An Extended Access Program to Assess Long-term Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension
Phase: PHASE3
Conditions: Pulmonary Hypertension
Sponsor: Biogen

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B A R D O X O L O N E M E T H Y L ( R T A 4 0 2) 
 
4 0 2- C- 1 6 0 2 
 
E U D R A C T N U M B E R : 2 0 1 6- 0 0 4 3 6 5-1 6  
 
A N E X T E N D E D A C C E S S P R O G R A M T O A S S E S S 
L O N G- T E R M S A F E T Y O F B A R D O X O L O N E M E T H Y L 
I N P A TI E N T S WI T H P U L M O N A R Y H Y P E R T E N SI O N 
Versi o n 3. 0 – 1 6 J ul y 2 0 1 8 
 
Pr ot oc ol Hist or y 
Versi o n 2. 0 – 0 5 Ja n uar y 2 0 1 7 
Versi o n 1. 0 – 2 7 Oct o ber 2 0 1 6 
 
T he i nf or mati o n c o ntai ne d herei n is c o nfi de ntial a n d t he 
pr o prietar y pr o pert y of R eata P har mace uticals, I nc . a n d a n y 
u na ut h orize d use or discl os ure of s uc h i nf or mati o n wit h o ut t he 
pri or writte n a ut h orizati o n of Reata P har mace uticals, I n c. is 
e x pressl y pr o hi bite d.  

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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 recei ve d a n d rea d t he I n v esti gat or’s Br oc h ure f or b ar d o x ol o ne met h yl.  I ha v e rea d t he 
4 0 2- C- 1 6 0 2 cli nical st u d y pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d.  I a gree t o 
mai ntai n t he c o nfi de ntial it y of all i nf or mati o n r ecei ve d or de v el o pe d i n c o n necti o n wit h t his 
pr ot oc ol.  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri nte d Na me of I n v esti gat or 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of I n vesti gat or 
 
  
  
  
  
  
  
 
Date 

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P R O C E D U R E S I N C A S E O F E M E R G E N C Y 
 
T a ble 1:  
E mer ge nc y C o nt a ct I nf or m ati o n 
R ole i n St u d y  
N a me  
A d dress a n d Tele p h o ne N u m ber  
Me dical a n d Scie ntific  
Lea der  
 
 
 
 
 
 
 
 
Cli nical St u d y 
Ma na ger  
 
 
 
 
 
 
Me dical M o nit or  
 
 
 
 
S A E Re p orti n g  
 
 
 
 
 
 
 
 
 
 
N o n -N ort h A merica n sites  will use access c o des s pecific t o t heir c o u ntr y.  
N u m bers f or n o n -N ort h A merica n sites f or S A E re p orti n g will be pr o vi de d 
b y t he cli nical tea m directl y t o t he sites f or re p orti n g a n d s u b mitti n g S A E 
i nf or mati o n t o  
  
 
 

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2.  
S Y N O P SI S 
N a me of S p o ns or/ C o m p a n y:  
Reata P har mace uticals, I nc.  
N a me of I n vesti g ati o n al Pr o d uct:  
Bar d o x ol o ne met h yl  
Title of St u d y:  
A n E xte n de d Access Pr o gra m t o Assess L o n g -T er m Safet y of Bar d o x ol o ne Met h yl i n Patie nts wit h 
P ul m o nar y H y perte nsi o n  
St u d y ce nter(s):  A p pr o xi matel y 1 5 0  st u d y ce nters  
St u die d peri o d:  U ntil c o m mercial a vaila bilit y of 
bar d o x ol o ne met h yl  
Esti mate d date first patie nt e nr olle d: Fe br uar y  2 0 1 7  
Esti mate d date last patie nt c o m plete d: Patie nt will 
re mai n i n t he st u d y u ntil bar d o x ol o ne met h yl is 
a vaila ble t hr o u g h c o m mercial c ha n nels or u ntil patie nt 
wit h dra wal, w hic he ver is s o o ner  
P h ase of de vel o p me nt:  
3 a 
P ri m ar y O bjecti ves:   
T o pr o vi de c o nti n ui n g  o pe n -la bel treat me nt wit h bar d o x ol o ne met h yl as part of t his e xte n de d access 
pr o gra m w hile  c ollecti n g o n g oi n g safet y a n d t olera bilit y data  of bar d o x ol o ne met h yl.   
P ri m ar y S afet y E n d p oi nt : 
Fre q ue nc y, i nte nsit y, a n d relati o ns hi p t o st u d y dr u g of a d verse e ve nts ( A Es) a n d seri o us a d verse e ve nts  
( S A Es), a n d c ha n ge fr o m baseli ne i n t he f oll o wi n g assess me nts: p h ysical e xa minati o ns, vital si g n 
meas ure me nts, B -t y pe natri uretic pe pti de ( B N P), N-ter mi nal pr o-brai n natri uretic pe pti de ( N T -pr o B N P) , 
a n d wei g ht. 
Met h o d ol o g y:  
T his e xte n de d access st u d y will assess t he l o n g-ter m safet y a n d t olera bilit y of bar d o x ol o ne met h yl i n 
q ual ifie d patie nts wit h p ul m o nar y h y perte nsi o n ( P H) w h o pre vi o usl y partici pate d i n c o ntr olle d cli nical 
st u dies wit h bar d o x ol o ne met h yl.  
Q ualifie d patie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her da y, t he n be gi n o nce  dail y 
d osi n g  at Wee k 4 ( u nless c o ntrai n dicate d cli nicall y) a n d c o nti n ue u ntil t he dr u g is a vaila ble t hr o u g h 
c o m mercial c ha n nels (i ncl u di n g rei m b urse me nt) or u ntil patie nt wit h dra wal, w hic he ver is s o o ner.  D ose 
de -escalati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y , if i n dicate d cli nicall y.    
All patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc he d ule.  P atie nts will be sc he d ule d t o 
be assesse d i n pers o n d uri n g treat me nt at Da y 1, Wee k 2, Wee k 4 , Wee k 6, Wee k 8, Wee k 2 4, a n d e ver y 
2 4 wee ks t hereafter.  Patie nts will als o be assesse d b y tele p h o ne c o ntact o n Da y s 3, 1 0 , 2 1, 3 1, a n d 3 8.  
Da y 1 f or t his e xte n de d access st u d y s h o ul d occ ur o n t he sa me da y as t he last visit i n t he c o ntr olle d 
cli nical st u d y.  Patie nt stat us s h o ul d be caref ull y m o nit ore d b y t he i n vest i gat or d uri n g t he first 8  wee ks of 
st u d y treat me nt.  Assess me nts re q uire d f or b ot h t he last visit i n t he c o ntr olle d st u d y a n d Da y 1 f or t his 
st u d y s h o ul d o nl y be c o m plete d o nce. 
Patie nts fr o m t he C A T A L Y S T st u d y: 
Da y 1 of t his e xte n de d access  st u d y will c oinci de wit h  t he Wee k 2 8 f oll o w-u p visit f or patie nts fr o m 

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C A T A L Y S T ( 4 0 2 -C -1 5 0 4 , N C T 0 2 6 5 7 35 6 , E u dra C T 2 0 1 6-0 0 0 1 9 6 -2 4 ).  If t his e xte n de d access pr o gra m 
is n ot yet o pe n f or e nr oll me nt at t he ti me of a patie nt’s Wee k 2 8 visit , t he Da y 1 visit (i.e., e nr oll me nt) 
m ust occ ur wit hi n 3 0 da ys of site acti vati o n.  E xce pti o ns all o wi n g C A T A L Y S T patie nts w h o ha ve 
c o m plete d 2 4 wee ks of treat me nt t o sc he d ule t heir f oll o w-u p assess me nts pri or t o Wee k 2 8 a n d still be 
c o nsi dere d eli gi ble  f or t his o pe n -la bel st u d y s h o ul d be disc usse d wit h t he C hief Me dical Officer at Reata, 
or desi g nee, a n d will be c o nsi dere d o n a case -b y -case basis.  
Patie nts fr o m t he L A RI A T st u d y :  
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h  t he E n d-of -St u d y visit f or patie nts fr o m L A RI A T 
( 4 0 2-C -1 3 0 2, N C T 0 2 0 3 6 9 7 0) .  
Sc he m a f or St u d y of B ar d o x ol o ne Met h yl i n P atie nts wit h P ul m o n ar y H y perte nsi o n  
6- Mi n ut e W al k T e st
T T el e p h o n e C o nt a ct
D o s e- Titr ati o n
( 1 0 m g B A R D Q O D)
W 2
W 1
W 8
D 1
D 3
T
D 1 0
T
D 2 1
T
W 4
M ai nt e n a n c e
( 1 0 m g B A R D Q D)
D 3 1
T
D 3 8
T
W 6
E n d of 
St u d y
W 2 4,
E v er y 
2 4 W K s
 
 
N u m ber of p atie nts ( pl a n ne d):  
Patie nt n u m bers will be deter mi ne d b y t h ose w h o are treat me nt -c o m plia nt a n d w h o ha ve pre vi o usl y 
partici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl .  
M ai n criteri a f or i ncl usi o n:  
Treat me nt -c o m plia nt patie nts w h o are partici pati n g i n q ualif yi n g o n g oi n g st u dies  a n d ha ve c o m plete d 
re q uire d E n d-of -Treat me nt  a n d/ or F oll o w -u p visits i n a pri or cli nical st u d y wit h bar d o x ol o ne m et h yl.   
M aj or e xcl usi o n criteri a:  
1.  Partici pati o n i n ot her i n vesti gati o nal cli nical st u dies i n v ol vi n g i nter ve nti o nal pr o d ucts bei n g 
teste d or use d i n a wa y differe nt fr o m t he a p pr o ve d f or m or w he n use d f or a n u na p pr o ve d 
i n dicati o n; 
2.  Patie nts w h o ha ve a n o n g o i n g S A E  fr o m a cli nical st u d y t hat is assesse d b y t he i n vesti gat or as 
relate d t o bar d o x ol o ne met h yl; 
3.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part ners of 
c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) w h ile ta ki n g st u d y dr u g;  
4.  W o me n w h o are pre g na nt or breastfee di n g;  
5.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na ble t o c o m pl y wit h t he re q uire me nts of t he st u d y 
pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n;  
6.  K n o w n  h y perse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g . 
I n vesti g ati o n al pr o d uct, d os a ge, m o de of a d mi nistr ati o n , a n d d ur ati o n of tre at me nt:  
Bar d o x ol o ne met h yl will be a d mi nistere d orall y (e ver y ot her da y or o nce dail y) at 1 0 m g u ntil it bec o mes 
c o m merciall y a vaila ble.  D ose de -escalati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y , if i n dicate d 
cli nicall y. 

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Ref ere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
N o ne.  
Criteri a f or e v al u ati o n:  
Safet y : Res ults of p h ysical e xa mi nati o ns, la b orat or y res ults, B N P, N T -Pr o B N P, vital si g n meas u re me nts, 
wei g ht, A Es , a n d S A Es.  
St atistic al met h o ds:  
Sa m ple size : T he ai m of t his l o n g -ter m e xte nde d access  st u d y is pri maril y t o pr o vi de c o nti n ui n g treat me nt 
t o patie nts wit h bar d o x ol o ne met h yl a n d t o assess  l o n g-ter m safet y a n d t olera bilit y, he nce n o si n gle 
pri mar y varia ble has bee n i de ntifie d.  Patie nt n u m bers will be deter mi ne d b y t h ose w h o ha ve bee n 
treat me nt-c o m plia nt  a n d w h o ha ve pre vi o usl y partici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl . 
Pri mar y a nal ysis  of safet y : As t he e xte nsi o n is of a n o pe n -la bel desi g n wit h n o c o m parat or gr o u p, all 
statistical a nal yses will be descri pti ve.  T he s u m mar y ta bles will be prese nte d f or t he o verall gr o u p of 
patie nts, a n d als o s plit b y pre vi o us treat me nt gr o u ps (i.e., bar d o x ol o ne met h yl or place b o) i n pri or 
bar d o x ol o ne met h yl cli nical st u dies .  

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3.  
T A B L E O F C O N T E N T S A N D LI S T O F T A B L E S  
T A B L E O F C O N T E N T S 
1.  
T I T L E P A G E ................................................................................................................ 1 
2.  
S Y N O P SI S ................................................................................................................... 5  
3.  
T A B L E O F C O N T E N T S A N D LI S T O F T A B L E S .................................................... 8  
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S............................. 1 3  
5.  
IN T R O D U C TI O N ...................................................................................................... 1 5  
5. 1.  
S t u d y R ati o nale ........................................................................................................... 1 7 
5. 2.  
C li nical E x perie nce wit h Bar d o x ol o ne Met h yl .......................................................... 1 7 
5. 2. 1.  
S afet y a n d T olera bilit y ............................................................................................... 1 7  
5. 2. 2.  
F l ui d O verl oa d ............................................................................................................ 1 7 
5. 2. 3.  
Tr a nsa mi nase a n d Ga m m a- Gl uta m yl Tra ns p e pti dase Ele vati o ns .............................. 1 8  
5. 2. 4.  
M uscle  S pas ms ........................................................................................................... 1 8 
5. 2. 5.  
W ei g ht L oss ................................................................................................................ 1 9  
5. 2. 6.  
H y p o ma g n esae mia ...................................................................................................... 1 9  
6.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .............................................................. 2 0  
6. 1.  
P ri mar y O bj ecti ves ..................................................................................................... 2 0 
6. 2.  
P ri mar y Safet y E n d p oi nt: ........................................................................................... 2 0 
7.  
IN V E S TI G A TI O N A L P L A N ..................................................................................... 2 1  
7. 1.  
O ve rall St u d y Desi g n .................................................................................................. 2 1 
7. 2.  
N u m be r of Patie nts ..................................................................................................... 2 1 
7. 3.  
Tr eat me nt Assi g n me nt ................................................................................................ 2 1  
7. 3. 1.  
D ose  Escalati o n a n d D os e De- Es calati o n ................................................................... 2 2 
7. 4.  
C riteria f or St u d y Ter mi nati o n ................................................................................... 2 2 
7. 5.  
Criteria f or Pre m at ure T er mi nati o n or S us pe nsi o n of I n vesti gati o nal Sites ............... 2 2  
7. 6.  
Pr oce d ures f or Pre mat ure Ter mi nati o n or S us pe nsi o n of t he St u d y or t he 
Partici pati o n of I n vesti gati o nal Sites .......................................................................... 2 2  
7. 7.  
S c he d ule of Assess me nts ............................................................................................ 2 2  
8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S .............................................. 2 5  
8. 1.  
Patie nt I ncl usi o n Criteria ............................................................................................ 2 5  
8. 2.  
Patie nt E x cl usi o n Criteria ........................................................................................... 2 5  

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8. 3.  
Patie nt Disc o nti n uati o n  .............................................................................................. 2 5  
9.  
T R E A T M E N T O F P A TI E N T S .................................................................................. 2 7  
9. 1.  
S elect Ma na ge m e nt G ui deli nes .................................................................................. 2 7  
9. 1. 1.  
Ma na ge me nt of Fl ui d Stat us ....................................................................................... 2 7  
9. 1. 2.  
Ma na ge me nt of El e vate d Tra nsa mi nase Le vels ( A L T a n d/ or A S T) .......................... 2 7  
9. 1. 3.  
Ma na ge me nt of M us cle S pas ms ................................................................................. 2 8  
9. 1. 4.  
W ei g ht L oss ................................................................................................................ 2 8  
9. 1. 5.  
H y p o ma g n esae mia ...................................................................................................... 2 8  
9. 1. 6.  
Na usea ......................................................................................................................... 2 8  
9. 2.  
De scri pti o n of St u d y Dr u g .......................................................................................... 2 9 
9. 3.  
C o nc o mita nt Me dicati o ns ........................................................................................... 2 9  
9. 3. 1.  
E x cl u de d Me dicati o ns ................................................................................................ 2 9  
9. 3. 2.  
P er mitte d Me dicati o ns ................................................................................................ 2 9  
9. 4.  
Tr eat me nt C o m plia nce ................................................................................................ 3 0  
9. 5.  
R a n d o mizati o n ............................................................................................................ 3 0  
9. 6.  
B li n di n g ...................................................................................................................... 3 0 
9. 7.  
U nsc he d ule d Visits ..................................................................................................... 3 0  
9. 8.  
P re g n a nc y ................................................................................................................... 3 0 
9. 8. 1.  
W o me n of C hil d beari n g P ote ntial .............................................................................. 3 0  
9. 8. 2.  
Me t h o ds of Birt h C o ntr ol............................................................................................ 3 0 
9. 8. 3.  
S us pecte d Pre g na n c y .................................................................................................. 3 1  
9. 9.  
S eri o us T o xicities ....................................................................................................... 3 2  
9. 1 0.  
S t u d y Pr oce d ures ........................................................................................................ 3 2 
9. 1 0. 1.  
I nf or me d C o nse nt ....................................................................................................... 3 2 
9. 1 0. 2.  
I n cl usi o n/ E xcl usi o n .................................................................................................... 3 2  
9. 1 0. 3.  
P ri or a n d C urre nt C o nc o mita nt Me dicati o ns .............................................................. 3 2 
9. 1 0. 4.  
C urre nt P A H  Bac k gr o u n d Me dicati o ns ...................................................................... 3 2 
9. 1 0. 5.  
Wei g ht a n d B o d y M ass I n de x ..................................................................................... 3 2  
9. 1 0. 6.  
Vital Si g n Meas ur e me nts ............................................................................................ 3 3  
9. 1 0. 7.  
P h ysical E x a mi nati o n ................................................................................................. 3 3  
9. 1 0. 8.  
Pre g n a nc y T est ............................................................................................................ 3 3  
9. 1 0. 9.  
St u d y Dr u g A d mi nistrati o n......................................................................................... 3 3  
9. 1 0. 1 0.  
St u d y Dr u g Dis pe ns ati o n a n d C ollecti o n ................................................................... 3 3  

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9. 1 0. 1 1.  
Tele p h o ne C o ntact ...................................................................................................... 3 3  
9. 1 0. 1 2.  
A d verse E v e nt C ollecti o n ........................................................................................... 3 4  
9. 1 0. 1 3.  
C li nical C he mistr y ...................................................................................................... 3 4 
9. 1 0. 1 4.  
N- Ter mi nal P r o- Brai n N atri uretic Pe pti de a n d Brai n Natri uretic Pe pti de ................. 3 4 
9. 1 0. 1 5.  
6- Mi n ute Wal k Test .................................................................................................... 3 4  
9. 1 0. 1 6.  
W H O/ N Y H A F u n cti o nal Class Assess me nt .............................................................. 3 5  
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T ........................................... 3 6  
1 0. 1.  
S t u d y Dr u g .................................................................................................................. 3 6 
1 0. 2.  
S t u d y Dr u g Pac k a gi n g a n d La b eli n g .......................................................................... 3 6 
1 0. 3.  
S t u d y Dr u g St ora ge ..................................................................................................... 3 6 
1 0. 4.  
S t u d y Dr u g A d mi nistrati o n......................................................................................... 3 6 
1 0. 5.  
S t u d y Dr u g A cc o u nta bilit y ......................................................................................... 3 7 
1 0. 6.  
S t u d y Dr u g H a n dli n g a n d Dis p osal ............................................................................ 3 7 
1 1.  
S A F E T Y A S S E S S M E N T S ........................................................................................ 3 8  
1 1. 1.  
S afet y Para met ers ....................................................................................................... 3 8  
1 1. 2.  
A d ve rse a n d Seri o us A d verse E ve nts ......................................................................... 3 8 
1 1. 2. 1.  
Defi niti o n of A d vers e E v e nts ..................................................................................... 3 8  
1 1. 2. 1. 1.  
A d ve rse E v e nt ............................................................................................................. 3 8 
1 1. 2. 1. 2.  
Seri o us A d verse E v e nt ................................................................................................ 3 8  
1 1. 3.  
Eliciti n g A d vers e E ve nt I nf or mati o n .......................................................................... 3 9  
1 1. 4.  
Asse ss me nt of Ca usalit y ............................................................................................. 4 0 
1 1. 5.  
Asse ss me nt of Se verit y ............................................................................................... 4 0 
1 1. 6.  
R ec or di n g A d verse E ve nts ......................................................................................... 4 0  
1 1. 7.  
Re p orti n g Seri o us A d v erse E ve nts ............................................................................. 4 1  
1 2.  
S T A TI S TI C S .............................................................................................................. 4 4  
1 2. 1.  
S a m ple Siz e ................................................................................................................ 4 4  
1 2. 2.  
St u d y Vari a bles ........................................................................................................... 4 4  
1 2. 2. 1.  
Safet y  Vari a bles .......................................................................................................... 4 4 
1 2. 3.  
S tatistical A nal yses ..................................................................................................... 4 4 
1 2. 3. 1.  
Pri mar y A n al ysis of Safet y ......................................................................................... 4 4  
1 3.  
D I R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S......................................... 4 5 
1 3. 1.  
St u d y- S pecific C o m mittees ........................................................................................ 4 5  
1 3. 2.  
St u d y M o nit ori n g ........................................................................................................ 4 5  

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1 3. 3.  
A u dits a n d I ns p ecti o ns ................................................................................................ 4 5  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ......................................... 4 6  
1 4. 1.  
Q ua lit y Ass ura nce ....................................................................................................... 4 6 
1 4. 2.  
F i na ncial Discl os ur e ................................................................................................... 4 6 
1 4. 3.  
S p o ns or O bli gati o ns.................................................................................................... 4 6  
1 4. 4.  
In v esti gat or D oc u me nt ati o n ........................................................................................ 4 6  
1 4. 5.  
C li nical St u d y I ns ura nce ............................................................................................. 4 7 
1 4. 6.  
Use  of I nf or mati o n ...................................................................................................... 4 7 
1 5.  
E T H I C S ...................................................................................................................... 4 8 
1 5. 1.  
Instit uti o nal Re vie w B oar d or Et hics C o m mittee Re vie w .......................................... 4 8  
1 5. 2.  
Et hi cal C o n d uct of t he St u d y ...................................................................................... 4 8  
1 5. 3.  
W ritte n I nf or m e d C o nse nt .......................................................................................... 4 8 
1 5. 4.  
C o nfi de ntialit y ............................................................................................................ 4 9  
1 5. 5.  
M o di ficati o n of t he Pr ot oc ol ....................................................................................... 4 9 
1 5. 6.  
P r ot oc ol De viati o ns .................................................................................................... 5 0 
1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G ....................................................... 5 1  
1 6. 1.  
R ete nti o n of Rec or ds .................................................................................................. 5 1  
1 6. 2.  
C ase Re p ort F or ms ..................................................................................................... 5 1  
1 7.  
P U B LI C A TI O N P O LI C Y .......................................................................................... 5 2  
1 8.  
R E F E R E N C E S ........................................................................................................... 5 3  
1 9.  
A P P E N DI X 1: A T S G UI D E LI N E S F O R T H E SI X- MI N U T E W A L K T E S T .......... 5 5  
2 0.  
A P P E N DI X 2: F U N C TI O N A L C L A S SI FI C A TI O N O F P U L M O N A R Y 
H Y P E R T E N SI O N M O D I FI E D A F T E R T H E N E W Y O R K H E A R T 
A S S O CI A TI O N F U N C T I O N A L C L A S SI FI C A TI O N A C C O R DI N G T O 
T H E W H O 1 9 9 8 ( G A LI E, 2 0 0 9) ............................................................................... 6 3  
2 1.  
A P P E N DI X 3:  B O R G C R 1 0 S C A L E ....................................................................... 6 4  
 

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LI S T O F T A B L E S 
Ta ble 1:  
E mer ge nc y C o nta ct I nf or mati o n ................................................................................... 4  
Ta ble 2:  
A b bre viati o ns a n d S peci alist Ter ms ........................................................................... 1 3  
Ta ble 3:  
Sc he d ule of  Assess me nts ............................................................................................ 2 3 
Ta ble 4:  
Bar d o x ol o ne Me t h yl Dr u g Pr o d uct I nf or mati o n ........................................................ 2 9 
Ta ble 5:  
S A E Re p orti n g C o ntact I nf or mati o n .......................................................................... 4 2  
 

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4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S 
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 2:  
A b bre vi ati o ns a n d S peci alist Ter ms 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
6 M W D  
6 -mi n ute wal k dista nce  
6 M W T  
6 -mi n ute wal k test  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
A T P  
A de n osi ne tri p h os p hate  
A T S  
A merica n T h oracic S ociet y  
B MI  
B o d y mass i n de x  
B N P  
B -t y pe natri uretic pe pti de 
C F R  
C o de of Fe deral Re g ulati o ns ( U S)  
C K  
Creati ne ki nase  
C K D  
C hr o nic ki d ne y disease  
C R O  
C o ntract researc h or ga nizati o n  
C T D -P A H  
C o n necti ve ti ss ue disease-ass ociate d p ul m o nar y arterial 
h y perte nsi o n  
E C  
Et hics C o m mittee  
e C R F 
Electr o nic case re p ort f or m  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I K K β 
I n hi bit or of n uclear fact or ka p pa β  ki nase beta s u b u nit  
I L D 
Interstitial l u n g disease  
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
Nrf 2  
N uclear fact or ( er yt hr oi d -d eri ve d 2) -relate d fact or 2 
N T -Pr o B N P  
N -T er mi nal Pr o -Brai n Nat ri uretic Pe pti de   

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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
N Y H A F C  
Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n  
P A H  
P ul m o nar y arterial h y perte nsi o n  
P H  
P ul m o nar y h y perte nsi o n  
R O S  
Reacti ve o x y ge n s pecies  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
T B L  
T otal bilir u bi n  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
W H O  
W orl d Healt h Or ga nizati o n  
W O C B P  
W o me n of c hil d beari n g p ote ntial  
 

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5.  
I N T R O D U C TI O N 
Bar d o x ol o ne met h yl a n d its a nal o gs are olea n olic aci d- deri ve d s y nt hetic triter pe n oi d c o m p o u n ds 
t hat p ote ntl y i n d uce t he Nrf 2- K ea p 1 p at h wa y (W u , 2 0 1 1; R ojas - Ri vera, 2 0 1 2).  T hr o u g h 
i nteracti o n wit h t he Nrf 2 re press or m olec ule, Kea p 1, bar d o x ol o ne met h yl a n d its a nal o gs 
pr o m ote tra nsl ocati o n of Nrf 2 t o t he n ucle us, w here Nrf 2 bi n ds t o a nti o xi da nt res p o nse ele me nts 
i n t he pr o m oter re gi o n of its tar get ge nes, lea di n g t o i n d ucti o n of ma n y a nti o xi da nt a n d 
c yt o pr ot ecti ve e nz y mes a n d relate d pr ot ei ns ( Lee , 2 0 0 9; Di n k o va - K ost o va, 2 00 5 ).  Bar d o x ol o ne 
met h yl a n d its a nal o gs are als o p ote nt i n hi bit ors of t he N F- κ B i nfla m mat or y pat h wa y t hr o u g h 
b ot h direct ( i.e., i n hi biti o n of I K K β ki nase acti vit y) a n d i n direct mec ha nis ms (i.e., det o xificati o n 
of r eacti ve o x y ge n s peci es [ R O S]) (Os b ur n , 2 0 0 8 ).  Beca use of t his d ual mec ha nis m of acti o n, 
bar d o x ol o ne met h yl a n d its a nal o gs are h y p ot hesi ze d t o ha ve p ote ntial t hera pe utic rel e va nce i n a 
variet y of diseas e setti n gs i n v ol vi n g o xi dati ve stress a n d i nfla m mati o n.  Acti vati o n of t he Nrf 2 
pat h wa y als o tra ns cri pti o nall y re g ulates m ulti ple ge nes t hat pr o m ote t he pr o d ucti o n of cell ular 
e ner g y wit hi n t he mit oc h o n dria a n d facilitates mit oc h o n drial h o me ostasis a n d efficie n c y.   
T hr o u g h i n d u cti o n of  Nrf 2 a n d s u p pressi o n of N F-κ B , bar d o x ol o ne met h yl has br oa d m olec ul ar 
a n d p har mac ol o gi cal effects t hat a d dress m ulti ple facets of t h e pat h o p h ysi ol o g y of p ul m o nar y 
arterial h y p erte nsi o n ( P A H).  I n d ucti o n of N F- κ B is mar ke dl y ele vat e d i n macr o p ha ges, 
e n d ot helial cells a n d s m o ot h m uscle cells of P A H patie nts ( Price , 2 0 1 0).  R ece nt e vi d e nce 
de m o nstrates t hat g e netic or p har mac ol o gi c i n d ucti o n of Nrf 2 s u p presses f or mati o n of t he P A H 
p he n ot y p e i n a m o use m o del of h y p o xic p ul m o nar y h y p erte nsi o n ( P H) ( E b a , 2 0 1 3).   
A d diti o nall y, a n e m er gi n g c o n ce pt i n t he pat h o ge nesis of P H is t he r ole of s yste mic meta b olic 
a n d s keletal m uscle d ysf u ncti o n as a maj or ca use of re d uce d f u ncti o nal ca p acit y a n d fati g ue, as 
well as disease pr o gressi o n.  A hi g h fre q ue n c y of i ns uli n resista nce a n d meta b olic s y n dr o m e-li ke 
feat ur es ha ve b ee n des cri be d i n patie nts wit h P H, a n d gl u c ose i nt olera n ce is ass ociate d wit h a 
decrease i n 6 - mi n ute wal k dista nce ( 6 M W D) (P u g h , 2 0 1 1).  P ul m o nar y h y p erte nsi o n patie nts 
ha ve decrease d a d e n osi ne tri p h os p hate ( A T P) pr o d ucti o n ( S ute n dra , 2 0 1 4), w hic h res ults i n 
s keletal m uscle d ysf u ncti o n a n d i m paire d f u ncti o nal ca pacit y (Mai n g u y , 2 0 1 0; B att, 2 0 1 4 ).  
I n d ee d, t he s k eletal m uscle wit hi n patie nts wit h P H dis pla ys a d ecreas e d e x pressi o n of 
mit oc h o n drial res pirati o n e nz y mes, defects i n mit oc h o n drial o xi dati ve p h os p h or ylati o n, a n d 
i m pair me nts i n mit oc h o n drial bi o ge n esis (Batt , 2 0 1 4; Ma le nfa nt, 2 0 1 5 ).  O verall, t hese d efects i n 
s keletal m uscle c o ntri b ut e t o m uscle wea k n ess a n d fati g u e, as w ell as i m paire d e x ercise ca pacit y 
i n patie nts wit h P H (Batt , 2 0 1 4).  
S e veral li nes of e vi d e nce s u g gest t hat Nrf 2 acti vati o n ca n i ncrease mit oc h o n drial res pirati o n a n d 
bi o ge n esis, i n a d diti o n t o i n d uci n g e x pressi o n of n u mer o us a nti o xi dati ve ge nes t o c o u nter R O S.  
S pecificall y, b y i ncreasi n g t he a vaila bilit y a n d pr o d ucti o n of re d uci n g e q ui vale nts s uc h as 
nic oti na mi de a de ni ne di n ucle oti de a n d fla vi n a de ni ne di n ucle oti de, Nrf 2 acti vati o n i m pr o ves 
mi t oc h o n drial A T P pr o d ucti o n a n d i m pr o ves t he effi cie nc y of mit oc h o n dri al res pirati o n a n d 
o x y ge n c o ns u m pti o n.  I n a d diti o n, Nrf 2 acti vati o n res ults i n i m pr o ve d beta- o xi dati o n of fatt y 
aci ds a n d i m pr o ve d u pta ke of gl uc ose, w hi c h lea ds t o i m pr o ve me nt i n mit oc h o n drial res pir ati o n, 
o x y ge n c o ns u m pti o n, a n d e ner g y pr o d u cti o n.  Si nce Nrf 2 acti vati o n ca n i n creas e mit oc h o n drial 
res pirati o n (H ol mstr ö m , 2 01 3 ; L u dt ma n n , 2 0 1 4 ), bar d o x ol o ne met h yl ma y rest ore meta b olic 
deficits i n P H, t here b y ac utel y i m pr o vi n g e ner g y pr o d ucti o n a n d 6 M W D. 

