Clinical trial NCT03366337
Conditions: IgA Nephropathy CKD Associated With Type 1 Diabetes Focal Segmental Glomerulosclerosis Autosomal Dominant Polycystic Kidney
Keywords: IgA Nephropathy CKD associated with type 1 diabetes Focal segmental glomerulosclerosis Autosomal dominant polycystic kidney disease IgAN FSGS ADPKD Bardoxolone methyl CDDO-ME RTA 402
Sponsor: Biogen
Start date: 2017-12-26; Completion date: 2019-01-29
Enrollment: 103 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi-center, open-label Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with the following rare chronic kidney diseases (CKD): CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), and autosomal dominant polycystic kidney disease (ADPKD). Patients will be enrolled in disease specific cohorts within the trial, and effectiveness of bardoxolone methyl in treating CKD will be assessed separately by cohort for each rare CKD.

All patients in the study will follow the same visit and assessment schedule. Following randomization on Day 1, patients will be scheduled to be assessed during treatment at Weeks 1, 2, 4, 6, 8, and 12, and by telephone contact on Days 3, 10, 21, 31, 38, and 45. Patients will also be scheduled to be assessed at an in-person follow-up visit at Week 16, four weeks after the end of treatment.

Detailed description:

Arms: arm 1: Participants with autosomal polycystic kidney disease (ADPKD) will receive bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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) daily. arm 2: Participants with IgA nephropathy (IgAN) will receive bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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) daily. arm 3: Participants with Type 1 diabetes (T1D) will receive bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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) daily. arm 4: Participants with focal segmental glomerulosclerosis (FSGS) will receive bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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) daily.
Interventions: intervention 1: Bardoxolone methyl capsules
Intervention descriptions: intervention 1: Bardoxolone 5 mg capsules

Protocol documents:
Prot_000.pdf: 
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A P H A S E 2 T RI A L O F T H E S A F E T Y A N D E F FI C A C Y 
O F B A R D O X O L O N E M E T H Y L I N P A TI E N T S WI T H 
R A R E C H R O NI C KI D N E Y DI S E A S E S  
V E R SI O N 1. 0  – 1 7 A U G U S T 2 0 1 7  
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I N V E S TI G A T O R’ S A G R E E M E N T 
 
I h a ve r ecei ve d a n d r ea d t he I n v esti gat or’s Br oc h ure f or b ar d o x ol o ne met h yl.  I ha v e rea d t he 
4 0 2- C- 1 7 0 2 cli nical st u d y pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d.  I a gree t o 
mai ntai n t he c o nfi de ntialit y of all i nf or mati o n recei ve d or de v el o pe d i n c o n necti o n wit h t his 
pr ot oc ol.  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri nte d Na me of I n v esti gat or 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
Si g nat ure of I n vesti gat or 
 
  
  
  
  
  
  
 
Date  


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P R O C E D U R E S I N C A S E O F E M E R G E N C Y  
 
T a ble 1:  
E m er ge nc y C o nt act I nf or m ati o n 
R ole i n St u d y  
N a me  
A d dress a n d Tele p h o ne N u m ber  
Me dical a n d Scie ntific  
Lea der  
 
 
 
 
 
 
 
 
Cli nical St u d y 
Ma na ger  
 
 
 
 
 
 
 
Me dical M o nit or  
 
 
 
 
 
 
 
S A E Re p orti n g 
  
 
 
 
 
 
 
 


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


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


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




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


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


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


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


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


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


P r otoc ol 4 0 2 - C-1 7 0 2  
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C o nfi de ntial  
 
Versi o n  1. 0 
1 5  
LI S T O F T A B L E S  
Ta ble 1:  
E mer ge nc y C o ntact I nf or mati o n ................................................................................... 4  
Ta ble 2:  
A b bre viati o ns a n d S peci alist Ter ms ........................................................................... 1 6  
Ta ble  3: 
Cr oss - St u d y C o m paris o n of I ncreases i n e G F R, I n uli n Cleara nce, a n d 
Creati ni ne Cleara nce wit h Bar d o x ol o ne Met h yl Treat me nt  ....................................... 2 3 
Ta ble  4: 
Bar d o x ol o ne Met h yl D os e b y St u d y Visit a n d Al b u mi n uria Stat us ........................... 2 9  
Ta ble 5:  
Sc he d ule of Assess me nts  ............................................................................................ 3 0 
Ta ble 6:  
Bar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or mati o n  ........................................................ 3 8 
Ta ble  7: 
S A E Re p orti n g C o ntact I nf or mati o n .......................................................................... 5 3  
 


P r otoc ol 4 0 2 - C-1 7 0 2  
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C o nfi de ntial  
 
Versi o n  1. 0 
1 6  
4.  
LI S T O F A B B R E VI A TI O N S  A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecial ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 2: 
A b bre vi ati o ns a n d S peci alist Ter ms  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
A C E  
A n gi ote nsi n c o n verti n g e nz y me 
A C R  
Al b u mi n t o creati ni ne rati o  
A D P K D  
A ut os o mal d o mi na nt p ol yc ystic ki d ne y disease 
A E  
A d verse e ve nt 
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A R B  
A n gi ote nsi n II rece pt or bl oc ker 
A S T  
As partate a mi n otra nsferase  
B MI  
B o d y mass i n de x  
B N P  
B-t y pe natri uretic pe pti de 
B P  
Bl o o d Press ure 
B U N  
Bl o o d urea nitr o ge n 
C F R  
C o de of Fe de ral Re g ulati o ns ( U S) 
 
 
C K  
Creati ne ki nase  
C K D  
C hr o nic ki d ne y disease 
C K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n 
Cr Cl  
Creati ni ne cleara nce  
C T M  
Cli nical trial material  
C V  
Car di o vasc ular  
E C  
E t hics C o m mittee 
e C R F 
Electr o nic case re p ort f or m  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic data ca pt ure  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
E o T  
E n d - of-treat me nt 
E R A  
E n d ot heli n rece pt or a nta g o nist 
E S R D  
E n d sta ge re nal disease  


P r otoc ol 4 0 2 - C-1 7 0 2  
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C o nfi de ntial  
 
Versi o n  1. 0 
1 7  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
F S G S  
F ocal se g me ntal gl o mer ul oscler osis  
F/ U  
F oll o w- u p 
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
H b A 1c  
He m o gl o bi n A 1c 
H C V  
He patitis C vir us  
H D P E  
Hi g h -de nsit y p ol yet h yle ne  
H g b  
He m o gl o bi n  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I g A 
I m m u n o gl o b uli n A 
I g A N 
I m m u n o gl o b uli n A ne p hr o pat h y 
I G F- 1 
I ns uli n-li ke gr o wt h fact or- 1 
I K K β 
I n hi bit or of n uclear fact or ka p pa β  ki nase beta s u b u nit  
I M P 
I n vesti gati o nal me dici nal pr o d ucts 
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-t o-treat 
J 2 R 
J u m p t o refere nce 
K DI G O  
Ki d ne y Disease: I m pr o vi n g Gl o bal O ut c o mes 
Kea p 1  
Kelc h -li ke E C H ass ociate d pr otei n- 1 
K f 
Ultrafiltrati o n c oefficie nt  
L D H  
Lactate de h y dr o ge nase  
M C H  
Mea n c or p usc ular he m o gl o bi n  
M C H C  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
M C V  
Mea n c or p usc ular v ol u me  
M M R M  
Mi xe d m o del re peate d meas ures  
M RI  
Ma g netic res o na nce i ma gi n g  
M T L D D  
Ma xi mall y t olerate d la bele d dail y d ose  
N F -κ B 
N uclear fact or ka p pa- li g ht-c hai n-e n ha ncer of acti vate d B -cells 
Nrf 2  
N uclear fact or ( er yt hr oi d-deri ve d 2) -relate d fact or 2 


P r otoc ol 4 0 2 - C-1 7 0 2  
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C o nfi de ntial  
 
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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
N T -Pr o B N P  
N- Ter mi nal Pr o -Brai n Natri uretic Pe pti de   
P B O  
Place b o  
 
 
P H  
P ul m o nar y h y perte nsi o n 
P K  
P har mac o ki netic  
P K D 1  
P ol yc ystic ki d ne y disease 1  
Q Tc  
C orrecte d Q T i nter val  
R B C  
Re d bl o o d cell 
R E M L  
Restricte d ma xi m u m li keli h o o d  
R N A  
Ri b o n ucleic aci d  
R O S  
Reacti ve o x y ge n s pecies  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
T 2 D  
T y pe 2 dia betes  
T B L  
T otal bilir u bi n  
U L N  
U p per li mit of n or mal 
U S  
U nite d States  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n 
W O C B P  
W o me n of c hil d beari n g p ote ntial 
 


P r otoc ol 4 0 2 - C-1 7 0 2  
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C o nfi de ntial  
 
Versi o n  1. 0 
1 9  
5.  
I N T R O D U C TI O N 
Bar d o x ol o ne met h yl a n d its a nal o gs are olea n olic aci d- deri ve d s y nt hetic triter pe n oi d c o m p o u n ds 
t hat p ote ntl y i n d uce t he Nrf 2-K ea p 1 p at h wa y (W u , 2 0 1 1; R ojas -Ri vera , 2 0 1 2).  T hr o u g h 
i nteracti o n wit h t he Nrf 2 re press or m olec ule, K ea p 1, bar d o x ol o ne met h yl a n d its a nal o gs 
pr o m ote tra nsl ocati o n of Nrf 2 t o t he n ucle us, w he re Nrf 2  bi n ds t o a nti o xi da nt res p o nse ele me nts 
i n t he pr o m oter re gi o n of its tar get ge nes, lea di n g t o i n d ucti o n of ma n y a nti o xi da nt a n d 
c yt o pr otecti ve e n z y mes a n d relate d pr ot ei ns ( Lee , 2 0 0 9; Di n k o va- K ost o va, 2 0 0 5 ).  Bar d o x ol o ne 
met h yl a n d its a nal o gs ar e als o p ote nt i n hi bit ors of t he N F- κ B i nfla m mat or y pat h wa y t hr o u g h 
b ot h direct ( i.e., i n hi biti o n of I K K β ki nase acti vit y) a n d i n direct mec ha nis ms (i.e., det o xificati o n 
of reacti ve o x y ge n s pecies) ( Os b ur n, 2 0 0 8 ).  Beca use of t his d ual mec ha nis m of acti o n, 
bar d o x ol o ne met h yl a n d its a nal o gs are h y p ot hesi ze d t o ha ve p ot e ntial t hera pe utic rel e va nce i n a 
variet y of diseas e setti n gs i n v ol vi n g o xi dati ve stress a n d i nfla m mati o n.    
M ulti ple st u dies vali date t he re nal pr ot ecti ve effect of Nrf 2 acti vati o n.  I n c o ntrast, Nrf 2 ge n e 
a blati o n i nte nsifies i nfla m mati o n, o xi dati ve stress, a n d re nal i nj ur y i n precli nical m o dels.  Nrf 2 -
k n oc k o ut mice e x hi bit a l u p us- li ke a ut oi m m u ne ne p hritis (Y o h, 2 0 0 1 ) a n d hist ol o gic a nal yses of 
ki d ne y tiss ue s h o w e nlar ge d gl o mer uli, mesa n gial cell pr oliferati o n, t hic ke ni n g of t he gl o mer ular 
base me nt me m bra n e, a n d gl o mer ul oscler osis ( Ma, 2 0 0 6 ).  Si milarl y, Nrf 2-k n oc k o ut mice ar e 
m ore s usce pti ble t o ne p hr ot o xic i ns ults a n d de vel o p m ore se vere re nal i m pair me nt.  Mec h a nistic 
st u dies de m o nstrate t hat Nrf 2 -me diat e d pr otecti o n a gai nst t hese effects is at least partiall y 
t hr o u g h i n hi biti o n of tra nsf or mi n g gr o wt h fact or-β 1 a n d re d ucti o n of e xtracell ular matri x 
pr o d ucti o n ( Jia n g, 2 0 1 0).  C ollecti vel y, t hese data esta blis h t hat Nrf 2 pla ys a n i m p orta nt r ole i n 
mai ntai ni n g t he f u ncti o n a n d str uct ure of t he ki d ne y a n d Nrf 2 acti vati o n offers pr otecti o n fr o m 
re nal i nj ur y a n d d ysf u n cti o n.   
C hr o nic ki d ne y disease ( C K D) is a disease of decrease d ki d n e y f u ncti o n t h at ca n pr o gress t o 
ki d ne y fail ure a n d e n d- st a ge re n al disease ( E S R D).  Rare f or ms of C K D i n cl u de C K D ass oci ate d 
wit h t y pe 1 dia betes ( T 1 D), I g A ne p hr o pat h y (I g A N), f ocal se g me ntal gl o mer ul oscler osis 
( F S G S), a n d a ut os o mal p ol yc ystic ki d ne y disease ( A D P K D).  Alt h o u g h GF R decli ne is i nitiate d 
b y differe nt p at h o ge nic sti m uli i n T 1 D C K D, I g A N, F S G S, a n d A D P K D, t he pat h o ge nic r ol e of 
i nfla m mat or y pr ocess es i n disease pr o gressi o n a n d decli ni n g re nal f u n cti o n is si milar acr oss eac h 
of t hese diseas es.  H y p o gl yce mia i n T 1 D, a b n or m al i m m u n o gl o b uli n A ( I g A) de p ositi o n a n d 
clear a nce i n I g A N, se g m e ntal scarri n g i n F S G S, a n d re nal c yst f or mati o n i n A D P K D, all tri g ger 
a casca de of pat h ol o gical i nfla m mat or y pr ocess es t hat, o ver pr ol o n ge d p eri o ds, res ult i n 
o xi dati ve stress, mesa n gi al matri x e x pa nsi o n, gl o mer ul oscler osis a n d f i br osis, decreas e d s urface 
area f or filtrati o n, a n d re d uce d re n al f u ncti o n.   
M ore s pecifi call y, t he c hr o nic acti vati o n of pr o-i nfla m mat or y pat h wa ys i n ki d ne y cells pr o m otes 
G F R l oss b y at least t hree mec ha nis ms: (a) i n gl o mer ular e n d ot h elial cells, i nfla m mati o n -
ass ociate d  r eacti ve o x y g e n s pecies ( R O S) i n d uce e n d ot helial nitric o xi de s y nt hase (e N O S) 
u nc o u pli n g a n d t he pr o d ucti o n of per o x y nitrite, w hic h de pletes vas o dilat or y nitric o xi de res ulti n g 
i n l oss of e n d ot helial f u ncti o n a n d re d uce d gl o mer ular s urface area f or filtrati o n ( i.e., decreases 
i n t he ultrafiltrati o n c oefficie nt, Kf); ( b) infl a m mati o n -ass ociate d R O S i n d uce  a c o ntractile 
res p o nse i n mesa n gial cells res ulti n g i n re d uce d Kf a n d G F R; a n d (c) R O S-me diate d  acti vati o n of 
i nfla m mat or y pat h wa ys l ea ds t o fi br osis, pr o m oti n g str uct ural alterati o ns i n t he mesa n gi u m a n d 


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gl o mer ular base m e nt me m bra ne t hic ke ni n g t hat c o ntri b utes t o G F R decli n e.  G F R decli ne fr o m 
t hese pr ocesses i ne vita bl y lea ds t o E S R D.   
T hr o u g h Nrf 2 acti vati o n a n d i n hi biti o n of N F- κ B, b ar d o x ol o ne met h yl a n d cl osel y relate d 
str uct ural a nal o gs h a ve b ee n s h o w n t o i m pr o ve re nal f u ncti o n, re d u ce i nfla m mati o n, a n d pre ve nt 
str uct ural i nj ur y i n m ulti ple m o dels of re nal i nj ur y a n d disease (Ta na k a, 2 0 0 8 ; Z oja, 2 0 1 0 ; 
W u,  2 0 1 1; A mi nza de h, 2 0 1 3 ; Di n g, 2 0 1 3 ).  I n p artic ular, se veral of t hese st u dies el uci date t he 
effects of bar d o x ol o n e met h yl a n d cl osel y rel ate d a nal o gs o n t he u n derl yi n g disease pr ocesses 
t hat pr o m ote re d uce d G F R.  S pecificall y, b ar d o x ol o ne met h yl a n d a nal o gs re vers e e n d ot helial 
d ysf u ncti o n ( Fer g us o n, 2 0 1 0 ) a n d mesa n gial cell c o ntracti o n, t here b y i n creasi n g gl o mer ular 
s urface ar ea ( Kf) a n d G F R (Di n g, 2 0 1 3 ).  F urt her, data fr o m a ni mal m o dels of c hr o nic re nal 
disease de m o nstrat e t hat t he c o m p o u n ds are a nti-fi br otic a n d ha ve pr otecti ve effects o n t he re nal 
i nterstiti u m i n res p o nse t o hi g h pr otei n (Z oja,  2 0 1 0) a n d press ure o verl oa d i n t he setti n g of 
h y perfiltrati o n  (A mi nza d e h, 2 0 1 3 ).   
Bar d o x ol o ne met h yl has c o nsiste ntl y i m pr o ve d para meters of re n al f u ncti o n i n m ulti ple cli nical 
st u dies i n patie nts wit h C K D ass ociate d wit h t y pe 2 dia betes ( T 2 D), ca n cer, a n d p ul m o nar y 
h y perte nsi o n ( P H) , wit h si g nifica nt i ncreas es i n i n uli n cleara n ce, creati ni ne cleara nce, a n d 
esti mate d e G F R.  T h e c h a n ges i n e G F R als o c orrelate i n re d ucti o ns i n ot her para meters s uc h as 
bl o o d urea nitr o ge n ( B U N ), uric aci d, a n d p h os p h ate, a n d n ot ass oci ate d wit h vali date d mar kers 
of re nal i nj ur y, pr o vi di n g c orr o b or ati o n t hat bar d o x ol o ne met h yl treat me nt is ass ociate d wit h 
i m pr o ve me nts i n ki d ne y f u ncti o n.   
T he pr ofile of e G F R i ncr eases wit h bar d o x ol o ne met h yl reflects its m ulti ple pr otecti ve a n d 
a nti-i nfla m mat or y effects.  Earl y i m pr o ve me nts i n e G F R e vi d e nt wit hi n t he first 4 wee ks of 
bar d o x ol o ne met h yl treat me nt are li kel y attri b ute d t o t he re vers al of ac ute, d y na mic 
i nfla m mati o n- me diate d pr ocesses s u c h e n d ot helial d ysf u ncti o n a n d mesa n gial cell c o ntracti o n 
res ulti n g i n gl o mer ular filtrati o n s urface area i ncreases.  T hese i n creases i n e G F R are s ustai ne d 
f or patie nts treate d wit h bar d o x ol o ne met h yl f or u p t o o ne year, wit h ret ai n e d e G F R i ncreases 
fr o m baseli ne e v e nt aft er wit h dra wal of dr u g treat me nt.  T he ma g nit u de a n d d ura bilit y  of t hese 
c ha n ges are q uite differ e nt fr o m t he patter n o bser ve d wit h e G F R i ncreas es d ue t o i ntra gl o mer ular 
press ure or h y perfiltrati o n.  O ver 4 0 0 pati e nts wit h T 2 D C K D ha ve b ee n treate d wit h 
bar d o x ol o ne met h yl f or 1 year or l o n g er, wit h n o e vi de nce of re nal t o xicit y, as assesse d b y 
vali date d mar kers of r e nal i nj ur y, pr o p orti o n of patie nts wit h cli nicall y mea ni n gf ul l oss of e G F R, 
re nal S A Es, a n d E S R D.  T h us, t he c ollecti ve data s u p p ort t hat bar d o x ol o ne met h yl ma y ha ve 
disease - m o dif yi n g effects i n t he ki d ne y (e. g., re v ersal of mesa n gial e x pa nsi o n a n d i nterstitial 
fi br osis) t hat are b e nefi cial a n d n ot deleteri o us.  O n t he basis of t hese res ults, bar d o x ol o ne 
met h yl is als o c urre ntl y b ei n g e val uate d i n a P hase 2/ 3 st u d y i n patie nts wit h Al p ort s y n dr o me. 
In p atie nts  wit h T 1 D C K D, I g A N, F S G S, a n d A D P K D, t he p ote ntial i m pact of a s ustai ne d e G F R 
i ncreas e wit h bar d o x ol o n e met h yl treat me nt is cli nicall y mea ni n gf ul an d c o ul d pr o vi de a m ulti-
year del a y i n disease pr o gressi o n t o E S R D. 
5. 1.  
Cli nic al E x perie nce wit h B ar d o x ol o ne Met h yl  
A p pr o xi matel y 1 9 5 0 i n di vi d uals ha ve bee n e x p ose d t o bar d o x ol o ne met h yl.  Si xtee n st u dies 
ha ve bee n c o m plete d (s e ve n i n patie nts wit h C K D w h o als o ha d t y pe 2 dia b etes, f o ur i n n o n-
C K D i n dicati o ns, a n d fi ve i n healt h y s u bjects), t w o st u dies are o n g oi n g i n patie nts wit h P H, a n d 
o ne st u d y is o n g oi n g i n patie nts wit h Al p ort s y n dr o me.   


