Clinical trial NCT03497689
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary hypertension Treprostinil Pulmonary arterial hypertension Remodulin Orenitram
Sponsor: United Therapeutics
Start date: 2019-01-31; Completion date: 2022-05-11
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a multicenter, open-label study to evaluate the dose of Orenitram® (treprostinil) Extended Release Tablets achieved at 16 weeks after a short-term course of Remodulin® (treprostinil) Injection in subjects with pulmonary arterial hypertension (PAH).

Detailed description:
Subjects were initiated on subcutaneous (SC) or intravenous (IV) treprostinil and titrated to a dose that improved the symptoms of PAH while minimizing excessive pharmacologic effects. After achieving a minimum SC/IV treprostinil dose of 20 ng/kg/min, subjects began a transition to oral treprostinil at the Transition Visit, which occurred at the Week 2, 4, or 8 study visit. After the Transition Visit, oral treprostinil titration continued through Week 16 to reach the maximum tolerated dose (MTD).

Arms: arm 1: Subjects began Remodulin at 2 ng/kg/min subcutaneously (SC) or intravenously (IV) and were optimized to their maximum tolerated dose (MTD) of Remodulin. Subjects were then transitioned to Orenitram XR tablets (oral) based upon their Remodulin dose. Subjects were optimized on Orenitram therapy to a MTD. There were no maximum Remodulin or Orenitram doses specified during the study.
Interventions: intervention 1: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil
Intervention descriptions: intervention 1: Short-term course of IV or SC treprostinil continuous infusion followed by transition to oral treprostinil extended-release (XR) tablets taken 3 times daily (TID)

Protocol documents:
Prot_000.pdf: 
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.  

SAP_001.pdf: 
United Therapeutics Corp. 
TDE-PH-402 
Protocol Title: 
Protocol Number: 
Protocol Version/Date: 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
EXPEDITE: A 16-Week, Multicenter, Open-label Study of 
Remodulin Induction Followed by Orenitram Optimization 
in Subjects with Pulmonary Arterial Hypertension 
TDE-PH-402 
Original, 
Amendment 1, 
Amendment 2, 
Amendment 3, 
22 February 2018 
09 April 2018 
23 August 2018 
24 June 2019 
lnvestigational Product: 
Remodulin Induction Followed by Orenitram Optimization 
Sponsor: 
UNITED THERAPEUTICS CORPORATION 
SAP Version/Date: 
2.0, 28 Apr 2022 
CONFIDENTIAL 
All content contained herein is confidential and proprietary information of United Therapeutics 
Corporation and shall not be disclosed in whole or in part except as permitted by a signed 
contract with United Therapeutics Corporation.© 2020 United Therapeutics Corporation 


United Therapeutics Corp. 
TDE-PH-402 
Protocol Title: 
Protocol Number: 
SAP Version/Date: 
CONFIDENTIAL 
SIGNATURE PAGE 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
EXPEDITE: A 16-Week, Multicenter, Open-label Study of 
Remodulin Induction Followed by Orenitram Optimization in 
Subjects with Pulmonary Arterial Hypertension 
TDE-PH-402 
2.0, 28 Apr 2022 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan: 
Signature 
Jinzhong Liu 
Biostatistician 
Medpace, Inc. 
Nicholas Alp 
Medical Director 
Medpace, Inc. 
Eric Shen 
Associate Director, Global Medical Affairs 
United Therapeutics Corporation 
Dana Johnson 
Statistical Scientist 
United Therapeutics Corporation 
Date 
2 


United Therapeutics Corp. 
TDE-PH-402 
VERSION HISTORY 
Version 
Version Date 
1.0 
11 May 2020 
2.0 
28 APR 2022 
CONFIDENTIAL 
Description 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
Original signed version 
SAP 2.0 
3 


United Therapeutics Corp. 
TDE-PH-402 
TABLE OF CONTENTS 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
1 
Introduction .......................................................................................................................... 7 
2 
Study Overview .................................................................................................................... 7 
2.1 
Study Objectives ........................................................................................................... ? 
2.1.1 
Primary Objective .................................................................................................. 7 
2.1.2 
Secondary Objective .............................................................................................. ? 
2.1.3 
Exploratory Objectives ........................................................................................... 7 
2.2 
Study Design ................................................................................................................ 7 
2.2.1 
Overview ................................................................................................................ ? 
2.2.2 
Randomization and Blinding ................................................................................ 12 
2.2.3 
Sample Size Determination .................................................................................. 12 
2.3 
Study Endpoints .......................................................................................................... 12 
2.3.1 
Primary Endpoint ................................................................................................. 12 
2.3.2 
Secondary Endpoints ........................................................................................... 12 
3 
Statistical Methodology ...................................................................................................... 14 
3 .1 
General Considerations .............................................................................................. 14 
3.1.1 
Analysis Day ........................................................................................................ 14 
3.1.2 
Analysis Visits ...................................................................................................... 14 
3.1.3 
Definition of Baseline and transition visit value ..................................................... 14 
3.1.4 
Definition of Treatment Phases ............................................................................ 15 
3.1.5 
Summary Statistics .............................................................................................. 15 
3.1.6 
Hypothesis Testing .............................................................................................. 15 
3.1.7 
Multiple comparisons and multiplicity ................................................................... 15 
3.2 
Analysis Populations ................................................................................................... 15 
3.2.1 
Safety Population ................................................................................................. 15 
3.2.2 
Per-protocol Population ....................................................................................... 15 
3.2.3 
Completer Population .......................................................................................... 15 
3.3 
Subject Data and Study Conduct ................................................................................ 16 
3.3.1 
Subject Disposition .............................................................................................. 16 
3.3.2 
Protocol Deviations .............................................................................................. 16 
3.3.3 
Analysis Populations ............................................................................................ 16 
3.3.4 
Demographic and Baseline Characteristics .......................................................... 16 
3.3.5 
French Non-invasive Risk Score .......................................................................... 18 
3.3.6 
Concomitant Medications ..................................................................................... 18 
3.3.7 
Study Drug Exposure ........................................................................................... 18 
3 .4 
Efficacy Assessment ................................................................................................... 19 
3.4.1 
Primary Efficacy Endpoint .................................................................................... 20 
3.4.2 
Secondary Efficacy Endpoints ............................................................................. 20 
3.4.3 
Exploratory Efficacy Endpoints ............................................................................ .21 
3.4.4 
Subgroup Analysis ............................................................................................... 22 
4 


United Therapeutics Corp. 
TDE-PH-402 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
3.5 
Pharmacokinetic Assessment ..................................................................................... 22 
3.6 
Pharmacodynamic Assessment .................................................................................. 22 
3.7 
Safety Assessment .................................................................................................... .22 
3.7.1 
Adverse Events (AEs) and Prostanoid AEs ......................................................... .22 
3.7.2 
Vital Signs and Clinical Laboratory Tests ............................................................ .24 
4 
Analysis Timing ................................................................................................................. .24 
4.1 
Interim Analysis ........................................................................................................... 24 
4.2 
Pre-Final Analysis ....................................................................................................... 25 
4.3 
Final Analysis .............................................................................................................. 25 
5 
Changes from Protocol-Specified Statistical Analyses ....................................................... 25 
6 
Programming Specifications .............................................................................................. 25 
Reference ................................................................................................................................. 27 
5 


United Therapeutics Corp. 
