assess me nt a n d c o n v ersati o ns a b o ut A Es 
t hat a s u bject is e x peri e n ci n g. 
E ve nts relate d t o pr osta n oi d t hera p y ca pt ure d b y t he A E B ot hers o me S ur ve y ( A p pe n di x E ) 
s h o ul d o nl y be rec or d e d as a n A E a n d s h o ul d o nl y be ca pt ure d as a n S A E if t he e ve nt is 
u n us ual wit h res pect t o i nte nsit y, fre q ue nc y, or d urati o n as c o m pare d wit h s y m pt o ms i n t he 
s u bject’s me dical hist or y. 
E ve nts attri b uta ble t o t he pr o gressi o n of t he diseas e u n der st u d y (liste d i n T a ble 9- 1 ) a n d 
e ve nts attri b uta ble t o P A H s y m pt o mat ol o g y ca pt ure d b y P A H S y m pt o m Sc ore ( Secti o n 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 2 
3. 3. 1. 2 ) s h o ul d o nl y be r ec or de d as a n A E if t he e ve nt is u n us ual wit h res pect t o i nte nsit y, 
fre q ue n c y, or d ur ati o n as c o m pare d wit h s y m pt o ms i n t he s u bject’s me dical hist or y, or if t here 
is a reas o na bl e p ossi bilit y t hat t he e ve nt was ca us e d b y t he st u d y dr u g 
3. 3. 2. 2  
Cli nic al L a b or at or y E v al u ati o ns 
A ce ntral cli nical la b orat or y will be use d t o sta n dar dize test res ults.  Cli nical la b orat or y 
assess me nts will be perf or me d  at t he ti me p oi nts liste d i n  Ta ble 3- 1 .  F or s u bjects wit h k n o w n 
h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n, C D 4  c o u nts ma y be meas ure d at Scree ni n g 
b y eit her a l ocal la b orat or y or ce ntr al la b orat or y .  Cl i nical la b orat or y para meters  a n d tests b y 
st u d y visit are dis pla ye d i n A p pe n di x D . 
3. 3. 2. 3  
Uri ne Pre g n a nc y Tests  
Uri ne pre g n a nc y tests will be c o n d ucte d o n all fe male s u bjects of c hil d beari n g p ote ntial.  A 
ne gati ve test is re q uir e d t o be eli gi ble f or t his st u d y a n d t o re mai n e nr oll e d as a s u bject.  
3. 3. 2. 4  
Vit al Si g ns  
Vital si g ns i ncl u de bl o o d press ure, h eart rate, res pirati o n rate, hei g ht, a n d wei g ht .  Vital si g ns 
s h o ul d be c ollecte d after 5 mi n utes of rest w hile seate d.  N o ot her meas ure me nts or 
pr oce d ures s h o ul d occ ur d uri n g t he 5 mi n utes of rest.  Vital si g ns will be c ollecte d pri or t o or 
at least 3 0 mi n utes after t he 6 M W T.  
3. 3. 2. 5  
P eri o dic C o nt act wit h St u d y S u bjects  
T he st u d y site will c o ntact s u bjects dail y d uri n g t he first 2 wee ks of t he st u d y, dail y d uri n g t he 
tra nsiti o n peri o d (ie, w hil e t h e s u bject is o n b ot h Re m o d uli n a n d Ore nitra m), a n d t wice 
wee kl y  f or t h e first 2 wee ks after tra nsiti o ni n g (ie, w hile t he s u bject is o n Ore nitra m a n d n o 
l o n ger o n Re m o d uli n).  At all ot her ti me p oi nts d uri n g t he st u d y, s u bjects will be c o ntacte d 
o nce wee kl y . 
S u bjects ma y be c o ntact e d via e mail i n lie u of a tele p h o ne call.  E mail s h o ul d n ot re place 
direct f oll o w - u p b y tele p h o ne or at t he st u d y site f or cli nicall y mea ni n gf ul S A Es or ot her 
e mer ge nt iss ues.  F or tele p h o ne calls, t he s u bject c o ntact l o g s h o ul d be c o m plete d a n d file d t o 
t he s u bject’s s o urce d oc u me ntati o n. F or e mails, a c o p y of t he e mail m ust b e i ncl u de d i n t he 
s u bject’s s o urce d oc u me ntati o n. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 3 
T he tele p h o ne calls  a n d/ or e mails  after i nitiati o n of st u d y dr u g a n d u p t o Wee k 1 6 are t o be 
ma de bet wee n t h e s u bject a n d st u d y site pers o n nel t o m o nit or st u d y dr u g c o m plia nce, A Es , 
P A H s y m pt o ms, use of c o nc o mita nt me dicati o ns, a n d t o assess d ose titrati o n. 
I n a d diti o n t o t he peri o dic c o ntact me nti o ne d a b o ve perf or me d b y t he st u d y site, t he 
I n v esti gat or ma y r e q uest t hat n ursi n g s u p p ort c o ntact t he s u bject t hr o u g h t h e d urati o n of 
Re m o d uli n t hera p y t o m o nit or st u d y dr u g c o m plia nce, A Es , P A H s y m pt o ms, use of 
c o nc o mita nt me dicati o ns, a n d t o assess d ose titrati o n. 
3. 3. 3  
O t her Testi n g  
3. 3. 3. 1  
P h ar m ac o ge n o mic ( Ge netic/ R N A ) a n d Bi o m ar ker Testi n g  ( O pti o n al) 
W here l o cal r e g ulati o ns all o w, t he s u bject’s bl o o d sa m ple will be c ollecte d f or 
p har mac o g e n o mic ( ge n etic /R N A ) a n d bi o mar ker a nal ysis at t he ti me p oi nts descri be d i n 
Ta ble 3- 1  f or t h ose s u bjects w h o c o nse nt t o t his o pti o nal testi n g.  Ge netic bl o o d sa m ples will 
be st ore d , a n d a nal yses ma y be perf or me d o n ge netic varia nts or g e ne e x pressi o n patter ns 
t h o u g ht t o pla y a r ole i n p ul m o nar y h y perte nsi o n t o e val uate t heir ass ociati o n wit h o bser ve d 
res p o nse t o pr ostac ycli n t hera p y, i ncl u di n g oral tre pr osti nil.  Bi o mar ker bl o o d sa m ples will be 
use d f or meta b ol o mics wit h Meta b ol o n , I n c. ( M orris ville, N C) a n d f or I P/ E P/ D P pa nels. 
3. 3. 3. 2  
He m o d y n a mics  
He m o d y na mics via S wa n - Ga nz ri g ht heart cat heterizati o n ( R H C) will be assesse d d uri n g 
Scree ni n g if t he s u bject has n ot ha d a n R H C wit hi n 1 8 0 da ys of Baseli ne wit h a car diac i n de x 
≥2. 0  L/ mi n/ m 2 wit h n o c ha n ges i n t heir P A H me dicati o n re gi me n (ie, b ot h d osi n g a n d dr u g) 
si nce t he R H C. 
If an R H C is perf or me d at Scree ni n g, val ues s h o ul d be o btai ne d f or m ea n ri g ht atrial press ure 
( m R A P) a n d p ul m o nar y vasc ular r esista nce ( P V R) t o calc ulate t h e Scree ni n g R E V E A L 2. 0 
ris k sc ore. 
3. 4  
N U M B E R  O F  C E N T E R S  
A p pr o xi matel y 1 3 ce nters i n t he U S will partici pate i n t he st u d y.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 4 
3. 5  
N U M B E R  O F S U B J E C T S  
A p pr o xi matel y 3 0 e val ua ble s u bjects will be e nr olle d i n t his st u d y. 
3. 6  
E S TI M A T E D  S T U D Y D U R A TI O N  
T he per -s u bj ect st u d y peri o d is defi ne d as t he date t he s u bject si g ns t he I C F u ntil t he Wee k 1 6 
Visit, t he date t he s u bject wit h dra ws fr o m t he st u d y, t he date a s u bject dies, or t he date a 
s u bject is l ost t o f oll o w- u p, w hic he ver occ urs first.  S u bjects w h o wit h dra w fr o m st u d y dr u g 
pri or t o Wee k 1 6 will be as ke d t o re mai n i n  t he st u d y u p t o Wee k 1 6 a n d c o m plete st u d y 
assess me nts off treat me nt.  
4  
S U B J E C T  E LI GI BI LI T Y  
4. 1  
I N C L U SI O N C RI T E RI A  
S u bjects w h o meet all t he f oll o wi n g i ncl usi o n criteria will be eli gi ble t o partici pate i n t he 
st u d y: 
1.  S u bjects w h o v ol u ntar y gi ve writte n i nf or me d c o nse nt t o partici pate i n st u d y 
2.  Males a n d fe m ale s u bjects a ge d 1 8 t o 7 5 years at Scree ni n g ( date t he s u bject pr o vi des 
writte n i nf or me d c o ns e nt t o partici pate i n st u d y) 
3.  S u bjects wit h a dia g n osis of W H O Gr o u p 1 p ul m o nar y h y pert e nsi o n: s y m pt o matic 
i di o pat hic or herita ble P A H; or P A H ass ociat e d wit h c o n necti ve tiss ue disease, HI V 
i nfecti o n, re p aire d c o n g e nital s yste mic-t o-p ul m o nar y s h u nt (at least 1 y ear si nce re p air 
wit h res pect t o t he dat e of pr o vi di n g i nf or me d c o nse nt), or a p petite s u p pressa nt/t o xi n 
use 
4.  S u bjects wit h W H O F C II or III s y m pt o ms at Baseli ne 
5.  S u bjects wit h 6 M W D > 2 5 0 meters at Baseli ne  
6.  S u bjects w h o are eit her n ot recei vi n g  P A H -tar gete d t hera p y or are c urre ntl y bei n g 
treate d wit h 1 or 2 or al F D A -a p pr o v e d P A H t hera pies c o nsisti n g of a n e n d ot heli n 
rece pt or a nta g o nist ( E R A) a n d/ or eit her a p h os p h o diesterase t y pe- 5 i n hi bit or ( P D E 5-I) 
or a s ol u ble g ua n ylate c y clase  (s G C) sti m ulat or f or ≥4 5 da ys, a n d o n a sta ble d ose f or 
≥3 0 da ys pri or t o t he Bas eli ne Visit  
7.  S u bjects s h o ul d be o n sta ble d oses of ot her me di cal t hera pies f or at least 1 0 da ys pri or 
t o t he Baseli ne V isit, wit h n o d ose a dj ust me nts, a d diti o ns, or disc o nti n uati o ns.  
E xce pti o ns t o t his are disc o nti n uati o n or d ose c ha n ges of a ntic oa g ul a nts a n d/ or 
di uretics.  S u bjects s h o ul d n ot ha ve e x perie n ce d rece nt c h a n ges t o n o n - p h ar mac ol o gic 
i nter ve nti o ns, s uc h as e x ercise, diet pla ns, p ul m o nar y re h a bilitati o n, slee p ap nea 
treat me nt, etc f or at least 1 0 da ys pri or t o Baseli ne Visit. 
8.  S u bjects wit h hist orical R H C wit h res ults c o nsiste nt wit h W H O  Gr o u p 1 P A H, as 
de m o nstrate d b y p ul m o nar y art er y press ure mea n  of ≥2 5 m m H g, a p ul m o nar y art er y 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 5 
we d ge pr ess ure ( P A W P) or left ve ntric ular e n d -di ast olic press ure ≤1 5 m m H g if a 
P A W P meas ure me nt is n ot a vaila ble, a n d a P V R > 3 W o o d u nits, i n t he a bse nce of 
u nre pair e d c o n ge nital h eart disease ( ot her t ha n p ate nt f ora me n o v ale)  
9.  S u bject has u n der g o ne a n R H C  wit hi n 1 8 0 da ys of Baseli ne  a n d ha d a car diac i n de x 
≥2. 0  L/ mi n/ m 2 wit h n o c ha n ges i n t heir P A H me dicati o n re gi me n (ie, b ot h d osi n g a n d 
dr u g) si nce t he R H C. 
1 0.  S u bjects i n w h o m t heir m ost rece nt hist orical ec h ocar di o gra p h y de m o nstrates 
cli nicall y n or mal left s yst olic a n d diast olic ve ntric ular f u ncti o n a n d a bse nce of a n y 
cli nicall y si g nifica nt left -si de d heart diseas e.  Su bjects wit h cli nicall y i nsi g nifica nt left 
ve ntric ular diast olic d ysf u ncti o n d ue t o t he effects of R V o verl oa d ( R V h y p ertr o p h y 
a n d/ or R V dilati o n) are eli gi ble . 
1 1.  S u bjects w h o a gree t o f oll o w t he s pecifie d preca uti o ns t o a v oi d pre g na nc y as f oll o ws: 
•  S u bjects  w h o are fe males of c hil d beari n g p ote ntial i ncl u de a n y fe m ale s u bject w h o 
has e x peri e nce d  m e nar c h e a n d w h o has n ot u n d er g o ne s uccessf ul s ur gical 
sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y) or is 
n ot p ost me n o pa usal ( defi ne d as a me n orr hea f or at least 1 2 c o nsec uti ve m o nt hs).  
F or f e male s u bjects of c hil d beari n g p ote ntial, a ne gati ve uri ne pre g na nc y t est is 
re q uire d at Scree ni n g a n d Baseli ne pri or t o i nitiati n g st u d y dr u g.  Fe male s u bjects 
of c hil d beari n g p ote ntial m ust f oll o w 1 of t he f oll o wi n g a p pr oac hes: 
•  P ractice actual a bsti ne nce fr o m i nterc o urse 
•  H a ve a p art ner wit h a vas ect o m y  
•  Ha ve a n i ntr a uteri ne d e vi ce  
•  M ust use 2 differe nt f or ms of hi g hl y effecti ve c o ntrace pti o n f or t h e d urati o n of 
t he st u d y, a n d f or at least 4 8 h o urs after dis c o nti n ui n g st u d y dr u g.  Me dicall y 
acce pta ble f or ms of effecti ve c o ntrace pti o n i ncl u de a p pr o ve d h or m o nal 
c o ntrace pti ves (s uc h as birt h c o ntr ol pills) or barri er met h o ds (s uc h as a 
c o n d o m or dia p hra g m). 
•  Male s u bjects wit h a part ner of c hil d beari n g p ote ntial m ust use a c o n d o m d uri n g 
i nterc o urse f or t he d ur ati o n of t he st u d y, a n d f or 4 8 h o urs after dis c o nti n ui n g st u d y 
dr u g. 
1 2.  H u ma n i m m u n o deficie nc y vir us- p ositi ve s u bjects m ust ha ve a C D 4 l y m p h oc yte c o u nt 
of at least 2 0 0 cells/ m m 3 wit hi n 3 0 da ys of Scree ni n g a n d be recei vi n g c urre nt 
sta n dar d of car e a nti-r etr o viral or ot her effecti ve me dicati o n f or t he treat m e nt of HI V, 
wit h n o c ha n ges f or at least 8 wee ks pri or t o e nr oll me nt. 
1 3.  S u bjects w h o, i n t he o pi ni o n of t he I n vesti gat or, are ca p a ble of c o m m u nicati n g 
effecti vel y wit h st u d y pers o n nel a n d are c o nsi dere d re lia ble, willi n g, a n d li kel y t o be 
c o o perati ve wit h pr ot oc ol re q uire me nts a n d atte n d all re q uire d st u d y visits  
1 4.  S u bjects w h o ha ve t he ca pa bilit y t o a ns wer s ur ve ys a n d q uesti o n naires writte n i n 
E n glis h 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 6 
4. 2  
E X C L U SI O N  C RI T E RI A  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e xcl u de d fr o m p artici pati o n i n t he 
st u d y: 
1.  Fe male s u bjects w h o ar e p re g na nt, lact ati n g, or pla n ni n g t o bec o me pre g na nt d uri n g 
t he st u d y 
2.  S u bjects wit h a c urre nt di a g n osis of u nc o ntr olle d slee p a p nea, as defi ne d b y t heir 
p h ysicia n 
3.  S u bjects wit h re nal i ns ufficie nc y , as d efi ne d b y re q uiri n g dial ysis or a n esti mate d 
creati ni ne clear a nce of < 3 0 m L / mi n, as calc ulate d b y t he C oc kcr oft - Ga ult e q uati o n 
(see A p p e n di x F ) 
4.  S u bjects wit h li ver d ysf u ncti o n defi ne d as ele vate d li ver f u ncti o n tests (ala ni ne 
a mi n otra nsfer ase or as partate a mi n otra nsferas e) ≥3 ti mes t he u p per li mit of n or mal at 
Sc ree ni n g, or s u bjects wit h C hil d- P u g h Class B or C he patic disease (see A p pe n di x F) 
5.  S u bjects wit h a ne mia , as defi ne d b y Scree ni n g he m o gl o bi n < 9 g/ d L 
6.  S u bjects wit h a n acti ve i nfecti o n or c o n diti o n t hat w o ul d i nterfere wit h i nter pretati o n 
of st u d y assess me nts 
7.  S u bjects wit h a hist or y of isc he mic heart disease ( defi ne d as s u bjects w h o re q uire a nti-
a n gi nal t hera p y wit hi n 6 m o nt hs of Scree ni n g or w h o ha ve e x p erie n ce d a d oc u me nte d 
m y ocar dial i nfarcti o n wit hi n 6 m o nt hs of Scree ni n g), or a hist or y of left-si de d 
m y ocar dial d ysf u ncti o n, as e vi de nce d b y a P A W P > 1 5  m m H g or left ve ntri c ular 
ejecti o n fr acti o n < 5 0 %  
8.  S u bjects wit h u nc o ntr olle d s yste mic h y perte nsi o n, as e vi de nce d b y s yst olic bl o o d 
press ure > 1 6 0 m m H g or diast olic bl o o d press ure > 1 0 0 m m H g at Baseli ne 
9.  S u bjects wit h se vere h y p ote nsi o n, as e vi de nce d b y s yst olic bl o o d press ure < 9 0 m m H g 
or diast olic bl o o d press ur e < 5 0 m m H g at Baseli ne 
1 0.  If a l u n g assess me nt h as bee n c o m plete d as per st a n dar d of care, a n y s u bject wit h 1 or 
m ore of t he f oll o wi n g si g ns of d oc u me nte d rele va nt l u n g disease wit hi n 1 8 0 da ys of 
Baseli ne: t otal l u n g ca pacit y < 6 0 % of pre dicte d, or f orce d e x pirat or y v ol u me i n 
1 sec o n d < 5 5 % of predi cte d n or mal 
1 1.  S u bjects wit h c hr o nic m usc ul os keletal dis or der or a n y ot her diseas e t hat w o ul d li mit 
a m b ulati o n, or w h o ar e c o n necte d t o a mac hi ne t h at is n ot p orta ble 
1 2.  S u bjects wit h a hist or y of alc o h ol a b use or illicit dr u g a b use wit hi n 1 2 m o nt hs of 
Baseli n e w hic h, i n t he I n vesti gat or’s o pi ni o n, w o ul d ma ke t he s u bject i na p pr o priate 
f or e nr oll me nt i n a cli nical st u d y 
1 3.  S u bjects wit h a n y ot her c o nc o mita nt disease wit h life e x pecta nc y of < 1 2 m o nt hs fr o m 
Baseli ne  
1 4.  S u bjects wit h a n u nsta ble ps yc hiatric c o n diti o n or t h ose n ot ca pa ble of u n dersta n di n g 
t he o bjecti ves, nat ur e, or c o nse q ue nces of t he st u d y, or w h o ha ve a n y c o n diti o n w hic h, 
i n t he I n v esti gat or’s o pi ni o n, w o ul d c o nstit ute a n u nacce pta ble ris k t o t he s u bject’s 
safet y 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 7 
1 5.  S u bjects w h o are c urr e ntl y recei vi n g a n i n v esti gati o nal dr u g, ha ve a n i n vesti gati o nal 
de vice i n place, or w h o h a ve partici p ate d i n a n i n v esti gati o nal dr u g or de vice st u d y 
wit hi n 1 8 0 da ys pri or t o Baseli ne.  Partici pati o n i n a n o bser vati o nal st u d y wit hi n 
1 8 0 da ys pri or t o Baseli ne d oes n ot dis q ualif y a s u bject fr o m e nr olli n g. 
1 6.  S u bjects w h o ha ve r ecei v e d a pr ostac ycli n -class t h era p y wit hi n 2 8 da ys of Baseli ne. 
1 7.  S u bjects w h o ha ve a Re gistr y t o E val uate Earl y a n d L o n g- Ter m P A H Disease 
Ma na ge me nt ( R E V E A L ) 2. 0 Ris k Sc ore of 1 0 or greater (see  A p pe n di x J ). 
4. 3  
P R E S C RI B E D  T H E R A P Y  
4. 3. 1  
C o nc o mit a nt Me dic ati o ns  
S u bjects are eli gi ble f or t his st u d y if t he y are  eit her n ot recei vi n g P A H -tar g ete d t hera p y or are 
c urre ntl y bei n g tr eate d wit h 1 or 2 F D A -a p pr o ve d oral P A H t hera pi es c o nsisti n g of a n E R A 
a n d/ or eit her a P D E 5 -I or a n s G C f or ≥4 5 da ys.  T he y m ust be recei vi n g a sta ble d ose f or 
≥3 0 da ys pri or t o t he Bas eli ne Visit.  If an F D A -a p pr o ve d treat me nt f or P A H ( ot her t ha n 
st u d y dr u g or a pr osta n oi d use d i n vas oreacti vit y testi n g) is a d de d d uri n g t h e st u d y, t he 
s u bject m ust be wit h dra w n fr o m t he st u d y.  
S u bjects s h o ul d be o n sta ble d oses of ot her me di cal t hera pies f or at least 1 0 da ys pri or t o 
Baseli ne Visit wit h n o d ose a dj ust me nts, a d diti o ns, or disc o nti n uati o ns.  E xce pti o ns t o t his are 
disc o nti n uati o n or d ose c ha n ges of a ntic o a g ula nts a n d/ or di uretics.  Me dicati o ns are als o 
all o we d t o be te m p oraril y disc o nti n ue d if necess ar y  f or t he safet y of st u d y-relate d me dical 
pr oce d ures, s uc h as R H C  d uri n g Scree ni n g.  S u bjects s h o ul d n ot ha ve e x perie nce d rece nt 
c ha n ges t o n o n- p h ar mac ol o gic i nter ve nti o ns, s uc h as e xercise, diet pla ns, p ul m o nar y 
