A Phase 2 Trial to Evaluate Safety, Tolerability, and Efficacy of Bardoxolone Methyl in Patients With Chronic Kidney Disease at Risk of Rapid Progression
Phase: PHASE2
Conditions: Chronic Kidney Diseases
Sponsor: Biogen

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A P H A S E 2 T RI A L T O E V A L U A T E S A F E T Y, 
T O L E R A BI LI 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 C H R O NI C KI D N E Y 
DI S E A S E  A T RI S K O F R A PI D P R O G R E S SI O N  
 
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T he i nf or mati o n c o ntai ne d herei n is c o nfi de ntial a n d t he pr o prietar y pr o pert y of Reata 
P har mace uticals, I nc. a n d a n y u n a ut h orize d use or discl os ure of s uc h i nf or mati o n wit h o ut t he 
pri or writte n a ut h orizati o n of Reata P har mace uticals, I n c. is e x pressl y pr o hi bite d.  

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I N V E S TI G A T O R’ S A G R E EM E N T  
 
I h a ve rea d t he 4 0 2 -C -2 0 0 2 cli nical st u d y pr ot o c ol , versi o n 2. 0, a n d a gree t o c o n d uct t he st u d y as 
o utli ne d.  I ha v e recei v e d a n d rea d t h e I n vesti gat or’s Br oc h ure f or bar d o x ol o ne met h yl .  I a gree 
t o mai ntai n t he c o nfi de ntialit y of all i nf or mati o n r ecei ve d or de vel o p e 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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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  
N a me of Acti ve I n gre die nt:  
bar d o x ol o ne met h yl   
P r ot oc ol N u m ber: 4 0 2 -C -2 0 0 2  
P h ase: 2  
C o u ntr y:  U nite d States  
Title of St u d y:  
A P hase 2 Trial t o E val uate Safet y, T olera bilit y , a n d Efficac y of Bar d o x ol o ne Met h yl i n Patie nts wit h 
C hr o nic Ki d ne y Disease at Ris k  of Ra pi d Pr o gressi o n ( M E R LI N) 
St u d y C e nter (s): U p t o 1 1  st u d y ce nters 
St u die d Pe ri o d ( ye ars):  
Esti mate d date first patie nt e nr olle d: Dece m ber 2 0 2 0  
Esti mate d date last patie nt c o m plete d: J ul y 2 0 2 1  
P h ase of D e vel o p me nt: 2  
 
P o p ul ati o n: Patie nts wit h C hr o nic Ki d ne y Disease ( C K D) at Ris k of Ra pi d Pr o gressi o n  
O bjecti ves:  
P ri m ar y:  
•  
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) at Wee k 1 2  
•  
T o assess t he safet y a n d t olera bilit y of bar d o x ol o ne met h yl  
Sec o n d ar y:  
•  
T o c haracterize t he e G F R res p o nse at Wee k 1 2 acr oss differe nt eti ol o gies of C hr o nic K i d ne y 
D isease 
E x pl or at or y:  
•  
T o c haracterize c ha n ge i n e G F R d uri n g t he off -treat me nt peri o d  
•  
  
Met h o d ol o g y:  
T his m ulti -ce nter, ra n d o mize d d o u ble -bli n d , place b o -c o ntr olle d , 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 C K D d ue t o m ulti ple 
eti ol o gies at ris k of ra pi d disease pr o gressi o n.  A p pr o xi matel y  7 0 patie nts will be e nr ol le d a n d 
ra n d o mize d 1: 1 t o eit her bar d o x ol o ne met h yl or place b o.  Ra n d o mizati o n will be stratifie d usi n g t he  
Ki d ne y Disease : I m pr o vi n g Gl o bal O utc o mes (K DI G O ) C K D pr o gressi o n  ris k heat ma p  (strat u m 1 = 
yell o w or ora n ge ; strat u m 2 = re d or dar k re d) base d o n  scree ni n g e G F R a n d U A C R usi n g 
Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt ( R T S M ). 
T ar get p atie nt p o p ulati o n: m ales a n d fe male s wit h C K D sec o n dar y t o var yi n g  eti ol o gies will be 
e nr olle d fr o m a ge 1 8 -7 5  ye ars wit h e G F R ≥ 2 0  t o <  6 0 m L/ mi n/ 1. 7 3 m 2 , a n d ot her ris k fact ors f or 
ra pi d pr o gressi o n of ki d ne y disease.  Patie nt s wit h gl o mer ul o ne p hritis re q uiri n g i m m u n os u p pressi ve 
treat me nt wit hi n 6 m o nt hs or  a hist or y of ra pi dl y pro gressi ve gl o mer ul o ne p hritis  will be e xcl u de d.  
N o si n gle C K D eti ol o g y ( h y perte nsi ve, dia betic, or ot her) ma y  e nr oll a p pr o xi matel y ≥ 4 0 % i n t he 
trial. 

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Trial desi g n i ncl u des scree ni n g, treat me nt peri o d, a n d off -treat me nt peri o d ( O T). 
Scree ni n g peri o d  i ncl u des 2 visits ( Scree n A a n d Scree n B), a n d t he d urati o n of scree ni n g (fr o m 
Scree n A t o Da y 1) ma y n ot e xcee d 4 wee ks.  T he Scree n A a n d B visits ma y be c o m plete d o n 
c o nsec uti ve da ys.  
 
Tre at me nt peri o d  ( Da y 1 t hr o u g h Wee k 1 2): Incl u des 1 3 visits (cli ni c a n d p h o ne visits).  Patie nts 
w h o s uccessf ull y meet t he e nr oll me nt criteria will be ra n d o mize d usi n g  R T S M .  P ost ra n d o mizati o n 
st u d y dr u g will be dis pe nse d acc or di n gl y.  Da y 1 of t he treat me nt peri o d is t he da y of ra n d o mizati o n . 
 
T he ma xi m u m bar d o x ol o ne m et h yl d ose will be deter mi ne d b y baseli ne pr otei n uria stat us.  Patie nts 
wit h baseli ne uri ne  al b u mi n  t o creati ni ne rati o ( UA 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 U 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.   
 
Q ualifie d p atie nts will be ra n d o mize d 1: 1 t o recei ve eit her bar d o x ol o ne met h yl or place b o o nce dail y 
( prefera bl y i n t he m or ni n g) t hr o u g h o ut a 1 2 -wee k  d osi n g peri o d .  Ra n d o mizati o n will be strat ifie d 
usi n g  t he K DI G O C K D pr o gressi o n ris k heat ma p (strat u m 1 = yell o w or ora n ge; strat u m 2 = re d or 
dar k re d) base d o n scree ni n g e G F R a n d U A C R  usi n g R T S M .  Patie nts  ra n d o mize d t o bar d o x ol o ne 
met h yl  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 U A C R >  3 0 0  m g/ g) u nless c o ntrai n dicate d 
cli nicall y, w hic h s h o ul d be disc usse d wit h t he me dical m o nit or.  Patie nts ra n d o mize d t o place b o will 
re mai n o n place b o t hr o u g h o ut t he st u d y a n d will f oll o w t he sa me titrati o n t o mai ntai n t he bli n d .  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. 
 
P atie 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.  Patie nts  will be assesse d 
d uri n g treat me nt at Da y 1, 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 5 , a n d 4 5.  Date of last d ose  a n d t he e n d-of -treat me nt assess me nts mar k t he e n d of t he treat me nt 
peri o d.  Patie nts will n ot recei ve st u d y dr u g d uri n g a 5 -wee k o ff-treat me nt peri o d bet wee n Wee ks 1 2 
a n d 17 .  
 
Off -tre at me nt peri o d ( O T):  Incl u de s 5 visits re q uiri n g vari o us assess me nts t o c haracterize e G F R 
fr o m t he ti me of st u d y dr u g disc o nti n uati o n t hr o u g h Da y 3 5 off -treat me nt.  Patie nts will be assesse d 
o n Da y 3 O T, Da y 7 O T, Da y 1 4 O T, Da y 2 1 O T, Da y 2 8 O T , a n d Da y 3 5  O T .  T he O T da y 
c orres p o n ds t o da ys after last d ose.  Da y 1 O T is t he first da y after recei vi n g t he last d ose.  A n y 
patie nt w h o per ma ne ntl y disc o nti n ues st u d y treat me nt earl y  will  f oll o w t he sa me O T assess me nt 
sc he d ule.  
 
E n d -of -st u d y ( E O S):  All patie nts , i ncl u di n g patie nts w h o disc o nti n ue treat me nt earl y,  s h o ul d 
c o m plete  t he E O S visit  1 7 wee ks after ra n d o mizati o n.  
 
All eff orts s h o ul d be ma de t o f oll o w all ra n d o mize d patie nts f or t he f ull O T peri o d  of t he trial, an d t he 
e n d-of -st u d y visit ( Wee k 1 7), i ncl u di n g patie nts w h o disc o nti n ue dr u g earl y.  
N u m ber of P atie nts (P l a n ne d):  
A p pr o xi matel y  7 0 patie nts will be e nr olle d.  

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Di a g n osis a n d M ai n C riteri a f or Incl usi o n:  
I ncl usi o n criteria: 
1.  Male a n d fe male patie nts 1 8 ≤ a ge ≤ 7 5  u p o n st u d y  c o nse nt; 
2.  Dia g n osis of C K D  wit h scree ni n g e G F R (a vera ge of Scree n A a n d Scree n B e G F R val ues) 
≥ 2 0  t o <  6 0 m L/ mi n/ 1. 7 3 m 2  
a. 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.  Patie nt m ust meet  at least  o ne of t he f oll o wi n g criteria : 
a. U A C R  ≥ 3 0 0 m g/ g; O R  
b.  e G F R decli ne at a rate of ≥ 4 m L / mi n/ 1. 7 3 m2 i n pri or year; O R  
c. He mat uria  ( gl o mer ular) defi ne d as >  5 -1 0 re d bl o o d cells (R B C s) per hi g h p o wer  fiel d 
( H P F, ma n ual met h o d ), or d oc u me nte d hist or y of p os iti ve uri nar y di pstic k  f or bl o o d i n 
pri or year , or macr osco pic he mat uria i n pri or 3 year s; 
4.  S yst olic bl o o d press ure ≤ 1 5 0 m m H g a n d diast olic bl o o d press ure ≤ 9 0 m m H g at Scree n A  or 
Scree n B  visit after a peri o d of rest  (≥ 5 mi n utes) ; 
5.  Treat me nt wit h  a n a n gi ote nsi n -c o n verti n g e nz y me i n hi bit or ( A C Ei) a n d/ or a n a n gi ote nsi n II 
rece pt or bl oc ker ( A R B) at t he ma xi mall y t olerate d la bele d dail y d ose  f or at least 6 wee ks 
pri or t o t he Scree n A visit a n d wit h n o a ntici pate d c ha n ges t o d ose(s) d uri n g st u d y 
partici pati o n .  If treat me nt wit h A C E i a n d/ or A R B is  c o ntrai n dicat e d or n ot i n dicate d , t he 
patie nt m ust n ot ha ve bee n e x p ose d t o  a n A C E i a n d/ or A R B f or at least 8 wee ks pri or t o t he 
Scree n A  visit ; 
6.  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 09/ L, he m o gl o bi n ( H g b) ≥ 8. 0 
g/ d L ; 
7.  T otal bilir u bi n ( T B L), 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 t he u p per li mit of n or mal  ( U L N) b ot h at Scree n A a n d Scree n B visits;  
8.  A ble t o s wall o w  ca ps ules; 
9.  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 0.  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 he patie nt 
has bee n i nf or me d of all perti ne nt as pects a n d ris k 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.  
E xcl usi o n criteria:  
1.  Pri or e x p os ure t o bar d o x ol o ne met h yl ; 
2.  C K D sec o n dar y t o or ass ociate d wit h a n y of t he f oll o wi n g : 
a. Hist or y of ra pi dl y pr o gressi ve gl o mer ul o ne p hritis ( R P G N)  
b.  Gl o mer ul o ne p hritis re q uiri n g i m m u n os u p pressi o n i n t he last 6 m o nt hs pri or t o Scree n A; 

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3.  C o nc o mita nt use of t ol va pta n.  Patie nts  pre vi o usl y treate d wit h t ol va pta n m ust ha ve 
disc o nti n ue d dr u g f or at least 3 m o nt hs pri or t o Scree n A visit ; 
4.  Patie nts treate d wit h p ol yc ystic ki d ne y disease -m o dif yi n g a ge nts (s o mat ostati n a nal o g ues) 
wit hi n 3 m o nt hs pri or t o t he Scree n A  visit;  
5.  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 Da y 1 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; 
6.  Patie nts c urre ntl y ta ki n g a s o di u m/ gl uc ose c otra ns p orter -2 i n hi bit or ( S G L T 2i), re q uiri n g 
d ose a dj ust me nts wi t hi n 1 2 wee ks pri or t o Da y 1 or if d ose is a ntici pate d t o c ha n ge d uri n g 
st u d y partici pati o n; 
7.  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;  
8.  U nc o ntr olle d dia betes ( H b A 1c > 1 1. 0 %) at Scree n A  visit;  
9.  Ser u m al b u mi n < 3 g/ d L at Scree n A  v isit; 
1 0.  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; 
1 1.  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;  
1 2.  Hist or y of 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. 
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 % ( base d o n hist or ical ec h ocar di o gra m)  
c. 
Hist or y of h os pitalizati o n f or heart  fail ure wit hi n 1 2 m o nt hs pr i or t o Scree n A 
d.  
Ne w Y or k Heart Ass ociati o n Class III or  I V c o n gesti ve heart fail ure (C H F ) 
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 unsta bl e a n gi na)  wit hi n 1 2 m o nt hs 
p ri or t o Scree n A 
f. 
Pericar dial c o nstricti o n ( base d o n hist orical ec h ocar di o gra m) 
g.  
Restricti ve or c o n gesti ve car di o m y o pat h y ( base d o n hist orical ec h ocar di o gra m)  
h.  
U nc o ntr olle d atrial  fi brillati o n 
i. 
Hist or y of u nsta ble  arr h yt h mias ; 
1 3.  S yst olic bl o o d press ure <  9 0 m m H g at Scree n A visit after a peri o d of  rest; 
1 4.  B o d y mass i n de x < 1 8. 5 k g/ m 2 at t he Scree n A  visit;  
1 5.  Hist or y of mali g na nc y wit hi n 5 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 6.  C or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) dia g n osis wit hi n 3 m o nt hs pri or t o Scree n A or ha ve 
e ver re q uire d C O VI D -1 9 relate d h os pitalizati o n;  

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1 7.  Partici pati o n i n ot her i nter ve nti o nal cli nical st u dies wit hi n 3  m o nt hs ( or if rele va nt 5 half -
li ves of t hat st u d y me dicati o n, w hic he ver is t he l o n ger) pri or t o Scree n B; 
1 8.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part ners of 
c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) 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 he last d ose of st u d y dr u g is  i n geste d; 
1 9.  W o me n w h o are pre g na nt or breastfee di n g;  
2 0.  Nee d f or o n g oi n g use of  str o n g a n d/ or m o derate  C Y P 3 A 4 i n hi bit ors a n d i n d ucers ; 
2 1.  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 2.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na ble t o c o m pl y wit h t he re q uire me nts of t he 
st u d y pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n. 
I n vesti g ati o n al P r o d uct , D os a ge a n d M o de of A d mi nistr ati o n :  
Bar d o x ol o ne met h yl at 5, 1 0, 2 0 or 3 0 m g  will be a d mi nistere d orall y o nc e dail y t hr o u g h Wee k 1 2 . 
D ur ati o n of T re at me nt :  
Bar d o x ol o ne met h yl will be a d mi nistere d o nce dail y t hr o u g h Wee k 1 2. 
Ref ere nce T her a p y, D os a ge a n d M o de of A d mi nistr ati o n:  
Matc hi n g p lace b o will be a d mi nistere d orall y o nce dail y t hr o u g h Wee k 1 2. 
Criteri a f or E v al u ati o n : 
Effic ac y  e n d p oi nts: 
Pri mar y efficac y e n d p oi nt: e G F R c ha n ge fr o m baseli ne at Wee k 1 2.  
Sec o n dar y efficac y e n d p oi nt: e G F R c ha n ge fr o m baseli ne at Wee k 1 2 b y C K D eti ol o g y. 
E x pl orat or y efficac y e n d p oi nt: e G F R c ha n ge fr o m baseli ne  at off -treat me nt Da ys 3, 7, 1 4, 2 1 , 2 8, a n d 
3 5 . 
S af et y  e n d p oi nts : 
L a b orat or y 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), vital si g n 
meas ure me nts, electr ocar di o gra m ( E C G) res ults, wei g ht, a d verse e ve nts ( A Es), a n d seri o us a d verse 
e ve nts ( S A Es). 
Ot her e n d p oi nts:  
C o m m o n g e netic  varia nts o verall a n d b y C K D eti ol o g y. 
St atistic al Met h o ds : 
Sa m ple size : 
Wit h 7 0 patie nts e nr olle d  (3 5 i n eac h gr o u p), t he st u d y will ha ve a p pr o xi matel y 8 0 % p o wer t o detect 
a differe nce bet wee n t he t w o treat me nt gr o u ps i n c ha n ge fr o m baseli ne i n e G F R  of 5. 9  m L/ mi n/ 1. 7 3 
m 2 f or t he pri mar y e n d p oi nt at Wee k 1 2.  T he p o wer calc ulati o n, w hic h was base d o n a t w o-si de d 
t w o-sa m ple t-test, ass u mes t he f oll o wi n g: 
•  
T w o -si de d T y pe I err or rate of 0. 0 5;  
•  
Sta n dar d de viati o n of c ha n ge fr o m baseli ne i n e G F R of 8  m L/ mi n/ 1. 7 3  m 2; 
•  
A c ha n ge fr o m baseli ne i n e G F R of a p pr o xi matel y 5. 9  m L/ mi n/ 1. 7 3 m 2;  
•  
1 5 % dr o p -o ut  a n d missi n g data will n ot be i m p ute d . 

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A nal ysis of t he  pri mar y e n d p oi nt will be base d o n t he i nte nt -t o-treat (I T T) p o p ulati o n a n d a nal yze d  
us i n g mi xe d -m o del re peat e d meas ures ( M M R M) wit h a n u nstr uct ure d c o varia nce str uct ure .  T he 
a nal ysis  met h o d is e x pecte d t o ha ve at least as m uc h  p o wer as  t he t w o-sa m ple t-test use d f or st u d y 
pla n ni n g.   A p pr o priate se nsiti vit y a nal yses of t he pri mar y a nal ysis will be s pecifie d i n t he S tatistical 
A nal ysis P la n (S A P ).  T he sec o n dar y efficac y e n d p oi nt will be teste d f or s ufficie ntl y lar ge s u b gr o u ps, 
b ut t he st u d y is n ot p o were d t o s h o w efficac y i n t he sec o ndar y effi cac y e n d p oi nt . 
 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 C K D at Ris k of R a pi d 
Pr o g ressi o n  
 
 
Sc = Scree n i n g, U A C R  = uri ne  al b u mi n t o creatini ne rati o , 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 O S = e n d of st u d y, O T = off -treat me nt peri o d. 

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3.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F 
FI G U R 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 EM 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, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ...............1 1  
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 8  
5.  
I N T R O D U C TI O N ......................................................................................................2 1  
5. 1.  
Cli nical E x perie nce wit h Bar d o x ol o ne Met h yl  ..........................................................2 1  
5. 1. 1.  
Efficac y  .......................................................................................................................2 2  
5. 1. 2.  
Safet y a n d T olera bilit y  ...............................................................................................2 6  
5. 1. 2. 1.  
Fl ui d O verl oa d  ............................................................................................................2 6  
5. 1. 2. 2.  
A mi n otra nsferase a n d Ga m ma -gl uta m yl Tra nsferase Ele vati o ns  ..............................2 6  
5. 1. 2. 3.  
M uscle S pas ms  ...........................................................................................................2 7  
5. 1. 2. 4.  
Wei g ht L oss  ................................................................................................................2 7  
5. 1. 2. 5.  
H y p o ma g n ese mia  .......................................................................................................2 7  
5. 1. 2. 6.  
I n creases i n Uri nar y Pr ot ei n .......................................................................................2 8  
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 9  
6. 1.  
St u d y O bjecti ves  .........................................................................................................2 9  
6. 1. 1.  
Pri mar y O bj ecti ves  .....................................................................................................2 9  
6. 1. 2.  
S ec o n dar y O bj ecti ve  ...................................................................................................2 9  
6. 1. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................2 9  
6. 2.  
St u d y E n d p oi nts  ..........................................................................................................2 9  
6. 2. 1.  
Pri ma r y Efficac y E n d p oi nt .........................................................................................2 9  
6. 2. 2.  
Sec o n dar y Efficac y E n d p oi nt  .....................................................................................2 9  
6. 2. 3.  
E x pl orat or y Effi cac y E n d p oi nt  ...................................................................................2 9  
6. 2. 4.  
Safet y E n d p oi nts  .........................................................................................................2 9  
6. 2. 5.  
Ot h er E n d p oi nt  ............................................................................................................2 9  
7.  
I N V E S TI G A TI O N A L P L A N .....................................................................................3 0  

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7. 1.  
O verall St u d y Desi g n  ..................................................................................................3 0  
7. 2.  
N u m ber of Patie nts  .....................................................................................................3 1  
7. 3.  
Treat me nt Assi g n me nt a n d Rati o nale  .........................................................................3 1  
7. 4.  
D ose A dj ust me nt Criteria  ...........................................................................................3 2  
7. 4. 1.  
D ose Escalati o n  ..........................................................................................................3 2  
7. 4. 2.  
D os e De-Escalati o n a n d Re -Escalati o n  ......................................................................3 2  
7. 5.  
Criteria f or St u d y Ter mi nati o n  ...................................................................................3 2  
7. 6.  
Sc he d ule of Assess me nts  ............................................................................................3 2  
7. 6. 1.  
Scree ni n g Peri o d ( Scree n A & Scree n B Visits)  ........................................................3 5  
7. 6. 2.  
Ra n d o mizati o n ( Da y 1 Visit)  ......................................................................................3 6  
7. 6. 3.  
Treat me nt Peri o d ( Fr o m Da y 1 t hr o u g h Wee k 1 2)  .....................................................3 7  
7. 6. 4.  
Wee k 1 2 ( E n d of Treat m e nt) Visit  .............................................................................3 8  
7. 6. 5.  
Off -Treat me nt Peri o d ( O T Da y 3 t o O T Da y 3 5)  .......................................................3 9  
7. 6. 6.  
E n d of St u d y ( E O S) Visit ( O T Da y 3 5)  ......................................................................3 9  
7. 6. 7.  
U nsc he d ule d Visits  .....................................................................................................4 0  
7. 7.  
H o me Healt h Pr o vi der Use  .........................................................................................4 0  
8.  
S E L E C TI O N A N D WI T H D R A W A L O F S U BJ E C T S  ..............................................4 2  
8. 1.  
S u bject I n cl usi o n Criteria  ...........................................................................................4 2  
8. 2.  
S u bject E x cl usi o n Criteria  ..........................................................................................4 3  
8. 3.  
Patie nt Disc o nti n uati o n a n d Ter mi nati o n  ...................................................................4 4  
8. 3. 1.  
Patie nt St u d y Dr u g Disc o nti n uati o n Criteria  ..............................................................4 4  
8. 3. 2.  
Patie nt St u d y T er mi nati o n Criteria  .............................................................................4 5  
9.  
T R E A T M E N T O F P A TI E N T S  ..................................................................................4 7  
9. 1.  
Select Ma na ge m e nt G ui deli nes  ..................................................................................4 7  
9. 1. 1.  
Ma na ge me nt of Fl ui d Stat us  .......................................................................................4 7  
9. 1. 2.  
Ma na ge me nt of El e vate d A mi n otra nsferase Le v els ( A L T a n d/ or A S T)  ....................4 7  
9. 1. 3.  
Ma na ge me nt of M us cle S pas ms  .................................................................................4 8  
9. 1. 4.  
Wei g ht L oss  ................................................................................................................4 8  
9. 1. 5.  
H y p o ma g n ese mia  .......................................................................................................4 8  
9. 1. 6.  
Ma na g e me nt of Uri nar y Pr otei n  .................................................................................4 8  
9. 1. 7.  
Ma na ge me nt of Bl o o d Press ure  ..................................................................................4 9  
9. 1. 8.  
Na usea  .........................................................................................................................4 9  
9. 1. 9.  
E n d Sta ge Ki d ne y Diseas e  ..........................................................................................4 9  