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patie nts wit h C T D- P A H ha d si milar s ustai ne d i ncreases i n 6 M W D t hr o u g h Wee k 3 2.  O n t he 
basis of t hese data, Reata e x pa n de d t he L A RI A T pr ot oc ol ( Versi o n 5. 0) t o i ncl u de P H patie nts 
wit h I L D, i n cl u di n g W H O Gr o u p III patie nts wit h C T D-ass ociate d I L D, i di o pat hic p ul m o nar y 
fi br osis, n o n-s pecific i nterstitial p ne u m o nia, a n d W H O Gr o u p V patie nts wit h sarc oi d osis.  Reata 
has als o i nitiate d a P hase 3 st u d y i n W H O Gr o u p I C T D- P A H patie nts ( 4 0 2- C- 1 5 0 4, 
C A T A L Y S T, N C T 0 2 6 5 7 3 5 6, E u dra C T 2 0 1 6- 0 0 0 1 9 6- 2 4) t o st u d y t he s afet y a n d effi cac y of 
bar d o x ol o ne met h yl i n t h ose patie nts.   
5. 1.  
St u d y R ati o n ale 
T he esta blis he d p har mac ol o gic effects of bar d o x ol o ne met h yl, i ncl u di n g t he s u p pressi o n of 
pat h ol o gic N F- κ B si g n ali n g a n d i nfla m m ati o n a n d mit oc h o n drial d ysf u ncti o n, are dir ectl y 
a p plica ble t o t he tre at me nt of P H .  Des pite a vaila ble t hera pies, t he pr o g n osis f or P H re mai ns 
p o or,  es peci all y f or patie nts wit h C T D (C h u n g , 2 0 1 4) a n d I L D.  Gi ve n t he se verit y of t he 
u n de rl yi n g dise ase, t his st u d y see ks t o offer patie nts w h o pre vi o usl y p artici pate d i n cli nical 
st u dies e xte n de d access t o bar d o x ol o ne met h yl u ntil it is a vaila ble t hr o u g h c o m mercial c h a n nels 
(i ncl u di n g rei mb urse me nt). 
F or f urt her i nf or m ati o n, refer t o t he I n vesti gat or’s Br oc h ure.  
5. 2.  
Cli nic al E x perie nce wit h B ar d o x ol o ne Met h yl 
A p pr o xi matel y 1 9 5 0 i n di vi d uals ha ve bee n e x p ose d t o bar d o x ol o ne met h yl at t he ti me of 
i nitiati o n of t his st u d y.  Si xtee n st u dies ha ve bee n c o m plete d ( 7 i n patie nts wit h c hr o ni c ki d ne y 
disease ( C K D) w h o a ls o ha d t y p e 2 dia betes, 4 i n n o n- C K D i n dicati o ns, a n d 5 i n healt h y 
s u bjects) a n d 2 st u dies are o n g oi n g i n patie nts wit h P H.   
5. 2. 1.  
S afet y a n d T oler a bilit y 
Please refer t o t he I n v esti gat or ’s Br oc h ure f or a detaile d disc ussi o n of safet y fi n di n gs wit h 
ba r d o x ol o ne met h yl f or st u dies i n healt h y s u bjects, o nc ol o g y, C K D, a n d patie nts wit h P H. 
5. 2. 2.  
F l ui d O verl o a d 
Si milar t o e n d ot heli n rece pt or a nta g o nists i n cert ai n patie nt p o p ulati o ns, i ncl u di n g b ose nta n i n 
a d va nce d c o n gesti ve h eart fail ure a n d a v ose nta n i n a d va nce d C K D, bar d o x ol o ne met h yl 
treat me nt was f o u n d t o b e ass ociate d wit h a n i ncrease d ris k f or fl ui d o verl oa d a n d heart fail ure 
h os pitaliz ati o ns i n a P hase 3 trial ( B E A C O N), w hi c h e nr olle d patie nts wit h Sta ge 4 C K D (e G F R 
of 1 5- 2 9 m L/ mi n/ 1. 7 3 m 2) a n d t y pe 2 dia betes.  T he o verall i ncreas e d ris k f or fl ui d o verl oa d a n d 
heart fail ure e v e nts wit h bar d o x ol o ne met h yl a p peare d t o be li mite d t o t he first t hree t o f o ur 
wee ks after i nitiati o n of treat me nt.  Ele vat e d B-t y pe natri uretic p e pti de ( B N P) a n d pri or 
h os pitaliz ati o n f o r heart fail ure were i de ntifie d as ris k fact ors t hat c o ntri b ute d t o i ncrease d ris k 
f or t hese e v e nts.  T he i ncrease d ris k f or t hes e e ve nts fr o m bar d o x ol o ne met h yl treat me nt ha d n ot 
bee n o bser ve d i n s i x pre vi o us C K D st u dies, w hic h were c o n d ucte d m ostl y i n patie nts wit h Sta ge 
3 b C K D (e G F R of 3 0- 4 4 m L/ mi n/ 1. 7 3 m 2), patie nts wit h he patic d ysf u ncti o n, ca ncer patie nts, or 
healt h y v ol u nteers.  
Re vie w of a d missi o n n otes a n d narrati ve des cri pti o ns f or heart fail ure h os pitalizati o ns i n 
B E A C O N i n dic ates t hat heart fail ure i n bar d o x ol o ne met h yl-treate d patie nts was ofte n prece d e d 
b y ra pi d fl ui d wei g ht gai n (se veral kil o gra ms wit hi n t he first wee ks of treat me nt i nitiati o n) a n d 

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was n ot ass ociate d wit h ac ute re n al dec o m pe ns ati o n or ac utel y re d uce d left ve ntric ular 
c o ntractilit y.  A v aila ble d ata fr o m B E A C O N a n d ot her st u dies s u g gest t hat bar d o x ol o ne met h yl 
treat me nt can differe ntiall y affect he m o d y na mic st at us acc or di n g t o t he cli nical c o n diti o n of 
patie nts a n d li kel y pr o m ot es fl ui d rete nti o n i n patie nts wit h m ore a d va n ce d re nal d ysf u ncti o n a n d 
ot her  rec o g niz e d ris k fact ors ass ociate d wit h heart fail ure at b aseli ne.   
I n a P hase 2 d ose-ra n gi n g st u d y of t he efficac y a n d safet y of bar d o x ol o ne met h yl i n patie nts wit h 
P H ( L A RI A T), ris k miti gati o n pr oce d ures were e m pl o ye d t o re d u ce t he p ote ntial f or 
bar d o x ol o ne met h yl -i n d u ce d fl ui d o verl o a d; t hese pr oce d ures e x cl u de d pati e nts wit h t he 
i de ntifie d ris k fact ors a n d e ns ure d cl os e m o nit ori n g f or fl ui d rete nti o n wit hi n t he first m o nt h of 
treat me nt.  T o date, t he ris k f or ac ute fl ui d o verl oa d a d verse e ve nts ( A Es) wit h bar d o x ol o ne 
met h yl i n late-sta ge C K D patie nts has n ot bee n o bser ve d i n P A H patie nts.   
5. 2. 3.  
T r a ns a mi n ase a n d G a m m a- Gl ut a m yl Tr a ns pe pti d ase Ele v ati o ns  
I n cli nical st u dies of bar d o x ol o ne met h yl, al m ost all patie nts ha d i ncreas es of tra nsa mi nase 
e nz y mes ab o v e baseli ne u p o n i nitiati o n of treat me nt, w hic h f oll o w e d a c o nsiste nt patter n.  T hese 
i ncreas es were n ot ass oci ate d wit h ele vati o ns i n bilir u bi n or ot her si g ns of li ver t o xicit y.  I n a 
lar ge P hase 3 stu d y t hat e nr olle d 2 1 8 5 patie nts wit h t y pe 2 dia betes a n d sta ge 4 C K D 
( B E A C O N), fe wer he pat o biliar y S A Es w ere o bs er ve d i n t he bar d o x ol o ne met h yl ar m t ha n i n t he 
place b o ar m.  T he ele v ati o ns be gi n i m me diatel y after i nitiati o n of treat me nt or a n i ncrease i n 
d ose; t h e y p ea k a p pr o xi matel y t w o t o f o ur wee ks later.  I n m ost patie nts, tra nsa mi nase ele vati o ns 
we re mil d, b ut a p pr o xi matel y 4 % t o 1 1 % of patie nts e x perie nce d a n ele vati o n greater t h a n 3 X 
t he u p per li mit of n o r mal ( U L N).  T h e ele vati o ns res ol ve d t o le vels less t ha n t he U L N i n m ost all 
patie nts wit h ele vati o ns, wit hi n t w o wee ks after pea k val ues w hile p atie nts c o nti n ue d ta ki n g 
st u d y dr u g.  Patie nts w h o e x perie nce d el e vati o ns t o greater t ha n 3 X t he U L N s o meti mes re q uire d 
a d diti o nal ti me t o res ol ve.  W hile s o me patie nts ha ve ha d ele vati o ns t o a b o ve 3 X t he U L N, 
persiste nt ele vati o ns t o a b o ve 3 X t he U L N ha ve n ot bee n o bser ve d, a n d t he ele vati o ns di d n ot 
rec ur o nce r es ol ve d, u nless ca use d b y ot her fact ors. 
Bar d o x ol o ne met h yl re g ulates ga m ma- gl uta m yl tra ns pe pti dase ( G G T), a k n o w n Nrf 2 tar get 
ge n e.  I n cli nic al st u dies, l o w le vel G G T ele vati o ns d uri n g tr eat me nt were c o m m o n, mil d, a n d 
t y picall y laste d l o n ger t ha n ala ni ne a mi n otra nsferase ( A L T)/as part ate a mi n otra nsferase ( A S T) 
ele vati o ns.  Bilir u bi n l e v els i n patie nts e x peri e nci n g tra ns a mi nase or G G T ele vati o ns d ue t o 
treat me nt wit h bar d o x ol o ne met h yl eit her re mai ne d at baseli ne le vels or d ecreas e d.  T he A L T, 
A S T, a n d G G T ele v ati o ns we re ge nerall y s elf-li miti n g i n patie nts w h o c o nti n ue d treat me nt wit h 
st u d y dr u g.  
5. 2. 4.  
M uscle S p as ms  
M uscle s pas m was t he m ost fre q ue ntl y re p orte d A E i n cli nical st u dies of bar d o x ol o ne met h yl i n 
patie nts wit h C K D  w h o als o ha d t y pe 2 dia betes.  T he m uscle s pas ms m ost ofte n ma nifeste d i n 
t he first t w o m o nt hs of treat me nt a n d res ol ve d s p o nta ne o usl y or wit h e m pirical treat me nt.  T he y 
occ urre d m ostl y at ni g ht, i n t he l o wer e xtre mities, a n d we re ge nerall y mil d t o m o derate i n 
se verit y.  M uscle s pas ms ha ve als o be e n re p orte d i n bar d o x ol o ne met h yl-tr eate d P A H patie nts 
b ut at l o wer i nci de nces t ha n t hat o bser ve d i n pri or C K D st u dies.  M ore o ver, t he i nci de nce of 
m uscle s pas ms is si milar t o t hat o bser ve d i n place b o-treate d P A H patie nts.  M uscle s pas ms ma y 
res ult fr o m i m pr o ve d i ns uli n se nsiti vit y a n d gl uc ose u pta ke i n s keletal m us cle cells.  I n creases i n 

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gl uc ose u pta ke, as assess e d b y t h e h y peri ns uli ne mic-e u gl yce mic cla m p pr o ce d ure, were 
o bser ve d i n res p o ns e t o b ar d o x ol o ne met h yl i n a d efi ne d s u bset of p atie nts e nr olle d i n a P hase 2 a 
st u d y.  T o date, i n t h ose cases w h ere s er u m creati ni ne ki nase ( C K) le vels ha ve bee n me as ure d, 
n o ass ociati o n has bee n o bser ve d bet w ee n m uscle s pas ms a n d ele vate d C K le vels i n patie nts 
treate d wit h bar d o x ol o ne met h yl.  Cli nical si g ns a n d la b orat or y fi n di n gs ass ociate d wit h t he 
re p orts of m uscle s p as ms ha ve n ot bee n c o nsiste nt wit h m uscle t o xicit y.  Bar d o x ol o ne met h yl 
s u bjects s h o we d n o i ncrease i n pr o mi ne nt la b orat or y fi n di n gs ass ociate d wit h m uscle t o xicit y, 
s uc h as i ncrease d le v els of ser u m mar kers, i ncl u di n g creati ni ne, lactate de h y dr o ge nase, bl o o d 
urea nitr o ge n, uric aci d, p h os p h or us, a n d p otassi u m, w hic h were m o nit ore d wee kl y d uri n g t he 
first t w o m o nt hs of a pri or st u d y ( B E A M) w he n m uscle s pas ms were m ost fre q ue ntl y re p orte d.  
I n creases i n t he w h ole- b o d y gl uc os e dis p osal rate ha ve bee n o bser ve d i n mice treat e d wit h 
bar d o x ol o ne met h yl, as well.  I n crease d gl uc os e u pta ke was o bser ve d i n is olate d calf m uscles of 
t he mice, b ut n ot i n w hite a di p ose tiss ue (Sa ha , 2 0 1 0).   
5. 2. 5.  
We i g ht L oss 
De creases i n w ei g ht a n d re p orts of a n ore xia/ decrease d a p petite ha ve bee n o bser ve d f oll o wi n g 
treat me nt wit h bar d o x ol o ne met h yl i n patie nts wit h C K D w h o als o ha d t y p e 2 dia betes.  I n 
st u dies of t hese patie nts, 1 7 % of bar d o x ol o ne met h yl patie nts re p orte d A Es of wei g ht decreas e or 
decrease d a p petite (irres p ecti ve of relati o ns hi p t o treat m e nt).  Wei g ht re d u cti o n was m ore 
pr o n o u nce d i n patie nts tr e ate d wit h bar d o x ol o ne met h yl t ha n i n t h ose gi ve n place b o. 
Wei g ht l oss of a p pr o xi matel y o n e kil o gra m per m o nt h was o bser ve d, wit h patie nts of hi g h er 
b o d y- mass i n d e x at baseli ne l osi n g m ore wei g ht (i n a bs ol ute ter ms) t ha n t h ose of n or mal or 
m o deratel y- ele vate d b o d y- mass i n d e x.   
Bar d o x ol o ne met h yl-treate d P A H patie nts ha ve als o ha d decreases i n wei g ht, wit h mea n wei g ht 
decrease s of a p pr o xi matel y 3 k g vers us place b o at Wee k 1 6.  Wei g ht l oss i n P A H pati e nts has 
n ot c oi nci de d wit h re p orts of de crease d a p petite or a n ore xia A Es. 
5. 2. 6.  
H y p o m a g nes ae mi a 
H y p o ma g n esae mia has n ot bee n re p orte d i n P A H patie nts t o date, b ut was re p orte d as a n A E f or 
1 5. 5 % of patie nts wit h C K D w h o als o ha d t y pe 2 dia betes w h o recei v e d bar d o x ol o ne met h yl.  
T he A E  of h y p o ma g n esae mia ( of a n y re p ort e d rel ati o ns hi p t o st u d y dr u g) was m ore fre q ue ntl y 
re p orte d i n bar d o x ol o ne met hyl-tr eate d patie nts t h a n i n patie nts gi ve n pl ace b o.  T he i n vesti gat ors 
c o nsi dere d al m ost all re p orte d e ve nts t o be mil d.  A d diti o nall y, patie nts treate d wit h bar d o x ol o ne 
met h yl ha d a g reater d ecrease fr o m baseli ne i n ser u m ma g nesi u m le vels t ha n patie nts gi ve n 
place b o; t he decrease w as e vi de nt wit hi n 4 wee ks a n d atte n uate d after 8 wee ks of starti n g 
t hera p y.  In b ar d o x ol o ne met h yl cli nical st u dies perf or me d t o date, a p ost- h oc a nal ysis i de ntifie d 
n o c orrel ati o n bet wee n h y p o ma g n esae mia a n d eit her gastr oi ntesti nal A Es or car di ac A Es, 
i ncl u di n g car diac d ysr h yt h mias a n d pr ol o n ge d Q T c.  T he 2 4- h o ur uri ne c oll ecti o ns fr o m t he 
B E A C O N a m b ulat or y bl o o d press ure m o nit ori n g s u b-st u d y s h o we d n o i ncrease i n uri n ar y 
ma g n esi u m le vels, i n dicati n g t hat re n al l oss of ma g nesi u m di d n ot acc o u nt f or t he re d u cti o ns i n 
ser u m ma g nesi u m o bser ve d wit h bar d o x ol o ne met h yl treat me nt i n C K D patie nts.  N ota bl y, a 
t h or o u g h Q T st u d y t hat teste d d oses of bar d o x ol o ne met h yl u p t o 8 0 m g, b ar d o x ol o ne met h yl 
s h o we d n o i ncrease i n th e Q T i nter val.  

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6.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S 
6. 1.  
Pri m ar y O bjecti ves 
T o pr o vi de c o nti n ui n g tr eat me nt wit h bar d o x ol o ne met h yl as part of t his e xte n de d access 
pr o gra m w hile c ollecti n g o n g oi n g safet y a n d t olera bilit y data of bar d o x ol o ne met h yl.  
6. 2.  
Pri m ar y  S afet y E n d p oi nt: 
Fre q u e nc y, i nte nsit y, a n d relati o ns hi p t o st u d y dr u g of a d verse e ve nts ( A Es) a n d seri o us a d v erse 
e ve nts ( S A Es), a n d c ha n ge fr o m baseli ne i n t he f oll o wi n g assess me nts: p h ysical e x a mi nati o ns, 
vital si g n meas ur e me nts, B N P, N-ter mi nal p r o- brai n natri uretic pe pti de ( N T- pr o B N P), a n d 
we i g ht. 

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7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n 
T his e xte n de d access st u d y will assess t he l o n g-ter m safet y a n d t olera bilit y of bar d o x ol o ne 
met h yl i n q ua lified patie nts wit h P H w h o pre vi o usl y partici p ate d i n c o ntr olle d cli nical st u dies 
wit h bar d o x ol o ne met h yl. 
Q ualifie d patie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her da y, t he n be gi n 
o nce dail y d osi n g at W ee k 4 ( u nless c o ntrai n dicate d cli nicall y) a n d c o nti n ue u ntil t he dr u g is 
availa ble t hr o u g h c o m mercial c ha n n els (i ncl u di n g rei m b urse me nt) or u ntil patie nt wit h dra wal, 
w hic he ver is s o o n er.  D ose de-es calati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y if 
i n dicate d cli nicall y.  Refer t o Secti o n  7. 3. 1  f or a d diti o nal details o n d ose de-escalati o n.  
All patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc h e d ule.  Patie nts will be 
sc he d ule d t o be ass esse d i n pers o n d uri n g treat me nt at Da y 1, Wee k 2, Wee k 4, Wee k 6, Wee k 8, 
W ee k 2 4, a n d ever y 2 4 w ee ks t hereafter.  Patie nts will als o be assesse d b y t ele p h o ne c o nt act o n 
Da ys 3, 1 0, 2 1, 3 1, a n d 3 8.  Da y 1 f or t his e xte n de d access st u d y s h o ul d occ ur o n t he sa me d a y 
as t he last visit i n the c o ntr olle d cli nical st u d y.  Patie nt stat us s h o ul d be caref ull y m o nit ore d b y 
t he i n vesti gat or d uri n g t h e first 8 wee ks of st u d y treat me nt.  Assess me nts re q uire d f or b ot h t he 
last visit i n t he c o ntr olle d st u d y a n d Da y 1 f or t his st u d y s h o ul d o nl y b e c o m plete d o nce. 
Patie nts fr o m t he C A T A L Y S T st u d y: 
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h t he Wee k 2 8 f oll o w- u p visit f or patie nts 
fr o m C A T A L Y S T ( 4 0 2- C- 1 5 0 4, N C T 0 2 6 5 7 3 5 6, E u dra C T 2 0 1 6- 0 0 0 1 9 6- 2 4).  If t his e xte n de d 
access pr o gra m is n ot yet o pe n f or e nr oll me nt at t he ti me of a patie nt’s Wee k 2 8 visit, t he Da y 1 
visit ( i.e., e nr oll me nt) m ust occ ur wit hi n 3 0 da ys of site acti vati o n.  E x ce pti o ns all o wi n g 
C A T A L Y S T patie nts w h o ha ve c o m plete d 2 4 wee ks of treat me nt t o sc he d ule t heir f oll o w- u p 
assess me nts pri or t o W ee k 2 8 a n d still be c o nsi dere d eli gi ble f or t his o pe n-l a bel st u d y s h o ul d be 
disc usse d wit h t he C hief Me dical Offi cer at Reata, or desi g n ee, a n d will be c o nsi dere d o n a cas e-
b y - case b asis.   
Patie nts fr o m t he L A RI A T st u d y: 
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h t he E n d- of- Treat me nt visit f or patie nts 
fr o m L A RI A T ( 4 0 2- C- 1 3 0 2, N C T 0 2 0 3 6 9 7 0).   
7. 2.  
N u m ber of P atie nts 
Patie nt n u m bers will be deter mi ne d b y t h ose w h o ha ve bee n treat me nt-c o m plia nt a n d w h o ha ve 
pre vi o usl y p a rtici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl. 
7. 3.  
Tre at me nt Assi g n me nt 
All patie nts will recei ve bar d o x ol o ne met h yl i n t his st u d y. 

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7. 3. 1.  
D ose Esc al ati o n a n d D ose De -Esc al ati o n  
P atie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her d a y, t he n be gi n o nce d ail y 
d osi n g at Wee k 4 u nless c o ntrai n dicate d cli nicall y.  T he i n vesti gat or s h o ul d disc uss a n y reas o ns 
f or n ot d ose-es calati n g t o o nce dail y d osi n g at Wee k 4 wit h t he me dical m o nit or.  
D ose de- escalati o n is per mitte d d uri n g t he st u d y a n d t he i n vesti gat or m a y c h o ose t o decrease t he 
patie nt’s d ose t o 5 m g  if cli nicall y i n dicat e d.  Reas o ns f or d ose de-escalati o n s h o ul d be disc usse d 
wit h t he me dical m o nit or pri or t o c ha n gi n g d ose.  O nce a p atie nt’s d ose has bee n decrease d t o 
5 m g, t he y ca n n ot d ose- escalate bac k t o 1 0 m g of bar d o x ol o ne met h yl. 
U nsc he d ule d visits d ue t o d ose de-es calati o n s h o ul d i ncl u de assess me nts detaile d i n Secti o n 9. 7 .  
7 . 4. 
Criteri a f or St u d y Ter mi n ati o n 
T he 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 at a n y ti me f or cli nical or a d mi nistrati ve 
reas o ns, or if re q uir e d b y re g ulat or y a ge ncies.  If t he S p o ns or disc o nti n ues t he st u d y, all st u d y 
dr u gs will be disc o nti n ue d a n d t he i n vesti gat or will be res p o nsi ble f or s ec uri n g a n y alter nati ve 
t hera p y t o be a d mi nistere d, as a p pr o pri ate. 
7. 5.  
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of I n vesti g ati o n al 
Sites 
A st u d y site ma y be t er mi nate d pre mat urel y or s us pe n de d if t he site (i ncl u di n g t he i n vesti gat or) 
is f o u n d i n si g nifica nt vi olati o n of G o o d Cli nical Practice ( G C P), pr ot oc ol, or c o ntract ual 
a gree m e nt wit h S p o ns or or t he site is u na ble t o e ns ure a de q u ate perf or ma n ce of t he st u d y. 
7. 6.  
Pr oce d ures f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he St u d y 
or t he P artici p ati o n of I n vesti g ati o n al Sites 
I n t he e ve nt t hat t he S p o ns or, a n i nstit uti o nal re vie w b oar d (I R B)/et hics c o m mittee ( E C), or 
re g ulat or y a ut h orit y el ects t o ter mi nate or s us pe n d t he st u d y or t he p artici pati o n of a n 
i n vesti gati o nal site, a st u d y-s p ecific pr oce d ure f or earl y ter mi nati o n or s us p e nsi o n will be 
pr o vi de d b y t he S p o ns or. 
7. 7.  
Sc he d ule of Assess me nts 
Ta ble 3  lists t he o verall s c he d ule of assess me nts f or t he st u d y. 
 

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T a ble 3:  
Sc he d ule of Assess me nts   
St u d y Wee k  
( D a y) 
Assess me nt  
D a y 1 a We e k 1  
( P h o ne) 
D a y 3 ± 2  
We e k 1   
D a y 7 ± 3  
We e k 2  
( P h o ne) 
D a y 1 0 ± 2  
We e k 2  
D a y 1 4 ± 3  
We e k 3  
( P h o ne) 
D a y 2 1 ± 2  
We e k 4  
D a y 2 8 ± 3  
We e k 4  
( P h o ne) 
D a y 3 1 ± 2  
We e k 5  
( P h o ne) 
 D a y 3 8 ± 2  
We e k 6  
D a y 4 2 ± 3  
We e k 8  
D a y 5 6 ± 3  
We e k 
2 4 ± 3,  
E ver y 2 4 
We e ks  
E n d of  
St u d y  
 Visit b 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt 
me dicati o ns  
X c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C urre nt P A H bac k gr o u n d 
me dicati o ns  
X c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Wei g ht at h o me  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Wei g ht i n cli nic  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
Vital si g n meas ure me nts  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
P h ysical e xa m i n ati o n 
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
Pre g na nc y test d 
X c 
 
 
 
 
 
 
 
 
 
 
X  
 
Dis pe nse st u d y dr u g  
X  
 
 
 
 
 
X  
 
 
 
 
X  
 
C ollect st u d y dr u g  
 
 
 
 
 
 
X  
 
 
 
 
X  
X  
Tele p h o ne c o ntact  
 
X  
 
X  
 
X  
 
X  
X  
 
 
 
 
A d verse e ve nt c ollecti o n  
X e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Cli nical C he mistries f 
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
B N P a n d / or N T -Pr o B N P  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
6 -mi n wal k test  
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
D ys p nea a n d fati g ue g 
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
W H O f u ncti o nal class  
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
a O n Da y 1, all pr oce d ures s h o ul d be perf or me d bef ore st u d y dr u g a d mi nistrati o n f or patie nts w h o are treat me nt-c o m plia nt a n d ha ve pre vi o usl y partici pate d i n 
cli nical st u dies wit h bar d o x ol o ne met h yl. 
b After t he W ee k 2 4 visit, patie nts will c o nti n ue t o be assesse d i n pers o n e ver y 2 4 wee ks u ntil bar d o x ol o ne met h yl b ec o mes c o m m erciall y a vaila ble.  T he 
E n d- of - St u d y visit s h o ul d occ ur wit hi n 3 0 da ys after bar d o x ol o ne met h yl bec o mes a vaila ble t hr o u g h c o m mercial c ha n nels.  P atie nts w h o will be disc o nti n ue d 
fr o m t he st u d y pri or t o c o m mercial a vaila bilit y of bar d o x ol o ne met h yl m ust als o c o m plete all En d -of - St u d y assess me nts.  
c Da y 1 assess me nts s h o ul d be perf or me d as part of E n d-of - Treat me nt or F oll o w- u p visit pr oce d ures fr o m a pri or st u d y wit h bar d o x ol o ne met h yl.  
d A ser u m pre g na nc y test will be perf or me d at a n y p oi nt i n ti me if a pre g na nc y is s us pecte d.  All ot her pre g na nc y assess me nts will be uri ne pre g na nc y t ests.  
A d diti o nal pre g na nc y assess me nts will be perf or me d m ore fr e q ue ntl y if re q uire d b y l ocal l a w or re q ueste d b y l ocal healt h a ut h orities or I R Bs/ E Cs .   

