Conditions: Chronic Kidney Diseases
Keywords: Advanced CKD Chronic Kidney Disease Bardoxolone methyl RTA 402 eGFR Advanced Chronic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
This multi-center, randomized, double-blind, placebo-controlled, Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with CKD due to multiple etiologies at risk of rapid disease progression. Approximately 70 patients will be enrolled and randomized 1:1 to either bardoxolone methyl or placebo. Patients with CKD secondary to varying etiologies will be enrolled from age 18-70 years with eGFR ≥ 20 to \< 60 mL/min/1.73 m2, and other risk factors for rapid progression of kidney disease.

The maximum target dose will be determined by baseline proteinuria status. Patients with baseline urine albumin to creatinine ratio (UACR) ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline UACR \> 300 mg/g will be titrated to a maximum dose of 30 mg. Qualified patients will be randomized 1:1 to receive either bardoxolone methyl or placebo once daily (preferably in the morning) throughout a 12-week dosing period.

Patients in the study will follow the same visit and assessment schedule. Patients will be assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on Days 3, 10, 21, 31, 35, and 45. Date of last dose and the end-of-treatment assessments mark the end of the treatment period. Patients will not receive study drug during a 5-week off-treatment period between Weeks 12 and 17. The off-treatment (OT) period includes 5 visits requiring various assessments to characterize eGFR from the time of study drug discontinuation through Day 35 off-treatment.

Detailed description:

Arms:
arm 1: Patients randomized to receive bardoxolone methyl capsules orally once daily for 12 weeks at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g)

Patients will be scheduled to be assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on Days 3, 10, 21, 31, 35, and 45. Patients will not receive any drug during a 5-week off-treatment period between Weeks 12 and 17. Patients will be assessed on Day 3 off-treatment (OT), Day 7 OT, Day 14 OT, Day 21 OT, Day 28 OT, and Day 35 OT. The OT day corresponds to days after last dose.

Patients will be assessed at and end-of-study (EOS) visit on Week 17. arm 2: Patients who received placebo, once-daily, orally, remained on placebo throughout the study duration of 12 weeks and followed the same titration to maintain the blind,

Patients will be scheduled to be assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on Days 3, 10, 21, 31, 35, and 45. Patients will not receive any drug during a 5-week off-treatment period between Weeks 12 and 17. Patients will be assessed on Day 3 off-treatment (OT), Day 7 OT, Day 14 OT, Day 21 OT, Day 28 OT, and Day 35 OT. The OT day corresponds to days after last dose.

Patients will be assessed at and end-of-study (EOS) visit on Week 17.

Interventions: intervention 1: Bardoxolone methyl oral capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Bardoxolone methyl capsules dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status intervention 2: Capsule containing an inert placebo

Protocol document:
Prot_000.pdf: 
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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  
 
V E R SI O N 2. 0  –  1 7  F E B  2 0 2 1  
 
 
 
 
 
Pr ot oc ol R e visi o n Hist or y  
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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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2 / 1 7 / 2 0 2 1  |  4 : 3 7 : 4 4  P M  C S T
2 / 1 8 / 2 0 2 1  |  7 : 2 1 : 5 7  A M  C S T
2 / 1 7 / 2 0 2 1  |  4 : 2 1 : 2 0  P M  C S T
2 / 1 8 / 2 0 2 1  |  8 : 3 9 : 5 3  A M  C S T
2 / 1 8 / 2 0 2 1  |  7 : 1 9 : 2 9  A M  C S T
2 / 1 8 / 2 0 2 1  |  9 : 1 4 : 4 2  A M  C S T


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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 


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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  
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  
 


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5.  
I N T R O D U C TI O N 
Bar d o x ol o ne met h yl 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.  


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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 


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str uct ural re m o d eli n g pr ocesses i n t he ki d ne y ass o ciate d wit h decli ni n g 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).  
 
 


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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) 


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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 .


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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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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.  


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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.  


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S T A TI S TI C A L A N A L Y SI S  P L A N  
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V E R SI O N: 2 . 0 
D A T E O F P L A N:  
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A p h ase 2 tri al t o ev al u ate s afety, t oler a bility, a n d effic acy of B ar d ox ol o ne Met hyl i n p atie nts 
wit h c hr o nic ki d ney dise ase at risk of r a pi d pr o gressi o n  
 
S P O N S O R:  
Re at a P h ar m ace utic als, I nc.  
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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 
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T E C H NI C A L S U M M A R Y R E P O R T ( T S R)  
N a me of S p o ns or/ C o m p a n y : 
Re at a P h ar m ace utic als, I nc.  
I n di vi d u al St u d y T a ble 
Ref erri n g t o P art of t he 
D ossier:  
V ol u me:  
( F or N ati o n al A ut h ority Use 
O nly) : 
N a me of Fi nis he d P r o d uct:  
Bar d o x ol o ne met h yl ca ps ules  
P a ge:  
 
N a me of Acti ve I n gre die nt:  
Bar d o x ol o ne met h yl  
 
 
Title o f 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 
I n vesti g at ors: 
St u d y Ce nter(s): 1 1 Sites use d  
St u die d peri 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 de vel o p me nt: 2  
O bjecti ves:  
Pri mar 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 dar 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 Ki d ne y 
Disease  
E x pl ora t 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 
 
 


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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 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) 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).  
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 : Incl 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): I ncl u des 1 3 visits (cli nic 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 met h yl d ose will be deter mi ne d b y baseli ne pr otei n uria stat us. Patie nts 
wit h baseli ne uri ne al b u mi n t o creati ni ne rati o ( 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 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 patie 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. R a 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. 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 w ill 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 bj ecti ve of t he hi g hest t olerate d d ose.  
Patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc he d ule. 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 off -treat me nt peri o d bet wee n Wee ks 1 2 
a n d 1 7.  
Off -tre at me nt peri o d ( O T): I ncl u des 5 visits re q uiri n g vari o us assess ments 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.  
N u m ber of S u bjects ( pl a n ne d a n d a n al yze 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 criteri a f or i ncl 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 m2  
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 m 2 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 Cs) 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 ve uri nar y di pstic k f or bl o o d i n 
pri or year, or macr osc 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 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 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 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;  
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 n ti 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; 


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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 Da y 1 or if d ose is a ntici pa te 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  visit;  
1 0.  Ki d ne y or a n y ot her s oli d or ga n tra ns pla nt re ci 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 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 II I 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 ble a n gi na) wit hi n 1 2 m o nt hs 
pri or t o Scree n A  
f. 
Pericar dial c o nstricti o n ( bas e 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 h a ve 
e ver re q uire d C O VI D -1 9 relate 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 m et 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.  




Statistical A nal ysis Pla n  v 2. 0   
 
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8  
C o nfi de ntial  
T A B L E O F C O N T E N T S  
SI G N A T U R E P A G E  .......................................................................................................................2  
T E C H NI C A L S U M M A R Y R E P O R T ( T S R)  ..................................................................................3  
1.  
IN T R O D U C TI O N  ......................................................................................................1 6  
1. 1.  
Trial Rati o nale  ............................................................................................................1 6  
1. 2.  
Bac k gr o u n d  .................................................................................................................1 7  
2.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  ..............................................................1 8  
2. 1.  
St u d y O bjecti ves  .........................................................................................................1 8  
2. 1. 1.  
Pri mar y O bj ecti ve  .......................................................................................................1 8  
2. 1. 2.  
Sec o n dar y O bj ecti ve  ...................................................................................................1 8  
2. 1. 3.  
E x pl orat or y O bjecti ves  ...............................................................................................1 8  
2. 2.  
St u d y E n d p oi nts  ..........................................................................................................1 8  
2. 2. 1.  
Pri mar y Efficac y E n d p oi nt  .........................................................................................1 8  
2. 2. 2.  
Sec o n dar y Efficac y E n d p oi nt  .....................................................................................1 8  
2. 2. 3.  
E x pl orat or y Effi cac y E n d p oi nt  ...................................................................................1 8  
2. 2. 4.  
Safet y E n d p oi nts  .........................................................................................................1 8  
2. 2. 5.  
Ot h er E n d p oi nt  ............................................................................................................1 8  
3.  
S T U D Y D E SI G N  .......................................................................................................1 9  
3. 1.  
S u m mar y of St u d y Desi g n  ..........................................................................................1 9  
3. 2.  
Defi niti o n of St u d y Dr u gs  ..........................................................................................2 0  
3. 3.  
Sa m ple Siz e C o nsi derati o ns  .......................................................................................2 0  
3. 4.  
Ra n d o mizati o n  ............................................................................................................2 0  
3. 5.  
Cli nical Assess me nts  ..................................................................................................2 1  
4.  
P L A N N E D A N A L Y S E S  ............................................................................................2 4  
4. 1.  
Fi nal A nal yses  ............................................................................................................2 4  
5.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D 
H A N D LI N G  ...............................................................................................................2 5  
5. 1.  
Ge neral S u m mar y T a ble a n d I n di vi d ual S u bject D ata Listi n g C o nsi derati o ns ..........2 5  
5. 2.  
Ge neral P ost Te xt S u m mar y Ta ble a n d I n di vi d ual S u bject Data Listi n g 
F or mat C o nsi derati o ns  ................................................................................................2 5  
5. 3.  
A nal ysis P o p ulati o ns  ..................................................................................................2 5  
5. 3. 1.  
I T T P o p ulati o n ............................................................................................................2 6  
5. 3. 2.  
Safet y P o p ulati o n  ........................................................................................................2 6  


Statistical A nal ysis Pla n  v 2. 0   
 
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C o nfi de ntial  
5. 4.  
Baseli ne Defi niti o n  .....................................................................................................2 6  
5. 4. 1.  
B aseli ne A ge  ...............................................................................................................2 6  
5. 4. 2.  
Esti mate d Gl o mer ular Filtrati o n Rate  .........................................................................2 6  
5. 4. 3.  
Ser u m Creati ni ne  ........................................................................................................2 6  
5. 4. 4.  
Uri ne Al b u mi n t o Creati ni ne Rati o  .............................................................................2 6  
5. 4. 5.  
Safet y Assess me nts  .....................................................................................................2 7  
5. 5.  
Deri ve d a n d Tra nsf or me d Data  ..................................................................................2 7  
5. 5. 1.  
St u d y Da y  ...................................................................................................................2 7  
5. 5. 2.  
C ha n ge fr o m Baseli ne  .................................................................................................2 7  
5. 5. 3.  
Visit Wi n d o ws  ............................................................................................................2 7  
5. 5. 3. 1.  
Off -Treat me nt Visit Wi n d o ws  ....................................................................................2 9  
5. 5. 4.  
La b orat or y E v al uati o ns I m p utati o ns  ...........................................................................2 9  
5. 5. 5.  
Esti mate d Gl o mer ular Filtrati o n Rate (e G F R)  ...........................................................2 9  
5. 5. 5. 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 or y  ...........................................3 0  
5. 5. 6.  
Uri ne Al b u mi n t o Creati ni ne Rati o ( U A C R)  ..............................................................3 0  
5. 5. 6. 1.  
Baseli ne Uri ne Al b u mi n t o Creati ni ne Rati o ( U A C R) Cate g orical Stat us  .................3 1  
5. 5. 6. 2.  
e G F R Cate g or y use d i n Stratif icati o n .........................................................................3 1  
5. 5. 6. 3.  
U A C R Cate g or y us e d i n Stratificati o n ( U A C R _ S T R A T)  ..........................................3 1  
5. 5. 7.  
Electr ocar di o gra m Fri dericia C orrect e d Q T I nter val  .................................................3 1  
5. 5. 8.  
Nat ural l o g( U A C R)/e G F R  ..........................................................................................3 1  
5. 5. 9.  
Trial D urati o n  .............................................................................................................3 1  
5. 5. 1 0.  
e G F R Sl o pe  .................................................................................................................3 2  
5. 6.  
Ha n dli n g of Missi n g Dat a  ...........................................................................................3 2  
5. 6. 1.  
Missi n g Efficac y E n d p oi nt Data  .................................................................................3 2  
5. 6. 1. 1.  
Missi n g e G F R f or M M R M A nal ys es  .........................................................................3 2  
5. 6. 1. 2.  
Missi n g e G F R f or A N C O V A A nal yses  .....................................................................3 2  
5. 6. 1. 3.  
Missi n g Start a n d St o p Dates f or C o nc o mita nt Me dicati o ns  ......................................3 2  
5. 6. 2.  
Missi n g Start a n d St o p Dates f or A d v erse E v e nts  ......................................................3 2  
6.  
S T U D Y P O P U L A TI O N  .............................................................................................3 4  
6. 1.  
S u bjects Dis p ositi o n  ...................................................................................................3 4  
6. 2.  
Scree n Fail ures  ............................................................................................................3 4  
6. 3.  
Pr ot oc ol De viati o ns  ....................................................................................................3 5  


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1 0  
C o nfi de ntial  
6. 4.  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................3 5  
6. 5.  
Listi n g of S u bject I ncl usi o n a n d E x cl usi o n Criteria  ...................................................3 5  
6. 6.  
Me dical Hist or y  ..........................................................................................................3 5  
7.  
P RI M A R Y E F FI C A C Y  ..............................................................................................3 6  
7. 1.  
Ge neral C o nsi derati o ns  ...............................................................................................3 6  
7. 2.  
S tate me nt of t he N ull a n d Alter nate H y p ot hesis ........................................................3 6  
7. 3.  
S u b gr o u p A n al ysis  ......................................................................................................3 6  
7. 4.  
Pri mar y Efficac y E n d p oi nt  .........................................................................................3 7  
7. 4. 1.  
Pri mar y A n al ysis of t he Pri mar y E n d p oi nt  .................................................................3 7  
7. 4. 1. 1.  
Se nsiti vit y A nal ysis of t h e Pri mar y E n d p oi nt –  N o I m p utati o n f or Missi n g 
Da ta .............................................................................................................................3 8  
7. 4. 1. 2.  
Se nsiti vit y A nal ysis of t h e Pri mar y E n d p oi nt –  I m p utati o n f or Missi n g Dat a ...........3 8  
7. 5.  
Sec o n dar y Efficac y E n d p oi nt  .....................................................................................3 8  
7. 5. 1.  
Pri mar y A n al ysis of t he Sec o n dar y E n d p o i nt .............................................................3 8  
7. 5. 1. 1.  
Se nsiti vit y A nal ysis of t h e Sec o n dar y E n d p oi nt  ........................................................3 9  
8.  
E X P L O R A T O R Y E F FI C A C Y  ...................................................................................4 0  
8. 1.  
E x pl o rat or y Effi cac y E n d p oi nt ...................................................................................4 0  
8. 1. 1.  
Off -Treat me nt M M R M e G F R A nal ysis  .....................................................................4 0  
8. 1. 1. 1.  
Se nsiti vit y A nal ysis of Off -Treat me nt e G F R a n al ysis –  N o I m p utati o n f or 
Missi n g Data  ...............................................................................................................4 0  
8. 1. 1. 2.  
Se nsiti vit y A nal ysis of Off -Treat me nt e G F R A nal ysis –  I m p utati o n f or 
Missi n g Data  ...............................................................................................................4 0  
8. 1. 1. 3.  
Off -Treat me nt M M R M e G F R A nal ysis f or Wee k 1 2 a n d Wee k 1 7 
C o m pleters  ..................................................................................................................4 1  
8. 1. 1. 4.  
Off -Treat me nt A N C O V A e G F R A nal ysis f or Wee k 1 2 a n d Wee k 1 7 
C o m pleters  ..................................................................................................................4 1  
8. 1. 1. 5.  
Off -Treat me nt N o n -li near Mi x e d M o del ....................................................................4 1  
 
