A Phase 2 Trial of the Safety and Efficacy of Bardoxolone Methyl in Patients With Rare Chronic Kidney Diseases
Phase: PHASE2
Conditions: IgA Nephropathy, CKD Associated With Type 1 Diabetes, Focal Segmental Glomerulosclerosis, Autosomal Dominant Polycystic Kidney
Sponsor: Biogen

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A P H A S E 2 T RI A L O F T H E S A F E T Y A N D E F FI C A C 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 
R A R E C H R O NI C KI D N E Y DI S E A S E S  
V E R SI O N 1. 0  – 1 7 A U G U S T 2 0 1 7  
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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 r ecei ve d a n d r ea 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 7 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 ntialit y of all i nf or mati o n recei 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 m er ge nc y C o nt act 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 
  
 
 
 
 
 
 
 

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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 P hase 2 Tria l of t he Safet y a n d Efficac y of Bar d o x ol o ne Met h yl in Patie nts w it h Rare C hr o nic 
Ki d ne y Diseases  
St u d y ce nter(s):  U p t o 6 0 st u d y ce nters  
St u die d peri o d:  1 year 
Esti mate d date first patie nt e nr olle d: Dece m ber 2 0 1 7 
Esti mate d date last patie nt c o m plete d: De ce m ber 2 0 1 8 
P h ase of de vel o p me nt:  
2 
O bjecti ves:   
F or patie nts wit hi n eac h rare c hr o nic ki d ne y disease ( C K D) c o h ort e nr olle d i n t his st u d y, t he pri mar y 
o bjecti ves are as f oll o ws:  
•  
T o assess t he c ha n ge fr o m baseli ne i n esti mate d gl o mer ular filtrati o n rate (e G F R) i n 
bar d o x ol o ne met h yl -treate d patie nts after 1 2 wee ks of treat me nt. 
•  
T o assess t he safet y of bar d o x ol o ne met h yl after 1 2 wee ks of treat me nt.  
Met h o d ol o g y:  
T his m ulti -ce nter, o pe n -la bel P hase 2 trial will st u d y t he safet y, t olera bilit y, a n d efficac y of 
bar d o x ol o ne met h yl i n q ualifie d patie nts wit h t he f oll o wi n g rare c hr o nic ki d ne y diseases  ( C K D): C K D 
ass ociate d wit h t y pe 1 dia betes ( T 1 D), I g A ne p hr o pat h y (I g A N), f ocal se g me ntal gl o mer ul oscler osis 
( F S G S), a n d a ut os o mal d o mi na nt p ol yc ystic ki d ne y disease ( A D P K D).  Patie nts will be e nr olle d i n 
disease s pecific c o h orts wit hi n t he trial, a n d effecti ve ness of bar d o x ol o ne met h yl i n treati n g C K D will 
be assesse d se paratel y b y c o h ort f or eac h rare C K D.  
P atie nts will recei ve bar d o x ol o ne met h yl  t hr o u g h o ut t he st u d y a n d the ma xi m u m bar d o x ol o ne met h yl 
d ose will be deter mi ne d b y baseli ne pr otei n uria stat us.  Patie nts wit h macr oal b u mi n uria 
( 3 0 0 m g / g < A C R ≤ 2 5 0 0 m g / g) at t he Scree n B visit will acc o u nt f or u p t o a p pr o xi matel y 5 0 % of 
patie nts e nr olle d wit hi n eac h c o h ort.  Patie nts wit h baseli ne A C R ≤ 3 0 0  m g/ g will be titrate d t o a 
ma xi m u m d ose of 2 0 m g, a n d patie nts wit h baseli ne A C R > 3 0 0 m g/ g will be t itrate d t o a ma xi m u m 
d ose of 3 0 m g.  Patie nts will start wit h o nce - dail y d osi n g at 5 m g a n d will d ose-escalate t o 1 0  m g at 
Wee k  2, t o 2 0  m g at Wee k 4, a n d t he n t o 3 0 m g at Wee k 6 ( o nl y if baseli ne A C R > 3 0 0  m g/ g) u nless 
c o ntrai n dicate d cli nicall y a n d a p pr o ve d b y 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 if i n dicate d cli nicall y, a n d s u bse q ue nt d ose re-escalati o n is als o per mitte d t o meet t he d osi n g 
o bjecti ve of t he hi g hest t olerate d d ose.  Please refer t o Secti o n  7. 3. 1  f or a d diti o nal details o n d ose 
escalati o n a n d 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 he d ule.  F oll o wi n g ra n d o mizati o n 
o n Da y 1 , patie nts will be sc he d ule d t o be assesse d d uri n g treat me nt at Wee ks 1, 2, 4, 6, 8, a n d 1 2, a n d 
b y tele p h o ne c o ntact o n Da ys 3, 1 0, 2 1, 3 1, 3 8, a n d 4 5 .  Patie nts will als o be sc he d ule d t o be assesse d 
at a n i n-pers o n f oll o w -u p visit at Wee k  1 6, f o ur wee ks after t he e n d of treat me nt. 

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N u m ber of p atie nts ( pl a n ne d):  
Eac h c o h ort will e nr oll a p pr o xi matel y 2 5 patie nts, f or a t otal of a p pr o xi matel y 1 0 0 patie nts i n t he trial.  
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
1.  Male a n d fe male patie nts  1 8 ≤ a ge ≤ 6 5 u p o n st u d y c o nse nt;  
2.  Scree ni n g e G F R (a vera ge of Scr ee n A a n d Scree n B e G F R val ues) ≥ 3 0 a n d 
≤ 9 0 m L/ mi n/ 1. 7 3 m2.  T he t w o e G F R val ues c ollecte d at Scree n  A a n d Scree n  B visits use d t o 
deter mi ne eli gi bilit y m ust ha ve a perce nt differe nce ≤ 2 5 %;  
3.  Al b u mi n t o creati ni ne rati o ( A C R) ≤ 2 5 0 0 m g / g at Scree n  B visit ; 
4.  If recei vi n g a n a n gi ote nsi n-c o n verti n g e nz y me ( A C E) i n hi bit or a n d/ or a n a n gi ote nsi n II 
rece pt or bl oc ker ( A R B), patie nts s h o ul d be prescri be d t he ma xi mall y t olerate d la bele d dail y 
d ose ( M T L D D), as defi ne d i n Secti o n  9. 1. 7 , f or at least 6 wee ks pri or t o t he Scree n A visit.  
T he d osa ge of A C E i n hi bit or a n d/ or A R B s h o ul d re mai n t he sa me t hr o u g h o ut t he re mai n der of 
t he st u d y (i.e., n o c ha n ge i n d osa ge or me dicati o n), a n d a n y p ote ntial c ha n ges s h o ul d be 
disc usse d wit h  t he me dical m o nit or.  Patie nts n ot ta ki n g a n A C E i n hi bit or a n d/ or A R B beca use 
of a me dical c o ntrai n dicati o n ma y be eli gi ble if t he y ha ve disc o nti n ue d treat me nt at least 
8 wee ks pri or t o t he Scree n  A visit (t hese patie nts m ust be disc usse d wit h  t he me dical m o nit or 
pri or t o e nr oll me nt) ; 
5.  F or patie nts e nr olli n g i n T 1 D C o h ort:  
a. Dia g n osis of t y pe 1 dia betes c o nfir me d b y fasti n g C - pe pti de le vel. Dia g n osis m ust 
ha ve bee n ma de ≤ 3 5 years of a ge ; 
b.  Prescri be d sta ble d ose of i ns uli n t o mai ntai n a de q uate gl uc ose c o ntr ol f or at least 
6 m o nt hs pri or t o t he Scree n A visit;  
6.  F or patie nts e nr olli n g i n I g A N C o h ort:  
a. Bi o ps y-c o nfir me d I g A ne p hr o pat h y; 
7.  F or patie nts e nr olli n g i n F S G S C o h ort: 
a. Bi o ps y-c o nfir me d F S G S t hat is n ot d ue t o k n o w n sec o n dar y ca uses i ncl u di n g m or bi d 
o besit y, decrease d re nal mass, viral i nfecti o ns, dr u g -i n d uce d ne p hr ot o xicit y, or pri or 
hist or y of vasc ulitis;  
8.  F or patie nts e nr olli n g i n A D P K D C o h ort:  
a. Ge netic c o nfir mati o n of P K D 1 m utati o n; 
9.  A de q uate b o ne marr o w reser ve a n d or ga n f u ncti o n at t he Scree n  A v isit as f oll o ws: 
a. He mat ol o gic: A bs ol ute ne utr o p hil c o u nt >  1. 5 x 1 0
9/ L, platelets > 1 0 0 x 1 0
9/ L, 
he m o gl o bi n ( H g b) ≥ 9 g/ d L;  
b.  He patic: T otal bilir u bi n  ( T B L) ≤ 1. 5 X t he u p per li mit of n or mal ( U L N), ala ni ne 
a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase  ( A S T) ≤ 1. 5 X U L N ; 
1 0.  A ble t o s wall o w ca ps ules; 
1 1.  Willi n g a n d a ble t o c o m pl y wit h sc h e d ule d visits, treat me nt pla n, la b orat or y tests, a n d ot her 
st u d y pr oce d ures; 
1 2.  E vi de nce of a pers o nall y si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat t he 
patie nt has bee n i nf or me d of all perti ne nt as pects of t he st u d y pri or t o i nitiati o n of a n y 
pr ot oc ol- ma n date d pr oce d ures.  
 

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M aj or e xcl usi o n criteri a:  
1.  Pri or e x p os ure t o bar d o x ol o ne met h yl; 
2.  Ki d ne y or a n y ot her s oli d or ga n tra ns pla nt reci pie nt or a pla n ne d tra ns pla nt d uri n g t he st u d y;  
3.  B-t y pe natri uretic pe pti de ( B N P) le vel > 2 0 0 p g/ m L at Scree n A visit;  
4.  Ac ute dial ysis or ac ute ki d ne y i nj ur y wit hi n 1 2 wee ks pri or t o  Scree n  A visit or d uri n g 
Scree ni n g; 
5.  Ser u m al b u mi n < 3 g/ d L at Scree n  A visit;  
6.  S yste mic i m m u n os u p pressi o n f or m ore t ha n 2 wee ks, c u m ulati vel y, wit hi n t he 1 2 wee ks pri or 
t o ra n d o mizati o n or a ntici pate d nee d f or i m m u n os u p pressi o n d uri n g t he st u d y.  Patie nts wit h 
I g A N or F S G S t hat are recei vi n g pre d nis o ne at d oses ≤ 1 0 m g/ da y are eli gi ble f or e nr oll me nt 
i n t he I g A N or F S G S c o h orts, b ut d oses m ust be sta ble f or 3 0 da ys pri or t o Scree n A visit a n d 
s h o ul d be a ntici pate d t o re mai n t he sa me t hr o u g h o ut t he st u d y.  Refer t o Secti o n  9. 3. 1  f or 
a d diti o nal details; 
7.  F or patie nts e nr olli n g i n I g A N C o h ort:  
a. S yste mic ma nifestati o ns of He n oc h -Sc h o nlei n p ur p ura wit hi n 1 year pri or t o Scree n A 
visit;  
b.  Ha ve use d beli m u ma b, ec uliz u ma b, or rit u xi ma b wit hi n 6 m o nt hs pri or t o Scree n A 
visit;  
8.  F or patie nts e nr olli n g i n A D P K D C o h ort:  
a. Recei vi n g tol va pta n;  
9.  Cere br o vasc ular e ve nt (str o ke, tra nsie nt isc he mic attac k) or a ne ur ys m wit hi n 6 m o nt hs pri or t o 
Scree n A visit or d uri n g Scree ni n g; 
1 0.  H ist or y of cli nicall y si g nifica nt left-si de d heart disease a n d/ or cli nicall y si g nifica nt car diac 
disease , i ncl u di n g b ut n ot li mite d t o a n y of t he f oll o wi n g: 
a. C li nicall y si g nifica nt co n ge nital or ac q uire d val v ular disease;  
b.  L eft ve ntric ular ejecti o n fracti o n  < 4 0 % ( base d o n ec h ocar di o gra m perf or me d at 
Scree n  A visit or wit hi n 6 m o nt hs  pri or t o Da y 1);  
c. Pericar dial c o nstricti o n ( base d o n ec h ocar di o gra m perf or me d at Scree n  A visit or 
wit hi n 6 m o nt hs  pri or t o Da y 1 ); 
d.  Restricti ve or c o n gesti ve car di o m y o pat h y ( base d o n ec h ocar di o gra m perf or me d at 
Scree n  A visit  or wit hi n 6 m o nt hs  pri or t o Da y 1 ); 
e. S y m pt o matic c or o nar y disease ( pri or m y ocar dial i nfarcti o n, perc uta ne o us c or o nar y 
i nter ve nti o n, c or o nar y arter y b y pass graft s ur ger y, or a n gi na); 
f. Hist or y of h o s pitalizati o n f or heart fail ure; 
g.  C ar diac i ns ufficie nc y, defi ne d as Ne w Y or k Heart Ass ociati o n Class >  2; 
h.  Hist or y of atrial fi brillati o n ; 
i. 
Hist or y of u nsta ble arr h yt h mias; 
1 1.  U nc o ntr olle d s yste mic h y perte nsi o n as e vi de nce d b y sitti n g s yst olic bl o o d press ure ( B P) 
> 1 6 0 m m H g or sitti n g diast olic B P  > 1 0 0 m m H g at Scree n A visit after a peri o d of rest; 
1 2.  S yst olic B P < 9 0 m m H g at Scree n A visit after a peri o d of rest; 
1 3.  Hist or y of mali g na nc y wit hi n 2 years pri or t o Scree n  A visit , wit h t he e xce pti o n of l ocalize d 
s ki n or cer vical carci n o mas; 
1 4.  U nc o ntr olle d dia betes ( H b A 1c >  1 0. 0 %) at Scree n A visit;  

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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 R are C hr o ni c Ki d ne y Dise ases  
 
S cr e e ni n g
D o s e -Titr ati o n P eri o d
W 2
W 1
W 8
Scr A
D 1
D 3
T
D 1 0
T
W 3
T
W 4
M ai nt e n a n c e
D 3 1
T
W 5
T
W 6
W 7
T
B A R D ( 5 m g)
B A R D ( 2 0 m g)
W 1 2
B A R D ( 1 0 m g)
P ri m ar y effic acy a n al ysis
O e G F R d et er mi n ati o n
T T el e p h o n e C o nt act
Scr B
B A R D ( 5 m g)
B A R D ( 2 0 m g)
B A R D ( 1 0 m g)
B A R D ( 3 0 m g)
B as eli n e A C R ≤ 3 0 0 m g / g
B as eli n e A C R > 3 0 0 m g / g
W 1 6
F/ U
Off 
St u dy 
Dr u g
 

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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.  
TI T L E P A G E  ................................................................................................................ 1 
S P O N S O R A P P R O V A L A N D SI G N A T U R E P A G E  ..................................................................... 2 
I N V E S TI G A T O R’ S A G R E E M E N T ............................................................................................... 3 
P R O C E D U R E S I N C A S E O F E M E R G E N C Y  ............................................................................... 4 
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  .................................................. 1 0 
T A B L E O F C O N T E N T S  ............................................................................................................... 1 0 
LI S T O F T A B L E S  ......................................................................................................................... 1 5 
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 6 
5.  
I N T R O D U C TI O N ...................................................................................................... 1 9 
5. 1.  
Cli nical E x perie nce wit h Bar d o x ol o ne Met h yl .......................................................... 2 0  
5. 1. 1.  
Efficac y  ....................................................................................................................... 2 1 
5. 1. 2.  
Safet y a n d T oler a bilit y  ............................................................................................... 2 4 
5. 1. 2. 1.  
Fl ui d O verl oa d ............................................................................................................ 2 4  
5. 1. 2. 2.  
Tra nsa mi nase a n d Ga m m a - gl uta m yl Tra ns pe pti das e ( G G T) Ele vati o ns ................... 2 4 
5. 1. 2. 3.  
M uscle S pas ms  ........................................................................................................... 2 5 
5. 1. 2. 4.  
Wei g ht L oss ................................................................................................................ 2 5  
5. 1. 2. 5.  
H y p o ma g nesae mia  ...................................................................................................... 2 6 
5. 1. 2. 6.  
I n creases i n Uri nar y Pr ot ei n ....................................................................................... 2 6 
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 7 
6. 1.  
Pri mar y O bjecti ves  ..................................................................................................... 2 7 
6. 2.  
Pri mar y Efficac y E n d p oi nt ......................................................................................... 2 7  
 