re ha bilitati o n, slee p a p nea treat me nt, et c, f or at least 1 0 da ys pri or t o Baseli ne. 
A n y c o nc o mita nt me dicati o ns ta ke n b y t he s u bject d uri n g t he st u d y s h o ul d be rec or de d i n t he 
s u bject’s s o urce d oc u me nts a n d tra nscri be d t o t he s u bject’s e C R F. 
4. 3. 2  
Ot her Tre at m e nts  
D uri n g t he st u d y, a dj ust me nts, a d diti o ns, or disc o nti n uati o ns of n o n- p har mac ol o gic 
i nter ve nti o ns, s uc h as e x ercise, diet pla ns, p ul m o nar y re h a bilitati o n, slee p a p nea treat me nt, 
me dicati o ns a p pr o ve d f or P A H, etc, s h o ul d n ot occ ur.  A dj ust me nts, a d diti o ns, or 
disc o nti n uati o ns of ot her c o nc o mita nt me dicati o ns f or ot her n o n- P A H dis eases ca n occ ur.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 8 
5  
S U B J E C T  E N R O L L M E N T  
A n y s u bject w h o meets t he i ncl usi o n a n d e xcl usi o n criteria will be eli gi ble t o e nr oll i n t his 
st u d y.  As t his is a n u nc o ntr olle d st u d y, meas ures t o mi ni mize bias a n d pr oce d ures relati n g t o 
ra n d o mizati o n ar e n ot a p plica ble.  
5. 1  
T R E A T M E N T  A S SI G N M E N T  
D uri n g t he st u d y, s u bjects will be recei vi n g  Ore nitra m a n d Re m o d uli n s u p plie d b y t he 
S p o ns or.  S u bjects w h o ha ve c o m plete d t he Wee k 1 6 Visit will be tra nsiti o ne d off cli nical 
st u d y material o nt o c o m m erciall y a vaila bl e Ore nitra m or Re m o d uli n, as cli nicall y 
a p pr o priate. 
5. 2  
R A N D O MI Z A TI O N  
T his st u d y d oes n ot e m pl o y ra n d o mizati o n. 
5. 3  
B LI N DI N G  
T his is a n o pe n-la bel st u d y. 
6  
D R U G S  A N D D O SI N G ( O R T R E A T M E N T P R O C E D U R E S)  
6. 1  
D R U G D O S A G E, A D MI NI S T R A TI O N A N D S C H E D U L E  
Re m o d uli n will be pr o vi de d i n vial stre n gt hs of 1 m g/ m L, 2. 5 m g/ m L, 5 m g/ m L, a n d 
1 0 m g/ m L.  F oll o wi n g c o m pleti o n of Baseli ne assess me nts, Re m o d uli n will be i nitiate d at 
2 n g/ k g/ mi n S C or I V i n a n i n patie nt or o ut patie nt setti n g.  I V Re m o d uli n ma y be 
a d mi nistere d t hr o u g h a n i n d welli n g ce ntral ve n o us cat heter or a  peri p herall y i nserte d cat h eter , 
as cli nicall y i n dicate d .  At t he re q uest of t he I n vesti gat or, n ursi n g s u p p ort will assist s u bjects 
wit h i nitiati o n of S C or I V Re m o d uli n, p u m p use, Re m o d uli n di s pe nsi n g, Re m o d uli n titrati o n, 
a n d a d vers e e v e nt ma na g e me nt.  If necessar y, s u bjects ca n s witc h fr o m I V t o S C Re m o d uli n, 
or S C t o I V Re m o d uli n, at t he discreti o n of t he I n vesti gat or. 
U p -titrati o n of Re m o d uli n will c o nti n ue as t olerat e d .  S u bjects s h o ul d be o pti mize d o n 
Re m o d uli n t hera p y pri or t o tra nsiti o n t o Ore nitra m; a d ose s h o ul d be ac hi e v e d t hat i m pr o ves 
t he s y m pt o ms of P A H w hile mi ni mizi n g e xcessi ve p har mac ol o gic effects of Re m o d uli n.  
T here is n o ma xi m u m Re m o d uli n d ose d uri n g t he st u d y. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 3 9 
S u bjects ma y tra nsiti o n at Wee ks 2, 4, or 8 if t he y ha ve ac hie ve d a mi ni m u m Re m o d uli n d ose 
of 2 0 n g/ k g/ mi n a n d t he I n vesti gat or dee ms t he s u bject s uita ble f or tra nsiti o n. S u bjects will 
tra nsiti o n fr o m Re mo d uli n t o Orenitra m  o ver t h e c o urse of 1 t o 2 1 da ys i n a n i n patie nt or 
o ut patie nt setti n g usi n g a cr oss-ta per met h o d (ie, d ecreases i n Re m o d uli n d ose c oi nci de wit h 
i ncreas es i n Ore nitra m d ose).  Or e nitra m will be pr o vi de d i n t he e xte n de d-release ta blet 
stre n gt hs of 0. 1 2 5 m g, 0. 2 5 m g, 1 m g, 2. 5 m g, a n d 5 m g.  S u bjects will be i nstr ucte d t o ta ke 
t he a p pr o priat e n u m ber of 0. 1 2 5 m g, 0. 2 5 m g, 1 m g, 2. 5 m g, a n d 5 m g ta blets base d u p o n 
t heir Re m o d uli n d ose a n d t he tra nsiti o n sc he d ule c h ose n b y t heir healt hcare pr o vi der. 
Tra nsiti o n ma y be re v ers e d or st o p pe d if t he I n v esti gat or feels it is necess ar y d ue t o 
si g nifica nt si g ns or s y m pt o ms of P A H or d ue t o seri o us safet y c o n cer ns .  If t he I n v esti gat or 
dee ms a s u bject u ns uita ble f or tra nsiti o n t o Ore nitra m d ue t o si g nifica nt si g ns or s y m pt o ms of 
P A H or a n y ot her s eri o us safet y c o n cer ns, t he s u bj ect ma y re m ai n o n Re m o d uli n f or t he 
d urati o n of t he st u d y.  H o we ver, t he s u bj ect s h o ul d be c o nti n uall y assesse d t o deter mi ne if 
t he y bec o me sta ble e n o u g h f or tra nsiti o n t o Ore nitra m.  All  s u bjects still o n Re m o d uli n at 
Wee k 8 s h o ul d tra nsiti o n t o Ore nitra m re g ar dless of t heir Re m o d uli n d ose u nless t he 
I n v esti gat or dee ms t he m u ns uita ble f or tra nsiti o n t o Ore nitra m d ue t o si g nifica nt si g ns a n d 
s y m pt o ms of P A H or a n y ot her seri o us safet y c o ncer ns. 
F oll o wi n g c o m pleti o n of tra nsiti o n, Ore nitra m d os e titrati o n will c o nti n ue i n t he o ut patie nt 
setti n g t hr o u g h Wee k 1 6 t o reac h t he m a xi m u m t olerate d d ose b y i n creasi n g t he d ose b y 
0. 1 2 5 m g TI D e ver y 3 t o 4 da ys as t olerate d, wit h t he g oal of ac hie vi n g a m a xi m u m t olerate d 
d ose b y t he e n d of Wee k 1 6.  A sl o wer titrati o n rat e ma y be use d if t h e s u bject e x perie nces 
a d verse eff ects.   T here is n o ma xi m u m Ore nitra m d ose d uri n g t he st u d y. 
Ore nitra m will be d ose d TI D  wit h f o o d.  D osi n g will ta ke place a p pr o xi matel y e ver y 6 t o 
8 h o urs, wit h a dj ust me nts per mitte d base d o n t he s u bject’s lifest yle a n d sc he d ule.  St u d y 
s u bjects s h o ul d ta ke t heir st u d y dr u g at a p pr o xi matel y the sa me ti me s eac h da y.  Ta blets m ust 
be s wall o we d w h ol e a n d n ot c he we d, as t his will res ult i n i na p pr o priate deli ver y of t he acti ve 
i n gre die nt.  If t he ta bl et is i na d verte ntl y da ma g e d d uri n g a d mi nistrati o n, t he s u bject/care gi ver 
s h o ul d c o ntact site pers o n nel t o be m o nit ore d f or t he o nset of s y m pt o ms d ue t o p ossible 
i na p pr o priate dr u g releas e.  S u bjects m ust n ot “ ma ke- u p” or “ d o u ble- u p ” o n misse d d oses of 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 0 
Ore nitra m.   If d osi n g is i nterr u pte d f or l o n ger t ha n 2 4 h o urs, c o nsi derati o n s h o ul d be gi ve n t o 
gra d uall y re-titrati n g t he s u bject’s d ose t o t he last d ose a d mi nistere d pri or t o t he d ose 
i nterr u pti o n, partic ularl y i n cases w here t he last d ose pri or t o i nterr u pti o n w as great er t ha n 
3 m g. 
I n t he e ve nt of a pla n ne d s h ort-ter m treat me nt i nterr u pti o n f or s u bjects u na ble t o ta ke oral 
me dicati o ns after b e gi n ni n g tra nsiti o n t o Ore nitra m, c o nsi der a te m p orar y i nf usi o n of S C or 
I V Re m o d uli n usi n g t he f oll o wi n g e q uati o n t o calc ulate t he d ose of Re m o d uli n: 
Re m o d uli n ( n g/ k g/ mi n) = ( 1 3 9 ×  Ore nitra m T D D [ m g]) ÷ wei g ht ( k g) 
S u bjects w h o c o m plete t he Wee k 1 6 Visit will be tra nsiti o ne d off cli nical st u d y material t o 
c o m merciall y a v aila ble Ore nitra m or Re m o d uli n, as cli nicall y a p pr o pri ate , t hr o u g h t heir 
healt h a n d/ or pr escri pti o n i ns ura nce.  F or s u bjects w h o are u ni ns ure d or u n deri ns ure d, t he 
st u d y site ca n hel p t he m a p pl y f or t he U nite d T h era pe utics Patie nt Assista nce Pr o gra m ( P A P). 
T hr o u g h t he P A P, s u bjects ca n recei ve a s u p pl y of Ore nitra m or Re m o d uli n free of c har ge f or 
a peri o d of 1 y ear if eli gi ble. After 1 y ear, s u bjects ma y a p pl y f or a re ne wal of P A P assista nce 
o n a n a n n ual basis. S u bjects’ eli gi bilit y t o partici pate i n t his pr o gra m is bas e d o n fi na ncial 
i na bilit y t o pa y f or t he dr u g, lac k of i ns ura n ce c o v era ge, a n d ot her criteria w hic h s u bjects can 
disc uss wit h t heir st u d y site . 
6. 2  
A C C E S S  T O B LI N D E D T R E A T M E N T A S SI G N M E N T  
T his st u d y is a n o pe n-la bel st u d y. 
6. 3  
C O M P LI A N C E  
It is a ntici pate d t hat s u bjects will f oll o w d osi n g a n d titrati o n re gi me ns c o nsiste nt wit h t he 
st u d y dr u g d osi n g i nstr ucti o ns of t he st u d y.  R o uti ne c o ntact b et wee n st u d y site pers o n nel a n d 
t he s u bject s h o ul d be c o n d ucte d t o m o nit or A Es  bet wee n s c h e d ule d st u d y visits.  St u d y site 
pers o n nel will rec or d st u d y dr u g d ose at e v er y st u d y visit i n t he s o urce d oc u me ntati o n. 
T he I n vesti gat or , ot her st u d y site pers o n nel, or n ursi n g s u p p ort u n der t he directi o n of t he 
I n v esti gat or, will be res p o nsi ble f or d ose titrati o n of st u d y dr u g.  D uri n g tel e p h o ne calls, st u d y 
site pers o n nel a n d/ or n ursi n g s u p p ort, wit h o versi g ht of t he I n vesti gat or, will e val uate a n d 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 1 
a dj ust t he c urrent d os e of st u d y dr u g a n d assess w het her t he s u bject is ta ki n g t he st u d y dr u g as 
prescri be d.  
Arra n g e me nts will be ma de t o e ns ure t he s u bject h as a de q uat e dr u g s u p pl y w it h res pect t o 
t heir st u d y visit sc he d ule.  A d diti o nal Re m o d uli n a n d/ or Ore nitra m s u p pl y ma y occ ur b et wee n 
pr ot oc ol st u d y visits if nee de d.  S u bjects s h o ul d be i nstr ucte d t o ret ur n all use d a n d u n use d 
Re m o d uli n a n d Ore nitra m , i ncl u di n g e m pt y vials/ b ottles, t o t he a p pr o priate st u d y pers o n nel 
o n a n o n g oi n g basis at e v er y st u d y visit. 
U p o n ret ur n of st u d y dr u g, st u d y pers o n nel or a p har macist m ust d oc u me nt t he n u m ber of 
ret ur ne d ta bl ets of eac h stre n gt h or vials of eac h stre n gt h o n t he s u bject’s st u d y dr u g 
acc o u nta bilit y l o g.  Use d a n d u n use d vials a n d b ottles of st u d y dr u g s h o ul d be retai ne d b y t h e 
st u d y site or p har mac y  a n d ret ur ne d t o a S p o ns or-desi g nate d l ocati o n f or d estr ucti o n , or 
destr o ye d a n d d o c u me nte d acc or di n g t o i nstit uti o nal p olic y f oll o wi n g c o ns ultati o n wit h t he 
S p o ns or after fi n al dr u g acc o u nta bilit y b y S p o ns or pers o n nel. 
E ver y s u bject will be as k e d at t he st u d y visits w het her he/s he has b ee n a d h ere nt  wit h d osi n g 
i nstr ucti o ns.  If a s u bject is n ot a d here nt , t he n st u d y site pers o n nel m ust re-e d ucate t h e s u bject 
o n pr o per d osi n g a n d its i m p orta nce.  C o nti n ue d n o na d here n ce  c o ul d lea d t o wit h dra wal of 
t he s u bject fr o m t he st u d y base d o n disc ussi o ns bet wee n t he I n vesti gat or a n d S p o ns or. 
7  
E X P E RI M E N T A L  P R O C E D U R E S  
T he f oll o wi n g st u d y visits will occ ur d uri n g t he 1 6 - wee k st u d y at t he f oll o wi n g ti me p oi nts: 
Scree ni n g, Baseli ne, Wee k 2 ( Da y 1 5 [ ± 3 da ys] ), Wee k 4 (Da y 2 9 [ ± 5 d a ys ]), Wee k 8 
(Da y  5 7 [± 5 d a ys] ), P ost Tra nsiti o n Visit ( 7 t o 1 4 da ys after Tra nsiti o n Visit ), Wee k  1 2 
(Da y  8 5 [± 5 d a ys ]), a n d Wee k 1 6/ Earl y St u d y Wit h dra wal ( D a y 1 1 3 [ ± 7 d a ys] ).  T he 
Tra nsiti o n Visit s h o ul d occ ur at Wee ks 2, 4, or 8.  
Writte n i nf or me d c o ns e nt m ust be o btai ne d fr o m all s u bjects (si g ne d a n d d ate d b y s u bject) 
pri or t o st u d y pr oce d ur es.  T he patie nt -re p orte d o utc o mes (ie, T S Q M  a n d t h e e m P Hasis - 1 0 
q uesti o n naire) s h o ul d be c o m plete d b y t he s u bjects pri or t o ot her assess me nts liste d i n  
Ta ble 3- 1 .  S u bject i nf or mati o n fr o m assess me nts liste d i n Ta ble 3- 1, i ncl u di n g t he 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 2 
p atie nt-re p ort e d o utc o mes, will be c ollecte d a n d rec or de d i nt o a n E D C s yste m b y st u d y site 
pers o n nel or t he I n vesti gat or. 
7. 1  
S C R E E NI N G  ( D A Y S - 2 8 T O - 1) 
At Scree ni n g, after a n I n vesti gat or re vie ws t h e s u bject’s I C F a n d o btai ns t he s u bject’s si g ne d 
a n d date d writte n I C F, t h e I n vesti gat or will re vi e w a n d verif y t h e s u bject’s i ncl usi o n criteria 
a n d e xcl usi o n criteria, a n d assi g n e ver y eli gi ble s u bject a u ni q ue s u bject i de ntificati o n.  If a 
s u bject wit h dra ws fr o m partici pati o n i n t he st u d y, t he n his/ her s u bject i de ntificati o n ca n n ot be 
re use d.  S u bjects w h o f ail t o meet t he eli gi bilit y criteria s h o ul d n ot, u n der a n y circ u msta nces, 
be e nr olle d.  
All s u bjects will be assesse d f or eli gi bilit y d uri n g t he 2 8 - da y Scree ni n g wi n d o w.  T he 
f oll o wi n g I n v esti gat or-r e p orte d assess me nts will be c o n d ucte d after t he s u bject si g ns t he I C F:  
•  W H O F C assess me nt  
•  Ser u m N T - pr o B N P (sa m ple m ust be dra w n pri or t o t he 6 M W T i nitiati o n) 
•  6 M W T (aft er 1 0 mi n utes rest [seat e d]) , i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore 
•  C li nical la b orat or y assess me nts 
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes of rest 
seate d) 
•  F ull p h ysical e xa mi nati o n  
•  C o nc o mita nt me dicati o ns  
•  C D 4 c o u nt f or s u bjects wit h HI V i nfecti o n 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est. 
•  S u bject A Es  will be rec or de d c o nti n u o usl y fr o m w he n t he s u bject si g ns t he I C F u ntil 
t he s u bject c o m pletes t he st u d y or is wit h dra w n fr o m t he st u d y. 
•  T he s u bject’s me dical hist or y, P A H hist or y, pri or P A H  me dicati o ns, a n d 
de m o gra p hics will be r ec or de d.  
•  Car diac i n de x meas ure d b y S wa n -Ga n z R H C  will  be assesse d d uri n g Scree ni n g if t he 
s u bject has n ot ha d a n R H C wit hi n 1 8 0 da ys of Baseli ne  wit h a car diac i n d e x 
≥2. 0  L/ mi n/ m 2 wit h n o c ha n ges i n P A H me dicati o n re gi me n si nce t he R H C  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 3 
7. 1. 1  
Re -scree ni n g of S u bjects 
S u bjects wit h s h ort-ter m m usc ul os keletal c o n diti o ns (e g, s prai ne d a n kle) ca n be re- s cree ne d.  
T he Baseli ne 6 M W T m ust be c o n d ucte d free of a n y u n us ual or e xte n uati n g circ u msta nces 
(e g, i nterc urre nt ill ness ot her t ha n t hat u n der st u d y, a n kle or k nee s prai ns, u n us ual pai n 
affecti n g t he l o wer li m bs, res pirat or y i nfecti o n, et c ).  If t here is a n y u n us u al or e xte n uati n g 
circ u msta nce at Baseli ne, t he visit s h o ul d be p ost p o ne d s o t hat t here is a d e q uate ti me f or t he 
rec o ver y of t he s u bject.  If t he 2 8- da y Scree ni n g wi n d o w is e xcee d e d b y t he s u bject’s 
rec o ver y, t he s u bject ca n be re-s cree ne d at a later ti me whe n t he u n us ual or e xte n uati n g 
circ u msta nce is a de q uat el y res ol ve d , s o as t o n ot i m pact t he res ults of t he Baseli ne 6M W T.  
7. 2  
B A S E LI N E  ( D A Y S - 1 4 T O - 1) 
T he f oll o wi n g s u bject-r e p orte d data wi ll be c o m pl ete d b y t he s u bject at Bas eli ne  pri or t o all 
ot her assess me nts : e m P H asis - 1 0 q uesti o n naire a n d TS Q M.  
Baseli ne assess me nts ca n be c o n d ucte d u p t o 1 4 d a ys pri or t o starti n g t he Re m o d uli n i nf usi o n.  
T he f oll o wi n g I n vesti gat or- re p orte d assess me nts will be c o n d ucte d: 
•  I n cl usi o n a n d e xcl usi o n criteria assess me nt 
•  E C H O  
•  W H O F C assess me nt  
•  Ser u m N T - pr o B N P (sa m ple m ust be dra w n pri or t o t he 6 M W T a n d Re m o d uli n 
i nitiati o n) 
•  6 M W T (aft er 1 0 mi n utes rest [seat e d]) , i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore 
•  C li nical la b orat or y assess me nts 
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after the 6 M W T, a n d after 5 mi n utes of rest 
seate d) 
•  C o nc o mita nt me dicati o ns  
•  O pti o nal p har mac o g e n o mic ( ge netic/ R N A ) a n d bi o mar ker bl o o d sa m ples 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  S u bject A Es  will be rec or de d  
•  A E B ot hers o me S ur ve y 
•  T he s u bject’s  me dical hist or y,  P A H s y m pt o m sc ore, a n d pri or P A H  me di cati o ns will 
be rec or de d.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 4 
7. 3  
T R E A T M E N T  P H A S E  
F oll o wi n g c o m pleti o n of Baseli ne assess me nts, Re m o d uli n wil l be i nitiate d at 2 n g/ k g/ mi n S C 
or I V i n a n i n patie nt or o ut patie nt setti n g .  I ntra v e n o us Re m o d uli n ma y be a d mi nistere d 
t hr o u g h a n i n d welli n g ce ntral ve n o us cat h eter or a  peri p herall y i nserte d cat heter as cli nicall y 
i n dicate d.  F or s u bj ects r ecei vi n g I V Re m o d uli n t hr o u g h a ce ntral ve n o us cat heter, it is 
rec o m me n de d t h at t he ce ntral ve n o us cat h eter be retai ne d f or at least 2 8 da ys after t he 
tra nsiti o n fr o m Re m o d uli n. 
U p -titrati o n of Re m o d uli n will c o nti n ue as t olerat e d.  S u bjects s h o ul d be o pti mize d o n 
Re m o d uli n t hera p y pri or t o tra nsiti o n t o Ore nitra m; a d ose s h o ul d be ac hi e v e d t hat i m pr o ves 
t he s y m pt o ms of P A H w hile mi ni mizi n g e xcessi ve p har mac ol o gic effects of Re m o d uli n. 