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9. 2.  
Descri pti o n of St u d y Dr u g  ..........................................................................................5 0  
9. 3.  
C o nc o mita nt Me dicati o ns  ...........................................................................................5 0  
9. 3. 1.  
E x cl u de d Me dicati o ns  ................................................................................................5 0  
9. 3. 2.  
Per mitte d Me dicati o ns  ................................................................................................5 1  
9. 4.  
Treat me nt C o m plia nce  ................................................................................................5 1  
9. 5.  
Ra n d o mizati o n  ............................................................................................................5 2  
9. 6.  
Bli n di n g  ......................................................................................................................5 2  
9. 7.  
U nsc he d ule d Vis its .....................................................................................................5 2  
9. 8.  
Pre g n a nc y  ...................................................................................................................5 3  
9. 8. 1.  
W o me n of C hil d beari n g P ote ntial a n d Fertile Mal es  .................................................5 3  
9. 8. 2.  
Met h o ds of Birt h C o ntr ol ............................................................................................5 3  
9. 8. 3.  
S us pecte d Pre g na n c y  ..................................................................................................5 4  
9. 9.  
Seri o us T o xicities  .......................................................................................................5 5  
9. 1 0.  
St u d y Pr oce d ures  ........................................................................................................5 5  
9. 1 0. 1.  
I nf or me d C o nse nt .......................................................................................................5 5  
9. 1 0. 2.  
I n cl usi o n/ E x cl usi o n ....................................................................................................5 5  
9. 1 0. 3.  
De m o gra p hics a n d Baseli ne Disease C haract eristics  .................................................5 5  
9. 1 0. 4.  
Pri or a n d C urre nt C o nc o mita nt Me dicati o ns  ..............................................................5 6  
9. 1 0. 5.  
Me dical Hist or y  ..........................................................................................................5 6  
9. 1 0. 6.  
C K D Eti ol o g y  .............................................................................................................5 6  
9. 1 0. 7.  
Hei g ht  .........................................................................................................................5 6  
9. 1 0. 8.  
Wei g ht a n d B o d y M ass I n de x ( B MI)  .........................................................................5 6  
9. 1 0. 9.  
Electr ocar di o gra ms ( E C G)  .........................................................................................5 6  
9. 1 0. 1 0.  
Vital Si g n Meas ur e me nts  ............................................................................................5 6  
9. 1 0. 1 1.  
P h ysical E x a mi nati o n & Tar gete d P h ysical E x a mi nati o n  ..........................................5 7  
9. 1 0. 1 2.  
Pre g n a nc y T est  ............................................................................................................5 7  
9. 1 0. 1 3.  
S t u d y Dr u g A d mi nistrati o n.........................................................................................5 7  
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  ...................................................................5 7  
9. 1 0. 1 5.  
Tele p h o ne C o ntact  ......................................................................................................5 8  
9. 1 0. 1 6.  
A d verse E v e nt C ollecti o n  ...........................................................................................5 8  
9. 1 0. 1 7.  
Ge netic Testi n g  ...........................................................................................................5 8  
9. 1 0. 1 8.  
Cli nical C he mistr y  ......................................................................................................5 8  
9. 1 0. 1 9.  
e G F R  ...........................................................................................................................5 8  

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9. 1 0. 2 0.  
N -Ter mi nal Pr o -B -t y pe Natri uretic Pe pti de ( N T-pr o B N P) a n d B -t y p e 
Natri uretic Pe pti de  ( B N P) ...........................................................................................5 9  
9. 1 0. 2 1.  
He m o gl o bi n A 1 c ( H b A 1 c)  .........................................................................................5 9  
9. 1 0. 2 2.  
He mat ol o g y  .................................................................................................................5 9  
9. 1 0. 2 3.  
Uri nal ysis a n d Micr osc o p y  .........................................................................................5 9  
9. 1 0. 2 4.  
Uri ne C ollecti o n f or Uri n e Al b u mi n t o Creati ni ne Rati o  ( U A C R) ............................5 9  
9. 1 0. 2 5.  
P har mac o ki netic ( P K) Bl o o d  Sa m ples  .......................................................................6 0  
9. 1 0. 2 6.  
Li ver a n d Ki d ne y I nj ur y Bi o mar kers  ..........................................................................6 0  
9. 1 0. 2 7.  
C -Reacti ve Pr otei n  ......................................................................................................6 0  
9. 1 0. 2 8.  
Pr ot hr o m bi n Ti me ( P T) / I nter nati o nal N or m alize d Rati o (I N R)  ...............................6 0  
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  ...........................................6 1  
1 0. 1.  
St u d y Dr u g  ..................................................................................................................6 1  
1 0. 2.  
St u d y Dr u g  Pac k a gi n g a n d La b eli n g  ..........................................................................6 1  
1 0. 3.  
St u d y Dr u g St ora ge  .....................................................................................................6 1  
1 0. 4.  
St u d y Dr u g A d mi nistrati o n .........................................................................................6 1  
1 0. 5.  
St u d y Dr u g A cc o u nta bilit y  .........................................................................................6 2  
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p osal  ............................................................................6 2  
1 0. 7.  
C o m plia nce  .................................................................................................................6 2  
1 1.  
S A F E T Y A S S E S S M E N T S  ........................................................................................6 3  
1 1. 1.  
Safet y Para met ers  .......................................................................................................6 3  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts  .........................................................................6 3  
1 1. 2. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................6 3  
1 1. 2. 1. 1.  
A d verse E v e nt  .............................................................................................................6 3  
1 1. 2. 1. 2.  
Seri o us A d verse E v e nt  ................................................................................................6 3  
1 1 . 3. 
Eliciti n g A d vers e E ve nt I nf or mati o n  ..........................................................................6 4  
1 1. 4.  
Assess me nt of Ca usalit y  .............................................................................................6 4  
1 1. 5.  
Assess me nt of Se verit y  ...............................................................................................6 5  
1 1. 6.  
Rec or di n g A d verse E ve nts  .........................................................................................6 5  
1 1 . 7. 
Re p orti n g Seri o us A d v erse E ve nts  .............................................................................6 6  
1 2.  
S T A TI S TI C S  ..............................................................................................................6 8  
1 2. 1.  
Sa m ple Siz e  ................................................................................................................6 8  
1 2. 2.  
St u d y Vari a bles  ...........................................................................................................6 8  
1 2. 2. 1.  
P har mac o ki netic Varia bl es  .........................................................................................6 8  

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1 2. 2. 2.  
Efficac y Varia bles  ......................................................................................................6 8  
1 2. 2. 3.  
Safet y Vari a bles  ..........................................................................................................6 8  
1 2. 3.  
St atistical A nal yses  .....................................................................................................6 8  
1 2. 3. 1.  
Pri mar y A n al ysis of Effi cac y  ......................................................................................6 9  
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 .........................................7 0  
1 3. 1.  
St u d y M o nit ori n g  ........................................................................................................7 0  
1 3. 2.  
A u dits a n d I ns p ecti o ns  ................................................................................................7 0  
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  .........................................7 1  
1 4. 1.  
Q ualit y Ass ura nce  .......................................................................................................7 1  
1 4. 2.  
Fi na ncial Discl os ur e  ...................................................................................................7 1  
1 4. 3.  
S p o ns or O bli gati o ns ....................................................................................................7 1  
1 4. 4.  
I nv esti gat or D oc u me nt ati o n  ........................................................................................7 1  
1 4. 5.  
Cli nical St u d y I ns ura nce  .............................................................................................7 2  
1 4. 6.  
Use of I nf or mati o n  ......................................................................................................7 2  
1 5.  
E T HI C S  ......................................................................................................................7 3  
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 .......................7 3  
1 5. 2.  
Et hical C o n d uct of t he St u d y  ......................................................................................7 3  
1 5. 3.  
Writte n I nf or m e d C o nse nt  ..........................................................................................7 3  
1 5. 4.  
C o nfi de ntialit y  ............................................................................................................7 4  
1 5. 5.  
M o dificati o n of t he Pr ot oc ol  .......................................................................................7 4  
1 5. 6.  
Pr ot oc ol De viati o ns  ....................................................................................................7 4  
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  .......................................................7 6  
1 6. 1.  
Rete nti o n of Rec or ds  ..................................................................................................7 6  
1 6. 2.  
Case Re p ort F or ms  .....................................................................................................7 6  
1 7.  
P U B LI C A TI O N P O LI C Y  ..........................................................................................7 7  
1 8.  
LI S T O F R E F E R E N C E S  ............................................................................................7 8  
1 9.  
A P P E N DI X .................................................................................................................8 0  
A P P E N DI X 1  .................................................................................................................................8 1  
 
 
 

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LI S T O F T A B L E S  
Ta ble 1:  
E mer ge nc y C o nta ct I nf or mati o n  ...................................................................................4  
Ta ble 2:  
A b bre viati o ns a n d S peci alist Ter ms  ...........................................................................1 8  
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 4  
Ta ble  4:  
Sc he d ule of Assess me nts  ............................................................................................3 3  
Ta ble  5:  
Bar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or mati o n  ........................................................5 0  
Ta ble  6:  
Place b o Pr o d uct I nf or mati o n  ......................................................................................5 0  
Ta ble  7:  
S A E Re p orti n g C o ntact I nf or mati o n  ..........................................................................6 6  
 

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LI S T O F FI G U R E S  
Fi g ure  1:  Sc he ma f or St u d y 4 0 2 -C -2 0 0 2  ...................................................................................3 1  
 
  

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4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol.  
T a ble 2 : 
A b bre vi ati o ns a n d S peci alist  Ter ms   
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
A C E i 
A n gi ote nsi n c o n verti n g e nz y me  i n hi bit or 
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 U N  
Bl o o d urea nitr o ge n  
C F R  
C o de of Fe deral Re g ulati o ns ( U S)  
C H F  
C o n gesti ve heart fail ure  
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  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
Cr Cl  
Creati ni ne cleara nce  
E C  
Et hics C o m mittee  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of st u d y  
E O T  
E n d of treat me nt  
E S K D  
E n d sta ge ki d ne y disease  
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
H b A 1c  
He m o gl o bi n A 1c  

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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  
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  
H P F  
Hi g h p o wer fiel d  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of T ec h nical 
Re q uire me nts f or P har mace uticals f or H u ma n Use  
I N R 
I nter nati o nal n or malize d rati o 
I P 
I n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-t o-treat 
K DI G O  
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc 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  
Nrf 2  
N uclear fact or (er yt hr oi d -d eri ve d 2) -relate d fact or 2 
N T -P r o B N P 
N -T er mi nal Pr o -Brai n Natri uretic Pe pti de  
O T  
Off -treat me nt  
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 T  
Pr ot hr o m bi n Ti me  
Q T c  
C orrecte d Q T i nter val  
R B C  
Re d bl o o d cell  
R P G N  
R a pi dl y pr o gressi ve gl o mer ul o ne p hritis  
R T S M  
Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S G L T 2i  
S o di u m/ gl uc ose c otra ns p orter -2  i n hi bit or 

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 0  
 
  
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
S N G F R  
S i n gle ne p hr o n gl o mer ular filtrati o n rate 
T 2 D  
T y pe 2 dia betes  
T B L  
T otal bilir u bi n  
U A C R  
Uri ne al b u mi n t o creati ni ne rati o  
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 O C B P  
W o me n of c hil d beari n g p ote ntial  
 

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 1  
 
  
 
5.  
I N T R O D U C TI O N 
Bar d o x ol o ne met h yl is a se mi -s y nt hetic triter pe n oi d t hat selecti vel y a n d re versi bl y bi n ds t o 
K elc h-li ke E C H-ass ociat e d pr otei n 1 ( Kea p 1), res ulti n g i n p ote nt acti vati o n of t he tra nscri pti o n 
fact or n u clear fact or (er yt hr oi d -deri ve d 2) -rel ate d fact or 2 (Nrf 2 ).  T hr o u g h acti vati o n of Nrf 2, 
bar d o x ol o ne met h yl m o d ulates t he tra nscri pti o n of h u n dre ds of ge n es i n v ol ve d i n i nfla m mati o n, 
o xi dati ve stress, a n d cell ular e ner g y meta b olis m (K o ba yas hi , 2 0 1 6; War d y n, 2 0 1 5 ). 
Data fr o m m ulti ple a ni mal m o dels of c hr o nic ki d n e y dise ase ( C K D ) de m o nstrate t hat 
bar d o x ol o ne  met h yl a n d cl osel y relate d str uct ural a nal o gs s u p press i nfla m mati o n a n d fi br osis,  
re d uce gl o mer ul oscler osis, pre ve nt t u b ul oi nterstitial da ma ge, a n d i m pr o ve ki d ne y f u ncti o n 
(A mi nz a de h, 2 0 1 4 ; Na gas u, 2 0 1 9 ; Z oja, 2 0 1 0 ).  A d diti o nal st u dies ha ve de m o nstrate d t hat ac ute 
treat me nt wit h bar d o x ol o ne met h yl r e verses e n d ot helial d ysf u ncti o n a n d m esa n gial cell 
c o ntracti o n, i ncreases gl o mer ular s urface area ( u ltrafiltrati o n c oefficie nt, K f), a n d rest or es si n gl e 
ne p hr o n gl o mer ular filtrati o n rate ( S N G F R) wit h o ut c ha n ges i n i ntra gl o mer ular press ur e  
(Di n g,  2 0 1 3 ; Ki d o k or o, 2 0 1 9 ). 
I n m ulti ple  cli nical st u dies, treat me nt wit h bar d o x ol o ne met h yl has c o nsiste ntl y i m pr o ve d ki d ne y 
f u ncti o n as assesse d b y eit her i n uli n cleara n ce, creati ni ne cleara nce, or esti mate d gl o mer ular 
filtrati o n rate (e G F R) (C hi n, 2 0 1 8 ; de Zee u w, 2 0 1 3 ; Na n ga k u, 2 0 2 0 ; Per g ol a, 2 0 1 1 ).  T he 
i ncreas es i n e G F R wit h bar d o x ol o ne met h yl o bser ve d wit hi n t he first 1 2 wee ks of treat me nt ha ve 
bee n s h o w n t o si g nifica ntl y c orrelate wit h l o n ger-ter m c ha n ges i n e G F R (C hi n, 2 0 1 8 ).  
M ore o ver,  i n m ulti ple, l o n g-ter m cli nical st u dies, t he treat me nt effect relati ve t o place b o h as 
bee n s h o w n t o  persist a p pr o xi matel y f o ur wee ks after cessati o n of dr u g (d e Zee u w, 2 0 1 3 ; 
C hi n,  2 0 1 8, Per g ola, 2 0 1 1 ).  T hese res ults are t h o u g ht t o reflect t he dr u g’s a nti-fi br otic effects 
a n d are c o nsiste nt wit h be ne ficial effects o n str uct ural re m o deli n g o bser ve d i n a ni mal m o dels.   
T he assess me nt of e G F R d uri n g t he off -tr eat me nt ( O T) peri o d is use d t o ass ess bar d o x ol o ne 
met h yl’s effect o n t he irre versi ble l oss of ki d ne y f u ncti o n as well as a n y disease m o dif yi n g 
effe cts.  A vaila ble cli nical p har mac o d y na mic a n d p har mac o ki netic data wit h bar d o x ol o ne met h yl 
s u g gest t hat a c ute effects o n e G F R are e x pecte d t o res ol ve  wit hi n 1 0 t o 1 4 da ys after st o p pi n g 
treat me nt.  I n t he prese nt st u d y, e G F R will be assesse d at m ulti ple i nter vals d uri n g t he O T peri o d 
t o c haracteriz e t he ti mec o urse of t he wa s h o ut of bar d o x ol o ne met h yl’s ac ute p har mac o d y na mic 
effects.  
Patie nt s wit h C K D  wit h ra pi d pr o gressi o n or  at ris k of ra pi d pr o gressi o n are defi ne d as t h ose 
wit h a s ustai ne d decli ne i n e G F R of m ore t ha n 4 t o 5  m L / mi n/ 1. 7 3 m2 per year  (K DI G O , 2 0 1 3).  
T he c ollecti ve cli nical a n d n o ncli nical data s u g gest t hat  bar d o x ol o ne met h yl ma y be effecti ve at 
a meli orati n g t h e rate of decli ne i n e G F R i n t his patie nt p o p ulati o n.  F urt her m ore, i ncreases i n 
e G F R o bser ve d a fter 1 2 wee ks of treat me nt  ma y tra nslate t o a s ustai ne d e G F R res p o nse .  I n 
patie nts wit h C K D at ris k of ra pi d pr o gressi o n , the p ote ntial i m pact of a s ustai ne d e G F R i ncrease 
wit h bar d o x ol o ne met h yl treat me nt ma y be cli nicall y mea ni n gf ul a n d c o ul d tra nslate t o a dela y i n 
pr o gressi o n t o e n d sta ge ki d ne y dise ase ( E S K D ).  
5. 1.  
Cli nic al E x perie nce wit h B ar d o x ol o ne Met h yl  
O verall, bar d o x ol o ne met h yl has bee n teste d i n m ulti ple C K D st u dies a n d o ver 3 0 0 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.  

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 2  
 
  
 
5. 1. 1.  
Effic ac y  
As see n i n Ta ble  3 , i m pr o ve me nts i n ki d ne y  f u ncti 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 C K D, ca ncer, a n d p ul m o nar y h y pert e nsi o n ( 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 patie 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 w as o bser v e d t o re d uce s er u m creati ni ne le vels, 
c orres p o n di n g t o a n i ncrease i n e G F R .  T he re 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-de pe n de nt a n d ma nifeste d i n a maj orit y ( 8 2 %) of t he patie nts  
st u die d.  I n s u bse q u e 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, 
bar 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 statisticall y 
si g nifica nt i m pr o ve m e nts i n e G F R t hat are d ura bl e f or at least o ne year in treate d patie nts.  
St u d y 4 0 2 -C -0 8 0 4 ( B E A M) 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 os e, P hase 2 b st u d y d esi g n e d t o assess t he efficac y a n d safet 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 on 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 m 2) a n d t y p e 2 dia betes (T 2 D ). 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 n e at Wee k 2 4, de m o nstrat e 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 ha 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 ustai ne d t hr o u g h Wee k 5 2 a n d o n a vera ge, p atie nts treate d wit h 
bar d o x ol o ne met h yl e x perie nce d a net i ncrease 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 bas eli 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 v al uati o n i n Patie nts wit h C hr o nic Ki d ne y 
Disease a n d T y p e 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 pare t he effic ac y a n d s afet y of bar 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 m 2) a n d T 2 D. A t otal of 2 1 8 5 p atie nts were 
ra n d o mize d 1: 1 t o o nce-dail y a d mi nistrati o n of t h e a m or p h o us s pra y -drie d dis persi o n 
f or m ulati o n of bar d o x ol o ne met h yl ( 2 0 m g) or place b o.  T he pri mar y efficac 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 ne d as E S K 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 vasc ular d eat h.  Si milar t o pri or st u dies, 
bar d o x ol o ne 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 b aseli ne t hr o u g h Wee k 4 8 ( o verall mea n i ncreas e of 5. 5 m L/ mi n/ 1. 7 3 m 2).  
I n c o ntrast, place b o-tr eat e d patie nts e x perie nce d a mea n decli ne 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 bet 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 dies 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 -wee k w it h dra wal 
peri o d f oll o wi n g t h e 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 ge i n e G F R fr o m 
baseli ne t o W ee k 5 6 f or patie nts w h o recei ve d st u d y dr u g f or 5 2 wee 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 dr a 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 W ee k 5 6.  Si milar res ults were o bser ve d i n B E A C O N f or 
patie nts t hat 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 

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 3  
 
  
 
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 ki d ne y  f u ncti o n, 
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 wal of dr u g. 
M ost rece ntl y, bar d o x ol o ne met h yl h as bee n s h o w n t o als o si g nifica ntl y i ncrease e G F R 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) 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; St u d y 4 0 2 -C -1 7 0 2).  
 
 

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 4  
 
  
 
T a ble  3 : 
Cr oss -St u d y C o 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 me nt 
D ur ati o n  
Pl ace b o -c o rrecte d 
∆e G F R  ( m L/ mi n/ 1. 7 3 m 2)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,  P arallel -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 W ee k 4 8 
6. 4 ( p < 0. 0 0 1 vs P B O)   
Cr Cl als o si g nifica ntl y i ncreas e d  
4 0 2 -C -1 1 0 2  
1/ U S  
M ulti -D ose,  M ultice nter, O pe n -
La b el  
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/ J a p a 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 2 0  
1 6 wee ks  
6. 6 (i n uli n G F R) ( p = 0. 0 0 8 vs 
P B O)  
4 0 2 -C -1 6 0 3  
2/ U S  
M ultice nter, O pe n -L a bel 
A ge 1 2 t o 6 5, Al p ort s y n dr o me  
3 0  
4 8 wee ks  
1 0. 4 ( p < 0. 0 0 1)  
4 0 2 -C -1 6 0 3  Year 1  
3/ Gl o bal  
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 2 t o 7 0, Al p ort sy n dr o me  
1 5 7  
4 8 wee ks  
9. 5 ( p < 0. 0 0 1 vs P B O)  
4 0 2 -C -1 7 0 2  
2/ U S  
M ultice nter, O pe n -La bel  
A ge ≥ 1 8, A D P K D  
3 1  
1 2 wee ks  
9. 3 ( p < 0. 0 0 1)  
4 0 2 -C -1 7 0 2  
2/ U S  
M ultice nter, O pe n -La bel  
A ge 1 8 t o 7 0,  I g A Ne p hr o pat h y 
2 6  
1 2 wee ks  
8. 0 ( p < 0. 0 0 0 1)  
4 0 2 -C -1 7 0 2  
2/ U S  
M ultice nter, O pe n -La bel  
A ge 1 8 t o 7 0, T 1 D C K D  
2 8  
1 2 wee ks  
5. 5 ( p = 0. 0 2 5)  
4 0 2 -C -1 7 0 2  
2/ U S  
M ultice nter, O pe n -La bel  
F S G S  
1 8  
1 2 wee ks  
7. 8 ( p = 0. 0 0 3)  
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-E scalati 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  
P a 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 n ces 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.   ( F O O T N O T E S C O N TI N U E D N E X T P A G E) 

Pr ot oc ol  
 
 
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Versi o n 2. 0  
 2 5  
 
  
 
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 i n C o h orts 1 a n d 2.  
e G F R =esti mat e d gl o mer ular filtrati o n rate, Cr Cl =creati n i ne cleara nce, T 1 D =t y pe 1 dia betes, T 2 D =t y pe 2 dia betes, C K D =c h r o nic ki d ne y disease, P B O = place b 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, I g A =i m m u n o gl ob uli n A, F S G S =f ocal  se g me ntal gl o mer ul oscler osis, P H = p ul m o nar y h y perte nsi o n .