 ................................................................................. 2 7 
6. 4.  
Safet y E n d p oi nts ......................................................................................................... 2 7  
7.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 2 8 
7. 1.  
O verall St u d y Desi g n .................................................................................................. 2 8  
7. 2.  
N u m ber of Patie nts ..................................................................................................... 2 8  
7. 3.  
T reat me nt Assi g n me nt a n d Rati o nale ......................................................................... 2 8 
7. 3. 1.  
D ose Escalati o n  .......................................................................................................... 2 9 

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7. 3. 2.  
D ose De -Escalati o n a n d Re -Escalati o n  ...................................................................... 2 9 
7. 4.  
Criteria f or St u d y Ter mi nati o n  ................................................................................... 2 9 
7. 5.  
Sc he d ule of Asses s me nts ............................................................................................ 2 9 
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  .............................................. 3 2 
8. 1.  
Patie nt I ncl usi o n Criteria  ............................................................................................ 3 2 
8. 2.  
Patie nt E xcl usi o n Criteria  ........................................................................................... 3 3 
8. 3.  
Scree ni n g Peri o d  ......................................................................................................... 3 4 
8. 4.  
Patie nt Re -Scree ni n g  .................................................................................................. 3 4 
8. 5.  
Patie nt Disc o nti n uati o n a n d Ter mi nati o n  ................................................................... 3 4 
8. 5. 1.  
Patie nt Disc o nti n uati o n Criteria  ................................................................................. 3 5 
8. 5. 2.  
Patie nt Ter mi nati o n Criteria  ....................................................................................... 3 5 
9.  
T R E A T M E N T O F P A TI E N T S  .................................................................................. 3 6 
9. 1.  
S elect Ma na ge m e nt G ui deli nes  .................................................................................. 3 6 
9. 1. 1.  
Ma na ge me nt of Fl ui d Stat us ....................................................................................... 3 6  
9. 1. 2.  
Ma na ge me nt of El e vate d Tra nsa mi nase L e vels ( A L T a n d/ or A S T)  .......................... 3 7 
9. 1. 3.  
Ma na ge me nt of M us cle S pas ms  ................................................................................. 3 7 
9. 1. 4.  
Wei g ht L oss ................................................................................................................ 3 7  
9. 1. 5.  
H y p o ma g nesae mia ...................................................................................................... 3 7  
9. 1. 6.  
Ma na ge me nt of Uri nar y Pr ote i n ................................................................................. 3 7 
9. 1. 7.  
Ma na ge me nt of Bl o o d Pr ess ure .................................................................................. 3 8  
9. 1. 8.  
Na usea  ......................................................................................................................... 3 8 
9. 2.  
Descri pti o n of St u d y Dr u g .......................................................................................... 3 8  
9. 3.  
C o nc o mita nt Me dicati o ns ........................................................................................... 3 9  
9. 3. 1.  
E xcl u de d Me dicati o ns ................................................................................................ 3 9  
9. 3. 2.  
Per mitte d Me dicati o ns  ................................................................................................ 3 9 
9. 4.  
Treat me nt C o m plia nce  ................................................................................................ 3 9 
9. 5.  
Ra n d o mizati o n ............................................................................................................ 3 9  
9. 6.  
Bli n d i n g ...................................................................................................................... 3 9 
9. 7.  
U nsc he d ule d Visits ..................................................................................................... 4 0  
9. 8.  
Pre g na nc y  ................................................................................................................... 4 0 
9. 8. 1.  
W o me n of C hil d beari n g P ote ntial .............................................................................. 4 0  
9. 8. 2.  
Met h o ds of Birt h C o ntr ol............................................................................................ 4 0  
9. 8. 3.  
S us pecte d Pre g na n c y  .................................................................................................. 4 1 

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1 2  
9. 9.  
Seri o us T o xicities  ....................................................................................................... 4 1 
9. 1 0.  
St u d y Pr oce d ures ........................................................................................................ 4 2  
9. 1 0. 1.  
I nf or me d C o nse nt ....................................................................................................... 4 2 
9. 1 0. 2.  
I n cl usi o n/ E xcl usi o n .................................................................................................... 4 2 
9. 1 0. 3.  
De m o gra p hics a n d Baseli ne Disease C haract eristics  ................................................. 4 2 
9. 1 0. 4.  
Pri or a n d C urre nt C o nc o mita nt Me dicati o ns .............................................................. 4 2  
9. 1 0. 5.  
Me dical Hist or y  .......................................................................................................... 4 2 
9. 1 0. 6.  
Hei g ht ......................................................................................................................... 4 2  
9. 1 0. 7.  
Wei g ht a n d B o d y Mass I n de x ( B MI) ......................................................................... 4 2  
9. 1 0. 8.  
Electr ocar di o gra ms ( E C G)  ......................................................................................... 4 3 
9. 1 0. 9.  
Ec h ocar di o gra m .......................................................................................................... 4 3  
9. 1 0. 1 0.  
Vital Si g n Meas ure me nts  ............................................................................................ 4 3 
9. 1 0. 1 1.  
P h ysical E xa mi nati o n  ................................................................................................. 4 3 
9. 1 0. 1 2.  
Pre g na nc y T est  ............................................................................................................ 4 3 
9. 1 0. 1 3.  
St u d y D r u g A d mi nistrati o n......................................................................................... 4 3 
9. 1 0. 1 4.  
St u d y Dr u g Dis pe nsati o n a n d C ollecti o n ................................................................... 4 4  
9. 1 0. 1 5.  
Tele p h o ne C o ntact ...................................................................................................... 4 4  
9. 1 0. 1 6.  
A d verse E v e nt C ollecti o n  ........................................................................................... 4 4 
9. 1 0. 1 7.  
Ki d ne y Bi o ps y ............................................................................................................ 4 4  
9. 1 0. 1 8.  
Fasti n g C- Pe pti de Le vels  ............................................................................................ 4 4 
9. 1 0. 1 9.  
Ge netic Testi n g  ........................................................................................................... 4 4 
9. 1 0. 2 0.  
Cli nical C he mistr y  ...................................................................................................... 4 4 
9. 1 0. 2 0. 1.  e G F R  ........................................................................................................................... 4 5 
9. 1 0. 2 1.  
N- Ter mi nal Pr o -Br ai n N atri uretic Pe pti de ( N T - Pr o B N P) a n d Brai n 
Natri uretic Pe pti de ( B N P)  ........................................................................................... 4 5 
9. 1 0. 2 2.  
I ns uli n-Li ke  Gr o wt h Fact or -1 (I G F - 1) a n d Ser u m Ket o nes ....................................... 4 5 
9. 1 0. 2 3.  
He m at ol o g y ................................................................................................................. 4 5  
9. 1 0. 2 4.  
Uri nal ysis a n d Micr osc o p y ......................................................................................... 4 6  
9. 1 0. 2 5.  
Uri ne C ollecti o n f or Al b u mi n t o Creati ni ne Rati o ( A C R)  ......................................... 4 6 
 
 ......................................................................... 4 6 
 
 .................................................................. 4 6 
9. 1 0. 2 8.  
Vir us Ser ol o g y ............................................................................................................ 4 6  
9. 1 0. 2 9.  
P har mac o ki netic ( P K) Bl o o d Sa m ples  ....................................................................... 4 6 

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1 3  
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  ........................................... 4 8 
1 0. 1.  
St u d y Dr u g .................................................................................................................. 4 8  
1 0. 2.  
St u d y Dr u g Pac ka gi n g a n d L a beli n g .......................................................................... 4 8 
1 0. 3.  
St u d y Dr u g St ora ge ..................................................................................................... 4 8  
1 0. 4.  
St u d y Dr u g A d mi nistrati o n......................................................................................... 4 8  
1 0. 5.  
St u d y Dr u g Acc o u nta b ilit y ......................................................................................... 4 9 
1 0. 6.  
St u d y Dr u g Ha n dli n g a n d Dis p osal ............................................................................ 4 9  
1 1.  
S A F E T Y A S S E S S M E N T S  ........................................................................................ 5 0 
1 1. 1.  
Safet y Para met ers  ....................................................................................................... 5 0 
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts ......................................................................... 5 0  
1 1. 2. 1.  
Defi niti o n of A d vers e E v e nts ..................................................................................... 5 0  
1 1. 2. 1. 1.  
A d verse E v e nt  ............................................................................................................. 5 0 
1 1. 2. 1. 2.  
Seri o us A d verse E v e nt ................................................................................................ 5 0  
1 1. 3.  
Eliciti n g A d verse E v e nt I nf or mati o n  .......................................................................... 5 1 
1 1. 4.  
Assess me nt of Ca usalit y  ............................................................................................. 5 1 
1 1. 5.  
As sess me nt of Se verit y ............................................................................................... 5 2 
1 1. 6.  
Rec or di n g A d verse E ve nts ......................................................................................... 5 2  
1 1. 7.  
Re p orti n g Seri o us A d verse E ve nts  ............................................................................. 5 3 
1 2.  
S T A TI S TI C S  .............................................................................................................. 5 5 
1 2. 1.  
Sa m ple Size  ................................................................................................................ 5 5 
1 2. 2.  
St u d y Varia bles ........................................................................................................... 5 5  
1 2. 2. 1.  
P har mac o ki netic V aria bl es  ......................................................................................... 5 5 
1 2. 2. 2.  
Efficac y Varia bles  ...................................................................................................... 5 5 
1 2. 2. 3.  
Safet y Vari a bles  .......................................................................................................... 5 5 
1 2. 3.  
Statistical A nal yses  ..................................................................................................... 5 5 
1 2. 3. 1.  
Pri mar y A nal ysis of Effi cac y  ...................................................................................... 5 6 
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 ......................................... 5 7 
1 3. 1.  
St u d y M o nit ori n g ........................................................................................................ 5 7  
1 3. 2.  
A u dits a n d I ns p ecti o ns ................................................................................................ 5 7  
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  ......................................... 5 8 
1 4. 1.  
Q ualit y As s ura nce ....................................................................................................... 5 8 
1 4. 2.  
Fi na ncial Discl os ur e  ................................................................................................... 5 8 
1 4. 3.  
S p o ns or O bli gati o ns.................................................................................................... 5 8  

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1 4  
1 4. 4.  
I n v esti gat or D oc u me nt ati o n ........................................................................................ 5 8 
1 4. 5.  
Cli nical  St u d y I ns ura nce ............................................................................................. 5 9 
1 4. 6.  
Use of I nf or mati o n  ...................................................................................................... 5 9 
1 5.  
E T HI C S  ...................................................................................................................... 6 0 
1 5. 1.  
I nstit uti o nal Re vie w B oar d (I R B) or Et hics C o m mittee ( E C) Re vie w ....................... 6 0 
1 5. 2.  
Et hical C o n d uct of t he St u d y ...................................................................................... 6 0  
1 5. 3.  
Writte n I nf or m e d C o nse nt .......................................................................................... 6 0  
1 5. 4.  
C o nfi de ntialit y  ............................................................................................................ 6 1 
1 5. 5.  
M o dificati o n of t he Pr ot oc ol ....................................................................................... 6 1  
1 5. 6.  
Pr ot oc ol De viati o ns .................................................................................................... 6 2  
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  ....................................................... 6 3 
1 6. 1.  
Rete nti o n of Rec or ds .................................................................................................. 6 3  
1 6. 2.  
Case Re p ort F or ms  ..................................................................................................... 6 3 
1 7.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 6 4 
1 8.  
R E F E R E N C E S  ........................................................................................................... 6 5 
 

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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 ntact 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 6  
Ta ble  3: 
Cr oss - St u d y C o m paris o n of I ncreases i n e G F R, I n uli n Cleara nce, a n d 
Creati ni ne Cleara nce wit h Bar d o x ol o ne Met h yl Treat me nt  ....................................... 2 3 
Ta ble  4: 
Bar d o x ol o ne Met h yl D os e b y St u d y Visit a n d Al b u mi n uria Stat us ........................... 2 9  
Ta ble 5:  
Sc he d ule of Assess me nts  ............................................................................................ 3 0 
Ta ble 6:  
Bar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or mati o n  ........................................................ 3 8 
Ta ble  7: 
S A E Re p orti n g C o ntact I nf or mati o n .......................................................................... 5 3  
 

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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 pecial 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 
A C E  
A n gi ote nsi n c o n verti n g e nz y me 
A C R  
Al b u mi n t o creati ni ne rati o  
A D P K D  
A ut os o mal d o mi na nt p ol yc ystic ki d ne y disease 
A E  
A d verse e ve nt 
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A R B  
A n gi ote nsi n II rece pt or bl oc ker 
A S T  
As partate a mi n otra nsferase  
B MI  
B o d y mass i n de x  
B N P  
B-t y pe natri uretic pe pti de 
B P  
Bl o o d Press ure 
B U N  
Bl o o d urea nitr o ge n 
C F R  
C o de of Fe de ral 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 K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
Cr Cl  
Creati ni ne cleara nce  
C T M  
Cli nical trial material  
C V  
Car di o vasc ular  
E C  
E t hics C o m mittee 
e C R F 
Electr o nic case re p ort f or m  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic data ca pt ure  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
E o T  
E n d - of-treat me nt 
E R A  
E n d ot heli n rece pt or a nta g o nist 
E S R D  
E n d sta ge re nal disease  

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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 
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
F S G S  
F ocal se g me ntal gl o mer ul oscler osis  
F/ U  
F oll o w- u p 
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
H b A 1c  
He m o gl o bi n A 1c 
H C V  
He patitis C vir us  
H D P E  
Hi g h -de nsit y p ol yet h yle ne  
H g b  
He m o gl o bi n  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I g A 
I m m u n o gl o b uli n A 
I g A N 
I m m u n o gl o b uli n A ne p hr o pat h y 
I G F- 1 
I ns uli n-li ke gr o wt h fact or- 1 
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 M P 
I n vesti gati o nal me dici nal pr o d ucts 
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 
I T T 
I nte nt-t o-treat 
J 2 R 
J u m p t o refere nce 
K DI G O  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes 
Kea p 1  
Kelc h -li ke E C H ass ociate d pr otei n- 1 
K f 
Ultrafiltrati o n c oefficie nt  
L D H  
Lactate de h y dr o ge nase  
M C H  
Mea n c or p usc ular he m o gl o bi n  
M C H C  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
M C V  
Mea n c or p usc ular v ol u me  
M M R M  
Mi xe d m o del re peate d meas ures  
M RI  
Ma g netic res o na nce i ma gi n g  
M T L D D  
Ma xi mall y t olerate d la bele d dail y d ose  
N F -κ B 
N uclear fact or ka p pa- li g ht-c hai n-e n ha ncer of acti vate d B -cells 
Nrf 2  
N uclear fact or ( er yt hr oi d-deri ve d 2) -relate d fact or 2 

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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 T -Pr o B N P  
N- Ter mi nal Pr o -Brai n Natri uretic Pe pti de   
P B O  
Place b o  
 