 
9.  
S A F E T Y A N D T O L E R A BI LI T Y  ..............................................................................4 3  
9. 1.  
A d verse E v e nt Preferre d Ter m a n d B o d y/ Or ga n S yste m S u m mar y Ta bles  ...............4 3  
9. 1. 1.  
Missi n g a n d Partial A E O nset Dates  ..........................................................................4 4  
9. 1. 2.  
S u m maries of A d vers e E ve nts  ....................................................................................4 4  
9. 2.  
E x p os ure a n d C o m plia nce  ..........................................................................................4 5  
9. 3.  
C o nc o mita nt Me dicati o ns  ...........................................................................................4 5  


Statistical A nal ysis Pla n  v 2. 0   
 
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1 1  
C o nfi de ntial  
9. 3. 1.  
Missi n g a n d Partial C o nc o mita nt a n d O t her Me dicati o n Start a n d St o p Dates ..........4 6  
9. 4.  
Pri or a n d C o nc o mita nt Pr oce d ures a n d S ur geries  ......................................................4 6  
9. 5.  
Cli nical La b orat or y E val uati o ns  .................................................................................4 6  
9. 5. 1.  
C o nti n u o us S u m maries of La b orat or y Res ults  ...........................................................4 6  
9. 5. 1. 1.  
Nat ural l o g( U A C R)/e G F R  ..........................................................................................4 7  
9. 5. 2.  
Cate g orical S u m maries of La b orat or y Res ults  ...........................................................4 7  
9. 5. 2. 1.  
Tra nsa mi nase  ..............................................................................................................4 8  
9. 6.  
Vital Si g ns  ..................................................................................................................4 8  
9. 6. 1.  
B o d y Wei g ht  ...............................................................................................................4 8  
9. 7.  
P h ysical E x a mi nati o n  .................................................................................................4 8  
9. 8.  
Ele ctr ocar di o gra m  .......................................................................................................4 8  
9. 9.  
Pre g n a nc y  ...................................................................................................................4 9  
1 0.  
P H A R M A C O KI N E TI C S  ...........................................................................................5 0  
1 1.  
C O VI D -1 9 I M P A C T  ..................................................................................................5 1  
1 1. 1.  
O perati o nal I m p act  .....................................................................................................5 1  
1 1. 2.  
I m pa ct o n Effi cac y ......................................................................................................5 2  
1 1. 3.  
I m pa ct o n Safet y .........................................................................................................5 2  
1 2.  
R E F E R E N C E S  ...........................................................................................................5 3  
1 3.  
A P P E N DI X .................................................................................................................5 4  
1 3. 1.  
S A P C ha n ge S u m mar y  ...............................................................................................5 4  
 


Statistical A nal ysis Pla n  v 2. 0   
 
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1 2  
C o nfi de ntial  
LI S T O F T A B L E S  
Ta ble  1:  
List of A b bre viati o ns  ..................................................................................................1 3  
Ta ble  2:  
Sc he d ule of Assess me nts  ............................................................................................2 2  
Ta ble  3:  
A nal ysis Visit Wi n d o ws f or O n -Treat me nt  ................................................................2 8  
Ta ble  4:  
A nal ysis Visits f or Off -Treat me nt assess me nts  ..........................................................2 9  
Ta ble  5:  
e G F R Cate g or y  ...........................................................................................................3 0  
Ta ble  6:  
Al b u mi n uria Cate g or y  ................................................................................................3 0  
Ta ble  7:  
M o del Para meter A b bre viati o ns  .................................................................................3 6  
Ta ble  8:  
Pre -S pecifie d T hres h ol d Le v els f or E C G Para met ers  ................................................4 8  
 
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  ...................................................................................2 0  
Fi g ure  2:  
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  .........................................2 1  
 
 


Statistical A nal ysis Pla n  v 2. 0   
 
4 0 2 -C -2 0 0 2  
 
 
Reata P har mace uticals, I nc . 
 
1 3  
C o nfi de ntial  
T a ble  1 : 
List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A C Ei  
A n gi ote nsi n c o n verti n g e n z 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  
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  


Statistical A nal ysis Pla n  v 2. 0   
 
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1 4  
C o nfi de ntial  
A b bre vi ati o n  
Ter m  
H G V S  
H u ma n Ge n o me V ariati o n S ociet y  
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 -Pr 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  
Ra 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 


Statistical A nal ysis Pla n  v 2. 0   
 
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1 5  
C o nfi de ntial  
A b bre vi ati o n  
Ter m  
S N G F R  
Si n gle ne p hr o n gl o mer ular filtrati o n rate  
S O P  
Sta n dar d o perati n g pr oce d ure  
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  
 


Statistical A nal ysis Pla n  v 2. 0   
 
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Reata P har mace uticals, I nc . 
 
1 6  
C o nfi de ntial  
1.  
I N T R O D U C TI O N 
1. 1.  
Tri al R ati o n ale  
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 
Kelc 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 uloi 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 ( ultrafiltrati 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 multi 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 ola, 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 neficial 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 
effects. 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 was 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 nts 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 m 2 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 after 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, t he 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).  
 


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1. 2.  
B ac k gr o u n d  
T he ori gi nal st u d y pr ot oc ol has u n der g o ne t he  f oll o wi n g a m e n d me nt.  
P r ot oc ol Re visi o n C hr o n ol o g y:  
Pr ot oc ol  
1 8 -N O V -2 0 2 0  
Ori gi nal  
Pr ot oc ol Versi o n 2  
1 7 -F E B -2 0 2 1  
A me n d me nt 1  
T his S A P was de vel o pe d i n acc or da nce wit h I C H E 9 g ui deli ne. All decisi o ns re gar di n g fi n al 
a nal ysis, as defi ne d i n t his S A P  d oc u me nt, will be ma de pri or t o u n bli n di n g  of t he st u d y d ata  as 
descri be d  i n Secti o n  5. 1 .   F urt her i nf or mati o n ca n be f o u n d i n t he pr ot oc ol.  
T he S A P is base d o n:  
•  Pr ot oc ol 4 0 2 -C -2 0 0 2, Versi o n 2 . 0, date d 1 7 -F E B -2 0 2 1  
•  I C H g ui deli nes E 4 a n d E 9 ( Statistical Pri nci ples f or Cli nical Trials)  
T his S A P descri bes t he st u d y p o p ulati o ns, h o w varia bles are d eri ve d, h o w missi n g data are 
ha n dle d, a n d det ails c o ncer ni n g t h e statistical met h o ds t o be use d t o a nal yz e t he safet y a n d 
effic ac y dat a fr o m St u d y 4 0 2 -C -2 0 0 2.  S h o ul d t he S A P a n d t he pr ot oc ol be i nc o nsiste nt wit h 
res pect t o t he pla n n e d a n al yses, t h e la n g ua ge of t h e S A P is g o ver ni n g. 
 


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2.  
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  
2. 1.  
St u d y O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti ve  
•  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.  
2. 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 gies of C hr o nic 
Ki d ne y Disease  ( C K D). 
2. 1. 3.  
E x pl or at o r 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.  
•  
 
2. 2.  
St u d y E n d p oi nts  
T he st u d y will c o m pare t h ose recei vi n g b ar d o x ol o ne met h yl t o t h ose recei vi n g place b o wit h 
res pect t o se v eral e n d p oi nts.  T he ti mi n g f or a n al yzi n g st u d y e n d p oi nts is d escri be d i n 
Secti o n  5. 5 .   Pri mar y efficac y a n al ys es are des cri be d i n  Secti o n  7 , a n d a d diti o nal e x pl orat or y 
efficac y a n al ys es are des cri be d i n Secti o n  8 . 
2. 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.  
2. 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 o g y.  
2. 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.  
2. 2. 4.  
S afet y E n d p oi nts  
•  La 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  ( wei g ht o nl y), electr ocar di o gra m ( E C G) res ults, a d verse e ve nts 
( A Es), a n d s eri o us a d verse e ve nts ( S A Es). 
2. 2. 5.  
Ot her E n d p oi nt  
•  
 


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3.  
S T U D Y  D E SI G N  
3. 1.  
S u m m ar y of 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 Me di data Ra n d o mizati o n a n d Trial 
S u p pl y M a 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 0 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 
disease. Patie nts 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 pr o gressi ve gl o mer ul o ne p hritis will be e x cl u de d. N o si n gl e C K D 
eti ol o g y (( h y p erte 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.  
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 creati ni ne rati o ( 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 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 patie 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.  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 c li 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.  
Pat ie 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 tr eat me nt at D a y 1, Wee ks 1, 2, 4, 6, 8, a n d 1 2 a n d b y t ele 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 h e 
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 FR 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, D a 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 rec ei vi n g t he last d ose. 
A n y p atie nt w h o per ma n e 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 g ure  2 : 
Pr o g n osis of C K D b y e G F R a n d Al b u mi n uri a C ate g ories  
 
 
3. 5.  
Cli nic al As sess me nts 
Patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc he d ule. Patie nts will be assesse d 
d uri n g tr eat me nt at D a y 1, Wee ks 1, 2, 4, 6, 8, a n d 1 2, a n d b y t ele 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 h e 
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.  






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4.  
P L A N N E D A N A L Y S E S  
4. 1.  
Fi n al A n al yses  
T he fi nal a n al ys es of effi cac y will be b ase d o n l oc ke d data a n d p erf or me d after all e nr olle d 
patie nts ha ve c o m plete d all effic ac y ass ess me nt s a n d data are u n bli n de d.  U n bli n di n g will occ ur 
acc or di n g t o Sta n dar d O perati n g Pr oce d ure ( S O P) BI -0 4 0. T he fi n al a nal ys es of safet y will be  
base d o n  l oc ke d d ata a n d perf or me d after all e nr olle d patie nts ha ve c o m plet e d all safet y 
assess me nts  a n d data are u n bli n de d . 


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5.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D 
H A N D LI N G  
T he effi cac y a n d safet y a nal yses us e t he  a n al ysis s ets defi ne d i n  Secti o n  5. 3 .  Patie nt listi n gs (as 
a p pr o priate) of all a n al ysis data t hat s u p p ort s u m mar y t a bles a n d/ or fi g ures are pr o vi de d al o n g 
wit h t heir s o urce dat a.   T he s u m mar y ta bles d o n ot i ncl u de meas ure m e nts fr o m patie nts e x cl u de d 
fr o m t he pre-defi ne d a nal ysis sets or e xtra meas ure me nts,  s uc h as val ues  n ot cl osest t o t he tar get 
st u d y da y u nless s pecifie d ot her wise, b ut t he patie nt listi n gs d o i ncl u de t hese data.   Missi n g d ata 
are n ot i m p ute d, u nless ot her wise s pecifie d.   I n ge neral, patie nt listi n gs are s orte d b y p atie nt 
n u m ber a n d ass ess me nt date (ti me a n d para meter, as a p plica ble).   A n y la b orat or y val ue 
(i ncl u di n g e G F R), vital si g n assess me nt, or E C G val ue c ollecte d after starti n g dial ysis or aft er 
recei vi n g a ki d n e y tra ns pla nt is c o nsi dere d i n vali d a n d will be treate d as missi n g.  If a s u bject has 
a m o derate, s e vere or seri o us  a d verse e ve nt of C O VI D, all safet y a n d efficac y fi n di n gs  e x ce pt 
A Es i n b ot h t he o n -treat me nt a n d off-tr eat me nt p eri o ds will n ot be s u m marize d after t he start 
dat e of t he C O VI D a d v erse e ve nt start dat e.    
5. 1.  
Ge ner al S u m m ar y T a ble a n d I n di vi d u al S u bject  D at a Listi n g 
C o nsi der ati o ns  
Res ults of statistical a nal ys es are re p orte d usi n g s u m mar y ta bl es, listi n gs, a n d fi g ures ( T L Fs).  
All T L Fs will use I C H n u m beri n g c o n ve nti o n s.  F or e n d p oi nts n ot descri be d i n Secti o n  7. 4 , t he 
re p orte d si g nifica nce l e v els are n o mi nal,  a n d t h e f oll o wi n g statistical c o n ve nti o ns are use d:  
•  U nless ot her wise n ote d, all statistical testi n g is t w o -si de d a n d is perf or me d at t he 0. 0 5 
si g nifica n ce le v el.  
•  Tests are d eclare d statisticall y si g nifica nt if t he calc ulate d p -val u e is < 0. 0 5.  
5. 2.  
Ge ner al P ost Te xt S u m m ar y T a ble a n d I n di vi d u al S u bject D at a 
List i n g F or m at C o nsi der ati o ns 
U nless ot her wise s pecifie d, descri pti ve statistics f or c o nti n u o us varia bles i n cl u de t he n u m ber of 
patie nts wit h data ( N), m ea n, sta n dar d de viati o n ( S D), me dia n, mi ni m u m, a n d ma xi m u m.  T he 
sa me n u m ber of d eci mal places as i n t he o bser ve d val ue are pres e nte d w he n re p orti n g mi ni m u m 
a n d ma xi m u m; 1 m ore deci mal place t h a n i n t he o bser ve d val u e is prese nt e d w he n re p orti n g 
mea n a n d q uartiles; a n d 2 m ore deci mal places t h a n i n t he o bser ve d v al ue is prese nte d w h e n 
re p orti n g S D.  
Cate g orical data are pres e nte d usi n g fre q u e nc y c o u nts a n d perce nta ges.  All perce nta ges are 
r o u n de d t o 1 deci mal place, u nless ot her wise s pecifie d.  Perce nt a ges e q u al t o 1 0 0 are prese nte d 
as 1 0 0 % a n d n o perce nta ges are prese nt e d f or zer o fre q ue n cies.  W here i n di vi d ual varia ble 
val ues are miss i n g, s u m maries of cate g orical dat a are b ase d o n re d uce d d e n o mi nat ors (i.e., t he 
de n o mi nat ors i ncl u de o nl y patie nts wit h a vaila ble data) a n d t he n u m b er of missi n g val ues is 
prese nte d.  F or s u m maries of A Es a n d c o n c o mita nt me dicati o ns ( C M), t he perce nt a ges a re bas e d 
o n t he t otal n u m ber of patie nts i n eac h treat me nt gr o u p.  
5. 3.  
A n al ysis P o p ul ati o ns  
A nal ysis p o p ulati o ns defi ne d i n t his secti o n pertai n t o patie nts e nr olle d i n t he M E R LI N st u d y.  