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 2 6  
 
  
 
5. 1. 2.  
S afet y a n d T oler a bilit y  
Please refer t o t he I n v esti gat or’s Br oc h ure f or a detaile d disc ussi o n of safet y fi n di n gs 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 i n cert ai n patie nt p o p ulati o ns, i ncl u di n g b ose nta n i n 
a d va nce d c o n gesti ve h eart fail ure a n d a v ose nta n i n a d va nce d C K D, bar d o x o l o ne met h yl 
treat me nt was f o u n d t o b e ass ociate d wit h a n i ncrease d ris k f or fl ui d o verl oa d a n d heart fail ure 
h os pitaliz ati o ns i n 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 m 2) a n d T 2 D.  T he o verall i ncrease d ris k f or fl ui d o verl oa d a n d heart fail ure e v e nts 
wit h bar d o x ol o ne met h yl a p peare d t o be li mite d t o u p  t o f o ur wee ks after i nitiati o n of treat me nt.  
Ele vate d B -t y pe natri uretic pe pti de ( B N P) a n d pri or h os pitalizati o n f or heart fail ure were 
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 hes e e ve nts.  T he i ncrease d ris k 
f or t hese e v e nts fr o m bar d o x ol o ne met h yl treat me nt ha d n ot bee n o bser ve d i n 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 m 2), patie nts wit h he patic d ysf u ncti o n, ca ncer patie nts, or healt h y v ol u nteers. 
Re vie w of a d missi o n n otes a n d narrati ve des cri pti o ns f or heart fail ure h os pitalizati o ns i n 
B E A C O N i n dicates t hat heart fail ure i n bar d o x ol o ne met h yl -treate d patie nts was ofte n prece d e d 
b y ra pi d fl ui d wei g ht gai n (se veral kil o gra ms wit hi n t he first wee ks of treat me nt i nitiati o n) a n d 
was n ot ass ociate d wit h ac ute re n al dec o m pe ns ati o n or ac utel y re d uce d left ve ntric ular 
c o ntractilit y. A v aila ble d ata fr o m B E A C O N a n d ot he r st u dies s u g gest t hat bar d o x ol o ne met h yl 
treat me nt ca n differe ntiall y affect he m o d y na mic st at us acc or di n g t o t he cli nical c o n diti o n of 
patie nts a n d li kel y pr o m 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 niz e d ris k fact ors ass ociate d wit h heart fail ure at b aseli ne. 
R is k miti gati o n pr oce d ures ha ve bee n e m pl o ye d i n s u bse q ue nt trials 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 u ce d fl ui d o verl o a d; t hese pr oce d ures e x cl u de d pati e nts wit h t he 
i de ntifie d ris k fact ors a n d e ns ure d cl os e m o nit ori n g f or fl ui d rete nti o n wit hi n t he first m o nt h of 
treat me nt.  
5. 1. 2. 2.  
A mi n o tr a nsfer ase a n d G a m m a -gl ut a m yl  Tr a ns fer ase Ele v ati o ns  
I n cli nical st u dies of bar d o x ol o ne met h yl, al m ost all patie nts ha d i ncreas es of a mi notra nsferase  
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 we d a c o nsiste nt patter n.  T hese 
i ncreas es were n ot ass oci ate d wit h ele vati o ns i n bilir u bi n or ot her si g ns of li ver t o xicit y.  I n 
B E A C O N, fe wer he p at o biliar y seri ous a d verse e v e nts ( S A Es ) were  o bser ve d i n t he bar d o x ol o ne 
met h yl ar m t ha n i n t he pl ace b o ar m.  T he ele vati o ns be gi n i m me diatel y after i nitiati o n of 
treat me nt or a n i n crease i n d ose; t he y p ea k a p pr o xi matel y t w o t o f o ur wee ks later.  I n m ost 
patie nts,  a mi n otra nsferas e  ele vati o ns were mi l d, b ut a p pr o xi matel y 4 % t o 1 1 % of patie nts 
e x perie nce d a n ele vati o n greater t ha n 3 X t he u p p er li mit  of n or mal ( U L N ).  T he ele vati o ns 
res ol ve d t o le vels less t ha n t he U L N i n m ost all patie nts wit h ele vati o ns, wit hi n t w o wee ks 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 nce 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 uire d a d diti o nal 
ti me t o res ol ve.  W hile s o me patie nts ha ve ha d el e vati o ns t o a b o ve 3 X t he U L N, persiste 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 vati o ns di d n ot rec ur o nce 
res ol ve d, u nless c a use d b y ot her fact ors. 
Bar d o x ol o ne met h yl re g ulates ga m ma -gl uta m yl tra nsfer as e (G G T ), a k n o w n Nrf 2 tar get ge ne 
pr otei n.  I n cli nical st u dies, l o w le vel G G T ele vati o ns d uri n g treat me nt were c o m m o n, mil d, a n d 
t y picall y laste d l o n ger t ha n ala nine/as p artate  a mi n otra ns ferase (A L T/ A S T ) ele vati o ns.  Bilir u bi n 
le vels i n patie nts e x perie nci n g a mi n otra ns ferase 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 base li ne le vels or decreas e d.  T he A L T, A S T, a n d G G T 
ele vati o ns were ge n erall 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 dverse e v e nt ( A E ) i n cli nical trials of 
bar d o x ol o ne m et h yl i n patie nts wit h C K D.  T he m uscle s pas ms m ost ofte n ma nifeste d i n t he first 
t w o m o nt hs of treat me nt a n d res ol ve d s p o nta ne o usl y or wit h e m pirical treat me nt.  T he y o cc urre d 
m ostl y at ni g ht, i n t he l o wer e xtre mities, a n d were ge nerall y mil d t o m o derate i n se verit y.  
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 assesse d b y t he h y p eri ns uli ne mic -e u gl yce mic 
cla m p pr oce d ure, w ere o bser ve d i n res p o ns e t o bar d o x ol o ne met h yl i n a d efi ne d s u bset of 
patie nts e nr olle d i n a P hase 2a st u d y.  T o date, i n t h ose cases w here ser u m creati ni ne ki nas e 
( C K) le vels ha v e bee n m eas ure d, n o ass ociati o n h as bee n o bser ve d b et wee 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 l a b orat or y 
fi n di n gs ass oci ate d wit h t he re p orts of m us cle s pas ms ha ve n ot bee n c o nsist e 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 ncreas e 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 n crease d le vels of ser u m mar kers, i ncl u di n g creati ni ne, 
lactate de h y dr o ge nas e ( L D H), bl o o d urea nitr o ge n ( 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 w ee 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 uscle s pas ms were m ost fre q ue ntl y  re p orte d. 
I n creases i n t he w h ole-b o d y gl uc os e dis p osal rate ha ve bee n o bser ve d i n mice treat e d wit h 
bar d o x ol o ne met h yl, as well .  I n crease d gl uc os e u pta ke was o bser ve d i n is olate d calf m uscles of 
t he mice, b ut n ot i n w hite a di p ose tiss ue ( Sa ha, 2 0 1 0 ). 
5. 1. 2. 4.  
Wei g ht L oss  
Decreases i n w ei g ht a n d re p orts of a n ore xia/ decrease d a p petite ha ve bee n o bser ve d f oll o wi n g 
treat me nt wit h bar d o x ol o ne met h yl i n patie nts wit h C K D.  I n st u dies of t hese patie nts, 1 7 % of 
bar d o x ol o ne met h yl patie nts re p orte d A Es of wei g ht decrease  or decreas e d a p petite (irres pecti ve 
of relati 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 n ce d i n p atie nts treate d wit h 
bar d o x ol o ne met h yl t ha n i n t h ose gi ve n  place b o.  
Wei g ht l os s of a p pr o xi matel y o n e kil o gra m per m o nt h was o bser ve d, wit h patie nts of hi g h er 
b o d y -mass i n d e x at baseli ne l osi n g m ore wei g ht (i n a bs ol ute ter ms) t ha n t h ose of n or mal or 
m o deratel y -ele vate d b o d y-mass i n d e x  (C hert o w , 2 0 1 8). 
5. 1. 2. 5.  
H y p o m a g nese mi a  
H y p o ma g n e se mia w a s re p orte d as a n A E f or 1 5. 5 % of patie nts wit h T 2 D C K D w h o recei ve d 
bar d o x ol o ne met h yl .  T h e A E of h y p o ma g n ese mia ( of a n y re p ort e d relati 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 -tr eate d patie nts t ha n i n patie nts gi ve n 

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place b o.  T he i n v esti gat ors c o nsi dere d al m ost all re p orte d e v e 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 decrease fr o m baseli ne i n ser u m 
ma g n esi u m le vels t ha n p atie nts gi ve n place b o; t he decrease was e vi de nt wit hi n 4 we e 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 orrelati o n bet wee n h y p o ma g n ese mi a a n d eit her 
gastr oi ntesti nal A Es or car diac 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 correcte d Q T 
i nter val (Q Tc ).  T he 2 4-h o ur uri ne c ollecti o ns fr o m t he B E A C O N a m b ulat or y bl o o d pr ess 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 nar y ma g n esi u m le vels, i n dicati n g t h at re nal l oss 
of ma g n esi u m di d n ot acc o u nt f or t he re d ucti o ns i n ser u m ma g nesi u m o bser ve d wit h 
bar d o x ol o ne met h yl treat me nt i n C K D patie nts. N ota bl y, a t h or o u g h Q T st u d y t hat teste d d os es 
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 he Q T  i nter val 
(C hi n , 2 0 1 9). 
5. 1. 2. 6.  
I ncreases  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 n e y dise ase.  T h e i ncreases are li kel y d ue t o bar d o x ol o ne met h yl’s 
p har mac ol o gic al 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 b ee 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 nre g ulate t he pri mar y pr otei 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 he 
me gali n -c u bili n c o m ple x  (Rei s ma n, 2 0 1 2).  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 u ce 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 r e u pta ke a n d i ncreasi n g uri n ar y pr otei n le v els. 
T heref or e, 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 x creti o n of al b u mi n.  
C o nsiste nt wit h bar d o x ol o ne met h yl -m e diate d pr otecti o n i n precli nical m o dels of pr otei n - 
o verl oa d -i n d uc e d ne p hr o pat h y, t hes e 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 x cessi 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 osis  (R ossi n g, 2 0 1 9 ). 

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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.  
St u d y O bjecti ves  
T he st u d y o bje cti ves are as f oll o ws:  
6. 1. 1.  
Pri m ar y O bjecti ve s 
•  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) at 
Wee k 1 2 . 
•  T o assess t he safet y a n d t olera bilit y of bar d o x ol o ne  met h yl.  
6. 1. 2.  
Sec o n d ar y O bjecti ve  
•  T o c haracteriz e t he e G F R res p o nse at Wee k 1 2 acr oss differe nt eti ol o gie s of C hr o nic 
Ki d ne y Disease ( C K D ). 
6. 1. 3.  
E x pl or at or y  O bjecti ves  
•  T o c haracteriz e c h a n ge i n e G F R d uri n g t he off -tr eat me nt peri o d.  
•  
 
6. 2.  
St u d y E n d p oi nts  
6. 2. 1.  
Pri m ar y Effic ac y E n d p oi nt  
•  e G F R c h a n ge fr o m baseli ne at Wee k 1 2 . 
6. 2. 2.  
Sec o n d ar y Effic ac y E n d p oi nt  
•  e G F R c h a n ge fr o m baseli ne at Wee k 1 2 b y C K D eti ol og y . 
6. 2. 3.  
E x pl or at or y Effic ac y E n d p oi nt  
•  e G F R c h a n ge fr o m baseli ne at off-tr eat me nt Da ys 3, 7, 1 4, 2 1, 2 8 , a n d 3 5 . 
6. 2. 4.  
S afet y E n d p oi nts  
•  L a b orat or y res ults (cli nic al c he mistr y, he mat ol o g y, uri nal ysis, a n d micr osc o p y), vital 
si g n meas ure me nts, ele ctr ocar di o gra m ( E C G) res ults, wei g ht, a d verse e v e nts ( A Es), 
a n d seri o us a d v erse e ve nts ( S A Es).  
6. 2. 5.  
Ot her E n d p oi nt  
•  
 

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7.  
I N V E S TI G A TI O N A L PL A N  
7. 1.  
O ver all St u d y Desi g n  
T his m ulti -ce nter, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d , 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 p atie nts wit h C K D  d ue t o 
m ulti ple eti ol o gies at ris k  of ra pi d diseas e pr o gressi o n .  A p pr o xi matel y 7 0  p atie nts will be 
e nr olle d a n d ra n d o mize d 1: 1 t o eit her bar d o x ol o ne met h yl or place b o.  Ra n d o mizati o n will be 
stratifie d usi n g t he Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes ( K DI G O ) C K D pr o gressi o n 
ris k heat ma p  (strat u m 1 = yell o w or ora n ge; strat u m 2 = re d or dar k re d) (Secti o n  1 9 , 
Le vi n,  2 0 1 4 ) base d o n s cree ni n g e G F R a n d U A C R  usi n g Ra n d o mizati o n  a n d Trial S u p pl y 
Ma na ge me nt ( R T S M ).   
Patie nts  wit h C K D sec o n dar y t o var yi n g  eti ol o gies will be e nr olle d fr o m a ge 1 8 -7 5  years wit h 
e G F R ≥ 2 0  t o <  6 0 m L/ mi n/ 1. 7 3 m 2, a n d ot her ris k fact ors f or ra pi d pr o gressi o n of ki d ne y dise ase.  
Patie nt s wit h gl o mer ul o n e p hritis re q uiri n g i m m u n os u p pressi ve treat me nt wit hi n 6 m o nt hs or a 
hist or y of ra pi dl y pr o gressi ve gl o mer ul o n e p hritis will be e x cl u de d .  N o si n gle C K D eti ol o g y 
(( h y perte nsi v e, dia betic, or ot her) ma y e nr oll a p pr o xi matel y ≥ 4 0 % i n t he  trial. 
T he ma xi m u m  tar get d os e will be deter mi ne d b y b aseli ne pr otei n uria st at us.  Patie nts wit h 
baseli ne uri ne al b u mi n t o cre ati ni ne rati o ( UA 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 U 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.   Q u alifie d p ati e nts will be ra n d o mize d 1: 1 t o  recei ve eit her bar d o x ol o ne met h yl or 
place b o o nce dail y ( prefera b l y i n t he m or ni n g) t hr o u g h o ut a 1 2 -wee k d osi n g peri o d .  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 W ee k 6 ( o nl y if b aseli ne U A C R >  3 0 0  m g/ g) , u nless 
c o ntrai n dicate d  cli nicall y, w hic h s h o ul d be disc usse d wit h  t he me dical m o nit or (Fi g ure  1 ).  D ose 
de -escalati o n is per mitte d d uri n g t he st u d y if i n di cate 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 bj ecti ve of t he hi g hest t olerate d  d ose.  
P atie 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.  Patie nts will be 
assesse d d uri n g treat me nt at Da y 1, 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 D a ys 
3, 1 0, 2 1, 3 1, 3 5 , a n d 4 5.  Date of last d ose a n d t he e n d -of -tr eat me nt ass ess me nts mar k t he e n d of 
t he treat me nt peri o d.  Patie nts will n ot recei ve st u d y dr u g d uri n g a 5 -wee k off -treat me nt peri o d 
bet wee n Wee ks 1 2 a n d 1 7 (Fi g ure  1 ).  
T he  off -tr eat me nt ( O T) peri o d i ncl u des 5 visits re q uiri n g vari o us assess me nts t o c haract erize 
e G F R fr o m t he ti me of st u d y dr u g disc o nti n uati o n t hr o u g h Da y 3 5 off -treat me nt.  Patie nts will 
be assesse d o n D a y 3 O T, Da y 7 O T, Da y 1 4 O T, Da y 2 1 O T, Da y 2 8 O T , a n d Da y 3 5 O T .  T h e 
O T da y c orres p o n ds t o d a ys after l ast d ose.  Da y 1 O T is t he first da y aft er recei vi n g t he last 
d ose.  A n y patie nt w h o p er ma ne ntl y disc o nti n ues st u d y treat me nt earl y will f oll o w t he sa me O T 
assess me nt sc he d ule .   
All patie nts , i ncl u di n g patie nts w h o disc o nti n ue treat me nt earl y, s h o ul d c o m plete t he e n d-of -
st u d y (E O S ) visit 1 7 wee ks after  ra n d o mizati o n. 
All eff orts s h o ul d be ma d e t o f oll o w all ra n d o mize d patie nts f or t he f ull O T peri o d of t he trial, 
a n d t he E O S  visit ( Wee k 1 7), i ncl u di n g patie nts w h o disc o nti n ue dr u g earl y.  

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Fi nal a nal ysis of t he pri mar y efficac y e n d p oi nt will occ ur  after all e nr olle d patie nts ha ve 
c o m plete d t heir Wee k 1 7 visit ( or ha ve ter mi nate d fr o m t he trial).  
Fi g ure  1 :  
Sc he m a f or St u d y 4 0 2 -C -2 0 0 2  
 
Sc = Scree ni n g, U A C R = uri ne  al b u mi n t o creati ni ne rati o, e G F R =esti mate d gl o mer ular filtr ati o n rate, E O T =e n d of 
treat me nt, E O S =e n d of st u d y, O T = off-treat me nt peri o d. 
7. 2.  
N u m ber of P atie n ts 
A p pr o xi matel y 7 0  p atie nts will be e nr olle d.  
7. 3.  
Tre at me nt Assi g n me nt  a n d R ati o n ale  
Q ualifie d patie nts will be ra n d o mize d 1: 1 t o recei v e eit her bar d o x ol o ne met h yl or place b o  o nce 
dail y t hr o u g h o ut a 1 2 -wee k d osi n g p eri o d.   Ra n d o mizati o n will be stratifie d usi n g t he  K DI G O 
C K D pr o gressi o n ris k heat ma p ( strat u m 1 = yell o w or ora n ge; strat u m 2 = re d or dar k re d) base d 
o n scree ni n g e G F R a n d U A C R usi n g R T S M .     
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 b ase 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 b ase d o n a patie nt’s pr otei n uri a stat us at baseli ne.  Base d o n res ults fr o m pri or 
trials i n patie nts wit h T 2 D a n d C K D, Reata has c o ncl u de d t hat hi g h er bar d o x ol o ne met h yl d oses 
ma y b e re q uir e d t o ha ve a n o pti mal effect o n e G F R f oll o wi n g dr u g wit h dra wal i n patie nts wit h 
macr oal b u mi n uria.  S pecificall y, e G F R i m pr o ve m e nts i n patie nts wit h n or m o - or micr o -
al b u mi n uria were o bser ve d wit h a 2 0 m g b ar d o x ol o ne met h yl d ose.  I n pati e nts wit h 
macr oal b u mi n uria, a 3 0 -m g d ose w as re q uir e d t o pr o d uce a res p o nse t h at was 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 p atie nts wit h U 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 p atie nts wit h U A C R > 3 0 0 m g/ g, as descri be d i n Secti o n  7. 4. 1 .  Fr o m a safet y 
pers pecti ve, t h e 3 0 m g d ose ma y be ass o ciate d wit h a n i ncreas e d i nci de n ce of na usea; h o w e ver, 
t he na usea e x perie nce d i n pre vi o us trials is ge n erall y mil d, tra nsie nt, a n d cli nicall y ma na gea ble. 

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7. 4.  
D ose A dj ust me nt Criteri a  
7. 4. 1.  
D ose Esc al ati o n  
Patie nts will recei ve eit h er bar d o x ol o ne met h yl or place b o  o nce dail y ( prefera bl y i n t he m or ni n g) 
t hr o u g h o ut t he st u d y.  Patie nts ra n d o mize d t o bar d o x ol o ne met h yl 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 (o nl y if bas eli ne U A C R > 3 0 0  m g/ g ) at Wee k 6  u nless c o ntrai n dicate d cli nicall y , w hi c h 
s h o ul d be disc usse d wit h t he me dical m o nit or.   Patie nts ra n d o mize d t o place b o will re mai n o n 
place b o t hr o u g h o ut t he st u d y a n d will f oll o w t he sa me titrati o n t o mai ntai n t he bli n d .  D ose 
escalati o n ma y nee d t o pr ocee d m or e sl o wl y  if t h e patie nt e x perie nces earl y ele vati o ns i n  
A L T/ A S T o v er U L N, e. g. at W ee k 2  (see Secti o n  9. 1. 2 ).  T he d osi n g o bjecti ve is t o titrate 
patie nts t o t he ma xi m u m tar get d ose det er mi ne d b y bas eli ne U A C R a n d mai ntai n t he ma xi m u m 
d ose after i nitial d ose -titr ati o n.  
7. 4. 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 decrease t he patie 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 dicat e d.  D ose de -es calati 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 -es calati o n s h o ul d be disc usse d wit h 
t he me dical m o nit or a n d m ust be d oc u me nte d.  
O nce a p atie nt’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 h er d ose is per mitte d t o 
meet t he d osi n g o bje cti 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 h e d ule d o ffice visit 2 wee ks ( ± 3 da ys) after d ose 
escalati o n t o c ollect cli nical c he mistr y, B N P, a n d N -ter mi nal pr o B N P ( N T-pr o B N P).  
U nsc he d ule d visits d ue t o d ose escal ati 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. 5.  
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 ves t he ri g ht t o 
disc o nti n ue t he st u d y at a n y ti me f or cli nical or a d mi nistrati ve reas o ns, or if re q uire d b y 
re g ulat or y a ge ncies.  If t he S p o ns or disc o nti n ues t he st u d y, all st u d y dr u 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. 6.  
Sc he d ule of Asses s me nts 
Ta ble  4  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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a If a patie nt p er ma ne ntl y disc o nti n ues st u d y dr u g earl y, t he patie nt s h o ul d ret ur n as s o o n as p ossi ble t o c o m plete E O T pr oce d u res (i.e., t h ose o utli ne d at t he 
W ee k 1 2 visit).  T he O T visits s h o ul d t he n be sc he d ule d bas e d o n t he date of t he last d ose of st u d y dr u g.  F oll o wi n g c o m pleti o n of t he O T visits, t he E O S visit 
will o cc ur at Wee k 1 7.  I n t his case, t here will be b ot h a n O T Da y 3 5 visit sc he d ule d 3 5 da ys f oll o wi n g t he last d ose of I P a n d a n E O S visit sc he d ule d 
a p pr o xi matel y 1 7 wee ks after Da y 1/ra n d o miz ati o n.  
b T otal Scree ni n g peri o d s h o ul d n ot e xcee d 4 wee ks.  
c Da y 1 is a d mi nistrati o n of t he first d ose.  O n D a y 1, all pr oce d ures m ust be  perf or me d b ef ore st u d y dr u g a d mi nistr ati o n.   
d 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 criteri a s h o ul d be e val uate d pr i 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.  
e A E assess me nts o n Da y 1 s h o ul d be perf or me d f oll o wi n g st u d y dr u g a d mi nistrati o n.  
f W ei 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 de d i n a patie nt diar y.  D uri n g t he first ei g ht wee ks, wei g hts wil l b e rec or de d dail y; wee kl y 
wei g hts will be rec or de d fr o m W ee k 8 t hr o u g h Wee k 1 2.  
g Bl o o d press ure f or i ncl usi o n criteria eli gi bilit y ca n be ta ke n at Scree n A or Scree n B.  Bl o o d press ure s h o ul d n ot b e c oll ect e d at Scree n B if Scree n A val ues 
met eli gi bilit y criteria.  
h I n vesti gat or s h o ul d e val uate if a tar gete d p h ysical e xa m is ne e de d, base d o n a n y s y m pt o mat ol o g y re p orte d t o t he st u d y te a m.  
i A ser u m pre g na nc y test will b e pe rf 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 p ecte d.  All ot her pre g na nc y 
assess me nts will be uri ne pre g na nc y tests.  A d diti o nal pre g na nc y assess me nts will be perf or me d m ore fre q ue ntl y if re q uire d b y  l ocal la w or re queste d b y l ocal 
re g ulat or y a ut h orities or I R Bs/ E Cs. 
 
 
k Uri ne 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.  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 t he c ollecti o n. 
l P atie nts m ust n ot ta ke st u d y dr u g o n t he da y of t he Wee k 1 2 visit si nce P K will be dra w n.  