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


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


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


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Please ref er t o t he I n v esti gat or ’s Br oc h ure f or a detaile d disc ussi o n of safet y fi n di n gs f or st u dies 
i n healt h y s u bjects, ca n cer, C K D, a n d P H patie nts wit h bar d o x ol o ne met h yl. 
5. 1. 2. 1.  
Fl ui d O verl o a d  
Si milar t o e n d ot heli n rece pt or a nta g o nists ( E R As) i n certai n patie nt p o p ulati o ns, i ncl u di n g 
b ose nta n i n a d va nce d c o n gesti ve heart fail ure a n d a v ose nta n i n a d va n ce d C K D, bar d o x ol o ne 
met h yl treat me nt was f o u n d t o be ass ociate d wit h a n i ncrease d ris k f or fl ui d o verl oa d a n d h eart 
fail ure h os pitalizati o ns i n t he B E A C O N  trial, w hic h e nr olle d patie nts wit h Sta ge 4 C K D 
(e G F R 1 5 t o 2 9 m L/ mi n/ 1. 7 3 m2) a n d t y pe 2 dia betes.  T he o verall i ncreas e d ris k f or fl ui d 
o verl oa d a n d h eart f ail ur e e ve nts wit h bar d o x ol o n e met h yl a p peare d t o be li mite d t o t he first 
t hree t o f o ur wee ks after i nitiati o n of treat me nt.  Ele vate d B N P  a n d pri or h os pitalizati o n f or heart 
fail ure w ere i de ntifie d as ris k fact ors t hat c o ntri b ute d t o i ncreas e d ris k f or t h ese e ve nts.  T h e 
i ncreas e d ris k f or t hes e e ve nts fr o m bar d o x ol o ne met h yl treat me nt ha d n ot bee n o bser v e d i n si x 
pre vi o us C K D st u dies, w hic h were c o n d ucte d m ostl y i n patie nts wit h Sta ge 3 b C K D (e G F R of 
3 0 t o 4 4 m L/ mi n/ 1. 7 3  m2), patie nts wit h he patic d ysf u ncti o n, ca ncer patie nts, or healt h y 
v ol u nteers.  
Re vie w of a d missi o n n otes a n d narrati ve des cri pti o ns f or heart fail ure h os pitalizati o ns i n 
B E A C O N i n dicates t hat heart f ail ure i n bar d o x ol o ne met h yl- treate d patie nts was ofte n prece d e d 
b y ra pi d fl ui d wei g ht gai n (se ver al kil o gra ms wit hi n t he first wee ks of treat me nt i nitiati o n) a n d 
was n ot ass ociate d wit h ac ute re n al dec o m pe ns ati o n or ac utel y re d uce d left ve ntric ular 
c o ntractilit y.   A vaila ble d ata fr o m B E A C O N a n d ot her st u dies s u g gest t hat bar d o x ol o ne met h yl 
treat me nt ca n differ e ntiall y affect he m o d y na mic st at us acc or di n g t o t he cli nical c o n diti o n of 
patie nts  a n d li kel y pr o m otes fl ui d rete nti o n i n patie nts wit h m ore a d va n ce d re nal d ysf u ncti o n a n d 
ot her rec o g nize d ris k f act ors ass ociate d wit h heart fail ure at b aseli ne.    
I n a P hase 2 d ose-ra n gi n g st u d y of t he efficac y a n d safet y of bar d o x ol o ne met h yl i n patie nts wit h 
p ul m o nar y h y perte nsi o n ( L A RI A T), ris k miti gati o n pr oce d ures were e m pl o ye d t o re d uce t he 
p ote ntial f or bar d o x ol o ne met h yl-i n d uce d fl ui d o v erl oa d ; t hese pr o ce d ures e xcl u de d patie nts 
wit h t he i de ntifie d ris k fact ors a n d e ns ure d cl ose m o nit ori n g f or fl ui d rete nti o n wit hi n t he first 
m o nt h of treat me nt.  T o date, t he ris k f or ac ute fl ui d o verl oa d A Es wit h bar d o x ol o ne met h yl i n 
late-sta ge C K D p atie nts has n ot bee n o bser ve d i n P H patie nts.   
5. 1. 2. 2.  
Tr a ns a mi n ase a n d G a m m a -gl ut a m yl Tr a ns pe pti d ase ( G G T) Ele v ati o ns  
I n cli nical st u dies of bar d o x ol o ne met h yl, al m ost all patie nts ha d i ncreas es of tra nsa mi nase 
e nz y mes a b o v e baseli ne u p o n i nitiati o n of treat me nt, w hic h f oll o w e d a c o nsiste nt patter n.  T hese 
i ncreas es wer e n o t ass oci ate d wit h ele vati o ns i n bilir u bi n or ot her si g ns of li ver t o xicit y.  I n 
B E A C O N, fe wer he p at o biliar y S A Es were o bs er ve d i n t he bar d o x ol o ne m et h yl ar m t ha n i n t he 
place b o ar m.  T he ele v ati o ns be g in i m me diatel y after i nitiati o n of treat me nt or a n i ncr ease i n 
d ose ; t he y pea k a p pr o xi matel y t w o t o f o ur wee ks later.  I n m ost patie nts, tra nsa mi nase ele vati o ns 
were  mil d, b ut a p pr o xi m atel y 4 % t o 1 1 % of patie nts e x perie nce d a n ele vati o n greater t h a n 3 X 
t he U L N.  T he ele vati o ns res ol ve d t o le vels less t h a n t he U L N i n m ost all patie nts  wit h 
ele vati o ns, wit hi n t w o wee ks aft er pea k val ues w hile patie nts c o nti n ue d ta ki n g st u d y dr u g.  
Patie nts w h o e x perie n ce d  ele vati o ns t o great er t ha n 3 X t he U L N s o meti mes re q uired a d diti o nal 
ti me t o res ol ve.  W hile s o me patie nts have ha d el e vati o ns t o a b o ve 3 X t he U L N, p ersiste nt 


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ele vati o ns t o a b o ve 3 X t h e U L N ha v e n ot bee n o bs er ve d, a n d t h e ele v ati o ns di d n ot rec ur o nce 
res ol ve d, u nless ca use d b y ot her fact ors. 
Bar d o x ol o ne met h yl re g ulates G G T, a k n o w n Nrf 2 tar get ge ne.  I n cli nical st u dies, l o w le vel 
G G T ele vati o ns d uri n g tr eat me nt wer e  c o m m o n, mil d, a n d t y picall y laste d l o n ger t ha n A L T/ A S T 
ele vati o ns.  Bilir u bi n le vels i n patie nts e x perie n ci n g tra nsa mi nase or G G T ele vati o ns d ue t o 
treat me nt wit h bar d o x ol o ne met h yl eit her re mai ne d at baseli ne le vels or d ecreas e d.  T he A L T, 
A S T, a n d G G T ele v ati o ns we re g e ner all y self-li miti n g i n patie nts w h o c o nti n ue d treat me nt wit h 
st u d y dr u g.  
5. 1. 2. 3.  
M uscle S p as ms  
M uscle s pas m was t he m ost fre q ue ntl y re p orte d A E i n cli nical trials of bar d o x ol o ne met h yl i n 
patie nts wit h C K D w h o als o ha d t y pe 2 dia betes.  T he m uscle s pas ms m ost ofte n ma nifest e d i n 
t he first t w o m o nt hs of treat me nt a n d res ol ve d s p o nta ne o usl y or wit h e m pirical treat me nt .  T he y 
occ urr e d  m ostl y at ni g ht, i n t he l o wer e xtre mities , a n d we re ge nerall y mil d t o m o derate i n 
se verit y.  M uscle s pas ms ha ve als o bee n re p orte d i n bar d o x ol o ne met h yl-treate d P H patie nts b ut 
at l o wer i nci de n ces t ha n t hat o bser ve d i n pri or C K D st u dies.  M ore o ver, t h e i nci de nce of m us cle 
s pas ms is si milar t o t hat o bser ve d i n place b o-treat e d P H patie nts.  M uscle s pas ms ma y res ult 
fr o m i m pr o ve d i ns uli n se nsiti vit y a n d gl uc ose u pta ke i n s keletal m uscle cells.  I ncreas es i n 
gl uc ose u pta ke, as assess e d b y t he h y peri ns uli ne mic- e u gl yce mic cla m p pr o ce d ure, were 
o bser ve d i n res p o ns e t o b ar d o x ol o ne met h yl i n a d efi ne d s u bset of p atie nts e nr olle d i n a P hase 2 a 
st u d y.  T o date, i n t h ose cases w h ere s er u m creati ni ne ki nase ( C K) le v els ha ve bee n meas ure d, 
n o ass ociati o n has bee n o bser ve d bet w ee n m uscle s pas ms a n d ele vate d C K le vels i n patie nts 
treate d wit h bar d o x ol o ne met h yl.  Cli nical si g ns a n d la b orat or y fi n di n gs ass ociate d wit h t he 
re p orts of m uscle s p as ms ha ve n ot bee n c o nsiste nt wit h m uscle t o xicit y.  Bar d o x ol o ne met h yl 
s u bjects s h o we d n o i ncr ease i n pr o mi ne nt la b orat or y fi n di n gs ass ociate d wit h m uscle t o xicit y, 
s uc h as i ncrease d le v els of ser u m mar k ers, i ncl u di n g creati ni ne, lactate de h y dr o ge nase ( L D H), 
B U N, uric aci d, p h os p h or us, a n d p otassi u m, w hic h were m o nit ore d wee kl y d uri n g t he first t w o 
m o nt hs of a pri or st u d y ( 4 0 2- C- 0 8 0 4) w he n m uscl e s pas ms were m ost fre q ue ntl y re p orte d.  
I n creases i n t he w h ole- b o d y gl uc ose dis p osal rate ha ve bee n o bser v e d i n mice treat e d wit h 
bar d o x ol o ne met h yl, as well.  I n cr ease d gl uc os e u pta ke was o bser ve d i n is olate d calf m uscles of 
t he mice, b ut n ot i n w hite a di p ose tiss ue (Sa ha , 2 0 1 0).   
5. 1. 2. 4.  
Wei g ht L oss 
Decr eases i n w ei g ht a n d re p orts of a n ore xia/ decrease d a p petite h a ve bee n o bser ve d f oll o wi n g 
treat me nt wit h bar d o x ol o ne met h yl i n patie nts wit h C K D w h o als o ha d t y p e 2 dia betes.  I n 
st u dies of t hese patie nts, 1 7 % of bar d o x ol o n e met h yl patie nts re p orte d A Es of wei g ht d ecreas e or 
decrease d a p petite (irr es p ecti ve of r elati o ns hi p t o treat me nt).  Wei g ht re d u cti o n was m ore 
pr o n o u nce d i n patie nts tr eate d wit h bar d o x ol o n e met h yl t ha n i n t h ose gi ve n place b o. 
Wei g ht l oss of a p pr o xi m atel y o ne kil o gra m per m o nt h was o bser ve d, wit h patie nts of hi g her 
b o d y- mass i n de x at baseli ne l osi n g m ore wei g ht (i n a bs ol ute ter ms) t ha n t h ose of n or mal or 
m o deratel y -ele vate d b o d y - mass i n de x.     
Bar d o x ol o ne met h yl- treate d P H patie nts ha ve als o ha d decreas es i n wei g ht, wit h  mea n wei g ht 
decreases of a p pr o xi matel y 3 k g vers us place b o at Wee k  1 6.  Wei g ht l oss i n P H patie nts has n ot 
c oi nci de d wit h re p orts of decrease d a p petite or a n ore xia A E s. 


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5. 1. 2. 5.  
H y p o m a g nes ae mi a 
H y p o ma g nesae mia has n ot bee n re p orte d i n P H patie nts t o date, b ut was re p orte d as a n A E f or 
1 5. 5 % of patie nts wit h C K D w h o als o ha d t y pe 2 dia betes w h o recei v e d bar d o x ol o ne met h yl.  
T he A E  of h y p o ma g n esae mia ( of a n y re p ort e d rel ati o ns hi p t o st u d y dr u g) was m ore fre q ue ntl y 
re p orte d i n bar d o x ol o ne met h yl-treate d patie nts t h a n i n patie nts gi ve n place b o.  T he i n vesti gat ors 
c o nsi dere d  al m ost all re p orte d e ve nts t o be mil d.   A d diti o nall y, patie nts treate d wit h bar d o x ol o ne 
met h yl ha d a greater d ecr ease fr o m baseli ne i n ser u m ma g nesi u m le vels t ha n patie nts g i ve n 
place b o; t he decrease w as e vi de nt wit hi n 4 wee ks a n d atte n uate d after 8 wee ks of starti n g 
t hera p y.  I n b ar d o x ol o ne met h yl cli nical st u dies perf or me d t o date, a p ost- h oc a nal ysis i de ntifie d 
n o c orrel ati o n bet wee n h y p o ma g nesae mia a n d eit her gastr oi ntesti nal A Es or car di ac A Es, 
i ncl u di n g car diac d ysr h yt h mias a n d pr ol o n ge d Q T c.  T he 2 4- h o ur uri ne c oll ecti o ns fr o m t he 
B E A C O N a m b ulat or y bl o o d press ure m o nit ori n g s u b-st u d y s h o we d n o i ncrease i n uri n ar y 
ma g nesi u m le vels, i n dicati n g t hat re nal l oss of ma g nesi u m di d n ot acc o u nt f or t he re d u cti o ns i n 
ser u m ma g nesi u m o bser v e d wit h bar d o x ol o ne met h yl treat me nt i n C K D patie nts.  N ota bl y, a 
t h or o u g h Q T st u d y t hat teste d d oses of bar d o x ol o ne met h yl u p t o 8 0 m g, bar d o x ol o ne met h yl 
s h o we d n o i ncrease i n t h e Q T i nter val.  
5. 1. 2. 6.  
I ncre ases i n Uri n ar y Pr otei n 
I n creases i n uri nar y al b u mi n ha ve bee n o bser ve d i n s o me patie nts treate d wit h bar d o x ol o ne 
met h yl wit h c hr o nic ki d ne y disease a n d t y pe 2 dia betes.  T he i ncreas es are li kel y d ue t o 
bar d o x ol o ne met h yl’s p h ar mac ol o gical m o d ulati o n of t u b ular pr otei n rea bs or pti o n a n d ha ve n ot 
bee n ass oci ate d wit h i nterstitial fi br osis or i nj ur y.  I n precli nical st u dies, bar d o x ol o ne met h yl has 
bee n s h o w n t o d o w nr e g ulate t he pri mar y pr ot ei ns i n v ol ve d i n pr otei n rea bs or pti o n i n t he 
pr o xi mal t u b ules: t h e me gali n -c u bili n c o m ple x.  M ore o ver, t he ma g nit u de of o bser ve d e G F R 
i ncreas es wit h bar d o x ol o ne met h yl treat me nt is t h o u g ht t o re d uce t he resi d e nce ti me of pr otei n i n 
t he pr o xi mal t u b ules, t here b y re d u ci n g pr otei n re u pta ke a n d i ncreasi n g uri n ar y pr otei n le vels.  
T heref ore, i ncreas e d e G F R, t o get her wit h decrease d me gali n e x pressi o n, is t h o u g ht t o res ult i n 
decrease d fracti o nal a bs or pti o n of al b u mi n a n d i ncrease d uri nar y e xcreti o n of al b u mi n.  
C o nsiste nt wit h bar d o x ol o ne met h yl- me diate d pr otecti o n i n precli ni cal m o dels of pr otei n -
o verl oa d-i n d uce d ne p hr o pat h y, t hese p har m ac ol o gical effects are t h o u g ht t o re d uce pr otei n 
o verl oa d a n d s ec o n dar y ne p hr o pat h y ca use d b y e xcessi ve al b u mi n u pta ke a n d t heref ore are n ot 
ass ociate d wit h tiss ue i nj ur y a n d i nterstitial fi br o sis. 
 


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


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


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bel o w.  Fr o m a saf et y pers pecti ve, t he 3 0 m g d ose ma y be ass ociat e d wit h a n i ncreas e d i nci de nce 
of na usea; h o w e ver, t he na usea e x p erie n ce d i n pre vi o us trials is ge nerall y mil d, tra nsie nt, a n d 
cli nicall y ma na gea bl e.  
7. 3. 1.  
D ose Esc al ati o n  
P atie nts will start wit h o nce- dail y d osi n g of bar d o x ol o ne met h yl at 5 m g  a n d will d ose-escalat e 
t o 1 0 m g  at Wee k 2, t o 2 0  m g  at Wee k 4, a n d t he n t o 3 0 m g  at Wee k 6 ( o nl y if baseli ne A C R 
> 3 0 0 m g / g) u nless c o ntrai n dicate d cli nicall y a n d a p pr o ve d b y t he me dical m o nit or ( Ta ble  4).  
T he d osi n g o bj ecti ve is t o titrate patie nts t o t he ma xi m u m d ose deter mi ne d b y baseli ne A C R, a n d 
mai ntai n t he ma xi m u m d ose after i nitial d ose -titrati o n.  T he i n vesti gat or s h o ul d disc uss a n y 
reas o n f or n ot d ose-es cal ati n g at Wee ks 2 a n d  4 wit h t he me dical m o nit or.  D ose e scalati o n at 
s u bse q ue nt visits is per mitte d t o meet t he d osi n g o bjecti ve.  
T a ble 4:  
B ar d o x ol o ne Met h yl D ose b y St u d y Visit a n d Al b u mi n uri a St at us 
B aseli ne A C R  
D a y 1 
Wee k 2  
Wee k 4  
Wee k 6 t o Wee k 1 2 
A C R ≤ 3 0 0 m g/ g  
5 m g 
1 0 m g 
2 0 m g 
2 0 m g 
3 0 0 m g/ g < A C R ≤ 2 5 0 0 m g/ g  
5 m g 
1 0 m g 
2 0 m g 
3 0 m g 
7. 3. 2.  
D ose De - Esc al ati o n a n d Re- Esc al ati o n 
T he i n vesti gat or ma y c h o ose t o decr ease t he p atie nt’s d ose t o t he pri or d ose (e. g., 2 0 m g t o 
1 0 m g, or 1 0 m g  t o 5 m g ), if cli nicall y i n dicate d.  D ose de-escalati o n ma y  occ ur m ore t ha n o nce, 
b ut t he mi ni m u m d ose per mitte d is 5  m g .  Reas o ns f or d ose de-escalati o n s h o ul d be disc usse d 
wit h t he me dical m o nit or pri or t o c ha n gi n g d ose a n d m ust be d oc u me nte d.  After d ose d e-
escalati o n, patie nts  s h o ul d ret ur n f or a n u nsc h e d ule d office visit wit hi n 4 wee ks ( ± 3 da ys) t o 
c ollect cli nical c h e mistr y a n d t o perf or m t he assess me nts detaile d i n Secti o n 9. 7 . 
O nce a p atie n t’s d ose has bee n re d u ce d, d os e re-es calati o n bac k t o a hi g her d ose is per mitte d t o 
meet t he d osi n g o bjecti ve.  H o we v er, patie nts w h o d ose re- escal ate m ust ha ve a tel e p h o ne call 
1 wee k after d ose escalati o n a n d a n u nsc he d ule d office visit 2 wee ks ( ± 3 d a ys) after d ose 
escalati o n t o c ollect cli n ical c he mistr y, B N P, a n d N T- pr o B N P.  U nsc he d ul e d visits d ue t o d ose 
escalati o n s h o ul d als o i ncl u de assess me nts detaile d i n Secti o n 9. 7 .  
7. 4.  
Criteri a f or St u d y Ter mi n ati o n  
Alt h o u g h t he S p o ns or i nte n ds t o c o m plete t he st u d y, t he S p o ns or reser v es t he ri g ht t o 
disc o nti n ue a c o h ort or t h e st u d y at a n y ti me f or cli nical or a d mi nistrati ve reas o ns, or if re q uire d 
b y re g ulat or y a g e ncies.  If t he S p o ns or disc o nti n ues t he st u d y, all st u d y dr u g will be disc o nti n ue d 
a n d t he i n vesti gat or will be res p o nsi ble f or sec uri n g a n y alter nati ve t h era p y t o be a d mi nistere d, 
as a p pr o priat e.  
7. 5.  
Sc he d ule of Assess me nts  
Ta ble 5  lists t he o verall s c he d ule of assess me nts f or t he st u d y. 