T here is n o ma xi m u m Re m o d uli n d ose d uri n g t he st u d y.  If n ecess ar y, s u bj ects ca n s witc h 
fr o m I V t o S C Re m o d uli n, or S C t o I V Re m o d uli n, at t he discreti o n of t he I n v esti gat or. 
Peri o dic c o ntact bet w ee n st u d y site pers o n nel a n d s u bjects s h o ul d be c o n d u cte d t o m o nit or 
A Es  bet wee n s c he d ule d st u d y visits (see S ecti o n 3. 3. 2. 5 ).  At t he re q u est of t he I n v esti gat or,  
n ursi n g s u p p ort will assist s u bjects wit h i nitiati o n of S C or I V R e m o d uli n, p u m p use, 
Re m o d uli n dis pe nsi n g, Re m o d uli n titrati o n, a d verse e ve nt ma na g e me nt, a n d tra nsiti o n 
assista nce.  O n ce t he s u bject f ull y tra nsiti o ns off Re m o d uli n, t he st u d y site will be t he 
s u bject’s pri mar y/s ole c o ntact.  St u d y site pers o n nel will rec or d t he st u d y dr u g d ose at e v er y 
st u d y visit i n t he s o urce d oc u me ntati o n. 
7. 3. 1  
Wee k  2 ( D a y 1 5 [ ± 3 D a ys]) 
S u bjects will c o nti n ue st u d y dr u g d osi n g i n t he o ut patie nt setti n g, as cli nicall y a p pr o priate. 
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f oll o wi n g I n v esti gat or-re p orte d 
assess me nts:  
•  Rec or d of A Es  
•  W H O F C  
•  6 M W T  (aft er 1 0 mi n utes rest [seat e d]), i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore.  If t h e s u bject is recei vi n g Ore nitra m, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he m ost rece nt d ose. 
•  C o nc o mita nt me dicati o ns  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 5 
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d)   
•  Dr u g acc o u nta bilit y (see Sect i o n 1 1. 5 ) 
•  If t he Tr a nsiti o n Visit occ urs at Wee k 2, please perf or m a d diti o nal assess m e nts liste d 
i n Secti o n 7. 3. 4 .  
7. 3. 2  
Wee k  4 ( D a y 2 9 [ ± 5 D a ys]) 
S u bjects will c o nti n ue st u d y dr u g d osi n g i n t he o ut patie nt setti n g, as cli nicall y a p pr o priate.  
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f ol l o wi n g I n v esti gat or-re p orte d 
assess me nts:  
•  R ec or d of A Es  
•  W H O F C  
•  6 M W T (aft er 1 0 mi n utes rest [seat e d]) , i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore.  If t h e s u bject is recei vi n g Ore nitra m, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he m ost rece nt d ose. 
•  C o nc o mita nt me dicati o ns  
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d) 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5) 
•  If t he Tr a nsiti o n Visit occ urs at Wee k 4, please perf or m a d diti o nal assess m e nts liste d 
i n Secti o n 7. 3. 4.  
N ote: If t he Tr a nsiti o n Visit occ urs at Wee k 2, t he Wee k 4 visit ca n b e s u bstit ute d f or t he P ost 
Tra nsiti o n Visit (ie, a n e xtra visit is n ot necessar y).  
7. 3. 3  
Wee k  8 ( D a y 5 7 [ ± 5 D a ys]) 
S u bjects will c o nti n ue st u d y dr u g d osi n g i n t he o ut patie nt setti n g, as cli nicall y a p pr o priate. 
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f oll o wi n g  I n v esti gat or-re p orte d 
assess me nts:  
•  R ec or d of A Es  
•  W H O F C  
•  6 M W T  (aft er 1 0 mi n utes rest [seat e d]), i m me diatel y f oll o we d b y heart  rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore. If t h e s u bject is recei vi n g Ore nitra m, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he m ost rece nt d ose. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 6 
•  C o nc o mita nt me dicati o ns  
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d) 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5 ) 
•  If t he Tr a nsiti o n Visit occ urs at Wee k 8, please perf or m a d diti o na l assess m e nts liste d 
i n Secti o n 7. 3. 4. 
7. 3. 4  
Tr a nsiti o n Visit  ( Wee k 2, 4, or 8) 
S u bjects ma y tra nsiti o n at Wee ks 2, 4, or 8 if t he y ha ve ac hie ve d a mi ni m u m Re m o d uli n d ose 
of 2 0 n g/ k g/ mi n a n d t he I n vesti gat or dee ms t he s u bject s uita ble f or tra nsiti o n.  S u bjects will 
tra nsiti o n fr o m Re m o d uli n t o Ore nitra m o ver t h e c o urse of 1 t o 2 1 da ys i n a n i n patie nt or 
o ut patie nt setti n g usi n g a cr oss-ta per met h o d (ie, d ecreases i n Re m o d uli n d os e c oi nci de wit h 
i ncreas es i n Ore nitra m d ose).  S u bjects will be i nstr ucte d t o ta ke t he a p pr o priate n u m ber of 
Ore nitra m ta blets bas e d u p o n t heir Re m o d uli n d ose a n d t he tra nsiti o n sc he d ule c h ose n b y 
t heir healt hcare pr o vi d er.  
At t he discreti o n of t he I n vesti gat or, tra nsiti o n ma y als o be re v erse d or st o p pe d if necessar y 
d ue t o si g nifica nt si g ns or s y m pt o ms of P A H or d ue t o seri o us safet y c o ncer ns.  If t he 
I n v esti gat or dee ms a s u bject u ns uita ble f or tra nsiti o n t o Ore nitra m d ue t o si g nifica nt si g ns a n d 
s y m pt o ms of P A H or a n y ot her seri o us safet y c o ncer ns, t he s u bject ma y re mai n o n Re m o d uli n 
f or t he d urati o n of t h e st u d y.  H o we ver, t he s u bject s h o ul d be c o nti n uall y assesse d t o 
deter mi ne if t he y b ec o me sta ble e n o u g h f or tra nsiti o n t o Ore nitra m.  All s u bjects still  o n 
Re m o d uli n at Wee k 8 s h o ul d tra nsiti o n t o Ore nitra m at Wee k 8 re g ar dless of t heir Re m o d uli n 
d ose u nless t he I n vesti gat or dee ms t he m u ns uita ble f or tra nsiti o n t o Ore nitra m d ue t o 
si g nifica nt si g ns a n d s y m pt o ms of P A H or a n y ot her seri o us safet y c o n cer ns. 
Tra nsiti o n will occ ur as f oll o ws:  
•  T he d ose of Re m o d uli n ca n be re d u ce d n o m ore t h a n 1 0 n g/ k g/ mi n per da y f or 
tra nsiti o ns i n t he o ut patie nt setti n g.  F or i n patie nt tra nsiti o ns, t here is n o li mit o n t he 
rate of Re m o d uli n d ose r e d ucti o n. 
•  T he  tar get d ose of Or e nitra m at t he e n d of tra nsiti o n  is de pe n de nt o n t he s u bject’s 
wei g ht a n d Re m o d uli n d ose.  U p -titrati o n of Ore nitra m s h o ul d c oi nci de wit h a 
re d ucti o n i n t he Re m o d uli n d ose.  T he tar get T D D of Ore nitra m  at t he e n d of 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 7 
tra nsiti o n will be calc ulat e d base d u p o n t he f oll o wi n g e q ui vale nce wei g ht -b ase d 
f or m ula: 
T D D [ m g] = 0. 0 0 7 2 * Re m o d uli n d ose [ n g/ k g/ mi n] * wei g ht [ k g]. 
•  T he Ore nitr a m u p -titrati o n d ose s h o ul d be ta ke n at a p pr o xi matel y t he sa me ti me t he 
Re m o d uli n d ose is decrease d. 
•  E xa m p les of tra nsiti o n sc he d ules f or vari o us s u bject b o d y wei g hts a n d Re m o d uli n 
d oses are liste d i n  A p pe n di x I .  
T he f oll o wi n g s u bject-r e p orte d data will be c o m pl ete d b y t he s u bject at  t he Tra nsiti o n Visit 
pri or t o all ot her assess m e nts a n d pri or t o i nitiati o n of Ore nitra m : e m P Hasis - 1 0 q uesti o n naire  
a n d T S Q M . 
T he f oll o wi n g assess me nts s h o ul d be perf or me d at t he Tra nsiti o n Visit: 
•  P A H s y m pt o m sc ore 
•  Rec or d of A Es 
•  A E  B ot hers o me S ur ve y 
•  W H O  F C  
•  Ser u m N T - pr o B N P (sa m ple m ust be dra w n pri or t o t he 6 M W T a n d Ore nitra m 
i nitiati o n) 
•  6 M W T (aft er 1 0 mi n utes rest [seat e d]) , i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore ( bef ore i nitiati n g t he tra nsiti on t o Ore nitra m)  
•  C o nc o mita nt me dicati o ns  
•  F ull p h ysical e xa mi nati o n  
•  E C H O  
•  Vital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d) 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5 ) 
•  Cli nical la b o rat or y assess me nts  
•  O pti o nal bi o mar ker bl o o d sa m ple 
F oll o wi n g tra nsiti o n, Ore nitra m d ose titrati o n ma y  c o nti nue i n t he o ut patie nt setti n g t hr o u g h 
Wee k 1 6 t o r eac h t h e ma xi m um t olerate d d ose b y i ncreasi n g t he d ose b y 0. 1 2 5 m g TI D  e ver y 
3 t o 4 da ys as t olerate d, wit h t he g oal of ac hie vi n g a ma xi m u m t olerate d d ose b y t he e n d of 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 8 
Wee k 1 6.  A sl o w er titrati o n rate ma y be us e d if t he s u bj ect e x perie nces a d v erse effects.   
T here is n o ma xi m u m Or e nitra m d ose d uri n g t he st u d y.  
7. 3. 5  
P ost Tr a nsiti o n Visit ( 7 t o 1 4 d a ys after Tr a nsiti o n Visit)  
S u bjects will c o nti n ue st u d y dr u g d osi n g i n t he o ut patie nt setti n g, as cli nicall y a p pr o priate.  
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f oll o wi n g I n v esti gat or -re p orte d 
assess me nts:  
•  R ec or d of A Es  
•  W H O F C  
•  6 M W T (aft er 1 0 mi n utes rest [seat e d]), i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore.  T he 6 M W T s h o ul d occ ur wit hi n 2 t o 6 h o urs of 
t he m ost rece nt d ose of Ore nitra m. 
•  C o nc o mita nt me dicati o ns  
•  Vital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5  mi n utes rest 
seate d) 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5 ) 
N ote: If t he Tr a nsiti o n Visit occ urs at Wee k 2, t he Wee k 4 visit ca n b e s u bstit ute d f or t he P ost 
Tra nsiti o n Visit (ie, a n e xtra visit is n ot necessar y).  
7. 3. 6  
Wee k 1 2  ( D a y 8 5 [ ± 5 D a ys]) 
S u bjects will c o nti n ue st u d y dr u g d osi n g i n t he o ut patie nt setti n g, as cli nicall y a p pr o priate.  
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f oll o wi n g  I n v esti gat or-re p orte d 
assess me nts:   
•  R ec or d of A Es  
•  W H O F C  
•  6 M W T  (aft er 1 0 mi n utes rest [seat e d]), i m me diatel y f oll o we d b y heart rate rec o ver y 
( 1 mi n ute) a n d B or g d ys p nea sc ore.  If t h e s u bject is recei vi n g Ore nitra m, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he m ost rece nt d ose. 
•  C o nc o mita nt me dicati o ns  
•  Vital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d) 
•  Fe male s u bjects of c hil d beari n g  p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5)  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 4 9 
7. 3. 7  
Wee k 1 6 / E arl y St u d y Wit h dr a w al ( D a y 1 1 3 [ ± 7 D a ys]) 
T he f oll o wi n g s u bject-r e p orte d data will be c o m pl ete d b y t he s u bject at t he Wee k 1 6/ Earl y 
St u d y Wit h dra wal Visit  pri or t o all ot her assess m e nts: e m P Hasis - 1 0 q uesti o n naire a n d 
T S Q M . 
T he  assess me nts of Wee k 1 6/ Earl y St u d y Wit h dra wal V isit ca n occ ur o v er 5 da ys s o t hat 
assess me nts ca n ta k e place o n se parate d a ys  if nee de d.  All assess me nts s h o ul d be c o n d ucte d 
pri or t o  wit h dra wi n g fr o m t he st u d y, pri or t o disc o nti n uati o n of Ore nitra m or Re m o d uli n, a n d 
as cl ose as p ossi ble t o t he last d ose ta ke n b y t he s u bjec t. 
S u bjects will ret ur n t o t he st u d y site cli nic f or t he f oll o wi n g I n v esti gat or -re p orte d 
assess me nts:  
•  P A H s y m pt o m sc ore 
•  R ec or d of A Es  
•  A E B ot hers o me S ur ve y 
•  E C H O  
•  W H O F C  
•  Ser u m N T - pr o B N P (sa m ples m ust be dra w n pri or t o t he 6 M W T) 
•  6 M W T  (aft er 1 0 mi n utes rest [seat e d]), i m me diatel y f oll o we d b y heart  rate rec o ver y 
( 1 mi n ute)  a n d B or g d ys p nea sc ore.  If t h e s u bject is recei vi n g Ore nitra m, t he 6 M W T 
s h o ul d occ ur wit hi n 2 t o 6 h o urs of t he m ost rece nt d ose. 
•  C li nical la b orat or y assess me nts 
•  V ital si g ns ( pri or t o or at least 3 0 mi n utes after t he 6 M W T, a n d after 5 mi n utes rest 
seate d) 
•  C o nc o mita nt me dicati o ns  
•  F ull p h ysical e xa mi nati o n  
•  O pti o nal bi o mar ker bl o o d sa m ple 
•  Fe male s u bjects of c hil d beari n g p ote ntial will u n der g o a uri n e pre g n a nc y t est 
•  Dr u g acc o u nta bilit y (see Secti o n 1 1. 5 ) 
S u bjects w h o c o m plete t he Wee k 1 6 Visit will be tra nsiti o ne d off cli nical st u d y material t o 
c o m merciall y a v a ila ble Ore nitra m or Re m o d uli n, as cli nicall y a p pr o pri ate.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 0 
8  
S T U D Y  T E R MI N A TI O N  
8. 1  
C RI T E RI A  F O R S U B J E C T WI T H D R A W A L  
A s u bject ma y v ol u ntaril y wit h dra w or be wit h dra w n fr o m t he st u d y a n d/ or st u d y dr u g b y t he 
I n v esti gat or at a n y ti me f or reas o ns i ncl u di n g, b ut n ot li mite d t o, t he f oll o wi n g: 
•  T he s u bject wis hes t o wit h dra w fr o m f urt her p artici pati o n. 
•  A seri o us or life -t hreate ni n g A E occ urs or t h e I n v esti gat or c o nsi ders t hat it is 
necessar y t o disc o nti n ue st u d y dr u g t o pr otect t he safet y of t he s u bje ct.  
•  T he s u bject de viat e d fr o m t he pr ot oc ol. 
•  T he s u bject’s be h a vi or is li kel y t o u n der mi ne t he vali dit y of his/ her res ults.  
If a s u bject is disc o nti n ue d fr o m t he st u d y pre mat urel y, t he I n vesti gat or m ust pr o vi de a n 
e x pla nati o n i n t he e C R F (I n vesti gat or’s C o m me nt L o g) a n d c o m plete t h e E n d of St u d y 
Rec or d f or t h at s u bject.  If st u d y dr u g has bee n a d mi nistere d, t he I n vesti gat or s h o ul d ma ke 
e ver y eff ort t o perf or m all sc he d ule d e val u ati o ns pri or t o disc har ge.  I n t he e ve nt t hat a s u bject 
disc o nti n ues st u d y dr u g pre mat urel y d u e t o a n A E, t he s u bject will be f oll o we d u ntil eit her t he 
I n v esti gat or deter mi nes t hat t he A E has res ol ve d, it is n o l o n ger c o nsi dere d cli nicall y 
si g nifica nt, t he s u bject is l ost t o f urt her f oll o w- u p, or f or 4 w ee ks if t he A E  e xte n ds be y o n d 
the fi nal visit.  
If a s u bject disc o nti n ues st u d y dr u g pri or t o c o m pleti n g t he Wee k 1 6 Visit assess me nts, t he 
I n v esti gat or will rec or d t he reas o n f or wit h dra wal (e g, t y pe of A E, lac k of res p o nse), t he 
d osi n g titrati o n sc he d ule ( date a n d d os e of last titrati o n, date a n d last d ose t a ke n bef ore st u d y 
dr u g disc o nti n uati o n), a n d if tra nsiti o ni n g t o a differe nt p ul m o nar y h y p erte nsi o n t hera p y, t he 
p ul m o nar y h y perte nsi o n dr u g t o w hic h t he s u bject is tra nsiti o ni n g. 
8. 2  
C RI T E RI A F O R  T E R MI N A TI N G T H E S T U D Y  
T he st u d y ma y be st o p pe d at a n y ti me if, i n t he o pi ni o n of t he I n v esti gat or a n d/ or S p o ns or, 
c o nti n uati o n of t he st u d y re pres e nts a seri o us me di cal ris k t o t he s u bjects.  T his ma y i ncl u de, 
b ut is n ot li mite d t o, t he prese nce of seri o us, life-t hreate ni n g, or fatal A Es  or A Es  t hat are 
u nacce pta ble i n nat ur e, s e verit y, or fre q ue n c y.  T h e S p o ns or reser ves t he ri g ht t o disc o nti n ue 
t he st u d y f or a n y r eas o n at a n y ti me. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 1 
8. 3  
C RI T E RI A  F O R DI S C O N TI N UI N G T H E SI T E  
T he st u d y ma y als o be ter mi nate d at a gi ve n ce nter if: 
•  T he I n vesti gat or elects  t o disc o nti n ue t he st u d y 
•  T he S p o ns or elects t o disc o nti n ue t he st u d y at t he st u d y site 
•  U nite d States F D A r e g ul ati o ns or I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
G o o d Cli nical Practice ( G C P) g ui deli nes are n ot o bser ve d 
•  T he pr ot oc ol is vi olate d or critical vi olati o ns are d oc u me nte d, or 
•  C ha n ges i n pers o n nel or facilities a d vers el y affect perf or ma n ce of t he st u d y  
9  
A D V E R S E  E V E N T R E P O R TI N G  
9. 1  
D E FI NI TI O N S  
9. 1. 1  
A d verse  E ve nt  
A n A E  is a n y u nt o war d me dical occ urre n ce i n a s u bject occ urri n g t o a s u bject d uri n g a 
cli nical st u d y w het her or n ot it is relate d t o  t he st u d y dr u g.  A n A E  ma y i ncl u de a n 
i nterc urr e nt ill ness, i nj ur y, or a n y ot her c o nc o mita nt i m pair me nt of t he s u bject’s healt h, as 
well as a b n or mal la b orat or y fi n di n gs if dee me d t o ha ve cli nical si g nifica n ce.  A d vers e e ve nts 
ma y als o i ncl u de w orse ni n g of a n e xisti n g s y m pt o m or c o n diti o n or p ost-treat me nt e ve nts t hat 
occ ur as a res ult of pr ot oc ol- ma n date d  pr oce d ures.  
E ve nts relate d  t o pr osta n oi d t hera p y ca pt ure d b y t he A E B ot hers o me S ur ve y (A p pe n di x E ) 
s h o ul d o nl y be rec or d e d as a n A E a n d s h o ul d o nl y be ca pt ure d as a n S A E if t he e ve nt is 
u n us ual wit h res pect t o i nte nsit y, fre q ue nc y, or d urati o n as c o m pare d wit h s y m pt o ms i n t he 
s u bject’s me dical hist or y. 
E ve nts attri b uta ble t o t he pr o gressi o n of t he diseas e u n der st u d y ( liste d i n T a ble 9- 1 ) a n d 
e ve nts attri b uta ble t o P A H s y m pt o mat ol o g y ca pt ure d b y P A H S y m pt o m Sc ore 
( Secti o n 3. 3. 1. 2 ) s h o ul d be rec or de d as a n A E  or ca pt ure d as a n S A E if t he e ve nt is u n us ual 
wit h res pect t o i nte nsit y, fre q ue n c y, or d urati o n as c o m pare d wit h s y m pt o ms i n t he s u bject’s 
me dical hist or y , or if t her e is a reas o na ble p ossi bilit y t hat t he e ve nt was ca use d b y t he st u d y 
dr u g. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 2 
T a ble 9- 1  
A d verse E ve nts Attri b ut a ble t o t he Pr o g ressi o n of Dise ase  
A n ore xia  
Pal pitati o ns  
A b d o mi nal pai n  
Peri p heral e de ma/ ge neralize d e de ma  
Dizzi ness  
Pres y nc o pe  
D ys p nea/ d ys p nea o n e xerti o n 
P ul m o nar y h y perte nsi o n, e xacer bati o n of  
E xercise t olera nce decrease d  
Ri g ht heart fail ure/ri g ht ve ntric ular fail ure  
Fati g ue  
S y nc o pe  
H y p o xia  
Wei g ht l oss  
Let har g y  
Wei g ht gai n  
L oss of c o nsci o us ness  
 