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7. 6. 1.  
S cree ni n g Peri o d ( Scree n A & Scree n B  Visits ) 
N o scree ni n g pr oce d ures ma y b e c o m plete d pri or t o o btai ni n g writte n i nf or me d c o nse nt .  T he  
Scree ni n g Peri o d i ncl u des 2 visits  (Scree n A a n d Scree n B ), a n d t he d urati o n of scree ni n g (fr o m 
Scree n A t o D a y 1 ) ma y  n ot e x cee d 4  wee ks.  T h e Scree n A a n d B visits ma y b e c o m plete d o n 
c o nsec uti ve da ys.  
T he Scree n A visit m ust i ncl u de t he f oll o wi n g assess me nts:  
•  O btai n i nf or me d c o nse nt  pri or t o a n y scree ni n g pr oce d ures b ei n g perf or me d  
•  O btai n de m o gra p hics i nf or mati o n  ( date of birt h, s e x, et h nicit y, race) 
•  Rec or d me dic al hist or y , i ncl u di n g C K D eti ol o g y a n d hist orical ser u m creati ni ne   
•  Perf or m vital si g n assess me nts (sitti n g bl o o d press ure  as o utli ne d i n  Secti o n  9. 1 0. 1 0 , 
p ulse, heart rate, te m perat ure, hei g ht, a n d wei g ht)  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Perf or m 1 2 lea d E C G (at rest)  
•  Perf or m a f ull p h ysical e x a mi nati o n 
•  C ollect bl o o d a n d uri ne s peci me ns f or cli nical la b orat or y tests :  
− Ser u m  pre g na n c y test (f or W O C B P ) 
− C li nical c he mistr y, i ncl u di n g e G F R 
− B N P a n d N T -pr o B N P  
− He m o gl o bi n A 1 c  
− H e mat ol o g y 
− U ri nal ysis a n d micr osc o p y  
•  Assess patie nt eli gi bilit y  
•  Dis pe nse s peci me n c ollecti o n c u p a n d pr o vi de i nstr ucti o ns f or c ollecti o n of first 
m or ni n g v oi d  
T he pri mar y p ur p os e of t he Scree n B visit is t o o btai n t he 2 n d baseli ne e G F R val ue .   
T he Scree n B visit m ust i ncl u de t he f oll o wi n g assess me nts:  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Perf or m uri ne pre g na n c y test, if a p plica ble  
•  C ollect bl o o d f or cli nica l c he mistr y, i n cl u di n g e G F R  
•  C ollect uri ne f o r U A C R (first m or ni n g v oi d br o u g ht t o cli nic b y patie nt ) 
Bl o o d press ur e ma y be ta ke n o n Scree n B f or I n cl usi o n criteria eli gi bilit y. 
 

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O nce all scree ni n g d ata h a ve bee n c ollecte d, eli gi bilit y f or t he patie nt s h o ul d be c o nsi dere d, a n d 
o nl y aft er c o nfir mati o n t he patie nt meets al l eli gi bilit y criteria s h o ul d t he patie nt be assi g ne d a 
treat me nt kit i n t he R T S M s yste m or ret ur n f or Da y 1 pr oce d ures.  
Patie nts ma y re peat scree ni n g o nce t o q ualif y f or t he st u d y (re-s cree ni n g m ust occ ur at least 2 
wee ks after t he s cree n fail).  If a patie nt is a p pr o ve d t o re -scree n, t he y are gi ve n a ne w patie nt 
n u m ber a n d all scree ni n g pr oce d ures are c o m plete d.  
7. 6. 2.  
R a n d o miz ati o n  ( D a y 1 Visit) 
S u bjects w h o s uccessf ull y c o m plet e t he scr ee ni n g peri o d a n d are dee me d eli gi ble will ret ur n t o 
t he cli nic f or Da y 1 pr oce d ures, i ncl u di n g ra n d o mizati o n.  Pri or t o c o m pleti n g Da y 1 pr oce d ures, 
c o nti n ue d eli gi bilit y m ust be c o nfir me d.  A n y A Es re p orte d pri or t o t he first d ose of st u d y dr u g 
s h o ul d be rec or de d i n t he me dical hist or y.  Ra n d o mizati o n occ urs w he n t he patie nt is eit her 
assi g ne d acti ve st u d y dr u g or place b o  usi n g  R T S M .   
Sites s h o ul d o btai n at least 2 alter nate p oi nts of c o ntact f or eac h p atie nt ra n d o mize d i n t he st u d y, 
i n a n eff ort t o a v oi d t he p atie nt bei n g l ost -t o-f oll o w u p a n d t he res ulti n g missi n g data.   
Da y 1 pr oce d ures i n cl u de t he f oll o wi n g: 
•  Assess a n d c o nfir m p atie nt eli gi bilit y  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es  
•  Perf or m vital si g n assess me nts (sitti n g bl o o d press ure, p ulse, heart rate, t e m perat ure, a n d 
wei g ht)  as o utli ne d i n Secti o n  9. 1 0. 1 0  
•  Dis pe nse scal e  
•  Dis pe nse wei g ht a n d I P diar y a n d trai n p atie nt o n pr o per diar y e ntr y f or rec or di n g dail y 
wei g ht a n d I P a d mi nistrati o n  
•  Perf or m a tar gete d p h ysi cal e x a mi nati o n, if nee de d  
•  Perf or m  uri ne pre g na n c y test, if a p plica ble  
•  Dis pe nse st u d y dr u g base d o n b ottle n u m ber or kit n u m ber o btai ne d fr o m R T S M a n d 
i nstr uct patie nt o n pr o per a d mi nistrati o n of st u dy  dr u g  
•  Perf or m a b uccal s w a b (c hee k s wa b) f or ge netic testi n g (at a n y visit bet wee n Da y 1  a n d 
t he E O S visit )  
•  C ollect bl o o d a n d uri ne f or cli nical la b orat or y tests:  
o  Cli nical c he mistr y, i ncl u di n g e G F R  
o  B N P a n d N T -pr o B N P  
o  He mat ol o g y  
o  Uri nal ysis a n d micr osc o p y  
o  Li ver a n d Ki d ne y I nj ur y Bi o mar kers  

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o  C -Reacti ve Pr otei n  
o  Pr ot hr o m bi n ti me (P T )/I nter nati o nal n or malize d rati o (I N R) 
•  A d mi nistrati o n of t he first d ose of st u d y dr u g  i n-cli nic (rec or d d os e i n t he d osi n g diar y) 
7. 6. 3.  
Tre at me nt Peri o d  (Fr o m D a y 1 t hr o u g h Wee k 1 2)  
T he Treat me nt Peri o d i ncl u des 1 3 visits  (cli nic a n d p h o ne visits).  D uri n g t he Treat me nt Peri o d, 
in cli nic visits ge nerall y ha ve a wi n d o w of ± 3 da ys , a n d ph o ne visits ge n erall y ha v e a wi n d o w of 
± 2 da ys.  Caref ul atte nti o n s h o ul d be pai d t o visit wi n d o ws be gi n ni n g wit h t he Wee k 1 2 / E O T 
visit , w hic h c o ntai ns o nl y a “ mi n us” wi n d o w (i.e., Wee k 1 2 s h o ul d occ ur o n Da y 84 −3 da ys ).  
O ut of wi n d o w visits will res ult i n pr ot oc ol de viati o ns.  
D uri n g t h e Treat me nt Peri o d, d ose titrati o n s h o ul d be c o m plete d as o utli ne d i n Secti o n 7. 4. 1 .   
T he Treat me nt Peri o d c o ncl u des at t he Wee k 1 2/ E O T Visit .   P atie nts s h o ul d be i nstr ucte d t o 
refr ai n fr o m t a ki n g I P o n t he d a y of t he Wee k 1 2 visit.  T he l ast d ose of st u d y dr u g s h o ul d 
be t he d a y pri or t o t he Wee k 1 2 visit.  
La bs o bt ai ne d at t his visit are i m p orta nt fr o m a n e n d p oi nt pers pecti ve, as t h e y pr o vi de t he fi n al 
o n -treat me nt e G F R val ues.  
F or detaile d i nf or mati o n o n t he Da y 1  visit , see Secti o n  7. 6. 2 . 
F or detaile d i nf or mati o n o n t he Wee k 1 2 visit, see Secti o n  7. 6. 4 . 
Treat me nt Peri o d cli nic v isits be t wee n Da y 1  a n d u p t o Wee k 1 2 (Wee k 1, Wee k 2 , Wee k 4, 
Wee k 6, a n d Wee k 8 ) m ust i ncl u de t he f oll o wi n g assess me nts: 
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es  
•  Perf or m vital si g n assess me nts (sitti n g bl o o d press ure, p ulse , heart rate, t e m perat ure, a n d 
wei g ht)  as o utli ne d i n Secti o n  9. 1 0. 1 0  
•  Dis pe nse wei g ht a n d I P diar y a n d trai n p atie nt o n pr o per diar y e ntr y f or rec or di n g dail y 
wei g ht a n d I P a d mi nistrati o n (Da y 1, Wee k 2, Wee k 4, Wee k 6, a n d Wee k 8)  
•  C ollect /re vie w wei g ht a n d I P d iar y (Wee k 1, Wee k 2, Wee k 4 , Wee k 6 , a n d Wee k 8)  
•  Perf or m a tar gete d p h ysi cal e x a mi nati o n, if nee de d  
•  Perf or m uri ne pre g na n c y test, if a p plica ble  
•  Dis pe nse st u d y dr u g  base d o n b ottle n u m ber or kit n u m ber o btai ne d fr o m R T S M a n d 
i nstr uct patie nt o n pr o per a d ministrati o n of st u d y  dr u g  ( Da y 1, Wee k 2, W ee k 4, Wee k 6, 
a n d Wee k 8)  
•  C ollect a n d re vie w st u d y dr u g ( Wee k 2, Wee k 4, Wee k 6, a n d Wee k 8 )  
•  Perf or m a b uccal s w a b (c hee k s wa b)  f or ge netic testi n g (at a n y visit bet wee n Da y 1 a n d 
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•  C ollect bl o o d a n d uri ne f or cli nical la b orat or y tests:  
o  C li nical c he mistr y, i ncl u di n g e G F R 
o  B N P a n d N T -pr o B N P  
o  He mat ol o g y  
o  Uri nal ysis a n d micr osc o p y  
o  Uri ne f or U A C R –  first m or ni n g v oi d s peci me n (Wee k 4  a n d Wee k 8 )  
o  Li ver a n d Ki d ne y I nj ur y Bi o mar kers ( Wee k  6 ) 
o  C -Reacti ve Pr o tei n ( Wee k 6) 
o  P T/ I N R ( Wee k 6)  
•  Dis pe nse s peci me n c ollecti o n c u p a n d pr o vi de i nstr ucti o ns f or c ollecti o n of first m or ni n g 
v oi d ( Wee k 2, Wee k 6 , a n d Wee k 8)  
P h o ne Visits ( Da y 3, Da y 1 0, Wee k 3, Da y 3 1,  Wee k 5, a n d Da y 4 5 ) m ust i ncl u de t he f oll o wi n g 
assess me nts:  
•  Re vie w a n d rec or d pri or c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es  
•  Re vie w wei g ht a n d I P di ar y  
7. 6. 4.  
Wee k 1 2 ( E n d of Tre at me nt ) Visit 
Wee k 1 2 is t he fi nal visit i n t he Treat me nt Peri o d , a n d it mar ks t he tra nsiti o n t o t he O T Peri o d .  
Caref ul atte n ti o n s h o ul d be pai d t o e ns ure t h e visit is sc he d ule d bet wee n Da y 8 1 a n d Da y 8 4 , as 
o utli ne d i n Ta ble  4 .   
P ati e nts s h o ul d be i nstr ucte d t o refr ai n fr o m t a ki n g I P o n t he d a y of t he Wee k 1 2 visit .  
T he l ast d ose of st u d y dr u g s h o ul d be t he d a y pri or t o t he Wee k 1 2 visit.  
If a patie nt p er ma ne ntl y disc o nti n ues st u d y dr u g earl y, pl ease refer t o Secti o n  8. 3 .  
Assess me nts t o be c o m plete d at t he Wee k 1 2/ E O T Visit i ncl u de t he f oll o wi n g:  
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es  
•  Perf or m vital si g n assess me nts (sitti n g bl o o d pres s ure, p ulse, heart rate, t e m perat ure, a n d 
wei g ht)  
•  C ollect/re vie w wei g ht a n d I P diar y  
•  Perf or m 1 2 lea d E C G at rest  
•  Perf or m a tar gete d p h ysi cal e x a mi nati o n, if nee de d  
•  Perf or m uri ne pre g na n c y test, if a p plica ble  
•  C ollect a n d re vie w st u d y dr u g  

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•  Perf or m a b uccal  s w a b (c hee k s wa b) f or ge netic testi n g (if n ot alrea d y c ollecte d)   
•  C ollect bl o o d a n d uri ne f or cli nical la b orat or y tests:  
o  Cli nical c he mistr y, i ncl u di n g e G F R  
o  B N P a n d N T -pr o B N P  
o  He m o gl o bi n A 1 c  
o  He mat ol o g y  
o  Uri nal ysis a n d micr osc o p y  
o  Uri ne f or U A C R  - first m or ni n g v oi d s peci me n  
o  Li ver a n d Ki d ne y I nj ur y Bi o mar ker s 
o  C -Reacti ve Pr otei n  
o  P T/I N R  
•  C ollect bl o o d f or P K   
7. 6. 5.  
Off -Tre at me nt Peri o d  (O T D a y 3 t o O T D a y 3 5 ) 
T he O T  Peri o d i ncl u des 5 visits a n d  i ncl u des vari o us assess me nts t o c haracterize e G F R fr o m t he 
ti me of dr u g disc o nti n uati o n t hr o u g h Da y 3 5 off-treat me nt.  A Es a n d S A Es s h o ul d c o nti n ue t o be 
c ollecte d d uri n g t his peri o d.  
All visits i n t he O T Peri o d s h o ul d be sc he d ule d base d o n t he date of t h e Wee k 1 2/ E O T visit.   
If a patie nt p er ma ne ntl y disc o nti n ues st u d y dr u g earl y, pl ease refer t o Secti o n 8. 3 .  
T he O T peri o d m ust i ncl u de t he f oll o wi n g assess me nts: 
•  Re vie w a n d rec or d pri or c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es  
•  C ollect bl o o d f or cli nical c he mistr y, i n cl u di n g e G F R  
•  C ollect bl o o d  f or P K  
7. 6. 6.  
E n d of St u d y ( E O S) Visit  (O T D a y 3 5 ) 
T he E n d of St u d y visit refers t o t he l ast visit f or a p atie nt  a n d m ust  i ncl u de t he f oll o wi n g 
assess me nts :    
•  Re vie w a n d rec or d c o nc o mita nt me dicati o ns  
•  Re vie w a n d rec or d A Es 
•  Perf or m vital si g n assess me nts (sitti n g bl o o d press ure, p ulse, heart rate, t e m perat ure, a n d 
wei g ht)  
•  Perf or m 1 2 lea d E C G (at rest)  
•  Perf or m a p h ysic al e x a mi nati o n  

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•  Perf or m a b uccal s w a b (c hee k s wa b) f or ge netic testi n g (if n ot alrea d y c ollecte d)  
•  C ollect bl o o d a n d uri ne s peci me ns f or cli nic al la b orat or y tests :  
o  Uri ne pre g n a nc y test (f or W O C B P)  
o  C li nical c he mistr y, i ncl u di n g e G F R 
o  B N P a n d N T -pr o B N P  
o  He mat ol o g y  
o  U ri nal ysis a n d micr osc o p y 
o  U ri ne f or U A C R  
o  Li ver a n d Ki d ne y I nj ur y Bi o mar kers  
o  C -Reacti ve Pr otei n  
o  P T/ I N R 
•  C ollect bl o o d f or P K  
If a patie nt p er ma ne ntl y disc o nti n ues st u d y dr u g earl y , pl ease refer t o Secti o n 8. 3 .  
7. 6. 7.  
U nsc he d ule d Visits  
U nsc he d ule d visits are d efi ne d as a n y visit o utsi de of  t he pr ot oc ol s pe cifie d visits  d ue t o a n y of 
t he reas o ns o utli ne d i n Secti o n 9. 7 .  At a mi ni m u m, u nsc he d ule d visits s h o ul d i ncl u de c ollecti o n 
of A Es, re view of c o n c o mita nt me dicati o ns , a n d meas ure me nt of vital si g ns .  U nsc he d ule d visits 
ma y als o i ncl u de  ot her assess me nts s uc h as la borat or y assess me nts , i ncl u di n g bl o o d c ollecti o n 
f or P T/I N R, p h ysic al e x a ms, etc.  A n y pr oce d ures c o m plete d at a n u nsc h e d ule d visit s h o ul d be 
f ull y d oc u me nt e d i n t he s o urce i n t he cli nical data base.  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.    
7. 7.  
H o me He alt h Pr o vi der Use  
D ue t o t he C O VI D -1 9 o ut brea k a n d restricti ve meas ures p ut i n place b y l o cal g o v er n me nts a n d 
sites, t he st u d y ma y face c halle n ges i ncl u di n g tra v el restricti o ns, li mite d a vaila bilit y of site 
access a n d pers o n n el, a n d li mitati o n o n t he m o ve me nt of i n di vi d uals .  T o a d dress t hese 
c halle n ges , h o me h ealt h ser vices ma y b e  i m ple me nte d b y t he S p o ns or  t o assist wit h t he 
c o m pleti o n  of st u d y re q uire d visits a n d la b orat or y assess me nts w hile g uara nteei n g t h e ri g hts, 
safet y, a n d w ell bei n g of partici pa nts a n d of t he trial sites’ staff.  T he us e of a c o m p a n y, del e gate d 
b y t he S p o ns or,  s pecializ e d i n h o me healt h ser vi ces e ns ures t he o n g oi n g safet y m o nit ori n g of 
trial partici pa nts a n d trial i nte grit y t hr o u g h t he c ollecti o n of critical d ata, i n acc or da nce wit h t he 
F o o d a n d Dr u g A d mi nistrati o n ( F D A ) a n d l o cal g ui deli nes a b o ut t he C O VI D -1 9 pa n d e mic 
ma na ge me nt.  T he site will be pr o vi de d wit h t he f oll o wi n g d oc u me ntati o n  f or a n y h o me healt h 
n urse c o n d ucti n g pr oce d ures  f or p atie nts e nr olle d at t hat site: si g ne d a n d d ate d c urric ul u m vitae, 
c urre nt N ursi n g Li ce ns ur e,  g o o d cli nical practic e ( G C P ) trai ni n g certificat e, a n d pr ot oc ol trai ni n g 
certificate.  T he h o me h ealt h n urse/ pr ofessi o nal will als o be i ncl u de d i n t he  site’s Dele gati o n of 
A ut h orit y  l o g. 

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T as ks dele gate d t o t he h o me healt h n urse/ pr ofessi o nal ma y i n cl u de  c ollecti o n of vital si g ns a n d 
wei g ht meas ure m e nts, c ollecti o n of i nf or mati o n a b o ut A Es  a n d c o nc o mita nt me dicati o ns, 
c ollecti o n of la b orat or y s a m ples ( bl o o d a n d uri ne), P K sa m ple c ollecti o n,  s u p pl y uri ne pre g na n c y 
test f or W O C B P f or self-rea di n g, dr u g dis p e ns ati o n a n d acc o u nta bilit y, a n d diar y 
dis pe nse/re vie w/ c ollecti o n.  L a b orat or y s a m ples will be  c ollecte d usi n g t h e ce ntral la b orat or y kit 
a n d will be pr ocess e d a n d s hi p pe d acc or di n g t o t h e la b orat or y m a n ual f or t he st u d y.  All c osts 
rele va nt t o t hese a d diti o nal ser vices will be c o vere d b y Reat a P har mace uticals. 