 
P H  
P ul m o nar y h y perte nsi o n 
P K  
P har mac o ki netic  
P K D 1  
P ol yc ystic ki d ne y disease 1  
Q Tc  
C orrecte d Q T i nter val  
R B C  
Re d bl o o d cell 
R E M L  
Restricte d ma xi m u m li keli h o o d  
R N A  
Ri b o n ucleic aci d  
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 2 D  
T y pe 2 dia betes  
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 B C  
W hite bl o o d cell  
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, K ea 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 he re 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 otecti ve e n z 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 0 0 5 ).  Bar d o x ol o ne 
met h yl a n d its a nal o gs ar e 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 reacti ve o x y ge n s pecies) ( 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 ot e 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.    
M ulti ple st u dies vali date t he re nal pr ot ecti ve effect of Nrf 2 acti vati o n.  I n c o ntrast, Nrf 2 ge n e 
a blati o n i nte nsifies i nfla m mati o n, o xi dati ve stress, a n d re nal i nj ur y i n precli nical m o dels.  Nrf 2 -
k n oc k o ut mice e x hi bit a l u p us- li ke a ut oi m m u ne ne p hritis (Y o h, 2 0 0 1 ) a n d hist ol o gic a nal yses of 
ki d ne y tiss ue s h o w e nlar ge d gl o mer uli, mesa n gial cell pr oliferati o n, t hic ke ni n g of t he gl o mer ular 
base me nt me m bra n e, a n d gl o mer ul oscler osis ( Ma, 2 0 0 6 ).  Si milarl y, Nrf 2-k n oc k o ut mice ar e 
m ore s usce pti ble t o ne p hr ot o xic i ns ults a n d de vel o p m ore se vere re nal i m pair me nt.  Mec h a nistic 
st u dies de m o nstrate t hat Nrf 2 -me diat e d pr otecti o n a gai nst t hese effects is at least partiall y 
t hr o u g h i n hi biti o n of tra nsf or mi n g gr o wt h fact or-β 1 a n d re d ucti o n of e xtracell ular matri x 
pr o d ucti o n ( Jia n g, 2 0 1 0).  C ollecti vel y, t hese data esta blis h t hat Nrf 2 pla ys a n i m p orta nt r ole i n 
mai ntai ni n g t he f u ncti o n a n d str uct ure of t he ki d ne y a n d Nrf 2 acti vati o n offers pr otecti o n fr o m 
re nal i nj ur y a n d d ysf u n cti o n.   
C hr o nic ki d ne y disease ( C K D) is a disease of decrease d ki d n e y f u ncti o n t h at ca n pr o gress t o 
ki d ne y fail ure a n d e n d- st a ge re n al disease ( E S R D).  Rare f or ms of C K D i n cl u de C K D ass oci ate d 
wit h t y pe 1 dia betes ( T 1 D), I g A ne p hr o pat h y (I g A N), f ocal se g me ntal gl o mer ul oscler osis 
( F S G S), a n d a ut os o mal p ol yc ystic ki d ne y disease ( A D P K D).  Alt h o u g h GF R decli ne is i nitiate d 
b y differe nt p at h o ge nic sti m uli i n T 1 D C K D, I g A N, F S G S, a n d A D P K D, t he pat h o ge nic r ol e of 
i nfla m mat or y pr ocess es i n disease pr o gressi o n a n d decli ni n g re nal f u n cti o n is si milar acr oss eac h 
of t hese diseas es.  H y p o gl yce mia i n T 1 D, a b n or m al i m m u n o gl o b uli n A ( I g A) de p ositi o n a n d 
clear a nce i n I g A N, se g m e ntal scarri n g i n F S G S, a n d re nal c yst f or mati o n i n A D P K D, all tri g ger 
a casca de of pat h ol o gical i nfla m mat or y pr ocess es t hat, o ver pr ol o n ge d p eri o ds, res ult i n 
o xi dati ve stress, mesa n gi al matri x e x pa nsi o n, gl o mer ul oscler osis a n d f i br osis, decreas e d s urface 
area f or filtrati o n, a n d re d uce d re n al f u ncti o n.   
M ore s pecifi call y, t he c hr o nic acti vati o n of pr o-i nfla m mat or y pat h wa ys i n ki d ne y cells pr o m otes 
G F R l oss b y at least t hree mec ha nis ms: (a) i n gl o mer ular e n d ot h elial cells, i nfla m mati o n -
ass ociate d  r eacti ve o x y g e n s pecies ( R O S) i n d uce e n d ot helial nitric o xi de s y nt hase (e N O S) 
u nc o u pli n g a n d t he pr o d ucti o n of per o x y nitrite, w hic h de pletes vas o dilat or y nitric o xi de res ulti n g 
i n l oss of e n d ot helial f u ncti o n a n d re d uce d gl o mer ular s urface area f or filtrati o n ( i.e., decreases 
i n t he ultrafiltrati o n c oefficie nt, Kf); ( b) infl a m mati o n -ass ociate d R O S i n d uce  a c o ntractile 
res p o nse i n mesa n gial cells res ulti n g i n re d uce d Kf a n d G F R; a n d (c) R O S-me diate d  acti vati o n of 
i nfla m mat or y pat h wa ys l ea ds t o fi br osis, pr o m oti n g str uct ural alterati o ns i n t he mesa n gi u m a n d 

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gl o mer ular base m e nt me m bra ne t hic ke ni n g t hat c o ntri b utes t o G F R decli n e.  G F R decli ne fr o m 
t hese pr ocesses i ne vita bl y lea ds t o E S R D.   
T hr o u g h Nrf 2 acti vati o n a n d i n hi biti o n of N F- κ B, b ar d o x ol o ne met h yl a n d cl osel y relate d 
str uct ural a nal o gs h a ve b ee n s h o w n t o i m pr o ve re nal f u ncti o n, re d u ce i nfla m mati o n, a n d pre ve nt 
str uct ural i nj ur y i n m ulti ple m o dels of re nal i nj ur y a n d disease (Ta na k a, 2 0 0 8 ; Z oja, 2 0 1 0 ; 
W u,  2 0 1 1; A mi nza de h, 2 0 1 3 ; Di n g, 2 0 1 3 ).  I n p artic ular, se veral of t hese st u dies el uci date t he 
effects of bar d o x ol o n e met h yl a n d cl osel y rel ate d a nal o gs o n t he u n derl yi n g disease pr ocesses 
t hat pr o m ote re d uce d G F R.  S pecificall y, b ar d o x ol o ne met h yl a n d a nal o gs re vers e e n d ot helial 
d ysf u ncti o n ( Fer g us o n, 2 0 1 0 ) a n d mesa n gial cell c o ntracti o n, t here b y i n creasi n g gl o mer ular 
s urface ar ea ( Kf) a n d G F R (Di n g, 2 0 1 3 ).  F urt her, data fr o m a ni mal m o dels of c hr o nic re nal 
disease de m o nstrat e t hat t he c o m p o u n ds are a nti-fi br otic a n d ha ve pr otecti ve effects o n t he re nal 
i nterstiti u m i n res p o nse t o hi g h pr otei n (Z oja,  2 0 1 0) a n d press ure o verl oa d i n t he setti n g of 
h y perfiltrati o n  (A mi nza d e h, 2 0 1 3 ).   
Bar d o x ol o ne met h yl has c o nsiste ntl y i m pr o ve d para meters of re n al f u ncti o n i n m ulti ple cli nical 
st u dies i n patie nts wit h C K D ass ociate d wit h t y pe 2 dia betes ( T 2 D), ca n cer, a n d p ul m o nar y 
h y perte nsi o n ( P H) , wit h si g nifica nt i ncreas es i n i n uli n cleara n ce, creati ni ne cleara nce, a n d 
esti mate d e G F R.  T h e c h a n ges i n e G F R als o c orrelate i n re d ucti o ns i n ot her para meters s uc h as 
bl o o d urea nitr o ge n ( B U N ), uric aci d, a n d p h os p h ate, a n d n ot ass oci ate d wit h vali date d mar kers 
of re nal i nj ur y, pr o vi di n g c orr o b or ati o n t hat bar d o x ol o ne met h yl treat me nt is ass ociate d wit h 
i m pr o ve me nts i n ki d ne y f u ncti o n.   
T he pr ofile of e G F R i ncr eases wit h bar d o x ol o ne met h yl reflects its m ulti ple pr otecti ve a n d 
a nti-i nfla m mat or y effects.  Earl y i m pr o ve me nts i n e G F R e vi d e nt wit hi n t he first 4 wee ks of 
bar d o x ol o ne met h yl treat me nt are li kel y attri b ute d t o t he re vers al of ac ute, d y na mic 
i nfla m mati o n- me diate d pr ocesses s u c h e n d ot helial d ysf u ncti o n a n d mesa n gial cell c o ntracti o n 
res ulti n g i n gl o mer ular filtrati o n s urface area i ncreases.  T hese i n creases i n e G F R are s ustai ne d 
f or patie nts treate d wit h bar d o x ol o ne met h yl f or u p t o o ne year, wit h ret ai n e d e G F R i ncreases 
fr o m baseli ne e v e nt aft er wit h dra wal of dr u g treat me nt.  T he ma g nit u de a n d d ura bilit y  of t hese 
c ha n ges are q uite differ e nt fr o m t he patter n o bser ve d wit h e G F R i ncreas es d ue t o i ntra gl o mer ular 
press ure or h y perfiltrati o n.  O ver 4 0 0 pati e nts wit h T 2 D C K D ha ve b ee n treate d wit h 
bar d o x ol o ne met h yl f or 1 year or l o n g er, wit h n o e vi de nce of re nal t o xicit y, as assesse d b y 
vali date d mar kers of r e nal i nj ur y, pr o p orti o n of patie nts wit h cli nicall y mea ni n gf ul l oss of e G F R, 
re nal S A Es, a n d E S R D.  T h us, t he c ollecti ve data s u p p ort t hat bar d o x ol o ne met h yl ma y ha ve 
disease - m o dif yi n g effects i n t he ki d ne y (e. g., re v ersal of mesa n gial e x pa nsi o n a n d i nterstitial 
fi br osis) t hat are b e nefi cial a n d n ot deleteri o us.  O n t he basis of t hese res ults, bar d o x ol o ne 
met h yl is als o c urre ntl y b ei n g e val uate d i n a P hase 2/ 3 st u d y i n patie nts wit h Al p ort s y n dr o me. 
In p atie nts  wit h T 1 D C K D, I g A N, F S G S, a n d A D P K D, t he p ote ntial i m pact of a s ustai ne d e G F R 
i ncreas e wit h bar d o x ol o n e met h yl treat me nt is cli nicall y mea ni n gf ul an d c o ul d pr o vi de a m ulti-
year del a y i n disease pr o gressi o n t o E S R D. 
5. 1.  
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.  Si xtee n st u dies 
ha ve bee n c o m plete d (s e ve n i n patie nts wit h C K D w h o als o ha d t y pe 2 dia b etes, f o ur i n n o n-
C K D i n dicati o ns, a n d fi ve i n healt h y s u bjects), t w o st u dies are o n g oi n g i n patie nts wit h P H, a n d 
o ne st u d y is o n g oi n g i n patie nts wit h Al p ort s y n dr o me.   

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Effic ac y  
As see n i n Ta ble  3, i m pr o ve me nts i n re nal f u n cti o n, i ncl u di n g e G F R, creati ni ne cleara nce, a n d 
i n uli n cleara nce, ha v e bee n o bser ve d wit h bar d o x ol o ne met h yl treat me nt i n m ulti ple cli nical 
st u dies, i ncl u di n g t h ose i n T 2 D  C K D, ca n cer, a n d P H patie nts.  Bar d o x ol o ne met h yl was 
ori gi nall y c o nsi dere d f or de vel o p me nt i n ca n cer p atie nts, a n d i n t w o P hase 1 st u dies, 
bar d o x ol o ne met h yl was o bser ve d t o re d uce s er u m creati ni ne le v els, c orres p o n di n g t o a n 
i ncreas e i n e G F R.  T he r e d ucti o ns of ser u m creati ni ne le vels a n d res ulta nt i ncreas es i n e G F R 
were ti me - d e pe n d e nt a n d ma nifeste d i n a maj orit y ( 8 2 %) of t he p atie nts st u die d.  I n s u bs e q ue nt 
st u dies t hat e nr olle d o ver 2 6 0 0 patie nts wit h t y pe 2 dia betes a n d C K D, b ar d o x ol o ne met h yl has 
bee n s h o w n t o c o nsiste ntl y pr o d uce cli nicall y a n d statist icall y si g nifica nt i m pr o ve me nts i n e G F R 
t hat are d ura ble f or at least o ne year i n treate d pati e nts.   
St u d y 4 0 2- C- 0 8 0 4 was a m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, parallel-
gr o u p, m ulti- d ose, P hase 2 b st u d y desi g ne d t o assess t he efficac y a n d s afet y of 3 d oses ( 2 5, 7 5, 
a n d 1 5 0 m g ) of t he cr ystalli ne f or m ulati o n of bar d o x ol o ne met h yl i n patie nts wit h Sta ge 3 b- 4 
C K D (e G F R 2 0 - 4 5 m L/ mi n/ 1. 7 3 m2) a n d t y pe 2 dia betes.  A nal ysis of t he pri mar y e n d p oi nt, t he 
c ha n ge i n e G F R val ues fr o m baseli ne a t Wee k  2 4, de m o nstrate d a cli nicall y a n d statisticall y 
si g nifica nt i ncreas e i n e G F R relati ve b ot h t o t he baseli ne val ue a n d t o t he c h a n ge wit h place b o 
( p < 0. 0 0 1) at eac h of t he 3 teste d d ose le vels (Per g ola,  2 0 1 1).  Mea n e G F R i ncreas es were 
lar gel y s ustaine d t hr o u g h Wee k  5 2 a n d o n a vera ge, patie nts treate d wit h bar d o x ol o ne met h yl 
e x perie n ce d a n et i ncreas e i n e G F R of 7. 4 ± 0. 8 m L/ mi n/ 1. 7 3 m 2 at Wee k 5 2 fr o m a baseli ne of 
3 2. 4 m L/ mi n/ 1. 7 3 m 2.   
St u d y 4 0 2- C- 0 9 0 3, title d " Bar d o x ol o ne Met h yl E val uati o n i n Patie nts wit h C hr o nic Ki d ne y 
Disease a n d T y pe 2 Dia b etes: T he Occ urre nce of Re nal E ve nts" ( B E A C O N), was a P has e  3, 
ra n d o mize d, d o u ble- bli n d, place b o- c o ntr olle d, parallel- gr o u p, m ulti nati o nal, m ultice nter st u d y 
desi g ne d t o c o m par e t he efficac y a n d s afet y of b ar d o x ol o ne met h yl t o place b o i n patie nts wit h 
Sta ge 4 C K D (e G F R 1 5 t o 2 9 m L/ mi n/ 1. 7 3 m2) a n d T y pe 2 dia betes.  A t ot al of 2 1 8 5 patie nts 
were ra n d o mize d 1: 1 t o o nce- dail y a d mi nistrati o n of t he a m or p h o us S D D f or m ulati o n of 
bar d o x ol o ne met h yl ( 2 0 m g ) or place bo.  T h e pri mar y effi cac y e n d p oi nt of t he st u d y was t he 
ti me-t o-first e ve nt i n t he c o m p osite e n d p oi nt defi n e d as e n d-Sta g e re n al disease ( E S R D; nee d f or 
c hr o nic dial ysis, re n al tra ns pla ntati o n, or re nal deat h) or car di o v asc ular ( C V) deat h.  Si milar t o 
pri or st u dies, bar d o x ol o n e met h yl patie nts ha d mea n i ncreases i n e G F R t hat occ urre d b y Wee k  4 
of treat me nt a n d re mai ne d a b o ve baseli ne t hr o u g h Wee k  4 8 ( o v erall mea n i ncreas e of 
5. 5 m L/ mi n/ 1. 7 3  m2).  I n c o ntrast, place b o-treate d patie nts e x perie n ce d a mea n declin e i n e G F R 
(−0. 9 m L/ mi n/ 1. 7 3 m 2, 9 5 % CI −1. 2 t o −0. 5 m L/ mi n/ 1. 7 3 m 2), c orres p o n di n g t o a relati ve 
differe n ce b et wee n gr o u ps of 6. 4 m L/ mi n/ 1. 7 3 m 2 ( 9 5 % CI 5. 9 t o 6. 9 m L/ mi n/ 1. 7 3 m2, p < 0. 0 0 1) 
(de Zee u w,  2 0 1 3).   
Patie nts i n St u d y 4 0 2- C- 0 8 0 4 a n d 4 0 2- C- 0 9 0 3 als o partici pate d i n a f o ur- w ee k wit h dra w al 
peri o d f oll o wi n g t he treat me nt peri o d.  I n 4 0 2- C- 0 8 0 4, a nal ysis of t he c ha n g e i n e G F R fr o m 
baseli ne t o Wee k  5 6 f or patie nts w h o recei ve d st u d y dr u g f or 5 2 w ee ks s h o we d t hat a p orti o n of 
t he i ncreas e i n e G F R is retai ne d f oll o wi n g wit h dra wal of t hera p y.  Patie nts treate d wit h 7 5 a n d 
1 5 0 m g of bar d o x ol o ne met h yl f or 5 2 wee ks h a d e G F R i ncreas es fr o m bas eli ne of 4. 0 a n d 
4. 3 m L/ mi n/ 1. 7 3 m 2, res pecti vel y, at Wee k 5 6.  Si milar res ults were o bs er ve d i n B E A C O N f or 
patie nts t ha t recei v e d at l east 4 8 wee ks of treat me nt.  T hese data s u p p ort t h at t he l o n ger- ter m 
pr otecti ve a n d a nti-i nfla m mat or y effects of bar d o x ol o ne met h yl ma y re verse s o me of t he 

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str uct ural re m o d eli n g pr ocesses i n t he ki d ne y ass o ciate d wit h decli ni n g re n al f u nct i on, res ulti n g 
i n s ustai ne d e G F R i m pr o ve me nt after wit h dra w al of dr u g.   
N ota bl y , Reata’s Asia n d e vel o p me nt part ner, K y o wa Ha k k o Kiri n, de m o nstrate d t hat 
bar d o x ol o ne met h yl treat me nt res ulte d i n a si g nifica nt i m pr o ve me nt i n G F R in Ja pa nese patie nts 
wit h C K D a n d t y pe 2 dia betes.  I m pr o ve me nts i n ot her meas ures of re nal f u ncti o n, i ncl u di n g 
B U N, uric aci d, a n d p h os p h or us, ha ve als o b ee n c o nsiste ntl y o bser ve d, pr o vi di n g f urt her 
e vi de nce t h at o bser ve d c ha n ges i n e G F R refl ect tr ue i m pr o ve me nts i n ki d ne y f u ncti o n.  M ostl y 
rece ntl y, bar d o x ol o ne met h yl has bee n s h o w n t o si g nifica ntl y i ncreas e e G F R after 1 2 wee ks of 
treat me nt i n a P hase 2 o p e n -la bel st u d y i n patie nts wit h Al p ort s y n dr o me ( St u d y 4 0 2- C- 1 6 0 3).   