N ote: S y m pt o ms of ri g ht ve ntric ular fail ure/ri g ht heart fail ure ca n i ncl u de, b ut are n ot li mite d t o, ascites, c ya n osis, 
tac h ycar dia, a n d ot her car diac arr h yt h mias.  T he effects of p ul m o nar y h y pertp e nsi o n a n d ri g ht ve ntric ular 
fail ure/ri g ht heart fail ure ca n i ncl u de car diac arrest a n d deat h.  
9. 1. 2  
Seri o us  A d verse E ve nt  
A n S A E is a n A E occ urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h  
•  A life -t hreate ni n g A E 
•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  A persiste nt or si g nifica nt disa bilit y/i nca p acit y 
•  A c o n ge nital a n o mal y/ birt h defect 
•  Res ults i n a me dicall y i m p orta nt e ve nt or reacti o n  
I n a d diti o n, i m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or 
re q uire h os pitalizati o n m a y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bj ect a n d re q uire me dical/s ur gical i nter ve nti o n t o 
pre ve nt 1 of t he o ut c o mes liste d a b o ve.  E xa m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, 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 t he de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e. 
Life -t hreate ni n g mea ns t hat t he s u bject was, i n t h e vie w of t he I n vesti gat or, at i m me diate ris k 
of deat h fr o m t he e ve nt as it occ urre d.  It d o es n ot mea n t hat t he e ve nt, ha d it occ urre d i n a 
m ore se ver e f or m, mi g ht ha ve ca use d deat h. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 3 
F or t his st u d y, S A E re p orti n g res p o nsi bilities will be as per Secti o n 9. 3 .  All S A Es t hat occ ur 
d uri n g t he st u d y will be f oll o we d u ntil res ol uti o n, deat h, or t he s u bject is l ost t o f oll o w- u p, 
e ve n if t he y are o n g oi n g m ore t ha n 3 0 da ys after c o m pleti o n of t he fi nal st u d y visit ( Wee k 1 6 
Visit  or Earl y Wit h dra w al Visit ). 
9. 2  
D O C U M E N T A TI O N  O F A D V E R S E E V E N T S  
A n A E  or S A E occ urri n g d uri n g t he st u d y m ust be d oc u me nte d i n t he s u bject’s s o urce 
d oc u me nts a n d o n t he a p pr o priate e C R F p a ge.  I nf or mati o n relati n g t o t he A E , s uc h as o nset 
a n d cessati o n dat es a n d ti mes, i nte nsit y, seri o us ness, relati o ns hi p t o t he st u d y dr u g, a n d 
o utc o me, is t o be d oc u me nte d i n t he e C R F ( s ee A p pe n di x C ).  If se v eral si g ns or s y m pt o ms 
are cl earl y r elate d t o a m e dicall y defi ne d di a g n osis or s y n dr o me, t he dia g n osis or s y n dr o me 
s h o ul d be rec or de d o n t h e e C R F pa g e, n ot t he i n di vi d ual si g ns a n d s y m pt o ms. 
All A Es  s h o ul d be f oll o we d u ntil eit her res ol uti o n ( or ret ur n t o n or mal or Baseli ne val ues), 
u ntil t he y are j u d ge d b y t he I n vesti gat or t o n o l o n ger be cli nicall y si g nifica nt, or f or at least 
4 wee ks  if t he A E e xte n ds be y o n d t he fi nal visit.  All S A Es t hat occ ur d uri n g t he st u d y will be 
f oll o we d u ntil res ol uti o n, deat h, or t he s u bject is l ot t o f oll o w- u p, e ve n if t he y are o n g oi n g 
m ore t ha n 4 wee ks after c o m pleti o n of t he fi nal visit.  S u p ple me ntal meas ure me nts a n d/ or 
e val uati o ns ma y be necessar y t o i n vesti gate f ull y t he nat ure a n d/ or ca usalit y of a n A E  or S A E .  
T his ma y i ncl u de a d diti o nal la b orat or y tests, dia g n ostic pr oce d ures, or c o ns ultati o n wit h ot her 
healt hcar e pr of essi o nals .  T he e C R F pa g es s h o ul d be u p date d wit h ne w or a d diti o nal 
i nf or mati o n. 
T he A Es  re p orte d b y t he s u bjects will be s u m marize d b y U nite d T hera p e utics C or p orati o n 
d uri n g t he st u d y at i nter vals ali g ne d wit h peri o dic safet y u p date re p orts a n d at t he e n d of t he 
st u d y.  
F or a n y n o ns eri o us A E  t hat is o utsi de t he sc o pe of t he pr osta n oi d A Es  ( h ea dac he, diarr hea, 
na usea, fl us hi n g, ja w p ai n, e xtre mit y pai n, a n d v o miti n g) t hat s u bjects will be re p orti n g 
d uri n g t his st u d y, t he I n v esti gat or w ill be i nstr ucte d t o re p ort t he A Es  i n c o m plia nce wit h t he 
F D A r e p orti n g res p o nsi bilities ( Me d Watc h/s p o nta ne o us). 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 5 
o utc o me of t he pr e g na nc y.  If t he o utc o me of t h e s u bject’s pre g n a nc y meets t he criteria f or 
i m me diate classificati o n of a n S A E (i ncl u di n g, b ut n ot li mite d t o, still birt h, s p o nta ne o us 
a b orti o n, p ost part u m c o m plicati o n, ne o natal deat h, or c o n ge nital a n o mal y), t he I n vesti gat or i n 
t he st u d y s h o ul d f oll o w t he ste ps f or re p orti n g a n S A E.  S u bjects w h o bec o me pre g na nt 
d uri n g t he st u d y will be wit h dra w n fr o m acti ve p artici pati o n i n t he st u d y a n d will disc o nti n ue 
st u d y dr u g. 
1 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
1 0. 1  
D A T A P R O C E S SI N G  
T he st u d y will c ollect data o btai ne d f r o m p artici pati n g s u bjects i n  t he Cli n Tra k E D C s yste m. 
1 0. 1. 1  
E D C  
Data will be rec or d e d o n t he e C R F, a n d e C R Fs will be c o m plete d f or eac h s u bject.   Li mite d 
data will be rec or d e d o n scree n fail ures.  D ata will be tra nscri be d i nt o a n e C R F b y t he 
a p pr o priate st u d y site pers o n nel f or eac h s u bject u ntil st u d y c o m pleti o n, or st u d y 
disc o nti n uati o n f or a n y r eas o n.  T he S p o ns or or d esi g nee will verif y e C R F data fiel ds a g ai nst 
s o urce d oc u m e ntati o n.  All data e ntere d i n t he e C R F b y t he st u d y site will be e ntere d i nt o a 
q ualit y ass ure d c o m p uterize d data b ase.  A n y discre pa ncies will be p oste d i n t he s yste m f or 
res ol uti o n b y t he site.  T he e C R F data f or e v er y s u bject is t o be re vie w e d b y t he I n v esti gat or 
f or c o m plete n ess a n d acc urac y. T h e I n vesti gat or m ust electr o nicall y si g n e ver y s u bject’s 
e C R F t o si g nif y t heir a p pr o val of t he dat a.  T he I n vesti gat or will be re q uire d t o re-si g n a n 
e C R F if c ha n g es ar e ma d e t o a s u bject’s  e C R F b y t he st u d y site after t he I n vesti gat or has 
a p plie d his/ her si g nat ure.  T he data bas e will be c o nsi dere d fi nal w h e n all o utsta n di n g q ueries 
ha ve bee n res ol ve d a n d all data ma na ge me nt q ualit y ass ura nce pr oce d ures are c o m plet e.  
1 0. 2  
S A M P L E  SI Z E  
A sa m ple size of a p pr o xi matel y 3 0 e val ua ble s u bj ects was set f or feasi bilit y a n d t o e ns ure a 
reas o na bl e dataset t o e v al uate t he Ore nitra m d ose ac hie ve d, t h e cli nical res p o nse wit h a n 
i n d ucti o n peri o d wit h Re m o d uli n, a n d t o assess t he safet y a n d t olera bilit y of Ore nitra m after 
i n d ucti o n t hera p y wit h Re m o d uli n.  N o f or mal sa m ple size c o m p utati o n w as perf or me d wit h 
res pect t o t he pri mar y e n d p oi nt. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 6 
1 0. 3  
A N A L Y SI S  P L A N  
N o f or mal h y p ot hesis is bei n g teste d.  T he efficac y a n d safet y d ata i n t he st u d y will be 
prese nte d i n s u m mar y ta bles a n d listi n gs i n t he fi nal cli nical st u d y re p ort.  Listi n gs will be 
s orte d b y s u bject, visit, a n d ti me p oi nt assess me nt (if a p plica ble).  F or s u m mar y ta bles, t he 
data will be s u m marize d b y visits a n d ti m e p oi nt assess me nt,  if a p pr o priate.  F or c o nti n u o us 
varia bles, des cri pti ve statistics will i ncl u de t he n u m ber of o bser v ati o ns, mea n, S D , me dia n, 
mi ni m u m, a n d ma xi m u m.   F or  cate g orical varia bl es, descri pti ve statistics will i ncl u de t he 
fre q ue n c y a n d p erce nta g e i n e ver y cate g or y.  Det ails of efficac y a n d safet y a nal yses are 
pr o vi de d bel o w.  F urt her details will be d oc u me nte d i n a statistical a nal ysis pla n.  
T he Safet y P o p ulati o n is defi ne d as all s u bjects i n t he st u d y w h o recei ve st u d y dr u g 
( Re m o d uli n or Ore nitra m).  All safet y a n d efficac y a nal yses will be perf or m e d o n t he Safet y 
P o p ulati o n. 
1 0. 3. 1  
P ri m ar y E n d p oi nt  
1 0. 3. 1. 1  
Effic ac y  E n d p oi nt  
T he pri mar y efficac y e n d p oi nt of t he perce nta ge of s u bjects ac hie vi n g a n Ore nitra m d ose of 
4 m g TI D ( or a t otal d ail y d ose of 1 2 m g) or hi g h er at Wee k 1 6 ( or a d ose of 0. 0 5 7 m g/ k g TI D 
[ or a t otal dail y d ose of 0. 1 7 1 m g/ k g] or greater f or s u bjects < 7 0 k g) will be calc ulate d a n d 
s u m marize d. 
1 0. 3. 2  
Sec o n d ar y  E n d p oi nts  
1 0. 3. 2. 1  
S afet y E n d p oi nts  
1 0. 3. 2. 1. 1  
Pr ost a n oi d A dverse Eve nts 
Pr osta n oi d A E  sc ores ca pt ure d b y t he Pr ostac ycli n Bot hers o me Sc ore will be s u m marize d at 
B aseli ne, t he Tra nsiti o n Visit, a n d Wee k 1 6/ Earl y St u d y Wit h dra wal. 
1 0. 3. 2. 2  
Effic ac y  E n d p oi nts  
T he f oll o wi n g sec o n dar y efficac y e n d p oi nts will be s u m marize d: 
•  C ha n ge i n 6 M W D fr o m B aseli ne t o t he Tra nsiti o n Visit  a n d Wee k 1 6 
•  C ha n ge i n B or g d ys p nea sc ore fr o m B aseli ne t o t he Tra nsiti o n Visit a n d Wee k 1 6 
•  C ha n ge i n W H O F C fr o m Baseli ne t o  t he Tra nsiti o n Visit a n d Wee k 1 6 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 7 
•  C ha n ge i n N T- pr o B N P l e vels fr o m B aseli ne t o t h e Tra nsiti o n Visit a n d Wee k 1 6 
•  Ec h ocar di o gra p hic p ara meters will be s u m marize d at Baseli ne, t he Tra nsiti o n Visit, 
a n d Wee k 1 6. 
•  P A H s y m pt o m sc ore at Baseli ne, t he Tra nsiti o n Visit , a n d Wee k 1 6  
•  Healt h -r elate d q ualit y of life (e m P Hasis- 1 0) at Baseli ne, t he Tra nsiti o n Visit, a n d 
Wee k 1 6  
•  T he per ce nta g e of s u bjects t hat i m pr o ve i n eac h of t he f oll o wi n g 4 i n di vi d ual cli nical 
para meters at Wee k 1 6 ( 6 M W D, N T - pr o B N P, W H O F C, ri g ht atrial area) t o a l o wer 
ris k stratu m, as defi ne d b y t he 2 0 1 5 E ur o pea n S ociet y of Car di ol o g y g ui deli nes, 
c o m pare d t o Baseli ne  
•  T he per ce nta g e of s u bjects t hat meet eac h of t he f oll o wi n g 4 i n di vi d ual cli nical 
para meters at Wee k  1 6 i n t he l o w ris k cate g or y, as defi ne d b y t he 2 0 1 5 E ur o pea n 
S ociet y of Car di ol o g y g ui deli nes: 6 M W D > 4 4 0 m eters, ser u m N T- pr o B N P 
< 3 0 0 n g/ L, W H O F C I or II, a n d ri g ht atri al area < 1 8 c m 2 
•  T he per ce nta g e of s u bjects t hat eit her ac hie v e a n Ore nitra m d ose of 4 m g TI D ( or a 
t otal dail y d ose of 1 2 m g) or hi g her at Wee k 1 6 ( or a d ose of 0. 0 5 7 m g/ k g TI D [ or a 
t otal dail y d ose of 0. 1 7 1 m g/ k g] or greater f or s u bjects < 7 0 k g) or t he p erce nta ge of 
s u bjects t hat ac hie v e a n Ore nitra m d ose ≥2 m g TI D a n d < 4 m g TI D ( or a t otal dail y 
d ose ≥6 m g a n d  < 1 2  m g) at Wee k 1 6, wit h at least 2 of t he f oll o wi n g 3 cli nical 
par a meters at Wee k 1 6 calc ulate d a n d s u m marize d: 6 M W D i ncrease b y ≥1 0 % or ≥3 0 
meters fr o m Baseli ne, s er u m N T -pr o B N P re d ucti o n > 3 0 % f r o m Bas eli ne, or W H O F C 
I or II 
•  T he per ce nta g e of s u bjects t hat s uccessf ull y tra nsiti o ne d t o Ore nitra m at a n y d ose a n d 
were s u ccessf ull y mai ntai ne d o n t hera p y at Wee k 1 6 
1 0. 3. 2. 2. 1  
P atie nt-re p orte d O utc o m es  
S u bjects’ T S Q M res p o ns es a n d e m P Hasis - 1 0 q uesti o n naires will be s u m marize d at B aseli ne, 
Tra nsiti o n Visit , a n d Wee k 1 6/ Earl y St u d y Wit h dra wal. 
1 0. 3. 3  
S afet y  A n al yses 
T he Safet y P o p ulati o n will be defi ne d as all s u bjects i n t he st u d y t hat recei v e st u d y dr u g.  All 
safet y a n al yses will be perf or me d o n t he Safet y P o p ulati o n.  Safet y will be e val uate d b y 
assess me nt of A Es , cli nical la b orat or y e val uati o ns, a n d vital si g ns .  All A Es as rec or de d b y 
t he I n v esti gat ors will be assi g ne d Me dical Dicti o n ar y f or Re g ul at or y Acti vities ( Me d D R A) 
Preferre d Ter ms b y t he S p o ns or f or re p orti n g p ur p oses.  F or all safet y e n d p oi nts, ta b ular 
s u m maries will be pr o vi de d. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 8 
1 0. 4  
I N T E RI M A N A L Y SI S  
N o i nteri m a nal ysis d uri n g t he st u d y is pla n ne d. 
1 0. 5  
O T H E R  A N A L Y S E S  
Ot her e x pl or at or y, p ost- h oc a nal yses ma y b e c o n d ucte d base d o n a vaila ble st u d y data. 
1 0. 6  
D A T A  LI S TI N G S A N D S U M M A RI E S  
All data gat her e d i n t his st u d y will be prese nte d i n s u m mar y ta bles a n d listi n gs i n t he fi nal 
cli nical st u d y re p ort.  I n ge neral, listi n gs will be s orte d b y s u bject a n d sc h e d ule d assess me nt 
(if a p plica ble).  F or s u m mar y ta bles, data will be s u m marize d b y sc he d ul e d assess me nt.  F or 
c o nti n u o us varia bles, des cri pti ve statistics will i ncl u de t he n u m ber of o bser vati o ns, mea n, S D , 
me dia n, i nter- q uartile ra n ge, mi ni m u m, a n d ma xi m u m.  F or cate g orical v aria bles, descri pti ve 
statistics will i ncl u de t he fre q ue n c y a n d p erce nt i n eac h cate g or y.  
1 1  
P A C K A GI N G  A N D F O R M U L A TI O N  
1 1. 1  
C O N T E N T S  O F S T U D Y D R U G  
U nite d T hera p e u tics C or p orati o n will s u p pl y st u d y dr u g f or a d mi nistrati o n d uri n g t he st u d y. 
T he oral tre pr osti nil ta blets are S R os m otic ta blets.  Acti ve treat me nt will be oral tre pr osti nil 
ta blets pr o vi de d as 0. 1 2 5-, 0. 2 5-, 1-, 2. 5-, a n d 5- m g stre n gt hs f or t he st u d y.  Eac h ta blet 
c o ntai ns eit her 0. 1 2 5 m g tre pr osti nil (e q ui vale nt t o 0. 1 5 9 m g tre pr osti nil di ola mi ne), 0. 2 5 m g 
tre pr osti nil (e q ui vale nt t o 0. 3 1 7 m g tre pr osti nil di ola mi ne), 1 m g tre pr osti nil (e q ui vale nt t o 
1. 2 7 m g tre pr osti nil di ola mi ne), 2. 5 m g tre pr osti nil (e q ui vale nt t o 3. 1 7 m g tre pr osti nil 
di ola mi ne), or 5 m g tre pr osti nil (e q ui vale nt t o 6. 3 4 tre pr osti nil di ola mi ne) .  T he 0. 1 2 5-, 0. 2 5-, 
1-, 2. 5-, a n d 5- m g ta blets are c ol ore d w hite , gree n, yell o w, pi n k, a n d re d, res pecti vel y.  Oral 
tre pr osti nil ta blets will be pr o vi de d i n c hil d resist a nt b ottles, eac h c o nt ai ni n g 1 0 0 ta blets. 
Pare nter al tre pr osti nil is s u p plie d as a sterile s ol uti o n f or m ulate d f or S C  or I V  a d mi nistrati o n.  
Re m o d uli n is s u p plie d i n 2 0- m L m ulti d ose vials i n 4 stre n gt hs, c o ntai ni n g 2 0 m g, 5 0 m g, 
1 0 0 m g, or 2 0 0 m g ( 1 m g/ m L, 2. 5 m g/ m L, 5 m g/ m L, or 1 0 m g/ m L , res pecti vel y) of 
tre pr osti nil.  Eac h m illiliter als o c o ntai ns 5. 3 m g s o di u m c hl ori de (e xce pt f or t he 1 0 m g/ m L 
stre n gt h, w hic h c o ntai ns 4. 0 m g s o di u m c hl ori de), 3 m g metacres ol, 6. 3 m g s o di u m citrate, 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 5 9 
a n d water f or i njecti o n.  S o di u m h y dr o xi de a n d h y dr oc hl oric aci d ma y be a d de d t o a dj ust p H 
bet wee n 6. 0 a n d 7. 2. 
S u bjects w h o ha ve c o m plete d t he Wee k 1 6 Visit will be tra nsiti o ne d off cli nical st u d y 
material t o c o m merci all y a vaila ble Ore nitra m or R e m o d uli n, as cli nicall y a p pr o priate. 
1 1. 2  
L A B E LI N G  
C o m mercial dr u g s u p pl y is bei n g use d i n t his st u d y.  E ver y b ottle of Ore nitra m a n d eac h 
pac ka g e of Re m o d uli n is la bele d i n acc or da n ce wit h a p plica ble nati o nal re g ulati o ns, t o 
i ncl u de at least t he f oll o wi n g i nfor mati o n: st u d y dr u g na me ; stre n gt h; q ua ntit y; r o ute of 
a d mi nistrati o n ; ma n ufact ure or e x pir y date; l ot n u m ber; S p o ns or na me, a d dress, a n d tele p h o n e 
n u m ber; a n d st ora ge c o n diti o ns. 
I n a d diti o n, Re m o d uli n a n d Ore nitra m pr o vi de d t o s u bjects will ha ve a n a d diti o nal cli nical 
st u d y la bel w hic h will bear t he f oll o wi n g: t he st u d y refere nce c o d e, a u ni q u e serialize d 
pac ka g e n u m ber, a n d t h e f oll o wi n g messa ge – “ C A U TI O N: N E W D R U G — LI MI T E D B Y 
F E D E R A L L A W T O I N V E S TI G A TI O N A L U S E .”  
1 1. 3  
S T O R A G E  A N D H A N D LI N G O F C LI NI C A L S T U D Y  M A T E RI A L  
St u d y dr u g at t he st u d y site will be st ore d i n a sec urel y l oc ke d ca bi net or e n cl os ure wit h 
a p pr o priate t e m perat ur e m o nit ori n g.  Access s h o ul d be strictl y li mite d t o t he I n vesti gat ors a n d 
t heir desi g nees.  All st u d y dr u g will be st ore d at a c o ntr olle d te m perat ure of 2 5° C ( 7 7° F), wit h 
e xc ursi o ns per mitte d t o 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F). 
Re m o d uli n st u d y dr u g vials m ust be use d or discar de d wit hi n 3 0 da ys of i nitial p u nct ure.  
Re m o d uli n s ol uti o n ca n be a d mi nistere d S C f or u p t o 7 2 h o urs at 3 7° C or I V f or u p t o 4 8 
h o urs at 4 0° C.  Br o k e n or da ma ge d  Ore nitra m  ta blets s h o ul d n ot be i n geste d b ut s h o ul d be 
ret ur ne d t o t he st u d y site. 
1 1. 4  
S U P P L Y  A N D R E T U R N O F C LI NI C A L S T U D Y  M A T E RI A L  
Arra n g e me nts will be ma de t o e ns ure t he s u bject h as a de q uat e dr u g s u p pl y wit h res pect t o 
t heir st u d y visit sc he d ule.  A d diti o nal Re m o d uli n a n d/ or Ore nitra m s u p pl y ma y occ ur b et wee n 
pr ot oc ol st u d y visits if nee de d.  S u bjects s h o ul d be i nstr ucte d t o ret ur n all use d a n d u n use d 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 0 
Re m o d uli n a n d Ore nitra m, i ncl u di n g e m pt y vials/ b ottles, t o t he a p pr o priate st u d y pers o n nel 
o n a n o n g oi n g basis at e v er y st u d y visit. 