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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 S U B J E C T S  
8. 1.  
S u bject I ncl usi o n Criteri a  
Dia g n osis a n d m ai n criteria f or i ncl usi o n:  
1.  Male a n d fe male patie nts 1 8 ≤ a ge ≤ 7 5  u p o n st u d y c o ns e nt;  
2.  Dia g n osis of C K D  wit h scree ni n g e G F R (a vera ge of Scree n A a n d Scree n B e G F R 
val ues) ≥ 2 0 t o <  6 0 m L/ mi n/ 1. 7 3 m 2 
a. 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 det er mi ne  
eli gi bilit y m ust ha ve a perce nt differe n ce ≤ 2 5 %;  
3.  Patie nt m ust meet o ne of t he f oll o wi n g criteria :  
a. U ri ne al b u mi n  t o creati ni ne rati o (U A C R) ≥ 3 0 0 m g/ g;  O R  
b.  e G F R decli ne at a rate of ≥ 4 m L/ mi n/ 1. 7 3 m 2 i n pri or year; O R  
c. He mat u ria ( gl o mer ular) defi ne d as > 5 -1 0 re d bl o o d cells (R B C s) per hi g h p o wer fiel d 
( H P F, ma n ual met h o d), or d oc u me nte d hist or y of p ositi v e uri nar y di pstic k  f or bl o o d 
i n pri or year, or macr os c o pic  he mat uria i n pri or 3 years ; 
4.  S yst olic bl o o d press ure ≤ 1 5 0 m m H g a n d diast olic bl o o d press ure ≤ 9 0 m m H g at Scree n 
A or Scree n B visit after a peri o d of rest  (≥ 5 mi n utes) ; 
5.  Treat me nt wit h a n a n gi ote nsi n -c o n verti n g e nz y me i n hi bit or ( A C Ei) a n d/ or a n a n gi ote nsi n 
II rece pt or bl oc ker ( A R B) at t he ma xi mall y t olerat e d la bele d dail y d ose f or at least 6 
wee ks pri or t o t he Scree n A visit a n d wit h n o a ntici pate d c ha n ges t o d ose(s) d ur i n g st u d y 
partici pati o n.  If treat me nt wit h A C Ei a n d/ or A R B is c o ntrai n dicate d or n ot i n dicate d, t he 
patie nt m ust n ot ha ve bee n e x p ose d t o a n A C Ei a n d/ or A R B f or at least 8 w ee ks pri or t o 
t he Scree n A visit; 
6.  A bs ol ute ne utr o p hil c o u nt > 1. 5 x 1 0 9/ L, pl atelets > 1 0 0 x 1 09/ L, he m o gl o bi n ( H g b) ≥8. 0  
g/ d L;  
7.  T otal bilir u bi n ( T B L), al a ni ne a mi n otra nsferas e ( A L T), a n d as p artate a mi n otra nsferase 
( A S T) ≤ 1. 5X  t he u p per li mit of n or mal ( U L N) b ot h at Scree n A a n d Scree n B visits ; 
8.  A ble t o s wall o w ca ps ules;  
9.  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 0.  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 h at 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 o r 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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8. 2.  
S u bject E xcl usi o n Criteri a  
All patie nts wit h a n y of t he f oll o wi n g c o n diti o ns or c haracteristics m ust be e x cl u de d fr o m t he 
st u d y: 
1.  Pri or e x p os ure t o bar d o x ol o ne met h yl ; 
2.  C K D sec o n dar y t o or ass ociate d wit h a n y of t he f oll o wi n g :  
a. Hist or y of ra pi dl y pr o gressi ve gl o mer ul o ne p hritis ( R P G N) 
b.  Gl o mer ul o ne p hritis re q uiri n g i m m u n os u p pressi o n i n t he 6 m o nt hs pri or t o Scree n A  
3.  C o nc o mita nt use of t ol va pta n.  Patie nts pre vi o usl y treate d wit h t ol va pta n m ust ha ve 
disc o nti n ue d dr u g f or at l east 3 m o nt hs pri or t o Scree n A visit ;  
4.  Patie nts  treate d wit h p ol yc ystic ki d ne y dis ease-m o dif yi n g a ge nts (s o mat ostati n 
a nal o g ues) wit hi n 3 m o nt hs pri or t o t he Scree n A  visit ; 
5.  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 ul ati vel y, wit hi n t he 1 2 wee ks 
pri or t o Da y 1 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 h e  st u d y; 
6.  Patie nts c urre ntl y ta ki n g a s o di u m/ gl uc ose c otra ns p orter -2 i n hi bit or ( S G L T 2i ), re q uiri n g 
d ose a dj ust me nts  wit hi n 1 2 wee ks pri or t o D a y 1 or if d ose is a ntici pate d t o c ha n ge 
d uri n g st u d y partici pati o n ; 
7.  B -t y pe n atri uretic p e pti de ( B N P) le vel > 2 0 0 p g/ m L at Scree n A visit ; 
8.  U nc o ntr olle d dia betes ( H b A 1c > 1 1. 0 %) at Scree n A  visit ; 
9.  Ser u m al b u mi n < 3 g/ d L at Scree n A  visit ; 
1 0.  Ki d ne y or a n y ot her s oli d or ga n tra ns pla nt r eci pie nt or a pla n ne d tr a ns pla nt d uri n g t he  
st u d y; 
1 1.  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 
Scree ni n g ; 
1 2.  Hist or y of cli nicall y si g nifica nt car diac dise ase, 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 uir e d val v ular  disease  
b.  Left ve ntric ular eje cti o n fracti o n < 4 0 % ( bas e d o n hist orical ec h ocar di o gra m)  
c. Hist or y of h os pitalizati o n f or heart  fail ure wit hi n 1 2 m o nt hs pri or t o Scree n A  
d.  Ne w Y or k Heart Ass ociati o n Class III or  I V c o n gesti ve heart fail ure ( C H F ) 
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 art er y b y pass graft s ur ger y, or u nsta ble  a n gi na) wit hi n 1 2 
m o nt hs pri or t o Scree n A  
f. Pericar di al c o nstricti o n ( base d o n hist orical ec h ocar di o gra m)  
g.  Restricti ve or c o n gesti ve car di o m y o pat h y ( base d o n hist orical ec h ocar di o gra m)  
h.  U nc o ntr olle d atrial  fi brill ati o n 

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i. Hist or y of u nsta bl e  arr h yt h mias; 
1 3.  S yst olic bl o o d press ure < 9 0 m m H g at Scree n A visit after a peri o d of rest ; 
1 4.  B o d y mass i n de x < 1 8. 5 k g/ m 2 at t he Scree n A visit ; 
1 5.  Hist or y of m ali g na n c y wit hi n 5 years pri or t o Scree n A visit, wit h t he e x ce pti o n of 
l ocalize d s ki n or cer vical carci n o mas; 
1 6.  C or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) dia g n osis wit hi n 3 m o nt hs pri or t o Scree n A or 
ha ve e v er re q uire d C O VI D -1 9 relat e d h os pitalizati o n ; 
1 7.  Partici pati o n i n ot her i nter ve nti o nal cli nical st u dies wit hi n 3  m o nt hs  ( or if rele va nt 5 half-
li ves of t hat st u d y me dicati o n, w hic he ver is t he l o n ger) pri or t o Scree n B; 
1 8.  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 9.  W o me n w h o are pre g na nt or breastf ee di n g;  
2 0.  Nee d f or o n g oi n g us e of str o n g a n d/ or m o derat e C Y P 3 A 4 i n hi bit ors a n d i n d ucers;  
2 1.  K n o w n h y p erse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g;  
2 2.  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.  
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 st u d y f oll o w -u p at a n y ti me 
f or a n y reas on, wit h o ut prej u dice t o t heir me dical care.  F urt h er m ore, t h e i n vesti gat or m a 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.  T he 
reas o n f or a patie nt’s dis c o nti n uati o n fr o m st u d y dr u g or st u d y t er mi nati o n will be rec or de d i n 
t he electr o nic case re p ort f or m (e C R F).  A n y patie nt w h o  disc o nti n ues st u d y dr u g f or 1 4 
c o nsec uti ve da ys or m ore m ust ha ve a p pr o val fr o m t he me dical m o nit or pri or t o res u mi n g 
treat me nt wit h st u d y dr u g. 
8. 3. 1.  
P ati e nt St u d y Dr u g Disc o nti n u ati o n Cri teri a 
St u d y dr u g 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 d e t he f oll o wi n g: 
•  A D V E R S E E V E N T  [ Occ urre n ce of a n A E or c ha n ge i n me di cal stat us t hat will lea d 
t he i n vesti gat or t o b e c o n cer ne d a b o ut t he patie nt’s welfare]; 
•  D E A T H ; 
•  L O S T T O F O L L O W U P  [ Patie nt l ost t o f oll o w-u p] ; 
•  N O N -C O M P LI A N C E WI T H S T U D Y D R U G [ S u bject has n ot a gree d wit h or n ot 
a de q uatel y f oll o w e d t he i nstr ucti o ns relate d t o t he st u d y me dicati o n]; 
•  O T H E R [ Ot her s peci fie d reas o n f or patie nt disc o nti n uati o n]; 
•  P H Y SI CI A N D E CI SI O N  [ S pecifie d me dical reas o n f or patie nt disc o nti n uati o n]; 

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•  P R E G N A N C Y [ Fe males w h o bec o me pre g na nt d uri n g t he st u d y] ; 
•  P R O T O C O L -S P E CI FI E D WI T H D R A W A L C RI T E RI A M E T  [ Reac he d E S K D]; 
•  P R O T O C O L D E VI A TI O N [ N o n -c o m plia nce wit h pr ot oc ol ] 
•  S T U D Y T E R MI N A T E D B Y S P O N S O R;  
•  SI T E T E R MI N A T E D B Y S P O N S O R ; 
•  WI T H D R A W A L B Y S U BJ E C T . 
T he te m p orar y dis c o nti n uati o n a n d reas o n f or dis c o nti n uati o n must be rec or de d in t he e C R F. 
Patie nts w h o per ma ne ntl y disc o nti n u e st u d y dr u g pri or t o t he Week 1 2 st u d y visit  s h o ul d be 
br o u g ht b ac k t o t he cli nic as s o o n as p ossi ble t o c o m plete t he pr oce d ures ass ociate d wit h t he 
Wee k 1 2 visit (i.e., e n d-of -treat me nt visit).  F or patie nts w h o  per ma ne ntl y disc o nti n ue  st u d y dr u g 
earl y, a n d d uri n g a sc h e d ule d st u dy visit , t he Wee k 1 2 assess me nts s h o ul d be c om plete d at t hat 
visit.  
T o mi ni mize missi n g data  i n t he O T  peri o d , all patie nts w h o per ma ne ntl y disc o nti n ue st u d y dr u g 
earl y s h o ul d be e n c o ura ge d t o c o m plete all visits a n d assess me nts  i n t he O T peri o d , a n d patie nts 
s h o ul d ret ur n t o c o m plete t he Wee k 1 7/ E O S visit as o utli ne d i n t he Sc he d ule of Assess me nt (see 
Ta ble  4 ) u nless, i n t he ra re occ urre n ce, t he patie nt ter mi nates partici pati o n i n t he st u d y.  As a n 
e x a m ple, if dr u g is per ma ne ntl y dis c o nti n ued  at Wee k 5 , t he patie nt w o ul d ret ur n as s o o n as 
p ossi ble  f or E O T pr o ce d ures.  T he dat e of t he p atie nt’s last d ose w o ul d be t he start of t he  O T 
peri o d , a n d the patie nt w o ul d c o m plete all O T visits a n d assess me nts ( O T Da ys 3, 7, 2 1, 2 8, a n d 
3 5) o ver t he n e xt 5 wee ks .  At t he patie nt’s tar get Wee k 1 7 date  ( bas e d o n date of 
ra n d o mizati o n), t he patie nt s h o ul d ret ur n t o t he cli nic t o c o m plete E OS  p r oce d ures as t he fi nal 
data c ollecti o n . 
8. 3. 2.  
P ati e nt St u d y  Ter mi n ati o n Criteri a  
St u d y t er mi nati o n refers t o a patie nt’s st o p pi n g all st u d y f oll o w-u p, w hi c h i ncl u des st u d y 
assess me nts, visits, a n d all c o ntact wit h t he site re gar di n g t h e trial.  Reas o ns f or earl y st u d y 
ter mi nati o n i ncl u de t he f oll o wi n g: 
•  D E A T H ; 
•  L O S T T O F O L L O W -U P ; 
•  WI T H D R A W A L O F C O N S E N T B Y S U BJ E C T . 
E ver y reas o na ble eff ort s h o ul d be ma de t o mai ntai n c o ntact wit h all patie nts e nr olle d i n t he 
st u d y.  If c o ntact is l ost, t he PI or  st u d y p ers o n nel s h o ul d atte m pt c o ntact wit h  t he alter nate 
c o ntacts pr o vi de d b y t he patie nt , t he site s h o ul d atte m pt t o reac h t he patie nt t hr o u g h a n y p ossi ble 
met h o d i ncl u di n g p h o ne, e mail, te xt, a n d t hr o u g h a certifie d letter.  C o ntact m ust ha ve bee n 
atte m pte d b y b ot h t he PI a n d  t he st u d y tea m, pri or t o a patie nt bei n g c o nsi dere d l ost t o f oll o w u p.  
Patie nts s h o ul d n ot be c o nsi dere d l ost t o f oll o w -u p u ntil t he sc he d ule d Wee k 1 7/ E O S  visit date.  
T he ter m “ wit h dra wal of c o nse nt” s h o ul d be use d o nl y w he n t h e patie nt n o l o n ger wis hes t o 
partici pate i n t he trial a n d n o l o n ger a ut h orizes i n vesti gat ors t o ma k e eff orts t o c o nti n ue t o o btai n 
t heir o utc o me data.  U nl ess t he patie nt pr o vi des t heir writte n wit h dra wal of c o nse nt or t here is 
ot her writte n d oc u me nt ati o n b y t he i n vesti gat or c o nfir mi n g t he patie nt’s ver bal i nte nt t o 

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c o m pletel y wit h dra w fr o m t he trial, patie nts s h o ul d be f oll o we d f or all pr ot oc ol s pecifie d 
e val uati o ns a n d assess me nts.  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 w al of 
c o nse nt, re q u est t he patie nt ret ur n all u n use d i n vesti gati o nal pr o d uct, re q uest 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 visits (if a p plica ble), a n d f oll o w -u p wit h t he patie nt 
re gar di n g a n y u nres ol ve d A Es.  Wit h dra wal of c o nse nt is a critical trial e ve nt a n d t heref ore 
s h o uld be a p pr oac he d wit h t he sa me de gree of i m p orta nce a n d care as is use d i n i nitiall y 
o btai ni n g i nf or me d c o nse nt.  T he reas o ns f or a p atie nt’s i nte n de d wit h dra wal nee d t o be 
c o m pletel y u n d erst o o d, d oc u me nte d a n d ma na ge d t o pr otect t he ri g hts of t h e patie nt a n d t he 
i nte grit y of t he tri al.   
If a s u bject is disc o nti n ue d earl y fr o m t he st u d y, t h e date t he s u bject is wit h dra w n fr o m t he st u d y 
a n d t he reas o n f or wit h dr a wal will be rec or de d o n t he e C R F.  
I n case of disc o nti n uati o n fr o m st u d y, t he E O T visit assess me nts s h o ul d be perf or me d, a n d a n y 
u nres ol ve d A Es or S A Es will be f oll o we d u p acc or di n g t o  Secti o n  1 1. 2. 1. 1 .  
Patie nts w h o disc o nti n ue d  dr u g a n d  als o c h o os e t o ter mi nate partici pati o n i n t he trial s h o ul d be 
br o u g ht b ac k t o t he cli nic as s o o n as p ossi ble f or earl y t er mi nati o n assess m e nts (i.e., Wee k 1 2 
e n d-of -tr eat me nt visit).  

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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 g ui d eli nes bel o w  a p pl y t o t he ma na ge me nt of st u d y partici p a nts.  
9. 1. 1.  
M a n a ge me nt of Fl ui d St at us  
S pecific ris k miti gati o ns pr oce d ures will be e m pl o ye d t o r e d uce t he p ote nti al f or bar d o x ol o ne 
met h yl -i n d uc e d fl ui d o verl oa d.  T hese pr oce d ures i ncl u de e x cl usi o n of patie nts wit h a n y s e vere 
ki d ne y dise ase, defi ne d as a n e G F R val ue of < 2 0 m L/ mi n/ 1. 7 3 m 2.  T o e x cl u de patie nts wit h 
si g nifica nt car diac d ysf u ncti on, t he st u d y will e x cl u de patie nts wit h a hist or y of cli nicall y 
si g nifica nt car diac diseas e.  Patie nts w h o ha ve e vi de nce of v ol u me o v erl oa d at baseli ne, defi ne d 
as B N P le vel of > 2 0 0 p g/ m L , will als o be e x cl u de d. 
La b orat or y d ata a n d ra pi d wei g ht gai n 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 w h o e x perie nce 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 ha ve a n u nsc h e d ule d tele p h o ne c o nt act i m me diatel y  (see 
Secti o n  9. 1 0. 1 5  f or descri pti o n of tele p h o ne c o ntact).  I n a d diti o n, patie nts will be gi ve n a 
S p o ns or -pr o vi de d scal e t o use at h o me t o c ollect a n d rec or d t h eir wei g hts d ail y d uri n g t he first 8 
wee ks of t he treat me nt p eri o d a n d wee kl y t hereaft er.  Patie nts w h o e x perie nce a  fi v e-p o u n d ( 2. 3 
kil o gra ms) or greater i ncrease i n w ei g ht si nce t heir Da y 1 wei g ht d uri n g t h e first 8 wee ks m ust 
ha ve a n u nsc h e d ule d tele p h o ne c o ntact i m me diatel y.  W het her d ue t o B N P ele vati o ns or wei g ht 
gai n, if cli nicall y i m p orta nt fl ui d rete nti o n is s us pecte d, t he patie nt m ust 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 be me dicall y e val uate d b y t he i n vesti gat or or a 
l ocal p h ysici a n wit hi n 1 t o 2 da ys. 
I n v esti gat ors are e nc o ura ge d t o c o nsi der starti n g or i ncreasi n g d os es of di uretics (t hiazi des, l o o p 
di uretics) earl y after rec o g niti o n of e de m a.   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 h as 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. 
Be y o n d W ee k 8, p atie nts w h o e x perie nce a wei g ht i ncreas e of fi ve  p o u n ds ( 2. 3 kil o gra ms) or 
greater c o m pare d t o Da y  1 will be i nstr ucte d t o c o ntact t he cli nic t o assess t he nee d f or a n 
u nsc he d ule d p h ysical e x a mi nati o n a n d la b orat or y assess me nt b y t h e 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 nless cli nicall y i m p orta nt fl ui d rete nti o n is s us pecte d.   If 
s us pecte d, t he patie nt m ust 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 
be me dicall y e val u ate d b y t he i n vesti gat or or a l ocal  p h ysicia n wit hi n 1 t o 2 da ys.  
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 m e diatel y if t he y e x perie nce s w olle n feet, c hest 
pai n, s h ort ness of breat h wit h  mil d e x erti o n or w hile l yi n g d o w n, or ot her rele va nt s y m pt o ms.  
T he i n vesti gat or m ust 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 
me dical ma na ge m e nt, as necessar y, i ncl 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 . 
9. 1. 2.  
M a n a ge me nt of Ele v ate d  A mi n otr a nsfer ase Le vels ( A L T a n d/ or A S T)  
Nearl y all i nsta nces of el e vate d a mi n otra nsferases  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.  S o me patie nts ma y e x perie nce m or e ra pi d i n creas es i n A L T/ A S T 

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val ues t ha n ot hers d uri n g t he d ose titrati o n peri o d.  I n v esti gat ors ma y c o nsi der e xte n di n g t he 
ti me bet wee n eac h d ose i ncreas e fr o m t w o wee ks t o f o ur wee ks t o ma na ge A L T/ A S T ele vati o ns.  
C hec k a mi n otra nsf eras e  le vels (as w ell as T B L, G G T, al kali ne p h os p hatas e ( A L P), a n d 
I nter nati o nal N or m alize d Rati o [I N R]) wit hi n 7 2 h o urs if t he f oll o wi n g o cc urs: 
•  A L T or A S T le vels > 3 X  U L N.  
Re peat testi n g e ver y 7 2 t o 9 6 h o urs u ntil a mi n otra nsferas e le vels are bel o w 3 X t he U L N f or at 
least o ne wee k.  P atie nt s h o ul d be f oll o we d u n til a mi n otra nsferas e  le vel ret ur ns t o n or mal.  
Testi n g f or patie nts n ot l ocate d near t he i n vesti gat or (s uc h t hat it is i mpractical t o ret ur n t o t he 
site at t he re q uire d i nter vals) ma y be perf or me d at a l ocal la b a n d s e nt t o t he i n vesti gat or a n d 
me dical m o nit or  f or re vie w, b y a p pr o val fr o m t he me dical m o nit or. 
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 ur: 
− A L T or A S T > 8 X  U L N;  
− A L T or A S T > 5 X U L N f or m ore t ha n 2  wee ks;  
− A L T or A S T > 3 X U L N a n d ( T B L > 2 X U L N or I N R > 1. 5);  
− A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, f e 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 ualiz e 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 s ec o n dar y t o ele vat e d tra nsa mi nase 
le vels.  A d diti o nal tests  a n d i ma gi n g ma y be warra nte d de pe n di n g o n t he cli nical prese nt ati o n.  
9. 1. 3.  
M a n a ge me nt of M uscle S p as ms  
Basic s y m pt o m atic relief is t he first ste p i n ma na gi n g m uscle s pas m, i ncl u di n g wal ki n g, a d e q uate 
h y drati o n, weari n g s o c ks, a n d stretc hi n g bef ore b e dti me.  Assess me nt of le vels of electr ol ytes 
s uc h as ma g nesi u m, cal ci u m, a n d p otassi u m ma y i n dicate t he nee d f or re place me nt.  Ser u m 
vita mi n D le vels ma y b e c ollect e d b y t he i n vesti gat or, i n t he e val uati o n of m uscle s pas ms.  If 
vita mi n D le vels are l o w, s u p ple me ntati o n ma y b e warra nte d.  M uscle rela xa 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 ass ess me nts t o e ns ure t hat t he patie nt is recei vi n g a d e q uate n utriti o n a n d c o nsi derati o n 
of ot her eti ol o gies of w ei g ht l oss ma y be warra nte d f or patie nts recei vi n g b ar d o x ol o ne met h yl.  
9. 1. 5.  
H y p o m a g nese mi a  
I n i nsta n ces w h ere a pati e nt e x perie nces h y p o ma g nese mia, defi n e d as ser u m ma g nesi u m less 
t ha n 1. 3 m E q/ L ( 0. 6 5 m m ol/ L), c o nsi derati o n s h o ul d be gi ve n t o re pleti o n of ser u m ma g nesi u m.  
9. 1. 6.  
M a n a ge me 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 
ki d ne y 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 x cee d 1 0 0 0 m g/ g f or pr otei n uria 
a n d s h o ul d c o ns ult t he me dical m o nit or f or a p pr o priate meas ures.  

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9. 1. 7.  
M a n a ge me nt of Bl o o d Press ure  
I n v esti gat ors s h o ul d atte m pt t o mai ntain t he bl o o d press ure wit hi n t he ra n ge rec o m me n d e d b y 
t he Ki d ne y Diseas e Bl o o d Press ure W or ki n g Gr o u p : ≤ 1 4 0 m m H g s yst oli c a n d  ≤ 9 0 m m H g 
diast olic f or patie nts wit h U A C R  < 3 0 m g/ g, a n d ≤ 1 3 0 m m H g s yst olic  a n d ≤ 8 0 m m H g  diast olic 
f or patie nts wit h U A C R > 3 0 m g/ g (K DI G O, 2 0 1 2 ). 
Patie nts bei n g treate d wit h a n A C E i a n d/ or A R B s h o ul d be recei vi n g t he m a xi mall y t olerate d 
la bele d dail y d ose ( M T L D D), defi n e d as t he d ose at or bel o w t he la b ele d d ose t hat d oes n ot 
e x hi bit a n y i nt olera ble a d verse effects (e. g., h y p ot e nsi o n, h y p er kale mia), base d o n t he 
i n vesti gat or's ass ess me nt.  If t he patie nt is c urre ntl y recei vi n g o ne dr u g ( A C Ei or A R B) bel o w 
t he ma xi m u m la bele d d ose, t he dr u g s h o ul d be titr ate d t o t he M T L D D bas e d o n t he assess ment 
of t olera bilit y b y t he i n vesti gat or at least 6 wee ks pri or t o t he Scree n A visit.  
Di uretics ma y be titrate d t o hel p mai ntai n bl o o d press ure tar get le vels . 
A n y c ha n ges i n A C E i or A R B use or di uretic t hera p y s h o ul d b e prece de d b y c o nsi derati o n of a n y 
releva nt c o ntrai n dicati o ns as per t he l ocal pr o d uct i nf or mati o n.  
9. 1. 8.  
N a use a  
Na usea ma y o cc ur wit h hi g her d os es of bar d o x ol o ne met h yl.  N a usea A Es are t y picall y mil d a n d 
re versi ble wit hi n a fe w wee ks aft er treat me nt i nitiati o n.  If s y m pt o ms d o n ot res ol ve, d ose d e- 
escalati o n, wit h c o ns ultati o n of t he me dical m o nit or, ma y b e reas o na ble.  
9. 1. 9.  
E n d St a ge Ki d ne y Dise ase  
Patie nts a p pr oac hi n g E S K D s h o ul d be cl osel y m o nit ore d b y t he  i n v esti gat or t o f ull y c h aracterize 
t heir pr o gressi o n.  F or patie nts wit h e G F R ≤ 1 5. 0  m L/ mi n/ 1. 7 3  m 2, i nitiate m ore fre q u e nt f oll o w-
u p t o cl osel y m o nit or safet y assess me nts (i.e., cli nical c he mistr y (i ncl. e G F R), he mat ol o g y, vital 
si g n assess me nts (i n cl. w ei g ht), B N P a n d N T-pr o B N P).  Si milar fre q u e nt f oll o w -u p ma y als o be 
i m ple me nte d f or patie nts wit h e G F R  >  1 5. 0 m L/ mi n/ 1. 7 3 m 2 w h o, i n t he i n vesti gat or’s o pi ni o n 
base d o n t he a ntici pat e d pr o gressi o n of t heir dise ase, ma y b e a p pr oac hi n g E S K D.  Patie nt 
f oll o w-u p s h o ul d be at least o nce e v er y 4 wee ks ( ± 2 wee ks), u ntil o ne of  t he f oll o wi n g o cc urs: 
•  I nitiati o n of dial y sis; 
•  Recei pt of  tra ns pla nt. 
If a patie nt will i m mi ne ntl y i nitiate dial ysis or recei ve a tra ns pla nt, t he p atie nt s h o ul d be br o u g ht 
i n f or a n E O T visit i n or der t o ha ve E O T/ Wee k 1 2 assess me nts c o n d ucte d, if at all p ossi ble ( pri or 
t o E S K D date).  
U p o n i nitiati o n of dial ysis  or recei pt of ki d ne y tra ns pla nt , st u d y dr u g s h o ul d be per ma n e ntl y 
disc o nti n ue d.  F oll o wi n g per ma ne nt st u d y dr u g dis c o nti n uati o n d ue t o i nitiati o n of  dial ysis or 
recei pt of ki d n e y tra ns pla nt, patie nts s h o ul d c o nti n ue t o be f oll o we d o nl y f or vital stat us a n d 
S A Es b y p h o ne or i n pers o n acc or di n g t o t he pla n ne d c o ntact sc h e d ule i n Secti o n  7. 6  t hr o u g h 
t heir sc he d ule d Wee k 1 7 visit date.  See Secti o n  8. 3  f or pr oce d ures  f oll o wi n g per ma ne nt st u d y 
dr u g disc o nti n uati o n.  I nitiati o n of dial ysis a n d recei pt of ki d ne y tra ns pla nt d ue E S K D s h o ul d be  
c o nsi dere d i m p orta nt me dical e ve nts, a n d as s uc h rec o r de d as S A Es. 