TDE-PH-402 
LIST OF ABBREVIATIONS 
Abbreviation 
6MWD 
ADaM 
AE 
ATC 
CDISC 
ECHO 
CRF 
CSR 
FC 
ICF 
IIT 
MedDRA 
NT-proBNP 
PAH 
RHC 
RNA 
RV 
SAE 
SAP 
SC 
SDTM 
SR 
TEAE 
TESAE 
TIO 
TSQM 
WHO 
CONFIDENTIAL 
Definition 
6-Minute Walk Distance 
Analysis Data Model 
Adverse event 
Anatomical therapeutic chemical 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
Clinical Data Interchange Standards Consortium 
Echocardiogram 
Case report form 
Clinical Study Report 
Functional Classification 
Informed consent form 
Intent-to-treat 
Medical Dictionary for Regulatory Activities 
N-terminal pro-brain natriuretic peptide 
Pulmonary Arterial Hypertension 
Right heart catheterization 
Ribonucleic acid 
Right ventricular 
Serious adverse event 
Statistical Analysis Plan 
Subcutaneous(ly) 
Study Data Tabulation Model 
Sustained release 
Treatment-emergent adverse event 
Treatment-emergent serious adverse event 
3 times daily 
Treatment Satisfaction Questionnaire for Medication 
World Health Organization 
6 


United Therapeutics Corp. 
TDE-PH-402 
1 
INTRODUCTION 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical 
methods to be implemented for the analysis of data from the study with protocol number 
TDE-PH-402. The SAP will be finalized prior to database lock. Any deviations from the SAP 
after database lock will be documented in the final Clinical Study Report (CSR). 
2 
STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the dose of Orenitram® (treprostinil) Extended 
Release Tablets achieved at 16 weeks after induction therapy with Remodulin® (treprostinil) 
Injection in Pulmonary Arterial Hypertension (PAH) patients. 
2.1.2 
Secondary Objective 
The secondary objective of the study is to assess the effect of treatment with Orenitram 
(treprostinil) Extended Release tablets at 16 weeks after induction therapy with Remodulin 
(treprostinil) Injection on clinical response, safety, and tolerability. 
2.1.3 
Exploratory Objectives 
Exploratory objectives of this study are evaluation of pharmacogenomics (genetidribonucleic 
acid [RNA] testing) and evaluation of biomarkers at Baseline, the Transition Visit, and Week 16. 
2.2 Study Design 
This is a 16-week, multicenter, open-label, uncontrolled study in subjects with PAH. 
2.2.1 
Overview 
The study is a 16-week, open-label, multicenter, uncontrolled study in subjects with PAH. 
The following study visits will occur during the 16-week study at the following time points: 
• 
Screening 
• 
Baseline 
• 
Week 2 (Day 15 [±3 days]), Week 4 (Day 29 [±5 days]), Week 8 (Day 57 [±5 days]), 
Week 12 (Day 85 [±5 days]), and Week 16/Early Study Withdrawal (Day 113[±7 days]) 
• 
Transition Visit may occur at Weeks 2, 4, or 8 if the subject has achieved a minimum 
Remodulin dose of 20 ng/kg/min and the Investigator deems the subject suitable for 
transition. Transition may be reversed or stopped if necessary due to significant signs or 
symptoms of PAH or due to serious safety concerns. 
• 
Post Transition Visit (7 to 14 days after the Transition Visit) 
7 


United Therapeutics Corp. 
TDE-PH-402 
Study Visit/Week 
Day 
Infonned consent 
Inclusion and exclusion criteria 
assessment 
Demographics 
P AH histo1,"1 
TSQM' 
em.PHasis-10 questionnaire• 
P AH symptom score 
WHOFC 
Swan-Ganz right heart 
catbeterizatiour 
Medical histo1y 
Prior P AH medicationss 
Concomitant medications&h 
Physical examination' 
Vital signs' 
CD4 count (for subjects with 
human inununodeficiency 
Yims) 
Screening• 
-28 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CONFIDENTIAL 
Table 1 Overall Schedule of Time and Events 
Treatment Phase 
Baseline•·b 
Post Transition 
Week 2' 
\Veek _.,.,. 
Week 8' 
Visit" 
-14 to -1 
15 (±3 days) 29 (±5 days) 57 (±5 days) 7 to 14 days after 
Transition Visit'" 
X 
X 
-------------X• ------------
X 
-------------x•-------------
X 
-------------x•------------
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-------------x• ------------
X 
X 
X 
X 
X 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2022 
Week 16/ 
Week 12 
Early Study 
Withdrawal< 
85 (±5 days) 113 (±7 days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


United Therapeutics Corp. 
TDE-PH-402 
t udy \'lslt Yeek 
Dnr 
Clinical labornrory pa1ame1e1~ 
(serum chenustry and 
bemarology) 
Urine preinancy 1es1t 
Echocardio!lf3m 
Serum ~
-proB~ 
Blood sample for 
phannacogenonuc 
(~ene1ic R.'-:A)m 
Blood sample for bioma1ke1 
e,·aluation ( optional)
1111 
6MWT followed by bean-rate 
reco,·ery ( 1 minute) and Borg 
dyspnea scoreD 
Snidy dmg dosin~ 
Recording of adYerse c\'ents 
AE Bothersome Sun:ey 
Periodic patient co111ac1" 
Drng accom11ability" 
ISn eeulug• Basellne•·b 
-28 to -1 
-U ro -1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X'' 
X 
X 
X 
X 
CONFIDENTIAL 
Treatment Phnse 
Post Trausltlou 
Week 2' 
\\'eek 4"' 
Week 81 
\'islt' 
15 (±3 days} 
29 (±5 da~·s) 57 (±5 days} 7 to 14 day nnrr 
Transition \'isW 
----·-··-· --x· ·-······-·-·· 
x• 
X 
X 
------------x· ---·····--·-
------------x· -----------.. 