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e A E assess me nts o n Da y 1 s h o ul d be perf or me d f oll o wi n g st u d y dr u g a d mi nistrati o n. 
f Cli nical c he mistries will be a n al yze d l ocall y. 
g D ys p nea a n d fati g ue m ust b e assesse d pri or t o be gi n ni n g a n d i m me diatel y f oll o wi n g c o m pleti o n of t he 6 M W T usi n g t he B or g scale. 
 
A b bre viati o ns: P A H, p ul m o nar y arterial h y perte nsi o n; B N P, B-t y pe natri uretic pe pti de; N T- pr o B N P, N-ter mi nal pr o B-t y pe natri uretic pe pti de; W H O, W orl d 
Healt h Or ga nizati o n; A E, a d verse e ve nt; 6 M W T, 6- mi n ute wal k test.

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8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S 
8. 1.  
P atie nt I ncl usi o n Criteri a 
Mai n criteria f or i ncl usi o n:  
Treat me nt- c o m plia nt patie nts w h o are p artici pati n g i n q ualif yi n g o n g oi n g st u dies a n d ha ve 
c o m plete d re q uir e d E n d- of- Treat me nt a n d/ or F oll o w- u p visits i n a pri or cli nical st u d y wit h 
bar d o x ol o ne met h yl.   
8. 2.  
P atie nt E xcl usi o n Criteri a 
All patie nts wit h a n y of t he f oll o wi n g c o n diti o ns or c haracteristics m ust be e x cl u de d fr o m t he 
st u d y: 
1.  Partici pati o n i n ot her i n vesti gati o nal cli nical st u dies i n v ol vi n g i nter ve nti o n al pr o d ucts 
bei n g teste d or use d i n a wa y differe nt fr o m t he a p pr o ve d f or m or w he n use d f or a n 
u na p pr o ve d i n dicati o n; 
2.  Patie nts w h o ha ve a n o n g oi n g seri o us a d verse e ve nt ( S A E) fr o m a cli nical st u d y t hat is 
assesse d b y t he i n ve sti gat or as relate d t o b ar d o x ol o ne met h yl; 
3.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part n ers 
of c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) w hile t a ki n g st u d y dr u g;  
4.  W o me n w h o are pre g na nt or breastf ee di n g; 
5.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na bl e t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n; 
6.  K n o w n h y p erse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g.  
8. 3.  
P atie nt Disc o nti n u ati o n a n d Ter mi n ati o n 
Patie nts ha ve t he ri g ht t o disc o nti n ue st u d y dr u g or wit h dra w fr o m t he st u d y at a n y ti me f or a n y 
reas o n, wit h o ut prej u dice t o t heir me dical care.  F urt her m ore, t he i n v esti gat or ma y disc o nti n ue a 
patie nt fr o m st u d y dr u g.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h d ra wi n g a patie nt fr o m t he st u d y.  T he reas o n f or a p atie nt’s 
disc o nti n uati o n fr o m st u d y dr u g or st u d y t er mi nati o n will be rec or de d i n t he electr o ni c cas e 
re p ort f or m (e C R F).  
Disc o nti n uati o n refers t o a patie nt’s st o p pi n g a d mi nistrati o n of st u d y dr u g a n d all st u d y 
assess me nts a n d visits.  Reas o ns f or st u d y dr u g disc o nti n uati o n ma y i ncl u de t he f oll o wi n g: 
 Oc c urre nce of a n A E or c ha n ge i n me dical stat us t hat will lea d t he i n vesti gat or t o be 
c o ncer ne d a b o ut t he p atie nt’s welfare; 
 A d mi nistrati ve reas o ns ( e. g., i na bilit y t o c o nti n ue); 
 S p o ns or ter mi nati o n of t he st u d y; 
 V ol u ntar y wit h dra w al; 

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 F e males w h o bec o me pre g na nt d uri n g t he st u d y; 
 P re mat ure ter mi nati o n or s us pe nsi o n of a n i n vesti gati o nal site; 
 L oss t o f oll o w- u p; 
 De at h; 
 W it h dra wal of c o nse nt. 
Patie nts m ust disc o nti n ue st u d y dr u g if a n y of t he f oll o wi n g occ ur. 
 A L T or A S T > 8 X U L N; 
 A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks; 
 A L T or A S T > 3 X U L N a n d (t otal bilir u bi n > 2 X U L N or I nter nati o nal N or malize d 
Rati o [I N R] > 1. 5); 
 A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
Patie nts w h o disc o nti n ue fr o m t he st u d y will be as ke d t o c o m plete t he E n d- of- St u d y pr oce d ures 
n ote d i n Ta ble 3 . 

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9.  
T R E A T M E N T O F P A TI E N T S 
9. 1.  
Select M a n a ge me nt G ui deli nes 
T he f oll o wi n g g ui d eli nes a p pl y t o t he ma n a ge me nt of st u d y partici pa nts: 
9. 1. 1.  
M a n a ge me nt of Fl ui d St at us 
S pecific ris k miti gati o n pr oce d ures will be e m pl o ye d t o re d uce t he p ote ntial f or bar d o x ol o ne 
met h yl-i n d uc e d fl ui d o verl oa d.  La b orat or y data, as well as B N P a n d/ or N T - pr o B N P, will als o be 
us e d t o m o nit or fl ui d stat us.  A d diti o nall y, p atie nts will be m o nit ore d f or ra pi d wei g ht gai n 
s u g gesti ve of fl ui d o verl oa d.  Patie nts will be gi v e n a S p o ns or- pr o vi de d s cale t o use at h o me t o 
m o nit or t heir wei g hts dail y d uri n g t he first 8 wee ks of t he treat me nt peri o d .  Patie nts w h o 
ex perie nce a 5- p o u n d ( 2. 3 kil o gra m) or greater i n creas e i n wei g ht si nce t h eir Da y 1 wei g ht 
d uri n g t he first 8 wee ks of t he treat me nt peri o d will be i nstr ucte d t o st o p ta ki n g t heir st u d y 
me dicati o n i m me dia tel y a n d ret ur n t o t he cli nic f or a n u nsc he d ul e d p h ysical e x a mi nati o n a n d 
la b orat or y ass ess me nt b y t he i n vesti gat or.  Patie nts ma y n ot r estart t heir st u d y me dicati o n u ntil 
t he i n vesti gat or h as c o m plete d a n d d oc u me nt e d a n assess me nt of fl ui d o verl oa d.  
In v esti gat or s s h o ul d a d vise patie nts t o watc h f or si g ns a n d s y m pt o ms of fl ui d o verl oa d.  Patie nts 
s h o ul d be i nf or me d t o n otif y t heir p h ysicia ns i m m e diatel y if t he y e x perie nce s w olle n feet, c hest 
pai n, s h ort ness of breat h wit h mil d e x erti o n or w hile l yi n g d o w n, or ot her rele va nt s y m pt o ms.  
T he i n vesti gat or s h o ul d i m me diatel y ass ess s y m pt o ms of fl ui d o verl oa d a n d deter mi ne 
ap pr o priate m e dica l ma n a ge me nt, as necessar y, i n cl u di n g w het her st o p pi n g dr u g a d mi nistrati o n 
will be re q uire d.  At t he earliest si g n of w orse ni n g or ne w o nset peri p heral e de ma, or ot her si g ns 
a n d s y m pt o ms o f ac ute v ol u me o verl oa d, i n vesti gat ors will als o be e x pecte d t o deter mi ne if 
c ha n ges t o a p atie nt’s di uretic re gi me n is nee de d. 
9. 1. 2.  
M a n a ge me nt of Ele v ate d Tr a ns a mi n ase Le vels ( A L T a n d/ or A S T) 
Tra nsa mi nases s h o ul d be m o nit ore d f oll o wi n g patie nt’s sta n dar d of care.  Nearl y all i nsta nces of 
ele vate d tra nsa mi nases are e x pecte d t o be as y m pt o matic.  Tra nsa mi nas e le vels (as well as t otal 
bilir u bi n [ T B L], G G T, al kali ne p h os p hatase, a n d I N R) will be c hec k e d wit hi n 4 8 t o 7 2 h o urs 
d uri n g a n u nsc he d ule d visit if t he f oll o wi n g occ urs: 
 A L T or A S T le vels > 3 X U L N. 
Testi n g will be re peat e d e ver y 7 2 t o 9 6 h o urs u ntil tra nsa mi nase le vels are bel o w 3 X t he U L N 
f or at least o ne wee k or u ntil t he patie nt wit h dra ws c o nse nt. 
St u d y dr u g a d mi nistrati o n will be per ma ne ntl y dis c o nti n ue d if a n y of t he f oll o wi n g occ urs: 
 A L T or A S T > 8 X U L N; 
 A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks; 
 A L T or A S T > 3 X U L N a n d ( T B L > 2 X U L N or I N R > 1. 5); 
 A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).  

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T he he pat o biliar y tr ee m ust be vis ualize d ( e. g., ultras o u n d, ma g netic res o n a nce i ma gi n g) a n d 
assesse d if a p atie nt disc o nti n ues ta ki n g st u d y dr u g sec o n dar y t o ele vate d tra nsa mi nase le vels.  
A d diti o nal tests/st u dies ma y b e warra nte d de pe n di n g o n t he cli nical prese ntati o n. 
9. 1. 3.  
M a n a ge me nt of M uscle S p as ms 
Basic s y m pt o matic relief is t he first ste p i n ma na gi n g m uscle s pas m, i ncl u di n g wal ki n g, a d e q uate 
h y drati o n, weari n g s o c ks, a n d stretc hi n g bef ore b e dti me.  Assess me nt of le vels of electr ol ytes 
s uc h as ma g nesi u m, cal ci u m a n d p otassi u m as part of patie nt’s sta n dar d of care ma y i n dicate t he 
nee d f or re pla ce me nt.  If vita mi n D le vels are l o w, s u p ple me ntati o n ma y b e warra nte d.  M uscl e 
rela x a nts ma y als o hel p r elie ve s y m pt o ms. 
9. 1. 4.  
We i g ht L oss 
O n g oi n g ass ess me nts t o e ns ure t hat t he patie nt is recei vi n g a d e q uate n utriti o n a n d c o nsi derati o n 
of ot her eti ol o gies of w ei g ht l oss ma y be warra nte d f or patie nts recei vi n g b ar d o x ol o ne met h yl.   
9. 1. 5.  
H y p o m a g nes ae mi a 
I n i nsta n ces w h ere a pati e nt e x perie nces h y p o ma g nesae mia (e val uate d as p art of patie nt’s 
sta n dar d of care), defi ne d as ser u m ma g nesi u m less t ha n 1. 3 m E q/ L ( 0. 6 5 m m ol/ L), 
c o nsi derati o n s h o ul d be gi ve n t o re pleti o n of ser u m ma g nesi u m. 
9. 1. 6.  
N a us e a 
Na usea ma y o cc ur wit h hi g her d os es of bar d o x ol o ne met h yl.  N a usea A Es are t y picall y mil d a n d 
re versi ble wit hi n a few wee ks aft er treat me nt i nitiati o n.  If s y m pt o ms will n ot res ol ve, d ose 
de-escalati o n, wit h c o ns ultati o n of t he me dical m o nit or, ma y be n ecessar y.   

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9. 2.  
Descri pti o n of St u d y Dr u g 
Bar d o x ol o ne met h yl ( R T A 4 0 2) dr u g pr o d u ct i nf or mati o n is s h o w n i n  Ta ble 4 .   
T a ble 4:  
B ar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or m ati o n 
Descri pti o n  
Bar d o x ol o ne met h yl ca ps ule ( 5  m g , 
1 0  m g ) 
I n gre die nts 
Bar d o x ol o ne met h yl  
Met hacr ylic Aci d –  Et h yl Acr ylate 
C o p ol y mer  
 T y pe A  
Silicifie d Micr ocr ystalli ne Cell ul ose  
H y dr o x y pr o p yl Met h ylcell ul ose  
Lact ose M o n o h y drate  
S o di u m La ur yl S ulfate  
C oll oi dal Silic o n Di o xi de  
Ma g nesi u m Stearate  
Gelati n ca ps ules  
Tita ni u m Di o xi de 
 
R o ute of A d mi nistr ati o n  
Oral  
9. 3.  
C o nc o mit a nt Me dic ati o ns 
9. 3. 1.  
E xcl u de d Me dic ati o ns 
N o ot her i n vesti gati o nal dr u g or de vic e s h o ul d be ta ke n as part of a n i nter ve nti o nal st u d y d uri n g 
t he c o n d uct of t his st u d y. 
Patie nts w h o ta ke i n vesti gati o nal dr u g or de vice d uri n g t he st u d y s h o ul d n ot disc o nti n ue st u d y 
dr u g s olel y o n t his basis.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h dra wi n g a patie nt fr o m t he st u d y. 
9. 3. 2.  
P er mitte d Me dic ati o ns 
P ul m o nar y arterial h y perte nsi o n-s pecific b ac k gr o u n d t hera p y s h o ul d be ta ke n as cli nicall y 
i n dicate d a n d prescri be d b y t he p h ysicia n f or t he d urati o n of t he st u d y. 
Refer t o Secti o n 9. 1 0. 1 5  f or g ui deli nes o n o x y ge n use d uri n g 6 M W Ts.  I nitiati o n of 
s u p ple me ntal l o n g-ter m o x y ge n t h era p y ( o x y ge n a p plicati o n f or m ore t h a n 3 0 c o nsec uti ve da ys ) 
or persiste nt m o dificati o n of a pre-e xisti n g s u p ple me ntal l o n g-ter m o x y ge n t hera p y ( i.e., n ee d f or 
a persiste nt i ncrease of t he a m o u nt of deli vere d o x y ge n f or m ore t ha n 3 0 da ys) d ue t o w orse ni n g 
P A H is per mitte d.  
Di uretics ma y be prescri be d as cli nicall y i n dicate d t hr o u g h o ut t he st u d y.  A n y c ha n ges t o t he 
d oses of o x y ge n or di ur etics t hr o u g h o ut t he c o urse of t he st u d y m ust be rec or de d i n t he 
electr o nic case re p ort f or m (e C R F).   

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9. 4.  
Tre at me nt C o m pli a nce 
T he i n vesti gat or or his/ her desi g nate d a n d q ualifi e d re prese ntati ves will o nl y dis pe nse st u d y dr u g 
t o patie nts e nr olle d i n t he st u d y i n acc or da n ce wit h t he pr ot oc ol.  T he st u d y dr u g m ust n ot be 
use d f or rea s o ns ot her t h a n t hat descri b e d i n t he pr ot oc ol.  
9. 5.  
R a n d o mi z ati o n 
N ot a p plica ble. 
9. 6.  
Bli n di n g 
N ot a p plica ble.  
9. 7.  
U nsc he d ule d Visits 
U nsc he d ule d visits are all o we d f or t he f oll o wi n g reas o ns: 
 Asse ss me nt of wei g ht gai n per Secti o n 9. 1. 1 ;  
 Ma na ge me nt of a n A E or S A E; 
 P erf or ma nce of a d diti o nal la b orat or y tests f or cli nicall y a b n or mal la b orat or y test 
val ues or t o c o nfir m a p ossi ble pre g na nc y; 
 D ose  de- escalati o n; 
 A n y ti me t he i n vesti gat or feels t hat it is cli nicall y a p pr o priate f or patie nt safet y. 
At a mi ni m u m, u nsc he d ule d visits s h o ul d i ncl u de c ollecti o n of A Es, c o n c o mita nt me dicati o ns 
a n d vital si g ns .  A d diti o nal c o n vers ati o ns ma y b e necessar y wit h t he me dical m o nit or f oll o wi n g 
a n u nsc he d ule d visit t o assess patie nt safet y. 
9. 8.  
Pre g n a nc y 
9. 8. 1.  
W o m e n of C hil d be ari n g P ote nti al 
W o me n of c hil d beari n g p ote ntial ( W O C B P) are t h ose w h o are n ot s ur gicall y sterile ( n o hist or y 
of bilateral t u bal li gati o n, h ysterect o m y, or bilateral sal pi n g o- o o p h orect o m y), d o n ot ha ve 
fall o pia n i nserts wit h c o nfir me d bl oc ka ge, ha ve n ot ha d re pr o d ucti ve p ote ntial ter mi nate d b y 
ra diati o n, a n d are n ot p ost me n o pa usal f or at least 1 year. 
9. 8. 2.  
M et h o ds of Birt h C o ntr ol 
W hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys f oll o wi n g a d mi nistrati o n of t he fi nal d ose of st u d y 
me dicati o n, W O C B P m ust practice o n e of t he f oll o wi n g acce pta ble met h o ds of birt h c o ntr ol: 
 Use d o u ble barrier c o ntrace pti o n met h o d defi ne d as male use of a c o n d o m a n d fe male 
use of a barrier m et h o d ( e. g., c o ntrace pti ve s p o n ge, s per mici dal jell y or crea m, or 
dia p hr a g m [ al wa ys use wit h s per mici dal jell y/crea m]); 
 Use  of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi n al, or tra ns der mal) f or at least 
9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 

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 Use  of a n i ntra uteri ne d e vice; 
 A bsta i n fr o m se x ual i nterc o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nly acce pt a ble if it is t he preferre d a n d us ual lifest yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d. 
W hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys after t h e fi nal d ose of st u d y me dicati o n is ta ke n, males 
w h o ha ve fe male part ners of c hil d beari n g p ote ntial m ust practice o ne of t h e f oll o wi n g met h o ds 
of birt h c o ntr ol: 
 Ha ve ha d a vasect o m y (at least 6 m o nt hs earlier); 
 Use  d o u ble barrier c o ntrace pti o n met h o d, defi ne d as mal e use of a c o n d o m a n d 
fe male use of a barrier met h o d (e. g., c o ntr ace pti ve s p o n ge, s p er mici dal jell y or crea m, 
or dia p hra g m [ al wa ys us e wit h s per mici dal jell y/ crea m]); 
 P art ner use of a n i ntra uteri ne de vice; 
 P art ner use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal or tr a ns der mal) f or 
at least 9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 
 A bstai n fr o m se x ual i nterc o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nly acce pt a ble if it is t he preferre d a n d us ual lifest yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d. 
9. 8. 3.  
S us pecte d Pre g n a nc y 
D uri n g t h e st u d y, all W O C B P m ust be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt (e. g., late or misse d me nstr ual peri o d).  Mal e patie nts m ust be 
i nstr ucte d t o c o ntact t he i n vesti gat or if a se x ual part ner s us pects s he m a y be pre g na nt. 
If a patie nt or i n v esti gat or s us pects t hat t he patie nt ma y b e pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t he res ults of a ser u m pre g na n c y test are a v aila ble.  If t h e ser u m pre g n a nc y test 
c o nfir ms t he pre g n a nc y, t he patie nt m ust per ma ne ntl y disc o nti n ue ta ki n g st u d y dr u g.  T h e 
i n vesti gat or m ust i m me diatel y re p ort t o t he me dical m o nit or a pre g na nc y ass ociate d wit h st u d y 
dr u g e x p os ure.  T he earl y disc o nti n uati o n pr ot oc ol-re q uire d pr oce d ures o utli ne d f or E n d- of-
St u d y visits m ust be perf or me d o n t he patie nt.  
Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, t he i n vesti gat or m ust f oll o w a pre g na nt p atie nt, or 
t he pre g na nt f e male part ner of a m ale patie nt (if c o nse nti n g), a n d re p ort f oll o w- u p i nf or mati o n 
re gar di n g t he c o urse of t he pre g na n c y, i ncl u di n g peri natal a n d n e o natal o utc o me.  I nfa nts 
res ulti n g fr o m s uc h pre g na ncies s h o ul d be f oll o we d f or a mi ni m u m of 8 wee ks.  Reata or 
desi g nee ma y c o nt act t he i n vesti gat or t o re q uest a d diti o nal i nf or mati o n t hr o u g h o ut t he c o urse of 
t he pre g na n c y. 
T he f oll o wi n g pre g na n c y o utc o mes m ust be c o nsi dere d S A Es a n d will re q uire a d diti o nal 
re p orti n g i n t he e C R F a n d re p orte d as a n S A E: 
 C o n ge nital a n o mal y/ birt h defect; 
 Still birt h; 
 S p o nta ne o us mis carria ge. 

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9. 9.  
Seri o us T o xicities 
I n t he cas e of seri o us t o xicities, t he i n vesti gat or m a y c h o ose t o i nterr u pt treat me nt wit h 
bar d o x ol o ne met h yl.  A si n gle d ose re d ucti o n (fr o m 1 0 m g t o 5 m g) is p er mitte d if cli nicall y 
i n dicate d t o ma na ge t olera bilit y iss ues.  O nce a patie nt’s d ose has bee n re d u ce d, t hat d ose m ust 
be mai ntai ne d.  Patie nts w h o res u me t hera p y after a n i nterr u pti o n will f oll o w t he ori gi nall y 
pla n ne d st u d y s c he d ule.  
9. 1 0.  
St u d y Pr oce d ures  
T he f oll o wi n g s ecti o ns d escri be eac h assess me nt.  T he ti mi n g of t h ese assess me nts is n ote d i n 
Ta ble 3 .  All Da y 1 pr oce d ures, e x ce pt A E ass ess me nts, s h o ul d be c o m plete d pri or t o 
a d mi nistrati o n of  first d ose of st u d y dr u g. 
9. 1 0. 1.  
I nf or me d C o nse nt 
Writte n i nf or me d c o nse nt (see  Secti o n 1 5. 3 ) m ust be o btai ne d fr o m t he p atie nt bef ore a n y 
st u dy-relate d pr oce d ures are perf or m e d, a n d a gai n if t here is a c h a n ge i n t h e st u d y pr oce d ures 
t hat w o ul d affect t he pati e nt’s willi n g ness t o parti ci pate. 
9. 1 0. 2.  
I ncl usi o n/ E xcl usi o n 
I n cl usi o n a n d e x cl usi o n criteria m ust be re vi e we d as i n dicate d i n Ta ble 3 .  Patie nts m ust meet all 
of t he i ncl usi o n a n d n o ne of t he e x cl usi o n criteria f or e ntr y i n t he st u d y.   
9. 1 0. 3.  
Pri o r a n d C urre nt C o n c o mit a nt Me dic ati o ns 
T he na me, d ose, a n d fre q ue nc y m ust be rec or de d f or all me dicati o ns t hat t he patie nt is ta ki n g.  
All all o we d a n d e x cl u de d me dicati o ns s h o ul d be rec or de d i ncl u di n g all prescri pti o n dr u gs, her bal 
pr o d ucts, vita mi ns, mi nerals, a n d o ver-t h e-c o u nt er me dicati o ns.  Tra de or ge neric dr u g n a mes 
s h o ul d be use d w here p ossi ble.  C o nc o mita nt me dicati o ns will be re vie we d as i n dicate d i n  
Ta ble 3  a n d all c h a n ges will be rec or de d. 
9. 1 0. 4.  
C urre nt P A H B ac k gr o u n d Me dic ati o ns 
T h e na me, d ose, a n d fre q ue nc y m ust be rec or de d f or all P A H bac k gr o u n d me dicati o ns t hat t he 
patie nt is ta ki n g.  P A H b ac k gr o u n d me dicati o ns are t h ose t hat ha ve bee n a p pr o ve d b y t he U S 
F o o d a n d Dr u g A d mi nistrati o n ( F D A) or t he l o cal healt h a ut h orit y f or t he tre at me nt of P A H.  
Tra de or ge neric dr u g na mes s h o ul d be use d w here p ossi ble.  P A H bac k gr o u n d me dicati o ns will 
be re vie we d as i n dicate d i n Ta ble 3  a n d all c h a n ges will be rec or de d.   
9. 1 0. 5.  
Wei g ht a n d B o d y M ass I n de x  
Wei g ht m ust be meas ure d as i n dicate d i n Ta ble 3 .  B o d y mass i n de x ( B MI) will be calc ulate d i n 
t he eC R F eac h ti me t he wei g ht is r ec or de d.  Patie nts will use S p o ns or- pr o vi de d scales t o meas ure 
wei g ht at h o me.  Patie nts will be i nstr ucte d t o st o p a d mi nisteri n g st u d y dr u g a n d c o ntact t he 
i n vesti gat or if t heir dail y wei g ht i ncreas es per t h e criteria o utli ne d i n Secti o n 9. 1. 1 .  Patie nts will 
be  pr o vi de d i nstr ucti o ns wit hi n t he I nf or me d C o nse nt F or m t o hel p e ns ure c o nsiste nt wei g ht 
c ollecti o n t hr o u g h o ut t he st u d y. 

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9. 1 0. 6.  
Vit al Si g n Me as ure me nts 
Vital si g n meas ur e me nts i ncl u de t he patie nt’s heart rate ( beats/ mi n ute ta ke n f or at least 
1 5 sec o n ds), res pirati o n rate, a n d b o d y te m perat ur e.  Bl o o d pr ess ure s h o ul d be ta ke n after t he 
pa tie nt has reste d i n a sitti n g p ositi o n f or at least 5 mi n utes.  T he sa me ar m ( us uall y t he n o n-
d o mi na nt ar m) a n d t he a p pr o priate size c uff s h o ul d be use d f or eac h meas ure me nt.  Vital si g n 
meas ure me nts s h o ul d be ta ke n as i n dicate d i n T a ble 3 .  
9. 1 0. 7.  
P h ysic al E x a mi n ati o n 
A c o m pre he nsi v e p h ysic al e x a mi nati o n m ust be perf or me d b y a p h ysicia n, p h ysicia n assista nt, or 
re gistere d n urse practiti o ner as i n dicat e d i n Ta ble 3  a n d as d oc u me nte d wit hi n t he ta ble 
f o ot n otes.  T he e x ami nati o n m ust i ncl u de t he f oll o wi n g or ga n or b o d y s yste m assess me nts: hea d, 
e yes, ears, n ose, t hr o at, m usc ul os keletal, car di o v asc ular, l y m p hatic, res pir at or y, a b d o me n, s ki n, 
e xtre mities, a n d ne ur ol o gical.  Assess me nts of a n y s pecific si g ns or s y m pt o ms re p orte d b y t he 
patie nt m ust als o be perf or me d a n d d oc u me nt e d al o n g wit h a n y ot her fi n di n gs of n ote.  Cli nicall y 
si g nifica nt fi n di n gs at D a y 1 m ust be rec or de d as me dical hist or y.  F oll o wi n g t he e x a mi nati o n o n 
Da y 1, ne w or c ha n ge d p h ysical e x a mi nati o n fi n di n gs meeti n g t he criteria f or a n a d verse e v e nt 
m ust be rec or de d as a n a d verse e v e nt.  If p ossi ble, t he sa me i n di vi d ual s h o ul d perf or m eac h 
p h ysical e x a mi nati o n o n a patie nt d uri n g t he st u d y.  
9. 1 0. 8.  
Pre g n a nc y Test 
W O C B P (see  Secti o n 9. 8 ) will c o m plete a pre g na n c y t est as i n dicate d i n Ta ble 3 , or at a n y ti me 
if pre g na n c y is s us pecte d.  Ne gati ve test res ults are re q uir e d o n Da y 1 b ef ore st u d y dr u g 
a d mi nistrati o n.  A n y pati e nt w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue ta ki n g 
st u d y dr u g i m me diatel y.  See Secti o n 9. 8. 3  f or a d escri pti o n of pr oce d ures t o be f oll o we d i n cas e 
of pr e g na n c y. 
9. 1 0. 9.  
St u d y Dr u g A d mi nistr ati o n 
Patie nts s h o ul d self-a d mi nister o ne ca ps ule orall y, o nce a d a y, prefera bl y i n t he m or ni n g, as 
i n dicate d i n Ta ble 3 .  A v o mite d d ose m ust n ot be re place d.  A d o u ble d ose (e. g., misse d d ose 
fro m pre vi o us da y a n d d ose f or c urre nt da y) m ust n ot be ta ke n. 
9. 1 0. 1 0.  
St u d y Dr u g Dis pe ns ati o n a n d C ollecti o n 
St u d y dr u g will be dis pe nse d t o t he patie nt a n d c ollecte d fr o m t he patie nt as i n dicate d i n Ta ble 3 .  
T he patie nt will be dis pe nse d 1 or m ore tr eat me nt kits at Da y 1, Wee k 4, Wee k 2 4, a n d e ver y 
2 4 wee ks t hereaft er f or t he d urati o n of t he st u d y.   Dis pe nse d treat me nt kits fr o m eac h visit 
s h o ul d be ret ur ne d t o t he site f or c ollecti o n at t he s u bse q ue nt visit. 
9. 1 0. 1 1.  
Tele p h o ne C o nt act 
Patie nts will be c o ntacte d b y tele p h o n e as i n dicat e d i n Ta ble 3 .  Patie nts will be as ke d a b o ut t heir 
b o d y w ei g ht a n d ot her si g ns of fl ui d rete nti o n, as well as A Es a n d a n y c ha n ges t o c o nc o mita nt 
me dicati o ns.  If fl ui d ret e nti o n is s us pecte d, t he patie nt m ust be br o u g ht i nt o t he cli nic a n d 
e val uate d b y t he i n v esti gat or as s o o n as p ossi ble, as detaile d i n  Secti o n  9. 1. 1 . 