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I T T P o p ul ati o n 
T he i nte nt -t o-treat a nal ysis set is defi ne d as all e nr olle d patie nts cate g orize d b y t heir ra n d o mize d 
treat me nt gr o u p (w h et her  or n ot t he y recei ve d st u d y dr u g).  T he pri mar y a n al ysis p o p ulati o n f or 
t he pri mar y a n d k e y sec o n dar y efficac y e n d p oi nts is t he I T T p o p ul ati o n. 
5. 3. 2.  
S afet y P o p ul ati o n  
Safet y a nal yses are b ase d o n  all e nr olle d patie nts.  T he safet y p o p ulati o n i ncl u des all patie nts 
w h o recei ve d at least 1 d ose of st u d y dr u g.  T he s afet y p o p ulati o n is use d f or e val uati o n of safet y 
varia bles.  Patie nts w h o r ecei ve d at least o ne d os e of bar d o x ol o ne met h yl will be class ifie d i n t he 
bar d o x ol o ne met h yl gr o u p.  Patie nts w h o recei v e d at least o ne d ose of pl ace b o a n d n o d ose of 
bar d o x ol o ne met h yl will be classifie d i n t he place b o gr o u p.   
5. 4.  
B aseli ne Defi niti o n  
Bel o w is a s u m mar y of baseli ne val ue calc ulati o ns. If t he first st u dy dr u g a d mi nistrati o n occ urs 
after t he d ate of ra n d o mi zati o n, t he last meas ure me nt pri or t o t he first st u d y dr u g a d mi nistrati o n 
is c o nsi dere d t he Da y 1 meas ure me nt f or t he calc ulati o n of baseli ne.   
Assess me nts wit h o ut ti mesta m p c ollecte d o n t he s a me date as t he first date of st u d y dr u g 
a d mi nistrati o n are c o nsi d ere d t o oc c ur bef ore t h e first d ose of st u d y dr u g a d mi nistrati o n.   
T his baseli ne val ue will be use d f or b ot h O n -Treat me nt a n d Off -Treat me nt a nal ys es.  
5. 4. 1.  
B aseli ne A ge  
Baseli ne a ge is defi ne d as t he a ge at c o ns e nt ( Scree n A).  
5. 4. 2.  
Esti m ate d Gl o mer ul ar Filtr ati o n R ate  
Baseli ne e G F R is defi ne d as t he a vera ge of scree ni n g a n d Da y 1 e G F R m eas ure m e nt, calc ulat e d 
as s h o w n bel o w:  
•  Scree ni n g e G F R = a vera ge of t he last t w o e G F R meas ure me nts c ollecte d  pri or t o t he 
Da y 1  e G F R c ollecti o n  
•  Da y 1 e G F R = t he meas ure me nt aft er scree ni n g b ut o n or bef ore t h e date of first st u d y 
dr u g a d mi nistrati o n  
•  Baseli ne e G F R = ( 0. 5 × Da y 1 e G F R) + ( 0. 5 × Scree ni n g e G F R)  
If t here are o nl y 2 o bs er vati o ns a vaila ble, t he n t he a vera ge of t he 2 val ues is use d as baseli ne.  
5. 4. 3.  
Ser u m Cre ati ni ne  
Baseli ne s er u m creati ni n e ( S Cr) is defi ne d i n t he s a me wa y as baseli ne e G F R (Secti o n  5. 4. 2 ) 
5. 4. 4.  
Uri ne A l b u mi n t o C re ati ni ne R ati o  
Baseli ne U A C R  is defi ne d as t he last val ue - c ollecte d pri or t o t he st u d y dr u g a d mi nistrati o n.   


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5. 4. 5.  
S afet y Assess me nts  
Baseli ne f or c o nti n u o us s afet y assess m e nts (i.e., vital si g n assess me nts  - wei g ht, B MI, a n d 
la b orat or y me as ure me nts) is defi ne d as t he a vera ge val ue of meas ure m e nts c ollecte d u p t hr o u g h 
t he date of, b ut not aft er, first st u d y dr u g a d mi nistrati o n. W he n t hree bl o o d press ure 
meas ure me nts are ta k e n o n o ne visit, t he a vera ge of t he sec o n d a n d t hir d meas ure m e nt will be 
use d f or t he af ore m e nti o ne d visit.  
F or all ot her sit uati o ns n ot descri be d a b o v e, b aseli ne val u es are t o be defi ne d as t he last n o n -
missi n g assess me nt pri or t o t he first st u d y dr u g a d mi nistrati o n, u nless ot her wise s pecifie d b el o w.  
5. 5.  
Deri ve d a n d Tr a nsf or me d D at a  
5. 5. 1.  
St u d y D a y  
St u d y d a y is t he da y relati ve t o t he date of ra n d o mizati o n.  Da y 1 is defi ne d as t he date of 
ra n d o mizati o n.  Assess me nts t hat occ ur after ra n d o mizati o n b ut bef ore t he first d ose of st u d y 
dr u g are c o nsi dere d t o oc c ur o n st u d y Da y 1.   
Assess me nts wit h o ut ti mesta m p c ollecte d o n t he s a me date as t he first date of st u d y dr u g 
a d mi nistrati o n  are c o nsi d ere d t o oc c ur bef ore t h e first d ose of st u d y dr u g a d mi nistrati o n.  
F or visits ( or e v e nts) after ra n d o mizati o n, da y is c alc ulate d as:  
•  St u d y d a y = visit ( or e ve nt) date - dat e of ra n d o mizati o n + 1  
F or visits ( or e v e nts) bef ore ra n d o mizati o n, da y is  calc ulate d as:  
•  St u d y d a y = visit ( or e ve nt) date - dat e of ra n d o mizati o n  
T he q ua ntit y ‘ da ys si nce first d ose’ is defi ne d as:  
•  da ys si nce first d ose  = visit ( or e ve nt) dat e –  date of first d ose  +  1  
T he q ua ntit y ‘ da ys si nce last d ose’ is defi ne d as:  
•  da ys si nce last d ose = visit ( or e ve nt) dat e - date of last d ose  
F or s u m maries t hat pr ese nt distri b uti o n of ti me e x presse d i n wee ks a n d m o nt hs, wee ks are 
defi ne d as d a ys di vi de d b y se v e n a n d m o nt hs as da ys di vi de d b y 3 0. 4.  
5. 5. 2.  
C h a n ge fr o m B aseli ne  
C ha n ge fr o m bas eli n e is calc ulate d usi n g t he baseli ne val ue ( Secti o n  5. 4 ) a n d t he val ue cl osest t o 
t he tar get st u d y da y, usi n g t he r ul es defi ne d i n Secti o n  5. 5. 3.  T he ‘ Safet y P o p ulati o n’ is defi ne d 
as all s u bjects w h o recei v e at least o ne d os e of st u d y me dicati o n.   T his p o p ulati o n will be use d i n 
t he assess me nt a n d re p orti n g of safet y data. 
5. 5. 3.  
Visit Wi n d o ws  
A nal ysis visits a n d t heir wi n d o ws are d efi ne d usi n g deri ve d st u d y da y ( Secti o n  5. 5. 1 ) i nstea d of 
rel yi n g o n visit la bels i n t he cli nical data b ase beca use cli nical visits ma y occ ur o utsi de 
pr ot oc ol -s pecifi e d wi n d o ws.  St u d y da y a n d d a ys after last d ose are calc ul ated  usi n g t he act ual 
date of eac h sc h e d ule d a n d u nsc he d ule d ass ess me nt a n d c o m pare d t o t he t ar get f or eac h a nal ysis 


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visit as s pecifie d i n Ta ble 3 a n d Ta ble  4 .  T h e y are i ncl u de d i n a nal yses of s afet y a n d efficac y as 
f oll o ws: 
•  Efficac y a nal ys es f or e n d p oi nts assesse d t hr o u g h Wee k 1 2  use t he a nal ysis wi n d o ws 
base d o n tar get st u d y da y i n Ta ble 3 , irres p ecti ve of w het her or n ot a patie nt is 
recei vi n g tr eat me nt of st u d y dr u g.  
•  Efficac y a nal ys es f or e n d p oi nts assesse d a fter Wee k 1 2  use t he off -treat me nt a nal ysis 
wi n d o ws base d o n da ys after  last d ose i n Ta ble 4 . 
•  Safet y a nal yses us e t he a nal ysis wi n d o ws defi ne d i n Ta ble  2  s o l o n g as t he patie nt is 
recei vi n g tr eat me nt of st u d y dr u g.  Safet y an d effi cac y f oll o w-u p at O T Da y 3 5  will 
als o be s u m marize d acc or di n g t o Ta bl e 4 . Si milarl y, safet y f oll o w -u p at O T Da y 3 5  is 
s u m marize d acc or di n g t o Ta ble 3 f or p atie nts c o m pleti n g treat me nt t hr o u g h Wee k 12 .  
If a patie nt p er ma ne ntl y disc o nti n ues st u d y tre at me nt bef ore Wee k 1 2 , safet y data are 
s u m marize d acc or di n g t o ti me si nce last d ose as d efi ne d i n Ta ble 4 . 
If a para meter is assesse d or meas ure d m ore t ha n o nce wit hi n a visit wi n d o w, t he o ne t ha.t is 
cl osest t o t he pr ot oc ol -sc he d ule d ti me p oi nt (i.e., target) is use d f or t he p ur p oses of data a nal ysis 
a n d s u m mar y.  If t w o assess me nts are e q ui dista nt fr o m a tar get, t he earlier assess me nt is use d.  If 
t he visit use d f or a nal ysis i ncl u des t w o assess me nts o n t he sa me da y, t he a v era ge of t he t w o 
meas ure me nts is use d.  
Rec or ds fr o m visits n ot cl osest t o t he tar get st u d y da y, a n d t heref ore n ot use d i n a nal yses, are 
prese nte d i n b y -s u bject d ata listi n gs. 
Maj orit y of t he ti me, t he use of n o mi nal visits s uffices i n a si n gl e st u d y. T h e u nsc he d ule d visit 
ca n be eit her be e x cl u de d fr o m t he s u m mar y a n d i ncl u de d i n t he listi n gs or o nl y use d f or 
assessi n g t he w orst res ult p ost -baseli ne. I n t he a b o ve cases, visit wi n d o ws are n ot necessar y.  
T a ble  3 : 
A n al ysis Visit Wi n d o ws  f or O n -Tre at me nt  
A n al ysis Visit  
L a bel  
T ar get  
A n al ysis Wi n d o w  
St u d y D a y a 
D a ys After 
L ast D ose  
0  
Da y 1 b 
1  
- 
1  
1  
Wee k 1  
7  
- 
2 ≤ st u d y da y ≤ 1 0  
2  
Wee k 2  
1 4  
- 
1 1 ≤ st u d y da y ≤ 2 1  
4  
Wee k 4  
2 8  
- 
2 2 ≤ st u d y da y ≤ 3 5  
6  
Wee k 6  
4 2  
- 
3 6 ≤ st u d y da y ≤ 4 9  
8  
Wee k  8  
5 6  
- 
5 0 ≤ st u d y da y ≤ 7 0  
1 2  
Wee k 1 2
c 
8 4  
- 
7 1 ≤ st u d y da y ≤ 9 8  d  
a St u d y Da y is relati ve t o t he date of ra n d o mizati o n ( Secti o n  5. 5. 1 ). 
b Da y 1 is t he last meas ure me nt pri or t o t he first st u d y dr u g a d mi nistrati o n.   
c W ee k 1 2  is t he e n d d osi n g i nt er val.  
d Data c ollecte d 2 or m ore da ys after last d ose will be e xcl u de d fr o m on treat me nt  
 


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5. 5. 3. 1.  
Off -Tre at me nt Visit Wi n d o ws  
Patie nts w h o per ma ne ntl y disc o nti n ue st u d y dr u g pri or t o Wee k 1 2  are as k e d t o res u me t he 
pla n ne d assess me nts acc or di n g t o t he st u d y sc he d ule i n t he pr ot oc ol.  Off -treat me nt val ues f or 
cli nical la b orat or y e val uati o ns  (Secti o n  9. 5 ), vital si g ns (Secti o n  9. 6 ), a n d electr ocar di o gra ms 
(Secti o n  9. 8 ) are t h ose t h at occ ur after t h e last d ose date f or patie nts per m a ne ntl y disc o nti n ui n g 
st u d y dr u g pri or t o W ee k 12  a n d is s u m marize d relati ve t o t heir last d ose of st u d y dr u g.  Off -
treat me nt safet y assess m e nts (cli nical la bs, vital si g ns, a n d electr o car di o gra ms) are gr o u pe d f or 
a nal ys es acc or di n g t o t he strate g y i n Ta ble 4 .  
T a ble  4 : 
A n al ysis Visits f or Off -Tre at me nt ass ess me nts  
Off -Tre at me nt  
A n al ysis Visit  
L a bel  
T ar get St u d y D a y  
( d a ys after l ast d ose) 
A n al ysis Wi n d o w  
3  
Off Treat me nt 
Da y 3 b 
3  
2 ≤ da ys after last d ose ≤ 4  
7  
Off Treat me nt 
Da y 7 b 
7  
5 ≤ da ys after last d ose ≤ 1 0  
1 4  
Off Treat me nt 
Da y 1 4 b 
1 4  
1 1 ≤ da ys after last d ose ≤ 1 7  
2 1  
Off Treat me nt 
Da y 2 1 b 
2 1  
1 8 ≤ da ys after last d ose ≤ 2 4  
2 8  
Off Treat me nt 
Da y 2 8 b 
2 8  
2 5 ≤ da ys after last d ose ≤ 3 1  
3 5  
Off Treat me nt 
Da y 3 5  b 
3 5  
3 2 ≤ da ys after last d ose ≤ 3 8  
a Last d a y of o n -treat me nt f or patie nts per ma ne ntl y disc o nti n ui n g st u d y dr u g pri or  or o n  t o Wee k 12 . Assess me nts 
t hat occ ur o n t he date of last d ose or less t ha n 2  da ys after last d ose are c o nsi dere d o n  treat me nt a n d s u m marize d 
usi n g T a ble  3  wi n d o ws.  
b T he off -treat me nt val ues i n dic ate t he val ue cl osest t o t he dat e of last d ose. 
 