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T a ble 5: Sc he d ule of A ssess m e nts  
Assess me nt  
Scree n 
A a 
Scree n 
B b 
D a y  
1 c 
W k 1 
( P h o ne) 
D a y 3 ± 2  
W k 1  
D a y  7 ± 3  
W k 2  
( P h o ne) 
D a y 1 0 ± 2  
W k 2  
D a y 1 4 ± 3  
W k 3  
( P h o ne) 
D a y 2 1 ± 2  
W k 4  
D a y 2 8 ± 3  
W k 4  
( P h o ne) 
D a y 3 1 ± 2  
W k 5  
( P h o ne) 
D a y 3 8 ± 2  
W k 6  
D a y 4 2 ± 3  
W k 7  
( P h o ne) 
D a y 4 5 ± 2  
W k 8  
D a y 
5 6 ± 3  
W k 1 2  
or E o T d 
D a y 8 4 ± 3  
W k 1 6   
or F / U 
D a y 1 1 2 ± 3  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ e xcl usi o n 
X  
 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d baseli n e 
disease c haracteristics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht i n cli nic / B MI  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Wei g ht at h o me  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Dis pe nse wei g ht diar y  
 
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
 
C ollect/re vie w wei g ht diar y  
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
E C G  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Ec h ocar di o gra m f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g n meas ure me nts  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
P h ysical e xa m  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Pre g na nc y test f or W O C B P g 
X  
X  
X  
 
 
 
 
 
X  
 
 
 
 
X  
X  
X  
St u d y dr u g a d mi nistrati o n  
 
 
---------------------------------------------X ----------------------------------------- 
 
Dis pe nse st u d y dr u g  
 
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
 
C ollect st u d y dr u g  
 
 
 
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
 
Tele p h o ne c o ntact  
 
 
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
 
 
A d verse e ve nt c ollecti o n  
 
 
X
h 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ki d ne y bi o ps y i 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasti n g C -pe pti de le vel j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge netic testi n g k 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical c he mistr y (i ncl. e G F R)   
X  
X  
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
B N P a n d N T -pr o B N P  
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
I G F-1 a n d ser u m ket o nes 
X  
 
X  
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
He mat ol o g y  
X  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Uri nal ysis a n d micr osc o p y  
X  
 
X  
 
  
 
X  
 
X  
 
 
X  
 
X  
X  
X  
Uri ne c ollecti o n f or A C R l 
 
X  
X  
 
 
 
 
 
X  
 
 
 
 
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Vir us ser ol o g y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P K sa m ples m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 


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


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


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


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e. S y m pt o matic c or o nar y disease ( pri or m y ocar dial i nfarcti o n, perc uta n e o us 
c or o nar y i nter ve nti o n, c or o nar y arter y b y p ass graft s ur ger y, or a n gi n a); 
f. Hist or y of h os pitalizati o n f or heart fail ure; 
g.  Car diac i ns uffici e nc y, defi ne d as Ne w Y or k H ea rt Ass ociati o n Class > 2; 
h.  Hist or y of atrial fi brillati o n;  
i. Hist or y of u nsta ble arr h yt h mias; 
1 1.  U nc o ntr olle d s yste mic h y perte nsi o n as e vi de n ce d b y sitti n g s yst olic bl o o d press ure ( B P) 
> 1 6 0 m m H g or sitti n g diast olic B P > 1 0 0 m m H g at Scree n  A visit aft er a perio d of rest; 
1 2.  S yst olic B P < 9 0 m m H g at Scree n  A visit aft er a peri o d of rest; 
1 3.  Hist or y of mali g na nc y wit hi n 2 years pri or t o Scree n  A visit , wit h t he e xce pti o n of 
l ocalize d s ki n or cer vical carci n o mas; 
1 4.  U nc o ntr olle d dia betes ( H b A 1c > 1 0. 0 %) at Scree n  A visit;  
1 5.  U ntreate d or u nc o ntr olle d acti ve bacterial, f u n g al, or viral i nfecti o n; 
1 6.  Partici pati o n i n ot her i nter ve nti o nal cli nical st u dies wit hi n 3 0 da ys pri or t o Da y 1; 
1 7.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part n ers 
of c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) d uri n g Scree ni n g, w hile 
ta ki n g st u d y dr u g, a n d f or at least 3 0 da ys after t h e last d ose of st u d y dr u g is i n geste d;  
1 8.  W o me n w h o are pr e g na nt or breastfee di n g; 
1 9.  K n o w n h y perse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g;  
2 0.  A n y a b n or mal la b or at or y le vel t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d p ut t he 
patie nt at ris k b y trial e nr oll me nt;  
2 1.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na bl e t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n; 
8. 3.  
Scree ni n g Peri o d  
T he scree ni n g peri o d m ust n ot e xcee d 6 m o nt hs.  T he Scree n B visit s h o ul d be n o m ore t ha n 
3 0 da ys pri or t o Da y 1. 
8. 4.  
P atie nt Re -Scree ni n g  
Patie nts t hat scree n f ail ma y re peat t he Scree ni n g pr oce d ures t o q ualif y f or t he st u d y wit h 
a p pr o val fr o m t he m e dical m o nit or. 
8. 5.  
P atie nt Disc o nti n u ati o n a n d Ter mi n ati o n  
Patie nts ha ve t he ri g ht t o disc o nti n ue st u d y dr u g or wit h dra w fr o m t he st u d y at a n y ti me f or a n y 
reas o n, wit h o ut prej u dice t o t heir me dical care.  F urt her m ore, t he i n v esti gat or ma y disc o nti n ue a 
patie nt fr o m st u d y dr u g.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h d ra wi n g a patie nt fr o m t he st u d y.  T he reas o n f or a p atie nt’s 


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disc o nti n uati o n fr o m st u d y dr u g or st u d y ter mi nati o n will be rec or d e d i n t he electr o ni c cas e 
re p ort f or m ( e C R F).  
8. 5. 1.  
P atie nt Disc o nti n u ati o n Criteri a  
Disc o nti n uati o n refers t o a patie nt’s st o p pi n g a d mi nistrati o n of st u d y dr u g.  Reas o ns f or st u d y 
dr u g disc o nti n uati o n ma y i ncl u de t he f oll o wi n g: 
•  Occ urre nce of a n A E or c ha n ge i n me dical stat us t hat lea ds t he i n vesti gat or t o be 
c o ncer n e d a b o ut t he p atie nt’s welfare  
•  A d mi nistrati ve reas o ns ( e. g., i na bilit y t o c o nti n ue) 
•  S p o ns or ter mi nati o n of t he st u d y 
•  V ol u ntar y wit h dra w al 
•  Fe males w h o bec o me pre g na n t d uri n g t he st u d y 
Patie nts m ust disc o nti n ue st u d y dr u g if a n y of t he f oll o wi n g occ ur. 
•  A L T or A S T > 8 X U L N;  
•  A L T or A S T > 5 X U L N f or m ore t ha n t w o wee ks; 
•  A L T or A S T > 3 X U L N a n d (t otal bilir u bi n > 2 X U L N or I N R > 1. 5); 
•  A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
Patie nts w h o are disc o nti n ue d fr o m st u d y dr u g s h o ul d still c o nti n ue i n t he st u d y, c o m plete all 
st u d y visits, a n d u n der g o all sc he d ule d st u d y assess me nts, if p ossi ble.   
8. 5. 2.  
P atie nt Ter mi n ati o n Criteri a  
Ter mi nati o n ref ers t o a p atie nt’s st o p pi n g st u d y dr u g a n d all st u d y assess me nts a n d visits.  
Reas o ns f or st u d y ter mi n ati o n i ncl u de t he f oll o wi n g: 
•  L oss t o f oll o w- u p 
•  Deat h  
•  Wit h dra wal of c o nse nt 
E ver y re as o na ble eff ort s h o ul d be ma de t o c o ntact patie nts w h o d o n ot ret ur n f or a s c he d ule d 
visit .  T he i n vesti gat or s h o ul d i n q uire a b o ut t he reas o n f or wit h dra wal, re q uest t he patie nt  ret ur n 
all u n use d i n vesti gati o nal pr o d uct, re q u est t he patie nt ret ur n f or e n d-of -treat me nt a n d f oll o w- u p 
visit s (if a p plica ble), a n d f oll o w- u p wit h t he patie nt  re gardi n g a n y u nres ol ve d A Es.   


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


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9. 1. 2.  
M a n a ge m e nt of Ele v ate d Tr a ns a mi n ase Le vels ( A L T a n d/ or A S T) 
Nearl y all i nsta nces of el e vate d tra ns a mi na ses d ue t o bar d o x ol o ne met h yl treat me nt are e x pecte d 
t o be as y m pt o matic.  C hec k tra nsa mi nase l e vels (as well as T B L, G G T , al k ali ne p h os p hatase 
( A L P), a n d I nter nati o nal N or malize d Rati o (I N R)) wit hi n 4 8 t o 7 2 h o urs d uri n g a n u nsc he d ule d 
visit if t he f oll o wi n g occ urs: 
•  A L T or A S T le vels > 5 X U L N  
Re peat testi n g e ver y 7 2 t o 9 6 h o urs u ntil tra nsa mi nase le vels are bel o w 5 X  t he U L N f or at least 
o ne wee k or u ntil t he patie nt wit h dra ws c o ns e nt. 
Disc o nti n ue st u d y dr u g a d mi nistrati o n per ma ne ntl y if a n y of t he f oll o wi n g occ urs:  
•  A L T or A S T > 8 X U L N  
•  A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks 
•  A L T or A S T > 3 X U L N a n d ( T B L > 2 X U L N or I N R > 1. 5) 
•  A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
T he he pat o biliar y tr ee m ust be vis ualize d ( e. g., ultras o u n d, ma g netic res o n a nce i ma gi n g [ M RI ]) 
a n d assesse d if a patie nt disc o nti n ues ta ki n g st u d y dr u g sec o n dar y t o ele vat e d tra nsa mi nase 
le vels.  A d diti o nal tests/st u dies ma y be warra nte d de pe n di n g o n t he cli nical prese ntati o n. 
9. 1. 3.  
M a n a ge m e nt of M uscle S p as ms  
Basic s y m pt o matic relief is t he first ste p i n ma na gi n g m uscle s pas m , i ncl u di n g wal ki n g, a de q uate 
h y drati o n, weari n g s oc ks, a n d stretc hi n g bef ore b e dti me.  Assess me nt of le vels of electr ol y tes 
s uc h as ma g nesi u m, cal ci u m a n d p otassi u m ma y i n dicate t he nee d f or re place me nt.  If vita mi n  D 
le vels are l o w, s u p ple m e ntati o n ma y be warra nte d.  M uscle rela x a nts ma y als o hel p relie ve 
s y m pt o ms. 
9. 1. 4.  
Wei g ht L oss 
O n g oi n g assess me nts t o e ns ure t hat t he p atie nt is recei vi n g a d e q uate n utriti o n a n d c o nsi derati o n 
of ot her eti ol o gies of w ei g ht l oss ma y be warra nte d f or patie nts recei vi n g b ar d o x ol o ne met h yl.   
9. 1. 5.  
H y p o m a g nes ae mi a 
I n i nsta n ces w h ere a pati e nt e x perie n ce s h y p o ma g nesae mia, defi ne d as s er u m ma g nesi u m less 
t ha n 1. 3 m E q/ L ( 0. 6 5 m m ol/ L), c o nsi derati o n s h o ul d be gi ve n t o re pleti o n of ser u m ma g nesi u m. 
9. 1. 6.  
M a n a ge m e nt of Uri n ar y Pr otei n 
Alt h o u g h i ncreases i n uri nar y pr otei n wit h bar d o x ol o ne met h yl ha ve n ot bee n ass ociate d wit h 
re nal i nj ur y or l oss of ki d ne y f u ncti o n, i n vesti gat ors s h o ul d cl osel y m o nit or patie nts if uri nar y 
al b u mi n t o creati ni ne rati os i ncrease b y m ore t ha n 1 0 0 % a n d e xcee d 1 0 0 0 m g/ g f or pr otei n uria 
ass ociate d wit h ne p hr otic s y n dr o me.  Ot her c o nc urre nt si g ns of ne p hr otic s y n dr o me i ncl u de 
ser u m al b u mi n le vels bel o w 3. 5 g/ d L, peri p heral e de ma, i ncrease d bl o o d press ure, i ncrease d 
B N P, or ot her si g ns of fl ui d rete nti o n.  If ne p hr otic s y n dr o me is s us pecte d, t he me dical m o nit or 
s h o ul d be c o ns ulte d t o disc uss a p pr o priat e meas ures, w hic h ma y i ncl u de d ose a dj ust me nt, 
te m p orar y st u d y dr u g dis c o nti n uati o n, a n d/ or a d mi nistrati o n of l o o p di uretics.  




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9. 3.  
C o nc o mit a nt Me dic ati o ns  
9. 3. 1.  
E xcl u de d Me dic ati o ns  
Patie nts ta ki n g t hese me dicati o ns or treat me nts will be i neli gi ble f or e nr oll me nt:  
•  A n y ot her i n vesti gati o nal dr u g or de vice as part of a n i nter ve nti o nal st u d y; 
•  C hr o nic ( > 2 w ee ks) i m m u n os u p pressi ve t hera p y, or nee d f or c ortic oster oi ds, 
i ncl u di n g t hera pies s uc h as gl uc oc ortic oi ds, o nc ol o gic pre parati o ns, a n d a nti-T N F α  
a ge nts [e. g., i nfli xi ma b ( Re mica de ®), a dali m u ma b ( H u mira ®), cert oliz u m a b pe g ol 
( Ci mzia ®), eta nerce pt ( E n brel ®)].  Gl uc o c ortic oi d i ntra- artic ular i njecti o ns, i n hale d 
pr o d ucts, t o pical pre p arati o ns, a n d nasal pre p arati o ns are all o w e d.  Patie nts wit h 
I g A N or F S G S t hat are r ecei vi n g pre d nis o n e at d oses ≤ 1 0 m g/ da y  are eli gi ble f or 
e nr oll me nt i n t he Ig A N or F S G S c o h ort, b ut pre d nis o ne d oses m ust be sta ble f or 
3 0 da ys pri or t o Scree n A visit a n d s h o ul d be a ntici pate d t o re mai n t he sa me f or t he 
re mai n der of t he st u d y.   
Patie nts w h o ta ke e xcl u d e d me dicati o ns d uri n g t h e st u d y s h o ul d n ot disc o nti n ue st u d y dr u g 
s olel y o n t his basis.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h d ra wi n g a patie nt fr o m t he st u d y. 
9. 3. 2.  
Per mitte d Me dic ati o ns  
All o we d c o nc o mita nt me dicati o ns i ncl u de t he f oll o wi n g: 
•  A nti bi otics;  
•  Dail y m ult i vita mi ns or rec o m me n de d dail y s u p ple me nts; 
•  Ot her me dicati o ns i nte n d e d t o ma na ge c o nc urre nt diseases, as a ut h orize d b y t he 
treati n g p h ysicia n; 
•  Oral, i m pla nta ble, or i njecta ble c o ntrace pti ves.  
Patie nts ta ki n g me dicati o n c hr o nicall y, i ncl u di n g A C E i n hi bit ors a n d A R Bs, s h o ul d be 
mai ntai ne d o n t h ose sa m e d oses a n d d ose s c he d ul es t hr o u g h o ut t he st u d y peri o d a n d s h o ul d n ot 
ha ve a d diti o ns or c h a n ges ma de t o t heir me dicati o ns, u nless me dicall y i n dicate d a n d disc uss e d 
wit h t he Me dical M o nit or.   
9. 4.  
Tre at me nt C o m pli a nce  
T he i n vesti gat or or his/ her desi g nate d a n d q ualifi e d re prese ntati ves will o nl y dis pe nse st u d y dr u g 
t o patie nt s e nr olle d i n t he st u d y i n acc or da n ce wit h t he pr ot oc ol.  T he st u d y dr u g m ust n ot be 
use d f or r eas o ns ot her t h a n t hat descri b e d i n t he pr ot oc ol. 
9. 5.  
R a n d o miz ati o n  
N ot a p plica ble.  
9. 6.  
Bli n di n g  
N ot a p plica ble.   


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9. 7.  
U nsc he d ule d Visits  
U nsc he d ule d visits are all o we d f or t he f oll o wi n g reas o ns: 
•  Assess me nt of wei g ht gai n per  Secti o n  9. 1. 1 ;  
•  Ma na ge me nt of a n A E or S A E; 
•  Perf or ma nce of a d diti o nal la b orat or y tests f or cli nicall y a b n or mal la b orat or y test 
val ues or t o c o nfir m a p ossi ble pre g na nc y; 
•  D ose re -escalati o n;  
•  D ose de- escalati o n;  
•  A n y ti me t he i n vesti gat or feels t hat it is cli nicall y a p pr o priate f or patie nt safet y.  
At a mi n i m u m, u nsc he d ule d visits s h o ul d i ncl u de c ollecti o n of A Es, cli nical c he mistr y, 
he mat ol o g y, c o nc o mita nt me dicati o ns a n d vital si g ns , as well as c ollecti o n/re vie w of w ei g ht 
diar y .  A d diti o nal c o n versati o ns ma y be necessar y wit h t he me dical m o nit or f oll o wi n g a n 
u nsc he d ule d visit t o assess patie nt safet y. 
9. 8.  
Pre g n a nc y  
9. 8. 1.  
W o m e n of C hil d be ari n g P ote nti al 
W o me n of c hil d beari n g p ote ntial ( W O C B P) are t h ose w h o are n ot s ur gicall y sterile ( n o hist or y 
of bilateral t u bal li gati o n, h ysterect o m y, or bilateral sal pi n g o - o o p h orect o m y) d o n ot ha ve 
fall o pia n i nserts wit h c o nfir me d bl oc ka g e, ha ve n ot ha d re pr o d u cti ve p ote ntial ter mi nate d b y 
ra diati o n, a n d are n ot p ost me n o pa usal f or at least 1 year. 
9. 8. 2.  
Met h o ds of Birt h C o ntr ol  
D uri n g Scree ni n g, w hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys f o ll o wi n g a d mi nistrati o n of t he fi nal 
d ose of st u d y me dicati o n, W O C B P m ust practice o ne of t he f oll o wi n g acce pta ble met h o ds of 
birt h c o ntr ol: 
•  Use d o u ble barrier c o ntrace pti o n met h o d defi ne d as male use of a c o n d o m a n d fe male 
use of a barrier m et h o d ( e. g., c ontrace pti ve s p o n g e, s per mici dal jell y or crea m, 
dia p hra g m [al w a ys use wit h s per mici dal jell y/crea m]);  
•  Use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal, or tra ns der mal) f or at least 
9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 
•  Use of a n i nt r a uteri ne d e vice; 
•  A bstai n fr o m se x ual i nter c o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nl y acce pt a ble if it is t he preferre d a n d us ual lifest yle of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d.   
D uri n g Scree ni n g, w hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys after t he fi nal d ose of st u d y 
me dicati o n is ta ke n, males w h o ha ve f e male part ners of c hil d beari n g p ote ntial m ust practice o n e 
of t he f oll o wi n g met h o ds of birt h c o ntr ol: 
•  Ha ve ha d a vasect o m y (at least 6 m o nt hs earlier);  


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•  Use d o u ble barrier c o ntrace pti o n met h o d, defi ne d as male use of a c o n d o m a n d 
fe male use of a barrier met h o d (e. g., c o ntrace pti ve s p o n ge, s per mici dal jell y or crea m, 
dia p hra g m [al w a ys use wit h s per mici dal jell y/crea m]);  
•  Part ner use of a n i ntra uteri ne de vice;  
•  Pa rt ner use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal or tra ns der mal) f or 
at least 9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 
•  A bstai n fr o m se x ual i nter c o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nl y acce pt a ble if it is t he preferre d a n d us ual lifest yle of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d.   
9. 8. 3.  
S us pecte d Pre g n a nc y  
D uri n g t he st u d y, all W O C B P m ust be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt (e. g., late or misse d me nstr ual peri o d).  Mal e patie nts m ust be 
i nstr ucte d t o c o ntact t he i n vesti gat or if a se x u al part ner s us pects s he m a y be pre g na nt. 
If a patie nt or i n v esti gat or s us pects t hat t he patie nt ma y be pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t h e res ults of a ser u m pre g na n c y test are a v aila ble.  If t h e ser u m pre g na nc y test 
c o nfir ms t he pre g n a nc y, t he patie nt m ust per ma ne ntl y disc o nti n ue ta ki n g st u d y dr u g.  T he 
i n vesti gat or m ust i m me diatel y re p ort t o t he me dical m o nit or a pre g na nc y ass ociate d wit h st u d y 
dr u g e x p os ure.  T h e earl y disc o nti n uati o n pr ot oc ol-re q uire d pr oce d ures o utli ne d f or E n d- of-
treat me nt a n d F oll o w- u p visits m ust be perf or me d o n t he patie nt.  
Pre g na nc y is n ot c o nsi dere d a n A E; h o w e ver, t he i n vesti gat or m ust f oll o w a pre g na nt p atie nt, or 
t he pre g na nt f e male part ner of a m ale patie nt (if c o nse nti n g), a n d re p ort f oll o w- u p i nf or mati o n 
re gar di n g t he c o urse of t he pre g na n c y, i ncl u di n g peri natal a n d n e o natal o utc o me.  I nfa nts 
res ulti n g fr o m s uc h pre g na ncies s h o ul d be f oll o w e d f or a mi ni m u m of 8 w ee ks.  Reata or 
desi g nee ma y c o nt act t he i n vesti gat or t o re q uest a d diti o nal i nf or mati o n t hr o u g h o ut t he c o urse of 
t he pre g na n c y. 
T he f oll o wi n g pre g na n c y o utc o mes m ust be c o nsi dere d S A Es a n d will re q uire a d diti o nal 
re p orti n g i n t he e C R F a n d re p orte d as a seri o us A E:  
•  C o n ge nital a n o mal y/ birt h defect; 
•  Still birt h;  
•  S p o nta ne o us miscarria g e. 
9. 9.  
Seri o us T o xicities  
I n t he cas e of seri o us t o xicities, t he i n vesti gat or ma y c h o ose t o i nterr u pt treat me nt wit h 
bar d o x ol o ne met h yl.  D ose re d ucti o ns are per mitte d t o ma na ge t olera bilit y iss ues.  Patie nts w h o 
res u me t hera p y aft er a n i nterr u pti o n will f oll o w t he ori gi nall y pla n ne d st u d y sc he d ule.  