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9. 1 0. 1 2.  
A d verse E ve nt C ollecti o n 
Patie nts will be o bser ve d f or ge neral a p peara nce, prese nce of ill ness or i nj ur y, or si g ns i n dic ati ve 
of a c o nc urre nt ill ness as i n dicate d i n Ta ble 3 .  Patie nts m ust be i nstr ucte d t o v ol u nteer a n y 
i nf ormati o n re gar di n g A Es o n or after t h e first d ose of st u d y dr u g or q uer y t he patie nts wit h a n 
o pe n q uesti o n re gar di n g a n y A Es t he y ma y be e x perie nci n g ( e. g., “ H o w ha ve y o u bee n feeli n g 
si nce y o ur last visit? ”).  A n y fi n di n gs are t o be d oc u me nte d.  Patie nts m ust be as ke d if t he y h a ve 
bee n h os pitaliz e d, ha d a n y acci de nts, use d a n y ne w me dicati o ns, or c h a n ge d c o nc o mita nt 
me dicati o n re gi me ns (i ncl u di n g pres cri pti o n dr u gs, o ver-t he-c o u nter m e dicati o ns, vita mi ns, 
her bal pr o d u cts, a n d mi nerals).  Res p o nses m ust b e d oc u me nte d i n t he s o urce d oc u me nts. 
9. 1 0. 1 3.  
Cli nic al C he mistr y 
S a m ples will be c ollecte d f or cli nical c he mistr y a nal yses as i n dicate d i n T a ble 3 .  Cli nical 
c he mistries will be a nal yze d l ocall y a n d s h o ul d i n cl u de t h ose r o uti nel y m o nit ore d per patie nt’s 
sta n dar d of care.  
9. 1 0. 1 4.  
N- Ter mi n al Pr o- Br ai n N atri ureti c Pe pti de a n d Br ai n N atri uretic Pe pti de  
Sa m ples will be  c ollecte d f or N T- Pr o B N P a n d/ or B N P as i n dicate d i n T a ble 3 .  As rece nt 
ex ercise ma y affect B N P a n d N T- Pr o B N P le vels, patie nts m ust be all o we d t o rest f or a 
mi ni m u m peri o d of 1 h o ur f oll o wi n g arri val at t he cli nic a n d pri or t o o btai ni n g t his bl o o d 
sa m ple.  Si milarl y, t his sa m ple m ust be ta ke n pri or t o t he 6 M W T or at least o ne h o ur aft er 
6 M W T.  T his sa m ple m ust be ta ke n wit h t he patie nt i n t he sa me p ositi o n at all a p pr o priate visits, 
e. g., sitti n g or se mi-rec u m be nt. 
9. 1 0. 1 5.  
6- Mi n ute W al k Test 
A 6 - mi n ute wal k test ( 6 M W T) will be perf or me d b y t he patie nts as i n dicat e d i n Ta ble 3 .  U nless 
ot her wise i n dicate d as descri be d bel o w, eac h t est m ust be perf or me d i n stri ct acc or da nce wit h t he 
A merica n T h oraci c S ociet y ( A T S) g ui d eli nes ( A T S  State me nt 2 0 0 2) pr o vi de d i n Secti o n 1 9 , 
A p pe n di x 1.  T he a p pr o priate la n g ua ge versi o n will be a p plie d f or patie nts wit h a n o n- E n glis h 
i nf or me d c o nse nt.  T h e wal ki n g c o urse m ust be 3 0 m i n le n gt h, e xce pt at sites gra nte d pri or 
S p o ns or a gree m e nt. 
Patie nts will rate t heir d ys p nea a n d o verall fati g ue usi n g t he B or g scale ( 2 0 0 4 versi o n, pr o vi de d 
i n Secti o n 2 1 , A p pe n di x 3) pri or t o be gi n ni n g a n d i m me diatel y f oll o wi n g c o m pleti o n of eac h 
6 M W T as  i n dicate d i n Ta ble 3 .   
T he  assess or of t he 6 M W T m ust n ot pr o vi de t he patie nt wit h t he res ults of t he assess me nt o nce 
c o m plete.  A patie nt s h o ul d wear t he s a me or si milar s h oes f or all 6 M W Ts.  A d diti o nall y, if a 
patie nt uses a wal ki n g ai d f or t he first test, t his sa me ai de s h o ul d be use d d uri n g all s u bse q ue nt 
tests.  T he s h oes w or n a n d wal ki n g ai d use d f or eac h 6 M W T s h o ul d be n ote d i n s o urce 
d oc u me nts.   
Patie nts w h o re q uire s u p ple me ntal o x y ge n wit h e x ercise ma y us e t heir prescri be d o x y ge n le vel 
d uri n g 6 M W Ts.  If a p atie nt’s healt h stat us deteri orates d uri n g st u d y partici pati o n a n d it is 
deter mi ne d b y  a p h ysici a n t hat t he patie nt re q uires a d diti o nal s u p ple me ntal o x y ge n, t h e patie nt 
ma y c o nti n ue  st u d y p arti ci pati o n.   

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9. 1 0. 1 6.  
W H O/ N Y H A F u ncti o n al Cl ass Assess me nt 
W H O / NY H A  f u ncti o nal class will be assesse d (Secti o n 2 0 , A p pe n di x 2) as i n dicate d i n Ta ble 3 .  
T o t he e xte nt fea si ble, t he sa me e v al uat or s h o ul d assess W H O/ N Y H A F C f or a partic ular p atie nt 
o ver t he e ntire c o urs e of t he st u d y.  

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1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T 
1 0. 1.  
St u d y Dr u g 
Bar d o x ol o ne met h yl ca ps ules, 5 m g  a n d 1 0 m g, will be use d i n t his st u d y. 
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g 
T he st u d y dr u g will be s u p plie d i n ta m per-e vi de nt kits c o ntai ni n g o ne 3 0-cc ( 5- m g ca ps ules, 
3 0 c o u nt), o ne 6 0- cc ( 5- m g ca ps ules, 9 0 c o u nt), or o ne 1 0 0-cc ( 1 0- m g ca ps ules, 9 0 c o u nt) hi g h-
de nsit y p ol yet h yle ne b ottle.  Eac h b ottle will utilize f oil i n d ucti o n-seal li ners a n d a c hil d-resista nt 
cl os ure.  Eac h b ottle of st u d y dr u g will c o ntai n 3 0 or 9 0 ca ps ules of 5 m g  or 1 0 m g stre n gt h 
ba r d o x ol o ne met h yl.  Eac h b ottle will als o c o ntai n a desicca nt i nsert t hat m ust n ot be i n geste d.  
La b eli n g o n eac h kit b ottle will c o ntai n at mi ni m u m t he f oll o wi n g i nf or mati o n: 
 Me dicati o n i de ntificati o n n u m ber; 
 P r ot oc ol 4 0 2- C- 1 6 0 2; 
 C a uti o n State me nt: Ne w Dr u g – Li mite d b y Fe d eral La w t o I n vesti gati o nal Use.  
Kee p o ut of si g ht a n d re ac h of c hil dre n; 
 C o ntr ol or l ot n u m ber 
 S t ore at 2 0° - 2 5° C ( 6 8° - 7 7° F), s h ort ter m e x c ursi o ns all o we d t o 
1 5° - 3 0° C ( 5 9° - 8 6° F); 
 R eata P har ma ce uticals, I nc., Ir vi n g, T X. 
A d o u ble pa nel la b el will be prese nt e d o n t he treat me nt b ottle c o ntai ni n g t his a n d ot her 
i nf or mati o n as well.  A d diti o nall y, l a beli n g i n t he rele va nt l ocal la n g ua ges f or i n vesti gati o nal 
me dici nal pr o d uct f or us e a n d distri b uti o n i n t he E U s hall a d here t o c urre nt E u drale x, V ol u me 4 
A n ne x 1 3 g ui da nce a n d re q uire me nts.   
1 0. 3.  
St u d y Dr u g St or a ge 
T he sta bilit y of t he dr u g pr o d uct has bee n a n d is c urre ntl y bei n g e v al uate d i n o n g oi n g st u dies. 
I n v esti gati ve sites m ust st ore t he i n vesti gati o nal pr o d uct i n a sec ure l ocati o n wit h r o o m 
te m perat ur e c o n diti o ns of 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F), wit h brief e x c ursi o ns all o we d t o 
1 5° C t o 3 0° C ( 5 9° F t o 8 6° F).   
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n 
Please refer t o  Secti o n  9. 1 0. 9  f or details o n st u d y dr u g a d mi nistrati o n.  Clear i nstr ucti o ns will be 
pr o vi de d t o t he patie nt re gar di n g t h e n u m ber a n d t y p e of ca ps ul es t o be i n geste d at eac h st u d y 
dr u g a d mi nistrati o n ti me p oi nt liste d i n Ta ble 3 .  Patie nts m ust be i nstr ucte d t o c o nti n ue ta ki n g 
st u d y dr u g u nless: ( 1) patie nt has bee n ot her wise i nstr u cte d b y t he i n vesti gat or or ( 2) t h e patie nt 
has bee n f or mall y dis c o nti n ue d fr o m t he st u d y.  

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1 0. 5.  
St u d y Dr u g Acc o u nt a bilit y 
T he i n vesti gat or, or desi g nee, will mai ntai n a rec or d of all st u d y dr u g recei v e d, dis pe nse d, a n d 
ret ur ne d t o t he S p o ns ors’ desi g nee.  N o st u d y dr u g s hall be destr o ye d b y t he cli nical site u nless 
directe d i n writi n g t o d o s o b y t he S p o ns or’s q u alit y ass ur a nce d e part me nt.  St u d y dr u g b ottles 
a n d a n y u n use d ca ps ules s h o ul d be ret ur ne d t o t he st u d y staff f or e v e nt ual dis p ositi o n b y t he 
S p o ns or.  T he n u m ber of ca ps ules ret ur ne d at eac h visit will be rec or de d f or eac h b ottle i n t he 
kit. 
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p os al 
At t he c o ncl usi o n of t he st u d y or i n a n i nsta nce of pla n ne d st u d y dr u g re place me nt, t he S p o ns or 
or its desi g nee will direct t he site re gar di n g t he fi n al dis p ositi o n of st u d y dr u g. 

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1 1.  
S A F E T Y A S S E S S M E N T S 
1 1. 1.  
S afet y P ar a meters 
T o a v oi d i nter- o bser v er varia bilit y, e v er y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns will c o m plete all safet y assess me nts.  
Safet y p ara meters will i n cl u de vital si g n meas ure me nts, p h ysical e x a mi nati o n res ults, A Es, 
S A Es, wei g ht, a n d assess me nt of B N P a n d/ or N T - Pr o B N P.  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts 
1 1. 2. 1.  
Defi niti o n of A d verse E ve nts 
1 1. 2. 1. 1.  A d verse E ve nt 
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a patie nt re gar dless of its ca usal 
relati o ns hi p t o st u d y dr u g.  A n A E ca n b e a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n y 
cli nicall y si g nifica nt a b n or mal la b orat or y test res ult), s y m pt o m, or disease te m p orall y ass ociate d 
wit h t he use of t he st u d y dr u g, w het her or n ot it is c o nsi dere d t o be st u d y- dr u g relate d.  I n cl u d e d 
i n t his defi niti o n are a n y ne wl y- occ urri n g e v e nts or pre vi o us c o n diti o n t hat has i ncrease d i n 
se verit y or fre q ue n c y si nce t he a d mi nistrati o n of st u d y dr u g. 
All A Es t hat are o bser ve d or re p orte d b y t he patie nt d uri n g t he st u d y (fr o m ti me of 
a d mi nistrati o n of t he first d ose at t he Da y 1 visit u ntil t he fi nal visit i n dicate d i n Ta ble 3 ) m ust be 
rep orte d, re gar dless of t h eir relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce. 
1 1. 2. 1. 2.  Seri o us A d verse E ve nt 
A n S A E is a n y A E occ urri n g at a n y d ose a n d re gar dless of ca us alit y t hat: 
 R es ults i n deat h; 
 Is life-t hreate ni n g; 
 R e q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 R es ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns; 
 Is a c o n ge nital a n o mal y or birt h defect i n a n offs pri n g of a patie nt ta ki n g st u d y dr u g; 
 Is a n i m p orta nt me dical e ve nt.  
T he ter m "life-t hr eate ni n g" refers t o a n e ve nt i n w hic h t he patie nt was at i m me diate ris k of deat h 
at t he ti me of t he e ve nt.  It d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e vere. 
I m p ort a nt me dical e v e nts are t h ose t hat ma y n ot m eet a n y of t he criteri a defi ne d a b o ve; h o we v er, 
t he y ma y b e c o nsi dere d s eri o us w he n, bas e d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y 
je o par dize t he patie nt a n d ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he S A E defi niti o n. 

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Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, i nf or mati o n will be c ollecte d f or a n y pre g na nci es 
t hat occ ur d uri n g t he st u dy (fr o m t he ti me of t he first d ose of st u d y dr u g u ntil t he fi nal visit 
i n dicate d i n Ta ble 3 , as a p pr o priate).  Certai n pre g na nc y o utc o mes will re q uire s u b missi o n as a n 
S A E ( See  Secti o n 9. 8 ). 
T he i n vesti gat or is res p o nsi ble f or re p orti n g t o Reata or desi g nee all A Es a n d S A Es t hat are 
o bser ve d or re p ort e d b y t he patie nt d uri n g t he st u d y (fr o m t he ti me of a d mi nistrati o n of t he first 
d ose of st u d y dr u g u ntil t he fi nal visit i n dicate d i n Ta ble 3 , as a p pr o priate), re gar dl ess of t heir 
relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce.   
T he S p o ns or, or t he C o ntract Rese arc h Or ga nizati o n ( C R O) o n t he be half of t he S p o ns or, m ust 
be n otifie d i m me diatel y re gar di n g t he occ urre nce of a n y S A E t hat occ urs after t he patie nt 
recei v es t he first d ose of st u d y dr u g a n d t hr o u g h o ut t he st u d y, re gar dless of st u d y dr u g 
a d mi nistrati o n, i ncl u di n g S A Es res ulti n g fr o m pr ot oc ol-ass ociate d pr oce d ures, as defi ne d i n 
rele va nt le gislati o n.  T he pr oce d ures f or re p orti n g all S A Es, re gar dless of ca usal relati o ns hi p, are 
as f oll o ws: 
 R ec or d t he S A E o n t he A E e C R F a n d c o m plete t h e “ Seri o us A d verse E v e nt Re p ort” 
f or m wit hi n t he electr o ni c data bas e; 
 In t he e ve nt t he electr o ni c data bas e is n ot f u ncti o nal, a pa per S A E f or m will be 
a vaila ble f or t he re p orti n g of S A Es. 
T he S p o ns or ma y re q u est a d diti o nal i nf or mati o n fr o m t he i n vesti gat or t o e ns ure t he ti mel y 
c om pleti o n of acc urate s afet y re p orts. 
All S A Es re p orte d or o bs er ve d d uri n g t he st u d y m ust be f oll o we d t o res ol uti o n or u ntil t he 
i n vesti gat or d ee ms t he e v e nt t o be c hr o nic or t he p atie nt t o be sta ble.  Reata or desi g n ee ma y 
c o ntact t he i n vesti gat or t o o btai n a d diti o nal i nf or mati o n o n a n y S A E w hic h has n ot res ol ve d at 
t he ti me t he patie nt c o m pletes t he st u d y. 
1 1. 3.  
Eliciti n g A d verse E ve nt I nf or m ati o n  
At e ver y st u d y visit, patie nts m ust be as ke d a sta n dar d, n o n directe d q uesti o n, s uc h as, “ H o w 
ha ve y o u bee n feeli n g si n ce y o ur last visit? ” t o elicit a n y me dicall y relate d c ha n ges i n t heir 
well- bei n g.  T he y ma y als o be as ke d if t he y h a ve bee n h os pitalize d, ha d a n y acci de nts, use d a n y 
ne w me dicati o ns, or c ha n ge d c o nc o mita nt me dicati o n re gi me ns (i ncl u di n g prescri pti o n dr u gs, 
o ver-t he- c o u nter m e dicati o ns, vita mi ns, her bal pr o d ucts, a n d mi nerals).  Res p o nses m ust be 
d oc u me nte d i n t he s o urce d oc u me nts. 
I n a d diti o n t o patie nt o bser vati o ns, A Es m ust be d oc u me nte d f or a n y cli nicall y si g nifica nt 
dia g n osis r es ulti n g fr o m a b n or mal la b orat or y test val ues t hat are m o nit ore d per patie nt’s sta n d ar d 
of care, p h ysical e x a mi nati o n fi n di n gs, or fr o m ot h er d oc u me nts t hat are rel e va nt t o patie nt 
safet y. 

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1 1. 4.  
Assess me nt of C a us alit y  
T he i n vesti gat or m ust use t he f oll o wi n g classificati o ns a n d criteria t o c haracterize t he 
relati o ns hi p or ass ociati o n of t he st u d y dr u g i n ca usi n g or c o ntri b uti n g t o t he A E: 
N ot Relate d: T his relati o ns hi p s u g gests t hat t here is n o ass ociati o n bet wee n t he st u d y dr u g a n d 
t he re p orte d e ve nt. 
U nli kel y Relate d: T his r elati o ns hi p s u g gests t hat t he te m p oral se q u e nce of t he e ve nt wit h st u d y 
dr u g a d mi nistrati o n ma kes a ca us al relati o ns hi p i m pr o ba ble a n d/ or ot her fact ors als o pr o vi de 
pla usi ble e x pla nati o ns. 
P ossi bl y Relate d: T his r elati o ns hi p s u g gests t hat treat me nt wit h t he st u d y dr u g ca use d or 
c o ntri b ute d t o t he A E.  T hat is, t he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m t he ti me 
of st u d y dr u g a d mi nistrati o n, a n d/ or, f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, b ut 
c o ul d ha ve bee n pr o d uce d b y ot her fact ors. 
Pr o ba bl y Relat e d: T his relati o ns hi p s u g gests t hat a reas o n a ble te m p or al se q ue nce of t h e e ve nt 
wit h st u d y dr u g a d mi nistrati o n e xists a n d, base d u p o n t he k n o w n p har mac ol o gical acti o n of t he 
dr u g, k n o w n or pre vi o usl y re p orte d a d verse reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt 
base d o n t he i n vesti ga t or’s cli nical e x perie nce, t he ass ociati o n of t he e v e nt wit h st u d y dr u g 
a d mi nistrati o n see ms li kel y. 
Defi nitel y R elate d: T his relati o ns hi p s u g gests t hat a defi nite ca usal rel ati o ns hi p e xists bet wee n 
t he dr u g a d mi nistrati o n a n d t he A E, a n d ot her c o n diti o ns (e. g., c o nc urre nt ill ness, 
pr o gr essi o n/e x pressi o n of disease state, or c o nc urre nt me dicati o n reacti o n) d o n ot a p pear t o 
e x plai n t he e ve nt.  
1 1. 5.  
Assess me nt of Se verit y 
T he i n vesti gat or will gra de t he se verit y of t h e A Es as mil d, m o derate, or se vere usi n g t he 
f oll o wi n g defi niti o ns: 
Mil d: S y m pt o ms ca usi n g n o or mi ni mal i nterfere n ce wit h us ual s ocial a n d f u ncti o nal acti vities; 
M o derate: S y m pt o ms c a usi n g greater t ha n mi ni m al i nterfere nce wit h us ual s ocial a n d f u ncti o nal 
acti vities; 
Se vere: S y m pt o ms c a usi n g i na bilit y t o p erf or m us ual s ocial a n d f u n cti o nal acti vities.  
1 1. 6.  
Rec or di n g A d verse E ve nts 
All c o n diti o ns prese nt pri or t o t he a d mi nistrati o n of t he first d ose of st u d y dr u g ( Da y 1) i n a 
pre vi o us st u d y wit h bar d o x ol o ne met h yl s ho ul d b e d oc u me nte d as me dical hist or y i n a pre vi o us 
st u d y wit h bar d o x ol o ne met hyl.  After t he first d ose, d oc u me ntati o n of A Es s hall c o nti n ue u ntil 
3 0 da ys f oll o wi n g a d mi nistrati o n of t he fi nal d ose of st u d y me dicati o n u n der t his pr ot oc ol or 
t hr o u g h 3 0 d a ys after c o m mercial a vaila bilit y of bar d o x ol o ne met h yl (i.e., t hr o u g h t he E n d- of-
Tr eat me nt visit), re gar dless of t he relati o ns hi p of t he A E t o st u d y dr u g.  I nf or mati o n t o be 
c ollecte d will i ncl u de t y p e of e ve nt, d ate of o nset, date of res ol uti o n, i n vesti gat or-s pecifie d 
assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g, seri o us ness, as well as a n y acti o n ta ke n.  

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W hile a n A E is o n g oi n g, c ha n ges i n t he se v erit y ( e. g., w orse ni n g a n d i m pr o vi n g) s h o ul d be 
n ote d i n t he s o urce d o c u me nts, b ut w he n d oc u me nti n g t he A E, o nl y t he t ot al d urati o n a n d 
greatest se v erit y s h o ul d be rec or de d i n t he e C R F.  A Es c haracterize d as i nter mitte nt will re q uire 
d oc u me ntati o n of o nset a n d d urati o n. 
All dr u g-relate d ( p ossi bl y, pr o ba bl y, or defi nitel y relate d, see  Secti o n 1 1. 4 ) A Es a n d a b n or m al 
la b orat or y test r es ults re p orte d or o bser ve d d uri n g t he st u d y m ust be f oll o w e d t o res ol uti o n 
(eit her ret ur n t o baseli ne or wit hi n n or mal li mits).  All ot her A Es will be f oll o we d t hr o u g h t he 
fi nal visit i n dicate d i n Ta ble 3 , as a p pr o priate. 
A E s res ulti n g fr o m c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt 
me dicati o ns, or pr o gressi o n of disease states m ust als o be re p ort e d.  Pree xisti n g c o n diti o ns 
( prese nt bef ore t h e start of t he A E c ollecti o n peri o d) will be c o nsi dere d c o n c urre nt me di cal 
c o n diti o ns a n d s h o ul d N O T be rec or de d as A Es.  H o we ver, if t he patie nt e x perie nces a 
w orse ni n g or c o m plicati o n of s uc h a c o n c urre nt c o n diti o n, t he w orse ni n g or c o m plicati o n s hall 
be rec or de d as a n A E.  I n vesti gat ors s h all e ns ure t hat t he A E ter m r ec or de d ca pt ures t he c ha n ge 
i n t he c o n diti o n (e. g., “ w orse ni n g of …”).  A n y i m pr o ve me nt i n c o n diti o n s hall be d oc u me nte d 
pe r Secti o n 9. 1 0. 7 . 
Eac h A E s hall be rec or de d t o re prese nt a si n gl e dia g n osis.  A cc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y test val ues) or s y m pt o ms s hall N O T be rec or de d as a d diti o nal A Es.  If a 
dia g n osis is u n k n o w n, si g n(s) or s y m pt o m(s) s hall be rec or de d as a n A E(s).  C ha n ges i n 
la b orat or y test val ues will o nl y be c o nsi dere d A Es if t he y are j u d ge d t o be cli nicall y si g nifica nt 
(i.e., if s o me acti o n or i nt er ve nti o n is re q uir e d or if t he i n vesti gat or j u d ges t he c ha n ge t o be 
be y o n d t h e ra n ge of n or mal p h ysi ol o gi cal fl uct uati o n).  If a b n or mal la b orat or y test val u es will be 
t he res ult of pat h ol o g y f or w hic h t here will be a n o verall dia g n osis (e. g., i ncrease d creati ni ne 
le vels i n re nal f ail ure), o nl y t he dia g n osis s hall be re p orte d as a n A E. 
Electi ve pr oce d ures (s ur geries or t hera pies) t h at will be sc he d ule d pri or t o t he start of A E 
c ollecti o n will n ot be c o nsi dere d A Es.  T h ese electi ve pr oce d ures s hall n ot be rec or de d as A Es, 
b ut s hall be d oc u me nte d i n t he patie nt’s s o urce d o c u me nts as electi ve ( e. g.,  electi ve peri o d o ntal 
s ur ger y).  H o we ver, if a pre- pla n n e d pr oce d ure will be perf or me d earl y (e. g., as a n e mer ge nc y) 
be ca use of a w orse ni n g of t he pree xisti n g c o n diti o n, t he w orse ni n g of t he c o n diti o n s hall be 
ca pt ure d as a n A E. 
1 1. 7.  
Re p orti n g Seri o us A d verse E ve nts 
A n y A E t he i n vesti gat or will c o nsi der seri o us acc or di n g t o t he pre vi o usl y descri be d criteria m ust 
be re p ort e d wit hi n 2 4 h o urs fr o m t he ti me t he site pers o n nel first lear n a b o ut t he e ve nt.  
T o r e p ort t he S A E, t he i n vesti gat or will c o m plete t he S A E f or m i n t he cli nical data b ase a n d s e n d 
t o  
 (fa x n u m bers liste d i n Ta ble 5 ) wit hi n 2 4 h o urs of a ware ness.  If t he cli nical 
da ta base is d o w n f or an y reas o n, t he ma n ual S A E f or ms will be utilize d; h o we ver sites are 
res p o nsi ble f or e ns uri n g t he i nf or mati o n o n t he ma n ual S A E f or ms is e ntere d i nt o t he cli nical 
data base o n ce a v aila ble. 

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T a ble 5:  
S A E Re p orti n g C o nt act I nf or m ati o n 
 
 
 
  
N o n -N ort h A merica n  sites will use access c o des 
s pecific t o t heir c o u ntr y.  C o ntact i nf or mati o n f or 
n o n -N ort h A merica n sites f or S A E re p orti n g will 
be pr o vi de d b y t he cli nical tea m directl y t o t he 
sites. 
F or q uesti o ns re g a r di n g S A E re p orti n g, c o nt act y o ur st u d y m a n a g er, m o nit or, o r  
 
 
F oll o w- U p Re p orts 
T he i n vesti gat or m ust c o nti n ue t o f oll o w t he patie nt u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o mes c hr o nic i n nat ure , sta bilizes (i n t he case of persiste nt i m pair me nt), or t he 
patie nt dies. 
W it hi n 2 4 h o urs of receipt of ne w i nf or mati o n, t h e S A E f or m s h o ul d be u p date d wit hi n t he 
cli nical data bas e a n d s u b mitte d al o n g wit h a n y s u p p orti n g d oc u me nt ati o n ( e. g., patie nt disc har ge 
s u m mar y or a ut o ps y re p orts).  If t he cli nical data b ase is d o w n f or a n y reas o n, t he ma n ual S A E 
f or ms s h o ul d be use d; h o we ver, sites are res p o nsi ble f or e ns uri n g t he u p date d i nf or mati o n o n t he 
ma n ual S A E f or ms is e ntere d i nt o t he cli nical d ata base o nce a vaila ble. 
T he S p o ns or or desi g nee will n otif y re g ulat or y a ge ncies of a n y fatal or life-t hreate ni n g 
u ne x pecte d e ve nts ass oci ate d wit h t he use of t he st u d y dr u g as s o o n as p ossi ble b ut n o later t ha n 
7 cale n dar da ys after t he i nitial recei pt of t he i nf or mati o n.  I nitial n otificati o n will be f oll o we d b y 
a writte n re p ort wit hi n t he ti mefra me esta blis he d b y t he a p pr o priat e re g ulat or y a ge nc y.  F or ot her 
S A Es t hat d o n ot meet t he fatal or life-t hreate ni n g u ne x pecte d criteria, b ut are re p orte d t o be 
ass ociate d wit h t he use of t he st u d y dr u g, Reata or desi g nee will n otif y t h e a p pr o priate re g ulat or y 
a ge ncies i n writi n g wit hi n t he ti mefra me est a blis he d b y t h os e re g ulat or y a ge ncies.  Reat a or 
desi g nee will pr o vi de c o pies of a n y re p orts t o re g ulat or y a ge nci es re gar di n g seri o us a n d 
u ne x pecte d S A Es t o t he i n vesti gat ors f or re vie w a n d s u b missi o n t o t heir I R B or E C, as 
a p pr o priate.  
Pri nci pal i n vesti gat ors will be res p o nsi ble f or i nf or mi n g t heir I R B/ E C of a n y S A Es at t heir site.  
S A E c orres p o n d e nce wit h re g ulat or y a ut h orities or I R Bs/ E Cs m ust be s u b mitte d t o t he S p o ns or 
or desi g n ee f or rec or di n g i n t he st u d y file. 
N ote t hat t he f oll o wi n g A Es w hic h are c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n will n ot be 
re p orte d t o r e g ulat or y a ut h orities as i n di vi d ual e x pe dite d re p orts, e x ce pt i n u n us ual 
circ u msta nc es: 
 S h ort ness of breat h; 
 Li g ht hea d e d ness/ dizzi ness; 
 S y nc o pe; 

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 C hest pai n; 
 P al pitati o ns; 
 F ati g ue; 
 E de ma/fl ui d rete nti o n; 
 E x erti o nal d ys p n ea; 
 H y p o x e mia. 
T hese e v e nts will be re vi e we d o n a re g ular basis i n a g gre gat e a n d will be re p orte d i n a n 
e x pe dite d ma n ner if a safet y si g nal is detecte d.  Re g ular s afet y st u d y u p dat es will be re p orte d t o 
re g ulat or y a ut h orities acc or di n g t o l ocal g ui deli nes. 