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9. 2.  
Descri pti o n of St u d y Dr u g  
Bar d o x ol o ne met h yl ( R T A 4 0 2) dr u g pr o d u ct i nf or mati o n is s h o w n i n Ta ble  5 .  I nf or mati o n 
re gar di n g t he m atc hi n g pla ce b o is s h o w n i n Ta ble  7 . 
T a ble  5 : 
B ar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or m ati o n  
Descri pti o n  
B ar d o x ol o ne met h yl c a ps ule ( 5 m g a n d  1 5 m g ) 
I n gre die nts 
Bar d o x ol o ne met h yl  
Met hacr ylic Aci d –  Et h yl Acr ylate C o p ol y mer 
( 1: 1), T y pe A 
Silicifie d Micr ocr ystalli ne Cell ul ose  
H y dr o x y pr o p yl Met h ylcell ul ose  
Lact ose M o n o h y drate  
S o di u m La ur yl S ulfate  
C oll oi dal Silic o n Di o xi de  
Ma g nesi u m Stearate  
Gelati n ca ps ules  
Tita ni u m Di o xi de (ca ps ule pi g me nt ) 
R o ute of A d mi nistrati o n  
Oral  
 
T a ble  6 : 
Pl ac e b o Pr o d uct I nf or m ati o n  
Descri pti o n  
Pl ace b o  c a ps ule ( 5 m g a n d  1 5 m g ) 
I n gre die nts 
Silicifie d Micr ocr ystalli ne Cell ul ose  
Lact ose M o n o h y drate  
Ma g nesi u m Stearate  
Gelati n ca ps ules 
Tita ni u m Di o xi de (ca ps ule pi g me nt)  
R o ute of A d mi nistrati o n  
Oral  
9. 3.  
C o nc o mit a nt Me dic ati o ns  
9. 3. 1.  
E xcl u de d Me dic ati o ns  
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: 
•  T ol va pta n;  
•  S o mat ostati n  a nal o g ues;  

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•  Ot her  i nter ve nti o nal cli nical st u dies wit hi n 3 m o nt hs  ( or if rele va nt 5 half-li ves of t hat 
st u d y me dicati o n, w hic h e ver is t he l o n ger) pri or t o Scree n B; 
•  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 uco c ortic oi ds, o nc ol o gic pre parati o ns, a n d a nti -T N F  
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 ma b pe g ol 
( Ci mzia ®), eta nerce pt ( E n brel ®)] wit hi n 1 2 wee ks pri or t o Da y 1 . 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 parati o ns, a n d nasal 
pre parati o ns are  all o we d. 
Patie nts w h o ta ke e x cl u de 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 dra wi n g a patie nt fr o m t he st u d y.  
C o nc o mita nt use wit h str o n g or m o d erate C Y P 3 A 4 i n hi bit ors a n d i n d ucers  is pr o hi bite d.  If a 
str o n g or m o d erate  C Y P 3 A 4 i n hi bit or /i n d ucer is me dicall y n ecess ar y, st u d y dr u g s h o ul d be 
te m p oraril y disc o nti n ue d.  E x a m ples i ncl u de  b ut are n ot li mite d t o : 
•  C Y P 3 A 4 I n hi bit ors: Itrac o naz ole, clarit hr o m yci n, er yt hr o m yci n, rit o na vir, i n di na vir, 
a n d vera p a mil  
•  C Y P 3 A 4 I n d ucers: car ba maze pi ne, p he n yt oi n, a pal uta mi de, b ose nta n, a n d efa vire nz  
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 ulti 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 pt i 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, A R Bs, a n d S G L T 2 i, s h o ul d be o n sta ble 
d oses at t he ti me of st u d y e nr oll me nt a n d  mai ntai n e d o n t h ose sa me d oses a n d d ose sc he d ules 
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 han ges ma de t o t heir me dicati o ns, 
u nless me dicall y i n dicate d.  
9. 4.  
Tre at me nt C o m pli a nce  
T he i n vesti gat or or his/ her desi g nate d a n d q ualifi e d re prese ntati ves will o nl y dis pe nse st u d y dr u g 
t o patie nts e nr olle d i n t he st u d y i n acc or da n ce wit h t he pr ot oc ol.  Patie nts s h o ul d a d mi nister 
st u d y dr u g e x actl y as i nstr ucte d b y t he site.  N o n -c o m plia nce is defi ne d as ta ki n g less t ha n 8 0 % or 
m ore t ha n 1 2 0 % of e x pecte d st u d y me dicati o n d uri n g a n y e val uati o n peri o d ( visit t o visit ).   
Patie nts s h o ul d rec or d i n t he patie n t diar y all a d mi nistere d a n d misse d d oses of st u d y dr u g.  T h e 
reas o n f or a misse d d ose s h o ul d be rec or de d i n t he patie nt diar y.  A misse d d ose i ncl u des dr u g 
h oli da ys a n d te m p orar y st u d y dr u g disc o nti n uati o ns.   Patie nts will be as ke d t o ret ur n all u n use d 
stu d y dr u g  (st u d y dr u g bottles a n d a n y u n use d ca ps ules ). 

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9. 5.  
R a n d o miz ati o n  
Q ualifie d patie nts will be ra n d o mize d 1: 1 t o bar d o x ol o ne met h yl or place b o  at Da y 1 usi n g 
R T S M .  Ra n d o mizati o n will be stratifie d usi n g t h e K DI G O C K D pr o gressi o n ris k heat ma p 
(strat u m 1 = yell o w or ora n ge; strat u m 2 = re d or dar k re d)  base d o n s cree ni n g e G F R a n d U A C R  
usi n g R T S M . 
9. 6.  
Bli n di n g  
I n t his d o u ble-bli n d, place b o -c o ntr olle d st u d y all patie nts, i n vesti gat ors, sit e pers o n nel, a n d 
la b orat ories wit h direct i n v ol ve me nt i n t he c o n d u ct of t h e st u d y or t heir desi g nees will be bli n de d 
t o treat me nt assi g n m e nts.  T o pre ve nt p ote ntial bias, a p pr o priate meas ures will be ta ke n t o e ns ure 
t he bli n d is mai ntai ne d f or t he patie nts a n d pers o n nel me nti o ne d pre vi o usl y.  T o mai ntai n t he 
bli n d, i n vesti gat ors  will distri b ute bli n de d st u d y dr u g b ottles a n d tr eat me nt kits t o patie nts as 
directe d b y t he R T S M.  I n vesti gat ors a n d patie nts will n ot be bli n de d t o d ose le vel, b ut will be 
bli n de d t o treat me nt assi g n me nt (i.e ., acti ve st u d y dr u g v ers us place b o). 
F or pat ie nt u n bli n di n g, t h e i n vesti gat or is e nc o ura ge d t o c o ntact t he me dical m o nit or t o disc uss 
sit uati o ns i n w hic h he or s he belie ves t hat t he bli n d s h o ul d be br o ke n, b ut ulti matel y t h e 
i n vesti gat or h as t he ri g ht t o brea k t he bli n d (e. g., i n t he e ve nt of a s erio us or life -t hreate ni n g 
me dical sit uati o n).  
If u n bli n di n g is re q uir e d, t he i n vesti gat or will utilize R T S M t o perf or m t he u n bli n di n g.  If a 
st u d y dr u g assi g n me nt is u n bli n de d, t he i n vesti gat or m ust descri be t he e ve nt t hat re q uire d 
u n bli n di n g i n t he patie nt’ s s o urce d oc u m e nts. 
Patie nts m ust disc o nti n ue ta ki n g t he st u d y dr u g if t heir treat me nt assi g n me nt has bee n u n bli n de d 
t o t he i n vesti gat or ( or desi g nee).  S uc h patie nts m ust u n der g o t h e sa me st u d y disc o nti n uati o n 
pr oce d ures as t h ose p atie nts w h o disc o nti n ue ta ki n g st u d y dr u g f or ot her reas o ns. 
Patie nt treat me nt assi g n me nts m ust n ot be u n bli n de d i n t he case of a n A E or S A E e x ce pt as 
descri be d a b o ve . 
U n bli n di n g f or Re g ulat or y S u b missi o n:  
I n sit uati o ns w here re g ulati o n re q uires u n bli n di n g a n d re p orti n g of a partic ular seri o us A E, t he 
a p pr o priate b o di es (e. g., E Cs, I R Bs, re g ulat or y a ge ncies) m ust be pr o vi d e d wit h u n bli n de d 
i nf or mati o n acc or di n g t o t he a p plica ble re g ulat or y re q uire me nt.  T his i nf or mati o n m ust n ot be 
c o n ve ye d t o a n y i n v esti gat or, site pers o n nel or p atie nt; t heref ore, t his t y pe of u n bli n di n g d oes n ot 
necessitate t hat t he p atie nt disc o nti n ue s ta ki n g st u d y dr u g.  I n cas es w he n u n bli n de d i nf or mati o n 
m ust be c o n ve ye d t o l ocal healt h a ut h orities, pers o n nel wit h o ut direct i n v ol ve me nt i n t he c o n d uct 
of t he st u d y m ust be res p o nsi ble f or u n bli n di n g t h e patie nt’s treat me nt utilizi n g  R T S M a n d 
c o n ve yi n g t he necessar y i nf or mati o n.  
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;  

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•  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;  
•  e G F R ≤ 1 5. 0 m L/ mi n/ 1. 7 3 m 2 per Secti o n  9. 1. 9 ; 
•  A n y ti me t he i n vesti gat or feels t hat it is cli nicall y  a p pr o priate f or patie nt  safet y.   
At a mi ni m u m, u nsc he d ule d visits s h o ul d i ncl u de c ollecti o n of A Es, c o n c o mita nt me dicati o ns, 
a n d vital si g ns.  A d diti o nal c o n vers ati o ns ma y b e necessar y wit h t he me dical m o nit or f oll o wi n g 
a n u nsc he d ule d visit t o assess pat ie nt safet y. 
9. 8.  
Pre g n a nc y  
9. 8. 1.  
W o me n of C hil d be ari n g P ote nti al a n d Fertile M ales  
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 ha ve e x perie nce d me narc he a n d are 
n ot  s ur gic all y sterile ( n o hist or y of bilateral t u bal li gati o n, h ysterect o m y, bilateral sal pi n g ect o m y, 
or bilateral o o p h or ect o m y), d o n ot h a ve fall o pia n i nserts wit h c o nfir me d bl oc ka ge (e. g., X -ra y, 
ultras o u n d), ha ve n ot ha d re pr o d ucti ve p ot e ntial ter mi nate d b y ra diati o n, a n d are  n ot 
p ost me n o pa usal ( defi n e d as n o me nses f or at least 1 year wit h o ut a n alter nati ve me dical ca us e).  
Fertile males are t h os e w h o ha ve e ntere d p u bert y or reac he d p h ysic al mat urati o n (after p u bert y) 
a n d are n ot s ur gicall y sterile ( n o hist or y of bilateral orc hiect o m y or vasect o m y at least 6 m o nt hs 
earlier wit h t he a p pr o pri ate p o st-pr oce d ure d oc u m e ntati o n of s ur gical s uc cess).  
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 oll o wi n g a d mi nistrati o n of t he 
fi nal d ose of st u d y me dicati o n, W O C B P m ust practice o 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 bar rier m et h o d ( e. g., c o ntrace pti ve s p o n ge, s per mici dal jell y or crea m, 
dia p hra g m [ al wa ys use wit h s per mici dal jell y/crea m]);  
•  Use of h or m o nal c o ntrace pti ves ( oral, pare nteral, i ntra va gi nal, or tra ns d er 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 nistr ati o n; 
•  Use of a n i ntra uteri ne  d e vice ; 
•  Vasect o miz e d part ner ( wit h vasect o m y p erf or me d at least 6 m o nt hs pri or t o scree ni n g 
wit h t he a p pr o priate p ost -pr oce d ure d oc u m e ntati o n of s ur gical s uc cess).  P art ner m ust  
be t he s ole part n er f or t h at patie nt;  
•  A bst ai n fr o m se x ual i nterc o urse c o m plet el y.   C o m plete a bsti ne nce fr o m het er o 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 yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot  per mitte d.  

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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, fertile males w h o ha v e fe m ale 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:  
•  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 ntr ace pti ve s p o n ge, s p er mici dal jell y or crea m, 
dia p hra g m [ al wa ys use wit h s per mici dal jell y/crea m]);  
•  Part ner c o ntr ace pti o n met h o ds; m ust be t he s ole part ner f or t hat patie nt:  
− Use of a n i ntra uteri ne  de vice;  
− Use of h or m o nal c o ntrace pti ves ( oral, pare nteral, i ntra va gi nal or tra ns d er m al)  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;  
− S ur gicall y sterile p art ner ( bilateral t u bal li gati o n, h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect o m y); fall o pia n i nserts wit h c o nfir me d 
bl oc ka ge (e. g. X -ra y, ultras o u n d); 
− Re pr o d ucti ve p ote ntial h as bee n ter mi nate d b y ra diati o n;  
− P ost me n o pa usal ( defi ne d as n o me nses f or at least 1 year) wit h o ut a n alter nati ve 
me dical ca us e ; 
•  A bstai n fr o m se x u al i nterc o urse c o m plet el y.   C o m plete a bsti ne nce fr o m het er ose 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 yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot  per mitte d.  
9. 8. 3.  
S us pecte d Pre g n a nc y  
D uri n g t h e st u d y, all W O C B P m ust be i n str ucte d t o c o ntact t he i n vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt ( e. g., late or misse d me nstr ual peri o d).  Mal e patie nts m ust be 
i nstr ucte d t o c o ntact t he i n vesti gat or if a se x ual part ner s us pects s he m a y be pre g na nt. 
If a patie nt or i n v esti gat or s us pects t hat t he patie nt ma y b e pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t he res ults of a ser u m pre g na n c y test are a v aila ble.  If t h e ser u m pre g n a nc y test 
c o nfir ms t he pre g n a nc y, t he patie nt m ust per ma ne ntl y disc o nti n ue ta ki n g st u d y d r u g.  T h e 
i n vesti gat or m ust i m me diatel y re p ort t o t he me dical m o nit or a pre g na nc y ass ociate d wit h st u d y 
dr u g e x p os ure.  T he earl y disc o nti n uati o n pr ot oc ol -re q uire d pr oce d ures o utli ne d f or E n d-of - 
treat me nt a n d F oll o w-u p visits m ust be perf or me d o n t he pati e nt. 
Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, t he i n vesti gat or m ust f oll o w a pre g na nt p atie nt, or 
t he pre g na nt f e male part ner of a m ale patie nt (if c o nse nti n g), a n d re p ort f oll o w-u p i nf or mati o n 
re gar di n g t he c o urse of t he pre g na n c y, i ncl u di n g peri natal a n d n e o natal o utc o me.   I nfa nts 
res ulti n g fr o m s uc h pre g na ncies s h o ul d be f oll o we d f or a mi ni m u m of 8 wee ks.  Reata or 
desi g nee ma y c o nt act t he i n vesti gat or t o re q uest a d diti o nal i nf or mati o n t hr o u g h o ut t he c o urse of 
t he pre g na n c y. 
 
 

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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 ge.  
9. 9.  
Seri o us T o xicities  
I n t he cas e of seri o us t o xicities, t he i n vesti gat or m ay 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 n all y pla n ne d st u d y sc h e d ule. 
9. 1 0.  
St u d y Pr oce d ures  
T he f oll o wi n g s ect i 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  4 .  All Da y 1 pr oce d ures, e x ce pt A E ass ess me nts, s h o ul d be c o m plete d pri or t o 
a d mi nistrati o n of first d ose of st u d y dr u g.  
A Ce ntral La b orat or y s h o ul d be use d f or all la b -b ase d assess me nts.  F or s pecific g ui da nce o n la b 
sa m ple c ollecti o n, pr ocessi n g, a n d s hi p me nt, pleas e refer t o t he La b orat or y Refere n ce M a n ual.  
9. 1 0. 1.  
I nf or me d C o nse nt  
Writte n i nf or me d c o nse nt (see Secti o n  1 5. 3 ) m ust be o btai ne d fr o m t he p atie nt bef ore a n y st u d y -
relate d pr oce d ures are perf or me d, a n d a gai n if there is a c h a n ge i n t he st u d y pr oce d ures t hat 
w o ul d affect t he patie nt’s willi n g ness t o partici pat e.   T he i nf or me d c o nse nt s h o ul d be re vie we d 
i n detail b y t he p atie nt a n d t he pri nci pal i n vesti gat or or his/ her desi g nee .  Sites m ust e ns ure all 
pa ges of t he i nf or me d c o nse nt are re vie we d, a n d i nitiale d a n d date d, as a p pr o priate, pri or t o 
c o m me nci n g st u d y pr oce d ures.  T he pri n ci pal i n vesti gat or or desi g nee m ust e ns ure  t he patie nt 
f ull y u n dersta n ds t he p ot e ntial ris ks a n d be nefits of trial partici pati o n.  A c o p y of t he si g n e d a n d 
date d i nf or me d c o nse nt f or m m ust be pr o vi de d t o t he patie nt.  T he ori gi nal  i nf or me d c o nse nt 
f or m s h o ul d be file d i n t he patie nt’s rec or ds a n d m ust be ma de a vaila bl e t o t he s p o ns or a n d/ or 
m o nit or.  
9. 1 0. 2.  
I ncl usi o n/ E xcl usi o n 
I n cl usi o n a n d e x cl usi o n criteria m ust be re vi e we d as i n dicate d i n Ta ble  4 .  Patie nts m ust meet all 
of t he i ncl usi o n a n d n o ne of t he e x cl usi o n criteria f or e ntr y i n t he st u d y.  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 u esti o ns re gar di n g eli gi bilit y pri or t o t he patie nt’s 
e nr oll me nt  i n t he st u d y 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 ollect e d as i n dicate d i n 
Ta ble  4 .  Baseli ne dise ase c haracteristics will be c ollecte d as i n dicate d i n T a ble  4 . 

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9. 1 0. 4.  
Pri o r a n d C urre nt C o n c o mit a nt Me dic ati o ns  
T he na me, d ose, a n d fre q ue nc y m ust be rec or de d f or all me dicati o ns t he patie nt is ta ki n g.  All 
all o we d a n d e x cl u de d me dicati o ns s h o ul d be rec or de d i ncl u di n g all prescri pti o n dr u gs, her bal 
pr o d ucts, vita mi ns, mi nerals, a n d o ver -t h e-c o u nt er me dicati o ns.  Tra de or ge neric dr u g n a mes 
s h o ul d be use d w here p ossi ble.  Pri or a n d c o nc o mita nt me dicati o ns (i.e., me dic ati o ns t he patie nt 
is ta ki n g or has ta k e n wit hi n 3 0 da ys pri or t o Da y 1) m ust be re vie we d as i n dicate d i n Ta ble  4  
a n d all c ha n ges rec or de d  i n t he s o urce doc u m e ntati o n a n d cli nical data b as e. 
9. 1 0. 5.  
Me dic al Hist or y  
A c o m plete me dical hist or y , c o veri n g t he past 5 years pri or t o s cree ni n g , as self-re p orte d b y t he 
patie nt , m ust be c ollecte d .  Me dical hist or y als o i ncl u des c ollecti o n of hist orical ser u m creati ni ne 
val ues f or t he p ast  5 years.  T here is n o mi ni m u m re q uire me nt f or t he n u m ber of hist orical v al ues  
c ollecte d.  Sites s h o ul d ai m t o o btai n 1 t o 2 val ues f or eac h year, f or t h e past 5 years pri or t o 
scree ni n g.  M e dical hist or y will be rec or de d as i n dicate d i n  Ta ble  4 . 
9. 1 0. 6.  
C K D Eti ol o g y  
C K D eti ol o g y(s) s h o ul d be c ollecte d a n d rec or de d as i n dicate d i n Ta ble  4 . 
9. 1 0. 7.  
Hei g ht  
Hei g ht s h o ul d be me as ur e d wit h o ut f o ot wear or pr ost hetics as i n dicate d i n Ta ble  4 . 
9. 1 0. 8.  
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  4 .  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 de d.  T he S p o ns or will pr o vi de scales f or distri b uti o n t o patie nts f or use at 
h o me t o meas ure w ei g ht, a n d a patie nt diar y will be pr o vi de d t o rec or d t he at -h o me wei g ht 
meas ure me nts .  Wei g hts rec or d e d i n patie nt diaries will n ot be e ntere d i n t h e 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 de d i n a patie nt diar y.  D uri n g t h e first ei g ht 
wee ks, w ei g hts will be rec or de d dail y; wee kl y wei g hts will be rec or de d t hr o u g h Wee k 1 2.  
Pat ie 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 w ei g ht i ncreas es 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 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. 9.  
Electr oc a r di o gr a m s ( E C G) 
A 1 2 -lea d E C G  will be rec or de d as i n dicate d i n T a ble  4  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 rate 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 ur e me nts. 
9. 1 0. 1 0.  
Vit al Si g n Me as ure me nts  
Vital si g n meas ur e me nts i ncl u de t he patie nt’s p uls e rate ( beats/ mi n ute ta ke n f or at least 1 5 
sec o n ds), res pirati o n rate, a n d b o d y t e m perat ure.  Bl o o d press ur e 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.  Ta ke a n d rec or d 3 b l o o d p ress ure 
rec or di n gs; e ac h rec or di n g m ust be 2 mi n utes a part.  Discar d t he 1st rea di n g a n d t he n a vera ge t h e 
2 n d a n d 3 r d rea di n gs.  T he a vera ge of t he 2n d a n d t he 3 r d rea di n gs m ust be us e d f or t he p ur p ose of 