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T a ble 3: 
Cr oss -St u d y  Co m p aris o n of I ncre ases i n e G F R, I n uli n Cle ar a nce, a n d 
Cre ati ni ne Cle ar a nce wit h B ar d o x ol o ne Met h yl Tre at me nt  
St u d y  
P h ase/  
C o u ntr y  
St u d y  
Desi g n  
St u d y  
P o p ul ati o n  
# of  
P atie nts  
Tre at m e nt 
D ur ati o n  
Pl ace b o -c orrecte d 
∆e G F R  
( m L/ mi n/ 1. 7 3 m2)a 
C K D St u dies  
4 0 2 -C -0 8 0 1  
( Strat u m 1) 
2a/  
U S  
M ultice nter, O pe n -
La bel, D ose -
Ra n gi n g, 
Ra n d o mize d  
A ge > = 1 8,  
Dia betic 
ne p hr o pat h y  
6 0  
2 8 da ys  
6. 7 b 
( p < 0. 0 0 1) 
4 0 2 -C -0 8 0 1  
( Strat u m 2) 
2 b/  
U S  
M ultice nter, O pe n -
La bel, D ose -
Ra n gi n g, 
Ra n d o mize d  
A ge > = 1 8,  
Dia betic 
ne p hr o pat h y  
2 0  
5 6 da ys  
7. 2 b 
( p < 0. 0 0 1) 
Cr Cl als o si g. 
i ncrease d  
4 0 2 -C -0 8 0 4  
( B E A M) 
2/  
U S  
M ultice nter, 
D o u ble -Bli n de d, 
Ra n d o mize d, 
Place b o -C o ntr olle d  
A ge > = 1 8,  
T 2 D a n d C K D  
2 2 7  
5 2 wee ks  
8. 6 at W K 5 2  
( p < 0. 0 0 1 vs P B O) 
4 0 2 -C -0 9 0 2  
2/  
U S  
M ultice nter, O pe n -
La bel, Ra n d o mize d, 
Parallel -Gr o u p, 
D ose -Ra n gi n g  
A ge > = 1 8, T 2 D 
a n d  C K D  
1 3 1  
8 5 da ys  
6. 5 b 
( p < 0. 0 0 1) 
4 0 2 -C -0 9 0 3  
( B E A C O N) 
3/  
Gl o bal  
M ulti nati o nal,  
M ultice nter, 
Ra n d o mize d, 
D o u ble -Bli n de d, 
Place b o -C o ntr olle d  
A ge > = 1 8,  
T 2 D a n d Sta ge 4 
C K D  
2 1 8 5  
Me dia n:  
7 m o nt hs wit h 
5 2 2 patie nts 
t hr o u g h Wee k 
4 8  
6. 4  
( p < 0. 0 0 1 vs P B O) 
Cr Cl als o 
si g nifica ntl y 
i ncrease d 
4 0 2 -C -1 1 0 2  
1/ U S  
M ulti -D ose, 
M ultice nter, O pe n -
La bel  
A ge > = 1 8,  
T 2 D a n d Sta ge 
3 b a n d 4 C K D  
2 4  
5 6 da ys  
9. 0  
( p < 0. 0 5) 
R T A 4 0 2 -0 0 5 
( T S U B A KI) 
2/  
Ja pa n 
Ra n d o mize d, 
D o u ble -Bli n de d, 
Place b o -C o ntr olle d  
A ge > = 2 0,  
T 2 D a n d Sta ge 3 
a n d 4 C K D  
1 0 8  
1 6 wee ks  
6. 6 (i n uli n G F R)  
( p = 0. 0 0 8 vs P B O) 
N o n -C K D St u dies  
4 0 2 -C -0 5 0 1  
1/  
U S  
O pe n -la bel, D ose-
escalati o n  
A ge > = 1 8,  
A d va nce d S oli d 
T u m ors or 
L y m p h oi d 
Mali g na ncies  
4 7  
Me dia n:  
5 6 da ys  
1 8. 2 b 
( p < 0. 0 0 0 1) 
4 0 2 -C -0 7 0 2  
1/ 2/  
U S  
D o u ble -Bli n de d, 
Ra n d o mize d  
Pa ncreatic 
Ca ncer  
3 4  
Me dia n:  
5 6 da ys  
3 2. 2 b 
( p = 0. 0 0 1) 
4 0 2 -C -1 3 0 2 
( L A RI A T) 
2/  
U S  
Ra n d o mize d, 
D o u ble -Bli n de d, 
Place b o -C o ntr olle d  
A ge 1 8 t o 7 5  
P H ( Baseli ne 
e G F R 8 2 
m L/ mi n/  
1. 7 3 m 2) 
5 4 c 
1 6 wee ks  
1 4. 7  
( p < 0. 0 0 1 vs P B O) 
a U nless n ote d,  data are differe nces bet wee n mea n e G F R c ha n ges  fr o m baseli ne f or bar d o x ol o ne met h yl vers us 
place b o gr o u ps a n d p -val ues calc ulate d c o m pari n g t he differe nce i n mea ns bet wee n bar d o x ol o ne met h yl a n d 
place b o gr o u ps.  
b Data are mea n e G F R c ha n ges fr o m baseli ne f or bar d o x ol o ne met h yl patie nts a n d p- val ues are calc ulate d fr o m t w o -
si de d paire d t-tests c o m pari n g e G F R c ha n ge t o 0. 
c N u m ber of patie nts e nr olle d C o h orts 1 a n d 2 . 

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S afet y a n d T oler a bilit y 
Please ref er 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 f or st u dies 
i n healt h y s u bjects, ca n cer, C K D, a n d P H patie nts wit h bar d o x ol o ne met h yl. 
5. 1. 2. 1.  
Fl 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 ( E R As) i n certai 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 heart fail ure a n d a v ose nta n i n a d va n ce 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 be ass ociate d wit h a n i ncrease d ris k f or fl ui d o verl oa d a n d h eart 
fail ure h os pitalizati o ns i n t he B E A C O N  trial, w hic h e nr olle d patie nts wit h Sta ge 4 C K D 
(e G F R 1 5 t o 2 9 m L/ mi n/ 1. 7 3 m2) 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 h eart f ail ur e e ve nts wit h bar d o x ol o n e 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 vate d B N P  a n d pri or h os pitalizati o n f or heart 
fail ure w ere i de ntifie d as ris k fact ors t hat c o ntri b ute d t o i ncreas e d ris k f or t h ese e ve nts.  T h e 
i ncreas e 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 v e d i n si 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 t o 4 4 m L/ mi n/ 1. 7 3  m2), 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 dicates t hat heart f ail 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 ver al kil o gra ms wit hi n t he first wee ks of treat me nt i nitiati o n) a n d 
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 vaila 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 ca n differ e 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 otes 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 nize d ris k f act 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 ul m o nar y h y perte nsi o n ( 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 uce t he 
p ote ntial f or bar d o x ol o ne met h yl-i n d uce d fl ui d o v erl oa d ; t hese pr o ce d ures e xcl u de d patie nts 
wit h t he i de ntifie d ris k fact ors a n d e ns ure d cl ose 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 Es wit h bar d o x ol o ne met h yl i n 
late-sta ge C K D p atie nts has n ot bee n o bser ve d i n P H patie nts.   
5. 1. 2. 2.  
Tr 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 ( G G T) 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 a b 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 wer e n o t 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 
B E A C O N, fe wer he p at o biliar y S A Es were o bs er ve d i n t he bar d o x ol o ne m et h yl ar m t ha n i n t he 
place b o ar m.  T he ele v ati o ns be g in i m me diatel y after i nitiati o n of treat me nt or a n i ncr ease i n 
d ose ; t he y pea 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 
were  mil d, b ut a p pr o xi m atel 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 L N.  T he ele vati o ns res ol ve d t o le vels less t h a 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 aft er pea k val ues w hile patie 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 n ce d  ele vati o ns t o great er t ha n 3 X t he U L N s o meti mes re q uired a d diti o nal 
ti me t o res ol ve.  W hile s o me patie nts have ha d el e vati o ns t o a b o ve 3 X t he U L N, p ersiste nt 

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ele vati o ns t o a b o ve 3 X t h e U L N ha v e n ot bee n o bs er ve d, a n d t h e ele v ati o ns di d n ot rec ur o nce 
res 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 G G T, a k n o w n Nrf 2 tar get ge ne.  I n cli nical st u dies, l o w le vel 
G G T ele vati o ns d uri n g tr eat me nt wer e  c o m m o n, mil d, a n d t y picall y laste d l o n ger t ha n A L T/ A S T 
ele vati o ns.  Bilir u bi n le vels i n patie nts e x perie n ci n g tra nsa 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 g e ner all y self-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. 1. 2. 3.  
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 trials 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 nifest e 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 urr e 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 bee n re p orte d i n bar d o x ol o ne met h yl-treate d P H patie nts b ut 
at l o wer i nci de n ces t ha n t hat o bser ve d i n pri or C K D st u dies.  M ore o ver, t h e i nci de nce of m us cle 
s pas ms is si milar t o t hat o bser ve d i n place b o-treat e d P 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 uscle cells.  I ncreas es i n 
gl uc ose u pta ke, as assess e d b y t he 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 v els ha ve bee n meas 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 ncr ease 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 k ers, i ncl u di n g creati ni ne, lactate de h y dr o ge nase ( L D H), 
B U 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 ( 4 0 2- C- 0 8 0 4) w he n m uscl e 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 ose dis p osal rate ha ve bee n o bser v e d i n mice treat e d wit h 
bar d o x ol o ne met h yl, as well.  I n cr ease 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. 1. 2. 4.  
Wei g ht L oss 
Decr eases i n w ei g ht a n d re p orts of a n ore xia/ decrease d a p petite h a 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 n e met h yl patie nts re p orte d A Es of wei g ht d ecreas e or 
decrease d a p petite (irr es p ecti ve of r elati o ns hi p t o treat me 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 eate d wit h bar d o x ol o n e 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 m atel y o ne kil o gra m per m o nt h was o bser ve d, wit h patie nts of hi g her 
b o d y- mass i n de 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 de x.     
Bar d o x ol o ne met h yl- treate d P H patie nts ha ve als o ha d decreas es i n wei g ht, wit h  mea n wei g ht 
decreases 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 H patie nts has n ot 
c oi nci de d wit h re p orts of decrease d a p petite or a n ore xia A E s. 

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5. 1. 2. 5.  
H y p o m a g nes ae mi a 
H y p o ma g nesae mia has n ot bee n re p orte d i n P 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 h yl-treate d patie nts t h a n i n patie nts gi ve n place 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 greater d ecr ease fr o m baseli ne i n ser u m ma g nesi u m le vels t ha n patie nts g i 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.  I n 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 nesae 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 nesi u m le vels, i n dicati n g t hat re nal 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 v e 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, bar d o x ol o ne met h yl 
s h o we d n o i ncrease i n t h e Q T i nter val.  
5. 1. 2. 6.  
I ncre ases i n Uri n ar y Pr otei n 
I n creases i n uri nar y al b u mi n ha ve bee n o bser ve d i n s o me patie nts treate d wit h bar d o x ol o ne 
met h yl wit h c hr o nic ki d ne y disease a n d t y pe 2 dia betes.  T he i ncreas es are li kel y d ue t o 
bar d o x ol o ne met h yl’s p h ar mac ol o gical m o d ulati o n of t u b ular pr otei n rea bs or pti o n a n d ha ve n ot 
bee n ass oci ate d wit h i nterstitial fi br osis or i nj ur y.  I n precli nical st u dies, bar d o x ol o ne met h yl has 
bee n s h o w n t o d o w nr e g ulate t he pri mar y pr ot ei ns i n v ol ve d i n pr otei n rea bs or pti o n i n t he 
pr o xi mal t u b ules: t h e me gali n -c u bili n c o m ple x.  M ore o ver, t he ma g nit u de of o bser ve d e G F R 
i ncreas es wit h bar d o x ol o ne met h yl treat me nt is t h o u g ht t o re d uce t he resi d e nce ti me of pr otei n i n 
t he pr o xi mal t u b ules, t here b y re d u ci n g pr otei n re u pta ke a n d i ncreasi n g uri n ar y pr otei n le vels.  
T heref ore, i ncreas e d e G F R, t o get her wit h decrease d me gali n e x pressi o n, is t h o u g ht t o res ult i n 
decrease d fracti o nal a bs or pti o n of al b u mi n a n d i ncrease d uri nar y e xcreti o n of al b u mi n.  
C o nsiste nt wit h bar d o x ol o ne met h yl- me diate d pr otecti o n i n precli ni cal m o dels of pr otei n -
o verl oa d-i n d uce d ne p hr o pat h y, t hese p har m ac ol o gical effects are t h o u g ht t o re d uce pr otei n 
o verl oa d a n d s ec o n dar y ne p hr o pat h y ca use d b y e xcessi ve al b u mi n u pta ke a n d t heref ore are n ot 
ass ociate d wit h tiss ue i nj ur y a n d i nterstitial fi br o sis. 
 

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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 
F or patie nts wit hi n eac h c o h ort e nr olle d i n t his st u d y, t he pri mar y o bjecti ves are as f oll o ws: 
•  T o assess t he c h a n ge fr o m baseli ne i n esti mate d gl o mer ular filtrati o n rat e (e G F R) i n 
bar d o x ol o ne met h yl-tr eat e d patie nts after 1 2 wee ks of treat me nt.  
•  T o assess t he saf et y of bar d o x ol o ne met h yl after 1 2 wee ks of treat me nt. 
6. 2.  
Pri m ar y Effic ac y E n d p oi nt  
•  C ha n ge fr o m bas eli ne i n e G F R at Wee k 1 2.  
 
 
 
 
 
 
6. 4.  
S afet y E n d p oi nts  
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 Es  a n d 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: vital si g n meas ure m e nts, 1 2-lea d E C Gs, cli ni cal la b orat or y 
meas ure me nts, a n d wei g ht.  