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1 2.  
S T A TI S TI C S 
1 2. 1.  
S a m ple Size 
T he ai m of t his l o n g-t er m e xte n de d access st u d y is pri maril y t o pr o vi de c o nti n ui n g treat me nt t o 
patie nts wit h bar d o x ol o ne met h yl a n d t o assess l o n g-ter m safet y a n d t olera bilit y, h e nce n o si n gle 
pri mar y varia bl e has bee n i de ntifie d.  Patie nt n u m bers will be deter mi ne d b y t h ose w h o h a ve 
bee n treat me nt-c o m plia nt a n d w h o ha ve pre vi o usl y partici pate d i n cli nical st u dies wit h 
ba r d o x ol o ne met hyl.  
1 2. 2.  
St u d y V ari a bles 
1 2. 2. 1.  
S afet y V ari a bles 
T he safet y v aria bles will i ncl u de res ults of p h ysical e xa mi nati o ns, la b orat or y test res ults ( B N P 
a n d N T- Pr o B N P), vital si g n meas ure me nts, wei g ht, A Es, a n d S A Es. 
1 2. 3.  
St atistic al A n al yses 
A statistical a nal ysis pla n ( S A P) detaili n g t he a nal ys es will be d e vel o pe d pri or t o t he data base 
l oc k.  All statistical a nal yses a n d data s u m mari es will be perf or me d usi n g S A S® ( Versi o n 9. 1 or 
hi g her) or ot her vali date d s oft ware.  T h e S A P will ser ve as t h e fi nal ar biter of all statistical 
a nal ys es.  Dat a will be s u m mariz e d o verall usi n g d escri pti ve statistics.  C o nti n u o us data will be 
s u m marize d wit h n u m ber of patie nts ( n), mea n, me dia n, mi ni m u m, ma xi m u m, rele va nt q uartiles, 
sta n dar d de viati o n, c o effi cie nt of vari ati o n, a n d ge o metric mea n ( w here a p plica ble).  Cate g ori cal 
data will be s u m mariz e d usi n g fre q ue n c y c o u nts a n d perce nt a ges.  
1 2. 3. 1.  
Pri m ar y A n al ysis of S afet y 
As t he e xte nsi o n is of a n o pe n-la bel desi g n wit h n o c o m parat or gr o u p, all statistical a nal ys es wi ll 
be descri pti ve.  Patie nts will be i ncl u de d i n t hese a nal ys es if t he y are i ncl u de d i n t he safet y 
a nal ysis a n d ha ve b ot h b aseli ne a n d p ost- bas eli ne data a vaila ble f or t he varia ble bei n g a nal yz e d.  
T he s u m mar y ta bles will be prese nt e d f or t he o verall gr o u p of patie nts, a n d als o s plit b y pre vi o us 
treat me nt gr o u ps i n pri or bar d o x ol o ne met h yl cli nical st u dies.   
 

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1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S 
1 3. 1.  
St u d y- S pecific C o m mittees  
N o steeri n g c o m mittee, d ata safet y m o nit ori n g c o m mittee, a dj u dicati o n c o m mittee, or cli nical 
e n d p oi nt c o m m ittee will be use d i n t his st u d y. 
1 3. 2.  
St u d y M o nit ori n g 
T he st u d y site will be m o nit ore d re m otel y b y t he C R O peri o dicall y d uri n g t he st u d y t o e ns ure 
t hat all as pects of t he pr ot oc ol will be f oll o we d a n d will i ncl u de a n electr o nic data c ollecti o n 
w hic h has a set of a ut o matic data c h ec ks wit h dat a q ueries f or pr o gra m me d data c ollecti o n.  
T here will be m o nit ori n g of st u d y site b y tele p h o n e t o e ns ure t hat t he dr u g s u p plies ha ve bee n 
pr o vi de d a n d pr ot oc ol i nstr ucti o ns are well u n derst o o d a n d a p plie d. 
T he S p o ns or or desi g nee will m o nit or all as pects of t he st u d y f or c o m plia nce wit h a p plica ble 
g o ver n me nt re g ul ati o n wit h res pect t o t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
g ui deli ne E 6( R 1): G o o d C li nical Practice: C o ns oli date d G ui deli ne a n d c urre nt sta n dar d o perati n g 
pr oce d ures. 
1 3. 3.  
A u dits a n d I ns pecti o ns 
Pri nci pal i n vesti gat ors a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit st u d y-relate d 
m o nit ori n g, a u dits, a n d I R B/ E C re vie w, a n d re g ul at or y i ns p ecti o ns, b y pr o vi di n g direct access t o 
all st u d y re c or ds.  I n t he e ve nt of a n a u dit, t he pri nci pal i n vesti gat or will a gree t o all o w t he 
S p o ns or, re pres e ntati ves of t he S p o ns or, t he F D A, a n d ot her rele va nt r e g ulat or y a ut h orities 
access t o all st u d y rec or ds. 
T he pri nci pal i n vesti gat or s hall pr o m ptl y n otif y t h e S p o ns or or desi g nee of a n y a u dits sc he d ule d 
b y a n y re g ulat or y a ut h orities a n d s hall pr o m ptl y f or war d c o pies of a n y a u dit re p orts recei ve d t o 
t he S p o ns or or desi g n ee. 

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1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E 
1 4. 1.  
Q u alit y Ass ur a nce 
T o e ns ure c o m plia n ce wit h G o o d Cli nical Practices a n d all a p plica ble re g ul at or y re q uir e me nts, 
Reata ma y c o n d u ct a q ualit y ass ura n ce a u dit of t h e i n vesti gat or’s cli nical site, i ncl u di n g 
C T M/I M P st ora ge facilities.   
1 4. 2.  
Fi n a nci al Discl os ure  
Pri nci pal i n vesti gat ors a n d s u b-i n vesti gat ors are re q uire d t o pr o vi de fi na n cial discl os ure 
i nf or mati o n pri or t o starti n g t he st u d y.  I n a d diti o n, t he pri nci pal i n vesti gat or a n d s u b-
i n vesti gat ors m ust pr o vi d e t he S p o ns or or desi g nee wit h u p date d i nf or mati o n, if a n y rele va nt 
c ha n ges occ ur d uri n g t he c o urse of t he i n v esti gati o n a n d f or o ne year f oll o wi n g t he c o m pleti o n 
of t he st u d y. 
N o  p ote ntial i n vesti gat or w h o has a veste d fi na nci al i nterest i n t he s uccess of t his st u d y ma y 
pa rtici pate i n t his st u d y. 
1 4. 3.  
S p o ns or O bli g ati o ns  
T he S p o ns or or desi g nee is n ot fi na nciall y res p o nsi ble f or f urt her testi n g/treat me nt of a n y 
me dical c o n diti o n t hat ma y b e dete cte d d uri n g t he Scree ni n g pr ocess.  I n a d diti o n, i n t he a bse nce 
of s pecific arr a n ge me nts, t he S p o ns or or desi g n ee is n ot fi na nciall y res p o nsi ble f or treat me nt of 
t he patie nt’s u n derl yi n g disease. 
1 4. 4.  
I n vesti g at or D oc u me nt ati o n 
Bef ore be gi n ni n g t he st u d y, t he pri n ci pal i n vesti gat or will be as ke d t o c o m pl y wit h I C H E 6( R 1) 
8. 2 a n d Title 2 1 of t he C o de  of Fe deral Re g ulati o ns ( C F R) b y pr o vi di n g t h e esse ntial d oc u me nts 
t o t he S p o ns or or desi gn ee, w hic h i ncl u de b ut are n ot li mite d t o t he f oll o wi n g: 
 A n or i gi n al i n vesti gat or-si g ne d i n vesti gat or a gree me nt pa ge of t he pr ot oc ol;  
 T he  I R B/ E C a p pr o val of t he pr ot oc ol; 
 T he  I R B- or E C-a p pr o ve d i nf or me d c o nse nt, sa m ples of site a d vertise me nts f or 
recr uit me nt f or t his st u d y, a n d a n y ot her writte n i nf or mati o n re gar di n g t his st u d y t hat 
is t o be pr o vi de d t o t he patie nt or le gal g uar dia ns; 
 A F or m F D A 1 5 7 2, f ull y e x ec ute d, a n d all u p dates o n a n e w f ull y e x ec ute d F or m 
F D A 1 5 7 2; 
 C urric ula vitae f or t he pri nci pal i n vesti gat or a n d eac h s u b-i n vesti gat or liste d o n F or m 
F D A 1 5 7 2.  A c urric ul a vitae a n d c urre nt lice ns ure, as a p plica bl e, m ust be pr o vi de d.  
T he c urri c ula vitae  m ust ha ve bee n si g n e d a n d dat e d b y t h e pri nci pal i n vesti gat ors 
a n d s u b-i n vesti gat ors wit hi n 2 years bef ore st u d y start- u p t o i n dicate t he d o c u me nts 
are acc urate a n d c urre nt; 

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 C o m plete d fi na ncial discl os ure f or ms ( Secti o n  1 4. 2 ) t o all o w t he S p o ns or or desi g n ee 
t o s u b mit c o m plete a n d acc urat e certificati o n or discl os ure state me nts re q uire d u n der 
U S Title 2 1 C F R 5 4.  I n a d diti o n, t he i n vesti gat ors m ust pr o vi de t o t he S p o ns or or 
desi g nee a c o m mit me nt t o u p date t his i nf or mati o n pr o m ptl y if a n y rele va nt c ha n ges 
occ ur d uri n g t he c o urse of t he i n vesti gati o n a n d f or 1 year f oll o wi n g t he c o m pleti o n 
of t he st u d y; 
 L a b orat or y certificati o ns a n d n or mal ra n ges f or a n y la b orat ories use d b y t h e site f or 
t he c o n d uct of t his st u d y. 
1 4. 5.  
Cli nic al St u d y I ns ur a nce 
I n acc or da n ce wit h t he res pecti ve nati o nal dr u g la ws, t he S p o ns or has ta ke n o ut patie nt lia bilit y 
i ns ura nce f or all patie nts w h o gi ve t h eir c o nse nt a n d e nr oll i n t his st u d y.  T his i ns ura nce c o v ers 
p ote ntial fatalities, p h ysi cal i nj uries, or da ma ge t o healt h t hat ma y occ ur d uri n g t he cli nical 
st u d y. 
1 4. 6.  
Use of I nf or m ati o n  
All i nf or mati o n re gar di n g bar d o x ol o ne met h yl s u p plie d b y t he S p o ns or t o t he i n vesti gat or is 
pri vile ge d a n d c o nfi de ntial.  T he i n vesti gat or a grees t o use t his i nf or mati o n t o acc o m plis h t he 
st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut c o nse nt fr o m t he S p o ns or.  F urt her m ore, t he 
i n vesti gat or is o bli gate d to pr o vi de t he S p o ns or wit h c o m plete data o btai ne d d uri n g t he st u d y.  
T he i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he de vel o p me nt of 
bar d o x ol o ne met h yl a n d ma y b e discl ose d t o re g ul at or y a ut h orities, ot her i n vesti gat ors, c or p orate 
part ners, or c o ns ul ta nts as re q uire d. 

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1 5.  
E T HI C S 
1 5. 1.  
I nstit uti o n al Re vie w B o ar d or Et hics C o m mittee Re vie w 
T he pr ot oc ol a n d t he pr o p ose d i nf or me d c o ns e nt f or m m ust be re vie we d a n d a p pr o ve d b y a 
pr o perl y c o nstit ute d I R B/ E C bef ore st u d y start.  E ac h i n vesti gat or m ust pr o vi de t he S p o ns or or 
its desi g nee a si g n e d a n d date d state me nt t hat t he pr ot oc ol a n d i nf or me d c o nse nt ha ve bee n 
a p pr o ve d b y t he I R B/ E C f or t hat site bef ore c o ns e nti n g patie nts.  Pri or t o st u d y i nitiati o n, t he 
i n vesti gat or is r e q uire d to si g n a pr ot o c ol si g nat ure pa ge c o nfir mi n g a gree me nt t o c o n d uct t he 
st u d y i n acc or da n ce wit h t his pr ot oc ol a n d t o gi ve access t o all rele va nt d ata a n d rec or ds t o t he 
S p o ns or, its desi g nee, a n d re g ulat or y a ut h orities as re q uire d. 
T he I R B/ E C c h air pers o n or desi g n ee m ust si g n all I R B/ E C a p pr o vals a n d m ust i de ntif y t he 
I R B/ E C b y na me a n d a d dress, t he cli nical pr ot o c ol, a n d t he date a p pr o val a n d/ or fa v ora ble 
o pi ni o n was gra nte d. 
T he pri nc i pal i n vesti gat or is res p o nsi ble f or o btai ni n g re vi e ws of t he cli nical researc h at i nter v als 
s pecifie d b y t he IR B/ E C, b ut n ot e x cee di n g 1 year.  T he pri nci pal i n vesti gat or m ust s u p pl y t he 
S p o ns or or desi g n ee  wit h writte n d oc u me ntati o n of re vie ws of t he cli nical r esearc h. 
1 5. 2.  
Et hic al C o n d uct of t he St u d y 
T his cli nical st u d y was d esi g ne d a n d s hall be i m pl e me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble l ocal 
re g ulati o ns (e. g., U S  C o d e of Fe deral Re g ulati o ns Title 2 1, E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C), 
a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.  
T he pri nci pal i n vesti gat or a grees t o c o n d uct t he st u d y i n acc or da nce wit h t he I nter n ati o nal 
C o nfere nce o n Har m o niz ati o n (I C H) f or G ui da nce f or I n d ustr y o n G C P I C H E 6( R 1) 
[htt p:// w w w.ic h. or g/file a d mi n/ P u blic
We b Site/I C H Pr o d ucts/ G ui deli nes/ Efficac y/ E 6/ E 6
R 1
G ui deli ne. p df ] a n d t he pri nci ples of t he Declarati o n of Helsi n ki 
[htt p:// w w w. w ma. net/e n/ 3 0 p u blicati o ns/ 1 0 p olicies/ b 3/ ].  T he pri nci pal i n vesti gat or m ust c o n d u ct 
all as pects of t his st u d y i n acc or da nce wit h all n ati o nal, state, a n d l ocal la ws or re g ulati o ns. 
1 5. 3.  
Writte n I nf or me d C o nse nt 
Beca use t he st u d y will be c o n d ucte d u n der a U S  I n vesti gati o nal N e w Dr u g A p plicati o n, a si g n e d 
i nf or me d c o nse nt f or m, i n c o m plia nce wit h Title 2 1 of t he U S C F R Part 5 0, will be o btai ne d 
fr o m eac h patie nt bef ore t he patie nt e nters t he st u d y.  F or sites o utsi de of t h e U S , t he si g n e d 
c o nse nt will be o bta i ne d i n acc or d wit h l ocal re g ul ati o ns, I C H E 6 ( R 1), a n d pri nci ples of t he 
Declarati o n of Helsi n ki.  A n i nf or me d c o ns e nt te m plate ma y be pr o vi de d b y t he S p o ns or or 
desi g nee t o t he i n vesti gat ors.  T he c o nse nt m ust be re vie we d b y t h e S p o ns or or desi g n ee b ef ore 
I R B/ E C s u b missi o n.  O nce re vi e we d, t he c o nse nt will be s u b mitte d b y t h e pri nci pal i n vesti gat or 
t o his or her I R B/ E C f or re vie w a n d a p pr o v al bef ore t he start of t h e st u d y.  If t he i nf or me d 
c o nse nt f or m is re vise d d uri n g t he c o urse of t he st u d y, all partici pa nts affecte d b y t he re visi o n 
m ust si g n t he re vise d I R B/ E C-a p pr o ve d c o nse nt f or m. 

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Bef ore e nr oll me nt, eac h pr os pecti ve patie nt will b e gi v e n a f ull e x pla nati o n of t he st u d y a n d be 
all o we d t o rea d t h e a p pr o ve d i nf or me d c o ns e nt f or m.  O nce t he pri nci p al i n vesti gat or or desi g nee 
is ass ure d t hat t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t h e st u d y, t he patie nt 
will be as ke d t o gi v e c o nse nt t o partici pate i n t he st u d y b y si g ni n g t he i nf or me d c o nse nt f or m.  
Eli gi ble patie nts ma y o nl y be i n cl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n), I R B/ E C-a p pr o ve d i nf or me d c o ns e nt.  I nf or m e d c o nse nt m ust be 
o btai ne d bef ore c o n d u cti n g a n y st u d y-s p ecific pr oce d ures ( i.e., all of t he pr oce d ures d escri b e d i n 
t he prot oc ol).  T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be d oc u me nte d i n t he patie nt 
s o urce d oc u m e nts. 
A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d b y t he i n vesti gat or m ust be a gree d t o b y 
t he S p o ns or bef ore s u b missi o n t o t he I R B/ E C, a n d a c o p y of t he a p pr o ve d versi o n a n d t he n otice 
of a p pr o val m ust be pr o vi de d t o t he S p o ns or’s desi g nate d m o nit or after I R B/ E C a p pr o val. 
T he pri nci pal i n vesti ga t or or desi g nee will pr o vi de a c o p y of t h e i nf or me d c o nse nt f or m (si g ne d 
c o p y t o b e pr o v i de d per a p plica ble la w) t o t he p atie nt a n d/ or le gal g uar dia n.  T he ori gi nal f or m 
will be mai ntai ne d i n t he pa tie nt’s me dical r ec or ds at t he site. 
1 5. 4.  
C o nfi de nti alit y 
All la b orat or y s peci me ns, e val uati o n f or ms, r e p orts, a n d ot her rec or ds will be i de ntifie d i n a 
ma n ner desi g ne d t o mai ntai n patie nt c o nfi de ntialit y.  All rec or ds will be ke pt i n a sec ure st or a ge 
area wit h l i mite d access.  Cli nical i nf or mati o n will n ot be releas e d wit h o ut t he writte n 
per missi o n of t he patie nt ( or t he patie nt’s g u ar dia n), e x ce pt as necessar y f or m o nit ori n g a n d 
a u diti n g b y t he S p o ns or, its desi g nee, t h e F D A or a p plica ble re g ulat or y a ut h orities, or t he 
I R B/ E C. 
T he pri nci pal i n vesti gat o r a n d all e m pl o yees a n d c o w or kers i n v ol ve d wit h t his st u d y m a y n ot 
discl ose or use f or a n y p ur p ose ot her t ha n perf or ma nce of t he st u d y, a n y data, rec or d, or ot her 
u n p u blis he d c o nfi de ntial i nf or mati o n discl ose d t o t he m f or t he p ur p ose of t he st u d y.  Pri or 
writte n a gre e me nt fr o m t he S p o ns or or desi g nee m ust be o btai ne d f or t he discl os ure of a n y s ai d 
c o nfi de ntial i nf or mati o n t o ot her parties. 
1 5. 5.  
M o dific ati o n of t he Pr ot oc ol 
A n y c ha n ges t h at arise after t he a p pr o val of t he pr ot oc ol m ust be d oc u me nte d as pr ot oc ol 
a me n d me nts.  T he F D A or ot her a p plica ble re g ul at or y a ge n cies m ust be n otifie d of pr ot oc ol 
a me n d me nts.  T he c h a n ges will bec o me effecti ve o nl y aft er a p pr o val of t he S p o ns or, t he 
i n vesti gat or, t he IR B/ E C, a n d w here necessar y, t h e a p plica ble re g ulat or y a ge n c y.  I n cases w he n 
t he prot oc ol is m o difie d t o e n ha nce patie nt safet y, c ha n ges ma y b e i m ple me nte d a n d t he 
a me n d me nt m ust be i m me diatel y s u b mitte d t o t he I R B/ E C. 
T he i n vesti gat or is res p o nsi ble f or i nf or mi n g t h e I R B/ E C of all pr o ble ms i n v ol vi n g ris ks t o 
pa tie nts acc or di n g t o n ati o nal le gislati o n.  I n case of ur ge nt safet y meas ures, t he S p o ns or will 
i m me diatel y n otif y t he i n vesti gat ors a n d rel e va nt r e g ul at or y a ge n cies, i ncl u di n g F D A i n acc or d 
wit h 2 1 C F R 3 1 2. 3 2. 

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1 5. 6.  
Pr ot oc ol De vi ati o ns 
T he pri nci pal i n vesti gat or or desi g nee m ust d oc u me nt a n y pr ot oc ol de viati o n.  T he I R B/ E C m ust 
be n otifie d of all pr ot oc ol de viati o ns i n a ti mel y m a n ner b y t he pri nci pal i n vesti gat or or desi g nee 
as a p pr o priat e.  Pr ot oc ol de viati o ns will be d oc u me nte d b y t he res p o nsi ble m o nit or d uri n g 
m o nit ori n g visits, a n d t h ose o bser vati o ns will be c o m m u nicate d t o t he i n vesti gat or. 
If t here is an i m me diate hazar d t o a patie nt t he pri nci pal i n vesti gat or ma y d e viate fr o m t he 
pr ot oc ol wit h o ut pri or S p o ns or a n d I R B/ E C a p pr o val.  T he S p o ns or a n d I R B/ E C m ust be 
n otifie d of t he de viati o n. 

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1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
1 6. 1.  
Rete nti o n of Rec or ds 
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H- G C P a n d a p plica ble re g ulat or y 
req uire me nt(s).  R ec or ds will be retai ne d f or at least 2 years aft er t he last m ar keti n g a p plicati o n 
s u b missi o n or 2 years aft er f or mal disc o nti n uati o n of t he cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d u ct.  If t he i n vesti gat or wit h dr a ws fr o m t he res p o nsi bilit y of kee pi n g t he 
st u d y recor ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o acce pt t he res p o nsi bilit y.  T he 
S p o ns or m ust be n otifie d i n wr iti n g if a c ust o dial c ha n ge o cc urs.  
1 6. 2.  
C ase Re p ort F or ms 
All case re p ort f or m dat a will be e ntere d i n pa p er or electr o ni c f or ms at t he i n vesti gati o nal site.  
A 2 1 C F R Part 1 1 c o m plia nt Electr o nic Dat a Ca pt ure s yste m will be use d t o ca pt ure d ata 
electr o nicall y f or all e nr olle d patie nts. 

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1 7.  
P U B LI C A TI O N P O LI C Y 
T he S p o ns or s u p p orts c o m m u nicati o n a n d p u blicati o n of st u d y res ults w hat e ver t he fi n di n gs of 
t he st u d y.   
T he S p o ns or reser ves t he ri g ht t o re vi e w all pla n ne d c o m m u nicati o ns a n d ma n uscri pts base d o n 
t he res ults of t his st u d y.  T his reser vati o n of t h e ri g ht is n ot i nte n de d t o restrict or hi n der 
p u blicati o n or a n y ot her disse mi nati o n of st u d y res ults, b ut t o all o w t he S p o ns or t o c o nfir m t he 
acc urac y of t he data, t o pr otect pr o priet ar y i nf or m ati o n, a n d t o pr o vi de c o m me nts base d o n 
i nf or mati o n t hat ma y n ot yet b e a vaila ble t o t he st u d y i n vesti gat ors.  T h e S p o ns or als o 
e nc o ura ges discl os ure of a n y c o nflict of i nterest fr o m all a ut h ors or i n vesti gat ors w he n 
ma n uscri pts are s u b mitte d f or p u blicati o n.  T h ose i n di vi d uals, w h o ha ve c o ntri b ute d greatl y t o 
t his st u d y, i ncl u di n g le a d e xter nal a d vis ors a n d sel ect pri nci pal i n vesti gat ors, ma y ser ve o n a n y 
p ote ntial p u blicati o ns c o m mittee f or t he st u d y. 

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1 8.  
R E F E R E N C E S 
A T S 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 orat 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 Care Me d. 
2 0 0 2; 1 6 6( 1): 1 1 1- 7. 
Batt J, A h me d S S, C orrea J, et al. S keletal m uscle d ysf u ncti o n i n i di o pat hic p ul m o nar y art erial 
h y perte nsi o n. A m J  Res pir Cell M ol Bi ol. 2 0 1 4; 5 0( 1): 7 4- 8 6. 
C h u n g L, D o msi c R T, Li n gal a B, et al.  S ur vi val a n d pre dict ors of m ortalit y i n s yste mic 
scler osis-ass oci ate d p ul m o nar y art erial h y perte nsi o n: o utc o mes fr o m t he p ul m o nar y h y p erte nsi o n 
assess me nt a n d rec o g niti o n of o utc o mes i n scler o der ma re gistr y. Art hritis Care Res ( H o b o k e n). 
2 0 1 4; 6 6( 3): 4 8 9- 9 5. 
Di n k o va- K ost o va A T, L i b y K T, Ste p he ns o n K K, et al. E xtre mel y p ote nt triter pe n oi d i n d ucers of 
t he p hase 2 res p o nse: c orrelati o ns of pr otecti o n a gai nst o xi da nt a n d i nfla m mat or y str ess.  
Pr oc Natl Aca d Sci U S A. 2 0 0 5; 1 0 2( 1 2): 4 5 8 4- 9. 
E ba  S, H os hi ka wa Y, M ori g uc hi T, et al. T he n u clear fact or er yt hr oi d 2-rel ate d fact or 2 acti vat or 
olti praz  atten uates c hr o ni c h y p o xia-i n d uce d car di o p ul m o nar y alterati o ns i n mice. A m J Res p ir 
Cell M ol Bi ol. 2 0 1 3; 4 9( 2): 3 2 4- 3 3. 
Galiè N, H oe p er M M, H u m bert M, et al. G ui deli n es f or t he dia g n osis a n d treat me nt of 
p ul m o nar y  h y p erte nsi o n: t he Tas k F orce f or t he Dia g n osis a n d Treat me nt of P ul m o nar y 
H y p erte nsi o n of t he E ur o pea n S ociet y of Car di ol o g y ( E S C) a n d t h e E ur o pea n Res pirat or y 
S ociet y ( E R S), e n d orse d b y t he I nt er nati o nal S oci et y of Heart a n d L u n g Tra ns pla ntati o n 
(I S H L T). E ur Heart J. 2 0 0 9; 3 0: 2 4 9 3- 5 3 7. 
G h ofra ni H A, Ga liè N, Gri m mi n ger F, et al. Ri oci g uat f or t he treat me nt of p ul m o nar y arteri al 
h y perte nsi o n . N E n gl J Me d. 2 0 1 3; 3 6 9( 4): 3 3 0- 4 0. 
H ol mstr ö m K M, Bair d L, Z ha n g Y, et al. Nrf 2 i m pacts cell ular bi oe ner getics b y c o ntr olli n g 
s u bstrate a vailabilit y f or mit oc h o n drial res pirati o n. Bi ol O pe n. 2 0 1 3; 0: 1- 1 0. 
Lee D F, K u o H P, Li u M, et al. K E A P 1 E 3 li gase- me diate d d o w nre g ul ati o n of N F- k B si g nali n g 
b y tar geti n g  I K K b eta. M ol Cell. 2 0 0 9; 3 6( 1): 1 3 1- 4 0. 
L u dt ma n n M H, A n ge l o v a P R, Z ha n g Y, et al. Nrf 2 i m pacts t he effici e nc y of mit oc h o n drial fatt y 
aci d o xi dati o n. Bi oc he m J. 2 0 1 4; 4 5 7( 3): 4 1 5- 2 4. 
Ma i n g u y V, M altais F, S ae y D, et al. Peri p heral m uscle d ysf u ncti o n i n i di o pat hic p ul m o nar y 
h y perte nsi o n. T h ora x. 2 0 1 0; 6 5( 2): 1 1 3- 7. 
Male nfa nt S, P ot us F, F o ur nier F, et al. S keletal m uscle pr ote o mic si g nat ur e a n d m eta b olic 
i m pair me nt i n p ul m o nar y h y perte nsi o n. J M ol Me d ( Berl). 2 0 1 5; 9 3( 5): 5 7 3- 8 4. 
Os b ur n W Oa n d, Ke nsler T W. Nrf 2 si g nali n g: A n a da pti ve res p o ns e pat h w a y f or pr otecti o n 
a gai nst e n vir o n me ntal t o xic i ns ults. M utat Res. 2 0 0 8; 6 5 9( 1- 2): 3 1- 9. 
Price L, Cara m ori G, D orf m uller P, et al.  E n d ot helial cell N F- k B acti vati o n is i ncrease d i n 
h u ma n i di o pat hic P A H. T h ora x. 2 0 1 0; 6 5( 4): A 8 8 - A 8 9. 

Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
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5 4   
P u g h M E; R o b bi ns, I M; Rice T W, et al. U nrec o g nize d gl uc ose i nt olera nce is c o m m o n i n 
p ul m o nar y a rteri al h y p ert e nsi o n. J Heart L u n g Tra ns pla nt. 2 0 1 1; 3 0( 8): 9 0 4- 1 1. 
R ojas- Ri vera J, Ortiz A, E gi d o J. A nti o xi da nts i n ki d ne y dise ases: T he i m p act of bar d o x ol o ne 
met h yl. I nt J Ne p hr ol. 2 0 1 2; 2 0 1 2: 1- 1 1. 
Sa ha P K, Re d d y  V T, K o n o ple va M, et al. T he trit er pe n oi d 2-c ya n o- 3, 1 2- di o x o olea na- 1, 9- die n-
2 8- o ic-aci d met h yl ester has p ote nt a nti dia betic effects i n diet-i n d uce d di a b etic mice a n d 
Le pr( d b/ d b) mice. J Bi ol C he m. 2 0 1 0; 2 8 5( 5 2): 4 0 5 8 1- 9 2. 
S ute n dra G, Mic hela kis E D. T he meta b olic b asis of p ul m o nar y arterial h y perte nsi o n. Cell Meta b. 
2 0 1 4; 1 9( 4): 5 5 8- 7 3. 
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 hest. 2 0 1 3; 1 4 4( 3): 9 5 2- 8. 
W u Q Q, Wa n g Y, Se nit k o M, et al. Bar d o x ol o ne met h yl ( B A R D) a meli orates isc he mic A KI a n d 
i ncreas es ex pressi o n of pr otecti ve ge n es Nrf 2, P P A R , a n d H O- 1. A m J P h ysi ol Re nal P h ysi ol. 
2 0 1 1; 3 0 0( 5): F 1 1 8 0- F 1 1 9 2. 
 