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t he trial (e. g., inc l usi o n/e x cl usi o n criteria).  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 priat e siz e c uff s h o ul d be use d f or eac h meas ure me nt.  Vital si g n meas ure me nts s h o ul d 
be ta ke n as i n dicate d i n Ta ble  4 . 
9. 1 0. 1 1.  
P h ysic al E x a mi n ati o n  & T ar gete d P h ysic al E x a mi n ati o n  
A c o m pre he nsi v e p h ysic al e x a mi nati o n m ust be perf or me d b y a p h ysicia n, p h ysicia n assista nt, or 
re gistere d n urse practiti o ner as i n dicat e d i n Ta ble  4  a n d as d oc u me nte d wit hi n t he ta ble 
f o ot n otes.  T he e x a 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 pir at or y, a b d o me n, s ki n, 
e xtre mities, a n d ne ur ol o gical.  Assess me nts of a n y s pecific si g ns or s y m pt o ms re p orte d b y t he 
patie nt m ust als o be perf or me d a n d d oc u me nt e d al o n g wit h a n y ot her fi n di n gs of n ote.  Cli nicall y 
si g nifica nt fi n di n gs at Scree ni n g m ust be a d dresse d i n me dical hist or y, (i. e., fi n di n gs s h o ul d be 
attri b uta ble t o a dia g n osis rec or de d i n me dical hist or y).  F oll o wi n g t he e x a mi nati o n at Scree ni n g, 
ne w or c h a n ge d p h ysic al e x a mi nati o n fi n di n gs meeti n g t he defi niti o n of a n A E m ust be re p orte d 
as a n A E.  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 ysic al e xa mi nati o n o n a 
patie nt d uri n g t he  st u d y.   
A tar gete d p h ysic al  e x a mi nati o n (s y m pt o m-directe d) will be  perf or me d as n ee de d at visits 
i n dicate d i n Ta ble  4 . 
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 t est as i n dicate d i n  Ta ble  4 , or at a n y ti me 
if pre g na n c y is s us pecte d.  Ne gati ve test res ults are re q uir e d o n Da y 1 b ef ore st u d y dr u g 
a d mi nistrati o n.  A n y pati e nt w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue ta ki n g 
st u d y dr u g i m me diatel y.  W O C B P  will re q uire a s er u m pre g n a nc y test ( 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.  
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 nc 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 t he n u m ber of ca ps ules i nstructe d fr o m eac h b ottle i ncl u de d i n 
t he st u d y dr u g b ottle /kit orall y o n ce 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 treat me nt, 
as i n dicate d i n Ta ble  4 .  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 matel y t h e 
sa me ti me eac h d a y, prefera bl y i n t he m or ni n g.  St u d y dr u g a d mi nistrati o n (I P) s h o ul d be 
rec or de d i n a patie nt diar y t hr o u g h o ut t he 1 2-wee k d osi n g peri o d .  P atie nts m ust n ot self -
a d mi nister st u d y dr u g  t he da y of t he Wee k 1 2 V isit.  T he last d ose of dr u g s h o ul d occ ur t he da y 
pri or t o t he Wee k 1 2 Visit.   
A v o mite d d ose m ust n ot be re pla ce 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 patie nt as i n dicate d i n Ta ble  4 .  
T he patie nt will be dis pe nse d o ne b ottle  at Da y 1 a n d treat me nt kits at Wee k 2, Wee k 4, Wee k 6 
( o nl y if b aseli ne A C R > 3 0 0 m g/ g) a n d Wee k 8.  O nl y  o ne treat me nt kit s h o ul d be o pe ne d at a 

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ti me.  Dis pe nse d treat me nt kits fr o m eac h visit (i ncl u di n g u nsc h e d ule d visits) s h o ul d be ret ur n e 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 n e as i n di cat e d i n Ta ble  4 .  Patie nts will be as ke d a b o ut t heir 
b o d y w ei g ht a n d ot her si g ns of fl ui d rete nti o n, as well as A Es a n d a n y c ha n ges t o c o nc o mita nt 
me dic ati o ns.  If fl ui d ret e nti o n is s us pecte d, t he patie nt s h o ul d be i nstr ucte d t o st o p ta ki n g st u d y 
me dicati o n i m me diatel y a n d be me dicall y e val uat e d b y t h e i n vesti gat or or a l ocal p h ysicia n 
wit hi n 1 t o 2 da ys, as det aile 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 peara 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  4 .  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 p e n q uesti o n re gar di n g a n y A Es t he y ma y be e x perie nci n g (e. g., “ H o w ha ve y o u bee n feeli n g 
si nce y o ur last visit? ”).  A n y fi n di n gs are t o be d oc u me nte d.  Patie nts m ust be as ke d if t he y h a ve 
bee n h os pitaliz e d, ha d a n y acci de nts, use d a n y ne w me dicati o ns, or c h a n ge d c o nc o mita nt 
me dicati o n re gi me ns (i ncl u di n g pres cri pti o n dr u gs, o ver -t he-c o u nter m e dicati o ns, vita mi ns, 
her bal pr o d u cts, a n d mi nerals).  Res p o nses m ust b e d oc u me nte d i n t he s o urce d oc u me nts.  
9. 1 0. 1 7.  
Ge neti c Testi n g  
A b uccal s w a b (c h ee k s w a b)  will be c ollect e d o n or bef ore t he E O S visit  t o be use d f or ge netic 
testi n g as i n dicat e d i n Ta ble  4 .  T he testi n g p a nel will assess a p pr o xi matel y 1 8 ge n es k n o w n t o 
be ass ociate d wit h c hr o ni c ki d ne y disease . 
9. 1 0. 1 8.  
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  4 : 
ferriti n, 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, L D H, ma g nesi u m, 
c hl oride, bicar b o nate, a n d G G T.  
9. 1 0. 1 9.  
e G F R  
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 ge 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 v e a perce nt differe nce  ≤ 
2 5 %, as deter mi ne d b y t h e 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 (S cree 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  
 
 

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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:  
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 4 1 × mi n( Scr/ κ, 1)α × ma x( S cr/ κ, 1)-1. 2 0 9 × 0. 9 9 3 A ge  ×  1. 0 1 8 [if 
fe male] × 1. 1 5 9 [if blac k] 
W here Scr is ser u m creati ni ne ( m g/ d L), κ is 0. 7 f or fe males or 0. 9 f or mal es, a n d α is -0. 3 2 9 f or 
fe males or -0. 4 1 1 f or mal es .  Mi n i n dicates t he mi ni m u m of Scr/ κ or 1 a n d ma x i n dicates t he 
ma xi m u m of Scr/ κ or 1. A ge i n dicates a ge at ti me of la b c ollecti o n.  
9. 1 0. 2 0.  
N -T er mi n al  Pr o -B -t y pe N atri ureti c Pe pti de ( N T -p r o B N P) a n d B -t y pe 
N atri ureti c Pe pti de  ( B N P) 
Sa m ple s 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  4 . As rece nt e xercise 
ma y affect B N P a n d N T -pr o B N P le vels, p atie 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 1.  
He m o gl o bi n A 1c  (H b A 1c ) 
Sa m ples will be c ollecte d f or H b A 1c  as i n dicate d i n Ta ble  4 .  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 ual pr o vi de d 
t o t he i n vesti gat or. 
9. 1 0. 2 2.  
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  4 : 
he mat ocrit, he m o gl o bi n, 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 dete cte d), l y m p h oc yt es, m o n oc yt es, bas o p hils (if detecte 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). 
9. 1 0. 2 3.  
Uri n al ysis a n d Micr osc o p y  
Sa m ples will be c ollecte d f or t he f oll o wi n g uri nal ysis a n d micr osc o p y assess me nts as i n dicate d 
i n Ta ble  4 : s pecific gra vit y, ket o nes, p H, pr otei n, bl o o d, gl uc ose, clarit y, c ol or, le u k oc yt es, 
nitrite, bilir u bi n, a n d a micr osc o pic e x a mi nati o n (if i n dicate d bas e d o n la b orat or y res ults).  
9. 1 0. 2 4.  
Uri ne C ollecti o n f or Uri ne Al b u mi n t o Cre ati ni ne R ati o ( U A C R) 
Uri ne 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 as 
i n dicate d i n Ta ble  4 .  A p pr o priate c o nt ai 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 t he c ollecti o n. 
Patie nts s h o ul d be i nstr ucte d h o w t o pr o perl y ca pt ure a sa m ple of t heir first m or ni n g v oi d, 
defi ne d as t heir first uri n ati o n after 5 A M.  F oll o wi n g Da y 1, if a p atie nt prese nts f or a visit a n d 
h as f or g otte n t o c ollect ( or bri n g) t he uri ne s a m ple(s) f or t hat visit, t he y m a y ret ur n wit hi n 7 da ys 
t o s u b mit t he sa m ple(s) c ollecte d t hat da y. 

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9. 1 0. 2 5.  
P h ar m a c o ki n etic ( P K) Bl o o d S a m ples  
Bl o o d sa m ples f or d eter mi nati o n of plas ma bar d o x ol o ne met h yl a n d p ot e ntial m eta b olite 
c o nce ntr ati o ns will be dra w n as i n dicate d i n T a ble  4 .  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 for t he Wee k 1 2 visit.  Patie nts will be as ke d b y site 
pers o n nel t o pr o vi de t he ti me of t heir last t w o a d mi nistrati o ns of st u d y dr u g pri or t o t he bl o o d 
sa m ple bei n g c ollecte d at Wee k 1 2 .  P atie nts s h o ul d be i nstr ucte d t o refr ai n fr o m t a ki n g I P 
o n t he d a y of  t he Wee k 1 2 visit.  T he l ast d ose of st u d y dr u g s h o ul d be t he d a y pri or t o t he 
Wee k 1 2 visit.   Bl o o d sa m ple c ollecti o n i nstr ucti o ns s h o ul d be refere n ce d i n t he la b orat or y 
ma n ual.   
T he date a n d ti me of c ollecti o n of all P K bl o o d sa m ples s h o ul d be rec or de d .  Dates i n t he cas e 
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 de 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 rec or de d as  s uc h. 
9. 1 0. 2 6.  
Li ver a n d Ki d ne y I nj ur y Bi o m ar kers  
Bl o o d sa m ples f or n o v el li ver a n d ki d ne y i nj ur y bi o mar kers will be dra w n as i n dicate d i n 
Ta ble  4 .  O n Da y 1, bl o o d sa m ple m ust be c olle ct e d bef ore st u d y dr u g a d mi nistrati o n.   
9. 1 0. 2 7.  
C -Re a cti ve Pr otei n  
Bl o o d sa m ple s will be dra w n as a mar ker of i nfla m mati o n as i n dicate d i n Ta ble  4 .  O n Da y 1, 
bl o o d sa m ple m ust be c ollecte d bef ore st u d y dr u g a d mi nistrati o n.  
9. 1 0. 2 8.  
Pr ot hr o m bi n Ti me ( P T) / I nter n ati o n al N or m alize d R ati o  (IN R )  
Bl o o d sa m ples will be dra w n t o hel p m o nit or t he cl ott i n g of t he bl o o d as i n dicate d i n Ta ble  4 . 

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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 a n d place b o ca ps ules, 5 m g (siz e # 4) a n d 1 5 m g (size # 1) will  be use d i n 
t his st u d y.  Kits will be pr o vi de d f or t he 1 0  m g, 2 0  m g, a n d 3 0  m g d oses usi n g a c o m bi nati o n of 
5  m g a n d/ or 1 5  m g ca ps ules.    
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 as eit her i n di vi d ual b ottles ( 5 m g d ose) or i n ta m per -e vi d e nt kits 
c o ntai ni n g t w o hi g h -d e nsit y p ol yet h yl e ne b ottles ( 1 0  m g, 2 0  m g , a n d 3 0 m g d oses ) or t he 
matc hi n g pla ce b o ca ps ul es .  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 bar d o x ol o ne met h yl  or matc hi n g 
place b o .  Eac h b ottle will als o c o ntai n a desic ca nt i nsert t hat m ust n ot be i n geste d.  La beli 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 m ati o n:  
•  Me dicati o n I D n u m ber;  
•  Bar d o x ol o ne met h yl ca ps ules  (stre n gt h) or mat c hi n g place b o  
•  Pr ot oc ol  4 0 2 -C -2 0 0 2;  
•  Ca uti o n State me nt: Ne w Dr u g –  Li mite d b y Fe d eral La w t o I n vesti gati o nal Use.   
•  Kee p o ut of reac h of  c hil dre n;  
•  C o ntr ol or l ot  n u m ber;  
•  St ore at 1 5° –  2 5° C ( 5 9° –  7 7° F);  
•  Reata P ha r mace uticals, I nc., Pla n o , T X  7 5 0 2 4 . 
W he n a p plica ble, a d o u bl e -pa nel la b el will be pres e nte 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.  A d diti o nall y, l a beli n g, i n t he rele va nt l ocal la n g ua ges f or 
i n vesti gati o nal me dici nal pr o d uct f or use a n d distri b uti o n i n t he Eur o pea n U ni o n  s hall a d here t o 
c urre nt E u drale x, V ol u me 4 A n ne x 1 3 g ui da nce a n d re q uire me nts.  
1 0. 3.  
St u d y Dr u g St or a ge  
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 on diti o ns of 1 5° - 2 5° C ( 5 9° - 7 7° F).  
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
Please refer t o Secti o n  9. 1 0. 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 o i nt liste d i n Ta ble  4 .  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 t hr o u g h o ut a 1 2-wee k d osi n g peri o d : ( 1) t he patie nt h as bee n ot her wise 
i nstr ucte d b y t h e 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.  P atie nts s h o ul d be i nstr ucte d t o refr ai n fr o m t a ki n g I P o n t he d a y of t he Wee k 
1 2 visit.  T he l ast d ose of st u d y dr u g s h o ul d be t he d a y pri or t o t he Wee k 1 2 visit. 

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1 0. 5.  
St u d y Dr u g Acc o u nt a bilit y  
T he i n vesti gat or , or desi g nee, will mai ntai n a rec or d of all st u d y dr u g recei v e d, dis pe nse d, a n d 
ret ur ne d t o t he S p o ns ors’ desi g nee.  N o st u d y dr u g s hall be destr o ye d b y t he cli nical site u nless 
directe d i n writi n g t o d o s o b y t he S p o ns or’s q u alit y ass ur a nce d e part me nt.  St u d y dr u g b ottles 
a n d a n y u n use d ca ps ules s h o ul d be ret ur ne d t o t he st u d y staff f or e v e nt ual dis p ositi o n b y t he 
S p o ns or.  T he n u m ber of ca ps ules ret ur ne d at eac h visit will be rec or de d b y t he site 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 wil l 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. 
1 0. 7.  
C o m pli a nce  
T he prescri be d d osa ge, ti mi n g , a n d m o de of a d mi nistrati o n of st u d y dr u g ma y n ot be c ha n ge d.  
Patie nt s will be as ke d q uesti o ns re gar di n g c o m plia nce  a n d a n y de part ures fr o m t he i nte n de d re gi me n 
m ust be rec or de d i n t he e C R F.   Patie nt s will be as ke d t o ret ur n all u n use d st u d y dr u g.  N o n -
c o m plia nce is defi ne d as ta ki n g less t ha n 8 0 % or m ore t ha n 1 2 0 % of st u d y dr u g d uri n g a n y 
e val uati o n peri o d ( visit t o visit ). 

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1 1.  
S A F E T Y  A S S E S S M E N T S  
1 1. 1.  
S afet y P ar a meters  
T o a v oi d i nter-o bser ver varia bilit y, e v er y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns 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 patie nt re gardless 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 o cc urri n g e ve nts or pre vi o us c o n diti o n t hat has i ncrease d i n 
se verit y or fre q ue n c y si nce t he a d mi nistrati o n of st u d y dr u g.  
All A Es t hat are o bser ve d or re p orte d b y t he  patie nt d uri n g t he st u d y (fr o m ti me of 
a d mi nistrati o n of t he first d ose at t he Da y 1 visit u ntil t he fi nal visit i n dicate d i n Ta ble  4 ) m ust be 
re p orte d, re gar dless of t h eir relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce. 
1 1. 2. 1. 2.  Seri o us A d verse E ve nt  
As S A E is a n y A E o cc 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 hr eate 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 ncti o ns; 
•  Is a c o n ge nital a n o mal y or birt h defect i n a n offs pri n g of a patie nt ta ki n g st u d y dr u g;  
•  Is a n i m p orta nt me dical  e ve nt. 
T he ter m "life -t hr eate ni n g" refers t o a n e ve nt i n w hic h t he patie nt was at i m me diate ris k of deat h 
at t he ti me of t he e ve nt.  It d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e vere. 
I m p ort a nt me dical e v e nts are t h ose t hat ma y n ot m eet a n y of t he criteri a defi ne d a b o ve; h o we v er, 
t he y ma y b e c o nsi dere d s eri o us w he n, bas e d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y 
je o par dize t he patie nt a n d ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he S A E defi niti o n.  

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Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, i nf or mati o n will be c ollecte d f or a n y pre g na nci es 
t hat occ ur d uri n g t he st u 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  4 , as a p pr o priate).  Certai n pre g na nc y o utc o mes will re q uire s u b missi o n as a n 
S A E (see Secti o n  9. 8 ). 
T he i n vesti gat or is res p o nsi ble f or re p orti n g t o Reata or desi g nee all A Es a n d S A Es t hat are 
o bser ve d or re p ort e d b y t he patie nt d uri n g t he st u d y (fr o m t he ti me of a d mi nistrati o n of t he first 
d ose of st u d y dr u g u ntil t he fi nal visit i n dicate d i n Ta ble  4 , as a p pr o priate), i ncl u di n g e v e nts 
res ulti n g fr o m pr ot oc ol-ass ociate d pr oce d ures as d efi 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 he S p o ns or ma y re q uest a d diti o nal 
i nf or mati o n fr o m t he i n v esti gat or t o e ns ure t he ti mel y c o m pleti on 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 d ee ms t he e v e nt t o be c hr o nic or t he p atie nt t o be sta ble.  Reata or desi g n ee ma y 
c o ntact t he i n vesti gat or t o o btai n a d diti o nal i nf or mati o n o n a n y S A E w hic h has n ot res ol ve d at 
t he ti me t he patie nt c o m pletes t he st u d y. 
1 1. 3.  
Eliciti n g A d verse E ve nt I nf or m ati o n 
At e ver y st u d y visit, patie nts m ust be as ke d a sta n dar d, n o n-directe d q uesti o n, s uc h as, “ H o w 
ha ve y o u bee n feeli n g si n ce y o ur last visit? ”  t o elicit a n y me dicall y relate d c ha n ges i n t heir well -
bei n g.  T h e y ma y als o be as ke d if t he y ha v e 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 ns es m ust be 
d oc u me nte d i n t he s o urce d oc u me nts.  
I n a d diti o n t o patie nt o bser vati o ns, A Es m ust be d oc u me nte d f or a n y cli nicall y si g nifica nt 
dia g n osis r es ulti n g fr o m a b n or mal la b orat or y test val ues, p h ysi cal e xa 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 wi n g classificati o ns a n d criteria t o c haracterize t he 
relatio ns hi p or ass ociati o n of t he st u d y dr u g i n ca usi n g or c o ntri b uti n g t o t he A E:  
N ot Relate d : T his relati o ns hi p s u g gests t hat t here is n o ass ociati o n bet wee n t he st u d y dr u g a n d 
t he re p orte d e ve nt. 
U nli kel y Relate d : T his r elati o ns hi p s u g gests t hat t he te m p oral se q u e nce of t he e ve nt wit h st u d y 
dr u g a d mi nistrati o n ma kes a ca us al relati o ns hi p i m pr o ba ble a n d/ or ot her fact ors als o pr o vi de 
pla usi ble e x pla nati o ns.  
P ossi bl y Relate d : T his r elati o ns hi p s u g gests t hat treat me nt wit h t he st u d y dr u g ca use d or 
c o ntri b ute d t o t he A E.  T hat is, t he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m t he ti me 
of st u d y dr u g a d mi nistrati o n, a n d/ or, f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, b ut 
c o ul d ha ve bee n pr o d uce d b y ot her fact ors.  
Pr o ba bl y Relat e d : T his relati o ns hi p s ug gests t hat a reas o n a ble te m p or al se q ue nce of t h e e ve nt 
wit h st u d y dr u g a d mi nistrati o n e xists a n d, base d u p o n t he k n o w n p har mac ol o gical acti o n of t he 
dr u g, k n o w n or pre vi o usl y re p orte d a d verse reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt 

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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 R elate d : T his relati o ns hi p s u g gests t hat a defi nite ca usal rel ati o ns hi p e xists bet wee n 
t he dr u g a d mi nistrati o n a n d t he A E, a n d ot her c o n diti o ns (e. g., c o n c urre nt ill ness, 
pr o gressi o n/e x pressi o n of disease state, or c o nc urre nt me dicati o n reacti o n) d o n ot a p pear t o 
e x plai n t he e ve nt.  
1 1. 5.  
Assess me nt of Se verit y  
T he i n vesti gat or  will gra de t he se verit y of t h e A Es as mil d, m o derate, or se vere u si 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, 
i nter ve nti o n n ot i n dicate d. 
M o derate : S y m pt o ms c a usi n g greater t ha n mi ni m al i nterfere nce wit h us ual s ocial a n d f u ncti o nal 
acti vities, l ocal or n o ni n vasi ve i nter ve nti o n i n dicat e d. 
Se vere : S y m pt o ms c a usi n g i na bilit y t o p erf or m us ual s ocial a n d f u n cti o nal acti vities, 
me dical/s ur gical i nter v e nti o n i n dicate d . 
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 nistrat i 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 t he last st u d y f oll o w -u p visit, re gar dless of t h e relati o ns hi p of t he A E t o st u d y dr u g.  
I nf or mati o n t o be c ollecte d i ncl u des t y p e of e ve nt, date of o nset, dat e of res ol uti o n, i n vesti gat or - 
s pecifie d ass ess me nt of s e 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 ot al d urati o n a n d 
greatest se v erit y s h o ul d be rec or de d i n t he e C R F.  A Es c haracterize d as i nter mitte nt re q uire 
d oc u me ntati o n of o nset a n d d urati o n.  
All dr u g -relate d ( p ossi bl y, pr o ba bl y, or defi nitel y relate d, see Secti o n  1 1. 4 ) A Es a n d a b n or m al 
la b orat or y test r es ults re p orte d or o bser ve d d uri n g t he st u d y m ust be f oll o w e d t o res ol uti o n 
(eit her ret ur n t o baseli ne or wit hi n n or mal li mits).  All ot her A Es will be f oll o we d t hr o u g h t he 
fi nal visit i n dicate d i n Ta ble  4 , 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 gressi o n of disease states m ust als o be re p ort e d.  Pree x isti 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 orse ni n g or c o m plicati o n of s uc h a c o n c urre nt c o n diti o n, t he w o rse 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 de 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 . 

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a ge ncies i n writi n g wit hi n t he ti mefra me est a blis he d b y t h os e  re g ulat or y a ge ncies.  Reat a or 
desi g nee will pr o vi de c o pies of a n y re p orts t o re g ulat or y a ge nci es re gar di n g seri o us a n d 
u ne x pecte d S A Es t o t he i n vesti gat ors f or re vie w a n d s u b missi o n t o t heir I 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 are res p o nsi ble f or i nf or mi n g t heir I R B/ E C of a n y S A Es at t heir site.  
S A E c orres p o n d e nce wit h re g ulat or y a ut h orities or I R Bs/ E Cs m ust be s u b mitte d t o t he S p o ns or 
or desi g n ee f or rec or di n g i n t he st u d y file.  
N ote t hat t h e f oll o wi n g S A E w hic h are c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n as part of 
C K D pr o gressi 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 ort, 
e x ce pt i n u n us ual circ u msta nces.  
•  I nitiati o n of dial ysis d ue t o e n d sta ge ki d ne y disease ; 
•  Ki d ne y tr a ns pla nt d ue t o e n d sta ge ki d ne y  diseas e . 
T hese e v e nts will be re vi e we d o n a re g ular basis i n a g gre gat e a n d will be re p orte d i n a n 
e x pe dite d ma n ner if a safet y si g nal is detecte d.  Re g ular s afet y st u d y u p dat es will be re p orte d t o 
re g ulat or y a ut h orities acc or di n g t o l ocal g ui deli nes. 