-----------X•-------------
xop 
xo, 
xop 
XP 
X'·' 
x•• 
X" 
X" 
X 
X 
X 
X 
------X'-----
X 
X 
X 
X 
X 
X 
X 
X 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
Week 16/ 
Week 12 
Early tudy 
Wltbdrawnlt 
85 (±5 day) 113 (±7 day ) 
X 
X 
X 
X 
X 
X 
).'9 
XP 
X" 
X" 
X 
X 
X 
X 
X 
X 
6MWD. 6-}.hmne W-111,; Di,;tnnec: 6~(\VT. 6-~limue W-111,; Te<;t: ECHO. eehoc:1rd1ogrnm: cCRF. electronic e3,;c repon fon11. FC. Functionnl C!n<;,;ific311on: I\'. 
intrnvcnousOy): 'l\1-proB~P. ~ -tcnninal pro-brain 031.riurctic pepride: PAH. pulmonary arterial hypertension: RHC. right heart carhe1erizario11: R."A. ribonucleic acid: 
SC. subcutaneou\(ly). TSQ}.(. Trc:umem Sati\focrion Qucscionnai.rc for Mcdicatton: WHO. World Hcahh Or2anizotio11 
crceom2 and Baseline assc\\meam can be conducted up 10 1S and 14 da~ pnor to \t.111m2 the Remodulio mfu\1011. mpectivel>· Screenin11 nmst occur prior to Bt\scline 
11\<;cssmetlt<; to c:onfinu cli(!:1b1liry SubJccts with \hon-1cm1 mmcu}o<;keleml c:ond111011s (e2. sprained ankle) can be re-,;c:rccncd so that nssessme111s aren't uupactcd by 
unusual or ciucnu.111112 c:ircunutancc,; 
9 


United Therapeutics Corp. 
TDE-PH-402 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
b Following completion of Baseline assessments. subjects will be initiated on Rcmoduli.t1 at 2 ng kg mm SC or IV in an inpatient or outpatient setting. IV Rcmodulin may 
be admmistered through an indwelling central venous catheter or a peripherally inserted catheter. as clinically indicated. For subjects receiving IV Remodulm through a 
central venous catheter. it is rcconuncndcd that the central venous catheter be retained for at least 28 days after the transition from Rcmodulin. 
c The assessments of Weck 16 Early Snidy Withdrawal Visit can occur over 5 days so that assessments can take place on separate days if needed. All assessments should 
be conducted p1ior 10 withdrawing from the study. prior to discontinuation of Orcnitram or Rcmodulin. and as close as possible to the last dose taken by the subject. 
d The subject's PAH diagnosis date. past (noncurrcnt) PAH medications. PAH etiology. and WHO FC will be recorded. 
• These patient-reported outcomes should be completed by subjects prior to other assessments and before i.tnpartmg news regardmg stants of tl1eir disease. Subjects should 
be allowed to complete the qucstio,maircs at their own pace. and with minimal help from others. 
Optional: RHC docs not need to be conducted if ilic patient h3s an RHC within 180 days of Basel me with a cardiac index ~2.0 L 11unm2 witl1 no changes in PAH 
medication regimen since the RHC. If an RHC is pcrfonncd at Screening. values should be obtai.t1cd for mean 1ight atrial pressure (mRAP) and pulmonary vascular 
resistance (PVR) to calculate ilic Scrccni.t1g RE\ 'EAL 2.0 risk score. 
g The subject's prior PAH medications and concomitant medications should be recorded on ilie cCRF. 
h The Investigator will record tl1c subject's concomitallt medications and record whether tl1c concomitant medication was used to treat an adverse event (includmg whctl1cr 
prostanoid adverse event or not). For this study. prostanoid ad,·crsc c\·cnts include headache. diarrhea. flushlllg. nausea. jaw pai.t1. extremity pain. and vomiting. 
1 A full physical cxami.trntion is an evaluation of general appearance: mental cxami.tiation: head. car. eyes. nose. and throat examinations: and examination of dcnnatologic. 
cardiovascular. respiratory. gastrointestinal. musculoskclctal. and ncurologic body systems. 
Vital signs include blood pressure. heart rate. respiration rate. height. and weight. Vital signs must be collected after 5 mi.tmtes of rest while seated. No other 
measurements or procedures should occur during the 5 mwute'> of rest. Vital signs will be collected p1ior to or at least 30 minutes after the 6M\VT. 
k Urine pregnancy tcm will be conducted on all female subjects of childbca1ing potential. A negative urine pregnancy test is required of all female subjects of childbearing 
potential to be eligible for the snidy and remain enrolled as a subject. 
Blood samples for ~T-proB~P must be drawn prior to conducii.t1g the 6MWT and will occur at the Screening Visit. Bascli.t1c Visit (p1ior 10 Rcmoduli.t1 initiation). ilic 
Transition Visit (prior to Orenitram witiation). and ilie Week 16/Early Study Wiilidrawal Yisit. 
m Where local regulations allow. the subject"s blood sample will be collected for phannacogcnomic (genetic R."\A) and biomarkcr analysis for those subjects who consent to 
the optioual testing. 
11 The subject should rest (seated) for 10 llllllUtcs before each 6MWT. If ilic 6MWT is conducted uswg supplemental oxygen at Basclwc. then all subscqucm 6MWTs 
druing the snidy should be conducted witl1 supplemental oxygen. Swularly. if the Basel we assessment is conducted witl1out supplemental oxygen. then subsequent 
assessments should also be conducted without oxygen. All cffo11s should be made to keep the supplemental oxygen flow rate consistent during the 6MWT. The 
supplemental oxygen flow rate must be recorded at every 6MWT. if applicable. The Borg dyspnca score and heart rate recovery (1 minmc) should take place 
llll.ll1cdiatcly following the 6MWT. 
0 At the Transition \"isit. 6MWT should occru· with the subject still on Rcmodulin therapy. before initiati.t1g the transition to Orcniu-am. 
P When the subject is receiving Oreni.tram. the 6MWT should occur within 2 to 6 hours of the subject's most recent dose. 
q Snidy dmg refers to both Rcmodulin and Orcnitrnm. 
' If the lnYestigator deems a subject 1u1suitable for transition to Orenitram due to significant signs and symptoms of P AH or any otl1er serious safety concems. the subject 
may rcmai.t1 on Rcmodulin for the duration of the study. The lnYcstigator may reverse. or stop the transition to Orcnitram due to conccms of subject safety. 
s In addition to tl1e scheduled assessments. additional testwg will be perfonued at ilie Transition Vi.sit as wdicated. Subjects may transition at Weeks 2. 4. or 8 if they have 
achieved a mmi.tnum Rcmodulm dose of 20 ng 'kg mi.t1 and the Investigator deems the subject suitable for transition. Transition may be reversed or stopped for subject 
safety. 
1 Subjects should be opti.tnized on Rcmoduli.t1 t1ijerapy prior to transition to Orcnitram: a dose should be achic\·cd that w1provcs the symptoms of P AH while mini.tuizing 
excessive pbannacologic effects of Rcmodulin. Transition from Rcmodulin to Orcnitram will occur over tl1c course of 1 to 21 days. 