5. 5. 4.  
L a b or at or y E v al u ati o ns  I m p ut ati o ns 
A n y la b orat or y assess me nts less t ha n t he l o wer li mit of detecti o n (i.e., <  L L D) are i m p ute d as 
L L D/ 2.  If n o L L D is a v aila ble, t he n t he i m p ute d val ue is t he mi ni m u m n u meric val ue liste d 
di vi de d b y 2 (e. g., <  2 5 is 2 5/ 2 = 1 2. 5).  La b orat or y ass es s me nts a b o ve t he U L D are i m p ute d as 
t he U L D.  If t h e la b res ult is q ualitati ve b ut prese nte d as > X a n d X is 1 0 ti mes greater t ha n t he 
U L N  or t he U L N is n ot prese nt , t he n t he v al ue X is use d i n t he a nal ysis.  
5. 5. 5.  
Esti m ate d Gl o mer ul ar Filtr ati o n R ate (e G F R)  
T he  e G F R is calc ulate d usi n g t he f or m ula bel o w acc or di n g t o patie nt’s a ge at t he date of c o nse nt.  
T he f or m ula will n ot c ha n ge t hr o u g h o ut t he st u d y.  T he C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n ( C K D -E PI) e q uati o n is use d f or a d ult patie nts (a ge at c o ns e nt at least 1 8 years):  


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•  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 S cr is ser u m creati ni ne ( m g/ d L), κ is 0. 7 f or fe males or 0. 9 f or males, 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 a n d 1, a n d ma x i n dicates t he 
ma xi m u m of S cr/ κ a n d 1.  A ge  i n dicates a ge at ti me of ser u m creati ni ne c ollecti o n as c ollect e d i n 
C R F.  
5. 5. 5. 1.  
Pr o g n osis of C K D b y e G F R a n d Al b u mi n uri a C ate g or y  
Pr o g n osis of C K D is de ter mi ne d b y t he i ntersecti o n of t he f oll o wi n g e G F R a n d al b u mi n uria 
cate g ories ( K DI G O 2 0 1 2 ): 
T a ble  5 : 
e G F R C ate g o r y  
e G F R C ate g or y 
e G F R ( m L/ mi n/ 1. 7 3 m 2) 
1  
≥ 9 0  
2  
6 0 t o <  9 0  
3a  
4 5 t o <  6 0  
3 b  
3 0 t o <  4 5  
4  
1 5 t o <  3 0  
5  
<  1 5  
 
T a ble  6 : 
Al b u mi n uri a C ate g or y  
U A C R C ate g or y  
U A C R ( m g/ g)  
1  
<  3 0  
2  
3 0 t o ≤ 3 0 0  
3  
>  3 0 0  
 
5. 5. 6.  
Uri ne Al b u mi n t o Cre ati ni ne R ati o ( U A C R)  
U A C R is pr o vi de d i n t he ce ntral la b orat or y dat a base as t he rati o of uri ne al b u mi n t o uri ne 
creati ni ne fr o m t he first m or ni n g v oi d ( F M V) uri ne c ollecti o n.  T he U A C R val ue is re p orte d i n 
t he ce ntral la b orat or y d ata base as missi n g w he n t h e F M V uri n e al b u mi n res ult is < L L D.  Uri ne 
al b u mi n res ults <  L L D a n d t he c orres p o n di n g U A C R missi n g val ues are i m p ute d as f oll o ws:  
•  If uri ne al b u mi n r es ult = < L L D, t he n  
− I m p ute d uri ne al b u mi n res ult ( m g/ d L) = L L D/ 2  
− I m p ute d U A C R( m g/ g) = (i m p ute d uri ne al b u mi n r es ult i n m g/ d L) / [( uri ne 
creati ni ne i n m g/ d L) / 1 0 0 0]  


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T he U A C R res ults are l o g -tr a nsf or me d f or a nal ysis t o pr o d uce data t h at are m ore n or mall y 
distri b ute d.  A n y i m p ute d U A C R res ult w here U A C R = 0 is c o nsi dere d t o be 0. 1 m g/ g f or 
p ur p oses of calc ulati n g t he ge o metric mea n.  
5. 5. 6. 1.  
B aseli ne Uri ne Al b u mi n t o Cre ati ni ne R ati o ( U A C R) C ate g o ric al St at us  
Baseli ne U A C R stat us will be gr o u pe d b y t h e f oll o wi n g cate g ories usi n g b aseli ne U A C R 
(see Secti o n  5. 4 ): 
•  U A C R < = 3 0 0 m g/ g  
•  U A C R > 3 0 0 m g/ g  
5. 5. 6. 2.  
e G F R C ate g o r y use d i n Str atific ati o n  
T he re will be n o m ulti ple baseli ne e G F R cat e g or ies use d f or stratificati o n  si nce t he i ncl usi o n 
criteria is as s uc h : 
•  2 0 m L/ mi n/ 1. 7 3 m 2 < = e G F R < 6 0 m L/ mi n/ 1. 7 3 m 2 
5. 5. 6. 3.  
U A C R C ate g or y use d i n Str atific ati o n ( U A C R _ S T R A T)  
T he U A C R cate g or y use d f or stratificati o n ( U A C R _ S T R A T) is deter mi ne d b y t he ra n d o mizati o n 
list wit h t he f oll o wi n g cate g ori es: 
•  U A C R < = 3 0 0 m g/ g  
•  U A C R > 3 0 0 m g/ g  
5. 5. 7.  
Ele ctr oc a r di o gr a m Fri derici a C orrecte d Q T I nter v al  
Electr ocar di o gra m i nter v als are assesse d l ocall y at eac h site.  T h e f oll o wi n g f or m ula is use d t o 
calc ulate t he Q Tc F i nter val f or a n al ysis fr o m Q T a n d R R i nter vals:  
•  𝑄𝑇𝑐𝐹=  𝑄𝑇/ √𝑅𝑅 
w here R R = 6 0 / ( Heart  Rate).  
5. 5. 8.  
N at ur al l o g( U A C R)/e G F R  
T o e val uate U A C R after a dj usti n g f or filtrati o n rat e, l n( U A C R )/e G F R ( Secti o ns 5. 5. 6  a n d 5. 5. 5 ) 
is assesse d. 
5. 5. 9.  
Tri al D ur ati o n  
Trial d urati o n is use d i n a nal ys es of efficac y t o calc ulate e G F R sl o pe i n t he calc ulati o n of  O n -
Treat me nt or Off -Treat me nt c ha n ge i n e G F R.    
Trial d urati o n use d i n t he calc ulati o n of c h a n ge i n e G F R i n t he O n-Treat me nt  p orti o n  is t he 
Wee k 1 2  or E n d of Treat me nt if disc o nti n ue d earl y  a n al ysis visit date mi n us t he date of t he 
baseli ne assess me nt pl us o ne.   
Trial d urati o n use d i n t he calc ulati o n of c h a n ge i n e G F R i n t he Off-Treat me nt p orti o n  is t he 
Wee k 1 7  date mi n us t he date of t he bas eli ne assess me nt pl us o ne.  N ote, t he sa me bas eli ne val ue 
will be use d f or b ot h O n -Treat me nt a n d Off -Treat me nt calc ulati o ns.  


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5. 5. 1 0.  
e G F R Sl o pe  
T he e G F R sl o pe f or eac h patie nt will be calc ulate d b y di vi di n g t h e c ha n ge fr o m baseli ne i n 
e G F R (s ee Secti o n  5. 5. 2 ) b y t he p atie nt’s O n -Treat me nt  trial d urati o n (f or t he Wee k 1 2  pri mar y 
e n d p oi nt) or Off -Treat me nt  trial d urati o n (f or t he Wee k 1 7  ke y sec o n d ar y e n d p oi nt).  Calc ulati o n 
of trial d urati o n is des cri be d i n Secti o n  5. 5. 9 . 
5. 6.  
H a n dli n g of Missi n g D at a  
5. 6. 1.  
Missi n g Effic ac y E n d p oi nt D at a  
5. 6. 1. 1.  
Missi n g e G F R f or M M R M A n al yses  
Missi n g e G F R data are n ot i m p ute d f or  t he pri mar y, sec o n dar y a n d e x pl orat or y e n d p oi nt 
M M R M a nal ysis ( Secti o n  7. 4. 1 , 7. 5. 1  a n d Secti o n  8. 1 ).  A set of se nsiti vit y a nal ys es is i ncl u de d 
t o assess t he r o b ust ness of c o ncl usi o ns (see Sect i o n 7. 4. 1. 1 , Secti o n  7. 5. 1. 1  a n d Secti o n  8. 1. 1. 1 . 
5. 6. 1. 2.  
Missi n g e G F R f or A N C O V A A n al yses  
I n t he s u bs et of treat me nt-base d m ulti ple i m p utati o n se nsiti vit y a nal yses, missi n g e G F R d ata is 
i m p ute d base d o n a n ass u m pti o n of  missi n g at ra n d o m  usi n g m ulti ple i m p utati o n base d o n t he 
treat me nt gr o u p t o w hic h t he patie nt is assi g ne d.  T he a nal ysis is perf or me d usi n g t he A N C O V A 
statistical m o del defi ne d i n Secti o n  7. 4. 1. 1 .  I n s h ort, the P R O C MI pr oce d ure i n S A S is use d t o 
ge n erat e 1 0 0 datas ets satisf yi n g t he ass u m pti o n of m o n ot o ne missi n g ness, i m p uti n g a n y missi n g 
e G F R val u es usi n g m ulti ple i m p utati o n.  I m p utati o n is base d o n t he n o n -missi n g o bser vati o ns 
wit hi n eac h treat me nt gr o u p.  S ee d s pecificati o n s use d i n m ulti ple i m p utati o n f or se nsiti vit y 
a nal ys es of t he pri mar y e n d p oi nt a n d f or se nsiti vit y a n al ys es of e x pl orat or y e n d p oi nts  will be 
pr o vi de d . 
5. 6. 1. 3.  
Missi n g St art a n d St o p D ates f or C o nc o mit a nt Me dic ati o ns   
Missi n g start dates f or c o nc o mita nt me dicati o ns are n ot i m p ute d.   
C o nc o mita nt me dicati o ns wit h i nc o m plete e n d dates are c o nsi dere d c o nc o mita nt me dicati o ns if:  
•  Da y a n d m o nt h are missi n g, a n d t h e year is e q ual t o or after t he year o f t he first date 
of st u d y dr u g a d mi nistrati o n.   
•  Da y is missi n g a n d t he year is aft er t he year of t he first date of st u d y dr u g 
a d mi nistrati o n.   
•  Da y is missi n g a n d t he year is e q u al t o t he year of t he first date of st u d y dr u g 
a d mi nistrati o n a n d t he m o nt h is e q ual t o or after t he m o nt h of t he first date of st u d y 
dr u g a d mi nistrati o n; or  
•  Year is missi n g.  
5. 6. 2.  
Missi n g St art a n d St o p D ates f or A d verse E v e nts  
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) are defi ne d i n Secti o n  9. 1 . 


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A d verse e ve nts wit h i nc o m plete start dates are c o nsi dere d aft er t he d ate of first d ose, a n d 
t heref ore treat me nt e mer ge nt, if: 
•  Da y a n d m o nt h are missi n g,  a n d t h e year is e q ual t o or after t he ye ar of t he first date 
of st u d y dr u g d osi n g;  
•  Da y is missi n g a n d t he year is aft er t he year of t he first date of st u d y dr u g d osi n g;  
•  Da y is missi n g a n d t he year is e q u al t o t he year of t he first date of st u d y dr u g d osi n g 
a n d t he m o nt h is e q ual t o or after t h e m o nt h of t he first date of st u d y dr u g d osi n g; or  
•  Year is missi n g.  
A d verse e ve nts wit h i nc o m plete start dates or e n d dates are c o nsi dere d o n or wit hi n 3 0 da ys of 
last d ose, if: 
•  Da y, m o nt h, a n d year are missi n g.  
•  Da y a n d m o nt h are missi n g,  a n d t h e year is e q ual t o or bef ore t h e year of t h e date of 
last d ose of st u d y dr u g pl us 3 0 da ys; 
•  Da y is missi n g a n d t he year is e q u al t o or bef ore t he year of t he dat e of last d ose of 
st u d y dr u g pl us 3 0 da ys a n d m o nt h is e q ual t o or bef ore t h e m o nt h of t he date of last 
d ose of st u d y dr u g pl us 3 0 da ys;  


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6.  
S T U D Y P O P U L A TI O N  
6. 1.  
S u bjects Dis p ositi o n  
A dis p ositi o n s u m mar y i ncl u des t he n u m ber a n d perce nt a ge of patie nts i n all a nal ysis 
p o p ulati o ns i n t he f oll o wi n g cate g ories:  
Dis p ositi o n  
•  I T T p o p ul ati o n 
•  Safet y p o p ulati o n  
•  C o m plete d treat me nt t hr o u g h Wee k 1 2  
− Wee k 1 2  visit i n a nal ysis wi n d o w  
− Wee k 1 2 visit o ut of a nal ysis wi n d o w  
− Wee k 1 2 visit missi n g  
•  Disc o nti n ue d treat me nt pri or t o Wee k 1 2  
− Reas o n f or disc o nti n ui n g treat me nt  
•  C o m plete d st u d y t hr o u g h Wee k 1 7  
− C o m plete d O n -treat me nt a n d Off -treat me nt visits 
− Disc o nti n ue d treat me nt earl y b ut c o m plete d i n -pers o n st u d y visits  
− Disc o nti n ue d treat me nt earl y b ut c o m plete d b y p h o ne  
•  Ter mi nate d fr o m t he st u d y bef ore Wee k 1 2  
− Reas o n f or st u d y ter mi nati o n  
•  Ter mi nate d fr o m t he st u d y bef ore Wee k 1 7  
− Reas o n f or st u d y ter mi nati o n  
•  C o m plete d t hr o u g h Wee k 1 7  
•  C o m plete d treat me nt t hr o u g h Wee k 1 2 a n d off -tr eat me nt assess me nts t hr o u g h 
Wee k  1 7  
•  S u m maries b y st u d y visit  
− O n treat me nt  
− Off treat me nt  
− I n st u d y 
− St o p pe d st u d y  
6. 2.  
Scree n F ail ures  
Scree n Fail ures  will  n ot  be s u m mariz e d .  