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1 2.  
S T A TI S TI C S  
1 2. 1.  
S a m ple Size  
Wit h 7 0  patie nts e nr olle d ( 3 5  i n eac h gr o u p), t he st u d y will ha ve a p pr o xi matel y 8 0 % p o wer t o 
detect a differe nce b et wee n t he t w o treat me nt gr o u ps i n c ha n ge fr o m baseli ne i n e G F R o f 5. 9  
m L/ mi n/ 1. 7 3 m 2 f or t he pri mar y e n d p oi nt at Wee k 1 2.  T he p o wer calc ul ati o n, w hic h was base d 
o n a t w o -si de d t w o-sa m ple t-test, ass u mes t he f oll o wi n g: 
•  T w o -si de d T y pe I err or rate of 0. 0 5; 
•  Sta n dar d de viati o n of c h a n ge fr o m b aseli ne i n e G F R of 8 m L/ mi n/ 1 . 7 3 m2; 
•  A c ha n ge fr o m bas eli ne i n e G F R of a p pr o xi matel y 5. 9  m L/ mi n/ 1. 7 3 m 2;  
•  1 5 % dr o p -o ut a n d missi n g dat a will n ot be i m p ute d . 
A nal ysis of t h e pri mar y e n d p oi nt will be base d o n t he i nte nt -t o-treat (I T T) p o p ulati o n a n d 
a nal yze d usi n g mi x e d -m o del re peate d m eas ures ( M M R M) wit h a n u nstr uct ure d c o varia nce 
str uct ure.  T he a nal ysis met h o d is e x pecte d t o ha ve at least as m uc h p o wer as t he t w o-sa m ple t-
test use d f or st u d y pla n ni n g.  A p pr o priate s e nsiti vit y a n al ys es of t he pri mar y a n al ysis will be 
s pecifie d i n t he S tatistical A nal ysis P la n (S A P ).  T he sec o n dar y efficac y e n d p oi nt will be teste d 
f or s ufficie ntl y lar ge s u b gr o u ps, b ut t he st u d y is n ot p o were d t o s h o w efficac y i n t he sec o n d ar y 
effic ac y e n d p oi nt.  
1 2. 2.  
St u d y V ari a bles  
1 2. 2. 1.  
P h ar m a c o ki ne tic V ari a bles  
T he p har mac o ki netic varia bles i ncl u de bar d o x ol o ne met h yl plas ma c o nce ntrati o n -ti me data a n d 
esti mate d p har mac o ki netic para met ers.  
1 2. 2. 2.  
Effic ac y V ari a bles  
C ha n ge fr o m bas eli ne i n e G F R will be use d t o det er mi ne t he pri mar y, s ec o n dar y, a n d 
e x pl orat or y effic ac y e n d p oi nts.  
1 2. 2. 3.  
S afet y V ari a bles  
T he safet y v aria bles i ncl u de res ults of 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), vital si g n meas ure me nts, E C G res ults, wei g ht, A Es, a n d S A Es.  
1 2. 3.  
St atistic al A n al yses  
A S A P detaili n g t he a n al ys es will be d e vel o pe d pri or t o data base l oc k .  All statistical a nal ys es 
a n d data s u m maries will be perf or me d usi n g S A S ®  ( Versi o n 9. 1 or hi g her) or ot her vali date d 
s oft ware.  T h e S A P will ser ve as t he fi nal ar biter of all statistical a nal ys es.  Data will be 
s u m marize d o verall usi n g des cri pti ve statistics.  C o nti n u o us data will be s u m marize d wit h 
n u m ber of patie nts ( n), m ea n, me dia n, mi ni m u m, ma xi m u m, rele va nt q uartiles, sta n dar d 
de viati o n, c oefficie nt of variati o n, a n d ge o metric mea n ( w here a p plica ble).  Cate g orical dat a will 
be s u m mariz e d usi n g fre q ue nc y c o u nts a n d  p erce nta ges.  

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1 2. 3. 1.  
Pri m ar y A n al ysis of Effic ac y  
T he I T T p o p ulati o n, w hi c h i ncl u des all e nr olle d p atie nts, will be use d as t he p o p ulati o n f or 
assess me nt of t he pri mar y effic ac y e n d p oi nt.  
T he pri mar y e n d p oi nt is c ha n ge i n e G F R at Wee k 1 2.   A m i x e d-m o del re peate d meas ures 
( M M R M) m o del will be use d t o c om pare  p atie nts ra n d o mize d t o bar d o x ol o ne met h yl t o patie nts 
ra n d o mize d t o place b o.  T he m o del will i ncl u de c ha n ge fr o m b aseli ne i n e G F R as t he de p e n de nt 
varia ble, ba s eline e G F R a n d C K D sta ge as c o vari ates, patie nt as a ra n d o m effect, a n d t he 
f oll o wi n g fi x e d fact ors: treat me nt gr o u p, pr ot o c ol -sc he d ule d n o mi nal ti me p oi nt, an d  t he 
i nteracti o n bet wee n treat me nt a n d ti me.  Ot her c o variates ma y b e s pecifi e d i n t he S A P.  Ti me 
o r deri n g is a re peat e d me as ure wit hi n patie nts.  It is ass u me d t hat err ors f or differe nt p atie nts are 
i n de pe n de nt wit h a n u nstr uct ure d c o varia n ce str u ct ure.  Missi n g data will n ot be i m p ute d f or t he 
pri mar y a nal ysis si nce all data c ollecte d will be i ncl u de d  i n t he M M R M a nal ysis.  A p pr o priate 
se nsiti vit y a nal yses will be perf or me d a n d d efi ne d i n t he S A P .  T he sec o n dar y efficac y e n d p oi nt 
will be teste d f or s uffi cie ntl y lar ge s u b gr o u ps, b ut t he st u d y is n ot p o were d t o s h o w efficac y i n 
t he sec o n dar y efficac y e n dp oi nt.  E x pl orat or y efficac y will be s u m marize d descri pti vel y.  

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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 re 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 tele 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 bs er vati o n, 
re view of st u d y rec 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 u ncil f or Har m o nisati o n of Tec h nical 
Re q uire me nts f or P har m ace uticals f or H u ma n Us e (I C H) g ui deli ne E 6( R 2): 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 ures.  
Eac h i n vesti gat or is e x pecte d t o ma ke a r eas 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 h e 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 a ccess 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 u ri n g t he visit. 
1 3. 2.  
A u dits a n d I ns pecti o ns  
Pri nci p al i n vesti gat ors a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit st u d y-relate d 
m o nit ori n g, a u dits, a n d I R B/ E C re vie w, a n d re g ul at or y i ns p ecti o ns, b y pr o vi di n g direct access t o 
all st u d y rec or ds.  I n t he e ve n t 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 D A, a n d ot her rele va 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 n ee 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 n ee. 

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

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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 ges f or a n y la b orat ories use d b y t h e site  f or 
t he c o n d uct of t his st u d y. 
1 4. 5.  
Cli nic al St u d y I ns ur a nce  
I n acc or da n ce w it h t he res pecti ve nati o nal dr u g la ws, t he S p o ns or has ta ke n o ut patie nt lia bilit y 
i ns ura nce f or all patie nts w h o gi ve t h eir c o nse nt a n d e nr oll i n t his st u d y.  T his i ns ura nce c o v ers 
p ote ntial fatalities, p h ysi cal i nj uries, or da ma ge t o healt h t hat ma y occ u r 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 n t of 
bar d o x ol o ne met h yl a n d ma y b e discl ose d t o re g ul at or y a ut h orities, ot her i n vesti gat ors, c or p orate 
part ners, or c o ns 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 n e d a n d date d state me nt t hat t he pr ot oc ol a n d i nf or me d c o nse nt ha ve bee n 
a p pr o ve d b y t he I R B/ E C  f or t hat site bef ore c o ns e nti n g patie nts.  Pri or t o st u d y i nitiati o n, t he 
i n vesti gat or is r e q uire d t o si g n a pr ot o c ol si g nat ure pa ge c o nfir mi n g a gree me nt t o c o n d uct t he 
st u d y i n acc or da n ce wit h t his pr ot oc ol a n d t o gi ve access t o all rele va nt d ata a n d rec or ds t o t he 
S p o ns or, its desi g nee, a n d re g ulat or y a ut h orities as re q uire d.  
T he I R B/ E C c h air pers o n or desi g n ee m ust si g n all I R B/ E C a p pr o vals a n d m ust i de ntif y t he 
I R B/ E C b y n a 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 gat or is res p o nsi ble f or o btai ni n g re vi e ws of t he cli nical researc h at i nter v als 
s pecifie d b y t he I R B/ E C, b ut n ot e x cee di n g 1 year.  T he pri nci pal i n vesti gat or m ust s u p pl y t he 
S p o ns or or desi g n ee wit h writte n d oc u me nt ati o n of re vie ws of t he cli nical r esearc h.  
1 5. 2.  
Et hic al C o n d uct of t he St u d y  
T his cli nical st u d y was d esi g ne d a n d s hall be i m pl e me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H Har m o 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 gulati o ns (e. g., U S C o d e of Fe deral Re g ulati o ns Title 2 1, E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C), 
a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.  T he pri nci pal 
i n vesti gat or a grees t o c o n d uct t he st u d y i n acc or da nce wit h t he I C H G ui da nce for I n d ustr y o n 
G o o d Cli nical Practice ( G C P) I C H E 6( R 2) 
[ htt ps:// w w w.ic h. or g/file a d mi n/ P u blic _ We b _ Site/I C H _ Pr o d u cts/ G ui deli nes/ Efficac y/ E 6/ E 6 _ R 2 _
_ Ste p _ 4 _ 2 0 1 6 _ 1 1 0 9. p df ] an d t he 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 nci pal i n vesti gat or m ust c o n d uct all as pects of t hi s 
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 n e d i nf or me d c o nse nt f or m, i n c o m plia nce wit h Title  2 1 of U S C F R Part 5 0, 
will be o btai ne d fr o m e ac h patie nt bef ore t he patie nt e nters t he st u d y.  F or sites o utsi de of t 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 2), 
a n d pri nci ples of t he Declarati o n of Helsi n ki.  A n i nf or me d c o 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 n ee t o t he i n vesti gat ors.  T h e c o nse nt m ust be re vie we 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 h e 
pri nci pal i n ves ti 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 ve d c o nse nt f or m . 
Bef or e e nr oll me nt, eac h pr os pecti ve patie nt will b e gi v e n a f ull e x pla nati o n of t he st u d y a n d be 
all o we d t o rea d t h e a p pr o ve d i nf or me d c o ns e nt f or m.  O nce t he pri nci p al i n vesti gat or or desi g nee 

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is ass ure d t hat t he patie nt u n dersta n ds t he i m plicati o ns of participati n g i n t h e st u d y, t he patie nt 
will be as ke d t o gi v e c o nse nt t o partici pate i n t he st u d y b y si g ni n g t he i nf or me d c o nse nt f or m.  
Eli gi ble patie nts ma y o nl y be i n cl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n), IR B/ E C -a p pr o ve d i nf or me d c o ns e nt.  I nf or m e d c o nse nt m ust be 
o btai ne d bef ore c o n d u cti n g a n y st u d y -s p ecific pr oce d ures (i.e., all of t he pr oce d ures d escri b e d i n 
t he 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 geste d b y t he i n vesti gat or m ust be a gree d t o b y 
t he S p o ns or bef ore s u b missi o n t o t he I R B/ E C, a n d a c o p y of t he a p pr o ve d versi o n a n d t he n otice 
of a p pr o val m ust be pr o vi de d t o t he S p o ns or’s desi g nate d m o nit or after I R B/ E C a p pr o val.  T h e 
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 ns e 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 a t t he site. 
1 5. 4.  
C o nfi de nti alit y  
All la b orat or y s peci me ns, e val uati o n f or ms, r e p orts, a n d ot her rec or ds will be i de ntifie d i n a 
ma n ner desi g ne d t o mai ntai n patie nt c o nfi de ntialit y.  All rec or ds will be ke pt i n a sec ure st or a ge 
area wit h li mite d access.  Cli nica l i nf or mati o n will n ot be releas e d wit h o ut t he writte n 
per missi o n of t he patie nt ( or t he patie nt’s g u ar dia n), e x ce pt as necessar y f or m o nit ori n g a n d 
a u diti n g b y t he S p o ns or, its desi g nee, t h e F D A or a p plica ble re g ulat or y a ut h orities, or t he 
I R B/ E C. 
T he pri nci pal i n vesti gat 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 m a y n ot 
discl ose or use f or a n y p ur p ose ot her t ha n perf or ma nce of t he st u d y, a n y data, rec or d, or ot her 
u n p u blis he d c o nfi de ntial i nf or mati o n discl ose d t o t he m f or t he p ur p ose of t he st u d y.  Pri or 
writte n a 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 val of t he pr ot oc ol m ust be d oc u me nte d as pr ot oc ol 
a me n d me nts.  T he F D A or ot her a p plica ble re g ul at or y a ge n cies m ust be n otifie d of pr ot oc ol 
a me n d me nts.  T he c h a n ges will bec o me effecti ve o nl y aft er a p pr o val of t he S p o ns or, t he 
i n vesti gat or, t he I R B/ E C, a n d w here necessar y, t h e a p plica ble re g ulat or y a ge n c y.  I n cases w h e n 
t he pr ot oc ol is m o difie d t o e n ha nce patie nt safet y, c ha n ges ma y b e i m ple me nte d, a n d t he 
a me n d me nt m ust be i m me diatel y s u b mitte d t o t he I R B/ E C.  
T he i n vesti gat or is res p o nsi ble f or i nf or mi n g t h e I R B/ E C of all pr o ble ms i n v ol vi n g ris ks t o 
patie nts acc or di n g t o n ati o nal le gislati o n.  I n case of ur ge nt safet y meas ures, t he S p o ns or will 
i m me diatel y n otif y t he i n vesti gat ors a n d rel e va nt r e g ul at or y a ge n cies, i ncl u di n g F D A i n acc or d 
wit h 2 1 C F R 3 1 2. 3 2.  
1 5. 6.  
Pr ot oc ol De vi ati o ns  
T he in vesti gat or a n d site staff  are re q uire d t o f oll o w t he st u d y pr oce d ures a n d sc he d ules as 
d oc u me nte d i n t he pr ot oc ol.  If a pr ot oc ol de vi ati o n occ urs, the pri nci pal i n vesti gat or or desi g nee 
m ust d oc u me nt t he de viati o n  i n t he De viati o n L o g F or m i n t he cli nical dat a base.  T he I R B/ E C 

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m ust be n otifie d of pr ot oc ol de viati o ns i n a ti mel y ma n ner b y t he pri n ci 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 re vie we 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 w ill be c o m m u nicate d t o t he i n vesti gat or.  Pr ot oc ol 
de viati o ns will be re vie we d a n d a n y t hat are a seri o us breac h of G C P a n d t he pr ot oc ol will be 
re p orte d t o t he rele va nt re g ul at or y a ge n c y, as re q uire d.   
Pr ot oc ol wai vers are n ot all o we d .  If t here is a n i mme 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 usi n g his/ her best me dical j u d ge me nt  t o e ns ure t he 
patie nt’s safet y .  If s uc h a de viati o n occ urs, t he site m ust n otif y t he S p o ns or a n d I R B/ E C  wit hi n 
4 8 h o urs.  

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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 vel o p me nt of t he 
i n vesti gati o nal pr o d u ct.  If t he i n vesti gat or wit h 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 pers o n willi n g t o acce pt t he res p o nsi bil it 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  occ urs.  
1 6. 2.  
C ase Re p ort F or ms  
All case re p ort f or m dat a will be e ntere d i n pa per 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 ure 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 hat e ver t he fi n di n gs of 
t he st u d y. 
T he S p o ns or reser ves t he ri g ht t o re vi e w all p la n ne d c o m m u nicati o ns a n d ma n uscri pts base d o n 
t he res ults of t his st u d y.  T his reser vati o n of t h e ri g ht is n ot i nte n de d t o restrict or hi n der 
p u blicati o n or a n y ot her disse mi nati o n of st u d y res ults, b ut t o all o w t he S p o ns or t o c o nfir m t he 
acc urac y of t he data, t o pr otect pr o priet ar y i nf or m ati o n, a n d t o pr o vi de c o m me nts base d o n 
i nf or mati o n t hat ma y n ot yet b e a vaila ble t o t he st u d y i n vesti gat ors.  T h e S p o ns or als o 
e nc o ura ges discl os ure of a n y c o nflict of i nterest fr o m all a ut h ors or i n vesti gat ors w he n 
ma n u scri pts are s u b mitte d f or p u blicati o n.  T h ose i n di vi d uals w h o ha ve c o ntri b ute d greatl y t o 
t his st u d y, i ncl u di n g le a d e xter nal a d vis ors a n d sel ect pri nci pal i n vesti gat ors, ma y ser ve o n a n y 
p ote ntial p u blicati o ns c o m mittee f or t he st u d y . 

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1 8.  
LI S T O F 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 Nrf 2 acti vit y a n d atte n u ates o xi dati ve stress, i nfla m mati o n, a n d fi br osis i n rats 
wit h c hr o nic ki d ne y dise ase. Xe n o bi otica 2 0 1 4; 4 4 ( 6): 5 7 0 -5 7 8.  
C hert o w, G M, A p pel , G B, Bl o c k G A, et al. Effects of Bar d o x ol o ne Met h yl o n B o d y Wei g ht, 
Waist Circ u mfere nce a n d Gl yce mic C o ntr ol i n O bese Patie nts wit h T y p e 2 Dia betes Mellit us a n d 
Sta ge 4 C hr o nic Ki d ne y Disease.  J Dia betes C o m plicati o ns. 2 0 1 8 Dec; 3 2( 1 2): 1 11 3 -1 1 1 7.  
C hi n M P, Ba kris G L, Bl oc k G A, C hert o w G M, et al.  Bar d o x ol o ne Met h yl  I m pr o v es Ki d ne y 
F u ncti o n i n Patie nts wit h C hr o nic Ki d ne y Diseas e Sta ge 4 a n d  T y pe 2 Dia b etes: P ost -H oc 
A nal ys es fr o m Bar d o x ol o ne Met h yl E v al 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 betes St u d y. A m J Ne p hr ol.  2 0 1 8; 4 7( 1): 4 0 -4 7.  
C hi n M P, Ric h S, G ol ds berr y A, et al.  Effects of Bar d o x ol o ne Met h yl o n Q T I nt er val i n Healt h y 
V ol u nteers. Car di or e nal Me d, 2 0 1 9; 1 -8.  
Di n g Y, Sti d ha m R D, B u meister R, et al. T he s y nt hetic tr iter 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 u ce d c o ntracti o n of gl o mer ular mesa n gial 
cells. Ki d ne y I nt 2 0 1 3; 8 3: 8 4 5 -5 4.  
de Zee u w D, A kiz a 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 di a betes a n d sta ge 4 
c hr o nic ki d ne y dise ase. N E n gl J Me d 2 0 1 3; 3 6 9: 2 4 9 2 -5 0 3.  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes ( K DI G O) Bl o o d Press ur e W or k Gr o u p.  C ha pter 2: 
Defi niti o n, i de ntificati o n, a n d pre dicti o n of C K D pr o gressi o n. Ki d ne y I nt S u p pl 2 0 1 3 ; 3( 1): 6 3-7 2.  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes ( K DI G O) Bl o o d Press ur e 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 ur e i n C hr o nic Ki d ne y Diseas e. 
Ki d ne y I nt S u p pl  2 0 1 2; 2: 3 3 7 – 4 1 4.  
Ki d o k or o K.  Acti vati o n of t he Kea p 1/ Nrf 2 pat h w a y i n crea si n g gl o mer ular effecti ve filtrati o n 
area wit h o ut affecti n g t h e affere nt/effere nt arteri ole rati o. A bstract. A m erica n S ociet y of 
Ne p hr ol o g y. 2 0 1 9.  
K o ba yas hi E, S uz u ki T, F u na ya m a R , et al. Nrf 2 s u p presses macr o p ha ge i nfla m mat or y res p o nse 
b y bl oc ki n g pr oi n fl a m mat or y c yt o ki ne tra nscri pti o n. Nat C o m m u n 2 0 1 6; 7, 1 1 6 2 4.  
Le vi n A, Ste v e ns P E . S u m mar y of K DI G O 2 0 1 2 C K D G ui da nce: b e hi n d t he sce nes, n ee d f or 
g ui da n ce a n d a fra me w or k f or m o vi n g f or war d . Ki d ne y I nt  2 0 1 4 ; 8 5:  4 9 -6 1.  
Na gas u H, S o ga w a Y, Ki d o k or o K, et al. Bar d o x ol o ne met h yl a nal o g atte n u ates pr otei n uria -
i n d uce d t u b ular da ma ge b y m o d ulati n g mit oc h o n drial f u ncti o n. F A S E B J. 2 0 1 9; 3 3: 1 2 2 5 3 –
1 2 2 6 3.  
Na n ga k u M, K a n da H, Ta ka ma H, et al.  Ra n d o mize d  Cli nical Trial o n t he Effect of Bar d o x ol o ne 
Met h yl o n G F R i n D ia betic Ki d ne y Disease Patie nts ( T S U B A KI St u d y). Ki d ne y I nt Re p. 
2 0 2 0 ;5( 6): 8 7 9 -8 9 0.  
Per g ola P E, Ras ki n P, T ot o R D, et al . Bar d o x ol o ne met h yl a n d ki d ne y f u ncti o n i n C K D wit h 
t y pe 2 dia b etes. N E n gl J Me d 2 0 1 1; 3 6 5: 3 2 7-3 6.  

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 7 9  
 
  
 
Reis ma n S A, C hert o w G M, He b bar S, et  al. Bar d o x ol o ne met h yl decreases me gali n a n d acti vates 
Nrf 2 i n t he ki d ne y.  J A m S oc Ne p hr ol 2 0 1 2; 2 3: 1 6 6 3 -7 3.  
R ossi n g P, Bl oc k G A, C hi n M P , et al. Effect of Bar d o x ol o ne Met h yl o n t h e Uri ne Al b u mi n -t o-
Creati ni ne Rati o i n Patie nts wit h T y pe 2 Dia b etes a n d S ta ge 4 C hr o nic Ki d ne y Disease. Ki d ne y 
I nt 2 0 1 9; 9 6( 4): 1 0 3 0 -1 0 3 6 . 
Sa ha P, Re d d y V, K o n o ple va M, et al . T he triter pe n oi d 2-c ya n o-3, 1 2 -di o x o olea na -1, 9 -die n -2 8 - 
oic -aci d met h yl ester has p ote nt a nti dia betic effects i n diet -i n d uce d dia betic mice a n d 
Le pr( d b/ d b) mice. J Bi ol C he m 2 0 1 0; 2 8 5: 4 0 5 8 1 -9 2.  
War d y n J D, P o nsf or d A H, Sa n ders o n C M. Dissecti n g m olec ul ar cr oss -tal k bet wee n Nrf 2 a n d 
N F -κ B res p o nse p at h wa ys. Bi oc he m S oc Tra ns. 2 0 1 5; 4 3( 4): 6 2 1 -6.  
Z oja C, C or na D, L ocat elli M, et al. Tar geti n g Kea p 1-Nrf 2 Pat h wa y A mel i orates Re nal 
I nfla m mati o n a n d Fi br osis i n Mice wit h Pr otei n-O verl oa d Pr otei n uria.  P ost er A meri ca n S ociet y 
of Ne p hr ol o g y Meeti n g, 2 0 1 0.  

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 8 0  
 
  
 
1 9.  
A P P E N DI X  

Pr ot oc ol  
 
 
4 0 2 -C -2 0 0 2  
Versi o n 2. 0  
 8 1  
 
  
 
A P P E N DI X 1  
Pr o g n osis of C K D b y e G F R a n d Al b u mi n uria Cat e g ories: K DI G O 2 0 1 2  (Le vi n, 2 0 1 4 )