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• The \l\ldy '>lie will c:ont.i t \\lbJ«I'> dn1I)' durinir the flf\t 2 ,,eeks of the \ludy. d:11ly d11rini the tfall\lllOn pcnod (ic. while: the \UbJcC:t ,., on both Rcmodulm :md 
Orcuitr.un). and twice ,,cc:ldy for the fll"'>t 2 week'> after tran\1t1onmi (1c. \\ hale the \UbJcct ,., on Orcmtrnm and no lon~cr on Rcmoduhn) At all other tw1c pomt<, dunng: 
the '>nldy. <,ubjcct<, will be contJctcd once ,,ccL:ly 
' The Post Tr.iim11011 \'1<,11 oc:c:u~ "' to 1"' da:,.'\ 3ftcr tr:um11on from Rcmoduhn to Orcnnram ,., m111:11cd If the T r.um11on \·mt occun nt \\'eel.: 2. the Weck 4 , mt can be 
\Ub\11nued for 1he Po-.t Tran<,lflon \'1rn (1e. an e:otO":I , , .. 11 1<, not ncce\ , f)•) 
• Sl\ldy \lie or phnnu.,C) pc~ollllcl ,hould 1<,<,e.,., dm2 retumed and do .. m2 infoniu11on to confinn dru2 1c:cotmtab1l11y 
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2.2.2 
Randomization and Blinding 
CONFIDENTIAL 
This study does not employ randomization. This is an open-label study. 
2.2.3 
Sample Size Determination 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
A sample size of approximately 35 evaluable subjects (i.e. completing the week 16 study visit 
without any major deviations which may interfere with study endpoints) was set for feasibility 
and to ensure a reasonable dataset to evaluate the Orenitram dose achieved, the clinical 
response to Orenitram after an induction period with Remodulin, and to assess the safety and 
tolerability of Orenitram after induction therapy with Remodulin. No formal sample size 
computation was performed with respect to the primary endpoint. 
2.3 Study Endpoints 
2.3.1 
Primary Endpoint 
The primary efficacy endpoint is the percentage of subjects achieving an Orenitram dose of 4 
mg TIO (or a total daily dose of 12 mg) or higher at Week 16 (or a dose of 0.057 mg/kg TIO [or a 
total daily dose of 0.171 mg/kg] or greater for subjects <70 kg). 
The prescribed total daily dose will be used for the primary efficacy endpoint. 
2.3.2 
Secondary Endpoints 
2.3.2.1 
Safety Endpoints 
Safety will be assessed using the Prostanoid Adverse Event (AE) scores captured by the AE 
Bothersome Survey at Baseline, the Transition Visit, and Week 16/Early Study Withdrawal. 
The Investigator will administer the AE Bothersome Survey (provided in protocol Appendix E) at 
time points listed in Table 1 to collect information about prostanoid-related effects experienced 
by the subject, including headache, diarrhea, nausea, flushing, jaw pain, extremity pain and 
vomiting. For each prostanoid-related effect, whether the patient has experienced the effect, the 
degree of bothersome (from 1 - bothers me a lot to 4 - not at all bothersome), and days 
experiencing it (1 to 7) will be recorded. 
Other safety assessments including the incidence of adverse events, clinical laboratory tests, 
vital signs, and physical examinations are described in Section 3.7. 
2.3.2.2 
Efficacy Endpoints 
The secondary efficacy endpoints are to assess the effect of treatment with Orenitram after an 
induction period with Remodulin on the following parameters: 
1. Change in 6-Minute Walk Distance (6MWD) from Baseline to the Transition Visit and 
Week 16 
2. Change in Borg dyspnea score from Baseline to the Transition Visit and Week 16 
3. Change in World Health Organization (WHO) Functional Classification (FC) from 
Baseline to the Transition Visit and Week 16 
4. Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels from Baseline to 
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5. Change in Echocardiographic parameters from Baseline to the Transition Visit and Week 
16 
Echocardiogram (ECHO) examinations as assessed by central reader will be conducted at the 
time points listed in Table 1. Several echocardiographic parameters will be collected, including: 
right atrial area (cm2), tricuspid annular plane systolic excursion (mm), RV free wall strain (%), 
RV/left ventricular ratio at diastole, RV diastole (mm), LV diastole (mm), Eccentricity Index 
systole, Eccentricity Index diastole, RV Myocardial Performance Index; Pulmonary Artery 
Acceleration Time (msec) and presence of PV Notching (Non-evaluable, Present or Not 
Present); LVOT dimension (mm), LVOT vti (cm), ECHO Heartrate (bpm), cardiac output 
(Doppler method) (Umin) and presence of pericardia! effusion (Present/ Not Present) 
6. Change in PAH symptom score from Baseline to the Transition Visit and Week 16 
7. The percentage of subjects that improve in each of the following 4 individual clinical 
parameters at Week 16 (6MWO, NT-proBNP, WHO FC, right atrial area) to a lower risk 
stratum, as defined by the 2015 European Society of Cardiology guidelines, compared to 
Baseline 
8. The percentage of subjects that meet each of the following 4 individual clinical 
parameters at Week 16 in the low risk category, as defined by the 2015 European 
Society of Cardiology guidelines: 6MWD >440 meters, serum NT-proBNP <300 ng/L, 
WHO FC I or II, and right atrial area <18 cm2 
9. The percentage of subjects that either achieve an Orenitram dose of 4 mg TIO (or a total 
daily dose of 12 mg) or higher at Week 16 (or a dose of 0.057 mg/kg TIO [or a total daily 
dose of 0.171 mg/kg] or greater for subjects <70 kg) or the percentage of subjects that 
achieve an Orenitram dose ~2 mg TIO and <4 mg TIO (or a total daily dose ~6 mg and 
<12 mg) at Week 16, with at least 2 of the following 3 clinical parameters at Week 16 
calculated and summarized: 6MWD increase by 2:10% or 2:30 meters from Baseline, 
serum NT-proBNP reduction >30% from Baseline, or WHO FC I or II. This will performed 
using both prescribed total daily dose as well as actual dose taken. 
10. The percentage of subjects that successfully transitioned to Orenitram at any dose and 
were successfully maintained on therapy at Week 16 
11. Change in Subjects' Treatment Satisfaction Questionnaire for Medication (TSQM) 
responses and Health-related quality of life (emPHasis-10) questionnaires from Baseline 
to the Transition Visit and Week 16 
The prescribed total daily dose will be used for secondary efficacy endpoints when applicable, 
unless otherwise stated. 
TSQM 
The questionnaire is provided in protocol Appendix G. The TSQM (version 1.4) comprises 14 
items across four domains focusing on effectiveness (three items Q1-Q3 ), side effects (five 
items Q4-Q8), convenience (three items Q9-Q11 ), and global satisfaction (three items Q12-
Q14) of the medication over the previous 2-3 weeks, or since the patient's last use. Except for 
item 4 (presence of side effects; yes or no), all items have five or seven responses, scored from 
one (least satisfied) to five or seven (most satisfied). Item scores are summed to give four 
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domain scores, which are in turn transformed to a scale of 0-100. Item 4 is not included for 
scoring. If an item score is missing and half of the items in the domain are complete, domain 
scores may be imputed from the person-specific mean score of completed items (i.e., the 
domain scores will be calculated as the total score of the completed items divided by the 
possible maximum total score of the completed items and times 100). For example, if a subject 
has Q1 = 5, Q2 = 2 and Q3 is missing, then domain score effectiveness= (5+2) / (7+7) * 100 
= 50. The calculated domain scores will be listed. 
emPHasis-1 O 
The questionnaire is provided in protocol Appendix H. The emPHasis-10 comprises 10 items. 