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6. 3.  
Pr ot oc ol De vi ati o ns  
All pr ot oc ol de viati o ns are liste d.   Pr ot oc ol de viati o ns ma y i ncl u de e x cl u de d me dicati o ns, 
patie nts e nteri n g t he st u d y des pite n ot satisf yi n g all e ntr y criteria, p atie nts r ecei vi n g wr o n g 
treat me nt or i nc orrect d ose, or ot her maj or pr ot oc ol de viati o ns.     
6. 4.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
S u m maries of de m o gra p hic a n d ot her bas eli ne c h aract eristic data are prese nte d b y tr eat me nt 
gr o u p f or all a n al ysis p o p ulati o ns.  T he y ma y als o be s u m marize d b y sel ect s u b g r o u p as 
a p pr o priate.   
T he de m o gra p hi c a n d ot her baseli ne c haracteristics i ncl u de:  
•  Baseli ne A ge  
•  Se x, Race, Et h nicit y  
•  Wei g ht ( k g), Hei g ht ( c m), B MI ( k g/ m
2) 
•  Diast olic a n d s yst olic bl o o d press ure ( m m H g), Heart rate ( b p m)  
•  Ser u m creati ni ne  
•  e G F R , e G F R cate g orical stat us (Ta ble  5 ), ( < 3 0; 3 0-< 4 5; > = 4 5), ( < 4 5; > = 4 5)  
•  U A C R, U A C R cate g orical stat us ( ≤ 3 0 0; >  3 0 0)  
•  Pr o g n osis  of C K D b y e G F R a n d Al b u mi n uria cate g ories  (l o w, m o derate, hi g h, ver y 
hi g h ) 
•  K DI G O Stratificati o n:  C K D  pr o gressi o n ris k heat ma p:  yell o w/ ora n ge; r e d/ dar k re d  
•  A n gi ote nsi n c o n v erti n g e nz y m e ( A C E) -i n hi bit or treat me nt a n d/ or A n gi ote nsi n II 
rece pt or bl oc ker ( A R B) ( yes/ n o) 
•  Ki d ne y Eti ol o gies  ( Di a betes, H y p erte nsi o n, a n d Ot her.) 
•  Fa mil y Hist or y of C K D  
•  Ot her baseli ne v aria bles of i nterest   
6. 5.  
Listi n g of S u bject I ncl usi o n a n d E xcl usi o n Criteri a  
A listi n g of e nr olle d p atie nts w h o di d n ot meet i ncl usi o n or e x cl usi o n criteria is ge nerate d.  
6. 6.  
Me dic al Hist or y  
Me dical hist or y is s u m m arize d b y tr eat me nt.  Me dical hist or y is c o d e d usi n g Me d D R A ( Me dical 
Dicti o nar y f or Re g ul at or y A cti vities) versi o n 2 1. 1.  Me dical hist or y ite ms are s u m marize d b y 
Me d D R A S O C a n d P T.  A b y -patie nt listi n g of m e dical hist or y will be pr o vi de d.  


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7.  
P RI M A R Y E F FI C A C Y  
A nal ys es of efficac y des cri be d i n t hi s secti o n are t he pri mar y a n al ys es of t he effi cac y e n d p oi nts, 
a n d pertai n t o t he I T T p o p ulati o n (i.e., all patie nts ra n d o mize d i n t he st u d y), u nless ot her wise 
s pecifie d.  T he trial i ncl u des e n d p oi nts at 1 2 wee ks o n -treat me nt a n d 5 wee ks off-treat me nt.  
A d d iti o nal details re gar di n g t he statistical a p pr oac h a n d pse u d o S A S c o de are a vaila bl e i n t he 
pr o gra m mi n g c o n ve nti o ns d oc u me nt.  
T he f oll o wi n g a b bre vi ati o ns are use d i n d escri pti o ns of t he A N C O V A a n d M M R M a nal ysis 
m o dels:  
T a ble  7 : 
M o del P a r a meter A b bre vi ati o ns  
A b bre vi ati o n  
M o del Ter m  
H E A T _ S T R A T  
K DI G O heat ma p stratificati o n (strat u m 1 a n d 2)  
T R T  
treat me nt gr o u p 
VI SI T  
a nal ysis visit use d as ti me  
T R T x VI SI T  
t he i nteracti o n bet wee n treat me nt a n d ti me 
 
7. 1.  
Ge ner al C o nsi der ati o ns  
R es ults will n ot be prese nte d b y i n di vi d ual st u d y ce nters.  A n al yses are perf or me d f or all 
bar d o x ol o ne met h yl patie nts i n c o m paris o n wit h all place b o patie nts.  S u m mar y st atistics f or 
o bser ve d val u es, c ha n ge fr o m baseli ne, a n d p erce nt c ha n ge  fr o m baseli ne are prese nte d b y 
ra n d o mize d treat me nt gr o u p.  Missi n g val ues are ha n dle d as des cri be d i n Secti o n  5. 6 . 
7. 2.  
St ate me nt of t he N ull a n d Alter n a te H y p ot hesis 
T he pri mar y effic ac y a n al ys is c o m pares t he c h a n ge fr o m baseli ne i n e G F R f or patie nts 
ra n d o mize d t o bar d o x ol o ne met h yl ( μ B A R D) t o t he c ha n ge fr o m bas eli ne i n e G F R f or p atie nts 
ra n d o mize d t o place b o ( μ place b o) at t he e n d p oi nt-s pecifie d visit acc or di n g t o t he f oll o wi n g 
h y p ot hes es:  
•  N ull h y p ot hesis, H 0: ( μ B A R D) –  ( μ place b o) = 0 m L/ mi n/ 1. 7 3 m 2  
•  Alter nati ve h y p ot hesis, H 1: ( μ B A R D) –  ( μ place b o) ≠ 0 m L/ mi n/ 1. 7 3 m 2 
Beca use e G F R d ecreases wit h disease pr o gressi o n, a n i ncrease i n e G F R rel ati ve t o place b o is 
c o nsi dere d e vi de nce of be nefit.  
7. 3.  
S u b gr o u p A n al ysis  
T he off -tr eat me nt effic ac y e n d p oi nts, t he pri mar y efficac y e n d p oi nt a n d s ec o n dar y efficac y 
e n d p oi nt, will be descri pti vel y a n al yze d f or s u b gr o u ps of i nterest t o assess t he ge neral 
c o nsiste nc y of res ults acr oss s u b gr o u ps.   


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T he f oll o wi n g s u b gr o u p a nal ys es are ta b ulate d:  
•  Se x: fe male; male  
•  Et h nicit y:  N o n -His pa nic/ Lati n o; His pa nic/ Lati n o  
•  Race: W hite; N o n -W hite  
•  Baseli ne B MI ( k g/ m 2): < 3 0; ≥ 3 0 
•  Baseli ne e G F R ( m L/ mi n/ 1. 7 3 m 2): < 3 0; 3 0-< 4 5; > = 4 5  
•  Baseli ne e G F R ( m L/ mi n/ 1. 7 3 m 2):  < 4 5; > = 4 5  
•  Baseli ne U A C R ( m g/ g): ≤ 3 0 0; > 3 0 0   
•  Fa mil y hist or y of C K D: Yes; N o  
•  Ki d ne y Eti ol o gies  ( Di a betes, H y p erte nsi o n, a n d Ot her) 
•  K DI G O Stratificati o n:  C K D pr o gressi o n ris k heat ma p: yell o w/ ora n ge; r e d/ dar k re d  
•  Patie nts w it h I P I nterr u pti o ns ( Yes/ N o) 
S u b gr o u p a n al ys es will i ncl u de n o mi nal si g nifica nce le vels f or descri pti ve p ur p oses o nl y.  T h e 
m o del use d f or s u b gr o u p a nal ys es is t he sa me as t he pri mar y a n al ys es ( Secti o n  7 ) wit h a d diti o nal 
ter ms of s u b gr o u p a n d s u b gr o u p-b y -treat me nt.   
7. 4.  
Pr i m ar y Effic ac y E n d p oi nt  
7. 4. 1.  
Pri m ar y A n al ysis of t he Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of t his st u d y is t he c h a n ge i n e G F R at Wee k 1 2.  T h e c ha n ge fr o m bas eli ne 
e G F R f or patie nts treat e d wit h bar d o x ol o ne met h yl is c o m pare d wit h place b o at Wee k 1 2 usi n g 
mi x e d m o dels re peate d meas ures ( M M R M) a nal ysis  wit h t he f oll o wi n g fi x e d fact ors:  K DI G O  
strata (H E A T _ S T R A T), treat me nt gr o u p ( T R T), ti me (i .e., VI SI T; a n al ysis visit n u m ber), a n d t he 
i nteracti o n bet wee n treat me nt a n d ti me ( T R T x VI SI T).   
T he trial desi g n se parates disc o nti n uati o n of st u d y dr u g fr o m disc o nti n uati o n of st u d y f oll o w -u p.  
T heref ore, p atie nts ma y disc o nti n ue earl y fr o m st u d y dr u g  w hile c o nti n ui n g f oll o w -u p wit h st u d y 
visits a n d assess me nts.  T he pri mar y a n al ysis of e G F R at Wee k 1 2 uses a v aila ble e G F R val ues 
irres pecti ve of w het h er  a patie nt is recei vi n g treat me nt.  T he M M R M a nal ysis uses all e G F R 
val ues c ollecte d t hr o u g h Wee k 1 2 a cc or di n g t o a n al ysis visits 1, 2, 4, 6, 8, a n d 1 2 ( Secti o n  5. 5. 3 ).  
A n u nstr uct ure d c o varia n ce matri x is use d.  
I n t he e ve nt t he M M R M m o del wit h a n u nstr ucture d c o vari a nce str u ct ure d oes n ot c o n ver ge, t he 
f oll o wi n g c o v aria n ce str u ct ures are s u bstit ute d, i n t he or der liste d.  Eac h s u bse q ue nt c o varia nce 
str uct ure is use d o nl y if eac h pre vi o us c o varia n ce str uct ure is use d a n d n o pre vi o us m o del 
c o n ver ge d.   
1.  Heter o ge n e o us T oe plitz c o varia n ce str uct ure (ass u mi n g differe nt varia nces at eac h ti me 
p oi nt a n d t hat meas ure m e nts ta ke n cl oser t o get her i n ti me are m ore hi g hl y c orrel ate d t ha n 
t h ose ta ke n fart her a part). 


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2.  T oe plitz c o varia nce str u ct ure (ass u mi n g meas ure me nts ta ke n cl oser t o get h er i n ti me are 
m ore hi g hl y c orrel ate d t h a n t h ose ta ke n fart her a p art).  
3.  First or der a ut o -re gressi v e [ A R( 1)] c o varia nce str uct ure (ass u mi n g meas ure me nts ta ke n 
cl oser t o get her i n ti me are m ore hi g hl y c orrelate d t ha n t h ose ta ke n fart her a part, b ut t he 
c orrel ati o n is m ore c o nstrai ne d t ha n t he T o e plitz str uct ure).  
4.  C o m p o u n d s y m metr y c o varia nce str uct ur e (ass u mi n g e q u al c orrelati o n f or meas ure me nts 
fr o m a patie nt, r e gar dl ess of h o w far a part i n ti me t he y were t a ke n).  A c o m p o u n d 
s y m metr y c o v aria n ce str uct ure was ass u me d i n t he sa m ple siz e calc ulati o n. 
If t he M M R M m o del d oes n ot c o n ver ge usi n g a n y of t he af ore me nti o ne d c o varia nce str uct ur es, 
varia bles fr o m t he m o del state me nt ma y b e re m o ve d.  
T he differe nce bet w ee n b ar d o x ol o ne  met h yl a n d place b o i n c ha n ge fr o m baseli ne of e G F R is 
esti mate d al o n g wit h t he 9 5 % c o nfi de n ce i nter val at Wee k 1 2 f or t he pri mar y a nal ysis of t he 
pri mar y e n d p oi nt.   
7. 4. 1. 1.  
Se nsiti vit y A n al ysis of t he Pri m ar y E n d p oi nt  –  N o I m p ut ati o n f or Missi n g D at a  
T he c ha n ge fr o m bas eli ne e G F R f or patie nts treat e d wit h bar d o x ol o ne met h yl is c o m pare d wit h 
place b o at W ee k 1 2 usi n g A N C O V A a n al ysis  wit h t he f oll o wi n g fi x e d fact ors:  K DI G O str ata 
( H E A T _ S T R A T) a n d tr eat me nt gr o u p ( T R T). 
T he A N C O V A a nal ysis uses e G F R v al ues c ollect e d i n t he Wee k 1 2 a nal ysi s wi n d o w (Ta ble  3 ).  
Missi n g Wee k 1 2 e G F R data are  n ot i m p uted.  
T he differe nce bet w ee n b ar d o x ol o ne met h yl a n d place b o i n c ha n ge fr o m baseli ne of e G F R is 
esti mate d al o n g wit h t he 9 5 % c o nfi de n ce i nter val at Wee k 1 2.   
7. 4. 1. 2.  
Se nsiti vit y A n al ysis of t he Pri m ar y E n d p oi nt –  I m p ut ati o n f or Missi n g D at a 
T he c ha n ge fr o m bas eli ne e G F R f or patie nts treat e d wit h bar d o x ol o ne met h yl is c o m pare d wit h 
place b o at W ee k 1 2  usi n g A N C O V A  a n al ysis  wit h t he f oll o wi n g fi x e d fact ors:  K DI G O s tr ata 
( H E A T _ S T R A T) a n d tr eat me nt gr o u p ( T R T). 
T he A N C O V A a nal ysis uses e G F R v al ues c ollect e d i n t he Wee k 1 2 a nal ysis wi n d o w (Ta ble 3 ).  
F or o ne a nal ysis, Missi n g Wee k 1 2 e G F R d ata are  i m p uted  acc or di n g t o S ecti o n  5. 6. 1. 2 . 
T he differe nce bet w ee n b ar d o x ol o ne met h yl a n d place b o i n c ha n ge fr o m baseli ne of e G F R is 
esti mate d al o n g wit h t he 9 5 % c o nfi de n ce i nter val at Wee k 1 2.   
7. 5.  
Sec o n d ar y Effic ac y E n d p oi nt  
7. 5. 1.  
Pri m ar y A n al ysis of t he  Sec o n d ar y E n d p oi nt  
T he sec o n d ar y e n d p oi nt of t his st u d y is t he c ha n ge i n e G F R at Wee k 1 2 b y C K D eti ol o gies  
( Dia betes, H y p erte nsio n , a n d Ot her).  T he c h a n ge fr o m baseli ne e G F R f or patie nts treate d wit h 
bar d o x ol o ne met h yl is c o m pare d wit h place b o at Wee k 1 2 b y C K D eti ol o g y usi n g mi x e d m o dels 
re peat e d meas ur es ( M M R M) a nal ysis as defi ne d i n Secti o n  7. 4. 1 . 