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9. 1 0.  
St u d y Pr oce d ures  
T he f oll o wi n g secti o ns d escri be eac h assess me nt.  T he ti mi n g of t hese assess me nts is n ote d i n 
Ta ble 5 .  All Da y 1 pr o ce d ures, e xce pt A E ass ess me nts, s h o ul d be c o m plete d pri or t o 
a d mi nistrati o n of first d ose of st u d y dr u g. 
9. 1 0. 1.  
I nf or m e d C o nse nt 
Writte n i nf or me d c o ns e nt (see  Secti o n  1 5. 3 ) m ust be o btai ne d fr o m t he p atie nt bef ore a n y 
st u d y-relate d pr o ce d ur es are perf or m e d, a n d a g ai n if t here is a c h a n ge i n t h e st u d y pr oce d ures 
t hat w o ul d affect t he pati e nt’s willi n g ness t o partici pate. 
9. 1 0. 2.  
I ncl usi o n/ E xcl usi o n 
I n cl usi o n a n d e xcl usi o n criteria m ust be re vi e we d as i n dicate d i n Ta ble 5 .  Patie nts m ust meet all 
of t he i ncl usi o n a n d n o ne of t he e xcl usi o n criteria f or e ntr y i n t he st u d y.  I n vesti gat ors s h o ul d 
c o ntact t he me dical m o nit or wit h a n y q uesti o ns re gar di n g eli gi bilit y pri or t o ra n d o mizi n g t he 
patie nt o n Da y 1. 
9. 1 0. 3.  
De m o gr a p hics a n d B aseli ne Dise ase C h ar acteristics  
De m o gra p hic d ata i ncl u di n g se x, a ge, race, a n d et h nicit y, will be c ollecte d as i n dicate d i n  
Ta ble 5 .  Baseli ne disease c har acteristics will be c ollecte d as i n dicate d i n T a ble 5 .   
9. 1 0. 4.  
Pri or a n d C urre nt C o n c o mit a nt Me dic ati o ns  
T he na me, d ose, a n d fr e q ue nc y m ust be rec or de d f or all me dicati o ns t hat t he patie nt is ta ki n g.  
All al l o we d a n d e x cl u de d me dicati o ns s h o ul d be rec or d e d i ncl u di n g all prescri pti o n dr u gs, her b al 
pr o d ucts, vita mi ns, mi nerals, a n d o ver- t h e-c o u nt er me dicati o ns.  Tra de or ge neric dr u g n a mes 
s h o ul d be use d w her e p ossi ble.  C o nc o mita nt me dicati o ns will be re vie w e d as i n dicate d i n  
Ta ble 5  a n d all c h a n ges will be rec or d e d . 
9. 1 0. 5.  
Me dic al Hist or y  
A c o m plete me dical hist or y ( e. g., per patie nt re p ort) t hat i ncl u des all me dical hist or y wit hi n t he 
past 5 years m ust be c oll ecte d.  Me dical  hist or y will be rec or d e d as i n dicat e d i n Ta ble 5 .   
9. 1 0. 6.  
Hei g ht  
Hei g ht s h o ul d be meas ur e d wit h o ut f o ot wear or pr ost hetics as i n dicate d i n Ta ble 5 . 
9. 1 0. 7.  
Wei g ht a n d B o d y M ass I n de x ( B MI) 
Wei g ht m ust be meas ure d as i n dicate d i n Ta ble 5 .  B MI will be calc ulate d i n t he e C R F eac h ti me 
t he wei g ht is rec or d e d.  T he S p o ns or will pr o vi de eac h p atie nt wit h a scale t o use at h o me t o 
meas ure w ei g ht, a n d a di ar y will be pr o vi de d t o rec or d t he at- h o m e wei g ht meas ure me nts.  
Wei g hts rec or de d i n pati e nt diaries will n ot be e nt ere d i n t he e C R F.  Wei g hts s h o ul d be ta ke n at 
t he sa me ti me eac h da y a n d rec or d e d i n a patie nt diar y.  D uri n g t he first ei g ht wee ks, wei g hts 
will be rec or d e d dail y; w ee kl y wei g hts will be rec or de d t hereafter.  Patie nts will be i nstr ucte d t o 
st o p a d mi nisteri n g st u d y dr u g a n d c o ntact t he i n vesti gat or if t heir dail y wei g ht i ncreases d uri n g 
t he first 8 wee ks p er t he criteria o utli ne d i n Secti o n  9. 1. 1 .  Patie nts will be pr o vi de d i nstr ucti o ns 


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wit hi n t he I nf or me d C o nse nt F or m t o hel p e ns ure c o nsiste nt wei g ht c ollecti o n t hr o u g h o ut t he 
st u d y.  
9. 1 0. 8.  
Electr oc a r di o gr a ms ( E C G)  
A 1 2 -lea d E C G will be r ec or de d as i n dicat e d i n T a ble 5  after t he patie nt has reste d f or at least 
1 0 mi n utes i n a s u pi ne p ositi o n.  T he heart rat e fr o m t he E C G mac hi ne s h o ul d n ot be use d as part 
of t he vital si g n meas ure me nts.  
9. 1 0. 9.  
Ec h oc ar di o gr a m 
A n ec h ocar di o gr a m will be rec or de d as i n dicate d i n Ta ble 5  t o deter mi ne p atie nt eli gi bilit y.     
9. 1 0. 1 0.  
Vit al Si g n Me as ure m e nts  
Vital si g n meas ure me nts i ncl u de t he patie nt’s heart rate ( beats/ mi n ute ta ke n f or at least 
1 5 sec o n ds), r es pirati o n r ate, a n d b o d y te m perat ure.  Bl o o d press ure s h o ul d be ta ke n after t he 
patie nt has reste d i n a sitti n g p ositi o n f or at least 5 mi n utes.  T he sa me ar m ( us uall y t he n o n-
d o mi na nt ar m) a n d t he a p pr o priate size c uff s h o ul d be use d f or eac h meas ure me nt.  Vi tal si g n 
meas ure me nts s h o ul d be ta ke n as i n dicate d i n T a ble 5 .  
9. 1 0. 1 1.  
P h ysic al E x a mi n ati o n 
A c o m pre he nsi v e p h ysical e xa mi nati o n m ust be perf or me d b y a p h ysicia n, p h ysicia n assista nt, or 
re gistere d n urse pr actiti o ner as i n dicat e d i n Ta ble 5  a n d as d oc u me nte d wit hi n t he ta ble 
f o ot n otes.  T he e xa mi nati o n m ust i ncl u de t he f oll o wi n g or ga n or b o d y s yste m assess me nts: hea d, 
e yes, ears, n ose, t hr o at, m usc ul os keletal, car di o v asc ular, l y m p hatic, res pirat or y, a b d o me n, s ki n, 
e xtre mities, a n d ne ur ol o gical.  Assess me nts of a n y s pecific si g ns or s y m pt o ms re p orte d b y t he 
patie nt m ust als o be perf or me d a n d d oc u me nt e d al o n g wit h a n y ot her fi n di n gs of n ote.  Cli nicall y 
si g nifica nt fi n di n gs at Scree ni n g m ust be rec or d e d as me dical hist or y.  F oll o wi n g t he 
e xa mi nati o n at Scree ni n g, ne w or c h a n ge d p h ysical e xa mi nati o n fi n di n gs meeti n g t he defi niti o n 
of a n a d verse e v e nt m ust be re p ort e d as a n a d vers e e ve nt. If p ossi ble, t he sa me i n di vi d ual s h o ul d 
perf or m eac h p h ysical e x a mi nati o n o n a patie nt d uri n g t he st u d y. 
9. 1 0. 1 2.  
Pre g n a nc y Test  
W O C B P  (see Secti o n  9. 8 ) will c o m plete a pre g na n c y test as i n dicate d i n Ta ble 5 , or at a n y ti me 
if pre gna n c y is s us pecte d .  Ne gati ve test res ults are re q uire d o n Da y 1 b ef ore st u d y dr u g 
a d mi nistrati o n.  A n y patie nt w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue ta ki n g 
st u d y dr u g i m me diatel y.  See  Secti o n  9. 8. 3  f or a d escri pti o n of pr oce d ures t o be f oll o we d i n cas e 
of pre g na n c y. 
9. 1 0. 1 3.  
St u d y Dr u g A d mi nistr ati o n  
Patie nts s h o ul d self-a d mi nister o ne ca ps ule fr o m eac h b ottle i ncl u de d i n t he st u d y dr u g kit orall y 
o nce a d a y be gi n ni n g o n Da y 1 t hr o u g h t he e n d of t he st u d y, as i n dicate d i n  
Ta ble 5 .  Eac h d ose of st u d y dr u g s h o ul d be a d mi nistere d at a p pr o xi mat el y t he sa me ti me eac h 
da y, pref era bl y i n t he m or ni n g.  O n da ys w he n P K sa m ples are c ollecte d, p atie nts m ust n ot self -
a d mi nister st u d y dr u g.  St u d y staff will a d mi nister st u d y dr u g at t he cli nic f oll o wi n g c ollecti o n of 
t he first P K sa m ple.   


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A v o mite d d ose m ust n ot be re place d.  A d o u ble d ose ( e. g., misse d d ose fr o m pre vi o us da y a n d 
d ose f or c urre nt d a y) m ust n ot be ta ke n. 
9. 1 0. 1 4.  
St u d y  Dr u g Dis pe ns ati o n a n d C ollecti o n  
St u d y dr u g will be dis pe nse d t o t he patie nt a n d c ollecte d fr o m t he p atie nt as i n dicate d i n Ta ble 5 .  
T he patie nt will be dis pe nse d o ne treat me nt kit at Da y 1, Wee k 2, Wee k  4, Wee k  6 ( o nl y if 
baseli ne A C R > 3 0 0  m g/ g) a n d Wee k 8.  Dis pe ns e d treat me nt kits fr o m eac h visit s h o ul d be 
ret ur ne d t o t he site f or c ollecti o n at t he s u bse q ue nt visit. 
9. 1 0. 1 5.  
Tele p h o ne C o nt act  
Patie nts will be c o ntacte d b y tele p h o ne as i n dicat e d i n Ta ble 5 .  Patie nts will be as ke d a b o ut t heir 
b o d y wei g ht a n d ot her si g ns of fl ui d rete nti o n, as well as A Es a n d a n y c ha n ges t o c o nc o mita nt 
me dicati o ns.  If fl ui d ret e nti o n is s us pecte d, t he patie nt m ust be br o u g ht i nt o t he cli nic a n d 
e valuate d b y t he i n v esti gat or as s o o n as p ossi ble, as detaile d i n  Secti o n  9. 1. 1 . 
9. 1 0. 1 6.  
A d verse E ve nt C ollecti o n  
Patie nts will be o bser ve d f or ge neral a p p eara nce, prese nce of ill ness or i nj ur y, or si g ns i n dicati ve 
of a c o nc urre nt ill ness as i n dicate d i n Ta ble 5 .  Patie nts m ust be i nstr ucte d t o v ol u nteer a n y 
i nf or mati o n re gar di n g A Es o n or after t h e first d ose of st u d y dr u g or q uer y t he patie nts wit h a n 
o pe n q uesti o n re gar di n g a n y A Es t he y ma y be e x perie nci n g ( e. g., “ H o w h a ve y o u bee n feeli n g 
si nce y o ur last visit?”).  A n y fi n di n gs are t o be d o c u me nte d.  Patie nts m ust be as ke d if t he y h a ve 
bee n h os pitalize d, ha d a n y acci de nts, use d a n y ne w me dicati o ns, or c h a n ge d c o nc o mita nt 
me dicati o n re gi me ns (i ncl u di n g prescri pti o n dr u gs, o ver-t he-c o u nter m e dicati o ns, vita mi ns, 
her bal pr o d u cts, a n d mi nerals).  Res p o nses m ust b e d oc u me nte d i n t he s o urce d oc u me nts. 
9. 1 0. 1 7.  
Ki d ne y Bi o ps y  
Ki d ne y bi o psies will be perf or me d as i n dicate d i n Ta ble 5  f or p atie nts e nr olli n g i n t he I g A N or 
F S G S c o h orts t o deter mi ne patie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be pr o vi de d i n a 
se parat e la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or.   
9. 1 0. 1 8.  
F asti n g C- Pe pti de Le vels  
Fasti n g C- pe pti de le vels will be assesse d as i n dicate d i n Ta ble 5  f or p atie nts e nr olli n g i n t he T 1 D 
c o h ort t o deter mi ne p atie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be pr o vi de d i n a se parate 
la b orat or y ma n u al pr o vi de d t o t he i n vesti gat or. 
9. 1 0. 1 9.  
Ge netic Testi n g  
Ge netic testi n g f or P K D 1 m utati o ns f or patie nts e nr olli n g i n t he A D P K D c o h ort will be 
perf or me d as i n dicate d i n Ta ble 5  t o deter mi ne p atie nt eli gi bilit y.  Detaile d i nstr ucti o ns will be 
pr o vi de d i n a se parate la b orat or y ma n ual pr o vi d e d t o t he i n vesti gat or 
9. 1 0. 2 0.  
Cli nic al C he mistr y  
Sa m ples will be c ollecte d f or t he f oll o wi n g cli nical c he mistr y a nal yses as i n dicate d i n Ta ble 5 : 
ferriti n, cr eati ne ki nas e ( C K), B U N, e nz y matic creati ni ne, e G F R, T B L, direct bilir u bi n, A L T, 
A S T, A L P , s o di u m, p otassi u m, calci u m, p h os p h or us, uric aci d, t otal pr otei n, gl uc ose, al b u mi n, 


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




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


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1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
1 0. 1.  
St u d y Dr u g  
Bar d o x ol o ne met h yl ca ps ules , 5 m g  a n d 1 5 m g, will be use d i n t his st u d y. 
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
T he st u d y dr u g will be s u p plie d i n ta m per-e vi de nt kits c o ntai ni n g t w o hi g h- de nsit y p ol yet h yle ne 
( H D P E) b ottles.  Eac h b ottle will utilize f oil i n d ucti o n-seal li ners a n d a c hil d-resista nt cl os ure.  
Eac h b ottle of st u d y dr u g will c o ntai n 3 0 ca ps ules of 5 m g  or 1 5 m g stre n gt h bar d o x ol o ne met h yl 
or t he matc hi n g place b o ca ps ules.  Eac h b ottle will als o c o ntai n a desicca nt i nsert t hat m ust n ot 
be i n geste d.  La b eli n g o n eac h kit b ottle will c o ntai n at mi ni m u m t he f oll o wi n g i nf or mati o n:  
•  Me dicati o n I D n u m ber; 
•  Pr ot oc ol 4 0 2- C- 1 7 0 2; 
•  Ca uti o n State me nt: Ne w Dr u g – Li mite d b y Fe d e ral La w t o I n vesti gati o nal Use.  
Kee p o ut of si g ht a n d r eac h of c hil dre n; 
•  C o ntr ol or l ot n u m ber; 
•  St ore at 2 0° – 2 5° C ( 6 8° – 7 7° F), s h ort ter m e xc ursi o ns all o we d t o 1 5° – 3 0° C ( 5 9° – 
8 6° F); 
•  Reata P har mace uticals, I nc., Ir vi n g, T X. 
A d o u ble- pa n el la bel will be prese nt e d o n t he treat me nt kit cart o n c o ntai ni n g t his a n d ot her 
i nf or mati o n as well.   
1 0. 3.  
St u d y Dr u g St or a ge  
T he sta bilit y of t he dr u g pr o d uct has bee n a n d is c urre ntl y bei n g e v al uate d i n o n g oi n g st u dies. 
I n v esti gati ve sites m ust st ore t he i n vesti gati o nal pr o d uct i n a sec ure l ocati o n wit h r o o m 
te m perat ur e c o n diti o ns of 2 0° - 2 5° C ( 6 8° - 7 7° F), wit h s h ort ter m e xc ursi o ns all o we d t o 1 5° – 
3 0° C ( 5 9° – 8 6° F).   
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
Please ref er t o  Secti o n  9. 1 0. 1 3  f or details o n st u d y dr u g a d mi nistrati o n.  Clear i nstr ucti o ns will 
be pr o vi de d t o t he patie nt re gar di n g t he n u m b er a n d t y pe of ca ps ules t o be i n geste d at eac h st u d y 
dr u g a d mi nistrati o n ti me p oi nt liste d i n Ta ble 5 .  Patie nts m ust be i nstr ucte d t o c o nti n ue ta ki n g 
st u d y dr u g o nce dail y u p t hr o u g h t heir Wee k 1 2 visit u nless: ( 1) t he patie nt has bee n ot her wise 
i nstr ucte d b y t he i n vesti gat or or ( 2) t h e patie nt has bee n f or m all y disc o nti n ue d fr o m st u d y 
treat me nt.    


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


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1 1.  
S A F E T Y A S S E S S M E N T S 
1 1. 1.  
S afet y P ar a meters  
T o a v oi d i n ter- o bser v er v aria bilit y, e ver y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns c o m pletes all safet y assess me nts.  Safet y 
para meters i ncl u de vital si g n meas ure me nts, E C G res ults, A Es, S A Es, wei g ht, a n d la b orat or y 
test res ults (cli nical c he mistr y, he mat ol o g y, uri nal ysis a n d micr osc o p y).  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts  
1 1. 2. 1.  
Defi niti o n of A d verse E ve nts  
1 1. 2. 1. 1.  A d verse E ve nt  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a p atie nt re g ar dless of its ca usal 
relati o ns hi p t o st u d y dr u g.  A n A E ca n b e a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n y 
cli nicall y si g nifica nt a b n or mal la b orat or y test res ult), s y m pt o m, or disease te m p orall y ass ociate d 
wit h t he use of t he st u d y dr u g, w het her or n ot it is c o nsi dere d t o be st u d y- dr u g relate d.  I n cl u de d 
i n t his defi niti o n are a n y ne wl y- occ urri n g e v e nts or pre vi o us c o n diti o n t hat has i ncrease d i n 
se verit y or fr e q ue n c y si nce t he a d mi nistrati o n of st u d y dr u g. 
All A Es t hat are o bser ve d or re p orte d b y t he patie nt d uri n g t he st u d y (fr o m ti me of 
a d mi nistrati o n of t he first d ose at t he Da y 1 visit u ntil t he fi nal visit i n dicate d i n Ta ble 5  m ust be 
re p orte d, r e gar dless of t h eir relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce. 
1 1. 2. 1. 2.  Seri o us A d verse E ve nt  
A n S A E is a n y A E occ urri n g at a n y d ose a n d re gar dless of ca us alit y t hat: 
•  Res ults i n deat h; 
•  Is life-t hreate ni n g; 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
•  Res ults i n persiste nt or si g nifica nt i nca pacit y  or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u n cti o ns; 
•  Is a c o n ge nital a n o mal y or birt h defect i n a n offs pri n g of a patie nt ta ki n g st u d y dr u g; 
•  Is a n i m p orta nt me dical e ve nt.  
T he ter m "life -t hr eate ni n g" refers t o a n e ve nt i n w hic h t he patie nt was at i m me diate ris k of deat h 
at t he ti me of t he e ve nt.  It d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e ver e. 
I m p ort a nt me dical e v e nts are t h ose t hat ma y n ot m eet a n y of t he criteri a defi ne d a b o ve; h o wev er, 
t he y ma y be c o nsi dere d s eri o us w he n, bas e d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y 
je o par dize t h e patie nt a n d ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he S A E defi niti o n. 


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Pre g na nc y is n ot c o nsi dere d a n A E; h o w e ver, i nf or mati o n will be c ollecte d f or a n y pre g na nci es 
t hat occ ur d uri n g t he st u d y (fr o m t he ti me of t he first d ose of st u d y dr u g u ntil t he fi nal visit 
i n dicate d i n Ta ble 5  or u ntil 3 0 da ys f oll o wi n g a d mi nistrati o n of t he fi nal d ose, as a p pr o priate ).  
Certai n pre g na n c y o utc o mes will re q uire s u b missi o n as a n S A E. ( See  Secti o n  9. 8 ). 
T he i n vesti gat or is res p o nsi ble f or re p orti n g t o Reata or desi g nee all A Es a n d S A Es t hat are 
o bser ve d or re p ort e d b y t he patie nt d uri n g t he st u d y (fr o m t he ti me of a d mi nistrati o n of t he first 
d ose of st u d y dr u g u ntil t he fi nal visit i n dicate d i n Ta ble 5  or u ntil 3 0 da ys f oll o wi n g 
a d mi nistrati o n  of t he fi nal d ose, as a p pr o pri ate), i n cl u di n g e ve nts res ulti n g fr o m pr ot oc ol-
ass ociate d pr o ce d ur es as defi ne d i n rel e va nt le gislati o n, a n d re gar dless of t heir relati o ns hi p t o 
st u d y dr u g or t heir cli nical si g nifica nce.  T h e S p o ns or ma y re q u est a d diti o nal i nf or mati o n fr o m 
t he i n vesti gat or t o e ns ure t he ti mel y c o m pleti o n of acc urate safet y re p orts. 
All S A Es re p orte d or o bs er ve d d uri n g t he st u d y m ust be f oll o we d t o res ol uti o n or u ntil t he 
i n vesti gat or dee ms t he e v e nt t o be c hr o nic or t he p atie nt t o be sta ble.  Reata or desi g nee ma y 
c o ntact t he i n vesti gat or t o o btai n a d diti o nal i nf or mati o n o n a n y S A E w hic h has n ot res ol ve d at 
t he ti me t he patie nt c o m pletes t he st u d y. 
1 1. 3.  
Eliciti n g A d verse E ve nt I nf or m ati o n  
At e ver y st u d y visit, patie nts m ust be as ke d a sta n dar d, n o n- directe d q uesti o n, s uc h as, “ H o w 
ha ve y o u bee n feeli n g si nce y o ur last visit?” t o elicit a n y me dicall y relate d c ha n ges i n t heir 
well - bei n g.  T he y ma y als o be as ke d if t he y h a ve bee n h os pitalize d, ha d a n y acci de nts, use d a n y 
ne w me dicati o ns, or c ha n ge d c o nc o mita nt me dicati o n re gi me ns (i ncl u di n g prescri pti o n dr u gs, 
o ver-t he- c o u nter m e dicati o ns, vita mi ns, her bal pr o d ucts, a n d mi nerals).  Res p o nses m ust be 
d oc u me nte d i n t he s o urce d oc u me nts. 
I n a d diti o n t o patie nt o bser vati o ns, A Es m ust be d oc u me nte d f or a n y cli nicall y si g nifica nt 
dia g n osis res ulti n g fr o m a b n or mal la b orat or y test val ues, p h ysical e x a mi nati o n fi n di n gs, or E C G 
a b n or malities, or fr o m ot her d oc u me nts t hat are rele va nt t o patie nt safet y. 
1 1. 4.  
Assess me nt of C a us alit y  
T he i n vesti gat or m ust use t he f oll o w i n g classificati o ns a n d criteria t o c h aracterize t h e 
relati o ns hi p or ass ociati o n of t he st u d y dr u g i n ca usi n g or c o ntri b uti n g t o t he A E: 
N ot Relate d : T his relati o ns hi p s u g gests t hat t here is n o ass ociati o n bet wee n t he st u d y dr u g a n d 
t he re p orte d e ve nt. 
U nl i kel y Relate d : T his relati o ns hi p s u g gests t hat t he te m p oral se q u e nce of t he e ve nt wit h st u d y 
dr u g a d mi nistrati o n ma kes a ca us al relati o ns hi p i m pr o ba ble a n d/ or ot her fact ors als o pr o vi de 
pla usi ble e x pla nati o ns. 
P ossi bl y Relate d : T his relati o ns hi p s u g gests t hat treat me nt wit h t he st u d y dr u g ca use d or 
c o ntri b ute d t o t he A E.  T hat is, t he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m t he ti me 
of st u d y dr u g a d mi nistrati o n, a n d/ or, f oll o ws a k n o w n res p o nse p atter n t o t he st u d y dr u g, b ut 
c o ul d ha ve bee n pr o d uce d b y ot her fact ors. 
Pr o ba bl y Relate d : T his relati o ns hi p s u g gests t hat a reas o n a ble te m p oral se q ue nce of t h e e ve nt 
wit h st u d y dr u g a d mi nistrati o n e xists a n d, base d u p o n t he k n o w n p har mac ol o gical acti o n of t he 
dr u g, k n o w n or pr e vi o usl y re p orte d a d vers e reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt 