Each item has a score scale of 0-5. The total score will be calculated as 
Total score of answered questions X 10 / Number of answered questions. 
The range of the total score is 0-50. If the number of answered questions is less than 7, the total 
score will be considered missing. The calculated total score will be listed. 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will be prespecified in this document but will be summarized 
at a later time by the study sponsorD. 
REVEAL 2.0 risk score and French non-invasive risk score (Boucly 2017) will be summarized at 
Baseline, the Transition Visit, and Week 16. Change from Baseline to Transition, Baseline to 
Week 16, and Transition to Week 16 will also be summarized. 
For subjects who consent to the optional pharmacogenomics (genetic/ribonucleic acid [RNA] 
testing) and biomarker testing, Baseline pharmacogenomics will be evaluated. Additionally, 
evaluation of biomarkers at Baseline, the Transition Visit, and Week 16, and change from 
Baseline to Transition, Baseline to Week 16, and Transition to Week 16 will be performed. 
3 
STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 
Analysis Day 
Analysis day will be calculated from the date of first dose of Remodulin. The day of the first dose 
of study drug will be Day 1, and the day immediately before Day 1 will be Day -1 . There will be 
no Day 0. 
3.1.2 Analysis Visits 
Nominal visits will be used for analysis. Number of weeks after transition visit will also be 
derived using the nominal visit. 
3.1.3 
Definition of Baseline and transition visit value 
Baseline is defined as the last measurement prior to the initiation of Remodulin. 
Transition visit value is defined as the last measurement prior to the first dose of Orenitram. 
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3.1.4 
Definition of Treatment Phases 
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Statistical Analysis Plan 
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"Remodulin phase" is defined as the portion of the study when a patient is receiving Remodulin 
only. 
"Transition phase" is defined as the portion of the study beginning at the Transition Visit when a 
patient is receiving both Remodulin and Orenitram. "Transition phase" ends at the last dose of 
Remodulin if the transition is "successful". "Transition phase" ends at the last dose of Orenitram 
if the transition is "unsuccessful" and reversed. "Transition phase" ends at the last dose of 
Orenitram and Remodulin if the transition is stopped. 
"Orenitram phase" is defined as the portion of the study when a patient is receiving Orenitram 
only. 
3.1.5 Summary Statistics 
The efficacy and safety data in the study will be presented in summary tables and listings in the 
final clinical study report. Listings will be sorted by subject, visit, and time point assessment (if 
applicable). For summary tables, the data will be summarized by visits (including the Transition 
Visit) and time point assessment, if appropriate. For continuous variables in general, descriptive 
statistics will include the number of observations (non-missing values), mean, standard 
deviation (SD), median, inter-quartile range, minimum, and maximum. Change from Baseline 
will also be provided if applicable. For categorical variables, descriptive statistics will include the 
frequency and percentage in every category. 
3.1.6 Hypothesis Testing 
No formal statistical testing will be performed. 
3.1.7 Multiple comparisons and multiplicity 
No adjustments for multiplicity will be made in these analyses. 
3.2 Analysis Populations 
3.2.1 
Safety Population 
The Safety Population is defined as all subjects in the study who received study drug 
(Remodulin or Orenitram). All safety analyses will be performed on the Safety Population. 
3.2.2 
Per-protocol Population 
The Per-protocol Population is defined as all subjects in the study who received study drug 
without any major deviations (which may interfere with efficacy evaluation). 
3.2.3 
Completer Population 
The Completer Population is defined as all subjects in the study who complete the study without 
any major deviations (which may interfere with efficacy evaluation) and are receiving Orenitram 
at Week 16. 
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3.3 Subject Data and Study Conduct 
3.3.1 
Subject Disposition 
Statistical Analysis Plan 
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Counts and percentages of subjects who were screened (signed informed consent}, 
discontinued early during screening (screen failures), and enrolled will be summarized in total 
based on all screened subjects. 
Counts and percentages of subjects who were enrolled, started Remodulin, began transition to 
Orenitram, completed transition to Orenitram, had to return to Remodulin, discontinued study 
drug prior to Week 16 visit assessments, and completed the study will be summarized based on 
all enrolled subjects. Reasons for early discontinuation from the study will also be summarized. 
3.3.2 
Protocol Deviations 
The following listings and summary table will be provided for Safety Population: 
1. Listing of Entry Criteria. 
2. Listing of Entry Criteria Violations. The status of the entry criteria will be listed for all 
subjects. The listing will include the date of the initial screening assessment and a list of 
any specific entry criteria that were not met. 
3. Summary of Entry Criteria Violations. If a sufficient number of violations occur, then the 
compliance to each criterion will be summarized. 
Additional protocol deviations not captured in the CRF may be tabulated and listed based on 
criteria to be determined upon preparation of the final study report. 
3.3.3 
Analysis Populations 
Counts and percentages of subjects in each of the 3 analysis populations (see section 3.2) will 
be summarized. 
3.3.4 
Demographic and Baseline Characteristics 
The following demographic and Baseline characteristics will be summarized for each of the 3 
analysis populations (see section 3.2): 
• 
Sex 
• 
Age 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2) 
• 
Counts and percentages of subjects by !'AH etiology will be provided. Days since initial 
PAH Diagnosis (as defined by RHC) will be summarized. Day of initial PAH Diagnosis 
will be imputed to the 15th if missing. 