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7.  
IN 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 m ulti -ce nter, o pe n -l a bel P hase 2 trial will st u d y t he safet y, t olera bilit y, a n d effi cac y of 
bar d o x ol o ne met h yl i n q ualifie d patie nts wit h t he foll o wi n g rare c hr o nic ki d ne y disease s: C K D 
ass ociate d wit h t y pe 1 di a betes ( T 1 D), I g A n e p hr o pat h y (I g A N), f ocal se g me ntal 
gl o mer ul oscler osis ( F S G S), a n d a ut os o mal d o mi na nt p ol yc ystic ki d ne y disease ( A D P K D). 
Patie nts will be e nr olle d i n disease s pecific c o h o rts wit hi n t he trial , a n d effecti ve ness of 
bar d o x ol o ne met h yl i n tr eati n g C K D will be assesse d se paratel y b y c o h ort f or eac h rare C K D. 
Patie nts will recei ve bar d o x ol o ne met h yl t hr o u g h o ut t he st u d y a n d t he ma xi m u m bar d o x ol o ne 
met h yl d ose will be deter mi ne d  b y baseli ne pr otei n uria stat us.  Patie nts wit h macr oal b u mi n uria 
( 3 0 0 m g/ g < A C R ≤ 2 5 0 0 m g/ g) at t he Scree n B visit will acc o u nt f or u p t o a p pr o xi matel y 5 0 % 
of patie nts e nr olle d wit hi n eac h c o h ort.  Patie nts wit h baseli ne A C R ≤ 3 0 0 m g/ g will be titrate d 
t o a ma xi m u m d ose of 2 0 m g, a n d patie nts wit h baseli ne A C R > 3 0 0 m g/ g will be titrate d t o a 
ma xi m u m d ose of 3 0 m g.  P atie nts will start wit h o nce - dail y d osi n g at 5 m g a n d will d ose-
escalate t o 1 0  m g at Wee k  2, t o 2 0 m g at Wee k 4, a n d t he n t o 3 0 m g at Wee k 6 ( o nl y if baseli ne 
A C R > 3 0 0 m g/ g) u nless c o ntrai n dicate d cli nicall y a n d a p pr o ve d b y 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 if i n dicate d cli nicall y, a n d s u bs e q ue nt d ose re-
escalati o n is als o per mitte d t o meet t he d osi n g o bjecti ve of t he hi g hest t olerate d d ose.  Please 
refer t o Secti o n  7. 3. 1  f or a d diti o nal details o n d ose escalati o n a n d d os e 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.  F oll o wi n g 
ra n d o mizati o n o n Da y 1, patie nts will be sc he d ule d t o be assesse d d uri n g treat me nt at Wee ks 1, 
2, 4, 6, 8, a n d 1 2, a n d b y tele p h o ne c o ntact o n Da ys 3, 1 0, 2 1, 3 1, 3 8, a n d 4 5.  Patie nts will als o 
be sc he d ule d t o be assess e d at a n i n pers o n f oll o w- u p visit at Wee k  1 6, f o ur wee ks after t h e e n d 
of treat me nt.  
7. 2.  
N u m ber of P atie nt s 
Eac h c o h ort will e nr oll a p pr o xi matel y 2 5 patie nts , f or a t otal of a p pr o xi mat el y 1 0 0 patie nts i n t he 
trial. 
7. 3.  
Tre at me nt Assi g n me nt  a n d R ati o n ale  
All patie nts will recei ve bar d o x ol o ne met h yl t hr o u g h o ut t he st u d y.  A d ose- titrati o n re gi me n is 
bei n g utilize d t o all o w f or i n di vi d ual d ose o pti mizati o n base d o n t olera bilit y a n d base d o n t he 
a ntici pate d ma xi mall y efficaci o us d ose of bar d o x ol o ne met h yl, w hic h ma y var y base d o n a 
patie nt’s pr otei n uria stat us at baseli ne.  Base d o n res ults fr o m pri or trials i n patie nts wit h t y pe 2 
dia betes a n d C K D, Reata has c o ncl u de d t hat lar ger bar d o x ol o ne met h yl d oses ma y be re q uire d t o 
ha ve a n o pti mal effect o n e G F R i n patie nts wit h macr oal b u mi n uria.  S pec ifi call y, e G F R 
i m pr o ve me nts i n patie nts wit h micr oal b u mi n uria were o bs er ve d wit h a 2 0 m g bar d o x ol o ne 
met h yl d ose.  I n p atie nts wit h macr oal b u mi n uria, a 3 0 m g d ose was re q uire d t o pr o d uce a 
res p o nse t hat w as si milar t o t he patie nts wit h micr oal b u mi n uria treate d at 2 0 m g.  C o nse q ue ntl y, 
t he st u d y i ncl u des d ose titrati o n u p t o a ma xi m u m d ose of 2 0 m g f or patie nts wit h A C R 
≤ 3 0 0 m g/ g a n d a ma xi m u m d ose of 3 0 m g f or patie nts wit h A C R > 3 0 0 m g/ g, as descri be d 

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bel o w.  Fr o m a saf et y pers pecti ve, t he 3 0 m g d ose ma y be ass ociat e d wit h a n i ncreas e d i nci de nce 
of na usea; h o w e ver, t he na usea e x p erie n ce d i n pre vi o us trials is ge nerall y mil d, tra nsie nt, a n d 
cli nicall y ma na gea bl e.  
7. 3. 1.  
D ose Esc al ati o n  
P atie nts will start wit h o nce- dail y d osi n g of bar d o x ol o ne met h yl at 5 m g  a n d will d ose-escalat e 
t o 1 0 m g  at Wee k 2, t o 2 0  m g  at Wee k 4, a n d t he n t o 3 0 m g  at Wee k 6 ( o nl y if baseli ne A C R 
> 3 0 0 m g / g) u nless c o ntrai n dicate d cli nicall y a n d a p pr o ve d b y t he me dical m o nit or ( Ta ble  4).  
T he d osi n g o bj ecti ve is t o titrate patie nts t o t he ma xi m u m d ose deter mi ne d b y baseli ne A C R, a n d 
mai ntai n t he ma xi m u m d ose after i nitial d ose -titrati o n.  T he i n vesti gat or s h o ul d disc uss a n y 
reas o n f or n ot d ose-es cal ati n g at Wee ks 2 a n d  4 wit h t he me dical m o nit or.  D ose e scalati o n at 
s u bse q ue nt visits is per mitte d t o meet t he d osi n g o bjecti ve.  
T a ble 4:  
B ar d o x ol o ne Met h yl D ose b y St u d y Visit a n d Al b u mi n uri a St at us 
B aseli ne A C R  
D a y 1 
Wee k 2  
Wee k 4  
Wee k 6 t o Wee k 1 2 
A C R ≤ 3 0 0 m g/ g  
5 m g 
1 0 m g 
2 0 m g 
2 0 m g 
3 0 0 m g/ g < A C R ≤ 2 5 0 0 m g/ g  
5 m g 
1 0 m g 
2 0 m g 
3 0 m g 
7. 3. 2.  
D ose De - Esc al ati o n a n d Re- Esc al ati o n 
T he i n vesti gat or ma y c h o ose t o decr ease t he p atie nt’s d ose t o t he pri or d ose (e. g., 2 0 m g t o 
1 0 m g, or 1 0 m g  t o 5 m g ), if cli nicall y i n dicate d.  D ose de-escalati o n ma y  occ ur m ore t ha n o nce, 
b ut t he mi ni m u m d ose per mitte d is 5  m g .  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 a n d m ust be d oc u me nte d.  After d ose d e-
escalati o n, patie nts  s h o ul d ret ur n f or a n u nsc h e d ule d office visit wit hi n 4 wee ks ( ± 3 da ys) t o 
c ollect cli nical c h e mistr y a n d t o perf or m t he assess me nts detaile d i n Secti o n 9. 7 . 
O nce a p atie n t’s d ose has bee n re d u ce d, d os e re-es calati o n bac k t o a hi g her d ose is per mitte d t o 
meet t he d osi n g o bjecti ve.  H o we v er, patie nts w h o d ose re- escal ate m ust ha ve a tel e p h o ne call 
1 wee k after d ose escalati o n a n d a n u nsc he d ule d office visit 2 wee ks ( ± 3 d a ys) after d ose 
escalati o n t o c ollect cli n ical c he mistr y, B N P, a n d N T- pr o B N P.  U nsc he d ul e d visits d ue t o d ose 
escalati o n s h o ul d als o 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  
Alt h o u g h t he S p o ns or i nte n ds t o c o m plete t he st u d y, t he S p o ns or reser v es t he ri g ht t o 
disc o nti n ue a c o h ort or t h e 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 uire d 
b y re g ulat or y a g e 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 g 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 sec uri n g a n y alter nati ve t h era p y t o be a d mi nistere d, 
as a p pr o priat e.  
7. 5.  
Sc he d ule of Assess me nts  
Ta ble 5  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 5: Sc he d ule of A ssess m e nts  
Assess me nt  
Scree n 
A a 
Scree n 
B b 
D a y  
1 c 
W k 1 
( P h o ne) 
D a y 3 ± 2  
W k 1  
D a y  7 ± 3  
W k 2  
( P h o ne) 
D a y 1 0 ± 2  
W k 2  
D a y 1 4 ± 3  
W k 3  
( P h o ne) 
D a y 2 1 ± 2  
W k 4  
D a y 2 8 ± 3  
W k 4  
( P h o ne) 
D a y 3 1 ± 2  
W k 5  
( P h o ne) 
D a y 3 8 ± 2  
W k 6  
D a y 4 2 ± 3  
W k 7  
( P h o ne) 
D a y 4 5 ± 2  
W k 8  
D a y 
5 6 ± 3  
W k 1 2  
or E o T d 
D a y 8 4 ± 3  
W k 1 6   
or F / U 
D a y 1 1 2 ± 3  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ e xcl usi o n 
X  
 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d baseli n e 
disease c haracteristics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht i n cli nic / B MI  
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  
X  
X  
 
Dis pe nse wei g ht diar y  
 
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
 
C ollect/re vie w wei g ht diar y  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
E C G  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ec h ocar di o gra m f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g n meas ure me nts  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
P h ysical e xa m  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Pre g na nc y test f or W O C B P g 
X  
X  
X  
 
 
 
 
 
X  
 
 
 
 
X  
X  
X  
St u d y dr u g a d mi nistrati o n  
 
 
---------------------------------------------X ----------------------------------------- 
 
Dis pe nse st u d y dr u g  
 
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
 
C ollect st u d y dr u g  
 
 
 
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
 
Tele p h o ne c o ntact  
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
 
 
A d verse e ve nt c ollecti o n  
 
 
X
h 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ki d ne y bi o ps y i 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasti n g C -pe pti de le vel j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge netic testi n g k 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical c he mistr y (i ncl. e G F R)   
X  
X  
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
B N P a n d N T -pr o B N P  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
I G F-1 a n d ser u m ket o nes 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
He mat ol o g y  
X  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Uri nal ysis a n d micr osc o p y  
X  
 
X  
 
  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Uri ne c ollecti o n f or A C R l 
 
X  
X  
 
 
 
 
 
X  
 
 
 
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Vir us ser ol o g y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P K sa m ples m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 

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a  T otal Scree ni n g peri o d s h o ul d n ot e xcee d 6 m o nt hs.  
b  Scree n B visit s h o ul d be n o m ore t ha n 3 0 da ys pri or t o Da y 1.  
c  Da y 1 is t he da y of a d mi nistrati o n of t he first d ose.  O n D a y 1, all pr oc e d ures s h o ul d be perf or m e d bef ore st u d y dr u g a d mi nistr ati o n.  
 
d  Patie nts w h o ter mi nate fr o m t he st u d y pri or t o t he Wee k  1 2  st u d y visit s h o ul d be br o u g ht bac k t o t he cli nic as s o o n as p ossi ble f or earl y ter mi nati o n assess me nts ( i.e., e n d -of - 
treat me nt visit) as well as a f oll o w-u p visit 4  wee ks later.   
e  Scree ni n g eli gi bilit y pr oce d ures d o n ot nee d t o be re peate d o n Da y 1; h o we ver, a re vie w of a n y c ha n ges i n eli gi bilit y criteria s h o ul d be e val uate d pri or t o Da y 1 pr oce d ures, a n d a 
uri ne pre g na nc y test s h o ul d be perf or me d f or W O C B P.  
f A n e c h ocar di o gra m  perf or me d at  t he Scree n  A visit or wit hi n 6 m o nt hs  pri or t o Da y 1 ma y be use d t o deter mi ne eli gi bilit y.  
g  A ser u m pre g na nc y test will be perf or me d at t he Scree n A visit f or W O C B P or 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 tests.     
h   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.  
i O nl y patie nts e nr olli n g i n t he I g A ne p hr o pat h y c o h ort or t he F S G S c o h ort are re q uire d t o ha ve a ki d ne y bi o ps y.  Patie nts wit h  defi niti ve dia g n osis of I g A ne p hr o pat h y or F S G S 
fr o m pre vi o us bi o ps y will n ot ha ve a ki d ne y bi o ps y as part of t he st u d y, b ut m ust pr o vi de dia g n osis d oc u me ntati o n fr o m pre vi o us ki d ne y bi o ps y f or eli gi bilit y.  
j O nl y patie nts e nr olli n g i n t he T 1 D c o h ort are re q uire d t o ha ve fasti n g C -pe pti de le vels ass esse d.  Patie nts s h o ul d be i nstr ucte d t o fast pri or t o st u d y visit.  
k  O nl y patie nts e nr olli n g i n t he A D P K D  disease c o h ort are re q uire d t o ha ve ge netic testi n g.  Patie nts wit h c o nfir me d P K D 1 m utati o ns fr o m pre vi o us ge netic testi n g will n ot ha ve 
ge netic testi n g perf or me d as part of t he st u d y, b ut m ust pr o vi de d oc u me ntati o n of ge netic m utati o n f or eli gi bilit y.  
l Al b u mi n t o creati ni ne rati o will be meas ure d b y first m or ni n g v oi d s p ot uri ne c ollecti o n.  A p pr o priate c o ntai ners f or t he c ollecti o n will be pr o vi de d t o t he patie nt at t he visit pri or 
t o c ollecti o n. 
m  Patie nts m ust be i nstr ucte d t o n ot ta ke t heir st u d y dr u g pri or t o c o mi n g t o t he cli nic f or visits w he n P K sa m ples will be c ollecte d.  Patie nts  m ust a d mi nister t he st u d y dr u g d ose i n 
t he cli nic o n P K sa m ple c ollecti o n visits after t he 0 h o ur P K bl o o d sa m ple is c ollecte d.  Patie nts will ha ve bl o o d sa m ples f or P K a nal ysis dra w n j ust pri or t o ( 0 h o ur) a n d after 
( 2 a n d 4 h o urs) d ose a d mi nistrati o n.   
 
 
A b bre viati o ns: E o T = e n d -of -treat me nt; E C G = electr ocar di o gra m,  F/ U = f oll o w -u p;  P K = p har mac o ki netic, W O C B P = w o me n of c hil d -bea ri n g p ote ntial 

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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 
Dia g n osis a n d mai n criteria f or i ncl usi o n:  
1.  M ale a n d f e male patie nts 1 8 ≤ a ge ≤ 6 0 u p o n st u d y c o nse nt; 
2.  Scree ni n g e G F R  ( a ver a g e of Scree n A a n d Scree n B e G F R val ues) ≥ 3 0 a n d 
≤ 9 0 m L/ mi n/ 1. 7 3 m2.  T he t w o e G F R val ues c oll ecte d at Scree n  A a n d Scree n  B visits 
use d t o deter mi ne eli gi bilit y m ust ha ve a perce nt differe n ce ≤ 2 5 %;    
3.  Al b u mi n t o creati ni ne rati o ( A C R) ≤ 2 5 0 0 m g/ g at Scree n  B visit ; 
4.  If recei vi n g a n a n gi ote nsi n c o n verti n g e nz y m e ( A C E) i n hi bit or a n d/ or a n a n gi ote nsi n II 
rece pt or bl oc ker ( A R B), patie nts s h o ul d be prescri be d t he ma xi mall y t olerate d la bele d 
dail y d ose ( M T L D D), as defi ne d i n Secti o n 9. 1. 7 , f or at least 6 w ee ks pri or t o t he 
Scree n  A visit.  T he d osa ge of A C E i n hi bit or a n d/ or A R B s h o ul d re mai n t he sa me 
t hr o u g h o ut t he re mai n der of t he st u d y (i.e., n o c ha n ge i n d osa ge or me di cati o n), a n d a n y 
p ote ntial c ha n ges s h o ul d be disc usse d wit h t he me dical m o nit or.  Patie nts n ot ta ki n g a n 
A C E i n hi bit or a n d/ or A R B beca use of a me dical c o ntrai n dicati o n ma y be eli gi ble if t he y 
ha ve disc o nti n ue d treat me nt at least 8  wee ks pri or t o t he Scree n A visit (t hese patie nts 
m ust be disc usse d wit h t he me dical m o nit or pri or t o e nr oll me nt) ; 
5.  F or patie nts e nr olli n g i n T 1 D C o h ort:  
a. Dia g n osis of t y pe 1 dia betes c o nfir me d b y fasti n g C- pe pti de le vel.  Dia g n osis m ust 
ha ve bee n ma de ≤ 3 5 years of a ge ; 
b.  Pres cri be d sta ble d os e of i ns uli n t o mai ntai n a de q uate gl uc ose c o ntr ol f or at least 
6 m o nt hs pri or t o t he Scree n A visit; 
6.  F or patie nts e nr olli n g i n I g A N C o h ort:  
a. Bi o ps y-c o nfir me d I g A n e p hr o pat h y; 
7.  F or patie nts e nr olli n g i n F S G S C o h ort: 
a. Bi o ps y-c o nfir me d F S G S t hat is n ot d ue t o k n o w n sec o n dar y ca uses i n cl u di n g m or bi d 
o besit y, decrease d r e nal mass, viral i nfecti o ns, dr u g-i n d uce d ne p hr ot o xicit y, or pri or 
hist or y of vasc ulitis; 
8.  F or patie nts e nr olli n g i n A D P K D C o h ort: 
a. Ge netic c o nfir mati o n of P K D 1 m utati o n;  
9.  A de q uate b o n e marr o w r eser ve a n d or ga n f u ncti o n at t he Scree n  A visit as f oll o ws: 
a. He mat ol o gic: A bs ol ute ne utr o p hil c o u nt > 1. 5 x 1 0
9/ L, platelets > 1 0 0 x 1 0
9/ L, 
he m o gl o bi n ( H g b) ≥ 9 g/ d L;  
b.  He patic: T otal bilir u bi n  ( T B L) ≤ 1. 5 X t he u p per li mit of n or mal ( U L N), al a ni ne 
a mi n otra nsfer ase ( A L T) a n d as part ate a mi n otra nsferas e  ( A S T) ≤ 1. 5 X U L N ; 
1 0.  A ble t o s wall o w ca ps ules ; 