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base d o n t he i n vesti gat or’s cli nical e x perie nce, t he ass ociati o n of t he e v e nt wit h st u d y dr u g 
a d mi nistrati o n see ms li kel y.  
Defi nitel y Relate d : T his relati o ns hi p s u g gests t hat a defi nite ca usal rel ati o ns hi p exists bet wee n 
t he dr u g a d mi nistrati o n a n d t he A E, a n d ot her c o n diti o ns (e. g., c o nc urre nt ill ness, 
pr o gressi o n/e x pr essi o n of disease state, or c o nc urre nt me dicati o n reacti o n) d o n ot a p pear t o 
e x plai n t he e ve nt. 
1 1. 5.  
Assess me nt of Se verit y  
T he i n vesti gat or will g ra de t he se verit y of t he A Es as mil d, m o derate, or se vere usi n g t he 
f oll o wi n g defi niti o ns: 
Mil d: S y m pt o ms ca usi n g n o or mi ni mal i nterfere n ce wit h us ual s ocial a n d f u ncti o nal acti vities  
M o derate : S y m pt o ms ca usi n g greater t ha n mi ni m al i nterfere nce wit h us ual s ocial a n d f u ncti o nal 
acti vities 
Se vere : S y m pt o ms ca usi n g i na bilit y t o perf or m us ual s ocial a n d f u n cti o nal acti vities  
1 1. 6.  
Rec or di n g A d verse E ve nts  
All c o n diti o ns prese nt pri or t o t he a d mi nistrati o n of t he first d ose of st u d y dr u g ( Da y 1) s h o ul d 
be d oc u me nte d as me dical hist or y.  After t he first d ose, d oc u me ntati o n of A Es s hall c o nti n ue 
u ntil 3 0 da ys ( +/- 3 da ys) f oll o wi n g a d mi nistrati o n of t he fi nal d ose of st u d y me dicati o n, 
re gar dl ess of t he r elati o ns hi p of t he A E t o st u d y dr u g.  I nf or mati o n t o be c ollecte d i ncl u des t y pe 
of e ve nt, date of o nset, d ate of r es ol uti o n, i n vesti gat or- s pecifie d assess me nt of se verit y a n d 
relati o ns hi p t o st u d y dr u g, seri o us ness, as well as a n y acti o n ta ke n.  
W hile a n A E is o n g oi n g, c ha n ges i n t he se v erit y ( e. g., w orse ni n g a n d i m pr o vi n g) s h o ul d be 
n ote d i n t he s o urce d o c u me nts, b ut w he n d oc u me nti n g t he A E, o nl y t he t otal d urati o n a n d 
greatest se v erit y s h o ul d be rec or de d i n t he e C R F.  A Es c haracterize d as i nter mitte nt re q uire 
d oc u me ntati o n of o nset a n d d urati o n. 
All dr u g- relate d ( p ossi bl y, pr o ba bl y, or defi nitel y relate d, see Secti o n  1 1. 4 ) A Es a n d a b n or m al 
la b orat or y test r es ults re p orte d or o bser v e d d uri n g t he st u d y m ust be f oll o we d t o res ol uti o n 
(eit her r et ur n t o baseli ne or wit hi n n or mal li mits).  All ot her A Es will be f oll o we d t hr o u g h t he 
fi nal visit i n dicate d i n Ta ble 5 , as a p pr o priate. 
A Es res ulti n g fr o m c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt 
me dicati o ns, or pr o gr essi o n of disease states m ust als o be re p ort e d.  Pree xisti n g c o n diti o ns 
( prese nt bef ore t h e start of t he A E c ollecti o n peri o d) are c o nsi dere d c o nc urre nt me dical 
c o n diti o ns a n d s h o ul d N O T be rec or de d as A Es.  H o we ver, if t he patie nt e x perie nces a 
w ors e ni n g or c o m plicati o n of s uc h a c o n c urre nt c o n diti o n, t he w orse ni n g or c o m plicati o n s h o ul d 
be rec or de d as a n A E.  I n vesti gat ors s h o ul d e ns ure t hat t he A E ter m rec or d e d ca pt ures t he 
c ha n ge i n t he c o n diti o n ( e. g., “ w ors e ni n g of …”).  A n y i m pr o ve me nt i n c o n diti o n s h o ul d be 
d oc u me nte d per  Secti o n  9. 1 0. 1 1 . 
Eac h A E s h o ul d be rec or de d t o re pr ese nt a si n gle dia g n osis.  Acc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b or at or y test val ues or E C G fi n di n gs) or s y m pt o ms s h o ul d N O T be rec or de d as 
a d diti o nal A Es.  If a dia g n osis is u n k n o w n, si g n(s) or s y m pt o m(s) s h o ul d be rec or d e d as a n 


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A E(s).  C ha n ges i n la b or at or y test val ues or E C G para meters are o nl y c o nsi dere d A Es if t he y are 
j u d ge d t o be cli nicall y si g nifica nt (i.e., if s o me acti on or i nter ve nti o n is re q uire d or if t he 
i n vesti gat or j u d ges t he c ha n ge t o be be y o n d t h e ra n ge of n or m al p h ysi ol o gical fl uct uati o n).  If 
a b n or mal la b or at or y test val ues or E C G fi n di n gs are t he res ult of pat h ol o g y f or w hic h t here is a n 
o verall dia g n osis ( e. g., i n creas e d cr eati ni ne le v els i n re nal fail ure), o nl y t he dia g n osis s h o ul d be 
re p orte d as a n A E. 
Electi ve pr oce d ures (s ur g eries or t hera pies) t h at w ere sc h e d ule d pri or t o t he start of A E 
c ollecti o n are n ot c o nsi dere d A Es.  T h ese electi ve pr oce d ures s h o ul d n ot be rec or de d as A Es, b ut 
s h o ul d be d oc u me nte d i n t he patie nt’s s o urce d oc u me nts as electi ve (e. g., el ecti ve peri o d o ntal 
s ur ger y).  H o we ver, if a pre- pla n n e d pr oce d ure is perf or me d earl y (e. g., as a n e mer g e nc y) 
beca use of a w orse ni n g of t he pree xisti n g c o n diti o n, t he w orse ni n g of t he c o n diti o n s h o ul d be 
ca pt ure d as a n A E.  
1 1. 7.  
Re p orti n g Seri o us A d verse E ve nts  
A n y A E t he i n vesti gat or c o nsi ders seri o us acc or di n g t o t he pre vi o usl y descri be d criteri a m ust be 
re p orte d wit hi n 2 4 h o urs fr o m t he ti me t he site pers o n nel first lear n a b o ut t h e e ve nt.  
T o re p ort t he S A E, f a x t he c o m plete d S A E f or m t o Me d pace (fa x n u m b ers liste d i n Ta ble  7) 
wit hi n 2 4 h o urs of a war e ness. 
T a ble 7: 
S A E Re p orti n g C o nt act I nf or m ati o n 
  
 
 
 
F or q uesti o ns re g ar di n g S A E re p orti n g, c o nt act y o ur st u d y m a n a ger, me dic al m o nit or, or 
Me d p ace Cli nic al S afet y . 
F oll o w- U p Re p orts  
T he i n vesti gat or m ust c o nti n ue t o f oll o w t he s u bject u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o mes c hr o nic i n nat ure, sta bilizes (i n t he case of persiste nt i m pair me nt) , or t he 
s u bject dies. 
Wit hi n 2 4 h o urs of recei pt of ne w i nf or mati o n, t h e u p date d f oll o w- u p S A E f or m, al o n g wit h a n y 
s u p p orti n g d oc u me ntati o n (e. g., s u bject disc har ge s u m mar y or a ut o ps y re p orts), s h o ul d be fa x e d 
t o Me d pace Cli nical Saf et y . 
T he S p o ns or or desi g nee will n otif y re g ulat or y a ge ncies of a n y fatal or life-t hreate ni n g 
u ne x pecte d e ve nts ass oci ate d wit h t he use of t he st u d y dr u g as s o o n as p ossi ble b ut n o later t ha n 
7 cale n da r da ys after t he i nitial recei pt of t he i nf or mati o n.  I nitial n otificati o n will be f oll o we d b y 
a writte n re p ort wit hi n t he ti mefra me esta blis he d b y t he a p pr o priat e re g ulat or y a ge nc y.  F or ot her 
S A Es t hat d o n ot meet t he fatal or lif e -t hreate ni n g u ne x pecte d criteria, b ut are re p orte d t o be 
ass ociate d wit h t he use of t he st u d y dr u g, Reata or desi g nee will n otif y t he a p pr o priate re g ulat or y 
a ge ncies i n writi n g wit hi n t he ti mefra me est a blis he d b y t h ose re g ulat or y a g e ncies.  Reat a or 
desi g nee will pr o vi de c o pies of a n y re p orts t o re g ulat or y a ge nci es re g ar di n g seri o us a n d 


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u ne x pecte d S A Es t o t he i n vesti gat ors f or re vie w a n d s u b missi o n t o t heir i nstit uti o nal re vie w 
b oar d (I R B) or Et hics C o m mittee ( E C), as a p pr o priate.  
Pri nci pal i n vesti gat ors ar e res p o nsi ble f or i nf o r mi n g t heir I R B/ E C of a n y S A Es at t heir site.  
S A E c orres p o n d e nce wit h re g ulat or y a ut h orities or I R Bs/ E Cs m ust be s u b mitte d t o t he S p o ns or 
or desi g nee f or rec or di n g i n t he st u d y file. 
N ote t hat t he f oll o wi n g A Es  w hic h ar e c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n will n ot be 
re p orte d t o r e g ulat or y a ut h orities as i n di vi d ual e x pe dite d re p orts, e x ce pt i n u n us ual 
circ u msta nces . 
•  H y p ote nsi o n 
•  H y per kale mia  
•  Fati g ue 
•  E de ma/fl ui d rete nti o n  
T hese e v e nts will be re vi e we d o n a re g ular basis i n a g gre gat e a n d will be re p orte d i n a n 
e x pe dite d ma n ner if a saf et y si g nal is detecte d.  Re g ular safet y st u d y u p dat es will be re p orte d t o 
re g ulat or y a ut h orities acc or di n g t o l ocal g ui deli nes. 






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1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
1 3. 1.  
St u d y M o nit ori n g  
T he st u d y m o nit or, as a r e prese nt ati ve of t he S p o ns or, is o bli gate d t o f oll o w t he st u d y c o n d uct 
cl osel y.  I n d oi n g s o, t he m o nit or will visit t he pri nci pal i n vesti gat or a n d st u d y facilities 
peri o dicall y, a n d will mai ntai n necessar y t ele p h o n e a n d letter c o ntact.  T he m o nit or will mai ntai n 
c urre nt k n o wl e d ge of t he st u d y acti vit y of t he i n vesti gat or a n d his/ her staff t hr o u g h o bser vati o n, 
re vie w of st u d y r ec or ds a n d s o urce d oc u m e ntati o n, a n d disc ussi o n of t he c o n d uct of t he st u d y 
wit h t he i n vesti gat ors a n d staff. 
T he S p o ns or or desi g nee will m o nit or all as pects of t he st u d y f or c o m plia nce wit h a p plica ble 
g o ver n me nt re g ul ati o n wit h res pect t o t he I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
g ui deli ne E 6( R 1): G o o d Cli nical Practice: C o ns oli date d G ui deli ne a n d c urre nt sta n dar d o perati n g 
pr oce d ur es. 
Eac h i n vesti gat or is e x p ecte d t o ma ke a reas o n a bl e eff ort t o acc o m m o dat e t he m o nit or w he n 
m o nit ori n g visits are necessar y a n d t o b e a vaila bl e d uri n g t he site visit.  F urt her m ore, t he 
m o nit or s h o ul d be pr o vi de d direct access t o s o urce data a n d d oc u m e nts f or trial- relat e d 
m o nit ori n g a n d i nter net d ur i n g t he visit. 
1 3. 2.  
A u dits a n d I ns pecti o ns  
Pri nci pal i n vesti gat ors a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit st u d y-relate d 
m o nit ori n g, a u dits, a n d I R B / E C re vie w, a n d re g ul at or y i ns pecti o ns, b y pr o vi di n g direct access t o 
all st u d y rec or ds.  I n t he e ve nt of a n a u dit, t he pri nci pal i n vesti gat or a grees t o all o w t he S p o ns or, 
re pres e ntati ves of t he S p o ns or, t he U S F o o d a n d Dr u g A d mi nistrati o n (F D A ), a n d ot her rele v a nt 
re g ulat or y a ut h orities access t o all st u d y rec or ds. 
T he pri nci pal i n vesti gat or s h o ul d pr o m ptl y n otif y t he S p o ns or or desi g nee of a n y a u dits 
sc he d ule d b y a n y re g ulat or y a ut h orities a n d pr o m ptl y f or war d c o pies of a n y a u dit re p orts 
recei v e d t o t he S p o ns or or desi g nee. 


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


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


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


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


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


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


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


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R E F E R E N C E S  
A mi nza de h M A, Reis ma n S A, Vaziri N D, et al. T he s y nt hetic triter pe n oi d R T A d h 4 0 4 ( C D D O-
d h T F E A) rest ores e n d ot h elial f u ncti o n i m paire d b y re d uce d Nrf 2 acti vit y i n c hr o nic ki d ne y 
disease.  Re d o x Bi ol 2 0 1 3; 1: 5 2 7- 3 1. 
de Zee u w D, A kiza wa T, A u d h ya P, et al. Bar d o x ol o ne met h yl i n t y pe 2 dia betes a n d sta g e 4 
c hr o nic ki d ne y disease.  N E n gl J Me d 2 0 1 3; 3 6 9: 2 4 9 2- 5 0 3. 
Di n g Y, Sti d ha m R D, B u meister R, et al. T he s y nt hetic triter pe n oi d, R T A 4 0 5, i ncreas es t he 
gl o mer ular filtrati o n rat e a n d re d uces a n gi ote nsi n II-i n d uce d c o ntr acti o n of gl o mer ula r mesa n gial 
cells.  Ki d ne y I nt 2 0 1 3; 8 3: 8 4 5- 5 4. 
Di n k o va- K ost o va A T, Li b y K T, Ste p he ns o n K K, et al. E xtre mel y p ote nt triter pe n oi d i n d ucers of 
t he p hase 2 r es p o nse: c orrelati o ns of pr otecti o n a g ai nst o xi da nt a n d i nfla m mat or y stress.  
Pr oc  Natl Aca d Sci U S A 2 0 0 5; 1 0 2: 4 5 8 4- 9. 
Fer g us o n D A, Wi gle y W C, Heiss E. Bar d o x ol o ne met h yl ( B A R D) i m pr o ves mar kers of 
e n d ot helial f u ncti o n i n c ult ure d cells.  P oster A m erica n S ociet y of Ne p hr ol o g y ( A S N) 2 0 1 0. 
Jia n g T, Tia n F, Z h e n g H, et al. Nrf 2 s u p press es l u pus ne p hritis t hr o u g h i n hi biti o n of o xi dati ve 
i nj ur y a n d t he N F- k B- me diate d i nfla m mat or y res p o nse.  Ki d ne y I nt 2 0 1 4; 8 5: 3 3 3- 4 3. 
Ki d ne y Disease: I m pr o vi n g Gl o bal O utc o mes ( K DI G O) Bl o o d Press ure W or k Gr o u p. K DI G O 
Cli nical Practice G ui deli ne f or t he Ma na ge me nt of Bl o o d Press ure i n C hr o nic Ki d ne y 
Disease.  Ki d ne y I nt S u p pl  2 0 1 2; 2: 3 3 7 – 4 1 4. 
Lee D - F, K u o H- P, Li u M, et al. K E A P 1 E 3 li gase- me diate d d o w nre g ulati o n of N F- k B si g nali n g 
b y tar geti n g I K K ß.  M olec ular Cell 2 0 0 9; 3 6: 1 3 1- 4 0. 
Ma Q, Battelli L, H u b bs A F. M ulti or ga n a ut oi m m u ne i nfl a m mati o n, e n ha n ce d 
l y m p h o pr oliferati o n, a n d i m paire d h o me ostasis of reacti ve o x y g e n s pecies i n mice lac ki n g t he 
a nti o xi da nt-acti vate d tr a nscri pti o n fact or Nrf 2.  A m J Pat h ol 2 0 0 6; 1 6 8: 1 9 6 0- 7 4. 
Os b ur n W O & Ke nsl er T W. Nrf 2 si g nali n g: A n a d a pti ve res p o nse p at h wa y f or pr otecti o n a g ai nst 
e n vir o n me ntal t o xic i ns ults.  M utat Res 2 0 0 8; 6 6 9: 3 1- 9. 
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 betes.  N E n gl J Me d 2 0 1 1; 3 6 5: 3 2 7- 3 6. 
Ratitc h  B, O’ Kell y M, T osiell o R. Mi ssi n g data i n cli nical trials: fr o m cli nical ass u m pti o ns t o 
statistical a nal ysis usi n g patter n mi xt ure m o dels.  P har m Stat 2 0 1 3; 1 2: 3 3 7- 4 7. 
R ojas - Ri vera J, Ortiz A, E gi d o J. A nti o xi da nts i n ki d ne y diseases: T he i m p act of bar d o x ol o ne 
met h y l.  I nt J Ne p hr ol 2 0 1 2; 2 0 1 2: 1- 1 1. 
Sa ha P, Re d d y V, K o n o ple va M, et al. T he triter p e 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. 
Ta na ka Y, Al e ks u nes L M, G oe d ke n MJ, et al. C o or di nate d i n d ucti o n of Nrf 2 tar g et ge nes 
pr otects a gai nst ir o n nitril otriacetate ( Fe N T A) -i n d uce d ne p hr ot o xicit y.  T o xic ol A p pl P har mac ol 
2 0 0 8; 2 3 1: 3 6 4- 7 3. 


Pr ot o c ol 4 0 2 - C-1 7 0 2  
Reata P har mace uticals, I nc.  
C o nfi de ntial  
Versi o n 1 . 0 
6 6   
W u Q Q, Wa n g Y, Se nit k o M, et al. Bar d o x ol o ne met h yl ( B A R D) a meli orates isc he mic A KI a n d 
i ncreas es e x pr essi o n of pr otecti ve ge n es Nrf 2, P P A R ga m ma, a n d H O- 1.  A m J P h ysi ol Re nal 
P h ysi ol 2 0 1 1; 3 0 0: F 1 1 8 0- F 1 1 9 2. 
Y o h K, It o h K, E n o m ot o A, et al. Nrf 2 -d eficie nt fe male mice de vel o p l u p us -li ke a ut oi m m u ne 
ne p hritis.  Ki d ne y I nt 2 0 0 1; 6 0: 1 3 4 3- 5 3. 
Z oja C, C or na D, L ocat elli M, et al. Tar geti n g Kea p 1-Nrf 2 Pat h w a 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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R e at a C o nfi d e nti al  
St atistic al A n al ysis Pl a n  
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P A TI E N T S WI T H R A R E C H R O NI C KI D N E Y DI S E A S E S  
Versi o n: 2. 0 
Date: J ul y 1 3, 2 0 1 8 
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 u c h 
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R e at a C o nfi d e nti al  
T A B L E O F C O N T E N T S  
1.  List of A b bre viati o ns a n d Defi niti o ns of Ter ms  ..................................................................................... 6 
2.  Re visi o n Hist or y a n d Rele va nt D oc u me nts ............................................................................................ 8  
3.  P ur p ose of T he A nal ysis Pla n................................................................................................................. 8  
4.  St u d y O bjecti ves a n d E n d p oi nts ........................................................................................................... 1 0  
4. 1.  O bjecti ves  ................................................................................................................................... 1 0 
4. 1. 1.  Pri mar y O bjecti ve  .......................................................................................................... 1 0 
4. 2.  E n d p oi nts .................................................................................................................................... 1 0  
4. 2. 1.  Pri mar y Efficac y E n d p oi nt ............................................................................................ 1 0  
 
 .................................................................................... 1 0 
4. 2. 3.  Safet y E n d p oi nts ............................................................................................................ 1 0  
5.  St u d y Desi g n ........................................................................................................................................ 1 0  
5. 1.  O verall St u d y Desi g n .................................................................................................................. 1 0  
5. 2.  Ra n d o mizati o n a n d D osi n g......................................................................................................... 1 1  
5. 3.  Assess me nts  ................................................................................................................................ 1 1 
5. 3. 1.  Effic ac y Meas ure me nt a n d Varia ble  ............................................................................. 1 5 
5. 3. 2.  Safet y Meas ure me nts a n d Varia bles  .............................................................................. 1 5 
5. 3. 3.  P har mac o ki netics Meas ure me nts a n d Varia bles ............................................................ 1 5 
6.  Sa m ple size a n d P o wer  ......................................................................................................................... 1 5 
7.  Ge neral C o nsi derati o ns ........................................................................................................................ 1 5  
7. 1.  Deri ve d Varia bles  ....................................................................................................................... 1 6 
7. 1. 1.  A ge  ................................................................................................................................ 1 6 
7. 1. 2.  St u d y Da y ...................................................................................................................... 1 6  
7. 1. 3.  Esti mate d Gl o mer ular Filtrati o n Rate  ............................................................................ 1 7 
7. 1. 4.  Uri ne Al b u mi n a n d Uri ne Al b u mi n t o Creati ni ne  Rati o ................................................ 1 7 
7. 1. 5.  Electr ocar di o gra m Fri dericia C orrecte d Q T I nter val..................................................... 1 7  
7. 2.  Baseli ne Val ues  .......................................................................................................................... 1 8 
7. 2. 1.  Esti mate d Gl o mer ular Filtrati o n Rate  ............................................................................ 1 8 
7. 2. 2.  Ser u m Creati ni ne  ........................................................................................................... 1 8 
7. 2. 3.  Vital Si g n A ssess me nts ................................................................................................. 1 8 
7. 2. 4.  Al b u mi n/ Creati ni ne Rati o ( A C R)  .................................................................................. 1 8 
7. 2. 5.  Nat ural l o g ( A C R)/e G F R  ............................................................................................... 1 8 
7. 3.  A nal ysis Wi n d o ws  ...................................................................................................................... 1 9 
8.  A nal ysis Sets  ........................................................................................................................................ 2 0 
8. 1.  Safet y A nal ysis Set  ..................................................................................................................... 2 0 
8. 2.  I T T A nal ysis Set ......................................................................................................................... 2 0 
8. 3.  Off -Treat me nt A nal ysis Sets  ...................................................................................................... 2 0 
8. 4.  P har mac o ki netics A nal ysis Set  ................................................................................................... 2 0 
9.  St u d y P o p ulati o n .................................................................................................................................. 2 0  