3.3.4.1 
Hemodynamics 
The following Right Heart Catheterization (RHC) parameters will be summarized for each of the 
3 analysis populations: 
• 
Mean pulmonary arterial pressure (mPAP) (mmHg) 
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• 
Pulmonary artery wedge pressure (PAWP) (mmHg) 
Statistical Analysis Plan 
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• 
Left ventricular end diastolic pressure (LVEDP) (mmHg) (if available) 
• 
Cardiac Index (Umin/m2) 
• 
Heart Rate (beats/min) 
• 
SAPs (mmHg) 
• 
SAPd (mmHg) 
• 
SAPm (mmHg) 
• 
PAPs (mmHg) 
• 
PAPd (mmHg) 
• 
RAPm (mmHg) 
• 
PVR 0!Jood Units) 
• 
PCWPm (mmHg) 
• 
Sa02 (%) 
• 
Sv02 (%) 
• 
CO Thermodilution (Umin) 
• 
CO Fick (Umin) 
• 
BSA (m2 ) 
3.3.4.2 
REVEAL 2.0 Risk Score 
The following parameters, which are the components of the REVEAL 2.0 risk score, will be 
summarized for each of the 3 analysis populations at Baseline: 
• 
WHO Group [APAH-CTD (+1 ), APAH-PoPH (+3), FPAH (+2), Other (+O), Not Available 
(+O)] 
• 
Sex and Age [Male Age > 60 yrs (+2), No (+O)] 
• 
eGFR (<60 mUmin/1.73m2 or (if eGFR unavailable) renal inefficiency (+1 ), No (+O), Not 
available (+O)] 
• 
NYHA/WHO Functional Class [I (-1 }, II (+O}, Ill (+1 ), IV (+2}] 
• 
Systolic blood pressure (SBP) [SBP < 110 mmHg (+1 ), 
110 mmHg (+O)J 
• 
Heart Rate (HR) [HR> 96 BPM (+1 ), ::s 96 BPM (+O)] 
• 
All-cause Hospitalizations within 6 months [Yes (+1 ) I No (+O)] 
• 
6-Minute Walk Test [ < 165 m (+1 ), 165 m to 319 m (+O), 320 m to 439 m (-1), 
440 m 
(-2)] 
• 
NT-proBNP [NT-proBNP < 300 pg/ml (-2), NT-proBNP 300 to 1099 pg/ml (+O), 
NT-proBNP 
1100 pg/ml (+2)] 
• 
Echocardiogram [Mild, Moderate, or Severe Pericardia! Effusion (+1 ), Trace or No 
Pericardia! Effusion (+O), Not Available (+O)] 
• 
Pulmonary Function Test[% predicted DLCO < 40% (+1 ), 
40% (+O), Not Available 
(+O)] 
• 
Right Heart Catheterization - mRAP [mRAP > 20 mmHg (+1 ) Is 20 mmHg (+O) I Not 
Available (+O)J 
• 
Right Heart Catheterization - PVR [PVR < 5 Wood units (-1 ) I 5 Wood units ( +O) I Not 
Available (+O)] 
REVEAL 2.0 risk score is also an exploratory efficacy endpoint and will be summarized at the 
Transition Visit and Week 16. Change from Baseline to Transition Visit, Baseline to Week 16, 
and Transition Visit to Week 16 will also be summarized. 
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3.3.5 
French Non-invasive Risk Score 
CONFIDENTIAL 
Statistical Analysis Plan 
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The French non-invasive method is performed according to the 2015 ESC/ERS pulmonary 
hypertension guidelines (Boucly 2017). This method evaluates the number of low-risk criteria 
using 3 modifiable clinical parameters, which are defined as the following: 
1) WHO functional class I or II 
2) 6-minute walk distance >440 meters 
3) NT-proBNP <300 ng/L 
The number of low-risk criteria is counted and thus, a patient can possess Oto 3 low-risk 
criteria. The French non-invasive risk score is an exploratory efficacy endpoint and will be 
summarized for each of the 3 analysis populations at Baseline, the Transition Visit, and Week 
16. Change from Baseline to Transition, Baseline to Week 16, and Transition to Week 16 will 
also be summarized. 
3.3.6 Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and 
preferred term using the WHO Drug Dictionary version WHO-DOE 82, Mar 201 ?E. For 
summary purposes, medications will be considered as concomitant medications if they were 
taken at any time after the first dose of Remodulin (i.e. were ongoing or started after the first 
dose of Remodulin). 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a 
medication should be considered prior or concomitant. If a medication start date is incomplete, 
the first day of the month will be imputed for missing day and January will be imputed for 
missing month. If a medication stop date is incomplete, the last day of the month will be imputed 
for missing day and December will be imputed for missing month. Incomplete start and stop 
dates will be listed as collected without imputation. 
Counts and percentages of subjects taking concomitant medications by A TC class and 
preferred term will be summarized based on the Safety Population. 
Counts and percentages of subjects' prior and current PAH background therapy (PDES-1/sGC 
alone; ERA alone; PDE5-l/sGC+ERA; none) will be summarized by PAH medications 
separately based on the Safety Population. 
3.3. 7 
Study Drug Exposure 
A listing of Orenitram and Remodulin dose levels for each subject at each timepoint will be 
provided by visit. 
A summary of Orenitram and Remodulin dose levels at each study visit will be provided for the 
Safety Population. Summary of dose levels at each study visit will also be provided for patients 
who transition at week 2, week 4, and week 8 separately. Change from baseline Remodulin 
dose levels will also be provided. 
Days of exposure to study drug (Remodulin and Orenitram) will be calculated as date of last 
dose of study drug - date of first dose of study drug+ 1. Note that the exposure calculation is 
intended to describe the length of time a subject was exposed to study drug and therefore does 
not take study drug interruptions into account. Days of exposure to study drug will be 
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summarized based on the Safety Population with descriptive statistics and with counts and 
percentages of subjects with exposure in the following categories: 
• 
<4 weeks (<28 days) 
• 
4 -<8 weeks (28 - 55 days) 
• 
8 - <12 weeks (56 - 83 days) 
• 
12 - <16 weeks (84-111 days) 
• 
::::16weeks (::::112days). 
Days of exposure to Remodulin and Days of exposure to Orenitram will also be summarized in 
the same way. 
Number and percentage of subjects who initiated Remodulin in an inpatient vs. outpatient 
setting will be summarized. 
Number and percentage of subjects who initiated Remodulin via IV or SC routes will be 
summarized 
Number and percentage of subjects who switched between IV and SC routes for Remodulin will 
be summarized 
For patients initiating Remodulin in the inpatient setting, the Remodulin dose at discharge will be 
summarized. 
Number and percentage of subjects who initiated transition from Remodulin to Orenitram in an 
inpatient vs. outpatient setting will be summarized. 
Summary statistics will be provided for: 
• 
Time to Transition to Orenitram, calculated as date of first dose of Orenitram - date of 
first dose of Remodulin + 1 
• 
Duration of inpatient stay (for applicable subjects) for Remodulin initiation 
• 
Duration of transition (days receiving both Remodulin and Orenitram) 
• 
Duration of inpatient stay (for applicable subjects) for transition to Orenitram 
• 
Dose of Remodulin (ng/kg/min) at Transition Visit 
• 
Prescribed total daily dose of Orenitram (mg) at the Post-Transition visit 
All the above summaries will be based on the Safety Population. 
3.4 Efficacy Assessment 
Efficacy data will be summarized as specified in 3.4.1 and 3.4.2. The Week 16 visit and early 
study withdrawal will be reported separately in the efficacy tables. 
The prescribed total daily dose will be used for the primary and secondary efficacy endpoints 
when applicable, unless otherwise specified. 
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3.4.1 
Primary Efficacy Endpoint 
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Statistical Analysis Plan 
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The number and percentage of subjects achieving an Orenitram dose of 4 mg 3 times daily 
(TIO) (or a total daily dose of 12 mg) or higher (or a dose of 0.057 mg/kg TIO [or a total daily 
dose of 0.171 mg/kg] or greater for subjects <70 kg) will be summarized for Week 16 for the 
Per-Protocol population. Subjects with missing data for prescribed total daily dose at Week 16 
will be considered as not achieving the primary efficacy endpoint. 