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1 1.  Willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, la b orat or y tests, a n d 
ot her st u d y pr oce d ures; 
1 2.  E vi de nce of a pers o n all y si g ne d a n d date d i nf or m e d c o nse nt d oc u me nt i n dicati n g t hat t he 
patie nt  has bee n i nf or me d of all perti ne nt as pects of t he st u d y pri or t o i nitiati o n of a n y 
patie nt -ma n date d pr oce d ures.  
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 xcl u de d fr o m t he 
st u d y: 
1.  Pri or e x p os ure t o bar d o x ol o ne met h yl; 
2.  Ki d ne y or ot her s oli d or g a n tra ns pla nt reci pie nt or a pla n ne d tra ns pl a nt d uri n g t he st u d y; 
3.  B- t y pe natri uretic p e pti de ( B N P) le vel > 2 0 0 p g/ m L at Scree n  A visit; 
4.  Ac ute dial ysis or ac ut e  ki d ne y i nj ur y wit hi n 1 2 wee ks pri or t o Scree n  A visit or d uri n g 
S cree ni n g;  
5.  Ser u m al b u mi n < 3 g/ d L at Scree n  A visit;  
6.  S yste mic i m m u n os u p pressi o n f or m ore t ha n 2 w ee ks, c u m ulati vel y, wit hi n t he 1 2 wee ks 
pri or t o ra n d o mizati o n or a ntici pate d nee d f or i m m u n os u p pressi o n d uri n g t he st u d y.  
Patie nts wit h I g A N or F S G S t hat are recei vi n g pre d nis o ne at d oses ≤ 1 0 m g/ da y are 
eli gi ble f or e nr oll me nt i n t he I g A N or F S G S c o h orts, b ut d oses m ust be sta ble f or 3 0 da ys 
pri or t o Scree n A visit a n d s h o ul d be a ntici pate d t o re mai n t he sa me t hr o u g h o ut t he st u d y.  
Refer t o Secti o n  9. 3. 1  f or a d diti o nal details;   
7.  F or patie nts e nr olli n g i n I g A N C o h ort:  
a. S yste mic ma nifestati o ns of He n oc h - Sc h o nlei n p ur p ura wit hi n 1 year pri or t o 
Scree n A visit;  
b.  Ha ve use d b eli m u ma b, ec uliz u ma b, or rit u xi ma b wit hi n 6 m o nt hs pri or t o Scree n 
A visit;  
8.  F or patie nts e nr olli n g i n A D P K D C o h ort: 
a. Recei vi n g t ol va pta n; 
9.  Cere br o vas c ular e ve nt (str o ke, tra nsie nt isc h e mic attac k)  or a n e ur ys m wit hi n 6 m o nt hs 
pri or t o Scree n A visit or d uri n g Scree ni n g; 
1 0.  Hist or y of cli nicall y si g nifica nt left -si de d h eart disease a n d/ or cli nicall y si g nifica nt 
car diac disease, i n cl u di n g b ut n ot li mite d t o a n y of t he f oll o wi n g: 
a. Cli nicall y si g nifica nt c o n ge nital or ac q uire d val v ular disease;  
b.  Left ve ntric ular ejecti o n fracti o n < 4 0 % ( bas e d o n ec h ocar di o gra m p erf or m e d at 
Scree n  A visit or wit hi n 6 m o nt hs pri or t o Da y 1 ); 
c. Pericar dial c o nstricti o n ( base d o n ec h o car di o gra m perf or me d at Scree n  A visit or 
wit hi n 6 m o nt hs pri or t o Da y 1 ); 
d.  Restricti ve or c o n gesti ve car di o m y o pat h y ( b ase d o n ec h ocar di o gra m p erf or me d at 
Scree n  A visit or wit hi n 6 m o nt hs pri or t o Da y 1 ); 

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e. S y m pt o matic c or o nar y disease ( pri or m y ocar dial i nfarcti o n, perc uta n e o us 
c or o nar y i nter ve nti o n, c or o nar y arter y b y p ass graft s ur ger y, or a n gi n a); 
f. Hist or y of h os pitalizati o n f or heart fail ure; 
g.  Car diac i ns uffici e nc y, defi ne d as Ne w Y or k H ea rt Ass ociati o n Class > 2; 
h.  Hist or y of atrial fi brillati o n;  
i. Hist or y of u nsta ble arr h yt h mias; 
1 1.  U nc o ntr olle d s yste mic h y perte nsi o n as e vi de n ce d b y sitti n g s yst olic bl o o d press ure ( B P) 
> 1 6 0 m m H g or sitti n g diast olic B P > 1 0 0 m m H g at Scree n  A visit aft er a perio d of rest; 
1 2.  S yst olic B P < 9 0 m m H g at Scree n  A visit aft er a peri o d of rest; 
1 3.  Hist or y of mali g na nc y wit hi n 2 years pri or t o Scree n  A visit , wit h t he e xce pti o n of 
l ocalize d s ki n or cer vical carci n o mas; 
1 4.  U nc o ntr olle d dia betes ( H b A 1c > 1 0. 0 %) at Scree n  A visit;  
1 5.  U ntreate d or u nc o ntr olle d acti ve bacterial, f u n g al, or viral i nfecti o n; 
1 6.  Partici pati o n i n ot her i nter ve nti o nal cli nical st u dies wit hi n 3 0 da ys pri or t o Da y 1; 
1 7.  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) d uri n g Scree ni n g, w hile 
ta ki n g st u d y dr u g, a n d f or at least 3 0 da ys after t h e last d ose of st u d y dr u g is i n geste d;  
1 8.  W o me n w h o are pr e g na nt or breastfee di n g; 
1 9.  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;  
2 0.  A n y a b n or mal la b or at or y le vel t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d p ut t he 
patie nt at ris k b y trial e nr oll me nt;  
2 1.  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; 
8. 3.  
Scree ni n g Peri o d  
T he scree ni n g peri o d m ust n ot e xcee d 6 m o nt hs.  T he Scree n B visit s h o ul d be n o m ore t ha n 
3 0 da ys pri or t o Da y 1. 
8. 4.  
P atie nt Re -Scree ni n g  
Patie nts t hat scree n f ail ma y re peat t he Scree ni n g pr oce d ures t o q ualif y f or t he st u d y wit h 
a p pr o val fr o m t he m e dical m o nit or. 
8. 5.  
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 

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disc o nti n uati o n fr o m st u d y dr u g or st u d y ter mi nati o n will be rec or d e d i n t he electr o ni c cas e 
re p ort f or m ( e C R F).  
8. 5. 1.  
P atie nt Disc o nti n u ati o n Criteri a  
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.  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: 
•  Occ urre nce of a n A E or c ha n ge i n me dical stat us t hat lea ds t he i n vesti gat or t o be 
c o ncer n e 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 
•  Fe males w h o bec o me pre g na n t d uri n g t he st u d y 
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 t w o 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 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 usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
Patie nts w h o are disc o nti n ue d fr o m st u d y dr u g s h o ul d still c o nti n ue i n t he st u d y, c o m plete all 
st u d y visits, a n d u n der g o all sc he d ule d st u d y assess me nts, if p ossi ble.   
8. 5. 2.  
P atie nt Ter mi n ati o n Criteri a  
Ter mi nati o n ref ers t o a p atie nt’s st o p pi n g 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 ter mi n ati o n i ncl u de t he f oll o wi n g: 
•  L oss t o f oll o w- u p 
•  Deat h  
•  Wit h dra wal of c o nse nt 
E ver y re as o na ble eff ort s h o ul d be ma de t o c o ntact patie nts w h o d o n ot ret ur n f or a s c he d ule d 
visit .  T he i n vesti gat or s h o ul d i n q uire a b o ut t he reas o n f or wit h dra wal, re q uest t he patie nt  ret ur n 
all u n use d i n vesti gati o nal pr o d uct, re q u est t he patie nt ret ur n f or e n d-of -treat me nt a n d f oll o w- u p 
visit s (if a p plica ble), a n d f oll o w- u p wit h t he patie nt  re gardi n g a n y u nres ol ve d A Es.   

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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 deli nes a p pl y t o t he ma na ge me nt of st u d y partici pa nts:   
9. 1. 1.  
M a n a ge m e nt of Fl u i d St at us 
S pecific ris k miti gati o n pr oce d ur es will  be e m pl o y e d t o re d uce t he p ote ntial f or bar d o x ol o n e 
met h yl-i n d uce d fl ui d o verl oa d.  T hese pr oce d ures i ncl u de e xcl usi o n of pati e nts wit h a n y se vere 
re nal diseas e, defi n e d as a n e G F R val ue of < 3 0 m L/ mi n/ 1. 7 3 m 2.  T o e xcl u de patie nts wit h 
si g nifica nt car diac d ysf u ncti o n, t he st u d y will e xcl u de patie nts wit h a hist or y of left -si de d h eart 
disease.  Patie nts w h o ha ve e vi de nce of v ol u me o verl oa d at bas eli ne, defi n e d as B N P le vel of 
> 2 0 0 p g/ m L, will als o be e xcl u de d.   
La b orat or y d ata will als o be use d t o m o nit or fl ui d stat us after ra n d o mizati o n.  Patie nts t hat 
e x perie n ce a B N P > 1 0 0 p g/ m L t hat re prese nts a d o u bli n g ( or m ore) of B N P le vels fr o m Da y 1 
s h o ul d 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 diatel y a n d ret ur n t o t he cli nic 
wit hi n 1 wee k ( ± 3 da ys) f or a n u nsc h e d ule d p h ysi cal e xa mi nati o n a n d la b orat or y assess me nt b y 
t he i n vesti gat or. 
A d diti o nall y, after ra n d o mizati o n patie nts will be cl osel y 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 ve n a S p o ns or- pr o vi de d s cale t o use at h o me t o 
c ollect a n d r ec or d t heir w ei g hts dail y d uri n g t he first 8 wee ks of t he treat me nt peri o d a n d wee kl y 
t hereafter.  Patie nts w h o  e x perie n ce a fi ve - p o u n d ( 2. 3 kil o gra m) or greater i ncreas e i n wei g ht 
si nce t heir Da y 1 wei g ht d uri n g t he first 8 wee ks 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 diatel 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 xa 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.   
I n v esti gat ors ar e e nc o ura ge d t o start or i ncrease d oses of di uretics (t hiazi des, l o o p di uretics) 
earl y after r ec o g niti o n of e de ma.  T his ca n be d o ne c o nc urre ntl y wit h te m p orar y dr u g 
disc o nti n uati o n a n d re- i nitiati o n.  Patie nts ma y n ot restart t heir st u d y me dicati o n u ntil t he 
i n vesti gat or has c o m plete d a n d d oc u me nte d a n ass ess me nt of fl ui d o verl oa d.  
Patie nts w h o e x perie n ce a fi ve - p o u n d ( 2. 3 kil o gra m) or great er i ncreas e i n wei g ht after t h e 
Wee k  8 st u d y visit will be i nstr ucte d t o ret ur n t o t he cli nic f or a n u nsc he d ule d p h ysical 
e xa mi nati o n a n d la b or at or y assess me nt b y t he i n vesti gat or.  St u d y me dicati o n s h o ul d n ot be 
disc o nti n ue d u ntil t he i n vesti gat or has c o m plete d a n d d oc u me nte d a n assess me nt of fl ui d 
o verl oa d. 
I n v esti gat ors 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 me diatel y if t he y e x p erie nce s w olle n feet, c hest 
pai n, s h ort ness of breat h wit h mil d e xerti 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 assess s y m pt o ms of fl ui d o verl oa d a n d deter mi ne 
a p pr o priate m e dical 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 
is re q uire d.  At t he earliest si g n of w orse ni n g or n e w o nset peri p h eral e d e ma or ot her si g ns a n d 
s ym pt o ms of ac ute v ol u me o verl oa d, i n vesti gat or s will be e x pecte d t o re p ort if c ha n ges t o a 
patie nt’s di uretic r e gi me n ha ve bee n re q uire d t o ma na ge e d e ma . 

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9. 1. 2.  
M a n a ge m e 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) 
Nearl y all i nsta nces of el e vate d tra ns a mi na ses d ue t o bar d o x ol o ne met h yl treat me nt are e x pecte d 
t o be as y m pt o matic.  C hec k tra nsa mi nase l e vels (as well as T B L, G G T , al k ali ne p h os p hatase 
( A L P), a n d I nter nati o nal N or malize d Rati o (I N R)) 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 > 5 X U L N  
Re peat testi n g e ver y 7 2 t o 9 6 h o urs u ntil tra nsa mi nase le vels are bel o w 5 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 ns e nt. 
Disc o nti n ue st u d y dr u g a d mi nistrati o n per ma ne ntl y 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 usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
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 [ M RI ]) 
a n d assesse d if a patie 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 vat e d tra nsa mi nase 
le vels.  A d diti o nal tests/st u dies ma y be 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 m e 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 de q uate 
h y drati o n, weari n g s oc ks, a n d stretc hi n g bef ore b e dti me.  Assess me nt of le vels of electr ol y tes 
s uc h as ma g nesi u m, cal ci u m a n d p otassi u m ma y i n dicate t he nee d f or re place me nt.  If vita mi n  D 
le vels are l o w, s u p ple m e ntati o n ma y be warra nte d.  M uscle rela x a nts ma y als o hel p relie ve 
s y m pt o ms. 
9. 1. 4.  
Wei g ht L oss 
O n g oi n g assess me nts t o e ns ure t hat t he p atie 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 n ce s h y p o ma g nesae mia, defi ne d as s er 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.  
M a n a ge m e nt of Uri n ar y Pr otei n 
Alt h o u g h i ncreases i n uri nar y pr otei n wit h bar d o x ol o ne met h yl ha ve n ot bee n ass ociate d wit h 
re nal i nj ur y or l oss of ki d ne y f u ncti o n, i n vesti gat ors s h o ul d cl osel y m o nit or patie nts if uri nar y 
al b u mi n t o creati ni ne rati os i ncrease b y m ore t ha n 1 0 0 % a n d e xcee d 1 0 0 0 m g/ g f or pr otei n uria 
ass ociate d wit h ne p hr otic s y n dr o me.  Ot her c o nc urre nt si g ns of ne p hr otic s y n dr o me i ncl u de 
ser u m al b u mi n le vels bel o w 3. 5 g/ d L, peri p heral e de ma, i ncrease d bl o o d press ure, i ncrease d 
B N P, or ot her si g ns of fl ui d rete nti o n.  If ne p hr otic s y n dr o me is s us pecte d, t he me dical m o nit or 
s h o ul d be c o ns ulte d t o disc uss a p pr o priat e meas ures, w hic h ma y i ncl u de d ose a dj ust me nt, 
te m p orar y st u d y dr u g dis c o nti n uati o n, a n d/ or a d mi nistrati o n of l o o p di uretics.  