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9. 1.  Patie nt Dis p ositi o n  ...................................................................................................................... 2 0 
9. 2.  Pr ot oc ol De viati o ns .................................................................................................................... 2 1  
9. 3.  De m o gra p hics a n d Baseli ne C haracteristics  ............................................................................... 2 1 
9. 4.  Me dical Hist or y  .......................................................................................................................... 2 2 
1 0.  St u d y Dr u g a n d Ot her Me dicati o ns ...................................................................................................... 2 2  
1 0. 1.  Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................................... 2 2  
1 0. 2.  D urati o n of St u d y Treat me nt a n d E x p os ure t o St u d y Dr u g ........................................................ 2 3  
1 1.  Efficac y A nal yses  ................................................................................................................................. 2 3 
1 1. 1.  Pri mar y Efficac y A nal ysis  .......................................................................................................... 2 3 
1 1. 1. 1.  Statistical H y p ot hesis  .................................................................................................... 2 4 
1 1. 1. 2.  Statistical M o del  ............................................................................................................ 2 4 
1 1. 1. 3.  Re p orti n g Res ults .......................................................................................................... 2 4  
1 1. 2.  A d diti o nal Efficac y A nal yses ..................................................................................................... 2 5  
 .............................................................................. 2 5 
1 1. 2. 2.  Hist orical e G F R Sl o pe Dataset  ...................................................................................... 2 6 
1 1. 2. 3.  Statistical M o del  ............................................................................................................ 2 7 
 ............................................................................ 2 8 
 .................................................... 2 8 
1 1. 3.  Se nsiti vit y A nal yses ................................................................................................................... 2 8  
 ................................................................................................. 2 9 
1 2.  Safet y A nal yses  .................................................................................................................................... 2 9 
1 2. 1.  A d verse E ve nts a n d Seri o us A d verse E ve nts  ............................................................................. 2 9 
1 2. 1. 1.  Treat me nt E mer ge nt A d verse E ve nts  ............................................................................ 2 9 
1 2. 1. 2.  S u m mar y of Treat me nt- E mer ge nt A d verse E ve nts a n d Seri o us A d verse E ve nts ......... 3 0  
1 2. 2.  Cli nical La b orat or y E val ua ti o n ................................................................................................... 3 0 
1 2. 3.  Vital Si g ns  .................................................................................................................................. 3 2 
1 2. 4.  B o d y Wei g ht ............................................................................................................................... 3 2  
1 2. 5.  1 2- lea d E C G ............................................................................................................................... 3 2 
1 2. 6.  P h ysical E xa mi nati o n ................................................................................................................. 3 3  
1 2. 7.  A nal yses of C o nti n u o us e G F R a n d A C R  ................................................................................... 3 3 
1 2. 7. 1.  C ha n ge fr o m Baseli ne i n e G F R at Wee k 1 6  .................................................................. 3 3 
1 2. 7. 2.  Rati o of Nat ural l o g ( A C R)/e G F R  ................................................................................. 3 3 
1 2. 7. 3.  C ha n ge fr o m Baseli ne i n A C R  ...................................................................................... 3 4 
1 3.  P har mac o ki netics A nal ysis  ................................................................................................................... 3 4 
 
 
 
 


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LI S T O F T A B L E S 
Ta ble 1:  
A b bre viati o ns a n d S pecialist Ter ms ................................................................................ 6  
Ta ble 2:  
Sc he d ule of Assess me nts  ............................................................................................... 1 2 
Ta ble 3:  
A nal ysis Wi n d o ws  ......................................................................................................... 1 9 
Ta ble 4:  
 .............................................................................. 2 6 
Ta ble 5:  
C o m paris o n of e G F R Sl o pe i n P H O E NI X vs. Hist orical e G F R Sl o pe ......................... 2 6  
Ta ble 6.  
 La bels f or S u m mar y of Hist orical a n d O n -Treat me nt C ha n ge i n e G F R  ...................... 2 7 
Ta ble 7:  
Pre -S pecifie d T hres h ol d Le vels f or Cate g orical La b orat or y S u m maries ...................... 3 1  
Ta ble 8:  
Pre -S pecifie d U p per Li mit of N or mal ( U L N) Le vels f or La b orat or y Para meters  ......... 3 1 
Ta ble 9:   
Pre -S pecifie d T hres h ol d Le vels f or E C G Para meters  ................................................... 3 2 
 
 
 


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R e at a C o nfi d e nti al  
1.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
T he f oll o wi n g a b bre vi ati o ns a n d s pecial ter ms are use d i n t his statistical a nal ysis pla n. 
T a ble 1: 
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  
an gi ote nsi n c o n verti n g e nz y me  
A C R  
al b u mi n t o creati ni ne rati o 
A D P K D  
a ut os o mal d o mi na nt p ol yc ystic ki d ne y disease  
A E  
ad verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase 
A R  
a ut o-re gressi ve 
A R B  
an gi ote nsi n II rece pt or bl oc ker  
A S T  
as partate a mi n otra nsferase 
A T C  
A nat o mical/ T hera pe utic/ C he mical  
A U C  
area u n der t he plas ma c o nce ntrati o n  c ur ve 
B A R D  
Bar d o x ol o ne met h yl  
B C V A  
best c orrecte d vis ual ac uit y  
B MI  
b o d y mass i n de x  
B N P  
B -t y pe natri uretic pe pti de 
B P  
b l o o d p ress ure 
CI  
c o nfi de nce i nter val 
C K D  
chr 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 M  
c o nc o mita nt me dicati o n 
C ma x  
ma xi m u m dr u g c o nce ntrati o n i n plas ma  
C S R  
cli nical st u d y re p ort 
e C R F 
electr o nic case re p ort f or m 
E C  
et hics c o m mittee 
E C G  
electr ocar di o gra m 
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 
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
F S G S  
f ocal se g me ntal gl o mer ul oscler osis 
G F R  
g l o mer ular filtrati o n rate 
H g b  
h e m o gl o bi n 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I g A N 
I g A ne p hr o pat h y 
I G F-1  
ins uli n -li ke gr o wt h fact or-1  


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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 
I N R 
inter nati o nal n or malize d rati o  
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
inte nt -t o-treat 
L L D  
lo wer li mit of detecti o n  
L S  
least s q uares 
M C H  
m ea n c or p usc ular he m o gl o bi n 
M C H C  
m ea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
M C V  
m ea n c or p usc ular v ol u me 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M M R M  
m i xe d m o del re peate d meas ures 
N T -Pr o B N P  
N -Ter mi nal Pr o -Brai n Natri uretic Pe pti de   
p H  
p ote ntial of h y dr o ge n  
P K  
p har mac o ki netic  
P T  
preferre d ter m  
Q Tc  
correcte d Q T i nter val  
R B C  
re d bl o o d cell 
R E M L  
restricte d ma xi m u m li keli h o o d 
S A E  
seri o us a d verse e ve nt  
S A P  
statistical a nal ysis pla n 
S Cr  
ser u m creati ni ne 
S D  
sta n dar d de viati o n 
S O C  
s yste m or ga n class 
T 1 D  
chr o nic ki d ne y disease  ass ociate d wit h t y pe 1 dia betes 
T B L  
total bilir u bi n  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt 
T L Fs  
ta bles, listi n gs, a n d fi g ures 
T ma x  
ti me w he n ma xi m u m dr u g c o nce ntrati o n i n plas ma is ac hie ve d  
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
W B C  
w hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
W H O D D  
W orl d Healt h Or ga nizati o n  Dr u g Dicti o nar y  
W O C B P  
w o me n of c hil d beari n g p ote ntial  
 
 


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R e at a C o nfi d e nti al  
 
2.  
R E VI SI O N H I S T O R Y A N D R E L E V A N T D O C U M E N T S  
Bel o w is a list of re visi o n s u m maries of t his statistical a nal ysis pla n. 
Versi o n  Date  
D oc u me nt 
O w ner  
Re visi o n S u m mar y 
1. 0 
A pril 1 8, 2 0 1 8 
 
I nitial versi o n. 
2. 0 
J ul y 1 3, 2 0 1 8 
 
S pecifie d a nal ysis met h o ds f or safet y 
a nal yses i n greater d etail  
A d de d s u m mar y of c ha n ge fr o m baseli ne 
i n A C R s u m marize d b y baseli ne A C R 
cate g or y ( A C R < = 3 0 0, A C R > 3 0 0) 
A d de d a nal ysis of c o vari a nce calc ulati o n 
of hist orical c ha n g e i n e G F R 
A d de d a nal ysis of c o vari a nce calc ula ti o n 
of c ha n ge i n e G F R w hile i n P H O E NI X 
A d de d c o m paris o n of e G F R bef ore a n d 
after p artici pati o n i n P H O E NI X  
C ha n ge d t he defi niti o n of baseli ne A C R 
T he a nal ysis pla n is base d o n t he i nf or mati o n fr o m t he f oll o wi n g d oc u me nt: 
Pr ot oc ol Versi o n 1. 0, 1 7 A u g ust 2 0 1 7 
3.  
P U R P O S E  O F T H E AN A L Y SI S  PL A N  
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o pre- s pecif y statistical a nal ysis met h o ds 
f or s u p p orti n g t he c o m pl eti o n of t he cli nical st u d y re p ort ( C S R) of st u d y 4 0 2- C- 1 7 0 2 f or t he 
i n vesti gati o nal pr o d uct bar d o x ol o ne met h yl ( B A R D).  T his S A P will be use d t o a nal yze t he 
safet y, t olera bilit y, a n d efficac y data c ollecte d d uri n g t he st u d y f or f o ur s pecifie d t y pes of rare 
c hr o nic ki d ne y disease ( C K D) c ollecte d d uri n g t he st u d y.  T his S A P c o m plies wit h t he 
I nternati o nal C o nfere nce o n Har m o nisati o n (I C H) g ui da nce a n d rele v a nt F o o d a n d Dr u g 
A d mi nistrati o n ( F D A ) g ui da nce d oc u m e nts.  T he a nal yses descri b e d i n t his pla n ha ve bee n 
pr os pecti vel y defi n e d pri or t o cli nical data bas e l oc k .  T he pla n ne d a n al yses i de ntifie d herei n  ma y  
be i ncl u de d i n re g ulat or y s u b missi o ns a n d/ or f ut ure ma n uscri pts.  E n d p oi nts will be assesse d f or 
eac h r ar e C K D c o h ort s e paratel y after t he d ata ha ve bee n l oc k e d.  


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T his pla n ma y be a me n d e d  f or r eas o ns s uc h as, b ut n ot li mite d t o, pr ot oc ol a me n d me nts, i nteri m 
a nal ysis res ults, a n d i nter nal data re vi e w s t hat ta ke place pri or t o cli nical data base l oc k  of t h e 
st u d y.  E x pl orat or y a nal yses, w hic h ar e n ot defi ne d i n t his S A P, ma y be perf or me d t o s u p p ort t he 
cli nical de vel o p me nt pr o gra m.  A n y p ost- h oc or u n pla n ne d a nal yses, w hic h are perf or m e d  f or 
t he C S R, b ut n ot defi ne d  i n t his S A P, will be clearl y i de ntifie d a n d d oc u me nte d i n t he C S R, as 
will a n y c ha n ges fr o m t he pla n ne d a n al yses as stat e d i n t he st u d y pr ot oc ol. 
 


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R e at a C o nfi d e nti al  
4.  
S T U D Y  O B JE C TI V E S A N D E N D P OI N T S  
4. 1.  
O bjecti ves  
F or patie nts wit hi n eac h r are C K D c o h ort e nr olle d i n t his st u d y, t he o bjecti ves are as f oll o ws:  
4. 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) i n 
bar d o x ol o ne met h yl- treat e d patie nts after 1 2 wee ks of treat me nt. 
•  T o assess t he saf et y of bar d o x ol o ne met h yl after 1 2 wee ks of treat me nt. 
4. 2.  
E n d p oi nts   
4. 2. 1.  
Pri m ar y Effic ac y E n d p oi nt 
•  C ha n ge fr o m bas eli ne i n e G F R at Wee k 1 2. 
 
 
 
 
 
 
4. 2. 3.  
S afet y E n d p oi nts  
Fre q u e nc y, i nte nsit y, a n d relati o ns hi p t o st u d y dr u g of A Es a n d S A Es, a n d c ha n ge fr o m baseli ne 
i n t he f oll o wi n g assess me nts: vital si g n meas ure me nts, 1 2-lea d E C Gs, cli ni cal la b orat or y 
meas ure me nts, a n d wei g ht . 
5.  
S T U D Y D E SI G N  
5. 1.  
O ver all St u d y Desi g n  
T his m ulti -ce nter, o pe n -l a bel P hase 2 trial will st u d y t he safet y, t olera bilit y, a n d effi cac y of 
bar d o x ol o ne met h yl i n q ualifie d patie nts wit h t he f oll o wi n g rare c hr o nic ki d ne y diseases: C K D 
ass ociate d wit h t y pe 1 di a betes ( T 1 D), I g A n e p hr o pat h y (I g A N), f ocal se g me ntal 
gl o mer ul oscler osis ( F S G S), a n d a ut os o mal d o mi na nt p ol yc ystic ki d ne y disease ( A D P K D). 
Patie nts will be e nr olle d i n disease s pecific c o h orts wit hi n t he trial, a n d effecti ve ness of 
bar d o x ol o ne met h yl i n tr eati n g C K D will be assesse d se paratel y b y c o h ort f or eac h rare C K D. 
T he trial will be o pe n -la b el a n d e nr oll a p pr o xi matel y  2 5 patie nts  i n eac h c o h ort of rare C KD 
eti ol o g y.   


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5. 2.  
R a n d o miz ati o n  a n d D osi n g  
Ra n d o mizati o n refers t o patie nts recei vi n g o pe n- l a bel bar d o x ol o ne m et h yl ( B A R D). All patie nts 
will recei ve B A R D t hr o u g h o ut t he st u d y as descri be d i n t he pr ot oc ol wit h the ma xi m u m 
bar d o x ol o ne met h yl d ose deter mi ne d b y uri ne al b u mi n -t o-creati ni ne rati o ( A C R) at Scree n B .  
T he dia gra m b el o w s h o ws d ose titrati o n a n d mai nte na nce sc he d ules acc or di n g t o t he baseli ne 
uri ne al b u mi n- t o-cr eati ni ne rati o ( A C R) ≤ 3 0 0 m g/ g or > 3 0 0 m g/ g.  Patie nts wit h 
macr oal b u mi n uria ( 3 0 0 m g/ g < A C R ≤ 2 5 0 0 m g/ g) at t he Scree n B visit will acc o u nt f or u p t o 
a p pr o xi matel y 5 0 % of p atie nts e nr olle d wit hi n eac h c o h ort.  Patie nts wit h A C R ≤ 3 0 0 m g/ g at 
Scree n B will be titrate d t o a ma xi m u m d ose of 2 0  m g  B A R D , a n d patie nts wit h A C R > 
3 0 0 m g/ g at Scree n B will be titrate d t o a ma xi m u m d ose of 3 0  m g  B A R 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- escal ate 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 Scree n B A C R > 3 0 0 m g/ g) u nless c o ntrai n dicate d 
cli nicall y a n d a p pr o v e d b y t he me dical m o nit or. 
Sc he m a f or St u d y of B ar d o x ol o ne Met h yl i n P atie nts wit h R are C hr o ni c Ki d ne y Dise ases  
 
 
5. 3.  
Assess me nts  
All patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me n t sc h e d ule.  Ta ble 2  lists t he 
o verall sc he d ul e of assess me nts f or t he st u d y. F oll o wi n g ra n d o mizati o n o n Da y 1, patie nts will 
be sc he d ule d f or ass ess me nts d uri n g treat me nt at Wee ks 1, 2, 4, 6, 8, a n d 1 2, a n d b y tele p h o ne 
c o ntact o n Da ys 3, 1 0, 2 1, 3 1, 3 8, a n d 4 5.  Patie nts will als o be sc he d ule d f or a n i n pers o n 
f oll o w- u p visit at Wee k 1 6, f o ur wee ks after t he e n d of treat me nt. 
 
 
S cr e e ni n g
D o s e -Titr ati o n P eri o d
W 2
W 1
W 8
Scr A
D 1
D 3
T
D 1 0
T
W 3
T
W 4
M ai nt e n a n c e
D 3 1
T
W 5
T
W 6
W 7
T
B A R D ( 5 m g)
B A R D ( 2 0 m g)
W 1 2
B A R D ( 1 0 m g)
P ri m ar y effic acy a n al ysis
O e G F R d et er mi n ati o n
T T el e p h o n e C o nt act
Scr B
B A R D ( 5 m g)
B A R D ( 2 0 m g)
B A R D ( 1 0 m g)
B A R D ( 3 0 m g)
B as eli n e A C R ≤ 3 0 0 m g / g
B as eli n e A C R > 3 0 0 m g / g
W 1 6
F/ U
Off 
St u dy 
Dr u g


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T a ble 2: Sc he d ule of Assess m e nts   
Assess me nt  
Scree n 
A a 
Scree n 
B b 
D a y  
1 c 
W k 1 
( P h o ne) 
D a y 3 ± 2  
W k 1  
D a y 7 ± 3  
W k 2  
( P h o ne) 
D a y 1 0 ± 2  
W k 2  
D a y 1 4 ± 3  
W k 3  
( P h o ne) 
D a y 2 1 ± 2  
W k 4  
D a y 2 8 ± 3  
W k 4  
( P h o ne) 
D a y 3 1 ± 2  
W k 5  
( P h o ne) 
D a y 3 8 ± 2  
W k 6  
Da y 
4 2 ± 3 
W k 7  
( P h o ne) 
D a y 4 5 ± 2  
W k 8  
D a y 
5 6 ± 3  
W k 1 2  
or E o T d 
D a y 8 4 ± 3  
W k 1 6  
or F/ U  
D a y 1 1 2 ± 3  
I nf or me d c o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ e xcl usi o n 
X 
 
X e 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d b aseli n e 
disease c haracteristics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Me dical hist or y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht i n cli nic/ B MI  
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Wei g ht at h o me  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dis pe nse wei g ht diar y  
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
C ollect/re vie w wei g ht diar y  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
E C G 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Ec h ocar di o gra m f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g n meas ure me nts  
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
P h ysical e xa m  
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Pre g na nc y test f or W O C B P g 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
St u d y dr u g a d mi nistrati o n  
 
 
--------------------------------------------- X----------------------------------------- 
 
Dis pe nse st u d y dr u g  
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
C ollect st u d y dr u g  
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Tele p h o ne c o ntact  
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
A d verse e ve nt c ollecti o n  
 
 
X h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ki d ne y bi o ps y i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasti n g C -pe pti de le v el j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Ge netic testi n g k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess me nt  
Scree n 
A a 
Scree n 
B b 
D a y  
1 c 
W k 1 
( P h o ne) 
D a y 3 ± 2  
W k 1  
D a y 7 ± 3  
W k 2  
( P h o ne) 
D a y 1 0 ± 2  
W k 2  
D a y 1 4 ± 3  
W k 3  
( P h o ne) 
D a y 2 1 ± 2  
W k 4  
D a y 2 8 ± 3  
W k 4  
( P h o ne) 
D a y 3 1 ± 2  
W k 5  
( P h o ne) 
D a y 3 8 ± 2  
W k 6  
Da y 
4 2 ± 3 
W k 7  
( P h o ne) 
D a y 4 5 ± 2  
W k 8  
D a y 
5 6 ± 3  
W k 1 2  
or E o T d 
D a y 8 4 ± 3  
W k 1 6  
or F/ U  
D a y 1 1 2 ± 3  
Cli nical c he mistr y (i n cl. e G F R)   
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
B N P a n d N T - pr o B N P 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
I G F-1 a n d ser u m ket o n es  
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
He mat ol o g y  
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Uri nal ysis a n d micr osc o p y  
X 
 
X 
 
  
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Uri ne c ollecti o n f or A C R e 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vir us ser ol o g y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P K sa m ples f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a  T otal Scree ni n g peri o d s h o ul d n ot e xcee d 6 m o nt hs.  
b  Scree n B visit s h o ul d be n o m ore t ha n 3 0 da ys pri or t o Da y 1.  
c  Da y 1 is t he da y of a d mi nistrati o n of t he first d ose.  O n D a y 1, all pr oce d ures s h o ul d be perf or m e d bef ore st u d y dr u g a d mi nistr ati o n.  
 
d  Patie nts w h o ter mi nate fr o m t he st u d y pri or t o t he Wee k  1 2  st u d y visit s h o ul d be br o u g ht bac k t o t he cli nic as s o o n as p ossi ble f or earl y ter mi nati o n assess me nts 
(i.e., e n d-of - treat me nt visit) as well as a f oll o w-u p visit 4  wee ks later.   
e  Scree ni n g eli gi bilit y pr oce d ures d o n ot nee d t o be re peate d o n Da y 1; h o we ver, a re vie w of a n y c ha n ges i n eli gi bilit y criteria s h o ul d be e val uate d pri or t o Da y 1 
pr oce d ures, a n d a uri ne pre g na nc y test s h o ul d be perf or me d f or W O C B P.  
f A n e c h ocar di o gra m  perf or me d at  t he Scree n  A visit or wit hi n 6 m o nt hs  pri or t o Da y 1 ma y be use d t o deter mi ne eli gi bilit y.  
g  A ser u m pre g na nc y test will be p erf or me d at t he Scree n A visit f or W O C B P or at a n y p oi nt i n ti me if a pre g na nc y is s us pecte d.  All ot her pre g na nc y assess me nt s will be 
uri ne pre g na nc y tests.     
h   A E assess me nts o n Da y 1 s h o ul d  be perf or me d f oll o wi n g st u d y dr u g a d mi nistrati o n.  
i O nl y patie nts e nr olli n g i n t he I g A ne p hr o pat h y c o h ort or t he F S G S c o h ort are re q uire d t o ha ve a ki d ne y bi o ps y.  Patie nts wit h  defi niti ve dia g n osis of I g A ne p hr o pat h y or 
F S G S fr o m pre vi o us bi o ps y will n ot ha ve a ki d ne y bi o ps y as part of t he st u d y, b ut m ust pr o vi de dia g n osis d oc u me ntati o n fr o m pre vi o us ki d ne y bi o ps y f or eli gi bilit y.  
j O n l y patie nts e nr olli n g i n t he T 1 D c o h ort are re q uire d t o ha ve fasti n g C-pe pti de le vels ass esse d.  Patie nts s h o ul d be i nstr ucte d t o fast pri or t o st u d y visit.  
k  O nl y patie nts e nr olli n g i n t he A D P K D  disease c o h ort are re q uire d t o ha ve ge netic testi n g.  Patie nts wit h c o nfir me d P K D 1 m utati o ns fr o m pre vi o us ge netic testi n g wi ll 
n ot ha ve ge netic testi n g perf or me d as part of t he st u d y, b ut m ust pr o vi de d oc u me ntati o n of ge netic m utati o n f or eli gi bilit y.  
l Al b u mi n t o creati ni ne rati o will be meas ure d b y first m or ni n g v oi d s p ot uri ne c ollecti o n.  A p pr o priate c o ntai ners f or t he c ol lecti o n will be pr o vi de d t o t he patie nt at t he 
visit pri or t o c ollecti o n.  