Use d a n d u n use d vials a n d b ottles of st u d y dr u g s h o ul d be retai ne d b y t he st u d y site a n d 
ret ur ne d t o a S p o ns or- desi g nate d l ocati o n f or destr ucti o n, or destr o ye d a n d d oc u me nte d 
acc or di n g t o i nstit uti o nal p olic y f oll o wi n g c o ns ultati o n wit h t he S p o ns or after fi nal dr u g 
acc o u nta bilit y b y S p o ns or pers o n nel or d ele gat e . 
1 1. 5  
D R U G  A C C O U N T A BI LI T Y  
T he I n vesti gat or is r es p o nsi ble f or st u d y dr u g acc o u nta bilit y a n d rec o nciliati o n o verall a n d o n 
a per s u bject basis.  Dr u g acc o u nta bilit y rec or ds will be mai ntai ne d d uri n g t he st u d y, a n d 
t hese rec or ds will i ncl u de t he a m o u nt of st u d y dr u g recei v e d fr o m t he S p o ns or, t he a m o u nt 
dis pe nse d t o eac h s u bject, a n d t he a m o u nt of u n us e d dr u g or e m pt y c o nt ai ners .  St u d y site or 
p har mac y  p ers o n nel s h o ul d assess  dr u g ret ur n e d a n d d osi n g i nf or mati o n t o c o nfir m dr u g 
acc o u nta bilit y.  O nce a r e prese nt ati ve fr o m t he S p o ns or is a ble t o c o nfir m dr u g acc o u nt a bilit y 
f or t hat s u bject, st u d y dr u g ca n be ret ur ne d t o a S p o ns or- desi g nate d l ocati o n f or destr ucti o n, 
or destr o ye d a n d d oc u me nte d acc or di n g t o i nstit uti o nal p olic y f oll o wi n g c o ns ultati o n wit h t he 
S p o ns or after fi n al dr u g acc o u nta bilit y b y S p o ns or pers o n nel or d ele gate . 
1 2  
R E G U L A T O R Y  A N D E T HI C A L O B LI G A TI O N  
1 2. 1  
U S F D A O R  A P P LI C A B L E R E G U L A T O R Y R E Q UI R E M E N T S  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h I C H a n d G C P g ui deli nes a n d all a p plica ble 
nati o nal re g ulati o ns.  T he S p o ns or will o btai n t he re q uire d a p pr o v al fr o m eac h nati o nal 
re g ulat or y a ut h orit y t o c o n d uct t he st u d y.  D uri n g t he c o n d uct of t he st u d y, a n a n n ual safet y 
re p ort will be c o m pile d b y t he S p o ns or f or s u b missi o n t o t h ose re g ulat or y a ut h orities a n d 
I R Bs/et hics c o m mittees  t hat re q uire it.  A n y a d dit i o nal nati o nal re p orti n g re q uire me nts as 
s pecifie d b y t he a p plica ble re g ulati o ns, re g ulat or y a ut h orities, or I R B/et hics c o m mittee will 
als o be f ulfille d d uri n g t h e c o n d uct of t he st u d y. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 1 
1 2. 2  
I N F O R M E D C O N S E N T R E Q UI R E M E N T S  
Bef ore a s u bj ect is e nr oll e d i n t he st u d y, t he I n vesti gat or or his/ her desi g nees m ust e x plai n t he 
p ur p ose a n d nat ure of t he st u d y, i ncl u di n g p ote ntial be nefits a n d ris ks a n d all st u d y 
pr oce d ures t o t he s u bject.  T he s u bject m ust si g n a n d date a n I R B/ et hics c o m mittee-a p pr o ve d 
I C F pri or t o t he c o n d u ct of a n y st u d y-rel ate d acti vities.  A c o p y of t he si g ne d c o nse nt f or m 
will be gi ve n t o t he s u bject, a n d t he ori gi nal will be retai ne d i n t he st u d y sit e’s rec or ds. 
T he I C F a n d a n y c h a n ges t o t he I C F ma de d uri n g t he c o urse of t he st u d y m ust be a gree d t o b y 
t he S p o ns or or desi g nee a n d t he I R B/I E C pri or t o its use a n d m ust be i n c o m plia nce wit h all 
I C H G C P, l ocal r e g ulat or y re q uire me nts, a n d l e gal re q uire me nts.   
T he ori gi nal si g ne d c o p y of t he I C F m ust be mai nt ai ne d b y t he I n vesti gat or a n d is s u bject t o 
i ns pecti o n b y a re pr ese nt ati ve of t he S p o ns or, t heir re prese ntati ves, a u dit ors, t he I R B/I E C, 
a n d/ or re g ulat or y a ge n cies. 
1 2. 3  
I N D E P E N D E N T E T HI C S C O M MI T T E E/I N S TI T U TI O N A L R E VI E W B O A R D  
Pri or t o st u d y i nitiati o n at eac h site, t he I n v esti gat or will o btai n a p pr o val f or t he st u d y fr o m a n 
a p pr o priate I R B/I E C a n d pr o vi de t he S p o ns or wit h a c o p y of t he a p pr o val l etter.  T he 
I R B/I E C m ust als o re vie w a n d a p pr o v e t he st u d y site’s I C F, pr ot oc ol, I n v esti gat or’s 
Br oc h ure, safet y u p dates, a n n ual pr o gress re p orts, a n d a n y ot her writte n i nf or mati o n pr o vi de d 
t o t he s u bject pri or t o e nr oll me nt, as well as a n y a d vertisi n g materials use d f or s u bject 
recr uit me nt.  C o pies of t he I C F a n d a d vertisi n g materials m ust be f or w ar d e d t o t he S p o ns or 
f or re vie w bef ore s u b missi o n t o t he I R B/I E C pri or t o t he start of t he st u d y. 
If, d uri n g t he st u d y, it is necessar y t o a me n d eit her t he pr ot oc ol or t he I C F, t he I n v esti gat or is 
res p o nsi ble f or o btai ni n g I R B/I E C a p pr o v al of t he a me n de d d oc u m e nts pri or t o 
i m ple me ntati o n.  C o pies of t he I R B/I E C c orres p o n de nce a n d a p pr o v al letters m ust be se nt t o 
t he S p o ns or. 
D uri n g t he c o n d uct of t h e st u d y, a n a n n ual pr o gress re p ort will be c o m pile d b y t he S p o ns or 
f or s u b missi o n t o t h ose I R Bs/I E Cs t hat re q uire it. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 2 
A writte n s u m mar y of t h e st u d y will be s u p plie d b y t he I n vesti gat or t o t he I R B/I E C f oll o wi n g 
st u d y c o m pleti o n or ter mi nati o n acc or di n g t o t he I R B’s or I E C’s sta n d ar d pr oce d ures.  
A d diti o nal u p dates will be s u p plie d i n acc or da nce wit h t he I R B/I E C’s sta n d ar d pr oce d ures. 
1 2. 4  
P R E S T U D Y  D O C U M E N T A TI O N R E Q UI R E M E N T S  
Pri or t o t he c o m me nce m e nt of t he cli nical st u d y, t he f oll o wi n g d oc u me nts will be pr o vi de d t o 
t he site: I n v esti gat or’s Br oc h ure, a p pr o ve d Ore nitra m U S PI, a p pr o ve d Re m o d uli n U S PI, 
pr ot oc ol, I C F, b u d get a gr ee me nt, a n d e C R F C o m pleti o n G ui deli nes. 
T he st u d y site will be re q uire d t o pr o vi de t he f oll o wi n g d oc u me nts t o U nite d T hera p e utics 
C or p orati o n or desi g nee pri or t o st u d y start: t he si g nat ure pa g e of t he pr ot o c ol, I R B/I E C 
C o m p ositi o n a n d R oster, I R B/I E C pr ot oc ol a n d i nf or me d c o nse nt f or m a p pr o val letters , 
F or m  F D A 1 5 7 2, Fi n a nci al Discl os ure F or m , a n d C urric ul u m Vitae of st u d y staff liste d o n t he 
F or m  F D A  1 5 7 2. 
1 2. 5  
S U B J E C T  C O N FI D E N TI A LI T Y  
E ver y eff ort will be ma d e t o kee p me d ical i nf or m ati o n c o nfi de ntial.  U nite d T hera p e utics 
C or p orati o n, t he F D A or ot her re g ulat or y b o di es, a n d t he I R B/ et hics c o m mittee g o ver ni n g 
t his st u d y ma y i ns pect t he me dical rec or ds of a n y s u bject i n v ol ve d i n t his st u d y.  T he 
I n v esti gat or ma y r elease t he s u bject’s me dical rec or ds t o e m pl o yees or a g e nts of t he S p o ns or, 
t he I R B/et hics c o m mittee  or t he F D A or a p pr o priate l ocal re g ulat or y a ge n cies f or p ur p os es of 
c hec ki n g t he acc urac y of t he data.  A n u m ber will be assi g ne d t o all s u bjects, a n d a n y re p ort 
p u blis he d will n ot i de ntif y t he s u bject’s na me. 
1 3  
A D MI NI S T R A TI V E  A N D L E G A L O B LI G A TI O N S  
1 3. 1  
P R O T O C O L  A M E N D M E N T S A N D S T U D Y T E R MI N A TI O N  
Pr ot oc ol a me n d me nts t hat c o ul d p ote ntiall y a d vers el y affect t he safet y of partici pati n g 
s u bjects or t hat alter t he s c o pe of t he i n vesti gati o n, t he scie ntific q ualit y of t he st u d y, t he 
e x peri me ntal desi g n, d os a ges, d urati o n of t hera p y, assess me nt varia bles, t h e n u m ber of 
s u bjects treate d, or s u bject selecti o n criteria ma y be ma de o nl y aft er c o ns ultati o n bet wee n 
U nite d T hera p e utics C or p orati o n or its desi g nee a n d t he I n vesti gat or. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 3 
All pr ot oc ol a me n d me nts m ust be s u b mitte d t o a n d a p pr o ve d b y t he a p pr o priate re g ul at or y 
a ut h orities a n d I R B/ E C pri or t o i m ple me ntati o n.  
A re p ort d oc u m e nti n g st u d y ter mi nati o n m ust als o be s u b mitte d t o a n d ac k n o wle d ge d b y t he 
a p pr o priate I R B/ E C f or eac h st u d y site. 
At t he e n d of t he st u d y, w here a p plica ble, a fi nal re p ort will be pr o vi de d t o t he l ocal 
re g ulat or y a g e ncies. 
1 3. 2  
S T U D Y  D O C U M E N T A TI O N A N D S T O R A G E  
I n acc or da n ce wit h fe d er al/ nati o nal re g ulati o ns, I C H, a n d G C P g ui deli nes, t he I n v esti gat or 
m ust retai n st u d y rec or ds f or at least 2 years after t he last a p pr o val of a mar keti n g a p plicati o n 
i n a n I C H re gi o n a n d u ntil t here ar e n o pe n di n g or c o nte m plate d mar k eti n g a p plicati o ns i n a n 
I C H re gi o n or at least 2 years ha v e ela ps e d si nce t he f or mal disc o nti n uati o n of cli nical 
de vel o p me nt of t he i n vesti gati o nal pr o d u ct.  T he I n vesti gat or m ust n otif y U nite d T hera p e utics 
C or p orati o n bef or e a n y dis p osal or c ha n ge i n l ocati o n of st u d y rec or ds. 
1 3. 3  
S T U D Y  M O NI T O RI N G A N D D A T A C O L L E C TI O N  
I n acc or da n ce wit h fe d er al/ nati o nal re g ulati o ns, I C H, a n d G C P g ui deli nes, m o nit ors f or 
U nite d  T hera p e utics C or p orati o n or its desi g nee will peri o dicall y c o ntact t he st u d y site a n d 
c o ul d c o n d uct o n- site visits.  D uri n g t hese visits, t he m o nit or will at a mi ni m u m c o nfir m 
et hical treat me nt of s u bj ects, assess st u d y pr o gress, re vie w dat a c ollect e d, c o n d uct s o urce 
d oc u me nt verificati o n, verif y dr u g acc o u nta bilit y peri o dicall y, a n d i de ntif y a n y iss ues 
re q uiri n g res ol uti o n. 
T he I n vesti gat or a grees t o all o w t he m o nit or direct access t o all rele va nt d o c u me nts a n d t o 
all ocate his/ her ti me a n d his/ her staff t o t he m o nit or t o disc uss a n y fi n di n gs or a n y rel e va nt 
iss ues. 
It is t he r es p o nsi bilit y of t he I n v esti gat or t o e ns ure t hat t he st u d y is c o n d ucte d i n acc or da nce 
wit h t he pr ot oc ol, Declar ati o n of Helsi n ki, I C H G C P, a n d a p plica ble re g ul at or y re q uire me nts, 
a n d t hat vali d data are e ntere d i n t he e C R F. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 4 
T o ac hie ve t his o bjecti ve, t he m o nit or’s d uties are t o ai d t he I n v esti gat or a n d t he S p o ns or i n 
t he mai nte na nce of c o m plete, le gi ble, well or ga ni ze d, a n d easil y retrie va bl e data.  Bef ore t he 
e nr oll me nt of a n y s u bject i n t his st u d y, t he S p o ns or or t heir desi g nee will re vie w wit h t he 
I n v esti gat or a n d site pers o n nel t he f oll o wi n g d oc u me nts: pr ot oc ol, I n v esti gat or’s Br oc h ure, 
e C R Fs a n d pr oce d ur es f or t heir c o m pleti o n, i nf or me d c o nse nt pr ocess, a n d t he pr ocess f or 
re p orti n g S A Es. 
T he I n vesti gat or will per mit t he S p o ns or or t heir desi g nee t o m o nit or t he st u d y as fre q ue ntl y 
as dee me d n ecess ar y t o d eter mi ne t hat data rec or di n g a n d pr ot oc ol a d here n ce are satisfact or y.  
D uri n g t he m o nit ori n g visits, i nf or mati o n rec or de d o n t he e C R Fs will be v erifie d a g ai nst 
s o urce d oc um e nts , a n d re q uests f or clarificati o n or c orrecti o n ma y be ma d e.  After t he e C R F 
data ar e e ntere d b y t he site, t he cli nical res earc h ass ociate will re vie w t he d ata f or safet y 
i nf or mati o n, c o m plete ness, acc ur ac y, a n d l o gical c o nsiste nc y.  C o m p uter pr o gra ms t hat 
i de ntif y data i nc o nsiste ncies ma y be use d t o hel p m o nit or t he cli nical st u d y.  If necessar y, 
re q uests f or clarificati o n or c orr ecti o n will be se nt t o I n vesti gat ors.  T h e I n vesti gat or a n d 
his / her staff will be e x p ecte d t o c o o perate wit h t h e m o nit or a n d pr o vi de a n y missi n g 
i nf or mati o n, w he ne v er p ossi ble. 
All m o nit ori n g acti vities will be re p orte d a n d arc hi ve d.   I n a d diti o n, m o nit ori n g visits will be 
d oc u me nte d at t he i n vesti gati o nal site b y si g nat ure a n d date o n t h e st u d y-s pecific m o nit ori n g 
l o g. 
1 3. 4  
E T HI C A L  C O N D U C T O F T H E S T U D Y  
G o o d Cli nical Practice is a n i nter nati o nal et hical a n d scie ntific q ualit y sta n dar d f or d esi g ni n g, 
c o n d ucti n g, rec or di n g, a n d re p orti n g st u dies t hat i n v ol ve h u ma n s u bjects.  C o m plia nce wit h 
t his sta n dar d pr o vi des p u blic ass ura nce t hat t he ri g hts, safet y, a n d w ell bei n g of st u d y s u bjects 
are pr ot ecte d, c o nsiste nt wit h t he pri nci ples t hat ha ve t heir ori gi n i n t he D eclarati o n of 
Helsi n ki, a n d t hat t he cli nical st u d y data are cre di ble.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 5 
1 4  
R E F E R E N C E S  
A merica n T h oraci c S ociet y  C o m mittee o n Pr oficie nc y Sta n dar ds f or Cli nical P ul m o nar y 
F u ncti o n La b or at ories.  A T S state me nt: g ui deli nes f or t he si x -mi n ute wal k test.  A m J Res pir 
Crit C are Me d .  2 0 0 2; 1 6 6( 1): 1 1 1 – 1 1 7. 
Balas u bra ma nia n V, M essic k C R, Br o deric k M, et al.  D osi n g c haracteristi cs of oral 
tre pr osti nil i n real-w orl d cli nical practice.  P oster p rese nte d at t he A merica n T h oracic S oci et y 
2 0 1 7 I nter nati o nal C o n ve nti o n; Ma y 1 9- 2 4, 2 0 1 7; Was hi n gt o n, D C. 
Be nza R L, Miller D P, G o m ber g - Maitla n d M, et al. Pre dicti n g s ur vi val i n p ul m o nar y arteri al 
h y perte nsi o n: i nsi g hts fr o m t he Re gistr y t o E val uate Earl y a n d L o n g- Ter m P ul m o nar y 
Arterial H y p erte nsi o n Disease Ma n a ge me nt ( R E V E A L). Circ ulati o n. 2 0 1 0; 1 2 2( 2): 1 6 4 – 7 2. 
Be nza R L, G o m ber g - Maitla n d M, Naeije R, et al.  Pr o g n ostic fact ors ass o ciate d wit h 
i ncreas e d s ur vi val i n pati e nts wit h p ul m o nar y arterial h y perte nsi o n treate d wit h s u bc uta ne o us 
tre pr osti nil i n ra n d o mize d, place b o-c o ntr olle d trials.  J He art L u n g Tr a ns pl a nt .  
2 0 1 1; 3 0( 9): 9 8 2 – 9 8 9. 
Be nza R L, G o m ber g - Maitla n d C G, Far ber H W, et al. C o m paris o n of T hree Ris k Assess me nt 
Strate gies as Pre dict ors of O ne - Y ear S ur vi val i n U S P ul m o nar y Arterial H y perte nsi o n ( P A H) 
Patie nts. P oster prese nte d at t he A merica n T h oracic S ociet y 2 0 1 8 I nt er nati o nal C o n ve nti o n; 
Ma y 1 8- 2 3, 2 0 1 8; Sa n Die g o, C A. 
C ha ki nala M M, Fel d ma n J P, Risc har d F, et al.   Tra nsiti o n fr o m pare nteral t o oral tre pr osti nil 
i n p ul m o nar y arterial h y p erte nsi o n.  J H e art L u n g Tr a ns pl a nt .  2 0 1 7; 3 6( 2): 1 9 3 – 2 0 1. 
Fijal k o ws ka A, K urz y na M, T or bic ki A, et al.  Ser u m N -ter mi nal brai n natri uretic pe pti de as a 
pr o g n ostic para met er i n patie nts wit h p ul m o nar y h y perte nsi o n.  C hest .  2 0 0 6; 1 2 9( 5): 1 3 1 3 –
1 3 2 1. 
Gr ü ni g E, Be nja mi n N, L a n ge TJ, et al.  Safet y, t olera bilit y a n d cli nical effects of a ra pi d dos e 
titrati o n of s u bc uta ne o us tre pr osti nil t hera p y i n p ul m o nar y arterial h y pert e nsi o n: a p r os pecti ve 
m ulti -ce ntre trial.  Res pir ati o n .  2 0 1 6; 9 2( 6): 3 6 2 – 3 7 0. 
Ha nse n L, Risc har d F, K n o per S.  Ra pi d i n patie nt t itrati o n of i ntra ve n o us tre pr osti nil f or 
se vere p ul m o nar y a rt erial h y perte nsi o n.  J H e art L u n g Tr a ns pl a nt .  2 0 1 4; 3 3( 4 S u p pl): S 3 0 9.  
[a bstract] 
Hire mat h J, T ha ni kac hal a m S, Pari k h K, et al.  E x ercise i m pr o ve m e nt a n d plas ma bi o mar ker 
c ha n ges wit h i ntra v e n o us tre pr osti nil t hera p y f or p ul m o nar y arteri al h y perte nsi o n: a 
place b o -c o ntr olle d trial.  J He art L u n g Tr a ns pl a nt .  2 0 1 0; 2 9( 2): 1 3 7 – 1 4 9. 
H olla n d A E, S pr uit M A, Tr o osters T, et al.  A n official E ur o pea n Res pirat or y 
S ociet y/ A merica n T h or acic S ociet y tec h nical sta n dar d: fiel d wal ki n g tests i n c hr o nic 
res pirat or y disease.  E ur  Res pir  J.  2 0 1 4; 4 4( 6): 1 4 2 8 – 1 4 4 6. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 6 
Ji n g Z C, Pari k h K, P uli d o T, et al.  Efficac y a n d safet y of oral tre pr osti nil m o n ot hera p y f or 
t he treat me nt of p ul m o nar y arteri al h y perte nsi o n: a ra n d o mize d, c o ntr olle d trial.  Circ ul ati o n .  
2 0 1 3; 1 2 7( 5): 6 2 4 – 6 3 3. 
K u mar P, Ar nes o n C, Lali berte K, et al.  D os e -res p o nse relati o ns hi p of o ral tre pr osti nil 
d i ola mi ne ( T R E) i n patie nts w it h p ul m o nar y a rteri al h y perte nsi o n ( P A H).  A m J Res pir Crit 
C are Me d .  2 0 1 3; 1 8 7: A 3 2 7 1.  [a bstract] 
Ore nitra m ®  [ pac ka ge i ns ert].  Researc h Tria n gle Par k, N C : U nite d T hera p e utics C or p; 2 0 1 7. 
Re m o d uli n ®  (tre pr osti nil s o di u m) I njecti o n [ pac k a ge i nsert].  Researc h Tria n gle Par k, N C: 
U nite d T hera p e utics C or p orati o n; 2 0 1 4. 
Si m o n nea u G, Barst RJ, Galie N, et al.  C o nti n u o us s u bc uta ne o us i nf usi o n of tre pr osti nil, a 
pr ostac ycli n a n al o g ue, i n patie nts wit h p ul m o nar y arterial h y p erte nsi o n: a d o u ble- bli n d, 
ra n d o mize d, place b o-c o ntr olle d trial.  A m J Res pir Crit C are Me d .  2 0 0 2; 1 6 5( 6): 8 0 0 – 8 0 4. 
Sit b o n O, Ma nes A, Jais X, et al.  Ra pi d s witc h fr o m i ntra ve n o us e p o pr ost e n ol t o i ntra ve n o us 
tre pr osti nil i n patie nts wit h p ul m o nar y arterial h y p erte nsi o n.  J C ar di ov asc P h ar m ac ol .  
2 0 0 7; 4 9( 1): 1 – 5. 
Ta ps o n V F, T orres F, Ker mee n F, et al.  Oral tre pr osti nil f or t he treat me nt of p ul m o nar y 
arterial h y p erte nsi o n i n p atie nts o n bac k gr o u n d e n d ot heli n rece pt or a nta g o nist a n d/ or 
p h os p h o diesterase t y pe 5 i n hi bit or t hera p y (t he F R E E D O M- C st u d y): a ra n d o mize d 