This will be repeated for the Completer Population. 
3.4.1.1 
Sensitivity analysis 
To support the robustness and assess the sensitivity of the primary efficacy endpoint, the 
primary efficacy endpoint in 3.4.1 will be calculated using the actual dose taken for Orenitram 
dose (the sum of the morning, afternoon, and evening dose, where a missed dose is considered 
0 mg). This analysis will be performed on both the Per-Protocol Population and the Completer 
Population. 
3.4.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be summarized by visit, as applicable. The change from 
Baseline at each visit will be summarized for each parameter. For study visits occurring after the 
Transition Visit, the change from Transition Visit will also be summarized for each parameter in 
addition to the change from Baseline. The continuous secondary endpoints will also be 
summarized on Transition Visit and X Weeks Post Transition Visit in addition to the nominal 
visits. The value of interest listed in section 2.3.2.2 will be provided. 
• 
6-Minute Walk Distance (6MWD) 
o 
The subjects receiving oxygen during the time of the test will be listed 
o 
The subjects having unusual circumstances that adversely affected the walk will 
be listed 
• 
Heart rate recovery after 6MWD 
• 
Borg dyspnea score 
o 
The Borg dyspnea scores and their respective shifts from baseline and Transition 
Visit will be summarized for each assessment (i.e. number and percent of 
subjects who improved, worsened, or had no change) 
• 
World Health Organization (WHO) Functional Classification (FC) 
o 
The functional class values and their respective shifts from baseline and 
Transition Visit will be summarized for each assessment (i.e. number and 
percent of subjects who improved, worsened, or had no change) 
• 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
o 
The percent change from Baseline and Transition Visit will also be provided. 
• 
Echocardiographic parameters 
• 
PAH symptom score 
o 
Severity grade values (i.e., 0, 1, 2, or 3) for each symptom of PAH (fatigue, 
dyspnea, edema, dizziness, syncope, chest pain, and orthopnea) will be listed for 
all subjects. The severity grades and their shifts from baseline and Transition 
Visit will be summarized for each assessment. 
• 
Subjects' TSQM responses and Health-related quality of life (emPHasis-10) 
questionnaires 
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• 
The number and percentage of subjects that successfully transitioned to Orenitram at 
any dose and were successfully maintained on therapy at Week 16 
• 
The number and percentage of subjects that improve in each of the following 4 individual 
clinical parameters (6MWO, NT-proBNP, WHO FC, right atrial area) to a lower risk 
stratum, as defined by the 2015 European Society of Cardiology guidelines, compared to 
Baseline will be provided for the Transition Visit and Week 16. 
• 
The number and percentage of subjects that meet each of the following 4 individual 
clinical parameters in the low risk category, as defined by the 2015 European Society of 
Cardiology guidelines: 6MWD >440 meters, serum NT-proBNP <300 ng/L, WHO FC I or 
11, and right atrial area <18 cm2. This will be provided for the Transition Visit and Week 
16. 
• 
The number and percentage of subjects that either achieve an Orenitram dose of 4 mg 
TIO (or a total daily dose of 12 mg) or higher (or a dose of 0.057 mg/kg TIO [or a total 
daily dose of 0.171 mg/kg] or greater for subjects <70 kg) or the percentage of subjects 
that achieve an Orenitram dose 2:2 mg TIO and <4 mg TIO (or a total daily dose 2:6 mg 
and <12 mg), with at least 2 of the following 3 clinical parameters: 6MWO increase by 
2:10% or .::30 meters from Baseline, serum NT-proBNP reduction >30% from Baseline, or 
WHO FC I or II. This will be provided for the Transition Visit and Week 16. This will be 
performed using both prescribed total daily dose as well as actual dose taken. 
The continuous secondary endpoints may be analyzed using linear regression models with the 
endpoint [such as change in 6-Minute Walk Distance, change in log(NT-proBNP}, and change in 
log(echocardiographic parameters) (performed by study sponsor at a later time) from Baseline 
to Transition Visit and Week 16) as the dependent variable and the baseline (or log(baseline)J 
value as a covariate. For endpoints modeled on the original scale, the predicted mean change 
from Baseline at the median baseline value will be provided, along with its associated standard 
error and 95% confidence interval. For endpoints modeled on the log scale, the predicted mean 
change from Baseline at the median log(baseline) value, with associated standard error and 
95% confidence interval, will be back-transformed to the original scale and presented as the 
predicted geometric mean ratio to Baseline at the median baseline value. For each model fitted, 
the slope and its standard error and p-value will also be provided. 
For patients in the Per-Protocol Population with a missing secondary efficacy endpoint at Week 
16 for 6MWO, WHO FC, NT-proBNP or Echocardiographic parameters, the last observation 
carried forward (LOCF) method will be used, in addition to a separate complete case analysis. 
No imputation is needed for the Completer population. 
The secondary efficacy endpoints will be summarized for the Per-Protocol Population, the 
Completer Population, and the subgroup of patients in the Completer Population who met the 
primary endpoint. 
3.4.3 
Exploratory Efficacy Endpoints 
Baseline pharmacogenomics (genetic/ribonucleic acid [RNA] testing) will be evaluated. 
Evaluation of biomarkers at Baseline, the Transition Visit, and Week 16, and change from 
Baseline to Transition and Transition to Week 16 will be performed. 
The exploratory efficacy endpoints will be prespecified in this document but performed at a later 
time by the study sponsor. 
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3.4.4 
Subgroup Analysis 
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Statistical Analysis Plan 
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The primary efficacy endpoint may be summarized for the Per-Protocol and Completer 
Population within subgroups defined by age (Median value of IIT Population), gender, 
background PAH therapy at Baseline (1. none, 2. Endothelin Receptor Antagonist [ERA] alone, 
3. Phosphodiesterase-5 [PDE-5] inhibitor/sGC stimulator alone, or 4. ERA+ PDE-5 
inhibitor/sGC stimulator), or baseline disease severity (as defined by 6MWD categories, WHO 
functional classification for PAH, REVEAL 2.0 risk score, time since PAH diagnosis). 
3.5 Pharmacokinetic Assessment 
No pharmacokinetic assessment is performed in this study. 
3.6 Pharmacodynamic Assessment 
No pharmacodynamic assessment is performed in this study. 
3.7 Safety Assessment 
Safety data will be summarized based on the Safety Population. 
3. 7.1 
Adverse Events {A Es) and Prostanoid AEs 
Adverse events will be captured from when the subject signs the informed consent form (ICF) 
until the subject completes the study or is withdrawn from the study. All AEs will be coded to 
system organ class and preferred term using MedDRA version v 21.0. Treatment-emergent 
adverse events (TEAEs) are defined as AEs that start after the first dose of Remodulin. 
Adverse events related to study drug will be those with a causality of possibly or probably 
related. 
The severity of a given AE is the maximum of all severities recorded during initial recording and 
all reassessments of the AE. 