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1 9.  
A P P E N DI X 1: A T S G UI D E LI N E S F O R T H E SI X- MI N U T E W A L K 
T E S T  

A m eric a n T h or acic S oci et y
 
A m J R es pir Crit C ar e M e d 
V ol 1 6 6. p p 1 1 1 – 1 1 7, 2 0 0 2
D OI: 1 0. 1 1 6 4 /r c c m. 1 6 6 / 1 / 1 1 1
I nt er n et a d dr ess: w w w. atsj o ur n als. or g
 
A T S S t a t e m e n t: G ui d eli n e s f o r t h e Si x- Mi n u t e W al k T e s t
 
T
 
HI S
 
 O
 
F FI CI A L
 
 S
 
T A T E M E N T
 
 
 
O F
 
 
 
T H E
 
 A
 
M E RI C A N
 
 T
 
H O R A CI C
 
 S
 
O CI E T Y
 
 
 
W A S
 
 
 
A P P R O V E D
 
 
 
B Y
 
 
 
T H E
 
 A T S B
 
O A R D
 
 
 
O F
 
 D
 
I R E C T O R S
 
M
 
A R C H
 
 2 0 0 2
 
C O N T E N T S
 
P ur p os e a n d Sc o p e
B ac k gr o u n d
I n dic ati o ns a n d Li mit ati o ns
C o ntr ai n dic ati o ns
S af et y Iss u es
T ec h nic al As p ects of t h e 6
 
-
 
Mi n ut e W al k T est
R e q uir e d E q ui p m e nt
P ati e nt Pr e p ar ati o n
M e as ur e m e nts
Q u alit y Ass ur a nc e
I nt er pr et ati o n
R ef er e nc es
 
P U R P O S E A N D S C O P E
 
T his st at e m e nt pr o vi d es pr actic al g ui d eli n es f or t h e 6- mi n ut e
w al k t est ( 6 M W T). S p ecific all y, it r e vi e ws i n dic ati o ns, d et ails
f act ors t h at i nfl u e nc e r es ults, pr es e nts a bri ef st e p- b y-st e p pr o-
t oc ol, o utli n es s af et y m e as ur es, d escri b es pr o p er p ati e nt pr e p-
ar ati o n a n d pr oc e d ur es, a n d off ers g ui d eli n es f or cli nic al i nt er-
pr et ati o n of r es ults. T h es e r ec o m m e n d ati o ns ar e n ot i nt e n d e d
t o li mit t h e us e of alt er n ati v e pr ot oc ols f or r es e arc h st u di es.
W e d o n ot disc uss t h e g e n er al t o pic of cli nic al e x ercis e t esti n g.
As wit h ot h er A m eric a n T h or acic S oci et y st at e m e nts o n
p ul m o n ar y f u ncti o n t esti n g, t h es e g ui d eli n es c o m e o ut of a
c o ns e ns us c o nf er e nc e. Dr afts w er e pr e p ar e d b y t w o m e m b ers
( P. L. E. a n d R.J. Z.) a n d w er e b as e d o n a c o m pr e h e nsi v e M e d-
li n e lit er at ur e s e arc h fr o m 1 9 7 0 t hr o u g h 2 0 0 1, a u g m e nt e d b y
s u g g esti o ns fr o m ot h er c o m mitt e e m e m b ers. E ac h dr aft r e-
s p o n d e d t o c o m m e nts fr o m t h e w or ki n g c o m mitt e e. T h e g ui d e-
li n es f oll o w pr e vi o usl y p u blis h e d m et h o ds as cl os el y as p ossi-
bl e a n d pr o vi d e a r ati o n al e f or e ac h s p ecific r ec o m m e n d ati o n.
T h e fi n al r ec o m m e n d ati o ns r e pr es e nt a c o ns e ns us of t h e c o m-
mitt e e. T h e c o m mitt e e r ec o m m e n ds t h at t h es e g ui d eli n es b e
r e vi e w e d i n fi v e y e ars a n d i n t h e m e a nti m e e nc o ur a g es f urt h er
r es e arc h i n ar e as of c o ntr o v ers y.
 
B A C K G R O U N D
 
T h er e ar e s e v er al m o d aliti es a v ail a bl e f or t h e o bj ecti v e e v al u-
ati o n  of  f u ncti o n al  e x ercis e  c a p acit y.  S o m e  pr o vi d e  a  v er y
c o m pl et e ass ess m e nt of all s yst e ms i n v ol v e d i n e x ercis e p er-
f or m a nc e ( hi g h t ec h), w h er e as ot h ers pr o vi d e b asic i nf or m a-
ti o n b ut ar e l o w t ec h a n d ar e si m pl er t o p erf or m. T h e m o d alit y
us e d s h o ul d b e c h os e n b as e d o n t h e cli nic al q u esti o n t o b e a d-
dr ess e d a n d o n a v ail a bl e r es o urc es. T h e m ost p o p ul ar cli nic al
e x ercis e t ests i n or d er of i ncr e asi n g c o m pl e xit y ar e st air cli m b-
i n g, a 6 M W T, a s h uttl e- w al k t est, d et ecti o n of e x ercis e-i n d uc e d
ast h m a, a c ar di ac str ess t est ( e. g., Br uc e pr ot oc ol), a n d a c ar di o-
p ul m o n ar y e x ercis e t est ( 1, 2). Ot h er pr of essi o n al or g a niz a-
ti o ns h a v e p u blis h e d st a n d ar ds f or c ar di ac str ess t esti n g ( 3, 4).
Ass ess m e nt  of  f u ncti o n al  c a p acit y  h as  tr a diti o n all y  b e e n
d o n e  b y  m er el y  as ki n g  p ati e nts  t h e  f oll o wi n g:  “ H o w  m a n y
fli g hts of st airs c a n y o u cli m b or h o w m a n y bl oc ks c a n y o u
w al k ? ” H o w e v er, p ati e nts v ar y i n t h eir r ec oll ecti o n a n d m a y
r e p ort o v er esti m ati o ns or u n d er esti m ati o ns of t h eir tr u e f u nc-
ti o n al  c a p acit y.  O bj ecti v e  m e as ur e m e nts  ar e  us u all y  b ett er
t h a n s elf-r e p orts. I n t h e e arl y 1 9 6 0s, B al k e d e v el o p e d a si m pl e
t est t o e v al u at e t h e f u ncti o n al c a p acit y b y m e as uri n g t h e dis-
t a nc e w al k e d d uri n g a d efi n e d p eri o d of ti m e ( 5). A 1 2- mi n ut e
fi el d  p erf or m a nc e  t est  w as  t h e n  d e v el o p e d  t o  e v al u at e  t h e
l e v el of p h ysic al fit n ess of h e alt h y i n di vi d u als ( 6). T h e w al ki n g
t est  w as  als o  a d a pt e d  t o  ass ess  dis a bilit y  i n  p ati e nts  wit h
c hr o nic br o nc hitis ( 7). I n a n att e m pt t o acc o m m o d at e p ati e nts
wit h r es pir at or y dis e as e f or w h o m w al ki n g 1 2 mi n ut es w as t o o
e x h a usti n g, a 6- mi n ut e w al k w as f o u n d t o p erf or m as w ell as
t h e 1 2- mi n ut e w al k ( 8). A r ec e nt r e vi e w of f u ncti o n al w al ki n g
t ests c o ncl u d e d t h at “t h e 6 M W T is e as y t o a d mi nist er, b ett er
t ol er at e d, a n d m or e r efl ecti v e of acti viti es of d ail y li vi n g t h a n
t h e ot h er w al k t ests ” ( 9).
T h e 6 M W T is a pr actic al si m pl e t est t h at r e q uir es a 1 0 0-ft
h all w a y  b ut  n o  e x ercis e  e q ui p m e nt  or  a d v a nc e d  tr ai ni n g  f or
t ec h nici a ns. W al ki n g is a n acti vit y p erf or m e d d ail y b y all b ut
t h e m ost s e v er el y i m p air e d p ati e nts. T his t est m e as ur es t h e dis-
t a nc e t h at a p ati e nt c a n q uic kl y w al k o n a fl at, h ar d s urf ac e i n a
p eri o d of 6 mi n ut es (t h e 6 M W D). It e v al u at es t h e gl o b al a n d i n-
t e gr at e d r es p o ns es of all t h e s yst e ms i n v ol v e d d uri n g e x ercis e,
i ncl u di n g t h e p ul m o n ar y a n d c ar di o v asc ul ar s yst e ms, s yst e mic
circ ul ati o n, p eri p h er al circ ul ati o n, bl o o d, n e ur o m usc ul ar u nits,
a n d m uscl e m et a b olis m. It d o es n ot pr o vi d e s p ecific i nf or m a-
ti o n o n t h e f u ncti o n of e ac h of t h e diff er e nt or g a ns a n d s yst e ms
i n v ol v e d i n e x ercis e or t h e m ec h a nis m of e x ercis e li mit ati o n, as
is p ossi bl e wit h m a xi m al c ar di o p ul m o n ar y e x ercis e t esti n g. T h e
s elf- p ac e d 6 M W T ass ess es t h e s u b m a xi m al l e v el of f u ncti o n al
c a p acit y. M ost p ati e nts d o n ot ac hi e v e m a xi m al e x ercis e c a p ac-
it y d uri n g t h e 6 M W T; i nst e a d, t h e y c h o os e t h eir o w n i nt e nsit y
of e x ercis e a n d ar e all o w e d t o st o p a n d r est d uri n g t h e t est.
H o w e v er, b ec a us e m ost acti viti es of d ail y li vi n g ar e p erf or m e d
at s u b m a xi m al l e v els of e x erti o n, t h e 6 M W D m a y b ett er r efl ect
t h e f u ncti o n al e x ercis e l e v el f or d ail y p h ysic al acti viti es.
 
I N DI C A TI O N S A N D LI MI T A TI O N S
 
T h e str o n g est i n dic ati o n f or t h e 6 M W T is f or m e as uri n g t h e r e-
s p o ns e t o m e dic al i nt er v e nti o ns i n p ati e nts wit h m o d er at e t o
s e v er e h e art or l u n g dis e as e. T h e 6 M W T h as als o b e e n us e d as
a o n e-ti m e m e as ur e of f u ncti o n al st at us of p ati e nts, as w ell as a
pr e dict or of m or bi dit y a n d m ort alit y (
 
see
 
 T a bl e 1 f or a list of
t h es e i n dic ati o ns). T h e f act t h at i n v esti g at ors h a v e us e d t h e
6 M W T i n t h es e s etti n gs d o es n ot pr o v e t h at t h e t est is cli nic all y
us ef ul ( or t h e b est t est) f or d et er mi ni n g f u ncti o n al c a p acit y or
c h a n g es i n f u ncti o n al c a p acit y d u e t o a n i nt er v e nti o n i n p a-
ti e nts wit h t h es e dis e as es. F urt h er st u di es ar e n ec ess ar y t o d e-
t er mi n e t h e utilit y of t h e 6 M W T i n v ari o us cli nic al sit u ati o ns.
Pr ot oc ol 4 0 2- C- 1 6 0 2
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1 1 2
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
F or m al c ar di o p ul m o n ar y e x ercis e t esti n g pr o vi d es a gl o b al
ass ess m e nt of t h e e x ercis e r es p o ns e, a n o bj ecti v e d et er mi n a-
ti o n of f u ncti o n al c a p acit y a n d i m p air m e nt, d et er mi n ati o n of
t h e a p pr o pri at e i nt e nsit y n e e d e d t o p erf or m pr ol o n g e d e x er-
cis e, q u a ntific ati o n of f act ors li miti n g e x ercis e, a n d a d efi ni-
ti o n of t h e u n d erl yi n g p at h o p h ysi ol o gic m ec h a nis ms s uc h as
t h e c o ntri b uti o n of diff er e nt or g a n s yst e ms i n v ol v e d i n e x er-
cis e. T h e 6 M W T d o es n ot d et er mi n e p e a k o x y g e n u pt a k e, di-
a g n os e  t h e  c a us e  of  d ys p n e a  o n  e x erti o n,  or  e v al u at e  t h e
c a us es or m ec h a nis ms of e x ercis e li mit ati o n ( 1, 2). T h e i nf or-
m ati o n pr o vi d e d b y a 6 M W T s h o ul d b e c o nsi d er e d c o m pl e-
m e nt ar y t o c ar di o p ul m o n ar y e x ercis e t esti n g, n ot a r e pl ac e-
m e nt f or it. D es pit e t h e diff er e nc e b et w e e n t h es e t w o f u ncti o n al
t ests,  s o m e  g o o d  c orr el ati o ns  b et w e e n  t h e m  h a v e  b e e n  r e-
p ort e d. F or e x a m pl e, a si g nific a nt c orr el ati o n (r 
  
 0. 7 3) b e-
t w e e n 6 M W D a n d p e a k o x y g e n u pt a k e h as b e e n r e p ort e d f or
p ati e nts wit h e n d-st a g e l u n g dis e as es ( 3 6, 3 7).
I n s o m e cli nic al sit u ati o ns, t h e 6 M W T pr o vi d es i nf or m a-
ti o n t h at m a y b e a b ett er i n d e x of t h e p ati e nt’s a bilit y t o p er-
f or m d ail y acti viti es t h a n is p e a k o x y g e n u pt a k e; f or e x a m pl e,
6 M W D c orr el at es b ett er wit h f or m al m e as ur es of q u alit y of
lif e ( 3 8). C h a n g es i n 6 M W D aft er t h er a p e utic i nt er v e nti o ns
c orr el at e  wit h  s u bj ecti v e  i m pr o v e m e nt  i n  d ys p n e a  ( 3 9,  4 0).
T h e r e pr o d uci bilit y of t h e 6 M W D ( wit h a c o effici e nt of v ari a-
ti o n of a p pr o xi m at el y 8 %) a p p e ars t o b e b ett er t h a n t h e r e-
pr o d uci bilit y of 1-s ec o n d f orc e d e x pir at or y v ol u m e i n p ati e nts
wit h c hr o nic o bstr ucti v e p ul m o n ar y dis e as e ( C O P D) ( 8, 4 1 –
4 3). Q u esti o n n air e i n dic es of f u ncti o n al st at us h a v e a l ar g er
s h ort-t er m v ari a bilit y ( 2 2 – 3 3 %) t h a n d o es t h e 6 M W D ( 3 7).
T h e s h uttl e- w al ki n g t est is si mil ar t o t h e 6 M W T, b ut it us es
a n a u di o si g n al fr o m a t a p e c ass ett e t o dir ect t h e w al ki n g p ac e
of t h e p ati e nt b ac k a n d f ort h o n a 1 0- m c o urs e ( 4 4 – 4 7). T h e
w al ki n g s p e e d is i ncr e as e d e v er y mi n ut e, a n d t h e t est e n ds w h e n
t h e p ati e nt c a n n ot r e ac h t h e t ur n ar o u n d p oi nt wit hi n t h e r e-
q uir e d ti m e. T h e e x ercis e p erf or m e d is si mil ar t o a s y m pt o m-
li mit e d, m a xi m al, i ncr e m e nt al tr e a d mill t est. A n a d v a nt a g e of
t h e s h uttl e w al ki n g t est is t h at it h as a b ett er c orr el ati o n wit h
p e a k o x y g e n u pt a k e t h a n t h e 6 M W D. Dis a d v a nt a g es i ncl u d e
l ess v ali d ati o n, l ess wi d es pr e a d us e, a n d m or e p ot e nti al f or
c ar di o v asc ul ar pr o bl e ms.
 
C O N T R AI N DI C A TI O N S
 
A bs ol ut e c o ntr ai n dic ati o ns f or t h e 6 M W T i ncl u d e t h e f oll o w-
i n g: u nst a bl e a n gi n a d uri n g t h e pr e vi o us m o nt h a n d m y oc ar-
di al i nf arcti o n d uri n g t h e pr e vi o us m o nt h. R el ati v e c o ntr ai n di-
c ati o ns i ncl u d e a r esti n g h e art r at e of m or e t h a n 1 2 0, a s yst olic
bl o o d pr ess ur e of m or e t h a n 1 8 0 m m H g, a n d a di ast olic bl o o d
pr ess ur e of m or e t h a n 1 0 0 m m H g.
P ati e nts wit h a n y of t h es e fi n di n gs s h o ul d b e r ef err e d t o t h e
p h ysici a n or d eri n g or s u p er visi n g t h e t est f or i n di vi d u al cli ni-
c al ass ess m e nt a n d a d ecisi o n a b o ut t h e c o n d uct of t h e t est.
T h e r es ults fr o m a r esti n g el ectr oc ar di o gr a m d o n e d uri n g t h e
pr e vi o us 6 m o nt hs s h o ul d als o b e r e vi e w e d b ef or e t esti n g. St a-
bl e e x erti o n al a n gi n a is n ot a n a bs ol ut e c o ntr ai n dic ati o n f or a
6 M W T, b ut p ati e nts wit h t h es e s y m pt o ms s h o ul d p erf or m t h e
t est aft er usi n g t h eir a nti a n gi n a m e dic ati o n, a n d r esc u e nitr at e
m e dic ati o n s h o ul d b e r e a dil y a v ail a bl e.
 
R ati o n al e
 
P ati e nts wit h t h e pr e vi o usl y m e nti o n e d ris k f act ors m a y b e at
i ncr e as e d ris k f or arr h yt h mi as or c ar di o v asc ul ar c oll a ps e d uri n g
t esti n g. H o w e v er, e ac h p ati e nt d et er mi n es t h e i nt e nsit y of t h eir
e x ercis e, a n d t h e t est ( wit h o ut el ectr oc ar di o gr a m m o nit ori n g)
h as b e e n p erf or m e d i n t h o us a n ds of ol d er p ers o ns ( 3 1, 4 8 – 5 0)
a n d t h o us a n ds of p ati e nts wit h h e art f ail ur e or c ar di o m y o p at h y
( 3 2, 5 1, 5 2) wit h o ut s eri o us a d v ers e e v e nts. T h e c o ntr ai n dic a-
ti o ns list e d pr e vi o usl y h er e w er e us e d b y st u d y i n v esti g at ors
b as e d o n t h eir i m pr essi o ns of t h e g e n er al s af et y of t h e 6 M W T
a n d t h eir d esir e t o b e pr u d e nt, b ut it is u n k n o w n w h et h er a d-
v ers e e v e nts w o ul d occ ur if s uc h p ati e nts p erf or m e d a 6 M W T;
t h e y ar e, t h er ef or e, list e d as r el ati v e c o ntr ai n dic ati o ns.
 
S A F E T Y I S S U E S
 
1. T esti n g s h o ul d b e p erf or m e d i n a l oc ati o n w h er e a r a pi d,
a p pr o pri at e r es p o ns e t o a n e m er g e nc y is p ossi bl e. T h e a p-
pr o pri at e l oc ati o n of a cr as h c art s h o ul d b e d et er mi n e d b y
t h e p h ysici a n s u p er visi n g t h e f acilit y.
2. S u p pli es t h at m ust b e a v ail a bl e i ncl u d e o x y g e n, s u bli n g u al
nitr o gl yc eri n e, as piri n, a n d al b ut er ol ( m et er e d d os e i n h al er
or n e b uliz er). A t el e p h o n e or ot h er m e a ns s h o ul d b e i n
pl ac e t o e n a bl e a c all f or h el p.
3. T h e t ec h nici a n s h o ul d b e c ertifi e d i n c ar di o p ul m o n ar y r e-
s uscit ati o n wit h a mi ni m u m of B asic Lif e S u p p ort b y a n
A m eric a n H e alt h Ass oci ati o n – a p pr o v e d c ar di o p ul m o n ar y
r es uscit ati o n c o urs e. A d v a nc e d c ar di ac lif e s u p p ort c ertifi-
c ati o n is d esir a bl e. Tr ai ni n g, e x p eri e nc e, a n d c ertific ati o n
i n r el at e d h e alt h c ar e fi el ds (r e gist er e d n urs e, r e gist er e d r e-
s pir at or y  t h er a pist,  c ertifi e d  p ul m o n ar y  f u ncti o n  t ec h ni-
ci a n, etc.) ar e als o d esir a bl e. A c ertifi e d i n di vi d u al s h o ul d
b e r e a dil y a v ail a bl e t o r es p o n d if n e e d e d.
4. P h ysici a ns ar e n ot r e q uir e d t o b e pr es e nt d uri n g all t ests.
T h e p h ysici a n or d eri n g t h e t est or a s u p er visi n g l a b or at or y
p h ysici a n  m a y  d eci d e  w h et h er  p h ysici a n  att e n d a nc e  at  a
s p ecific t est is r e q uir e d.
5. If a p ati e nt is o n c hr o nic o x y g e n t h er a p y, o x y g e n s h o ul d b e
gi v e n at t h eir st a n d ar d r at e or as dir ect e d b y a p h ysici a n or
a pr ot oc ol.
R e as o ns f or i m m e di at el y st o p pi n g a 6 M W T i ncl u d e t h e f oll o w-
i n g: (
 
1
 
) c h est p ai n, (
 
2
 
) i nt ol er a bl e d ys p n e a, (
 
3
 
) l e g cr a m ps, (
 
4
 
)
st a g g eri n g, (
 
5
 
) di a p h or esis, a n d (
 
6
 
) p al e or as h e n a p p e ar a nc e.
T ec h nici a ns m ust b e tr ai n e d t o r ec o g niz e t h es e pr o bl e ms
a n d t h e a p pr o pri at e r es p o ns es. If a t est is st o p p e d f or a n y of
t h es e r e as o ns, t h e p ati e nt s h o ul d sit or li e s u pi n e as a p pr o pri-
at e d e p e n di n g o n t h e s e v erit y or t h e e v e nt a n d t h e t ec h nici a n’s
ass ess m e nt of t h e s e v erit y of t h e e v e nt a n d t h e ris k of s y nc o p e.
T h e f oll o wi n g s h o ul d b e o bt ai n e d b as e d o n t h e j u d g m e nt of
t h e t ec h nici a n: bl o o d pr ess ur e, p uls e r at e, o x y g e n s at ur ati o n,
a n d a p h ysici a n e v al u ati o n. O x y g e n s h o ul d b e a d mi nist er e d as
a p pr o pri at e.
 
T A B L E 1. I N DI C A TI O N S F O R T H E SI X- MI N U T E  W A L K T E S T
 
Pr etr e at m e nt a n d p osttr e at m e nt c o m p aris o ns
L u n g tr a ns pl a nt ati o n ( 9, 1 0)
L u n g r es e cti o n ( 1 1)
L u n g v ol u m e r e d u cti o n s ur g er y ( 1 2, 1 3)
P ul m o n ar y r e h a bilit ati o n ( 1 4, 1 5)
C O P D ( 1 6 – 1 8)
P ul m o n ar y h y p ert e nsi o n
H e art f ail ur e ( 1 9, 2 0)
F u n cti o n al st at us (si n gl e m e as ur e m e nt)
C O P D ( 2 1, 2 2)
C ysti c fi br osis ( 2 3, 2 4)
H e art f ail ur e ( 2 5 – 2 7)
P eri p h er al v as c ul ar dis e as e ( 2 8, 2 9)
Fi br o m y al gi a ( 3 0)
Ol d er p ati e nts ( 3 1)
Pr e di ct or of m or bi dit y a n d m ort alit y
H e art f ail ur e ( 3 2, 3 3)
C O P D ( 3 4, 3 5)
Pri m ar y p ul m o n ar y h y p ert e nsi o n ( 1 0, 3 6)
D efi niti o n of a b br e vi ati o n
 
: C O P D 
  
 c hr o ni c o bstr u cti v e p ul m o n ar y dis e as e.
Pr ot oc ol 4 0 2- C- 1 6 0 2
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5 7

 
A m eri c a n T h or a ci c S o ci et y
1 1 3
 
T E C H NI C A L A S P E C T S O F T H E 6 M W T
 
L o c ati o n
 
T h e 6 M W T s h o ul d b e p erf or m e d i n d o ors, al o n g a l o n g, fl at,
str ai g ht, e ncl os e d c orri d or wit h a h ar d s urf ac e t h at is s el d o m
tr a v el e d. If t h e w e at h er is c o mf ort a bl e, t h e t est m a y b e p er-
f or m e d o ut d o ors. T h e w al ki n g c o urs e m ust b e 3 0 m i n l e n gt h.
A 1 0 0-ft h all w a y is, t h er ef or e, r e q uir e d. T h e l e n gt h of t h e c or-
ri d or s h o ul d b e m ar k e d e v er y 3 m. T h e t ur n ar o u n d p oi nts s h o ul d
b e m ar k e d wit h a c o n e (s uc h as a n or a n g e tr affic c o n e). A st art-
i n g li n e, w hic h m ar ks t h e b e gi n ni n g a n d e n d of e ac h 6 0- m l a p,
s h o ul d b e m ar k e d o n t h e fl o or usi n g bri g htl y c ol or e d t a p e.
 
R ati o n ale.  
 
A s h ort er c orri d or r e q uir es p ati e nts t o t a k e m or e
ti m e t o r e v ers e dir ecti o ns m or e oft e n, r e d uci n g t h e 6 M W D.
M ost st u di es h a v e us e d a 3 0- m c orri d or, b ut s o m e h a v e us e d
2 0-  or  5 0- m  c orri d ors  ( 5 2 – 5 5).  A  r ec e nt  m ultic e nt er  st u d y
f o u n d n o si g nific a nt eff ect of t h e l e n gt h of str ai g ht c o urs es
r a n gi n g fr o m 5 0 t o 1 6 4 ft, b ut p ati e nts w al k e d f art h er o n c o n-
ti n u o us ( o v al) tr ac ks ( m e a n 9 2 ft f art h er) ( 5 4).
T h e us e of a tr e a d mill t o d et er mi n e t h e 6 M W D mi g ht s a v e
s p ac e a n d all o w c o nst a nt m o nit ori n g d uri n g t h e e x ercis e, b ut
t h e us e of a tr e a d mill f or 6- mi n ut e w al k t esti n g is n ot r ec o m-
m e n d e d. P ati e nts ar e u n a bl e t o p ac e t h e ms el v es o n a tr e a d-
mill. I n o n e st u d y of p ati e nts wit h s e v er e l u n g dis e as e, t h e
m e a n dist a nc e w al k e d o n t h e tr e a d mill d uri n g 6 mi n ut es ( wit h
t h e s p e e d a dj ust e d b y t h e p ati e nts) w as s h ort er b y a m e a n of
1 4 % w h e n c o m p ar e d wit h t h e st a n d ar d 6 M W D usi n g a 1 0 0-ft
h all w a y ( 5 7). T h e r a n g e of diff er e nc es w as wi d e, wit h p ati e nts
w al ki n g b et w e e n 4 0 0 – 1, 3 0 0 ft o n t h e tr e a d mill w h o w al k e d
1, 2 0 0 ft i n t h e h all w a y. Tr e a d mill t est r es ults, t h er ef or e, ar e
n ot i nt erc h a n g e a bl e wit h c orri d or t ests.
 
R E Q UI R E D E Q UI P M E N T
 
1.  C o u nt d o w n ti m er ( or st o p w atc h)
2.  M ec h a nic al l a p c o u nt er
3. T w o s m all c o n es t o m ar k t h e t ur n ar o u n d p oi nts
4.  A c h air t h at c a n b e e asil y m o v e d al o n g t h e w al ki n g c o urs e
5.  W or ks h e ets o n a cli p b o ar d
6.  A s o urc e of o x y g e n
7. S p h y g m o m a n o m et er
8. T el e p h o n e
9.  A ut o m at e d el ectr o nic d efi brill at or
 
P A TI E N T P R E P A R A TI O N
 
1.  C o mf ort a bl e cl ot hi n g s h o ul d b e w or n.
2.  A p pr o pri at e s h o es f or w al ki n g s h o ul d b e w or n.
3. P ati e nts s h o ul d us e t h eir us u al w al ki n g ai ds d uri n g t h e t est
(c a n e, w al k er, etc.).
4. T h e p ati e nt’s us u al m e dic al r e gi m e n s h o ul d b e c o nti n u e d.
5.  A li g ht m e al is acc e pt a bl e b ef or e e arl y m or ni n g or e arl y af-
t er n o o n t ests.
6. P ati e nts s h o ul d n ot h a v e e x ercis e d vi g or o usl y wit hi n 2 h o urs
of b e gi n ni n g t h e t est.
 
M E A S U R E M E N T S
 
1.  R e p e at t esti n g s h o ul d b e p erf or m e d a b o ut t h e s a m e ti m e
of d a y t o mi ni miz e i ntr a d a y v ari a bilit y.
2.  A “ w ar m- u p ” p eri o d b ef or e t h e t est s h o ul d n ot b e p erf or m e d.
3. T h e p ati e nt s h o ul d sit at r est i n a c h air, l oc at e d n e ar t h e
st arti n g p ositi o n, f or at l e ast 1 0 mi n ut es b ef or e t h e t est
st arts. D uri n g t his ti m e, c h ec k f or c o ntr ai n dic ati o ns, m e a-
s ur e p uls e a n d bl o o d pr ess ur e, a n d m a k e s ur e t h at cl ot h-
i n g a n d s h o es ar e a p pr o pri at e. C o m p et e t h e first p orti o n
of t h e w or ks h e et (
 
see
 
 t h e A
 
P P E N DI X
 
).
4. P uls e o xi m etr y is o pti o n al. If it is p erf or m e d, m e as ur e a n d
r ec or d b as eli n e h e art r at e a n d o x y g e n s at ur ati o n ( S p O
 
2
 
)
a n d f oll o w m a n uf act ur er’s i nstr ucti o ns t o m a xi miz e t h e si g-
n al a n d t o mi ni miz e m oti o n artif act ( 5 6, 5 7). M a k e s ur e t h e
r e a di n gs ar e st a bl e b ef or e r ec or di n g. N ot e p uls e r e g ul arit y
a n d w h et h er t h e o xi m et er si g n al q u alit y is acc e pt a bl e.
 