c o ntr olle d trial.  C hest .  2 0 1 2; 1 4 2( 6): 1 3 8 3 – 1 3 9 0. 
Ta ps o n V F, Ji n g Z C, X u K F, et al.  Oral tre pr osti nil f or t he treat me nt of p ul m o nar y arterial 
h y perte nsi o n i n patie nts r ecei vi n g bac k gr o u n d e n d ot heli n rece pt or a nta g o nist a n d 
p h os p h o diesterase t y pe 5 i n hi bit or t hera p y (t he F R E E D O M- C 2 st u d y): a ra n d o mize d 
c o ntr olle d trial.  C hes t.  2 0 1 3; 1 4 4( 3): 9 5 2 – 9 5 8. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 7 
1 5  
A P P E N DI C E S  
A p pe n di x A.  
6- Mi n ute  W al k Test a n d B or g D ys p ne a Sc ore 
T he 6 -mi n ute wal k test ( 6 M W T) s h o ul d be a d mi nistere d b y t he sa me test er at eac h st u d y site 
t hr o u g h o ut t he st u d y. 
T he a d mi nistrati o n of t he test a n d s pecificati o ns of t he testi n g area s h o ul d b e ge nerall y 
c o nsiste nt wit h t he A merica n T h oracic S ociet y g ui deli nes a n d t he us ual practice of t he st u d y 
site.  If t h e s u bject w as assesse d at Baseli ne usi n g o x y ge n t hera p y, t he n all 6 M W Ts d uri n g t he 
st u d y s h o ul d be c o n d ucte d wit h t he sa me o x y ge n fl o w rate a n d m o de of a d mi nistrati o n. 
Si milarl y, if t he Baseli ne assess me nt was c o n d u ct e d wit h o ut o x y ge n t hera p y, t he n s u bse q ue nt 
assess me nts s h o ul d als o be c o n d ucte d wit h o ut o x y ge n t hera p y.  Bef ore eac h 6 M W T, t he 
s u bject s h o ul d rest (seat e d) f or at least 1 0 mi n utes. 
T he ar ea use d f or t he 6 M W T s h o ul d be pre meas ure d at a p pr o xi matel y 3 0 m eters i n le n gt h 
( b ut n o s h orter t ha n 1 5 m eters [ 1 6 yar ds or 5 0 feet] i n le n gt h) a n d at least 2 t o 3 meters i n 
wi dt h.  T here m ust be n o t ur ns or si g nifica nt c ur v es t o t he 6 M W T area.  T he le n gt h s h o ul d be 
mar ke d wit h gra d ati o ns t o e ns ure t he acc urate meas ure me nt of t he dista n ce wal ke d.  T he area 
s h o ul d be well ve ntilate d.  T he tester ma y b e at t h e starti n g e n d of t he c orri d or or at t he 
mi d p oi nt of t he c orri d or wit h a st o p- watc h.  I nter mitte nt rest peri o ds are all o we d if t he s u bject 
ca n n o l o n ger c o nti n ue.  If t he s u bject nee ds t o rest briefl y, he/s he ma y sta n d or sit a n d t he n 
be gi n a gai n w he n h e/s he is s ufficie ntl y reste d, b ut t he cl oc k will c o nti n ue t o r u n.  At t he e n d 
of 6 mi n utes, t he tester will call “st o p wal ki n g w here y o u are” w hile si m ulta ne o usl y st o p pi n g 
t he watc h, a n d t h e n meas ure t he dista nce wal ke d. 
Tester I nstr ucti o ns t o  t he S u bject  
S u bjects will be i nstr ucte d t hat t he prece di n g meal s h o ul d be li g ht.  S u bjects s h o ul d be t ol d t o 
wear c o mf orta ble cl ot hi n g a n d s nea kers or c o mf orta ble wal ki n g s h oes.  T he pers o n 
a d mi nisteri n g t he test will use t he f oll o wi n g  e x act dial o g ue wit h t he s u bject: 
“ T he p ur p ose of t his test is t o fi n d o ut h o w far y o u ca n wal k i n 6 mi n utes.  Y o u will start 
wal ki n g fr o m t his p oi nt a n d f oll o w t he hall wa y t o t he mar ker (e g, c h air) at t he e n d, t ur n 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 8 
ar o u n d a n d w al k bac k.  W he n y o u arri ve bac k at t he starti n g p oi nt y o u will wal k bac k a n d 
f ort h a gai n.” 
“ Y o u will wal k bac k a n d f ort h as ma n y ti mes as y o u ca n i n t he 6- mi n ute peri o d.  Y o u ma y 
st o p wal ki n g a n d rest if y o u nee d t o rest.  J ust re m ai n w here y o u are u ntil y o u ca n wal k a gai n.  
H o we ver, t he m ost i m p orta nt t hi n g a b o ut t he test is t hat y o u c o ver as m uc h gr o u n d as y o u 
p ossi bl y ca n d uri n g t he 6 mi n utes.  I will tell y o u  t he ti me, a n d I will let y o u k n o w w he n t he 
6 mi n utes are u p.  W h e n I s a y S T O P, please sta n d ri g ht w here y o u are. ”  
After t hese i nstr u cti o ns are gi ve n t o t he s u bject, t h e pers o n a d mi nisteri n g t h e test will t he n 
as k: 
“ D o y o u ha ve a n y q uesti o ns a b o ut t he test?” 
T he pers o n a d mi nisteri n g t he test will t he n start t he test b y sa yi n g t he f oll o wi n g t o t he s u bject:  
“ Are y o u rea d y ?”  
“ Start wal ki n g w he n I s a y ‘ G o.’” 
T he pe rs o n a d mi nisteri n g t he test will tell t he s u bject t he ti me at eac h mi n ute b y sa yi n g: 
“ Y o u ha ve 5 mi n utes t o g o.” 
“ Y o u ha ve 4 mi n utes t o g o.” 
“ Y o u ha ve 3 mi n utes t o g o.” 
“ Y o u ha ve 2 mi n utes t o g o.” 
“ Y o u ha ve 1 mi n ute t o g o.” 
At 6 mi n utes, t he pers o n a d mi nis teri n g t he test will tell t he s u bject:  
“ St o p w here y o u are. ” 
N o ot her i nstr ucti o n or e nc o ura ge m e nt will be gi ve n d uri n g t he test.  E ye c o ntact wit h t he 
s u bject s h o ul d be a v oi de d d uri n g t he test. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 6 9 
B or g D ys p ne a Sc ore 
I m me diat el y after t he wal k, t he pers o n a d mi nisteri n g t he test will o btai n a rati n g of d ys p nea 
usi n g t he B or g d ys p nea s cale.  T he p ers o n will use t he f oll o wi n g dial o g ue:  
“I w o ul d li ke t o use t he f oll o wi n g scale t o descri b e h o w o ut of breat h y o u are (scale s h o w n t o 
s u bject).  T his scale us es 0 f or n o s h ort ness of breat h at all a n d 1 0 is t he w orst s h ort ness of 
breat h y o u ha v e e ver ha d .  Please p oi nt t o a n u m ber t hat tells me h o w s h ort of breat h y o u feel 
ri g ht n o w.” 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 0 
A p pe n di x B.  
W orl d He alt h Or g a niz ati o n F u ncti o n al Cl assific ati o n f or P ul m o n ar y 
H y perte nsti o n  
Cl ass I : S u bjects wit h p ul m o nar y h y perte nsi o n b ut wit h o ut res ulti n g li mitati o n of p h ysical 
acti vit y.  Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue d ys p nea or fati g u e, c hest pai n, or 
near s y nc o p e.  
Cl ass II : S u bjects wit h p ul m o nar y h y perte nsi o n res ulti n g i n sli g ht li mitati o n of p h ysical 
acti vit y.  T hese s u bjects are c o mf orta ble at rest, b ut or di nar y p h ysical acti vit y ca uses u n d ue 
d ys p nea or f ati g ue, c hest pai n, or near s y nc o pe. 
Cl ass III : S u bjects wit h p ul m o nar y h y perte nsi o n res ulti n g i n mar ke d li mitati o n of p h ysical 
acti vit y.  T hese s u bjects are c o mf orta ble at rest.  Or di nar y acti vit y ca uses u n d ue d ys p nea or 
fati g ue, c hest p ai n, or near s y nc o pe. 
Cl ass I V : S u bjects wit h p ul m o nar y h y perte nsi o n wit h i na bilit y t o carr y o ut a n y p h ysical 
acti vit y wit h o ut s y m pt o ms.  T hese s u bjects ma nifest si g ns of ri g ht heart fail ures.  D ys p nea 
a n d/ or fati g ue c o ul d be prese nt e v e n at rest.  Disc o mf ort is i ncrease d b y a n y p h ysic al acti vit y. 
 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 1 
A p pe n di x C.  
G ui deli nes a n d Defi niti o ns f or Rec o r di n g A d verse E ve nts  
T he I n vesti gat or or a desi g nate d me m ber of his/ her staff will pr o be e ver y s u bject f or a n y 
a d verse e ve nts t hat c o ul d ha ve occ urre d.  T he I n v esti gat or s h o ul d al wa ys as k t he sa me 
q uesti o n w he n c o n d ucti n g t he ver bal pr o b e t o e ns ure u nif or mit y bet wee n s u bjects.  T he 
I n v esti gat or s h o ul d as k:  
“ H o w are y o u d oi n g (f eeli n g)?” 
Base d o n t he s u bject’s r es p o nse t o t his q uesti o n, t he I n vesti gat or s h o ul d as k a d diti o nal 
q uesti o ns rele va nt t o t he s pecific c o m plai nt s uc h as: 
“ H o w se v ere is/ was t he s y m pt o m?”  
“ H o w ofte n di d t he s y m pt o m occ ur?” 
“ H o w l o n g di d t he s y m pt o m last?” 
It is t he I n v esti gat or’s r es p o nsi bilit y t o re vie w t he res ults of all dia g n ostic a n d la b orat or y tests 
as t he y bec o me a vaila ble a n d ascertai n if t here is a cli nicall y si g nifica nt c ha n ge fr o m 
Baseli ne.  If t he r es ults ar e deter mi ne d t o be a cli ni call y si g nifica nt c ha n g e fr o m Baseli ne, it 
s h o ul d be re p orte d as a n a d verse e ve nt.  T he I n vesti gat or ca n re peat t he dia g n ostic pr ocess or 
la b orat or y test or r e q uest a d diti o nal tests t o verif y t he res ults of t he ori gi nal tests.  W he n 
p ossi ble, a dia g n osis ass ociate d wit h t he s u bject’s a b n or malit y s h o ul d be use d as t he re p orte d 
a d verse e ve nt.  
Usi n g pr o vi de d defi niti o ns, t he I n v esti gat or will t he n:  
1.  Rate t he i nte nsit y a n d seri o us ness of t he a d verse e ve nt  
2.  Esti mate t he ca usalit y of t he a d vers e e ve nt t o st u d y dr u g 
3.  N ote acti o ns ta ke n t o c o u nteract t he a d vers e e ve nt  
Defi niti o ns of I nte nsit y, Seri o us ness, C a us alit y, Acti o n T a ke n, a n d O utc o me 
I nte nsit y 
A n assess me nt of t he r elati ve i nte nsit y (se verit y) of a n a d verse e v e nt is base d o n t he 
I n v esti gat or’s cli nical j u d ge me nt.  T he m a xi m u m i nte nsit y e nc o u ntere d d uri n g t he e val uati o n 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 2 
peri o d s h o ul d be c hec ke d.  T he assess me nt of i nte nsit y s h o ul d be i n de pe n de nt of t he 
assess me nt of t he seri o us ness of t he a d v erse e ve nt.  
Seri o us ness  
A seri o us a d verse e v e nt ( S A E) is o ne t hat re prese nts a n a ct ual or p ote ntial si g nifica nt hazar d.  
T his i ncl u des, b ut is n ot li mite d t o, a n e ve nt t hat is fatal, life -t hreate ni n g, per ma ne ntl y or 
se verel y disa bli n g, r e q uir es or pr ol o n gs i n patie nt h os pitalizati o n *, is a c o n ge nital a b n or malit y 
( offs pri n g of s u bject), or is me dicall y si g nifica nt (i m p orta nt me dical e ve nts t hat ma y n ot 
res ult i n deat h, be life-t hr eate ni n g, or re q uire h os pitalizati o n ca n be c o nsi dere d a n S A E w he n, 
base d u p o n a p pr o priate me dical j u d g me nt, t he y c o ul d je o par dize t he s u bj ect a n d c o ul d re q uire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he defi niti o n). 
* H os pitalizati o ns t hat w o ul d n ot be c o nsi dere d S A Es i ncl u de t h ose f or:  
•  R o uti ne treat me nt or m o nit ori n g of t he st u d y i n dicati o n n ot ass ociate d wit h a n y 
deteri orati o n  i n c o n diti o n (e g, h os pitalizati o n f or a r o uti ne ri g ht heart cat het erizati o n).  
•  Treat me nt w hic h was electi ve or pre pl a n ne d, f or a pre-e xisti n g c o n diti o n n ot 
ass ociate d wit h a n y d eteri orati o n i n c o n diti o n ( e g, pre pla n ne d o p erati o n w hi c h d oes 
n ot lea d t o f ur t her c o m plicati o ns, etc). 
•  Treat me nt of a n y e mer ge nc y, i n a n o ut patie nt setti n g f or a n e v e nt n ot f ulfilli n g a n y of 
t he defi niti o ns of seri o us ness as liste d a b o ve a n d n ot res ulti n g i n h os pital a d missi o n. 
C a us alit y 
A n esti mate of ca usalit y bet wee n a s pecifi e d a d verse e ve nt a n d t he st u d y dr u g is ma de b y t he 
I n v esti gat or.  Se ver al fact ors s h o ul d be c o nsi dere d w he n deter mi ni n g ca usalit y.  T hese fact ors 
i ncl u de te m p oral r elati o ns hi p a n d res p o nse t o wit h dra wal or rei ntr o d ucti o n of t he st u d y dr u g. 
Defi niti o ns of t he ca us alit y cate g ories are as f oll o ws:  
•  N O T R E L A T E D – T h ere is n ot a te m p oral relati o ns hi p t o st u d y dr u g a d mi nistrati o n 
(t o o earl y, or lat e, or st u d y dr u g n ot ta ke n), or t here is a reas o na ble ca usal relati o ns hi p 
bet wee n a n ot her dr u g, or c o nc urre nt disease a n d t he S A E, or a n y of t h e f oll o wi n g: 
•  A n e ve nt t hat prece d es t he first a d mi nistrati o n of st u d y dr u g 
•  A n e ve nt f or w hic h t he ca use is clearl y relate d t o a n e xter n al e ve nt  
•  Te m p oral rel ati o ns hi p t o st u d y dr u g is at y pic al 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 3 
•  Is rea dil y e x plai n e d b y a n i nterc urre nt ill ness A N D has a n e x p ecte d le v el of 
se verit y, d urati o n a n d res ol uti o n 
•  A n alter nati ve e x pla nati o n (c o nc o mita nt dr u g, i nterc urre nt ill ness) is li kel y  
•  P O S SI B L E – T here is a r eas o na ble ca usal relati o ns hi p bet wee n t he  st u d y dr u g a n d t he 
S A E.  Dec halle n g e i nf or mati o n is lac ki n g or u nclear, st u d y dr u g a d mi nistrati o n was 
n ot m o difie d i n res p o nse t o t he S A E, or a n y of t he f oll o wi n g: 
•  Has a r eas o na ble t e m p or al relati o ns hi p t o st u d y dr u g 
•  T he e ve nt has a pla usi ble bi ol o gical li n k t o t he acti vit y of t he st u d y dr u g 
•  Is u nli kel y t o be r elate d t o a n i nterc urre nt ill ness or has a n u ne x p ecte d d e gree 
of se verit y, d ur ati o n, or c o m plicati o n 
•  P R O B A B L E – T here is a reas o na bl e ca us al relati o ns hi p bet wee n t he st u d y dr u g a n d 
t he S AE.  T he e ve nt r es p o n ds t o dec halle n ge – t he e ve nt res ol ves or i m pr o ves wit h 
m o dificati o n of t he st u d y dr u g a d mi nistrati o n. Rec halle n ge (t he ori gi nal st u d y dr u g 
was restarte d) is n ot re q uire d, or a n y of t he f oll o wi n g:  
•  Has a r eas o na ble t e m p oral relati o ns hi p t o st u d y dr u g 
•  T he e ve nt has a pla usi ble bi ol o gic li n k t o t he acti vit y of t he st u d y dr u g 
•  N ot rea dil y e x plai ne d b y a n i nterc urre nt ill ness 
•  N ot rea dil y e x plai ne d b y e xter nal e v e nt 
•  I m pr o v es o n disc o nti n uati o n of st u d y dr u g 
•  If st u d y dr u g has bee n disc o nti n ue d, c o ul d rec ur or rei ntr o d ucti o n of st u d y 
dr u g 
Acti o n T a ke n  
S T U D Y D R U G D O S E M O DI FI C A TI O N  
•  D ose N ot C ha n ge d – T h e d ose or re gi me n of t he st u d y dr u g was n ot c ha n g e d 
•  D ose I ncreas e d – T he d ose or re gi me n of st u d y dr u g was i ncrease d 
•  D ose Decrease d – T he d ose or re gi me n of st u d y dr u g was decrease d 
•  Dr u g I nterr u pte d – A d mi nistrati o n of t he st u d y dr u g was st o p pe d te m p oraril y 
•  Dr u g Wit h dra w n – A d mi nistrati o n of t he st u d y dr u g was st o p pe d per m a ne ntl y a n d n ot 
restarte d 
•  U n k n o w n – C ha n ges t o t he a d mi nistrati o n of t he st u d y dr u g ca n n ot be det er mi ne d. 
•  N ot A p plica ble 
N O T E: O nl y t he last st u d y dr u g acti o n s h o ul d be rec or de d i n t he e C R F.  F or e xa m ple, if t he 
st u d y dr u g is wit h dra w n a n d t he n t he decisi o n is ma de t o restart, t he d os e m o dificati o n of 
“ Dr u g i nterr u pte d” s h o ul d be re p ort e d o n t he S A E f or m. 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 4 
O utc o m e  
•  Fatal – T he st u d y s u bject die d. 
•  N ot Rec o ver e d/ N ot Res ol ve d – T he a d verse e v e nt was o n g oi n g at t he ti me of deat h or 
at t he ti me t he s u bject was l ost t o f oll o w u p.  
•  Rec o ver e d/ Res ol ve d – T he a d vers e e v e nt res ol ve d.  
•  Rec o ver e d/ Res ol ve d wit h Se q uelae – T he a d verse e ve nt is c o nsi dere d res ol ve d; 
h o we ver, t here is r esi d ual se q uelae.  S o me e v e nts d o n ot ret ur n t o baseli ne, s uc h as 
metastasis or pr o gressi o n of disease; h o w e ver, o n ce t hese e v e nts are d eter mi ne d b y t he 
I n v esti gat or t o be sta ble or c hr o nic, t he I n vesti gat or ma y c o nsi der t he e ve nt t o be 
res ol ve d or r es ol ve d wit h se q uelae. 
•  Rec o veri n g/ Res ol vi n g – T he a d verse e v e nt is i m pr o vi n g b ut is n ot yet c o m pletel y 
rec o vere d/r es ol ve d. 
•  U n k n o w n – T he o utc o me of t he a d verse e v e nt ca n n ot b e deter mi ne d.  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 5 
A p pe n di x D.  
Cli nic al L a b or at or y P ar a meters 
Ser u m  C he mistr y  
He m at ol o g y 
Ot her  
S o di u m  
P otassi u m  
C hl ori de 
Bicar b o nate/ C O 2 
Bl o o d urea nitr o ge n/ urea 
Al b u mi n 
Al kali ne p h os p hatase  
Ala ni ne a mi n otra nsferase ( A L T)  
As partate a mi n otra nsferase ( A S T)  
Ga m ma -gl uta m yl tra nsferase ( G G T)  
T otal bilir u bi n  
I n direct bilir u bi n 
Direct bilir u bi n  
Creati ni ne  
Re d bl o o d cell c o u nt  
He m o gl o bi n  
He mat ocrit  
Platelet c o u nt 
W hite bl o o d cell c o u nt 
Pr ot hr o m bi n 
ti me/I nter nati o nal 
N or malize d Rati o  
C D 4 c o u nt (f or s u bjects wit h 
h u ma n i m m u n o deficie nc y 
vir us [ HI V])  
N T -pr o B N P ( ser u m) 
Uri ne pre g na nc y test  (f or fe male 
s u bjects of c hil d beari n g p ote ntial) 
N T -pr o B N P , N-ter mi nal pr o-brai n  natri uretic pe pti de  
Tests b y St u d y Visit  
St u d y Visit  
Cli nic al L a bs  
Scree ni n g 
C he mistr y, he mat ol o g y, N T -pr o B N P, uri ne pre g na nc y test (f or fe male 
s u bjects of c hil d beari n g p ote ntial), C D 4 c o u nt (f or s u bjects wit h HI V) 
Baseli ne  
C he mistr y, he mat ol o g y, N T -pr o B N P, uri ne pre g na nc y test (f or fe male 
s u bjects of c hil d beari n g p ote ntial), a n d o pti o nal phar mac o ge n o mics  
(ge netic /R N A ) a n d bi o mar ker sa m ple  
Tra nsiti o n Visit 
C he mistr y, he mat ol o g y, N T -pr o B N P , uri ne pre g na nc y test (f or fe male 
s u bjects of c hil d beari n g p ote ntial), a n d bi o mar ker testi n g  i n a d diti o n t o 
sc he d ule d testi n g f or t hat st u d y visit 
Wee k 4  
Uri ne pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial)  
Wee k 8  
Uri ne pre g na nc y test (f or fe male s u bjects of c hil d b eari n g p ote ntial) 
Wee k 1 2  
U ri ne pre g na nc y test (f or fe male s u bjects of c hil d beari n g p ote ntial) 
Wee k 1 6 / Earl y St u d y 
Wit h dra wal  
C he mistr y, he mat ol o g y, N T -pr o B N P, uri ne pre g na nc y test (f or fe male 
s u bjects of c hil d beari n g p ote ntial), a n d o pti o nal bi o mar ker sa m ple  
HI V , h u ma n i m m u n o deficie nc y vir us; N T -pr o B N P , N-ter mi nal pr o-brai n  natri uretic pe pti de; R N A , ri b o n ucleic aci d  