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7. 5. 1. 1.  
Se nsiti vit y A n al ysis of t he S ec o n d ar y E n d p oi nt  
Se nsiti vit y a n al ysis of t h e sec o n dar y e n d p oi nt b y treat me nt gr o u p a n d eti ol o g y is r u n acc or di n g 
t o Secti o n  7. 4. 1. 1 . 


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8.  
E X P L O R A T O R Y E F FI C A C Y  
T he f oll o wi n g d ata s u m maries a n d a n al ys es are prese nte d f or t he I T T a nal ysis set.  A d diti o nal 
se nsiti vit y a nal yses ma y be perf or me d as a p pr o pri ate. 
All data val ues wit hi n  t he a p pr o pri ate visit wi n d o ws c o ntri b ute t o t he a nal ysis. 
All a nal ys es use I T T p o p ulati o n.  
8. 1.  
E x pl or at or y Effic ac y E n d p oi nt  
8. 1. 1.  
Off -Tre at me nt M M R M e G F R A n al ysis  
T he e x pl orat or y e n d p oi nt of t his st u d y is t he c ha n ge i n e G F R at  Da y 3, 7, 1 4, 2 1, 2 8, a n d 3 5  
d uri n g t he Off -Treat me nt p orti o n of t he st u d y.  T h e c ha n ge fr o m bas eli ne e G F R f or p atie nts 
treate d wit h bar d o x ol o ne met h yl is c o m pare d wit h place b o at Da y 3, 7, 1 4, 2 1, 2 8, a n d 3 5  usi n g 
mi x e d m o dels re peate d meas ures ( M M R M) a nal ysis  wit h t he f oll o wi n g fi x e d fact or s:  K DI G O 
strata ( H E A T _ S T R A T), treat me nt gr o u p ( T R T), ti me (i.e., VI SI T; a n al ysis visit n u m ber), a n d t he 
i nteracti o n bet wee n treat me nt a n d ti me ( T R T x VI SI T).  
T he M M R M a nal ysis uses all e G F R val ues c ollect e d fr o m Wee k 1 2 t o Wee k 1 7  acc or di n g t o off -
treat me nt a nal ysis visits 3, 7, 1 4, 2 1, 2 8, a n d 3 5 ( Secti o n  5. 5. 3. 1 ).  A n u nstr uct ure d c o varia nce 
matri x is use d.   Baseli ne val ue is ori gi n al  O n -Treat me nt baseli ne  val ue.  
1.  I n t he e ve nt t he M M R M m o del wit h a n u nstr uct ur e d c o vari a nce str u ct ure d oes n ot 
c o n ver ge, t h e c o varia nce str uct ures are s u bstit ute d  as defi ne d  i n Secti o n  7. 4. 1 . 
8. 1. 1. 1.  
Se nsiti vit y A n al ysis of Off -Tre at me nt e G F R a n al ysis  –  N o I m p ut ati o n f or 
Missi n g D at a  
T he c ha n ge fr o m bas eli ne e G F R f or patie nts treat e d wit h bar d o x ol o ne met h yl is c o m pare d wit h 
place b o usi n g A N C O V A a nal ysis  wit h t he f oll o wi n g fi x e d fact ors:  K DI G O strata 
( H E A T _ S T R A T) a n d tr eat me nt gr o u p ( T R T). 
T he A N C O V A a nal ysis uses e G F R v al ues c ollect e d i n eac h off -tr eat me nt visit ( 3,7, 1 4, 2 1, 2 8, a n d 
3 5)  a nal ysis wi n d o w  (T a ble  4 ). Missi n g  e G F R dat a per visit are n ot  i m p ute d. 
T he differe nce bet w ee n b ar d o x ol o ne met h yl a n d place b o i n c ha n ge fr o m baseli ne of e G F R is 
esti mate d al o n g wit h t he 9 5 % c o nfi de n ce i nter val at eac h off-tr eat me nt visit ( 3, 7, 1 4, 2 1, 2 8, a n d 
3 5) . 
8. 1. 1. 2.  
Se nsiti vit y A n al ysis of Off -Tre at me nt e G F R A n al ysis  –  I m p ut ati o n f or Missi n g 
D at a  
T he c ha n ge fr o m bas eli ne e G F R f or patie nts treat e d wit h bar d o x ol o ne met h yl is c o m pare d wit h 
place b o usi n g A N C O V A  a nal ysis  wit h t he f oll o wi n g fi x e d fact ors:  K DI G O strata 
( H E A T _ S T R A T) a n d tr eat me nt gr o u p ( T R T). 
T he A N C O V A a nal ysis uses e G F R v al ues c ollect e d i n eac h off-tr eat me nt visit ( 3, 7, 1 4, 2 1, 2 8, a n d 
3 5) a nal ysis wi n d o w (T a ble 4 ).  F or o ne a n al ysis, Missi n g e G F R da ta per off -treat me nt visit are 
i m p uted acc or di n g t o Secti o n  5. 6. 1. 2 . 


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T he differe nce bet w ee n b ar d o x ol o ne met h yl a n d place b o i n c ha n ge fr o m baseli ne of e G F R is 
esti mate d al o n g wit h t he 9 5 % c o nfi de n ce i nter val at eac h off-tr eat me nt visit ( 3, 7, 1 4, 2 1, 2 8, a n d 
3 5) . 
8. 1. 1. 3.  
Off -Tre at me nt M M R M e G F R A n al ysis  f or Wee k 1 2 a n d Wee k 1 7 C o m pleters 
A nal ys es will be c o n d uct e d as descri be d i n Secti o n  8. 1. 1  f or patie nts w h o ha ve c o m plete d 1 2 
wee ks of treat me nt a n d h a ve off -treat me nt e G F R val ues c ollecte d wit hi n eac h of t he a nal ysis 
visit wi n d o ws  t hro u g h Wee k 1 7  (T a ble  4 ). 
8. 1. 1. 4.  
Off -Tre at me nt A N C O V A  e G F R A n al ysis  f or Wee k 1 2 a n d Wee k 1 7 C o m pleters 
A nal ys es will be c o n d uct e d as descri be d i n Secti o n  8. 1. 1. 1  f or patie nts w h o ha ve c o m plete d 1 2 
wee ks of treat me nt a n d h a ve off -treat me nt e G F R val ues c ollecte d wit hi n eac h of t he a nal ysis 
visit wi n d o ws t hr o u g h Wee k 1 7 ( T a ble 4 ). 
8. 1. 1. 5.  
Off -Tre at me nt N o n -li ne ar Mi xe d M o del 
A series of n o nli ne ar mi xe d m o dels will be use d t o fit t he off -treat me nt e G F R c ha n ge fr o m 
baseli ne res ults f or t h e Bar d o x ol o ne Met h yl treate d s u bjects.   T he m o del li n g is t o e x a mi ne t he 
be ha vi or  of e G F R a m o n g treate d s u bje cts  o nce tr eat me nt is disc o nti n ue d.  I nitiall y, t h e f oll o wi n g 
m o del will be fit t o t he data:  
𝑄
=  𝑇
+  𝑐
∗𝐹𝑄𝑇𝑅
∗𝑅
+ 𝑒, 
w here Y ij de n ote t he e G F R val ue f or t he i t h s u bject at t he jt h ti me p oi nt, β0i is t he as y m pt ote, β1i is 
referre d t o as t he a m o u nt, β2i is referre d t o as t he d eca y rate, tij de n otes t he ti me f or t he i t h s u bject 
at t he j t h ti me p oi nt, a n d ei de n otes t he err or ter m. I n t he m o del w here all effects are fi x e d, t he βs 
are defi ne d as f oll o ws:  
•  β 0i = β 0 
•  β 1i = β 1 
•  β 2 i = β 2 
T he ra n d o m effects are i ntr o d uce d i nt o a se q u e nce of m o dels as des cri be d bel o w:  
1)  First a ra n d o m effect f or β 0i will be i ntr o d uce d a n d defi ne d as β 0i + U oi, w here Uoi is t he 
ra n d o m effect. 
2)  T he sec o n d m o del t o be fit will i ncl u de a ra n d o m effect f or b o t h β0i a n d β 1i, wit h t he 
ra n d o m effect f or β1i is defi ne d as β1i + U 1i. 
3)  T he t hir d m o del t o be fit will i ncl u de a ra n d o m effect f or all t hree c o effi cie nts, wit h t he 
ra n d o m effect defi ne d as β2i + U 2i. 
Eac h a d diti o nal ra n d o m effect will be a d de d t o t h e m o del  if t he m o del is sta ble. T he A kai ke 
i nf or mati o n criteria will be use d t o select t he fi nal m o del (l o wer is better).  If n o ne of  t he n o n-
li near mi x e d m o dels c o n ver ge, ot her m o dels ma y be i m ple me nte d s uc h as a q ua dratic m o d el.  
 


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9.  
S A F E T Y A N D T O L E R A BI LI T Y  
Safet y a n d t olera bilit y are e val uat e d b y A Es, S A Es, cli nical la b orat or y test res ults, b o d y wei g ht, 
vital si g ns, 1 2 -lea d E C G fi n di n gs, a n d p h ysic al e xa mi nati o n.  All a nal ys es of t he safet y d ata are 
perf or m e d usi n g t he s afet y a n al ysis s et.  Descri pti ve statistics are prese nte d b y treat me nt gr o u p 
assi g n me nt i n t he safet y a nal ysis s et.  N o f or mal statistical testi n g is perf or me d f or safet y 
a nal ys es.  Safet y is als o s u m marize d b y a p orti o n  of t he s u b gr o u ps defin e d i n Secti o n  7. 3 .  O n -
treat me nt val ues are s u m mariz e d acc or di n g t o t he a nal ysis st u d y wi n d o ws i n Secti o n  5. 5. 3 ; off-
treat me nt val ues are s u m mariz e d acc or di n g t o t he a nal ysis st u d y wi n d o ws i n Secti o n 5. 5. 3. 1 .  
Safet y d ata s u m maries are gr o u pe d b y tr eat me nt.  
C o nti n u o us safet y para m eters (i ncl u di n g selecte d cli nical c he mistries a n d vital si g ns) ma y be 
s u m marize d usi n g t he met h o d ol o g y des cri be d i n Sec ti o n 9. 5. 1  a n d Secti o n  9. 6 .  O nl y t he visit 
w i n d o ws o utli ne d i n Secti o n  5. 5. 1  are i ncl u de d i n t hese a nal yses.  
9. 1.  
A d verse E ve nt Preferre d Ter m a n d B o d y/ Or g a n S yste m S u m m ar y 
T a bles  
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) are s u m marize d b y treat me nt as defi ne d b y t he 
safet y a n al ysis set.   
Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es) are e ve nts t hat eit her:  
•  Ha ve a d ate of o ns et o n or after t h e date of first d ose a n d n ot m ore t ha n 3 0 da ys after 
t he date of t he last d ose of st u d y dr u g, or  
•  Ha ve n o rec or de d date of o nset wit h a st o p date aft er t he first d ose of st u d y dr u g, or  
•  Ha ve n o rec or de d date of o nset or st o p date.  
Ge neral c o nsi derati o ns f or T E A E s u m maries are:  
•  M ulti ple e ve nts b y pref erre d ter m ( P T) a n d s yste m or ga n class ( S O C) are c o u nte d 
o nce o nl y per patie nt f or s u m maries of T E A E i nci de nce.  
•  F or s u m maries of T E A E i nci de nce b y se v erit y, o nl y t he m ost se vere e v e nt is c o u nte d 
per patie nt.  
•  F or s u m maries of T E A E i nci de nce b y relati o ns hi p,  o nl y t he m ost relat e d e v e nt is 
c o u nte d per patie nt.  
•  A T E A E wit h a missi n g res ol uti o n date or i nc o m plete date t hat is n ot i de ntifie d as 
c o nti n ui n g is ass u me d t o be c o nti n ui n g.  
•  F or s u m maries of t he n u m ber of T E A E e ve nts, all T E A Es are c o u nte d.  
•  Wit h dra wal T E A Es i ncl u de t he s u bset of T E A Es t hat starte d o ne t o 3 0 da ys after t he 
last d ose of st u d y dr u g. 
Off -tr eat me nt A Es are e v e nts wit h a start date m ore t ha n 3 0 da ys after last d ose a n d n ot 
c o nsi dere d tr eat me nt e m er ge nt.  Off -treat me nt A Es will be s u m marize d se paratel y.  