T h e r ati o n al e f or m e as uri n g o x y g e n s at ur ati o n is t h at al-
t h o u g h t h e dist a nc e is t h e pri m ar y o utc o m e m e as ur e, i m-
pr o v e m e nt d uri n g s eri al e v al u ati o ns m a y b e m a nif est eit h er
b y a n i ncr e as e d dist a nc e or b y r e d uc e d s y m pt o ms wit h t h e
s a m e dist a nc e w al k e d ( 3 9). T h e S p O
 
2
 
 s h o ul d n ot b e us e d f or
c o nst a nt  m o nit ori n g  d uri n g  t h e  e x ercis e.  T h e  t ec h nici a n
m ust n ot w al k wit h t h e p ati e nt t o o bs er v e t h e S p O
 
2
 
. If w or n
d uri n g t h e w al k, t h e p uls e o xi m et er m ust b e li g ht w ei g ht (l ess
t h a n 2 p o u n ds), b att er y p o w er e d, a n d h el d i n pl ac e ( p er h a ps
b y a “f a n n y p ac k ”) s o t h at t h e p ati e nt d o es n ot h a v e t o h ol d
or st a biliz e it a n d s o t h at stri d e is n ot aff ect e d. M a n y p uls e
o xi m et ers h a v e c o nsi d er a bl e m oti o n artif act t h at pr e v e nts
acc ur at e r e a di n gs d uri n g t h e w al k. ( 5 7)
 
5.  H a v e t h e p ati e nt st a n d a n d r at e t h eir b as eli n e d ys p n e a
a n d o v er all f ati g u e usi n g t h e B or g sc al e (
 
see
 
 T a bl e 2 f or
t h e B or g sc al e a n d i nstr ucti o ns [ 5 8]).
6. S et t h e l a p c o u nt er t o z er o a n d t h e ti m er t o 6 mi n ut es. As-
s e m bl e all n ec ess ar y e q ui p m e nt (l a p c o u nt er, ti m er, cli p-
b o ar d, B or g Sc al e, w or ks h e et) a n d m o v e t o t h e st arti n g
p oi nt.
7. I nstr uct t h e p ati e nt as f oll o ws:
 
“ T h e o bj ect of t his t est is t o w al k as f ar as p ossi bl e f or 6
mi n ut es. Y o u will w al k b ac k a n d f ort h i n t his h all w a y. Si x
mi n ut es is a l o n g ti m e t o w al k, s o y o u will b e e x erti n g y o ur-
s elf.  Y o u  will  pr o b a bl y  g et  o ut  of  br e at h  or  b ec o m e  e x-
h a ust e d. Y o u ar e p er mitt e d t o sl o w d o w n, t o st o p, a n d t o
r est as n ec ess ar y. Y o u m a y l e a n a g ai nst t h e w all w hil e r est-
i n g, b ut r es u m e w al ki n g as s o o n as y o u ar e a bl e.
Y o u will b e w al ki n g b ac k a n d f ort h ar o u n d t h e c o n es.
Y o u s h o ul d pi v ot bris kl y ar o u n d t h e c o n es a n d c o nti n u e
b ac k t h e ot h er w a y wit h o ut h esit ati o n. N o w I’ m g oi n g t o
s h o w y o u. Pl e as e w atc h t h e w a y I t ur n wit h o ut h esit ati o n. ”
D e m o nstr at e  b y  w al ki n g  o n e  l a p  y o urs elf.  W al k  a n d
pi v ot ar o u n d a c o n e bris kl y.
“ Ar e  y o u  r e a d y  t o  d o  t h at ?  I  a m  g oi n g  t o  us e  t his
c o u nt er t o k e e p tr ac k of t h e n u m b er of l a ps y o u c o m pl et e. I
will clic k it e ac h ti m e y o u t ur n ar o u n d at t his st arti n g li n e.
R e m e m b er t h at t h e o bj ect is t o w al k A S F A R A S P O S SI-
B L E f or 6 mi n ut es, b ut d o n’t r u n or j o g.
St art n o w, or w h e n e v er y o u ar e r e a d y. ”
 
T A B L E 2. T H E B O R G S C A L E
 
0  
N ot hi n g at all
0. 5 V er y, v er y sli g ht (j ust n oti c e a bl e)
1 
V er y sli g ht
2 
Sli g ht (li g ht)
3  
M o d er at e
4 
S o m e w h at s e v er e
5 
S e v er e ( h e a v y)
6
7 
V er y s e v er e
8
9
1 0 
V er y, v er y s e v er e ( m a xi m al)
T his B or g s c al e s h o ul d b e pri nt e d o n h e a v y p a p er ( 1 1 i n c h es hi g h a n d p er h a ps l a mi-
n at e d) i n 2 0- p oi nt t y p e siz e. At t h e b e gi n ni n g of t h e 6- mi n ut e e x er cis e, s h o w t h e s c al e
t o t h e p ati e nt a n d as k t h e p ati e nt t his: “ Pl e as e gr a d e y o ur l e v el of s h ort n ess of br e at h
usi n g t his s c al e. ” T h e n as k t his: “ Pl e as e gr a d e y o ur l e v el of f ati g u e usi n g t his s c al e. ”
At t h e e n d of t h e e x er cis e, r e mi n d t h e p ati e nt of t h e br e at hi n g n u m b er t h at t h e y
c h os e b ef or e t h e e x er cis e a n d as k t h e p ati e nt t o gr a d e t h eir br e at hi n g l e v el a g ai n. T h e n
as k t h e p ati e nt t o gr a d e t h eir l e v el of f ati g u e, aft er r e mi n di n g t h e m of t h eir gr a d e b e-
f or e t h e e x er cis e.
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1 1 4
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
8. P ositi o n t h e p ati e nt at t h e st arti n g li n e. Y o u s h o ul d als o
st a n d n e ar t h e st arti n g li n e d uri n g t h e t est. D o n ot w al k
wit h t h e p ati e nt. As s o o n as t h e p ati e nt st arts t o w al k,
st art t h e ti m er.
9.  D o n ot t al k t o a n y o n e d uri n g t h e w al k. Us e a n e v e n t o n e
of v oic e w h e n usi n g t h e st a n d ar d p hr as es of e nc o ur a g e-
m e nt. W atc h t h e p ati e nt. D o n ot g et distr act e d a n d l os e
c o u nt of t h e l a ps. E ac h ti m e t h e p artici p a nt r et ur ns t o t h e
st arti n g li n e, clic k t h e l a p c o u nt er o nc e ( or m ar k t h e l a p
o n t h e w or ks h e et). L et t h e p artici p a nt s e e y o u d o it. E x-
a g g er at e t h e clic k usi n g b o d y l a n g u a g e, li k e usi n g a st o p-
w atc h at a r ac e.
 
Aft er t h e first mi n ut e, t ell t h e p ati e nt t h e f oll o wi n g (i n
e v e n t o n es): “ Y o u ar e d oi n g w ell. Y o u h a v e 5 mi n ut es t o
g o. ”
W h e n t h e ti m er s h o ws 4 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ K e e p u p t h e g o o d w or k. Y o u h a v e 4
mi n ut es t o g o. ”
W h e n t h e ti m er s h o ws 3 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ Y o u ar e d oi n g w ell. Y o u ar e h alf w a y
d o n e. ”
W h e n t h e ti m er s h o ws 2 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ K e e p u p t h e g o o d w or k. Y o u h a v e o nl y
2 mi n ut es l eft. ”
W h e n t h e ti m er s h o ws o nl y 1 mi n ut e r e m ai ni n g, t ell t h e
p ati e nt: “ Y o u ar e d oi n g w ell. Y o u h a v e o nl y 1 mi n ut e t o
g o. ”
D o n ot us e ot h er w or ds of e nc o ur a g e m e nt ( or b o d y l a n-
g u a g e t o s p e e d u p).
If t h e p ati e nt st o ps w al ki n g d uri n g t h e t est a n d n e e ds a
r est, s a y t his: “ Y o u c a n l e a n a g ai nst t h e w all if y o u w o ul d
li k e; t h e n c o nti n u e w al ki n g w h e n e v er y o u f e el a bl e. ” D o
n ot st o p t h e ti m er. If t h e p ati e nt st o ps b ef or e t h e 6 mi n ut es
ar e  u p  a n d  r ef us es  t o  c o nti n u e  ( or  y o u  d eci d e  t h at  t h e y
s h o ul d n ot c o nti n u e), w h e el t h e c h air o v er f or t h e p ati e nt t o
sit o n, disc o nti n u e t h e w al k, a n d n ot e o n t h e w or ks h e et t h e
dist a nc e, t h e ti m e st o p p e d, a n d t h e r e as o n f or st o p pi n g pr e-
m at ur el y.
W h e n t h e ti m er is 1 5 s ec o n ds fr o m c o m pl eti o n, s a y t his:
“I n a m o m e nt I’ m g oi n g t o t ell y o u t o st o p. W h e n I d o, j ust
st o p ri g ht w h er e y o u ar e a n d I will c o m e t o y o u. ”
W h e n t h e ti m er ri n gs ( or b uzz es), s a y t his: “ St o p! ” W al k
o v er t o t h e p ati e nt. C o nsi d er t a ki n g t h e c h air if t h e y l o o k
e x h a ust e d. M ar k t h e s p ot w h er e t h e y st o p p e d b y pl aci n g a
b e a n b a g or a pi ec e of t a p e o n t h e fl o or.
 
1 0. P ost-t est: R ec or d t h e p ost w al k B or g d ys p n e a a n d f ati g u e
l e v els a n d as k t his: “ W h at, if a n yt hi n g, k e pt y o u fr o m w al k-
i n g f art h er ? ”
1 1. If usi n g a p uls e o xi m et er, m e as ur e S p O
 
2
 
 a n d p uls e r at e
fr o m t h e o xi m et er a n d t h e n r e m o v e t h e s e ns or.
1 2.  R ec or d t h e n u m b er of l a ps fr o m t h e c o u nt er ( or tic k m ar ks
o n t h e w or ks h e et).
1 3.  R ec or d t h e a d diti o n al dist a nc e c o v er e d (t h e n u m b er of m et ers
i n t h e fi n al p arti al l a p) usi n g t h e m ar k ers o n t h e w all as dis-
t a nc e g ui d es. C alc ul at e t h e t ot al dist a nc e w al k e d, r o u n di n g t o
t h e n e ar est m et er, a n d r ec or d it o n t h e w or ks h e et.
1 4.  C o n gr at ul at e t h e p ati e nt o n g o o d eff ort a n d off er a dri n k
of w at er.
 
Q U A LI T Y A S S U R A N C E
 
S o ur c es of V ari a bilit y
 
T h er e ar e m a n y s o urc es of 6 M W D v ari a bilit y (
 
see
 
 T a bl e 3).
T h e s o urc es of v ari a bilit y c a us e d b y t h e t est pr oc e d ur e its elf
s h o ul d b e c o ntr oll e d as m uc h as p ossi bl e. T his is d o n e b y f ol-
l o wi n g t h e st a n d ar ds f o u n d i n t his d oc u m e nt a n d b y usi n g a
q u alit y- ass ur a nc e pr o gr a m.
 
Pr a cti c e T ests
 
A  pr actic e  t est  is  n ot  n e e d e d  i n  m ost  cli nic al  s etti n gs  b ut
s h o ul d b e c o nsi d er e d. If a pr actic e t est is d o n e, w ait f or at l e ast
1 h o ur b ef or e t h e s ec o n d t est a n d r e p ort t h e hi g h est 6 M W D as
t h e p ati e nt’s 6 M W D b as eli n e.
 
R ati o n ale.  
 
T h e 6 M W D is o nl y sli g htl y hi g h er f or a s ec o n d
6 M W T p erf or m e d a d a y l at er. T h e m e a n r e p ort e d i ncr e as e
r a n g es fr o m 0 t o 1 7 % ( 2 3, 2 7, 4 0, 4 1, 5 4, 5 9). A m ultic e nt er
st u d y of 4 7 0 hi g hl y m oti v at e d p ati e nts wit h s e v er e C O P D p er-
f or m e d t w o 6 M W Ts 1 d a y a p art, a n d o n a v er a g e, t h e 6 M W D
w as o nl y 6 6 ft ( 5. 8 %) hi g h er o n t h e s ec o n d d a y ( 5 4).
P erf or m a nc e ( wit h o ut a n i nt er v e nti o n) us u all y r e ac h es a
pl at e a u aft er t w o t ests d o n e wit hi n a w e e k ( 8, 6 0). T h e tr ai ni n g
eff ect m a y b e d u e t o i m pr o v e d c o or di n ati o n, fi n di n g o pti m al
stri d e  l e n gt h,  a n d  o v erc o mi n g  a n xi et y.  T h e  p ossi bilit y  of  a
pr actic e or tr ai ni n g eff ect fr o m t ests r e p e at e d aft er m or e t h a n
a m o nt h h as n ot b e e n st u di e d or r e p ort e d; h o w e v er, it is li k el y
t h at t h e eff ect of tr ai ni n g w e ars off ( d o es n ot p ersist) aft er a
f e w w e e ks.
 
T e c h ni ci a n Tr ai ni n g a n d E x p eri e n c e
 
T ec h nici a ns w h o p erf or m 6 M W Ts s h o ul d b e tr ai n e d usi n g t h e
st a n d ar d pr ot oc ol a n d t h e n s u p er vis e d f or s e v er al t ests b ef or e
p erf or mi n g t h e m al o n e. T h e y s h o ul d als o h a v e c o m pl et e d c ar-
di o p ul m o n ar y r es uscit ati o n tr ai ni n g.
 
R ati o n ale.  
 
O n e  m ultic e nt er  st u d y  of  ol d er  p e o pl e  f o u n d
t h at aft er c orr ecti o n f or m a n y ot h er f act ors, t w o of t h e t ec h ni-
ci a ns h a d m e a n 6 M W Ds t h at w er e a p pr o xi m at el y 7 % l o w er
t h a n t h e ot h er t w o sit es ( 3 1).
 
E n c o ur a g e m e nt
 
O nl y t h e st a n d ar diz e d p hr as es f or e nc o ur a g e m e nt ( as s p eci-
fi e d pr e vi o usl y h er e) m ust b e us e d d uri n g t h e t est.
 
R ati o n ale.  
 
E nc o ur a g e m e nt si g nific a ntl y i ncr e as es t h e dis-
t a nc e w al k e d ( 4 2). R e pr o d uci bilit y f or t ests wit h a n d wit h o ut
e nc o ur a g e m e nt is si mil ar. S o m e st u di es h a v e us e d e nc o ur a g e-
m e nt e v er y 3 0 s ec o n ds, e v er y mi n ut e, or e v er y 2 mi n ut es. W e
h a v e c h os e n e v er y mi n ut e a n d st a n d ar d p hr as es. S o m e st u di es
( 5 3) h a v e i nstr uct e d p ati e nts t o w al k as f ast as p ossi bl e. Al-
t h o u g h l ar g er m e a n 6 M W Ds m a y b e o bt ai n e d t h er e b y, w e r ec-
o m m e n d t h at s uc h p hr as es n ot b e us e d, as t h e y e m p h asiz e i ni-
ti al  s p e e d  at  t h e  e x p e ns e  of  e arli er  f ati g u e  a n d  p ossi bl e
e xc essi v e c ar di ac str ess i n s o m e p ati e nts wit h h e art dis e as e.
 
T A B L E 3. 6 M W D S O U R C E S  O F V A RI A BI LI T Y
 
F a ct ors r e d u ci n g t h e 6 M W D
S h ort er h ei g ht
Ol d er a g e
Hi g h er b o d y w ei g ht
F e m al e s e x
I m p air e d c o g niti o n
A s h ort er c orri d or ( m or e t ur ns)
P ul m o n ar y dis e as e ( C O P D, ast h m a, c ysti c fi br osis, i nt erstiti al l u n g dis e as e)
C ar di o v as c ul ar dis e as e ( a n gi n a, MI, C H F, str o k e, TI A, P V D, A AI)
M us c ul osk el et al dis or d ers ( art hritis, a nkl e, k n e e, or hi p i nj uri es, m us cl e w asti n g, etc.)
F a ct ors i n cr e asi n g t h e 6 M W D
T all er h ei g ht (l o n g er l e gs)
M al e s e x
Hi g h m oti v ati o n
A p ati e nt w h o h as pr e vi o usl y p erf or m e d t h e t est
M e di c ati o n f or a dis a bli n g dis e as e t a k e n j ust b ef or e t h e t est
O x y g e n s u p pl e m e nt ati o n i n p ati e nts wit h e x er cis e-i n d u c e d h y p o x e mi a
D efi niti o n of a b br e vi ati o ns
 
: C O P D 
  
 c hr o ni c o bstr u cti v e p ul m o n ar y dis e as e; 6 M W D 
  
 
6- mi n ut e w al ki n g dist a n c e.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
5 9

 
A m eri c a n T h or a ci c S o ci et y
1 1 5
S u p pl e m e nt al O x y g e n
 
If o x y g e n s u p pl e m e nt ati o n is n e e d e d d uri n g t h e w al ks a n d s e-
ri al t ests ar e pl a n n e d ( aft er a n i nt er v e nti o n ot h er t h a n o x y g e n
t h er a p y), t h e n d uri n g all w al ks b y t h at p ati e nt o x y g e n s h o ul d
b e d eli v er e d i n t h e s a m e w a y wit h t h e s a m e fl o w. If t h e fl o w
m ust b e i ncr e as e d d uri n g s u bs e q u e nt visits d u e t o w ors e ni n g
g as e xc h a n g e, t his s h o ul d b e n ot e d o n t h e w or ks h e et a n d c o n-
si d er e d d uri n g i nt er pr et ati o n of t h e c h a n g e n ot e d i n 6 M W D.
T h e t y p e of o x y g e n d eli v er y d e vic e s h o ul d als o b e n ot e d o n
t h e r e p ort: f or i nst a nc e, t h e p ati e nt c arri e d li q ui d o x y g e n or
p us h e d or p ull e d a n o x y g e n t a n k, t h e d eli v er y w as p uls e d or
c o nti n u o us, or a t ec h nici a n w al k e d b e hi n d t h e p ati e nt wit h t h e
o x y g e n s o urc e ( n ot r ec o m m e n d e d). M e as ur e m e nts of p uls e
a n d S p O
 
2
 
 s h o ul d b e m a d e aft er w aiti n g at l e ast 1 0 mi n ut es af-
t er a n y c h a n g e i n o x y g e n d eli v er y.
 
R ati o n ale.  
 
F or p ati e nts wit h C O P D or i nt erstiti al l u n g dis-
e as e, o x y g e n s u p pl e m e nt ati o n i ncr e as es t h e 6 M W D ( 1 7, 5 9,
6 1, 6 3). C arr yi n g a p ort a bl e g as c o nt ai n er ( b ut n ot usi n g it f or
s u p pl e m e nt al o x y g e n) r e d uc e d t h e m e a n 6 M W D b y 1 4 % i n
o n e st u d y of p ati e nts wit h s e v er e r es pir at or y dis a bilit y, b ut us-
i n g t h e c o nt ai n er t o d eli v er s u p pl e m e nt al o x y g e n d uri n g t h e
e x ercis e i ncr e as e d t h e m e a n 6 M W D b y 2 0 – 3 5 % ( 5 9).
 
M e di c ati o ns
 
T h e t y p e of m e dic ati o n, d os e, a n d n u m b er of h o urs t a k e n b e-
f or e t h e t est s h o ul d b e n ot e d.
 
R ati o n ale.  
 
Si g nific a nt i m pr o v e m e nt i n t h e dist a nc e w al k e d,
or t h e d ys p n e a sc al e, aft er a d mi nistr ati o n of br o nc h o dil at ors
h as b e e n d e m o nstr at e d i n p ati e nts wit h C O P D ( 6 2, 6 3), as w ell
as c ar di o v asc ul ar m e dic ati o ns i n p ati e nts wit h h e art f ail ur e ( 1 9).
 
I N T E R P R E T A TI O N
 
M ost 6 M W Ts will b e d o n e b ef or e a n d aft er i nt er v e nti o n, a n d
t h e  pri m ar y  q u esti o n  t o  b e  a ns w er e d  aft er  b ot h  t ests  h a v e
b e e n c o m pl et e d is w h et h er t h e p ati e nt h as e x p eri e nc e d a cli ni-
c all y si g nific a nt i m pr o v e m e nt. Wit h a g o o d q u alit y- ass ur a nc e
pr o gr a m, wit h p ati e nts t est e d b y t h e s a m e t ec h nici a n, a n d af-
t er o n e or t w o pr actic e t ests, s h ort-t er m r e pr o d uci bilit y of t h e
6 M W D is e xc ell e nt ( 3 7). It is n ot k n o w n w h et h er it is b est f or
cli nic al p ur p os es t o e x pr ess c h a n g e i n 6 M W D as (
 
1
 
) a n a bs o-
l ut e v al u e, (
 
2
 
) a p erc e nt a g e c h a n g e, or (
 
3
 
) a c h a n g e i n t h e p er-
c e nt a g e of pr e dict e d v al u e. U ntil f urt h er r es e arc h is a v ail a bl e,
w e r ec o m m e n d t h at c h a n g e i n 6 M W D b e e x pr ess e d as a n a b-
s ol ut e v al u e ( e. g., t h e p ati e nt w al k e d 5 0 m f art h er).
A  st atistic all y  si g nific a nt  m e a n  i ncr e as e  i n  6 M W D  i n  a
gr o u p of st u d y p artici p a nts is oft e n m uc h l ess t h a n a cli nic all y
si g nific a nt i ncr e as e i n a n i n di vi d u al p ati e nt. I n o n e st u d y of
1 1 2 p ati e nts ( h alf of t h e m w o m e n) wit h st a bl e, s e v er e C O P D,
t h e s m all est diff er e nc e i n 6 M W D t h at w as ass oci at e d wit h a
n otic e a bl e cli nic al diff er e nc e i n t h e p ati e nts’ p erc e pti o n of e x-
ercis e p erf or m a nc e w as a m e a n of 5 4 m ( 9 5 % c o nfi d e nc e i n-
t er v al, 3 7 – 7 1 m) ( 6 4). T his st u d y s u g g ests t h at f or i n di vi d u al
p ati e nts wit h C O P D, a n i m pr o v e m e nt of m or e t h a n 7 0 m i n
t h e 6 M W D aft er a n i nt er v e nti o n is n ec ess ar y t o b e 9 5 % c o nfi-
d e nt t h at t h e i m pr o v e m e nt w as si g nific a nt. I n a n o bs er v ati o n al
st u d y of 4 5 ol d er p ati e nts wit h h e art f ail ur e, t h e s m all est dif-
f er e nc e i n 6 M W D t h at w as ass oci at e d wit h a n otic e a bl e diff er-
e nc e i n t h eir gl o b al r ati n g of w ors e ni n g w as a m e a n of 4 3 m
( 2 0). T h e 6 M W D w as m or e r es p o nsi v e t o d et eri or ati o n t h a n
t o i m pr o v e m e nt i n h e art f ail ur e s y m pt o ms.
 
R e p ort e d M e a n C h a n g es i n 6 M W D Aft er I nt er v e nti o ns
 
S u p pl e m e nt al o x y g e n ( 4 L/ mi n) d uri n g e x ercis e i n p ati e nts wit h
C O P D or i nt erstiti al l u n g dis e as e i ncr e as e d m e a n 6 M W D b y
a p pr o xi m at el y 9 5 m ( 3 6 %) i n o n e st u d y ( 5 9). P ati e nts t a ki n g
 
a n i n h al e d c ortic ost er oi d e x p eri e nc e d a m e a n 3 3 m ( 8 %) i n-
cr e as e i n 6 M W D i n a n i nt er n ati o n al C O P D st u d y ( 1 6). P a-
ti e nts wit h C O P D i n a st u d y of t h e eff ects of e x ercis e a n d di a-
p hr a g m atic str e n gt h tr ai ni n g e x p eri e nc e d a m e a n i ncr e as e i n
6 M W D of 5 0 m ( 2 0 %) ( 6 5). L u n g v ol u m e r e d ucti o n s ur g er y i n
p ati e nts wit h v er y s e v er e C O P D h as b e e n r e p ort e d t o i ncr e as e
6 M W D b y a m e a n of 5 5 m ( 2 0 %) ( 1 3).
C ar di ac r e h a bilit ati o n i n p ati e nts r ef err e d wit h v ari o us h e art
dis e as es i ncr e as e d 6 M W D b y a m e a n of 1 7 0 m ( 1 5 %) i n a r ec e nt
st u d y ( 6 6). I n 2 5 ol d er p ati e nts wit h h e art f ail ur e, a n a n gi ot e nsi n-
c o n v erti n g  e nz y m e  i n hi bit or  m e dic ati o n  ( 5 0  m g  c a pt o pril  p er
d a y) i m pr o v e d 6 M W D a m e a n of 6 4 m ( 3 9 %) c o m p ar e d wit h a
m e a n i ncr e as e of o nl y 8 % i n t h os e r ec ei vi n g a pl ac e b o ( 1 9).
 
I nt er pr eti n g Si n gl e M e as ur e m e nts of F u n cti o n al St at us
 
O pti m al r ef er e nc e e q u ati o ns fr o m h e alt h y p o p ul ati o n- b as e d
s a m pl es usi n g st a n d ar diz e d 6 M W T m et h o ds ar e n ot y et a v ail-
a bl e. I n o n e st u d y, t h e m e di a n 6 M W D w as a p pr o xi m at el y 5 8 0
m f or 1 1 7 h e alt h y m e n a n d 5 0 0 m f or 1 7 3 h e alt h y w o m e n ( 5 0).
A m e a n 6 M W D of 6 3 0 m w as r e p ort e d b y a n ot h er st u d y of 5 1
h e alt h y ol d er a d ults ( 5 5). Diff er e nc es i n t h e p o p ul ati o n s a m-
pl e d, t y p e a n d fr e q u e nc y of e nc o ur a g e m e nt, c orri d or l e n gt h,
a n d n u m b er of pr actic e t ests m a y acc o u nt f or r e p ort e d diff er-
e nc es i n m e a n 6 M W D i n h e alt h y p ers o ns. A g e, h ei g ht, w ei g ht,
a n d  s e x  i n d e p e n d e ntl y  aff ect  t h e  6 M W D  i n  h e alt h y  a d ults;
t h er ef or e,  t h es e  f act ors  s h o ul d  b e  t a k e n  i nt o  c o nsi d er ati o n
w h e n i nt er pr eti n g t h e r es ults of si n gl e m e as ur e m e nts m a d e t o
d et er mi n e f u ncti o n al st at us. W e e nc o ur a g e i n v esti g at ors t o p u b-
lis h r ef er e nc e e q u ati o ns f or h e alt h y p ers o ns usi n g t h e pr e vi-
o usl y m e nti o n e d st a n d ar diz e d pr oc e d ur es.
A l o w 6 M W D is n o ns p ecific a n d n o n di a g n ostic. W h e n t h e
6 M W D is r e d uc e d, a t h or o u g h s e arc h f or t h e c a us e of t h e i m-
p air m e nt is w arr a nt e d. T h e f oll o wi n g t ests m a y t h e n b e h el p-
f ul: p ul m o n ar y f u ncti o n, c ar di ac f u ncti o n, a n kl e – ar m i n d e x,
m uscl e str e n gt h, n utriti o n al st at us, ort h o p e dic f u ncti o n, a n d
c o g niti v e f u ncti o n.
 
C o n cl usi o ns
 
T h e 6 M W T is a us ef ul m e as ur e of f u ncti o n al c a p acit y t ar g et e d
at p e o pl e wit h at l e ast m o d er at el y s e v er e i m p air m e nt. T h e t est
h as b e e n wi d el y us e d f or pr e o p er ati v e a n d p ost o p er ati v e e v al-
u ati o n a n d f or m e as uri n g t h e r es p o ns e t o t h er a p e utic i nt er-
v e nti o ns f or p ul m o n ar y a n d c ar di ac dis e as e. T h es e g ui d eli n es
pr o vi d e a st a n d ar diz e d a p pr o ac h t o p erf or mi n g t h e 6 M W T.
T h e c o m mitt e e h o p es t h at t h es e g ui d eli n es will e nc o ur a g e f ur-
t h er r es e arc h i nt o t h e 6 M W T a n d all o w dir ect c o m p aris o ns
a m o n g diff er e nt st u di es.
 
T his st at e m e nt w as d e v el o p e d b y t h e A T S C o m mitt e e o n Pr ofi ci e n c y St a n-
d ar ds f or Cli ni c al P ul m o n ar y F u n cti o n L a b or at ori es.
M e m b ers of t h e c o m mitt e e ar e:
R
 
O B E R T
 
 O. C
 
R A P O
 
, M. D., 
 
C h air
 
*
R
 
I C H A R D
 
 C
 
A S A B U RI
 
, P
 
H
 
. D, M. D.
A
 
L L A N
 
 L. C
 
O A T E S
 
, M. D.
P
 
A U L
 
 L. E
 
N RI G H T
 
, M. D.*
N
 
EI L
 
 R. M
 
A C
 
I
 
N T Y R E
 
, M. D.
R
 
O Y
 
 T. M
 
C
 
K
 
A Y
 
, P
 
H
 
. D.
D
 
O U G L A S
 
 J
 
O H N S O N
 
, M. D.
J
 
A C K
 
 S. W
 
A N G E R
 
, M. S.
R. J
 
O R G E
 
 Z
 
E B A L L O S
 
, M. D.*
A d H o c C o m mitt e e m e m b ers ar e:
V
 
E R A
 
 B
 
I T T N E R
 
, M. D.
C
 
A R L
 
 M
 
O T T R A M
 
, R. R. T.
* Writi n g C o m mitt e e M e m b ers
 
R ef er e n c es
 
1.  W ass er m a n K, H a ns e n J E, S u e D Y, C as a b uri R, W hi p p BJ. Pri nci pl es of
e x ercis e t esti n g a n d i nt er pr et ati o n, 3r d e diti o n. P hil a d el p hi a: Li p pi n-
c ott, Willi a ms & Wil ki ns; 1 9 9 9.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 0

 
1 1 6
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
2.  W eis m a n I M, Z e b all os RJ. A n i nt e gr at e d a p pr o ac h t o t h e i nt er pr et ati o n
of c ar di o p ul m o n ar y e x ercis e t esti n g. 
 