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 7 7 
A p pe n di x F.  
C oc kcr oft -G a ult E q u ati o n a n d C hil d -P u g h Sc ore  
C oc kcr oft -G a ult E q u ati o n  
Cr Cl  ( m L/ mi n) = [( 1 4 0 - a ge) x Aj B W  ( k g)] / ( S Cr [ m g/ d L] x 7 2) 
N ote: m ulti pl y res ults b y 0. 8 5 f or fe mal es.  
 
Calc ulati o n of a dj uste d b o d y wei g ht i n k g: 
Aj B W = I B W + 0. 4( A B W - I B W) 
 
Calc ulati o n  of i deal b o d y wei g ht i n k g: 
Males: I B W = 5 0 k g + 2. 3 k g f or eac h i nc h o ver 5 feet 
Fe males: I B W = 4 5. 5 k g + 2 . 3 k g f or eac h i nc h o v er 5 feet 
A b bre viati o ns: Cr Cl – cr eati ni ne cleara n ce; Aj B W – a dj uste d b o d y wei g ht; A B W – act ual 
b o d y wei g ht; I B W – i d eal b o d y wei g ht; S Cr – ser u m creati ni ne  
 
C hil d -P u g h Sc o re 
P ar a meter 
P oi nts  
1 
2 
3 
He patic e nce p hal o pat h y  
N o ne ( he patic 
e nce p hal o pat h y  is a bse nt) 
Sta ge I t o II ( mil d or 
s u p presse d wit h 
me dicati o n)  
Sta ge III t o I V 
(se vere or 
refract or y) 
Ascites  
N o ne (ascites is a bse nt) 
Mil d -m o derate 
(s u p presse d wit h 
me dicati o n)  
M o derate- se vere 
(refract or y) 
T otal bilir u bi n µ m ol/ L ( m g/ d L)  
< 3 4 ( < 2)  
3 4 t o 5 0 ( 2 t o 3)  
> 5 0 ( > 3)  
Ser u m al b u mi n ( g/ d L)  
> 3. 5  
2. 8 t o 3. 5  
< 2. 8  
Pr ot hr o m bi n ti me(s)/  
I nter nati o nal N or malize d Rati o 
< 4 ( < 1. 7) 
4 t o 6 ( 1. 7 1 t o 2. 2 0) 
> 6 ( > 2. 2 0) 
 