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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  
Patie nts ta ki n g t hese me dicati o ns or treat me nts will be i neli gi ble f or e nr oll me nt:  
•  A n y ot her i n vesti gati o nal dr u g or de vice as part of a n i nter ve nti o nal st u d y; 
•  C hr o nic ( > 2 w ee ks) i m m u n os u p pressi ve t hera p y, or nee d f or c ortic oster oi ds, 
i ncl u di n g t hera pies s uc h as gl uc oc ortic oi ds, o nc ol o gic pre parati o ns, a n d a nti-T N F α  
a ge nts [e. g., i nfli xi ma b ( Re mica de ®), a dali m u ma b ( H u mira ®), cert oliz u m a b pe g ol 
( Ci mzia ®), eta nerce pt ( E n brel ®)].  Gl uc o c ortic oi d i ntra- artic ular i njecti o ns, i n hale d 
pr o d ucts, t o pical pre p arati o ns, a n d nasal pre p arati o ns are all o w e d.  Patie nts wit h 
I g A N or F S G S t hat are r ecei vi n g pre d nis o n e at d oses ≤ 1 0 m g/ da y  are eli gi ble f or 
e nr oll me nt i n t he Ig A N or F S G S c o h ort, b ut pre d nis o ne d oses m ust be sta ble f or 
3 0 da ys pri or t o Scree n A visit a n d s h o ul d be a ntici pate d t o re mai n t he sa me f or t he 
re mai n der of t he st u d y.   
Patie nts w h o ta ke e xcl u d e d me dicati o ns d uri n g t h e 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 d ra wi n g a patie nt fr o m t he st u d y. 
9. 3. 2.  
Per mitte d Me dic ati o ns  
All o we d c o nc o mita nt me dicati o ns i ncl u de t he f oll o wi n g: 
•  A nti bi otics;  
•  Dail y m ult i vita mi ns or rec o m me n de d dail y s u p ple me nts; 
•  Ot her me dicati o ns i nte n d e d t o ma na ge c o nc urre nt diseases, as a ut h orize d b y t he 
treati n g p h ysicia n; 
•  Oral, i m pla nta ble, or i njecta ble c o ntrace pti ves.  
Patie nts ta ki n g me dicati o n c hr o nicall y, i ncl u di n g A C E i n hi bit ors a n d A R Bs, s h o ul d be 
mai ntai ne d o n t h ose sa m e d oses a n d d ose s c he d ul es t hr o u g h o ut t he st u d y peri o d a n d s h o ul d n ot 
ha ve a d diti o ns or c h a n ges ma de t o t heir me dicati o ns, u nless me dicall y i n dicate d a n d disc uss e d 
wit h t he Me dical M o nit or.   
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 nt s 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 r eas 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 miz ati o n  
N ot a p plica ble.  
9. 6.  
Bli n di n g  
N ot a p plica ble.   

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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: 
•  Assess 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; 
•  Perf 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 re -escalati o n;  
•  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 n i 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, cli nical c he mistr y, 
he mat ol o g y, c o nc o mita nt me dicati o ns a n d vital si g ns , as well as c ollecti o n/re vie w of w ei g ht 
diar y .  A d diti o nal c o n versati o ns ma y be 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 g e, ha ve n ot ha d re pr o d u cti 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.  
Met h o ds of Birt h C o ntr ol  
D uri n g Scree ni n g, w hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys f o ll 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 ne 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 ontrace pti ve s p o n g e, s per mici dal jell y or crea m, 
dia p hra g m [al w a 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 nal, 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; 
•  Use of a n i nt r a uteri ne d e vice; 
•  A bstai n fr o m se x ual i nter c 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 nl y acce pt a ble if it is t he preferre d a n d us ual lifest yle of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d.   
D uri n g Scree ni n g, w hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys after t he fi nal d ose of st u d y 
me dicati o n is ta ke n, males w h o ha ve f e male part ners of c hil d beari n g p ote ntial m ust practice o n e 
of t he 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);  

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•  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 met h o d (e. g., c o ntrace pti ve s p o n ge, s per mici dal jell y or crea m, 
dia p hra g m [al w a ys use wit h s per mici dal jell y/crea m]);  
•  Part ner use of a n i ntra uteri ne de vice;  
•  Pa rt ner use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal 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; 
•  A bstai n fr o m se x ual i nter c 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 nl y acce pt a ble if it is t he preferre d a n d us ual lifest yle 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 he 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 u al 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 be pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t h e 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 na 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 he 
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 h e 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-
treat me nt a n d F oll o w- u p visits m ust be perf or me d o n t he patie nt.  
Pre g na 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 w e d f or a mi ni m u m of 8 w ee 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 seri o us 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 miscarria g e. 
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 ma 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.  D ose re d ucti o ns are per mitte d t o ma na ge t olera bilit y iss ues.  Patie nts w h o 
res u me t hera p y aft er 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 sc he d ule.  

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9. 1 0.  
St u d y Pr oce d ures  
T he f oll o wi n g secti o ns d escri be eac h assess me nt.  T he ti mi n g of t hese assess me nts is n ote d i n 
Ta ble 5 .  All Da y 1 pr o ce d ures, e xce 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 m e d C o nse nt 
Writte n i nf or me d c o ns e 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 d y-relate d pr o ce d ur es are perf or m e d, a n d a g ai 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 partici 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 xcl usi o n criteria m ust be re vi e we d as i n dicate d i n Ta ble 5 .  Patie nts m ust meet all 
of t he i ncl usi o n a n d n o ne of t he e xcl usi o n criteria f or e ntr y i n t he st u d y.  I n vesti gat ors s h o ul d 
c o ntact t he me dical m o nit or wit h a n y q uesti o ns re gar di n g eli gi bilit y pri or t o ra n d o mizi n g t he 
patie nt o n Da y 1. 
9. 1 0. 3.  
De m o gr a p hics a n d B aseli ne Dise ase C h ar acteristics  
De m o gra p hic d ata i ncl u di n g se x, a ge, race, a n d et h nicit y, will be c ollecte d as i n dicate d i n  
Ta ble 5 .  Baseli ne disease c har acteristics will be c ollecte d as i n dicate d i n T a ble 5 .   
9. 1 0. 4.  
Pri or 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 fr e 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 al l o we d a n d e x cl u de d me dicati o ns s h o ul d be rec or d e d i ncl u di n g all prescri pti o n dr u gs, her b al 
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 her e p ossi ble.  C o nc o mita nt me dicati o ns will be re vie w e d as i n dicate d i n  
Ta ble 5  a n d all c h a n ges will be rec or d e d . 
9. 1 0. 5.  
Me dic al Hist or y  
A c o m plete me dical hist or y ( e. g., per patie nt re p ort) t hat i ncl u des all me dical hist or y wit hi n t he 
past 5 years m ust be c oll ecte d.  Me dical  hist or y will be rec or d e d as i n dicat e d i n Ta ble 5 .   
9. 1 0. 6.  
Hei g ht  
Hei g ht s h o ul d be meas ur e d wit h o ut f o ot wear or pr ost hetics as i n dicate d i n Ta ble 5 . 
9. 1 0. 7.  
Wei g ht a n d B o d y M ass I n de x ( B MI) 
Wei g ht m ust be meas ure d as i n dicate d i n Ta ble 5 .  B MI will be calc ulate d i n t he e C R F eac h ti me 
t he wei g ht is rec or d e d.  T he S p o ns or will pr o vi de eac h p atie nt wit h a scale t o use at h o me t o 
meas ure w ei g ht, a n d a di ar y will be pr o vi de d t o rec or d t he at- h o m e wei g ht meas ure me nts.  
Wei g hts rec or de d i n pati e nt diaries will n ot be e nt ere d i n t he e C R F.  Wei g hts s h o ul d be ta ke n at 
t he sa me ti me eac h da y a n d rec or d e d i n a patie nt diar y.  D uri n g t he first ei g ht wee ks, wei g hts 
will be rec or d e d dail y; w ee kl y wei g hts will be rec or de d t hereafter.  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 ncreases d uri n g 
t he first 8 wee ks p er t he 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 

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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.  
9. 1 0. 8.  
Electr oc a r di o gr a ms ( E C G)  
A 1 2 -lea d E C G will be r ec or de d as i n dicat e d i n T a ble 5  after t he patie nt has reste d f or at least 
1 0 mi n utes i n a s u pi ne p ositi o n.  T he heart rat e fr o m t he E C G mac hi ne s h o ul d n ot be use d as part 
of t he vital si g n meas ure me nts.  
9. 1 0. 9.  
Ec h oc ar di o gr a m 
A n ec h ocar di o gr a m will be rec or de d as i n dicate d i n Ta ble 5  t o deter mi ne p atie nt eli gi bilit y.     
9. 1 0. 1 0.  
Vit al Si g n Me as ure m e nts  
Vital si g n meas ure 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), r es pirati o n r ate, a n d b o d y te m perat ure.  Bl o o d press ure s h o ul d be ta ke n after t he 
patie 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.  Vi tal 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 5 .  
9. 1 0. 1 1.  
P h ysic al E x a mi n ati o n 
A c o m pre he nsi v e p h ysical e xa 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 pr actiti o ner as i n dicat e d i n Ta ble 5  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 xa mi 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 pirat 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 Scree ni n g m ust be rec or d e d as me dical hist or y.  F oll o wi n g t he 
e xa mi nati o n at Scree ni n g, ne w or c h a n ge d p h ysical e xa mi nati o n fi n di n gs meeti n g t he defi niti o n 
of a n a d verse e v e nt m ust be re p ort e d as a n a d vers e e ve 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. 1 2.  
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 test as i n dicate d i n Ta ble 5 , or at a n y ti me 
if pre gna n c y is s us pecte d .  Ne gati ve test res ults are re q uire 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 patie 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 pre g na n c y. 
9. 1 0. 1 3.  
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 fr o m eac h b ottle i ncl u de d i n t he st u d y dr u g kit orall y 
o nce a d a y be gi n ni n g o n Da y 1 t hr o u g h t he e n d of t he st u d y, as i n dicate d i n  
Ta ble 5 .  Eac h d ose of st u d y dr u g s h o ul d be a d mi nistere d at a p pr o xi mat el y t he sa me ti me eac h 
da y, pref era bl y i n t he m or ni n g.  O n da ys w he n P K sa m ples are c ollecte d, p atie nts m ust n ot self -
a d mi nister st u d y dr u g.  St u d y staff will a d mi nister st u d y dr u g at t he cli nic f oll o wi n g c ollecti o n of 
t he first P K sa m ple.   

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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 fr o m pre vi o us da y a n d 
d ose f or c urre nt d a y) m ust n ot be ta ke n. 
9. 1 0. 1 4.  
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 p atie nt as i n dicate d i n Ta ble 5 .  
T he patie nt will be dis pe nse d o ne treat me nt kit at Da y 1, Wee k 2, Wee k  4, Wee k  6 ( o nl y if 
baseli ne A C R > 3 0 0  m g/ g) a n d Wee k 8.  Dis pe ns e 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 5.  
Tele p h o ne C o nt act  
Patie nts will be c o ntacte d b y tele p h o ne as i n dicat e d i n Ta ble 5 .  Patie nts will be as ke d a b o ut t heir 
b o d y wei 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 valuate 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 . 
9. 1 0. 1 6.  
A d verse E ve nt C ollecti o n  
Patie nts will be o bser ve d f or ge neral a p p eara nce, prese nce of ill ness or i nj ur y, or si g ns i n dicati ve 
of a c o nc urre nt ill ness as i n dicate d i n Ta ble 5 .  Patie nts m ust be i nstr ucte d t o v ol u nteer a n y 
i nf or mati 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 h a 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 o c u me nte d.  Patie nts m ust 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 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 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 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 7.  
Ki d ne y Bi o ps y  
Ki d ne y bi o psies will be perf or me d as i n dicate d i n Ta ble 5  f or p atie nts e nr olli n g i n t he I g A N or 
F S G S c o h orts t o deter mi ne patie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be pr o vi de d i n a 
se parat e la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or.   
9. 1 0. 1 8.  
F asti n g C- Pe pti de Le vels  
Fasti n g C- pe pti de le vels will be assesse d as i n dicate d i n Ta ble 5  f or p atie nts e nr olli n g i n t he T 1 D 
c o h ort t o deter mi ne p atie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be pr o vi de d i n a se parate 
la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or. 
9. 1 0. 1 9.  
Ge netic Testi n g  
Ge netic testi n g f or P K D 1 m utati o ns f or patie nts e nr olli n g i n t he A D P K D c o h ort will be 
perf or me d as i n dicate d i n Ta ble 5  t o deter mi ne p atie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be 
pr o vi de d i n a se parate la b orat or y ma n ual pr o vi d e d t o t he i n vesti gat or 
9. 1 0. 2 0.  
Cli nic al C he mistr y  
Sa m ples will be c ollecte d f or t he f oll o wi n g cli nical c he mistr y a nal yses as i n dicate d i n Ta ble 5 : 
ferriti n, cr eati ne ki nas e ( C K), B U N, e nz y matic creati ni ne, e G F R, T B L, direct bilir u bi n, A L T, 
A S T, A L P , s o di u m, p otassi u m, calci u m, p h os p h or us, uric aci d, t otal pr otei n, gl uc ose, al b u mi n, 

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lactate de h y dr o ge nas e ( L D H), ma g nesi u m, c hl ori d e, bicar b o n ate, a n d G G T.  W o me n of c hil d-
beari n g p ote nt ial will re q uire a ser u m pre g na n c y t est ( h C G-Q ual) at t he Scree n  A visit or at a n y 
p oi nt i n ti me if a pre g na n c y is s us pecte d. 
9. 1 0. 2 0. 1.  e G F R 
 
T he e G F R val ue will be calc ulate d b y a ce ntral la b orat or y a n d pr o vi de d t o t he i n vesti gat or b y a 
facsi mile re p ort.  T he e G F R val ues c ollecte d at Scree n A a n d Scree n  B visits will be a vera g e d t o 
deter mi ne eli gi bilit y.  T he t w o e G F R val ues use d t o deter mi ne eli gi bilit y m ust ha ve a perc e nt 
differe n ce ≤ 2 5 %, as deter mi ne d b y t he f oll o wi n g calc ulati o n:   
Perce nt Differe nce = | X -Y| / (( X + Y)/ 2)  
X = 1 st e G F R v al ue ( Scree n A) 
Y = 2 n d e G F R v al ue ( Scree n B) 
| X- Y| = a bs ol ute v al ue of t he differe nce b et wee n t he t w o e G F R v al ues  
T he C hr o nic Ki d ne y Dis ease E pi de mi ol o g y C olla b orati o n ( C K D- E PI) e q u ati o n will be use d t o 
calc ulate e G F R f or eac h patie nt t hr o u g h o ut t he st u d y, usi n g t he patie nt’s a ge o n t he date of 
c o nse nt: 
eG F R ( m L/ mi n/ 1. 7 3 m2) = 1 4 1 × mi n( S cr/ κ, 1)α × ma x( S cr/ κ, 1)-1. 2 0 9 × 0. 9 9 3A ge  ×  
1. 0 1 8 [if fe male] × 1. 1 5 9 [if blac k] 
9. 1 0. 2 1.  
N- Ter mi n al Pr o -Br ai n N atri ureti c Pe pti de  ( N T-Pr o B N P) a n d Br ai n N atri uretic 
Pe pti de ( B N P)  
Sa m ples will be c ollecte d f or N T - Pr o B N P a n d B N P as i n dicate d i n Ta ble 5 .  As rece nt e xercise 
ma y  aff ect B N P a n d N T - Pr o B N P le vels, patie nts s h o ul d be all o we d t o rest f or o ne 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.  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. 
Detaile d i nstr ucti o ns o n c ollecti o n, st ora ge a n d s hi p me nt of t he sa m ple will be pr o vi de d i n a 
se parat e la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or.   
9. 1 0. 2 2.  
I ns uli n-Li ke Gr o wt h F act or -1 (I G F -1) a n d Ser u m Ket o nes  
Sa m ples will be c ollec te d f or I G F- 1 a n d s er u m ket o nes as i n dicate d i n Ta bl e 5 .  Detaile d 
i nstr ucti o ns o n c ollecti o n, st ora ge a n d s hi p me nt of t he sa m ples will be pr o vi de d i n a se parate 
la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or.   
9. 1 0. 2 3.  
He m at ol o g y 
Sa m ples will be c ollecte d f or t he f oll o wi n g he mat ol o g y assess me nts as i n dicate d i n Ta ble 5 : 
he mat ocrit, he m o gl o bi n, he m o gl o bi n A 1c, re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C) 
c o u nt, ne utr o p hils, ba n ds (if detect e d), l y m p h oc yt es, m o n oc ytes, bas o p hils (if detect e d), 
e osi n o p hils (if detecte d), a bs ol ute platelet c o u nt, mea n c or p us c ular he m o gl o bi n ( M C H), mea n 
c or p usc ular v ol u me ( M C V), a n d mea n c or p us c ular he m o gl o bi n c o nce ntrati o n ( M C H C). 

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Sa m ple ti me de viati o ns will be s u m marize d i n t he st u d y re p ort.  D ates i n t he case re p ort f or m 
s h o ul d be rec or de d i n a n u na m bi g u o us f or mat (e. g., D D M M M Y Y Y Y) a n d ti me s h o ul d be 
rec or d e d t o t he nearest mi n ute (e. g., H H: M M usi n g t he 2 4- h o ur cl oc k).  Bl o o d sa m ples n ot 
dra w n s h o ul d be r ec or d e d as s uc h. 