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m  Patie nts m ust be i nstr ucte d t o n ot ta ke t heir st u d y dr u g pri or t o c o mi n g t o t he cli nic f or visits w he n P K sa m ples will be c ol lecte d.  Patie nts m ust a d mi nister t he st u d y 
dr u g d ose i n t he cli nic o n P K sa m ple c ollecti o n visits after t he 0 h o ur P K bl o o d sa m ple is c ollecte d.  Patie nts will ha ve bl o o d sa m ples f or P K a n al ysis dra w n j ust pri or t o 
( 0 h o ur) a n d after ( 2 a n d 4 h o urs) d ose a d mi nistrati o n.   
 
 
A b bre viati o ns: E o T = e n d -of -treat me nt; E C G =  electr ocar di o gra m,  F/ U = f oll o w -u p;  P K = p har mac o ki netic, W O C B P = w o me n of c hil d -beari n g p ote ntial  




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s pecifie d ot her wise, b ut will be i ncl u de d i n t he patie nt listi n gs.  Missi n g data will n ot be 
i m p ute d, u nless ot her wise s pecifie d.  I n ge neral, a se parat e set of ta bles, listi n gs, a n d fi g ures will 
be ge ner ate d f or eac h c o h ort.  Select ta bles ma y b e ge nerate d as a p pr o pri ate t hat s u m marize d ata 
f or all c o h orts p o ole d. Patie nt listi n gs will be s orte d b y patie nt  n u m ber first, t he n assess me nt date 
(ti me a n d par a meter , as a p plica ble).   
U nless ot her wise s pecifie d, descri pti ve statistics  f or c o nti n u o us varia bles will i ncl u de t he n u m ber 
of patie nt s wit h data (N), mea n, sta n dar d d e 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  will be 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 v al ue will be prese nte d 
w he n re p orti n g mea n a n d me dia n ; a n d 2 m ore deci mal places t ha n i n t he o bser ve d val u e  will be 
prese nte d w h e n re p orti n g S D.  
C ate g orical/ q ualitati ve d ata will be pres e nte d usi n g fre q ue n c y c o u nts a n d p erce nt a ge s.  All 
perce nt a ge s will be r o u n de d t o 1 deci mal place, u nless ot her wise s pecifie d.  Perce nta g e s e q ual t o 
1 0 0 will be prese nte d as 1 0 0 % a n d n o perce nta g es will be prese nte d f or zer o fre q u e ncies.  W here 
i n di vi d ual varia ble val ues are missi n g, cate g ori cal data will be s u m marize d base d o n re d u ce d 
de n o mi nat ors (i.e., o nl y patie nt s wit h a vaila ble data will be i ncl u de d i n t he de n o mi nators).  F or 
s u m maries of A Es a n d c o nc o mita nt me dicati o ns ( C M), t he perce nta ges will be base d o n t he 
n u m ber of patie nt s w h o r ecei ve d st u d y dr u g. 
Res ults of statistical a nal yses will be re p orte d b y rare C K D c o h ort usi n g s u m mar y ta bles, 
listi n gs, a n d fi g ures (T L Fs).  T he I C H n u m beri n g c o n ve nti o n will be use d f or all T L Fs.  T he 
f oll o wi n g c o n ve nti o ns will be f oll o we d: 
•  U nless ot her wise n ote d, all statistical testi n g will be t w o -si de d a n d will be perf or me d 
at t he 0. 0 5 si g nifica nce le vel. 
•  Tests will be declar e d stat isticall y si g nifica nt if t he calc ul ate d p-val u e is < 0. 0 5. 
All a nal yses a n d s u m maries will be pr o d uce d usi n g S A S ®  versi o n 9. 3 ( or hi g her). 
7. 1.  
Deri ve d V ari a bles  
7. 1. 1.  
A ge  
A ge ( years) will be calc ulate d as t he n u m ber of years bet wee n date of birt h a n d date of i nf or me d 
c o nse nt , e x pr esse d as a n i nte ger. 
7. 1. 2.  
St u d y D a y  
St u d y Da y will f oll o w t he C DI S C S D T M sta n dar d a n d is defi ne d as f oll o ws: 
•  assess me nt  date – dat e of first st u d y dr u g d osi n g + 1, w here t he assess me nt date is o n 
or after t h e date of first st u d y dr u g d osi n g;  


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•  assess me nt date – dat e of first st u d y dr u g d osi n g, w here t he assess me nt dat e is bef ore 
t he date of first st u d y dr u g d osi n g.   
7. 1. 3.  
Esti m ate d Gl o m er ul ar Filtr ati o n R ate  
Esti mate d gl o mer ular filtrati o n rate ( e G F R) val ue will be calc ulate d at t he ce ntral la b orat or y  a n d 
use d i n data a nal ys es .  T he e q uati o n use d t o calc ulate e G F R f or eac h patie nt will be 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 u ati o n: 
•  eG F R ( m L/ mi n/ 1. 7 3 m2) = 1 4 1 × mi n( S cr/ κ, 1)α × ma x( S cr/ κ, 1)-1. 2 0 9 × 0. 9 9 3A ge  ×  
1. 0 1 8 [if fe male] × 1. 1 5 9 [if blac k]. 
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.  
H istorical ser u m cr eati ni ne a n d e G F R val ues will be treate d s e paratel y fr o m data c ollecte d as 
part of t he trial’s ce ntr al la b assess me nts.  Hist orical e G F R val ues will be cal c ulate d fr o m 
hist orical ser u m cr eati ni ne res ults.  
Missi n g e G F R val ues will n ot be i m p ute d f or t he pri mar y a nal ysis of efficac y. T he e G F R val ues 
c ollecte d after t he wi n d o w of t he date of last d ose f or patie nts w h o d o n ot c o m plete st u d y 
treat me nt will n ot be i ncl u de d i n t he a nal ysis. 
7. 1. 4.  
Uri ne Al b u mi n a n d Uri ne Al b u mi n t o Cre ati ni ne R ati o  
U ri ne al b u mi n t o creati ni ne rati o ( A C R) will be calc ulate d at t he ce ntral la b orat or y usi n g t he 
f or m ula bel o w:  
•  A C R  = Uri ne Al b u mi n ( m g/ d L) / Uri ne Creati ni n e ( g/ d L )  
Uri ne cr eati ni ne ma y n ee d t o be c o n verte d fr o m m g/ d L t o g/ d L.  T he ce ntral la b orat or y uses a n 
assa y t hat has a l o w er li mit of detecti o n ( L L D)  a n d a n u p per li mit of detecti o n ( U L D) f or uri ne 
al b u mi n.  Uri ne al b u mi n res ults bel o w L L D will be i m p ute d wit h L L D/ 2 i n m g/ d L.  Uri ne 
al b u mi n res ults a b o ve U L D will be i m p ute d wit h t he U L D  val ue.  W here i m p utati o n is 
necessar y, t he i m p ute d uri ne al b u mi n res ults will be use d al o n g wit h t he uri ne creati ni ne res ult 
pr o vi de d b y t he ce ntral la b orat or y f or calc ul ati n g A C R.     
7. 1. 5.  
Electr 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, i ncl u di n g t he Fri deri cia correct e d Q T inter val ( Q Tc F) , will be  
assesse d  l ocall y at eac h site.  I n t he e ve nt t hat Q T c F i nter v al is n ot pr o vi de d, it will be calc ulate d 
fr o m Q T a n d R R i nter vals usi n g t he f oll o wi n g f or m ula:  
•  𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄=  𝑄𝑄𝑄𝑄/ √𝑅𝑅𝑅𝑅
3
 
W here R R = 6 0 / ( Heart Rate).  


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7. 2.  
B aseli ne V al ues  
Baseli ne val ues are 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 
d osi n g, u nless ot her wise s pecifie d bel o w.   
7. 2. 1.  
Esti m ate d Gl o m er ul ar Filtr ati o n R ate  
T he Scree ni n g e G F R val ue is t he a ver a ge of t h e last t w o e G F R meas ure me nt s c ollected pri or t o 
Da y 1, f or e xa m ple ( Scree n A e G F R + Scree n B e G F R) / 2 .  U nsc h e d ule d e G F R val ues c ollecte d 
pri or t o Da y 1 will be use d i n t he calc ulati o n of Scree ni n g e G F R if t he u nsc he d ule d e G F R val ues 
are wit hi n t he last t w o e G F R meas ur e me nts c ollecte d pri or t o Da y 1.  Bas eli ne e G F R will be 
calc ulate d as a w ei g hte d a vera g e of t he Da y 1 meas ure me nt a n d t h e Scree ni n g meas ure me nt as 
s h o w n bel o w:  
•  Baseli ne e G F R = 0. 5 × D a y 1 e G F R + 0. 5 × Scree ni n g e G F R  
H o we ver, if n o Da y 1 e G F R val ue e xists or D a y 1 st u d y dr u g a d mi nistrati o n occ urre d bef ore 
Da y 1 la b c ollecti o n, t he n Baseli ne e G F R will e q ual Scree ni n g e G F R. 
7. 2. 2.  
Ser u m Cre ati n ine  
T he Scree ni n g S Cr  val ue is t he a vera g e of t he last t w o S Cr  meas ure me nt s c ollecte d pri or t o Da y 
1 , f or e xa m ple ( Scree n A e G F R + Scree n B e G F R) / 2.  U nsc he d ule d S Cr v al ues c ollecte d pri or 
t o Da y 1 will be use d i n t he calc ul ati o n of Scree ni n g S Cr if t he u nsc he d ule d S Cr  val ues are 
wit hi n t he last t w o S Cr  meas ure m e nts c ollecte d pri or t o Da y 1.  Baseli ne S Cr will be calc ulate d 
as a wei g hte d a ve r a ge of t he Da y 1 meas ure me nt a n d t he Scree ni n g meas ure me nt as s h o w n 
bel o w:  
•  Baseli ne S Cr  = 0. 5 × Da y 1 S Cr  + 0. 5 × Scree ni n g S Cr   
H o we ver, if n o Da y 1 S Cr val ue e xists or D a y 1 st u d y dr u g a d mi nistrati o n occ urre d bef ore D a y 1 
la b c ollecti o n, t he n Baseli ne S Cr will e q ual Scree ni n g S Cr.  
7. 2. 3.  
V it al Si g n Assess m e nts 
Baseli ne vital si g n assess me nts  are defi ne d as t he a vera g e val ue of meas ure me nts (fr o m 
sc he d ule d a n d u ns c he d ul e d visits) c ollecte d u p t hr o u g h Da y 1, pri or t o first d ose of st u d y dr u g.     
7. 2. 4.  
Al b u mi n/ Cre ati n i ne R ati o ( A C R) 
Baseli ne A C R is defi ne d as t he a vera ge of Scree n B a n d Da y 1 A C R val ues.  
7. 2. 5.  
N at ur al l o g ( A C R)/ e G F R 
Baseli ne of nat ur al l o g( A C R)/e G F R is defi ne d as t he rati o of t he n at ural l o g of baseli ne A C R 
( defi ne d i n Secti o n 7. 2. 4 ) di vi de d b y baseli ne e G F R ( defi ne d i n Secti o n 7. 2. 1 ). 


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7. 3.  
A n al ysis Wi n d o ws  
Beca use  cli nical visits ma y occ ur o utsi de pr ot oc ol s pecifie d wi n d o ws, i nstea d of rel yi n g s olel y 
o n visit la bels i n t he cli nical data b ase, a n al ysis visit s a n d t heir wi n d o ws are defi ne d usi n g St u d y 
Da y  ( See Secti o n 7. 1. 2 ).  A nal ysis visit wi n d o ws are prese nte d i n T a ble 3  b y t y pe of assess me nts 
a n d/ or meas ur e me nts .   
If m ore t ha n o n e o n-treat me nt assess me nts  a n d/or meas ure me nts e xists f or a para m eter wit hi n a 
visit wi n d o w, t he o ne t hat is cl osest t o t he pr ot oc ol sc he d ule d ti me p oi nt ( or tar get St u d y Da y) 
will be use d f or a n al ysis a n d s u m mar y.  If m ore t ha n o ne o ff-treat me nt assess me nt e xists, t he o ne 
cl osest t o t he tar get st u d y da y will be use d f or a nal ysis a n d s um mar y .  
T a ble 3:  
A n al ysis Wi n d o ws 
Visit  
Sc he d ule d  
Ti me P oi nt  
T ar get 
St u d y D a y  
A n al ysis Visit Wi n d o ws  
All Ot her 
Assess me nts  
1 2 -le a d E C G 
Scree n A  
-6 0  
-1 8 0 t o -2  
-1 8 0 t o 1  
Scree n B a 
-1  
-3 0 t o -1  
- 
Da y 1  
1  
1  
- 
Wee k 1  
7  
2 t o 1 0  
- 
Wee k 2  
1 4  
1 1 t o 2 1  
- 
Wee k 4  
2 8  
2 2 t o 3 5  
- 
Wee k 6  
4 2  
3 6 t o 4 9  
- 
Wee k 8  
5 6  
5 0 t o 7 0  
- 
Wee k 1 2  
8 4  
7 1 t o 9 8  
2 t o 98  
Wee k 1 6  
1 1 2  
> 9 8  
- 
aScree n B is after Scree n A, a n d n o m ore t ha n 3 0 d a ys pri or t o Da y 1 
N ote: St u d y Da y is relati ve t o t he first date of st u d y dr u g a d mi nistrati o n ( St u d y Da y 1).  Visit 
Sc he d ule d Ti me P oi nt  = A nal ysis Visit ( A VI SI T), after a p pl yi n g t he a nal ysis wi n d o ws descri be d 
a b o ve.  T he Wee k 1 6 visit has t he a d diti o nal restri cti o n t hat assess me nts m ust be c ollecte d after 
last d ose of st u d y treat me nt.  F or patie nts w h o ter mi nate d treat me nt pri or t o Wee k 1 2, us e Wee k 
1 6 as f oll o w- u p visit. 
If m ore t ha n o n e meas ur e me nt is c ollecte d e q ui dista nt t o t he tar get St u d y Da y a n d o n differe nt 
c ollecti o n date/ti me, t he first meas ure me nt will be fla g ge d f or a nal ysis a n d s u m mar y.  If m ore 
t ha n o ne meas ur e me nt is cl osest t o t he tar get St u d y Da y a n d c ollecte d o n t he sa me date, t h e 
a vera g e of t h ose meas ure me nts will be use d  f or a n al ysis a n d s u m mar y. 


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8.  
A N A L Y SI S S E T S  
T he a nal ysis sets defi n e d bel o w will be defi ne d f or  eac h rare C K D  c o h ort: C K D ass ociate d wit h 
T 1 D, I g A N, F S G S, a n d A D P K D.    
8. 1.  
S afet y A n al ysis Set  
Safet y a nal ysis set  is defi ne d as all patie nt s w h o recei ve d a n y a m o u nt  of st u d y dr u g.  T he safet y 
a nal ysis set will be use d f or e val u ati o n of safet y v aria bles.   
8. 2.  
I T T A n al ysis Set 
T he i nte nt- t o-treat anal ysis set is defi ne d as all e nr olle d patie nt s.   
8. 3.  
Off- Tre at me nt A n al ysis Sets  
T he Wee k 1 6 off -treat me nt a nal ysis set is defi ne d as all ra n d o mize d p atie nt s w h o were d osi n g 
c o m plia nt t hr o u g h Wee k 1 2 as defi ne d b y: 
•  Still ta ki n g st u d y me dicati o n  at t he Wee k 1 2 i n - p ers o n visit; a n d 
•  H a d a Wee k 1 6 assess me nt.  
T he  off -tr eat me nt a n al ysis sets will be use d f or e v al uati o n of off -treat me nt safet y at Wee k 1 6. 
8. 4.  
P h ar m ac o ki netics  A n al ysis Set  
P har mac o ki netics a n al ysis set is defi ne d as all pati e nt s w h o recei ve d a n y a m o u nt  of st u d y dr u g 
a n d ha d at least o ne bar d o x ol o ne met h yl plas ma c o nce ntrati o n meas ure me nt.  T he P K  a nal ysis 
set will be use d f or e v al u ati o n of p har mac o ki netics. 
9.  
S T U D Y P O P U L A TI O N  
9. 1.  
P atie nt  Dis p ositi o n  
E nr oll me nt a n d d is p ositi o n will be s u m marize d b y rare C K D  c o h ort.  A p atie nt will be defi ne d as  
e nr olle d if t he y si g n t he i nf or me d c o ns e nt f or m.  T he patie nt  dis p ositi o n s u m mar y will i ncl u de 
t he n u m ber of patie nts w h o:  
•  e nr olle d i n t he st u d y  
•  are i n t he safet y a n al ysis set 
•  are i n t he I T T a n al ysis set  
•  are i n t he Wee k 1 6 off -tr eat me nt a nal ysis set 
•  c o m plete d st u d y treat me nt 


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•  pre mat urel y disc o nti n ue d st u d y treat me nt 
•  c o m plete d st u d y visits  
•  pre mat urel y ter mi nate d fr o m t he st u d y. 
T he dis p ositi o n s u m mar y will als o i ncl u de t he pri mar y reas o n f or wit h dra wal fr o m t he st u d y.   
Patie nt s w h o c o m plete d st u d y treat me nt are defi ne d as t h ose w h o recei ve d treat me nt t hr o u g h t he 
Wee k 1 2 visit .  Patie nts w h o c o m plete d st u d y visits are defi ne d as t h ose w h o c o m plete d t he 
Wee k 1 6 visit.  A listi n g of dis p ositi o n will be pr o vi de d f or all e nr olle d p atie nt s, i ncl u di n g 
patie nt s o urce.   
9. 2.  
Pr ot oc ol De vi ati o ns  
W here a vaila ble, pr ot oc ol de viati o ns will be liste d b y de viati o n cate g or y (e. g., eli gi bilit y criteria, 
o ut of wi n d o w visit, seri o us a d verse e ve nt ( S A E) re p orti n g, st u d y pr oce d ures, treat me nt 
pr oce d ur es).  All de viati o ns, i ncl u di n g maj or pr ot oc ol de viati o ns t hat c o ul d p ote ntiall y affect t he 
efficac y or s afet y c o n cl usi o ns of t he st u d y, will be i de ntifie d pri or t o data b ase l oc k.  Maj or 
pr ot oc ol de viati o ns will be liste d i n a data listi n g .   
9. 3.  
De m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hics a n d baseli ne c har acterist ics will be s u m marize d b y rare C K D  c o h ort f or t h e safet y 
a nal ysis set.   De m o gra p hic c har acteristics will i ncl u de a ge, ge n d er, race, a n d et h nicit y.  Baseli ne 
A C R will be s u m marize d b y baseli ne A C R val ues, n ot t he stratificati o n c o h ort t o w hic h a patie nt 
was ra n d o mize d. T he bas eli ne c har acteristics i ncl u de:  
•  Baseli ne wei g ht, 
•  Hei g ht, 
•  B o d y mass i n de x ( B MI), a n d B MI cate g or y: < 3 0, ≥ 3 0, 
•  Baseli ne val ues of e G F R, baseli ne C K D sta ge ( Sta ge 3: e G F R 3 0 t o < 6 0 ; Sta ge 2 : e G F R 
≥6 0 t o < 9 0 ; Sta ge 1: e G F R ≥ 9 0), 
•  B aseli ne ser u m cr eati ni n e , 
•  Baseli ne A C R , 
•  Baseli ne A C R stat us ( A C R ≤ 3 0 0 m g/ g; 3 0 0 m g/ g < A C R ≤ 1 0 0 0 m g/ g; A C R > 1 0 0 0 
m g/ g ), 
•  A ge of t he dia g n os is ( T 1 D c o h ort o nl y) 
•  C- pe pti de le vel ( T 1 D c o h ort o nl y),  
•  Prescri be d a st a ble d ose of i ns uli n ( T 1 D c o h ort o nl y), a n d  


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•  Baseli ne A n gi ote nsi n c o n verti n g e nz y me ( A C E)-i n hi bit or a n d A n gi ote nsi n II rece pt or 
bl oc ker ( A R B) use: 
o  O nl y A C Ei  treat me nt; 
o  O nl y A R B treat me nt;  
o  A C Ei a n d A R B treat me nt  
o  N o A C Ei or A R B treat me nt.  
T he a b o ve i nf or mati o n will be liste d b y patie nt . 
9. 4.  
Me dic al Hist or y  
Me dical hist or y will be ma p pe d t o pref erre d ter ms ( P T) a n d s yste m or ga n classes ( S O C) usi n g 
t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A® ) Dicti o nar y ( versi o n 1 4. 1).  
M e dical hist or y ite ms will be s u m marize d b y Me d D R A S O C , c o h ort, a n d P T a n d patie nt  listi n g 
will be pr o vi de d.   
1 0.  
S T U D Y D R U G A N D O T H E R  M E DI C A TI O N S  
1 0. 1.  
Pri or a n d C o nc o mit a nt M e dic ati o ns 
Pri or a n d c o nc o mita nt m e dicati o n ver b ati m ter ms o n e C R Fs will be ma p pe d t o 
A nat o mical/ T hera pe utic/ C he mical ( A T C) class a n d preferre d n a mes usi n g t he W orl d Healt h 
Or ga nizati o n Dr u g Dicti o nar y ( W H O D D ) ( E n ha nce d versi o n, Se pte m b er 2 0 1 1, B 2 f or mat). 
A p ri or me dicati o n is a n y me dicati o n t hat is ta ke n a n d st o p pe d pri or t o t he first d ose of st u d y 
dr u g.  Me dicati o ns ar e st o p pe d o n t he date of first st u d y dr u g a d mi nistrati o n are pri or 
me dicati o ns. A c o nc o mit a 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 starte d after t h e start of st u d y dr u g d osi n g.  S pecificall y, 
c o nc o mita nt me dicati o ns are me dicati o ns  
•  t hat are c o nti n ue d fr o 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. 
Pri or  a n d c o nc o mita nt m e dicati o ns will be s u m marize d wit hi n eac h  rare c hr o nic ki d ne y disease 
c o h ort b y W H O D D A T C class a n d  preferre d na me.  T hese s u m maries will prese nt t he n u m ber 
a n d perce nta ge of patie nt s usi n g eac h me dicati o n.  Patie nt s ma y ha ve m ore t ha n o ne me dicati o n 
per A T C class a n d preferre d na me.  At eac h l e vel of patie nt  s u m marizati o n, a patie nt  is c o u nte d 
o nce if he/s he re p ort e d o ne or m ore me di cati o ns at t hat le vel.  Eac h s u m mar y will be or dere d b y 
desce n di n g or d er of i nci d e nce of A T C class a n d preferre d na m e wit hi n eac h A T C class.  
I n a d diti o n, patie nt s w h o ta ke e xcl u d e 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 he st u d y will be liste d. 