Class A ( mil d) = 5 t o 6 p oi nts 
Class B ( m o derate) = 7 t o 9 p oi nts 
Class C (se vere) = 1 0 t o 1 5 p oi nts 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 8 1 
A p pe n di x H.  
e m P H asis- 1 0 Q uesti o n n aire 
 
N H S/ H o s pit al  n u m b er:  
 
 
 
 
N a m e:  
 
D at e  of  birt h:  
 
 
 
 
T hi s q u e sti o n n air e  i s d e si g n e d t o d et er mi n e  h o w  p ul m o n ar y  
h y p ert e n si o n  ( P H) aff e ct s y o ur  lif e. Pl e a s e  a n s w er  e v er y  
q u e sti o n  b y  pl a ci n g  a ti c k o v er t h e  O N E N U M B E R  t h at b e st  
d e s cri b e s  y o ur  r e c e nt e x p eri e n c e  of li vi n g  wit h  P H  
F or  e a c h  it e m b el o w,  pl a c e  a  ti c k ( ) i n t h e b o x  t h at b e st  d e s cri b e s  y o ur  e x p eri e n c e.  
 
 
 
I a m  n ot  fr u str at e d b y m y  
br e at hl e s s n e s s  
 
B ei n g br e at hl e s s  n e v er  
i nt err u pt s m y  c o n v er s ati o n s  
 
I d o n ot  n e e d t o r e st d uri n g  
t h e d a y 
I d o n ot  f e el e x h a u st e d  
I h a v e  l ot s of  e n er g y  
 
 
W h e n  I w al k  u p o n e  fli g ht of  
st air s  I a m  n ot  br e at hl e s s  
 
I a m  c o nfi d e nt  o ut  i n p u bli c 
pl a c e s/ cr o w d s  d e s pit e  m y  P H  
 
 
P H  d o e s  n ot  c o ntr ol  m y  lif e 
 
 
I a m  i n d e p e n d e nt 
 
 
I n e v er  f e el li k e a  b ur d e n  
I a m  v er y  fr u str at e d b y  m y  
br e at hl e s s n e s s  
 
B ei n g br e at hl e s s  al w a y s  
i nt err u pt s m y  c o n v er s ati o n s  
 
I al w a y s  n e e d t o r e st d uri n g  
t h e d a y 
 
 
I al w a y s  f e el e x h a u st e d  
I h a v e  n o e n er g y  at  all  
W h e n  I w al k  u p o n e  fli g ht 
of  st air s  I a m  v er y  br e at hl e s s  
 
I a m  n ot  c o nfi d e nt  at  all i n p u bli c  
pl a c e s/ cr o w d s  b e c a u s e  of  m y  P H  
 
P H  c o m pl et el y  
c o ntr ol s  m y  lif e 
 
 
I a m  c o m pl et el y  d e p e n d e nt  
 
 
I al w a y s  f e el l k e a  b ur d e n  
 
 
 
T ot al:  
D at e:  
 
 
 
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 0 2 
A p pe n di x J.  
R E V E A L 2. 0 Ris k Sc ore  
 

U nite d T her a pe utics C or p.  
T D E -P H - 4 0 2 Pr ot oc ol A me n d me nt 3 
 
Re m o d uli n; Ore nitr a m  
Versi o n D ate 2 4 J u ne 2 0 1 9 
C o nfi de nti al  
P a ge 1 0 3 
I nstr ucti o ns:  
A b o ve is t he u p date d R E V E A L 2. 0 ris k sc ore cal c ulat or, w hic h has bee n m o difie d fr o m t he 
ori gi nal t o refi ne sc ori n g f or se veral ris k varia bles ( Be nza 2 0 1 0; Be nza 2 0 1 8).  S u bjects wit h 
a sc ore of 1 0 or hi g her at Scree ni n g are i neli gi ble f or t he st u d y.  
•  At least 7 of t he a b o v e 1 2 varia bles ( wit h m R A P a n d P V R c o nsi dere d 2 se parate 
varia bles wit hi n t he Ri g ht Heart Cat heterizati o n) m ust be use d t o calc ulate a vali d ris k 
sc ore. 
•  3 of t he ≥7  varia bles us e d f or t he calc ulati o n m ust i ncl u de t he Scree ni n g res ults f or 
W H O F u n cti o nal Class, N T - pr o B N P, a n d 6-Mi n ute Wal k Test.   
•  A d diti o nall y, vital si g ns ( S B P a n d H R) a n d S Cr  ( use d t o calc ulate d e G F R) o btai ne d at 
scree ni n g s h o ul d be i ncl u de d i n t he ris k sc ore.  
•  Hist orical test res ults ma y be use d t o calc ul ate t he ris k sc ore:  
•  A hist orical ec h o car di o gra m ma y be use d if t he ec h ocar di o gra m was perf or me d 
wit hi n 6 0 da ys of Scree ni n g. A sc ore of + 1 will be gi ve n f or peri car di al eff usi o n 
t hat is gra de d as mil d, m o derate, or se vere.  A s c ore of 0 will be gi ve n f or trace 
pericar dial eff usi o n.  
•  A hist orical p ul m o nar y f u ncti o n test ma y be use d if it was per f or me d wit hi n 
6 0 da ys of scr ee ni n g.  
•  A hist orical ri g ht heart cat heterizati o n ( R H C) s h o ul d be use d if it was perf or me d 
wit hi n  1 8 0 da ys of Baseli ne a n d t he s u bject h as ha d n o c ha n ges i n t heir P A H 
me dicati o n re gi me n (ie, b ot h d osi n g a n d dr u g) si nce t he R H C.  If t he s u bject 
recei v es a n R H C at t heir Scree ni n g visit, t he Scree ni n g R H C s h o ul d be use d i n t he 
s u bject’s R E V E A L 2. 0 s c ore.