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A Es are c o de d usi n g Me d D R A ( Me dical Di cti o nar y f or Re g ulat or y Acti vities) versi o n 2 1. 1.  I n 
Me d D R A, eac h ver bati m ter m is ma p pe d t o a preferre d t er m a n d hi g h le vel ter m ( H L T), w hic h is 
t he n ma p pe d t o a s yste m or ga n class ( S O C).   
T he i n vesti gat or gra d es t he se verit y of t he A Es as mil d, m o derate, or se vere as defi ne d i n t he 
st u d y pr ot oc ol.  T he i n v esti gat or gra des ass o ciati o n or relate d n ess t o t he st u d y me dicati o n 
acc or di n g t o criteria s p ecifie d i n Secti o n 1 1. 4 of t he pr ot oc ol.  
As defi ne d i n t he pr o t oc ol, a seri o us a d verse e v e nt ( S A E) is a n a d verse e v e nt ( occ urri n g at a n y 
d ose a n d re gar dless of ca usalit y) t hat:  
•  Res ults i n deat h;  
•  Is life-t hreate ni n g;  
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;  
•  Res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u 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.  
9. 1. 1.  
Missi n g a n d  P arti al A E O nset D ates  
R ules f or ha n dli n g missi n g or partial A E O ns et D ates are i ncl u de d i n Secti o n  5. 6. 2 . 
9. 1. 2.  
S u m m aries of A d vers e E ve nts  
T E A Es a n d O T A Es are s u m marize d b y treat me nt base d o n year of A E o ns et a n d o verall.  F or 
eac h tr eat me nt, S O C, a n d P T, t he n u m ber a n d perce nta ge of patie nts re p orti n g a n e ve nt is 
calc ulate d.  I n s u m mar y t a bles, S O C is prese nte d al p ha beticall y a n d e v e nts wit hi n eac h S O C  are 
prese nte d b y d ecreasi n g fre q ue nc y c o u nt.  
S u m mar y ta bles ( n u m b er a n d perce nta ge of patie nts a n d e ve nts) of T E A Es ( b y S O C a n d P T) are 
pr o vi de d b y treat me nt as f oll o ws:  
•  All T E A Es  
•  All relate d T E A Es ( defi nitel y, pr o ba bl y, or p ossi bl y rel ate d)  
•  All T E A Es b y s e verit y 
•  All seri o us T E A Es (i ncl u di n g deat hs)   
•  All n o n -serio us T E A Es  
•  All relate d seri o us A Es (i ncl u di n g deat hs)  
•  All T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y dr u g  
•  T E A Es b y ti me t o o nset ( ≤ 1 2 wee ks a n d > 1 2 wee ks)  
•  T E A Es e x hi bite d i n > 5 % of patie nt s 


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Listi n gs are pr o vi de d s h o wi n g:  
•  All A Es  
•  Deat hs  
•  Seri o us a d verse e ve nts  
•  A Es lea di n g t o per ma n e nt disc o nti n uati o n of st u d y dr u g  
•  A Es lea di n g t o de -es calati o n of st u d y dr u g  
9. 2.  
E x p os ure a n d C o m pli a nce  
T he d urati o n of st u d y dr u g e x p os ure is defi n e d as t he n u m ber of da ys o n treat me nt fr o m t he first 
d ose of st u d y dr u g u ntil t he last d ose of st u d y dr u g (last d os e –  first d ose + 1).  St u d y dr u g 
e x p os ure is s u m marize d b y des cri pti ve statistics.  S u m maries i nc l u de t he t otal d ose ( m g) 
recei v e d ( bas e d o n t he n u m ber of pills ret ur ne d), st u d y dr u g c o m plia nce, a n d d urati o n ( da ys) of 
e x p os ure d uri n g t he st u d y treat me nt peri o d.  I n a d diti o n, a s u m mar y of t he n u m ber a n d 
perce nt a ge of patie nts e x p ose d b y d os e ( place b o, 5 m g, 1 0 m g, 2 0 m g, 3 0 m g) a n d b y visit is 
ge n erat e d.  If a patie nt recei ve d m ore t h a n o ne d os e d uri n g a visit wi n d o w, t he d urati o n of t he 
l o n gest d ose is use d t o c alc ulate e x p os ure.  S u m maries of t he n u m ber a n d p erce nt a ge of patie nts 
e x p ose d b y d ose i ncl u de s u b gr o u p a nal yses b y bas eli ne U A C R ( U A C R  ≤ 3 0 0 m g/ g vs. 
U A C R  >  3 0 0 m g/ g).  
T otal n u m ber of d oses dis pe nse d a n d t otal d ose ( m g) dis pe ns e d is calc ulat e d fr o m t otal n u m ber 
of kits ( b ottles) rec or de d o n t he St u d y Dr u g Dis pe nsati o n e C R F.  T otal n u m ber of d ose s recei ve d 
is calc ulate d fr o m i nf or m ati o n o n t he e C R F of St u d y Dr u g Ret ur n a n d St u d y Dr u g Dis pe nsati o n, 
as t he (t otal n u m ber of d oses dis pe nse d –  t otal n u m ber of d oses ret ur ne d).  If a kit is n ot ret ur ne d 
b ut t he patie nt ha d a s u bs e q ue nt dis pe nsati o n, t he n  t he n o n-ret ur n e d kit is ass u me d t o ha ve bee n 
ta ke n i n f ull.  H o we ver, if a kit is n ot ret ur ne d a n d n o kit is s u bse q ue ntl y dis pe nse d, t he n t he n o n-
ret ur ne d kit is ass u me d t o n ot ha ve bee n t a ke n.  St u d y dr u g c o m plia nce ( %) is calc ulate d as 
1 0 0  × t otal n u m be r of d oses recei ve d / t otal n u m ber of st u d y da ys of st u d y partici pati o n, 
e x cl u di n g t he off -treat me nt peri o d.  
Patie nts n ot at per -pr ot oc ol d ose are liste d i ncl u di n g reas o ns . 
9. 3.  
C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt me dicati o ns are c o d e d usi n g t he W orl d Healt h O r ga nizati o n ( W H O) dr u g 
dicti o nar y ( E n ha n ce d versi o n, Marc h 2 0 1 9, B 3 f or mat) f or a n at o mical t hera pe utic c he mical 
classificati o n ( A T C) a n d preferre d dr u g na me.  A patie nt w h o use d m ulti ple me dicati o ns is 
c o u nte d o nl y o n ce f or eac h A T C a n d preferre d dr u g na m e .  A T C a n d preferre d dr u g n a me wit hi n 
eac h A T C are s ort e d al p h a beticall y.   C o de d c o n c o mita nt me dicati o ns are s u m marize d b y 
treat me nt b y W H O A T C class a n d preferre d n a me.  A patie nt w h o use d m ulti ple me dicati o ns is 
c o u nte d o nl y o n ce f or eac h A T C a n d preferr e d dr u g na m e.  Perce nta ges are base d o n t he n u m ber 
of patie nts i n t he safet y a nal ysis set.  Eac h s u m mar y is or d ere d b y d esce n di n g or der of i n ci de nce 
of A T C class a n d preferre d na me wit hi n eac h A T C class.  C o nc o mita nt me dicati o ns will be 
s u m marize d b y treatme nt year a n d o v erall.  


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A c o nc o mita nt me dicati o n is a n y me dicati o n ta ke n at t he ti me of first st u d y treat me nt or a 
me dicati o n t hat was start e d after t he start of st u d y dr u g d osi n g.  S pecificall y, c o n c o mita nt 
me dicati o ns are m e dicati o ns  
•  t hat are c o nti n ue d fro m s cree ni n g a n d c o nti n ue d after t he first st u d y dr u g d osi n g, or  
•  t hat ha ve start dat es or st o p dates wit hi n t he treat me nt peri o d, or 
•  t hat ha ve n o e n d d ate.  
Me dicati o ns wit h a n e n d date o n t he date of first st u d y dr u g a d mi nistrati o n are n ot c o nsi dere d 
c o nco mita nt me dicati o ns.  
Patie nts w h o ta ke e x cl u de d me dicati o ns ( defi ne d i n t he Pr ot oc ol Secti o n 9. 3. 1 ) d uri n g t h e st u d y 
are liste d.  
9. 3. 1.  
Missi n g a n d P arti al C o nc o mit a nt a n d Ot her Me dic ati o n St art a n d St o p D ates  
Missi n g a n d partial c o nc o mita nt me dicati o n start a n d st o p dates are detaile d i n Secti o n  5. 6. 1. 3 . 
9. 4.  
Pri or a n d C o nc o mit a nt Pr oce d ures a n d S ur geries  
Pri or a n d c o nc o mita nt pr oce d ures a n d s ur geries are liste d.  
9. 5.  
Cli nic al L a b or at or y E v al u ati o ns  
La b orat or y d ata are s u m mariz e d at baseli ne a n d at eac h ti me p oi nt b y tr eat me nt.  
9. 5. 1.  
C o nti n u o us S u m m aries of L a b or at or y Res ults  
La b orat or y e val uati o ns a n d c ha n ge fr o m baseli ne are s u m marize d b y treat me nt, la b orat or y 
cate g or y ( he mat ol o g y, c h e mistr y, uri nal ysis a n d micr osc o p y), test, a n d st u d y visit usi n g 
c o nti n u o us statistics.  T he esti mate d gl o mer ular filtrati o n rate (e G F R) res ults are calc ulate d usi n g 
f or m ulas descri be d i n Sect i o n 5. 5. 5 . 
T he c ha n ge fr o m bas eli ne i n select la b orat or y e v al uati o ns at t he pr ot oc ol -d efi ne d o n treat me nt  
e n d p oi nt ti me p oi nts (i.e., Wee k 1 ,2, 4, 6, 8, a n d  1 2 ) f or patie nts treate d wit h bar d o x ol o ne met h yl 
c o m pare d t o place b o ma y be p erf or me d usi n g M M R M  m o del descri be d i n Secti o n  7. 4  a n d t he 
A N C O V A  se nsiti vit y a n al ysis des cri be d i n  Secti o n  7. 4. 1. 1 . 
T he c ha n ge fr o m bas eli ne i n select la b orat or y e v al uati o ns at t he pr ot oc ol -d efi ne d off treat me nt 
e n dp oi nt ti me p oi nts (i.e., Da y 0, 3, 7, 1 4, 2 1, 2 8, a n d 3 5)  f or patie nts treate d wit h bar d o x ol o ne 
met h yl c o m pare d t o place b o ma y be perf or me d usi n g M M R M m o del descri be d i n Secti o n  8. 1 . 
B o x pl ots a n d li ne gra p hs are ge n erate d f or selecte d la b orat or y test res ults, s uc h as e G F R, 
U A C R, ala ni ne a mi n otra nsferas e ( A L T), as partate a mi n otra nsferase ( A S T), t otal bilir u bi n, B N P, 
B U N, uri c aci d, ma g n esi u m, creati ni ne, a n d creati ne ki nase ( C K).  Li n e gra p hs i ncl u de 
mea n  ±  S E o ver ti me f or b ot h t he o bser ve d val u es a n d f or c h a n ge fr o m baseli ne.  
S u m maries of c o nti n u o us statistics are pr o vi de d f or t he f oll o wi n g uri nal ysis para meters: 
al b u mi n, creati ni ne, p H, er yt hr oc ytes, a n d s p ecifi c gra vit y.  Q ualitati ve la b res ults are i ncl u d e d i n 
t he listi n gs b ut are n ot s u m marize d.  La b orat or y res ults t hat are a b o ve or bel o w n or mal li mits are 
fla g ge d i n t he listi n gs.  


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S u m maries of U A C R ( Secti o n  5. 5. 6 ) will use t he ge o metric mea n ( wit h sta n dar d err or) wit h 9 5 % 
c o nfi de nce i nter vals i nste a d of t he arit h metic mea n a n d will dis pla y U A C R res ults i n ori gi nal 
u nits of m g/ g.  C ha n ges fr o m baseli ne i n U A C R are calc ul ate d as t he rati o of eac h visit t o 
baseli ne a n d re p orte d as t he p ost -baseli ne/ bas eli ne rati os a n d are s u m marize d b y ge o metric 
mea ns wit h 9 5 % c o nfi de nce i nter vals at eac h ti me p oi nt.  Si milar  O n Treat me nt M M R M  
a nal ys es as des cri be d i n Secti o n  7. 4. 1  a n d t he A N C O V A a nal ysis descri be d i n  Secti o n  7. 4. 1. 1 . 
will be perf or me d f or U A C R rati o t o baseli ne.  T he c ha n ge fr o m bas eli ne f or U A C R rati o n t o 
baseli ne at t he pr ot o c ol -d efi ne d e n d p oi nt ti me p oi nts W ee k 1 7 f or patie nts treate d wit h 
bar d o x ol o ne met h yl c o m pare d t o place b o ma y be perf or me d usi n g  t he A N C O V A m o dels 
descri be d i n Secti o n  7. 4. 1. 1 a n d Secti o n  8. 1. 1. 1 .  A d diti o nall y, U A C R is s u m marize d b y bas eli ne 
U A C R q uartile.  S u m maries of U A C R i ncl u de val ues f or sc h e d ule d visits.  
9. 5. 1. 1.  
N at ur al l o g( U A C R)/e G F R  
Mea n rati os of n at ural l o g( U A C R)/e G F R ( Secti o n  5. 5. 8 ) are s u m marize d at eac h ti me p oi nt.  T he 
rati o of nat ural l o g(U A C R)/e G F R b y a n al ysis visit is s u m marize d b y arit h metic mea ns.  
9. 5. 2.  
C ate g oric al S u m m a ries of L a b or at or y Res ults  
Select la b orat or y p ara m eters will be s u m marize d usi n g s hift ta bles.  S hift ta bles are s u m marize d 
b y treat me nt, la b orat or y cate g or y ( he mat ol o g y, c h e mistr y, uri nal ysis, a n d micr osc o p y), a n d 
la b orat or y test a n d prese nt s hifts fr o m baseli ne stat us ( N or mal, L o w, Hi g h) t o w orst o n st ud y 
treat me nt stat us ( N or mal, L o w, Hi g h).  T he w orst a b n or malit y v al ues are d efi ne d as t he 
ma xi m u m val ues w hile o n st u d y treat me nt, wit h t he e x ce pti o n of ma g nesi u m a n d he m o gl o bi n.  
T he w orst a b n or m al val u es f or ma g nesi u m a n d h e m o gl o bi n are d efi ne d as t he mi ni m u m val ues 
w hile o n st u d y treat me nt.   
A d diti o nall y, la b orat or y para meters of s pecific i nt erest ( A L T, A S T, U A C R) are s u m marize d 
usi n g s hift ta bles t hat s u m marize s hifts fr o m ( 1) baseli ne stat us t o e n d of treat me nt stat us, ( 2) 
w orst o n -treat me nt stat us t o w orst off -treat me nt stat us ( 3) w orst o n-tr eat me nt stat us t o Da y 3 5 
off -treat me nt stat us, a n d ( 4) baseli ne stat us t o w orst o n-treat me nt stat us (5)  baseli ne t o w orst off -
treat me nt, a n d ( 6) w orst o n-treat me nt stat us t o best (l o west) off-tr eat me nt stat us. T he  n u m ber 
a n d perce nta ge of patie nts are s u m marize d.  F or U A C R, s u m maries will prese nt s hifts fr o m/t o 
t he cate g ori es liste d i n Secti o n 5. 5. 6. 1 .  F or A L T a n d A S T, s u m maries will prese nt s hifts fr o m/t o 
t he f oll o wi n g cate g ori es:  
•  ≤ U L N  
•  > U L N t o ≤ 3 x U L N  
•  >  3 x U L N  
I n a d diti o n, a s u m mar y ta ble is pr o vi de d f or t h e n u m ber a n d perce nt a ge of patie nts meeti n g t he 
f oll o wi n g t hres h ol d le v els at a n y ti me d uri n g t h e st ud y:  
•  > 5 x U L N f or m ore t ha n 2 wee ks  
•  > 3 x U L N a n d ( T B L > 2 x U L N or I N R > 1. 5)  
•  > 3 x U L N wit h t he a p p eara nce of fati g ue, n a usea, v o miti n g, ri g ht u p per q ua dra nt pai n 
or te n der ness, fe v er, ras h, a n d/ or e osi n o p hilia ( >  5 %).  