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1 0. 2.  
D ur ati o n of St u d y Tre at me nt a n d E x p os ure  t o St u d y Dr u g 
T otal n u m ber of d oses r ecei ve d a n d t otal d ose ( m g) recei ve d will be calc ul ate d fr o m st u d y dr u g 
dis pe nsati o n a n d ret ur n i nf or mati o n.  D escri pti ve su m maries f or d urati o n of st u d y treat me nt will 
i ncl u de t he n u m ber of d oses recei ve d, a v era g e dail y d ose ( m g), 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.   
T he d urati o n of st u d y treat me nt (i.e., dr u g e x p os ure) is defi n e d as t he n u m ber of da ys e x p ose d t o 
treat me nt, starti n g wit h t he first d ose of st u d y dr u g t hr o u g h t he last d ose of st u d y dr u g 
•  D urati o n of st u d y treat m e nt = (last d ose – first d ose + 1).   
If all dis pe nse d kits a n d b ottles are ret ur ne d, t he t otal n u m ber of d oses recei ve d will be 
calc ulate d as f oll o ws:  
•  N u m ber of d oses recei ve d = T otal n u m ber of d os es dis pe nse d – t otal n u m ber of d oses 
ret ur ne d.   
If a dis pe nse d kit or b ottl e is n ot ret ur ne d, t he t otal n u m ber of d oses recei ve d will be calc ulate d 
as f oll o ws:  
•  N u m ber of d oses recei ve d = 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 – t otal n u m ber of misse d d oses 
•  St u d y dr u g c o m plia nce ( %) = 1 0 0 × t otal n u m ber of d oses recei ve d / t otal n u m ber of 
d oses e x pect e d i n eac h tr eat me nt p eri o d.   
A d ult patie nts are e x p ect e d t o recei ve o ne d os e dail y, t heref ore 8 4 d os es are e x pecte d at Wee k 
1 2.   
All st u d y dr u g dis pe nsati o n a n d acc o u nta bilit y data will be liste d. 
1 1.  
E F FI C A C Y A N A L Y S E S 
1 1. 1.  
Pri m ar y Effic ac y A n al ysis  
A m i xe d- m o del f or r e peate d meas ures ( M M R M ) will be use d t o a nal yze t h e pri mar y efficac y 
varia ble .  T h e M M R M  res ults will be re p orte d b y rare C K D  c o h ort.  T h e I T T p o p ulati o n will be 
use d f or a n al ysis of t he pri mar y efficac y o bjecti ve.  All e G F R val ues c ollecte d cl osest t o t he 
tar get st u d y da y ( Secti o n 7. 3 ) t hr o u g h t he Wee k 1 2 visit will c o ntri b ute t o t he pri mar y a n al ysis.  
T he pri mar y efficac y varia ble,  t he cha n g e fr o m b aseli ne i n e G F R val u e,  will be calc ulate d f or 
eac h first p ost- first d ose ti me p oi nt t hr o u g h Wee k 1 2 visit (i.e., Wee ks 1, 2, 4, 6, 8, a n d 1 2).  
M issin g data will n ot be i m p ute d f or t he pri mar y a nal ysis.  T he pri mar y i nfere nce will be t he test 
of L S mea n at eac h ti me p oi nt.   T he pri mar y e n d p oi nt is t he mea n c ha n ge fr o m baseli ne i n e G F R 
at Wee k 1 2.   


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T he e G F R val ues c ollecte d after t he st u d y wi n d o w of st u d y dr u g disc o nti n uati o n will be n ot be 
use d i n pri mar y or e x pl or at or y effi cac y a nal yses. 
1 1. 1. 1.  
St atistic al H y p ot hesis  
F or t he pri ma r y efficac y o bjecti ve, t he n ull h y p ot hesis is t he Wee k 1 2 mea n ( μ B A R D ) c ha n ge 
fr o m baseli ne i n e G F R  = 0  m L/ mi n/ 1. 7 3 m2.  T he alter nati ve h y p ot hesis is t he Wee k 1 2 mea n  
( μ B A R D ) c ha n ge fr o m bas eli ne i n e G F R ≠ 0 m L/ mi n/ 1. 7 3 m2. 
1 1. 1. 2.  
St atistic al M o del  
T he M M R M m o del will i ncl u de t he c h a n ge fr o m baseli ne i n e G F R val ue as t he de pe n de nt 
varia ble , pr ot o c ol sc he d ule d ti me p oi nt (a nal ysis visit ) as a fi xe d effect, patie nt as a ra n d o m 
effect, a n d t he b aseli ne e G F R a n d l o g-tra nsf or me d baseli ne A C R  as c o nti n u o us c o variates.  
Wit hi n -patie nt  c orr elati o ns will be m o dele d usi n g a n u nstr uct ure d c o vari a n ce str uct ure.  Ti me 
or deri n g is a r e peat e d meas ure wit hi n patie nt s.  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 .  T he esti mati o n met h o d f or t he m o del 
will be restricte d ma xi m u m li keli h o o d ( R E M L).  T he S A S pse u d o-c o de is as f oll o ws: 
p r o c  m i x e d  d a t a = e f f i c a c y  m e t h o d = r e m l ;  
   c l a s s  u s u b j i d  a v i s i t n ;  
   m o d e l  c h g = a v i s i t n  b a s e _ e g f r  l b a s e _ a c r ;  
   r e p e a t e d  a v i s i t n  /  s u b j e c t = u s u b j i d  t y p e = u n  r c o r r ;  
   l s m e a n s  a v i s i t n  /  d i f f  c l  a l p h a = 0 . 0 5 ;  
r u n ;  
I n t he e ve nt t he M M R M m o del wit h a n u nstr uct ure d c o vari a nce str u ct ure d oes n ot c o n ver g e, t he 
f oll o wi n g c o varia n ce str u ct ures will be as s u bstit uti o n i n t he f oll o wi n g or der.  Eac h s u bse q u e nt 
c o varia n ce str uct ure will be use d o nl y if all pre vi o us c o varia n ce str uct ure(s) is (are ) use d a n d t h e 
m o del(s) di d n ot c o n ver g e. 
1.  T oe plitz  c o varia n ce str u ct ure ( ass u mi n g meas ure me nts fr o m sa m ples ta ke n cl oser 
t o get her i n ti me are m or e hi g hl y c orrelate d t h a n t h ose fr o m sa m ples ta ke n fart her a part). 
2.  First or der of a ut o-re gr essi ve [ A R( 1)] c o vari a nce str uct ure (ass u mi n g meas ure me nts fr o m 
sa m ples ta ke n cl oser t o get her i n ti me are m ore hi g hl y c orrelat e d t ha n t h ose fr o m sa m ples 
ta ke n fart her a p art). 
3.  C o m p o u n d s y m metr y c o varia nce str uct ure (ass u mi n g e q ual 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 w he n t he y were ta k e n).  
A se par ate M M R M  m o del will be a nal yze d f or eac h rare C K D c o h ort.  
1 1. 1. 3.  
Re p orti n g Res ults  
T he least s q uar es ( L S ) m ea n, sta n dar d err or ( S E) of t he L S mea n, t w o-si de d 9 5 % c o nfi de n ce 
i nter val (CI ) of t h e L S mea n  a n d p-v al ue  will be re p orte d at eac h ti me p oi nt.  S tatistical testi n g 
will be perf or me d at e ver y ti me p oi nt t hat e G F R is meas ure d.  T h e c ha n g e fr o m baseli ne i n 












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R e at a C o nfi d e nti al  
•  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 he 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.  
Relate d A Es ar e t h ose wit h relati o ns hi p t o st u d y dr u g re p orte d as “ p ossi bl y relate d ”, “ pr o b a bl y 
relate d”, or “d efi nitel y  relate d”.  If s e verit y (relati o ns hi p t o st u d y dr u g) of a n A E t o st u d y dr u g is 
n ot rec or d e d, t he se verit y ( relati o ns hi p t o st u d y dr u g) will be i m p ute d as ‘s e vere’ (‘d efi nitel y 
relate d’). 
All re p orte d A Es (i ncl u di n g n o n- T E A Es ), S A E, a n d deat hs will be liste d i n se parat e patie nt 
listi n gs. 
1 2. 1. 2.  
S u m m ar y of Tre at m e nt -E mer ge nt A d verse E ve nts  a n d Seri o us A d verse E ve nts  
T E A E a n d S A E pr ese ntati o ns will s u m marize res ults b y ra re C K D c o h ort. All T E A E s u m mar y 
ta bles will i ncl u de t he n u m ber a n d perce nt a ges of patie nt s re p orti n g T E A Es.  A s u m mar y of 
T E A Es b y se verit y, seri o us ness, a n d relati o n t o st u d y dr u g will be ta b ulate d.  I n a d diti o n, T E A Es 
will be s u m marize d b y Me d D R A  s yste m or ga n class a n d preferre d ter m.  T hese s u m maries wi ll 
i ncl u de t he f oll o wi n g: 
•  All T E A Es  
•  T E A Es b y w orst se verit y 
•  Relate d T E A Es  
•  T E A Es  lea di n g t o st u d y dr u g i nterr u pti o n (if a n y) 
•  T E A Es  lea di n g t o st u d y dr u g disc o nti n uati o n (if a n y) 
•  All treat me nt-e mer ge nt S A Es  
•  Treat me nt -e mer ge nt S A Es  b y w orst se verit y 
•  Relate d treat me nt-e mer g e nt S A Es . 
At eac h le v el of patie nt  s u m marizati o n, a patie nt  is c o u nte d o nce if h e/s he re p orte d o ne or m ore 
T E A E  at t hat le vel.  If a patie nt  re p orte d t h e sa me T E A E  o n m ulti ple occasi o ns, t he hi g hest 
se verit y (se v ere > m o der ate > mil d) or st u d y dr u g relati o ns hi p (relat e d > pr o ba ble > p ossi ble > 
u nli kel y > u nrelate d) rec or de d f or t he e ve nt will b e s u m marized.  E ac h s u m mar y will be or dere d 
b y desce n di n g or d er of i n ci de nce of s yste m or ga n class a n d preferre d ter m wit hi n eac h s yste m 
or ga n clas s.  
1 2. 2.  
Cli nic al L a b or at or y E v al u ati o n  
Cli nical l a b orat or y test (s er u m c he mistr y [i ncl u di n g N T - Pr o B N P, B N P, I G F- 1 a n d s er u m 
ket o nes], he mat ol o g y [i n cl u di n g he mat ocrit, he m o gl o bi n ( H g b), re d bl o o d cell ( R B C) c o u nt, 
w hite bl o o d cell ( W B C) c o u nt, ne utr o p hils, ba n ds (if detect e d), l y m p h oc yt es, m o n oc ytes, 
bas o p hils (if 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 usc ul ar he m o gl o bi n 
c o nce ntr ati o n ( M C H C )], s p ot uri ne, a n d uri nal ysis of p H a n d s pecific gra vit y) res ults fr o m t he 


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R e at a C o nfi d e nti al  
ce ntral la b orat or y , w h ere a vaila ble, will be s u m marize d b y rare c hr o ni c ki d ne y disease c o h ort 
usi n g descri pti ve statistics at eac h s c he d ule d ti me p oi nt.  La b orat or y assess me nts bel o w L L D 
will be i m p ute d as L L D/ 2.  La b orat or y assess me nts a b o ve t he U L D will be i m p ute d as t he U L D. 
C ha n ges fr o m bas eli ne will als o be s u m marize d  b y ti me p oi nt.  S u m maries of A C R will use t he 
ge o metric mea n wit h 9 5 % c o nfi de n ce i nter v als i nstea d of t he arit h metic mea n, a n d will di s pla y 
A C R res ults i n u nits  of m g/ g .  C ha n ges fr o m bas eli ne i n A C R will be re p orte d as t he p ost-
baseli ne/ baseli ne r ati os a n d will be s u m marize d b y ge o metric mea ns wit h 9 5 % c o nfi de n ce 
i nter vals at eac h ti me p oi nt.  Mea n rati os of nat ural l o g( A C R )/e G F R will als o be s u m marize d at 
eac h ti me p oi nt.  T he r ati o of nat ural l o g( A C R )/e G F R b y a nal ysis visit will be s u m marize d b y 
arit h metic mea ns .  B o x pl ot gra p hs a n d li ne gra p hs ma y be ge nerate d f or selecte d la b orat or y 
tests, s uc h as A C R, A L T, A S T, B U N, uri c aci d, m a g nesi u m, a n d creati ni ne.  Li ne gra p h s will 
i ncl u de mea n  ± S E o ver ti me f or b ot h t he o bser v e d val ues a n d f or t he c ha n ge fr o m baseli ne 
val ues . 
A d diti o nal s u m mar y ta bles  will be pr o vi de d t hat i ncl u des t hat n u m ber a n d perce nt a ge of p atie nt s 
meeti n g t he f oll o wi n g 1) pre -s pecifie d t hres h ol d le vel at a n y ti me d uri n g t he st u d y (Ta ble 7 ) a n d 
2) U L N t hres h ol ds at a n y ti me d uri n g t he st u d y ( Ta ble 8 ).  
T a ble 7:  
Pre -S pecifie d T hres h ol d Le vels f or C ate g o ric al L a b or at or y S u m m aries  
L a b  P ar a m eter  
Pre -S pecifie d Le vel  
A C R  
> 3 5 0 0 m g/ g  
Ma g nesi u m  
<  1. 3 m E q/ L ( 0. 6 5 m m ol/ L)  
B N P  
>  2 0 0 p g/ m L  
A L T, A S T  
>  3  × u p per li mit of n or mal ( U L N)  
A L T, A S T  
>  8  × U L N  
A L T, A S T  
>  5  × U L N f or m ore t ha n 2 wee ks 
A L T, A S T, T B L, I N R  
>  3  × U L N  a n d ( T B L > 2  ×  U L N or I N R > 1. 5 ×  U L N ) 
T a ble 8:  
Pre -S pecifie d U p per Li mit of N or m al ( U L N) Le vels f or L a b or at o r y 
P ar a m eters  
L a b P ar a m eter  
Se x  
A ge  
U L N  
A L T  
Fe male  
All  
3 4 U/ L  
Male  
All  
4 3 U/ L  
A S T  
Fe male  
< 1 8  
4 0 U/ L  
≥ 1 8  
3 4 U/ L  
Male  
< 1 8  
4 0 U/ L  
≥ 1 8  
3 6 U/ L  
T B L  
 
 
Ce ntral la b U L N  
I N R 
 
 
Ce ntral la b U L N  
Uri nal ysis  res ults ot her t ha n p H a n d s pecific gra vit y will n ot be s u m marize d.  Res ults n ot 
s u m marize d i ncl u de of k et o nes, pr otei n, bl o o d, gl uc ose, clarit y, c ol or, le u k oc ytes, nitrite, 


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bilir u bi n, a n d micr osc o pic e xa mi nati o ns (if i n dicat e d base d o n la b orat or y res ults), uri ne 
micr osc o pic fi n di n gs, a n d pre g na nc y t est res ults will n ot be s u m marize d .   
La b orat or y res ults t hat ar e a b o ve or b el o w n or mal li mits will be fla g ge d  i n t he listi n gs.   
1 2. 3.  
Vit al Si g ns  
Descri pti ve statistics f or bl o o d press ure, heart rate, res pirat or y rate, a n d t e m perat ure i n cl u di n g 
baseli ne val ues a n d c ha n ge fr o m baseli ne v al ues, will be s u m marize d b y ti me p oi nt f or eac h rare 
C K D  c o h ort.   
1 2. 4.  
B o d y Wei g ht  
Descri pti ve statistics f or b o d y wei g ht t hat are c ollecte d o n t he e C R F a n d c ha n ge fr o m b aseli ne 
val ues will be  s u m marize d b y ti me p oi nt f or eac h rare C K D  c o h ort.  I n a d diti o n, n u m ber a n d 
perce nt a ge of p atie nt s w h o e x perie n ce a fi ve - p o u n d ( 2. 3 kil o gra m) or greater i ncrease i n wei g ht  
will be s u m marize d b y ti me p oi nt.   B o x pl ot a n d li ne gra p hs of c ha n g e fr o m baseli ne o ver ti me 
f or wei g ht will be pl otte d. S u m mar y ta bles f or b o d y wei g ht will be re peate d f or t he f oll o wi n g 
s u b gr o u ps:  
•  Wei g ht c ha n g e will als o be s u m marize d b y b aseli ne B MI ( > 3 0 a n d ≤3 0 k g/ m 2), a n d  
•  B aseli ne a ge ( > 1 8 a n d ≤1 8 ). 
1 2. 5.  
1 2 -le a d E C G 
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 , ve ntric ular rat e  a n d 
i nter val assess me nts of P R, Q R S,  Q T, a n d Q Tc F, will be c ollecte d o n t he e C R F .  Descri pti ve 
statistics f or o bser ve d val ues a n d c ha n g e fr o m bas eli ne at eac h ti me p oi nt will be prese nte d f or 
t hese 1 2-lea d E C G i nter v al assess me nts b y rare C K D  c o h ort.  I n a d diti o n, n u m ber a n d 
perce nt a ge of p atie nt s 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 hres h ol d) will be 
s u m marize d b y ti me p oi nt a n d o verall w hile o n st u d y dr u g.  T he pre-s pecifie d le vels of E C G 
Q Tc t hres h ol ds are c o nsiste nt wit h F D A g ui da nce.   
T a ble 9 :   
Pre -S pecifie d T hres h ol d Le vels f or E C G P ar a meters  
E C G P ar a m eter  
Pre -S pecifie d Le vel  
P R  
> 2 0 0 msec  
Q Tc F  
> 4 5 0, > 4 8 0 or > 5 0 0 msec > 3 0 or > 6 0 msec i ncrease fr o m baseli ne  
Heart rate  
< 4 0, > 1 0 0 beats/ mi n  
A n y  res ults t hat e xcee d t he a b o ve le v els ( pr o vi de d i n t he a b o ve ta ble) will be fla g ge d  i n t he 
listi n g. 




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R e at a C o nfi d e nti al  
I n t he e ve nt t he M M R M m o del wit h a n u nstr uct ure d c o vari a nce str u ct ure d oes n ot c o n ver g e, t he 
f oll o wi n g c o varia n ce str u ct ures will be as s u bstit uti o n i n t he f oll o wi n g or der.  Eac h s u bse q u e nt 
c o varia n ce str uct ure will be use d o nl y if all pre vi o us c o varia n ce str uct ure(s) is (are) use d a n d t h e 
m o del(s) di d n ot c o n ver g e. 
1.  T oe plitz c o varia n ce str u ct ure ( ass u mi n g meas ure me nts fr o m sa m ples ta ke n cl oser 
t o get her i n ti me are m or e hi g hl y c orrelate d t h a n t h ose fr o m sa m ples ta ke n fart her a part). 
2.  First or der of a ut o-re gr essi ve [ A R( 1)] c o vari a nce str uct ure (ass u mi n g meas ure me nts fr o m 
sa m ples ta ke n cl oser t o get her i n ti me are m ore hi g hl y c orrelat e d t ha n t h ose fr o m sa m ples 
ta ke n fart her a p art). 
3.  C o m p o u n d s y m metr y c o varia nce str uct ure (ass u mi n g e q ual 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 w he n t he y were ta k e n).  
1 2. 7. 3.  
C h a n ge fr o m B aseli ne i n A C R  
Wit hi n eac h r are C K D c o h ort, t he c ha n ge fr o m bas eli ne A C R will be s u m marize d f or all 
patie nts, as well as b y  baseli ne A C R cate g or y ( A C R ≤3 0 0, A C R > 3 0 0). S u m maries of A C R 
will use t he ge o metric m ea n wit h 9 5 % c o nfi de nce i nter vals i nstea d of t he arit h metic mea n, 
a n d will dis pla y A C R res ults i n u nits of m g/ g.  C ha n ges fr o m bas eli ne i n A C R will be 
re p orte d as t he p ost-baseli ne/ baseli ne rati os a n d will be s u m marize d b y ge o metric mea ns wit h 
9 5 % c o nfi de n ce i nter v als at eac h ti me p oi nt.   
1 3.  
P H A R M A C O KI N E TI C S  A N A L Y SI S  
Bl o o d sa m ples f or deter mi nati o n of plas ma bar d o x ol o ne met h yl a n d p ote ntial meta b olite 
c o nce ntr ati o ns will be dra w n as s h o w n i n Ta bl e 3 .  T he P K pr ofile of b ar d o x ol o ne met h yl will be 
e val uate d fr o m plas ma c o nce ntrati o n data fr o m i n di vi d ual patie nts .  T he  P K para met ers, s uc h as 
C ma x , Tma x , a n d A U C 0-t will be deter mi ne d b y Reat a or a t hir d part y ve n d or .  T he bar d o x ol o ne 
met h yl plas ma c o nce ntr ati o n data, al o n g wit h P K para meters,  will be liste d.  T he P K para m eters  
will be s u m marize d descri pti vel y  b y rare C K D c o h ort.  A d diti o nal a nal yses a n d s u m maries ma y 
be perf or me d, if w arr a nte d.