An overview of AEs will be provided including counts and percentages of subjects and event 
counts (an AE record regardless of reassessment, only contributes once into the event count) 
with the following: 
• 
Any TEAEs (overall and by maximum severity) 
• 
Any serious AEs (SAEs) 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any TEAEs leading to discontinuation of study 
• 
Any TEAEs leading to discontinuation of Remodulin 
• 
Any TEAEs leading to discontinuation of Orenitram 
• 
Any SAEs leading to death 
Counts and percentages of subjects and event counts will also be presented by system organ 
class and preferred term for each of the categories in the overview, except SAEs, if there are at 
least 5 adverse events in the categories. 
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Figures for visualizing the number of days an AE falls into each AE severity category (Mild, 
Moderate, Severe) and changes in AE severity over time may be provided by sponsor. 
For each of the "Prostanoid AEs" defined by section 3.3.1.9 of the protocol (headache, diarrhea, 
nausea, flushing, jaw pain, extremity pain, and vomiting): 
• 
The counts and percentages of patients and event counts who report the Prostanoid AE 
will be summarized, as well as a breakdown of the maximum severity reported (e.g. mild, 
moderate, severe). 
• 
This will be reported separately for each treatment phase. 
• 
AEs that occur in more than one treatment phase (e.g. a 'severe' headache that began 
in the Remodulin phase that continued as a 'severe' or 'mild' to the Transition phase will 
be counted in both treatment phases, with corresponding severities based on the 
maximum severity in each phase) will be counted in each treatment phase. 
• 
Changes in severity of Prostanoid AEs over the entire study period may be listed, 
summarized, and/or depicted graphically for each patient. This may be performed by the 
study sponsor. 
• 
The number of days which the AE was reported and the corresponding severity may be 
summarized for each treatment phase (i.e. Remodulin phase, Transition phase, 
Orenitram phase). For these summaries, the AE Reassessment date will be used as the 
start and end dates for an AE which changes in severity, and the AE End Date will be 
the end date for the AE. This may be performed by the study sponsor. 
o 
Example: 
Headache occurring in Remodulin phase 
AE Start Date: 1/10/2022 
severity: mild 
AE Reassessment Date 1: 1/22/2022 
severity: moderate 
AE Reassessment Date 2: 2/01/2022 
severity: moderate 
AE End Date: 2/05/2022 
Mild: 12 days (1/10/2022 to 1/22/2022) 
Moderate: 14 days (1/22/2022 to 2/5/2022) 
Severe: O days 
A by subject listing will be provided for all of the AEs and listings will also be presented 
specifically for SAEs and TEAEs leading to discontinuation of study drug. 
3. 7.1.1 
AE Bothersome Survey 
Investigators will ask subjects about the prostanoid-related effects they experienced using the 
AE Bothersome Survey. For this study, adverse events of interest include headache, diarrhea, 
nausea, flushing, jaw pain, extremity pain, and vomiting. The survey is provided in protocol 
Appendix E. The number and percentage of subjects reporting each of the adverse events of 
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interest at Baseline, the Transition Visit, and Week 16/Early Study Withdrawal will be provided 
(Question 1 ). 
For each symptom (headache, diarrhea, nausea, flushing, jaw pain, extremity pain, and 
vomiting), AE Bothersome Survey scores will be summarized at Baseline, the Transition Visit, 
and Week 16/Early Study Withdrawal for each question (Question 2, and Question 3). In 
addition, change from Baseline and change from Transition Visit will be provided. For each 
symptom, the following scoring system will be utilized and an overall Burden Score will be 
provided: 
1 day 
2 days 
3 days 
4 days 
5 days 
Not at all 
0 
0 
0 
0 
0 
Bothers 
3 
4 
5 
6 
7 
me a little 
Bothers 
5 
6 
7 
8 
9 
me some 
Bothers 
8 
9 
10 
11 
12 
me a lot 
Points 
Burden Score 
0 
Not at all burdensome 
3 to 6 
Mildly burdensome 
7 to 9 
Moderately burdensome 
10 to 14 
Very burdensome 
3. 7.2 
Vital Signs and Clinical Laboratory Tests 
Vital signs and clinical laboratory tests will not be listed or summarized. 
4 
ANALYSIS TIMING 
4.1 Interim Analysis 
6 days 
7 days 
0 
0 
8 
9 
10 
11 
13 
14 
An interim analysis will be performed when there are about 10 subjects that have conducted the 
Week 16/ Early Study Withdrawal Visit, to evaluate the safety of Orenitram after induction 
therapy with Remodulin. The safety profile will be used to check if it is consistent with the 
historical data on transitions gathered from previous studies. 
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The following summary tables and listings will be generated for the interim analysis based on 
the enrolled subjects who have conducted the Week 16/ Early Study Withdrawal Visit: 
• 
Summary of disposition on enrolled subjects as described in section 3.3.1 
• 
Summary of demographic and baseline characteristics will be provided as described in 
section 3.3.4 
• 
Summary of REVEAL 2.0 risk score as described in section 3.3.5 
• 
Summary of current PAH background medications as described in section 3.3.6 
• 
Summary of study drug exposure (dosage and transition) will be provided as described 
in section 3.3.7 
• 
The primary and key secondary endpoints (6MWD, Borg dyspnea score, WHO FC and 
NT-proBNP) will be summarized as described in section 3.4.1 and 3.4.2 
• 
A listing of Remodulin and Orenitram dose levels for each subject at each timepoint will 
be provided by visit 
• 
Overview summary of AEs as described in section 3.7.1 
4.2 Pre-Final Analysis 
After the database is locked and exclusions from analysis populations have been finalized, the 
pre-final analysis will be generated. Pre-final TFLs will be provided approximately 3 weeks after 
database lock. 
4.3 Final Analysis 
After all comments on the pre-final analysis have been resolved and the study database is 
declared final, the final analysis will be generated. Final TFLs will be provided approximately 1 
week after the study database is declared final. If there were no changes to the pre-final 
analysis or the study database, the pre-final TFLs will be considered final. In addition to TFLs, 
SDTM data and ADaM data along with associated files will be provided. Associated files will 
include: annotated case report forms (CRFs), reviewer's guide, SDTM specifications, SDTM 
programs, ADaM specifications, ADaM programs, TFL programs, and Clinical Data Interchange 
Standards Consortium (CDISC) Define packages for both SDTM and ADaM data. 
5 
CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL ANALYSES 
An informal interim analysis is planned for publication purposes, targeting presentation at a PH 
conference occurring May 2020. 
Sample size is updated to include approximately 35 evaluable subjects. 
6 
PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher. All available data will be 
presented in subject data listings which will be sorted by subject and visit date as applicable. 
Detailed Programming Specifications will be provided in a separate document. 
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REFERENCE 
CONFIDENTIAL 
Statistical Analysis Plan 
Version 2.0, 28 Apr 2021 
[1] Boucly, Athena"is, et al. "Risk assessment, prognosis and guideline implementation in 
pulmonary arterial hypertension." European Respiratory Journal 50.2 (2017). 
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