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•  B N P > 2 0 0 p g/ m L   
•  Ma g n esi u m < 1. 3 m E q/ L ( 0. 6 5 m m ol/ L) 
•  N T -pr o B N P > 1 0 0 0 p g/ m L  
 
9. 5. 2. 1.  
Tr a ns a mi n ase  
E val uati o n of Dr u g -I n d u ce d Seri o us He p at ot o xicit y (e DI S H) pl ots are ge n erate d f or A L T a n d 
A S T vers us T B L.  
A listi n g of s u bjects wit h a b n or mal A L T, A S T, or T B L will als o be pr o vi de d.  
9. 6.  
Vit al Si g ns  
Vital si g n s assess me nts will i ncl u de wei g ht ( k g) a n d als o i ncl u de ot her m eas ure m e nts s uc h as 
bl o o d press ure a n d t e m perat ur e .  W he n t hree bl o o d press ure meas ure m e nts are ta ke n, t he 
a vera ge of t he s ec o n d a n d t hir d res ults will be use d f or t he gi ve n visit.  
9. 6. 1.  
B o d y Wei g ht  
B o d y wei g ht, as c ollecte d d uri n g eac h i n -office visit, is  s u m marize d usi n g descri pti ve statistics 
f or o bser ve d res ults a n d c ha n ge fr o m baseli ne at ti me p oi nt.  I n a d diti o n, n u m ber a n d perce nt a ge 
of patie nts e x perie nci n g a fi ve p o u n d ( 2. 3 kil o gra m) or great er i ncreas e i n wei g ht are 
s u m marize d b y ti me p oi nt.  B o x pl ots a n d li ne gra p hs of c ha n ge fr o m bas eli ne o ver ti me f or 
wei g ht are pl otte d.  
9. 7.  
P h ysic al E x a mi n ati o n  
P h ysical e x a m res ults are liste d.  
9. 8.  
Electr oc ar di o gr a m  
Electr ocar di o gra m ( E C G) data, s uc h as cli nical i nter pret ati o n of E C Gs, heart rate a n d i nter val 
assess me nts of P R, Q R S, a n d Q T are c ollecte d o n t he e C R F.  Q Tc F is cal c ulate d f or a n al ysis 
(Secti o n  5. 5. 7 ).  Des cri pti ve statistics f or o bser ve d val ues a n d c h a n ge fr o m baseli ne at eac h ti me 
p oi nt are pres e nte d f or t h ese 1 2 -le a d E C G i nter val assess me nts.  I n a d diti o n, n u m ber a n d 
perce nt a ge of patie nts wit h a n y a b n or mal val ues (i.e., a b o ve a pre -s pecifi e d t hresh ol d) at a n y 
ti me d uri n g t he st u d y are s u m mariz e d b y ti me p oi nt a n d o verall.  T he pre-s pecifie d le vels of 
E C G Q Tc t hres h ol ds ( T a ble 8 ) are c o nsiste nt wit h F D A g ui da nce: 
T a ble  8 : 
Pre -S pecifie d T hres h ol d Le vels f or E C G P a r a meters  
E C G P ar a meter  
P re -S pecifie d Le vel  
P R  
>  2 0 0 msec  
Q T c F  
>  4 5 0 a n d ≤ 4 8 0 msec  
>  4 8 0 a n d ≤ 5 0 0 msec  
>  5 0 0  


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E C G P ar a meter  
P re -S pecifie d Le vel  
C ha n ge fr o m baseli ne: > 3 0 a n d ≤ 6 0 msec  
C ha n ge fr o m baseli ne: >  6 0 msec  
Heart rate  
<  4 0 beats/ mi n  
>  1 0 0 beats/ mi n T a ble   
 
B o x pl ots  a n d li ne gra p hs of c ha n ge fr o m bas eli ne o ver ti me f or E C G para m eters are pl otte d.  
9. 9.  
Pre g n a nc y  
A listi n g is pr o vi de d f or ser u m a n d uri ne pre g na n c y res ults of all o n -st u d y pre g na nci es. 


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1 0.  
P H A R M A C O KI N E TI C S  
P har mac o ki netic c o n ce ntrati o n  data will be liste d.  Dra ws will be gi n o n Wee k 1 2.   A se parate 
d oc u me nt c o ntai ns details re gar di n g ot her pla n ne d p har mac o ki netic a nal yses.  


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1 1.  
C O VI D -1 9 I M P A C T 
1 1. 1.  
O per ati o n al I m p act  
T he  C O VI D -1 9  p a n de mi c  has  i m pacte d t he c o n d u ct  of  t he st u d y p er  pr ot o c ol.   T o  mi ni mize  
st u d y disr u pti o ns,  alter nati ve  dr u g  dis pe ns ati o n  met h o ds  a n d re m ote visit  c o m pleti o n  met h o ds  
are a v aila ble if it is ina d visa ble f or a p atie nt t o be see n f or a n i n -pers o n cli nic visit or if a patie nt 
is u n willi n g t o c o me t o t he cli nic.  A n y st u d y pr oce d ures t h at ca n n ot be c o n d ucte d re m otel y will 
be n ote d as missi n g.   
S ites s h o ul d rec or d if visits,  data  c ollecti o n,  dr u g  dis pe nsati o n,  a n d dr u g  a d mi nistrati o n  are 
i m pacte d b y  or  relate d t o C O VI D -1 9.    
T he n u m ber a n d p erce nta ge of patie nts are s u m marize d b y visit a n d treat me nt  gr o u p f or t he 
f oll o wi n g cate g ories: 
•  Visit i m pact b y C O VI D -1 9  
− Visit n ot d o ne  
− Visit c o n d ucte d o ut of wi n d o w  
− O ne or m ore pr oce d ures c o ul d n ot be perf or me d  
•  Alter nati ve data c ollecti o n met h o ds  
− N o c ha n ge ( occ urre d as e x pecte d per pr ot oc ol)  
− Tele p h o ne visit  
− Vi de o c o nfere n ce visit  
− H o me healt h care visit  
− L ocal la b  
− Ot her  
•  Dr u g dis pe nsati o n i m pact  
− N o c ha n ge ( office visit)  
− I P dis pe nse n ot sc h e d ule d (tele p h o ne visit) 
− Maile d t o patie nt  
− H o me healt h care pr o vi de d  
− D ose n ot escal ate d  
− D ose de -escalat e d  
− Ot her  


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T he n u m ber a n d p erce nta ge of patie nts are s u m marize d treat me nt gr o u p f or Dr u g I nterr u pti o n 
d ue t o C O VI D -1 9:  
•  Teste d p ositi ve f or C O VI D -1 9 ( yes, n o, n ot teste d)  
•  Pri mar y reas o n f or i nterr u pti o n ( me dical m o nit or/s p o ns or rec o m me n d ati o n, site 
ma n date, patie nt c h oic e, i ns ufficie nt I P s u p pl y, ot her)  
A b y -patie nt listi n g of all st u d y visits t hat were affecte d d ue t o C O VI D -1 9 i ncl u di n g a 
descri pti o n of h o w t he patie nt’s partici pati o n was altere d will be pr o vi d e d.  
Earl y disc o nti n uati o ns of st u d y dr u g or st u d y d ue t o C O VI D -1 9 will be s u m marize d a n d liste d i n 
dis p ositi o n s u m mar y ta bl es a n d t he dis p ositi o n listi n g ( des cri be d i n Secti o n  6. 1 ), res pecti vel y. 
All de viati o ns d ue t o t he i m pacts of C O VI D -1 9 will be i de ntifie d a n d d oc u me nte d acc or di n gl y 
b y t he site a n d t h e S p o ns or.  T he fail ure t o c o m plete a pr ot oc ol visit will n ot be c o nsi dere d as a 
reas o n f or st u d y disc o nti n uati o n a n d will n ot be c o nsi dere d as a maj or de vi ati o n.  All C O VI D-
1 9 -relate d d e viati o ns will be i de ntifie d i n t he pr ot o c ol de viati o n listi n g ( Secti o n 6. 3 ). 
1 1. 2.  
I m p act o n E ffic ac y  
T he pri mar y a n d k e y sec o n dar y e n d p oi nts, as w ell as t he sec o n d ar y e n d p oi nts are la b -b ase d 
e n d p oi nts (i.e, c ha n ge i n e G F R).  H o m e healt h care visits a n d/ or l ocal la b orat ories are a vaila bl e 
t o c ollect safet y la bs, i ncl u di n g e G F R, f or p atie nts w h o are u n a ble or u n willi n g t o c o me f or i n-
cli nic visits.  Ce ntral la b orat or y kits are utilize d at i n -cli nic visits, h o me healt h care visits, a n d 
l ocal la b orat or y visits.  T heref ore, t he c o nti n ge nc y meas ures p ut i n place t o c ollect t his critical 
effic ac y dat a are n ot e x pecte d t o i m pact t he efficac y res ults.  Missi n g data d ue t o C O VI D -1 9 is 
ha n dle d as des cri be d i n Secti o n  5. 6 . 
Se nsiti vit y a n al ys es ma y be perf or me d as a p pr o pri ate t o assess t he p ote ntial i m pact of t he 
C O VI D -1 9 pa n d e mic o n t he treat me nt effect o n efficac y o utc o m es.   
1 1. 3.  
I m p act o n S afet y  
Patie nt narrati ves will be pr o vi de d f or all patie nts w h o test p ositi ve f or se vere ac ut e res pir at or y 
s y n dr o me c or o na vir us 2 ( S A R S-C o V -2), t he ca us ati ve a ge nt of C O VI D -1 9.  
F or patie nts w h o are u n a ble t o c o m plete a n i n -cli nic visit, safet y assess me nts ca n be  perf or me d 
t hr o u g h alter nati ve re m ote visit met h o ds.  Ce ntral la b orat or y kits are use d t o assess safet y 
la b orat or y i nf or m ati o n re gar dless of visit met h o d; t heref ore, t he c o nti n ge n c y meas ures p ut i n 
place t o c ollect t his critic al safet y dat a are n ot e x pecte d t o i m pact t he safet y la b orat or y res ults.   
S u b gr o u p a n al ys es ma y be perf or me d as a p pr o pri ate t o assess t he p ote ntial i m pact of t he 
C O VI D -1 9 pa n d e mic o n t he treat me nt effect o n safet y o ut c o mes.  


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C o nfi de ntial  
1 2.  
R E F E R E N C E S  
C hi n M P, Ba kris G L, Bl oc k G A, C hert o w G M, et al. B ar 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 Disease Sta ge 4 a n d T y p e 2 Dia betes: 
P ost -H oc A nal yses fr o m Bar d o x ol o ne Met h yl E val uati o n i n Patie nts wit h C hr o nic Ki d ne y 
Disease a n d T y p e 2 Dia b etes St u d y. A m J Ne p hr ol. 2 0 1 8; 4 7( 1) : 4 0-4 7.  
Di n g Y, Sti d ha m R D, B u meister R, et al. T he s y nt hetic triter pe n oi d, R T A 4 0 5, i ncreas es t he 
gl o mer ular filtrati o n rat e a n d re d uces a n gi ote nsi n II -i n d u ce d c o ntracti o n of gl o mer ular 
mesa n gi al 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 n e y disease. 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 o k or o K. Acti vati o n of t he Kea p 1/ Nrf 2 pat h w a y i n creasi 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 merica n 
S ociet y of Ne p hr ol o g y. 2 0 1 9.  
K o b a 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 nfla m mat or y c yt o ki ne tr a 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 dance a n d a fra m e 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 wa Y, Ki d o k or o K, et al. 
Bar d o x ol o ne 
met h yl a n al o g atte n uates 
pr otei n uria - i n d uc e 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 Dia 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.  
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 ns e pat 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 meli 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.  
 


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A P P E N DI X  
1 3. 1.  
S A P C h a n ge S u m m ar y  
 
S A P Re visi o n C hr o n ol o g y:  
Versi o n  
Date  
C ha n ges  
Mai n Rati o nale  
S A P versi o n 1  
1 0 -J U N-2 0 2 1  
Ori gi nal  
N/ A  
S A P versi o n 2  
( A me n d me nt 1) 
0 6 -O C T -2 0 2 1  
•  
U p date d C O VI D re q uire me nts f or 
s u m marizati o n 
•  
Re m o ve d I n -cli nic/ P h o ne visits cate g ories fr o m 
t he dis p ositi o n b y vis it s u m mar y 
•  
Pr ot oc ol De viati o n classificati o n b y bli n de d 
tea m re m o ve d 
•  
A d de d N o n -li near m o delli n g of Off-Treat me nt 
e G F R res ults a n d/ or c ha n ge fr o m baseli ne i n t he 
Bar d o x ol o ne Met h yl treate d s u bjects  
•  
A d de d All n o n -seri o us T E A E s u m marizati o n 
•  
A d de d a d diti o nal la b t hres h ol d  le vels t o 
s u m marize 
A d diti o nal  A nal ysis