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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 5 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 t w o hi g h- de nsit y p ol yet h yle ne 
( H D P E) b ottles.  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 ca ps ules of 5 m g  or 1 5 m g stre n gt h bar d o x ol o ne met h yl 
or t he matc hi n g place b o ca ps ules.  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 D n u m ber; 
•  Pr ot oc ol 4 0 2- C- 1 7 0 2; 
•  Ca uti o n State me nt: Ne w Dr u g – Li mite d b y Fe d e ral La w t o I n vesti gati o nal Use.  
Kee p o ut of si g ht a n d r eac h of c hil dre n; 
•  C o ntr ol or l ot n u m ber; 
•  St ore at 2 0° – 2 5° C ( 6 8° – 7 7° F), s h ort ter m e xc ursi o ns all o we d t o 1 5° – 3 0° C ( 5 9° – 
8 6° F); 
•  Reata P har mace uticals, I nc., Ir vi n g, T X. 
A d o u ble- pa n el la bel will be prese nt e d o n t he treat me nt kit cart o n c o ntai ni n g t his a n d ot her 
i nf or mati o n as well.   
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° - 2 5° C ( 6 8° - 7 7° F), wit h s h ort ter m e xc ursi o ns all o we d t o 1 5° – 
3 0° C ( 5 9° – 8 6° F).   
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
Please ref er t o  Secti o n  9. 1 0. 1 3  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 he n u m b er a n d t y pe of ca ps ules 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 5 .  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 o nce dail y u p t hr o u g h t heir Wee k 1 2 visit u nless: ( 1) t he patie nt has bee n ot her wise 
i nstr ucte d b y t he i n vesti gat or or ( 2) t h e patie nt has bee n f or m all y disc o nti n ue d fr o m st u d y 
treat me nt.    

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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 ualit y ass ura 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 n ter- o bser v er v aria bilit y, e ver 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 c o m pletes all safet y assess me nts.  Safet y 
para meters i ncl u de vital si g n meas ure me nts, E C G res ults, A Es, S A Es, wei g ht, a n d la b orat or y 
test res ults (cli nical c he mistr y, he mat ol o g y, uri nal ysis a n d micr osc o p y).  
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 p atie nt re g ar 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 de 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 fr e 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 5  m ust be 
re p orte d, r e 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: 
•  Res ults i n deat h; 
•  Is life-t hreate ni n g; 
•  Re 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; 
•  Res 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 n cti 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 ver e. 
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 wev er, 
t he y ma y be 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 h e 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 na 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 d y (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 5  or 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, as a p pr o priate ).  
Certai n pre g na n c 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 5  or 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, as a p pr o pri ate), i n cl u di n g e ve nts res ulti n g fr o m pr ot oc ol-
ass ociate d pr o ce d ur es as defi ne d i n rel e va nt le gislati o n, a n d re gar dless 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 h e 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 o m pleti o n of acc urate safet 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 dee 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 nee 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 nce 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 res ulti n g fr o m a b n or mal la b orat or y test val ues, p h ysical e x a mi nati o n fi n di n gs, or E C G 
a b n or malities, or fr o m ot her d oc u me nts t hat are rele va nt t o patie nt safet y. 
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 w i n g classificati o ns a n d criteria t o c h aracterize t h e 
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 nl i kel y Relate d : T his relati 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 relati 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 p atter 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 Relate d : T his relati o ns hi p s u g gests t hat a reas o n a ble te m p oral 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 pr e vi o usl y re p orte d a d vers e reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt 

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base d o n t he i n vesti gat 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 Relate 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 exists 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 gressi o n/e x pr essi 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 g ra de t he se verit y of t he 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 ca 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 ca usi n g i na bilit y t o perf 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) s h o ul d 
be d oc u me nte d as me dical hist or y.  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 ( +/- 3 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, 
re gar dl ess of t he r elati 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 i ncl u des t y pe 
of e ve nt, date of o nset, d ate of r es 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.  
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 otal 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 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 v e 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 
(eit her r et 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 5 , as a p pr o priate. 
A Es 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 gr essi 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) are c o nsi dere d c o nc urre nt me dical 
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 ors e 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 h o ul d 
be rec or de d as a n A E.  I n vesti gat ors s h o ul d e ns ure t hat t he A E ter m rec or d e d ca pt ures t he 
c ha n ge i n t he c o n diti o n ( e. g., “ w ors e ni n g of …”).  A n y i m pr o ve me nt i n c o n diti o n s h o ul d be 
d oc u me nte d per  Secti o n  9. 1 0. 1 1 . 
Eac h A E s h o ul d be rec or de d t o re pr ese nt a si n gle dia g n osis.  Acc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b or at or y test val ues or E C G fi n di n gs) or s y m pt o ms s h o ul d 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 h o ul d be rec or d e d as a n 

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A E(s).  C ha n ges i n la b or at or y test val ues or E C G para meters are o nl y 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 on or i nter ve nti o n is re q uire 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 m al p h ysi ol o gical fl uct uati o n).  If 
a b n or mal la b or at or y test val ues or E C G fi n di n gs are t he res ult of pat h ol o g y f or w hic h t here is a n 
o verall dia g n osis ( e. g., i n creas e d cr eati ni ne le v els i n re nal fail ure), o nl y t he dia g n osis s h o ul d be 
re p orte d as a n A E. 
Electi ve pr oce d ures (s ur g eries or t hera pies) t h at w ere sc h e d ule d pri or t o t he start of A E 
c ollecti o n are n ot c o nsi dere d A Es.  T h ese electi ve pr oce d ures s h o ul d n ot be rec or de d as A Es, b ut 
s h o ul d be d oc u me nte d i n t he patie nt’s s o urce d oc u me nts as electi ve (e. g., el ecti 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 is perf or me d earl y (e. g., as a n e mer g e nc y) 
beca 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 h o ul d 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 c o nsi ders seri o us acc or di n g t o t he pre vi o usl y descri be d criteri a m ust be 
re p orte 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 h e e ve nt.  
T o re p ort t he S A E, f a x t he c o m plete d S A E f or m t o Me d pace (fa x n u m b ers liste d i n Ta ble  7) 
wit hi n 2 4 h o urs of a war e ness. 
T a ble 7: 
S A E Re p orti n g C o nt act I nf or m ati o n 
  
 
 
 
F or q uesti o ns re g ar 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 ger, me dic al m o nit or, or 
Me d p ace Cli nic al S afet y . 
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 s u bject 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 
s u bject dies. 
Wit hi n 2 4 h o urs of recei pt of ne w i nf or mati o n, t h e u p date d f oll o w- u p S A E f or m, al o n g wit h a n y 
s u p p orti n g d oc u me ntati o n (e. g., s u bject disc har ge s u m mar y or a ut o ps y re p orts), s h o ul d be fa x e d 
t o Me d pace Cli nical Saf et y . 
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 da r 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 lif e -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 he 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 ose re g ulat or y a g e 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 g ar di n g seri o us a n d 

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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 nstit uti o nal re vie w 
b oar d (I R B) or Et hics C o m mittee ( E C), as a p pr o priate.  
Pri nci pal i n vesti gat ors ar e res p o nsi ble f or i nf o r 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 nee 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 ar e 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 nces . 
•  H y p ote nsi o n 
•  H y per kale mia  
•  Fati g ue 
•  E de ma/fl ui d rete nti o n  
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 saf et y si g nal is detecte d.  Re g ular safet 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 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 M o nit ori n g  
T he st u d y m o nit or, as a r e prese nt ati ve of t he S p o ns or, is o bli gate d t o f oll o w t he st u d y c o n d uct 
cl osel y.  I n d oi n g s o, t he m o nit or will visit t he pri nci pal i n vesti gat or a n d st u d y facilities 
peri o dicall y, a n d will mai ntai n necessar y t ele p h o n e a n d letter c o ntact.  T he m o nit or will mai ntai n 
c urre nt k n o wl e d ge of t he st u d y acti vit y of t he i n vesti gat or a n d his/ her staff t hr o u g h o bser vati o n, 
re vie w of st u d y r ec or ds a n d s o urce d oc u m e ntati o n, a n d disc ussi o n of t he c o n d uct of t he st u d y 
wit h t he i n vesti gat ors a n d staff. 
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 nfere nce o n Har m o nisati o n (I C H) 
g ui deli ne E 6( R 1): G o o d Cli 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 ur es. 
Eac h i n vesti gat or is e x p ecte d t o ma ke a reas o n a bl e eff ort t o acc o m m o dat e t he m o nit or w he n 
m o nit ori n g visits are necessar y a n d t o b e a vaila bl e d uri n g t he site visit.  F urt her m ore, t he 
m o nit or s h o ul d be pr o vi de d direct access t o s o urce data a n d d oc u m e nts f or trial- relat e d 
m o nit ori n g a n d i nter net d ur i n g t he visit. 
1 3. 2.  
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 pecti o ns, b y pr o vi di n g direct access t o 
all st u d y rec 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 a grees 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 U S F o o d a n d Dr u g A d mi nistrati o n (F D A ), a n d ot her rele v a nt 
re 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 h o ul d pr o m ptl y n otif y t he 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 pr o m ptl y f or war d c o pies of a n y a u dit re p orts 
recei v e d t o t he S p o ns or or desi g nee. 

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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 uire me nts, 
Reata ma y c o n d u ct a q ualit y ass ura nce 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 f acilities .   
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 de 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 v a 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 y ear 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 
partici 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 be detecte d d uri n g t he Scree ni n g  pr o cess.  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 nee 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 nci 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 der al Re g ulati o ns ( C F R ) b y pr o vi di n g t he esse ntial d oc u me nts 
t o t he S p o ns or or desi g nee, 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 ori gi nal 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 xec 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 ne d a n d dat e d b y t he pri nci pal i n vesti gat or s 
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 nee 
t o s u b mit c o m plete a n d acc urate 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; 
•  La b orat or y certificati o ns a n d n or mal ra n g es 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 r es 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 heir 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 ysical i nj uries, or da ma g e 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 t o 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 be 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 ulta 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 (I R B) or Et hics C o m mittee ( E C) 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 ne 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 re q uire d t o si g n a pr ot oc 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 hair pers o n or desi g nee 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 nci pal i n vesti ga t or is res p o nsi ble f or o btai ni n g re vie ws of t he cli nical researc h at i nter v als 
s pecifie d b y t he I R B/ E C, b ut n ot e xcee 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 nee wit h writte n d oc u me ntati o n of re vie ws of t he cli nical researc 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 desi 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 d a nce wit h t he 
I C H H ar m o nise d Tri p artite 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 der al Re g ula ti 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 H elsi 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 d a nce wit h t he I nter n ati o nal 
C o nfere nce o n Har m o nizati o n (I C H) f or G ui da nce f or I n d ustr y o n G o o d Cli nical Practice ( G C P) 
I C H E 6( R 1) [htt p:// w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d u cts/ G ui deli nes/ 
Effic ac y/ E 6/ E 6 _ R 1 _ G ui deli ne. p df ] a n d t h e pri nci ples of t he Declarati o n of Helsi n ki 
[htt ps:// w w w. w ma. net/ p olicies - p ost/ w ma-decl arati o n - of- helsi n ki-et hical- pri nci ples-f or-m e dical -
researc h-i n v ol vi n g- h u ma n-s u bjects/].  T he pri n ci pal i n vesti gat or m ust c o n d uct all as pects of t his 
st u d y i n acc or da n ce wit h all nati 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 nite d States I n v esti gati o nal Ne w Dr u g 
A p plicati o n, a si g ne 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 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 o r sites o utsi de of t he 
U nite d States, t he si g ne d c o nse nt will be o btai 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 D eclarati o n of Helsi n ki.   A n i nf or me d c o nse nt te m plat e 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 w e d b y t he S p o ns or or 
desi g nee bef ore I R B / E C s u b missi o n.  O nce re vie we d, t he c o ns e nt will be s u b mitte d b y t he 
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 val bef ore t he start of t he 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 v e 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 ve n a f ull e x pla n ati o n of t he st u d y a n d be 
all o wed 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 he st u d y, t he patie nt 
will be as ke d t o gi ve 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 ncl 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 r e g ulati o n), I R B/ E C-a p pr o v e 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 or e c o n d u cti n g a n y st u d y-s pecific pr o ce d ures ( i.e., all of t he pr oce d ures d escri b e d i n 
t he pr ot 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 g este 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 gat 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 be pr o vi de d per a p plica ble la w) t o t he p atie nt.  T he ori gi nal f or m will be mai ntai ne d i n 
t he patie 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, re 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 li 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 xce 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 he 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 or 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 ma y n ot 
discl ose or use f or a n y p ur p ose ot her t ha n p erf 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 gree 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 v al 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 g es will bec o me effecti ve o nl y after a p pr o val of t he S p o ns or, t he 
i n vesti gat or, t he I R B/ E C, a n d w her e necessar y, t h e a p plica ble re g ulat or y a ge nc y.  I n cases w h e n 
t he pr ot oc ol is m o difie d t o e n ha nce patie nt s afet 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 he I R B/ E C of all pr o ble ms i n v ol vi n g ris ks t o 
patie nts acc or di n g t o nati 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 re g ulat 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 u st 
be n otifie d of all pr ot oc ol de viati o ns i n a ti mel y ma 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 a n 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 
re q uire me nt(s).  Rec 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 v el o p me nt of t he 
i n vesti gati o nal pr o d uct.  If t he i n vesti gat or wit h dra ws fr o m t he res p o nsi bilit y of kee pi n g t he 
st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a p ers 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 writi 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 r e 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 ( E D C) will be use d t o ca pt u re d ata 
electr o nicall y f or all pati e nts e nr olle d i n t he st u d y. 

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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 hate 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 vie w all pla n n e 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 ur ac y of t he data, t o pr o tect 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 be a vaila ble t o t he st u d y i n vesti gat ors.  T he S p o ns or als o 
e nc o ura g es 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 lea 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 mi nza de h M A, Reis ma n S A, Vaziri N D, et al. T he s y nt hetic triter pe n oi d R T A d h 4 0 4 ( C D D O-
d h T F E A) rest ores e n d ot h elial f u ncti o n i m paire d b y re d uce d Nrf 2 acti vit y i n c hr o nic ki d ne y 
disease.  Re d o x Bi ol 2 0 1 3; 1: 5 2 7- 3 1. 
de Zee u w D, A kiza wa T, A u d h ya P, et al. Bar d o x ol o ne met h yl i n t y pe 2 dia betes a n d sta g e 4 
c hr o nic ki d ne y disease.  N E n gl J Me d 2 0 1 3; 3 6 9: 2 4 9 2- 5 0 3. 
Di n g Y, Sti d ha m R D, B u meister R, et al. T he s y nt hetic triter pe n oi d, R T A 4 0 5, i ncreas es t he 
gl o mer ular filtrati o n rat e a n d re d uces a n gi ote nsi n II-i n d uce d c o ntr acti o n of gl o mer ula r mesa n gial 
cells.  Ki d ne y I nt 2 0 1 3; 8 3: 8 4 5- 5 4. 
Di n k o va- K ost o va A T, Li 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 r es p o nse: c orrelati o ns of pr otecti o n a g ai nst o xi da nt a n d i nfla m mat or y stress.  
Pr oc  Natl Aca d Sci U S A 2 0 0 5; 1 0 2: 4 5 8 4- 9. 
Fer g us o n D A, Wi gle y W C, Heiss E. Bar d o x ol o ne met h yl ( B A R D) i m pr o ves mar kers of 
e n d ot helial f u ncti o n i n c ult ure d cells.  P oster A m erica n S ociet y of Ne p hr ol o g y ( A S N) 2 0 1 0. 
Jia n g T, Tia n F, Z h e n g H, et al. Nrf 2 s u p press es l u pus ne p hritis t hr o u g h i n hi biti o n of o xi dati ve 
i nj ur y a n d t he N F- k B- me diate d i nfla m mat or y res p o nse.  Ki d ne y I nt 2 0 1 4; 8 5: 3 3 3- 4 3. 
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes ( K DI G O) Bl o o d Press ure W or k Gr o u p. K DI G O 
Cli nical Practice G ui deli ne f or t he Ma na ge me nt of Bl o o d Press ure i n C hr o nic Ki d ne y 
Disease.  Ki d ne y I nt S u p pl  2 0 1 2; 2: 3 3 7 – 4 1 4. 
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