Cli n C hest Me d
 
 1 9 9 4; 1 5: 4 2 1 – 4 4 5.
3. Fl etc h er G F, B al a d y G, Fr o elic h er V F, H artl e y L H, H as k ell W L, P ol-
l oc k M L. E x ercis e st a n d ar ds: a st at e m e nt f or h e alt hc ar e pr of essi o n als
fr o m t h e A m eric a n H e art Ass oci ati o n: writi n g gr o u p. 
 
Circ ul ati o n
 
 1 9 9 5;
9 1: 5 8 0 – 6 1 5.
4. Pi n a I L, B al a d y GJ, H a ns o n P, L a b o vitz AJ, M a d o n n a D W, M y ers J. G ui d e-
li n es f or cli nic al e x ercis e t esti n g l a b or at ori es: a st at e m e nt f or h e alt hc ar e
pr of essi o n als fr o m t h e C o m mitt e e o n E x ercis e a n d C ar di ac R e h a bilit a-
ti o n, A m eric a n H e art Ass oci ati o n. 
 
Circ ul ati o n
 
 1 9 9 5; 9 1: 9 1 2 – 9 2 1.
5.  B al k e B. A si m pl e fi el d t est f or t h e ass ess m e nt of p h ysic al fit n ess. 
 
C A RI
Re p ort
 
 1 9 6 3; 6 3: 1 8.
6.  C o o p er K H. A m e a ns of ass essi n g m a xi m al o x y g e n i nt a k e: c orr el ati o n
b et w e e n fi el d a n d tr e a d mill t esti n g. 
 
J A M A
 
 1 9 6 8; 2 0 3: 2 0 1 – 2 0 4.
7.  Mc G a vi n C R, G u pt a S P, Mc H ar d y GJ R. T w el v e- mi n ut e w al ki n g t est f or
ass essi n g dis a bilit y i n c hr o nic br o nc hitis. 
 
B MJ
 
 1 9 7 6; 1: 8 2 2 – 8 2 3.
8.  B utl a n d RJ A, P a n g J, Gr oss E R, W o o dc oc k A A, G e d d es D M. T w o-,
si x-, a n d 1 2- mi n ut e w al ki n g t ests i n r es pir at or y dis e as e. 
 
B MJ
 
 1 9 8 2;
2 8 4: 1 6 0 7 – 1 6 0 8.
9. S ol w a y S, Br o o ks D, L ac ass e Y, T h o m as S. A q u alit ati v e s yst e m atic
o v er vi e w of t h e m e as ur e m e nt pr o p erti es of f u ncti o n al w al k t ests us e d
i n t h e c ar di or es pir at or y d o m ai n. 
 
C hest
 
 2 0 0 1; 1 1 9: 2 5 6 – 2 7 0.
1 0.  K a di k ar A, M a ur er J, K est e n S. T h e si x- mi n ut e w al k t est: a g ui d e t o as-
s ess m e nt f or l u n g tr a ns pl a nt ati o n. 
 
J He art L u n g Tr a ns pl a nt
 
 1 9 9 7; 1 6:
3 1 3 – 3 1 9.
1 1.  H ol d e n D A, Ric e T W, St el m ac h K, M e e k er D P. E x ercis e t esti n g, 6 mi n
w al k, a n d st air cli m b i n t h e e v al u ati o n of p ati e nts at hi g h ris k f or p ul-
m o n ar y r es ecti o n. 
 
C hest
 
 1 9 9 2; 1 0 2: 1 7 7 4 – 1 7 7 9.
1 2. Sci ur b a F C, R o g ers R M, K e e n a n RJ, Sli v k a W A, G orcs a n J 3r d, F ers o n
P F, H ol b ert J M, Br o w n M L, L a n dr e n e a u RJ. I m pr o v e m e nt i n p ul m o-
n ar y f u ncti o n a n d el astic r ec oil aft er l u n g-r e d ucti o n s ur g er y f or diff us e
e m p h ys e m a. 
 
N E n gl J Me d
 
 1 9 9 6; 3 3 4: 1 0 9 5 – 1 0 9 9.
1 3.  Cri n er GJ, C or d o v a F C, F ur u k a w a S, K uz m a A M, Tr a v ali n e J M, L e y e n-
s o n V, O’ Bri e n G M. Pr os p ecti v e r a n d o miz e d tri al c o m p ari n g bil at er al
l u n g v ol u m e r e d ucti o n s ur g er y t o p ul m o n ar y r e h a bilit ati o n i n s e v er e
C O P D. 
 
A m J Res pir Crit C are Me d
 
 1 9 9 9; 1 6 0: 2 0 1 8 – 2 0 2 7.
1 4. Si ncl air DJ M, I n gr a m C G. C o ntr oll e d tri al of s u p er vis e d e x ercis e tr ai n-
i n g i n c hr o nic br o nc hitis. 
 
B MJ
 
 1 9 8 0; 2 8 0: 5 1 9 – 5 2 1.
1 5.  R o o mi J, J o h ns o n M M, W at ers K, Y o h a n n es A, H el m A, C o n n oll y MJ.
R es pir at or y  r e h a bilit ati o n,  e x ercis e  c a p acit y  a n d  q u alit y  of  lif e  i n
c hr o nic air w a ys dis e as e i n ol d a g e. 
 
A ge A gei n g
 
 1 9 9 6; 2 5: 1 2 – 1 6.
1 6. P a g gi ar o P L, D a hl e R, B a kr a n I, Frit h L, H olli n g w ort h K, Eft hi mi o u J.
M ultic e ntr e  r a n d o mis e d  pl ac e b o-c o ntr oll e d  tri al  of  i n h al e d  fl utic a-
s o n e pr o pi o n at e i n p ati e nts wit h C O P D. 
 
L a ncet
 
 1 9 9 8; 3 5 1: 7 7 3 – 7 8 0.
1 7. L e g g ett RJ, Fl e nl e y D C. P ort a bl e o x y g e n a n d e x ercis e t ol er a nc e i n p a-
ti e nts wit h c hr o nic h y p o xic c or p ul m o n al e. 
 
B MJ
 
 1 9 7 7; 2: 8 4 – 8 6.
1 8. S p e nc e D P S, H a y J G, C art er J, P e ars o n M G, C al v erl e y P M A. O x y g e n
d es at ur ati o n a n d br e at hl ess n ess d uri n g c orri d or w al ki n g i n C O P D: ef-
f ect of o xitr o pi u m br o mi d e. 
 
T h or a x
 
 1 9 9 3; 4 8: 1 1 4 5 – 1 1 5 0.
1 9.  D e B oc k V, M ets T, R o m a g n oli M, D er d e M P. C a pt o pril tr e at m e nt of
c hr o nic h e art f ail ur e i n t h e v er y ol d. 
 
J Ger o nt ol
 
 1 9 9 4; 4 9: M 1 4 8 – M 1 5 2.
2 0.  O’ K e eff e S T, L y e M, D o n n n ell a n C, C ar mic h a el D N. R e pr o d uci bilit y
a n d r es p o nsi v e n ess of q u alit y of lif e ass ess m e nt a n d si x mi n ut e w al k
t est i n el d erl y h e art f ail ur e p ati e nts. 
 
He art
 
 1 9 9 8; 8 0: 3 7 7 – 3 8 2.
2 1.  B er nst ei n M L, D es p ars J A, Si n g h N P, A v al os K, St a ns b ur y D W, Li g ht
R W. R e- a n al ysis of t h e 1 2 mi n ut e w al k i n p ati e nts wit h C O P D. 
 
C hest
 
1 9 9 4; 1 0 5: 1 6 3 – 1 6 7.
2 2.  H ajir o T, Nis hi m ur a K, Ts u ki n o M, I k e d a A, K o y a m a H, Iz u mi T. A n al-
ysis  of  cli nic al  m et h o ds  us e d  t o  e v al u at e  d ys p n e a  i n  p ati e nts  wit h
C O P D. 
 
A m J Res pir Crit C are Me d
 
 1 9 9 8; 1 5 8: 1 1 8 5 – 1 1 8 9.
2 3.  G ul m a ns V A M, v a n V el d h o v e n N H MJ, d e M e er K, H el d ers PJ M. T h e
si x- mi n ut e w al ki n g t est i n c hil dr e n wit h c ystic fi br osis: r eli a bilit y a n d
v ali dit y. 
 
Pe di atr P ul m o n ol
 
 1 9 9 6; 2 2: 8 5 – 8 9.
2 4.  Ni x o n P A, J os wi a k M L, Fric k er FJ. A si x- mi n ut e w al k t est f or ass essi n g
e x ercis e t ol er a nc e i n s e v er el y ill c hil dr e n. 
 
J Pe di atr
 
 1 9 9 6; 1 2 9: 3 6 2 – 3 6 6.
2 5.  Bitt n er V. Si x- mi n ut e w al k t est i n p ati e nts wit h c ar di ac d ysf u ncti o n. 
 
C ar-
di ol o gi a
 
 1 9 9 7; 4 2: 8 9 7 – 9 0 2.
2 6. P e et ers P, M ets T. T h e 6 mi n ut e w al k as a n a p pr o pri at e e x ercis e t est i n
el d erl y  p ati e nts  wit h  c hr o nic  h e art  f ail ur e.  
 
J  Ger o nt ol
 
 1 9 9 6; 5 1 A:
M 1 4 7 – M 1 5 1.
2 7.  Z u gc k  C,  Kr u g er  C,  D urr  S,  G er b er  S H,  H a u nst ett er  A,  H or ni g  K,
K u bl er W, H a ass M. Is t h e 6- mi n ut e w al k t est a r eli a bl e s u bstit ut e f or
p e a k  o x y g e n  u pt a k e  i n  p ati e nts  wit h  dil at e d  c ar di o m y o p at h y ?  
 
E ur
He art J
 
 2 0 0 0; 2 1: 5 4 0 – 5 4 9.
2 8.  M o nt o g o m er y P S, G ar d n er A W. T h e cli nic al utilit y of a si x- mi n ut e w al k
t est i n p eri p h er al art eri al occl usi v e dis e as e p ati e nts. 
 
J A m Geri atr S oc
 
1 9 9 8; 4 6: 7 0 6 – 7 1 1.
 
2 9.  C a h a n M A, M o nt g o m er y P, Otis R B, Cl a nc y R, Fli n n W, G ar d n er A.
T h e eff ect of ci g ar ett e s m o ki n g st at us o n si x- mi n ut e w al k dist a nc e i n
p ati e nts wit h i nt er mitt e nt cl a u dic ati o n. 
 
A n gi ol o g y
 
 1 9 9 9; 5 0: 5 3 7 – 5 4 6.
3 0.  Ki n g S, W ess el J, B h a m b h a ni Y, M ai k al a R, S h olt er D, M a ks y m o w yc h
W. V ali dit y a n d r eli a bilit y of t h e 6 mi n ut e w al k i n p ers o ns wit h fi br o-
m y al gi a. J R he u m at ol 1 9 9 9; 2 6: 2 2 3 3 – 2 2 3 7.
3 1.  E nri g ht P L, Mc B ur ni e M A, Bitt n er V, Tr ac y R P, Mc N a m ar a R, N e w-
m a n A B, t h e C ar di o v asc ul ar H e alt h St u d y. T h e si x mi n ut e w al k t est: a
q uic k m e as ur e of f u ncti o n al st at us i n el d erl y a d ults. C hest  (I n pr ess)
3 2.  Bitt n er V, W ei n er D H, Y us uf S, R o g ers WJ, McI nt yr e K M, B a n g di w al a
SI, Kr o n e n b er g M W, K ostis J B, K o h n R M, G uill ott e M, et al. Pr e dic-
ti o n of m ort alit y a n d m or bi dit y wit h a 6- mi n ut e w al k t est i n p ati e nts
wit h l eft v e ntric ul ar d ysf u ncti o n. J A M A 1 9 9 3; 2 7 0: 1 7 0 2 – 1 7 0 7.
3 3.  C a h ali n L P, M at hi er M A, S e mi gr a n MJ, D ec G W, Di S al v o T G. T h e si x-
mi n ut e w al k t est pr e dicts p e a k o x y g e n u pt a k e a n d s ur vi v al i n p ati e nts
wit h a d v a nc e d h e art f ail ur e. C hest  1 9 9 6; 1 1 0: 3 2 5 – 3 3 2.
3 4.  C ot e C G, C elli B R. I n p ati e nts wit h C O P D, t h e 6 mi n ut e w al ki n g dis-
t a nc e is a b ett er pr e dict or of h e alt h c ar e utiliz ati o n t h a n F E V 1, bl o o d
g as es, a n d d ys p n e a [ a bstr act]. E ur Res pir J  1 9 9 8; 3 8 3.
3 5.  K essl er R, F all er M, F o ur g a ut G, M e n n eci er B, W eitz e n bl u m E. Pr e dic-
ti v e f act ors of h os pit aliz ati o n f or ac ut e e x ac er b ati o n i n a s eri es of 6 4
p ati e nts wit h c hr o nic o bstr ucti v e p ul m o n ar y dis e as e. A m J Res pir Crit
C are Me d  1 9 9 9; 1 5 9: 1 5 8 – 1 6 4.
3 6.  C a h ali n L, P a p p a gi a n o p o ul os P, Pr e v ost S, W ai n J, Gi n ns L. T h e r el ati o n-
s hi p of t h e 6- mi n w al k t est t o m a xi m al o x y g e n c o ns u m pti o n i n tr a ns-
pl a nt c a n di d at es wit h e n d-st a g e l u n g dis e as e. C hest  1 9 9 5; 1 0 8: 4 5 2 – 4 5 9.
3 7.  G u y att  G H,  T h o m ps o n  PJ,  B er m a n  L B,  S ulli v a n  MJ,  T o w ns e n d  M,
J o n es N L, P u gsl e y S O. H o w s h o ul d w e m e as ur e f u ncti o n i n p ati e nts
wit h c hr o nic h e art a n d l u n g dis e as e ? J C hr o nic Dis 1 9 8 5; 3 8: 5 1 7 – 5 2 4.
3 8.  G u y att G H, T o w ns e n d M, K ell er J, Si n g er J, N o gr a di S. M e as uri n g f u nc-
ti o n al st at us i n c hr o nic l u n g dis e as e: c o ncl usi o ns fr o m a r a n d o m c o n-
tr ol tri al. Res pir Me d  1 9 9 1; 8 5( S u p pl B): 1 7 – 2 1.
3 9.  Ni e d er m a n M S, Cl e m e nt e P H, F ei n A M, F ei nsil v er S H, R o bi ns o n D A,
Il o wit e J S, B er nst ei n M G. B e n efits of a m ulti disci pli n ar y p ul m o n ar y
r e h a bilit ati o n pr o gr a m: i m pr o v e m e nts ar e i n d e p e n d e nt of l u n g f u nc-
ti o n. C hest  1 9 9 1; 9 9: 7 9 8 – 8 0 4.
4 0.  N os e d a A, C ar pi a u x J, Pri g o gi n e T, Sc h m er b er J. L u n g f u ncti o n, m a xi-
m u m a n d s u b m a xi m u m e x ercis e t esti n g i n C O P D p ati e nts: r e pr o d uc-
i bilit y o v er a l o n g i nt er v al. L u n g  1 9 8 9; 1 6 7: 2 4 7 – 2 5 7.
4 1.  K n o x AJ, M orris o n J F, M u ers M F. R e pr o d uci bilit y of w al ki n g t est r e-
s ults i n c hr o nic o bstr ucti v e air w a ys dis e as e. T h or a x  1 9 8 8; 4 3: 3 8 8 – 3 9 2.
4 2.  G u y att G H, P u gsl e y S O, S ulli v a n MJ, T h o m ps o n PJ, B er m a n L B, J o n es
N L, F all e n E L, T a yl or D W. Eff ect of e nc o ur a g e m e nt o n w al ki n g t est
p erf or m a nc e. T h or a x  1 9 8 4; 3 9: 8 1 8 – 8 2 2.
4 3. L e g er L A. A m a xi m al m ultist a g e 2 0- m s h uttl e r u n t est t o pr e dict V O 2
m a x. E ur J A p pl P h ysi ol  1 9 8 2; 4 9: 1 – 1 2.
4 4. Si n g h SJ, M or g a n M D L, Sc ott S, W alt ers D, H ar d m a n A E. D e v el o p-
m e nt of a s h uttl e w al ki n g t est of dis a bilit y i n p ati e nts wit h c hr o nic air-
w a ys o bstr ucti o n. T h or a x  1 9 9 2; 4 7: 1 0 1 9 – 1 0 2 4.
4 5.  R e vill S M, M or g a n M D L, Si n g h SJ, Willi a ms J, H ar d m a n A E. T h e e n d ur-
a nc e s h uttl e w al k: a n e w fi el d t est f or t h e ass ess m e nt of e n d ur a nc e c a p ac-
it y i n c hr o nic o bstr ucti v e p ul m o n ar y dis e as e. T h or a x  1 9 9 9; 5 4: 2 1 3 – 2 2 2.
4 6. Si n g h SJ, M or g a n M D L, H ar d m a n A E, R o w e C, B ar dsl e y P A. C o m p ar-
is o n of o x y g e n u pt a k e d uri n g a c o n v e nti o n al tr e a d mill t est a n d t h e
s h uttl e w al ki n g t est i n c hr o nic airfl o w li mit ati o n. E ur Res pir J  1 9 9 4; 7:
2 0 1 6 – 2 0 2 0.
4 7.  M or al es FJ, M arti n ez A, M e n d ez M, A g arr a d o A, Ort e g a F, F er n a n d ez-
G u err a J, M o nt e m a y or T, B ur g os J. A s h uttl e w al k t est f or ass ess m e nt of
f u ncti o n al c a p acit y i n c hr o nic h e art f ail ur e. A m He art J  1 9 9 9; 1 3 8: 2 9 2 – 2 9 8.
4 8.  E nri g ht P L, S h errill D L. R ef er e nc e e q u ati o ns f or t h e si x- mi n ut e w al k i n
h e alt h y a d ults. A m J Res pir Crit C are Me d  1 9 9 8; 1 5 8: 1 3 8 4 – 1 3 8 7.
4 9.  B arst RJ, R u bi n LJ, Mc G o o n M D, C al d w ell EJ. L o n g W A, L e v y P S.
S ur vi v al i n pri m ar y p ul m o n ar y h y p ert e nsi o n wit h l o n g-t er m c o nti n u-
o us i ntr a v e n o us pr ost ac ycli n. A n n I nter n Me d  1 9 9 4; 1 2 1: 4 0 9 – 4 1 5.
5 0. Mi y a m ot o S, N a g a y a N, S at o h T, K y ot a ni S, S a k a m a ki F, F ujit a M, N a-
k a nis hi N, Mi y at a k e K. Cli nic al c orr el at es a n d pr o g n ostic si g nific a nc e
of si x- mi n ut e w al k t est i n p ati e nts wit h pri m ar y p ul m o n ar y h y p ert e n-
si o n. A m J Res pir Crit C are Me d  2 0 0 0; 1 6 1: 4 8 7 – 4 9 2.
5 1.  G u y att G H, S ulli v a n MJ, T h o m ps o n PJ, F all e n E L, P u gsl e y S O, T a yl or
D W, B er m a n L B. T h e 6- mi n ut e w al k: a n e w m e as ur e of e x ercis e c a-
p acit y i n p ati e nts wit h c hr o nic h e art f ail ur e. C a n Me d Ass oc J  1 9 8 5;
1 3 2: 9 1 9 – 9 2 3.
5 2. Li p ki n D P, Scri vi n AJ, Cr a k e T, P o ol e- Wils o n P A. Si x mi n ut e w al ki n g
t est f or ass essi n g e x ercis e c a p acit y i n c hr o nic h e art f ail ur e. B MJ  1 9 8 6;
2 9 2: 6 5 3 – 6 5 5.
5 3. Tr o ost ers T, G oss eli n k R, D ecr a m er M. Si x mi n ut e w al ki n g dist a nc e i n
h e alt h y el d erl y s u bj ects. E ur Res pir J  1 9 9 9; 1 4: 2 7 0 – 2 7 4.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 1

A m eri c a n T h or a ci c S o ci et y
1 1 7
5 4.  W eiss R A, et al. Si x mi n ut e w al k t est i n s e v er e C O P D: r eli a bilit y a n d ef-
f ect of w al ki n g c o urs e l a y o ut a n d l e n gt h. P a p er pr es e nt e d at A C C P
C o nf er e nc e; S e pt e m b er 2 0 0 0; S a n Fr a ncisc o.
5 5. St e v e ns D, El p er n E, S h ar m a K, Szi d o n P, A n ki n M, K est e n S. C o m p ar-
is o n of h all w a y a n d tr e a d mill si x- mi n ut e w al k t ests. A m J Res pir Crit
C are Me d  1 9 9 9; 1 6 0: 1 5 4 0 – 1 5 4 3.
5 6. J e ns e n L A, O n ys ki w J E, Pr as a d N G N. M et a- a n al ysis of art eri al o x y g e n
s at ur ati o n m o nit ori n g b y p uls e o xi m etr y i n a d ults. He art L u n g  1 9 9 8;
2 7: 3 8 7 – 4 0 8.
5 7.  B art h el e m y J C, G e yss a nt A, Riff at J, A nt o ni a dis A, B err u y er J, L a C o ur
J R. Acc ur ac y of p uls e o xi m etr y d uri n g m o d er at e e x ercis e: a c o m p ar a-
ti v e st u d y. Sc a n d J Cli n L a b I n vest  1 9 9 0; 5 0: 5 3 3 – 5 3 9.
5 8.  B or g G A V. Ps yc h o- p h ysic al b as es of p erc ei v e d e x erti o n. Me d Sci S p orts
E xerc  1 9 8 2; 1 4: 3 7 7 – 3 8 1.
5 9. L e ac h R M, D a vi ds o n A C, C hi n n S, T w ort C H C, C a m er o n I R, B at e m e n
N T. P ort a bl e li q ui d o x y g e n a n d e x ercis e a bilit y i n s e v er e r es pir at or y
dis a bilit y. T h or a x  1 9 9 2; 4 7: 7 8 1 – 7 8 9.
6 0.  M u n g all I P F, H ai ns w ort h R. Ass ess m e nt of r es pir at or y f u ncti o n i n p a-
ti e nts wit h c hr o nic o bstr ucti v e air w a ys dis e as e. T h or a x  1 9 7 9; 3 4: 2 5 4 – 2 5 8.
6 1.  R o b erts C M, B ell J, W e dzic h a J A. C o m p aris o n of t h e effic ac y of a d e-
m a n d o x y g e n d eli v er y s yst e m wit h c o nti n u o us l o w fl o w o x y g e n i n s u b-
j ects wit h st a bl e C O P D a n d s e v er e o x y g e n d es at ur ati o n o n w al ki n g.
T h or a x  1 9 9 6; 5 1: 8 3 1 – 8 3 4.
6 2.  H a y  J G,  St o n e  P,  C art er  J,  C h urc h  S,  E yr e- Br o o k  A,  P e ars o n  M G,
W o o dc oc k A A, C al v erl e y P M. Br o nc h o dil at or r e v ersi bilit y, e x ercis e
p erf or m a nc e a n d br e at hl ess n ess i n st a bl e c hr o nic o bstr ucti v e p ul m o-
n ar y dis e as e. E ur Res pir J  1 9 9 2; 5: 6 5 9 – 6 6 4.
6 3.  Gr o v e A, Li p w ort h BJ, R ei d P, S mit h R P, L a m a g e L, I n gr a m C G, J e n ki ns
RJ, Wi nt er J H, D hill o n D P. Eff ects of r e g ul ar s al m et er ol o n l u n g f u ncti o n
a n d e x ercis e c a p acit y i n p ati e nts wit h C O P D. T h or a x  1 9 9 6; 5 1: 6 8 9 – 6 9 3.
6 4.  R e d el m ei er D A, B a y o u mi A M, G ol dst ei n R S, G u y att G H. I nt er pr eti n g
s m all diff er e nc es i n f u ncti o n al st at us: T h e si x mi n ut e w al k t est i n c hr o nic
l u n g dis e as e p ati e nts. A m J Res pir Crit C are Me d  1 9 9 7; 1 5 5: 1 2 7 8 – 1 2 8 2.
6 5.  W ei n er P, M a g a dl e R, B er ar- Y a n a y N, D a vi d o vic h A, W ei n er M. T h e
c u m ul ati v e  eff ect  of  l o n g- acti n g  br o nc h o dil at ors,  e x ercis e,  a n d  i n-
s pir at or y  m uscl e  tr ai ni n g  o n  t h e  p erc e pti o n  of  d ys p n e a  i n  p ati e nts
wit h a d v a nc e d C O P D. C hest  2 0 0 0; 1 1 8: 6 7 2 – 6 7 8.
6 6.  Bitt n er V, S a n d ers o n B, Br el a n d J, A d a ms C, Sc h u m a n C. Ass essi n g
f u ncti o n al c a p acit y as a n o utc o m e i n c ar di ac r e h a bilit ati o n: r ol e of t h e
6 mi n ut e w al k t est. Cli nic al E xercise P h ysi ol o g y 2 0 0 0.
A P P E N DI X
T h e f oll o wi n g el e m e nts s h o ul d b e pr es e nt o n t h e 6 M W T w or ks h e et a n d r e p ort:
L a p c o u nt er: 
_ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _
P ati e nt n a m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
P ati e nt I D # _ _ _ _ _ _ _ _ _ _ _
W al k # _ _ _ _ _ _ 
T ec h I D: _ _ _ _ _ _ _ _ _  D at e: _ _ _ _ _ _ _ _ _ _
G e n d er:  M F  
A g e: _ _ _ _  
R ac e: _ _ _ _  
H ei g ht: _ _ _ft _ _ _ _i n, _ _ _ _ m et ers
W ei g ht: _ _ _ _ _ _ l bs, _ _ _ _ _ k g  
Bl o o d pr ess ur e: _ _ _ _ _ / _ _ _ _ _
M e dic ati o ns t a k e n b ef or e t h e t est ( d os e a n d ti m e): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S u p pl e m e nt al o x y g e n d uri n g t h e t est:  N o  
Y es, fl o w _ _ _ _ _ _ L/ mi n, t y p e _ _ _ _ _
B as eli n e  
E n d of T est
Ti m e 
_ _ _: _ _ _
_ _ _: _ _ _
H e art R at e _ _ _ _ _
_ _ _ _ _
D ys p n e a 
_ _ _ _
_ _ _ _ ( B or g sc al e)
F ati g u e 
_ _ _ _
_ _ _ _ ( B or g sc al e)
S p O 2
_ _ _ _ %
_ _ _ _ %
St o p p e d or p a us e d b ef or e 6 mi n ut es ?  N o  
Y es, r e as o n: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Ot h er s y m pt o ms at e n d of e x ercis e: a n gi n a 
dizzi n ess 
hi p, l e g, or c alf p ai n
N u m b er of l a ps: _ _ _ _ (
6 0 m et ers) 
 fi n al p arti al l a p: _ _ _ _ _ m et ers
T ot al dist a nc e w al k e d i n 6 mi n ut es: _ _ _ _ _ _ m et ers
Pr e dict e d dist a nc e: _ _ _ _ _ m et ers 
P erc e nt pr e dict e d: _ _ _ _ _ %
T ec h c o m m e nts:
I nt er pr et ati o n (i ncl u di n g c o m p aris o n wit h a pr ei nt er v e nti o n 6 M W D):
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 2

Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
Versi o n 3. 0 
6 3   
2 0.  
A P P E N DI X 2: F U N C TI O N A L C L A S SI FI C A TI O N O F 
P U L M O N A R Y H Y P E R T E N SI O N M O DI FI E D A F T E R T H E N E W 
Y O R K H E A R T A S S O CI A TI O N F U N C TI O N A L 
C L A S SI FI C A TI O N A C C O R DI N G T O T H E W H O 1 9 9 8 
(G A LI E, 2 0 0 9 ) 
W orl d He alt h Or g a niz ati o n f u ncti o n al assess me nt cl assific ati o n   
Cl ass 
I:  
Patie nts wit h p ul m o nar y h y perte nsi o n ( P H)  b ut wit h o ut res ulti n g li mitati o n of p h ysic al 
acti vit y. Or di n ar y p h ysic al acti vit y d oes n ot ca use u n d ue d ys p n ea or fati g u e, c hes t pai n, 
or near s y n c o pe.  
Cl ass 
II:  
Patie nts  wit h P H res ulti n g i n sli g ht li mitati o n of p h ysical acti vit y. T h e y are c o mf orta ble 
at rest. Or di nar y p h ysical acti vit y ca uses u n d ue d ys p nea or fati g u e, c hest p ai n, or near 
s y nc o p e. 
Cl ass 
III:  
Patie nts  wit h P H res ulti n g i n mar ke d li mitati o n of p h ysical acti vit y. T h e y are 
c o mf orta ble at rest. Less t ha n or di nar y acti vit y ca uses u n d ue d ys p nea or fati g ue, c h est 
pai n, or near s y nc o pe.  
Cl ass 
I V:  
Patie nts  wit h P H 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 patie nts  ma nifest si g ns of ri g ht -h eart fail ure. D ys p n ea a n d/ or fati g ue ma y e ve n be 
prese nt at rest. Disc o mf ort is i ncrease d b y a n y p h ysical acti vit y.  

Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
Versi o n 3. 0 
6 4   
2 1.  
A P P E N DI X 3:  B O R G C R 1 0 S C A L E