A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Effect of RBT-1 on Preconditioning Response Biomarkers in Subjects Undergoing Coronary Artery Bypass Graft (CABG) and/or Cardiac Valve Surgery (The START Study)
Phase: PHASE2
Conditions: AKI
Sponsor: Renibus Therapeutics, Inc.

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Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 2 of 3 6  
T a ble of C o nte nts 
1  
S T U D Y TI T L E ............................................................................................................ 4  
2  
S P O N S O R I N F O R M A TI O N ...................................................................................... 4  
2. 1  
S p o ns or: ............................................................................................................... 4  
2. 2  
S p o ns or Re prese ntati ve: ....................................................................................... 4  
3  
LI S T O F A B B R E VI A TI O N S ..................................................................................... 5  
4  
S T U D Y S Y N O P SI S .................................................................................................... 6  
5  
E V E N T S C H E D U L E ................................................................................................ 1 1  
6  
I N T R O D U C TI O N ..................................................................................................... 1 3 
6. 1  
Bac k gr o u n d I nf or mati o n .................................................................................... 1 3  
6. 2  
St u d y Dr u g ......................................................................................................... 1 3  
6. 3  
Precli nical E x perie nce ....................................................................................... 1 4  
6. 4  
Cli nical E x perie nce ............................................................................................ 1 4  
7  
S T U D Y O BJ E C TI V E S ............................................................................................. 1 4  
7. 1  
Pri mar y O bjecti ve .............................................................................................. 1 4  
7. 2  
Sec o n dar y O bjecti ve .......................................................................................... 1 5  
7. 3  
E x pl orat or y O bjecti ves ...................................................................................... 1 5  
8  
I N F O R M E D C O N S E N T ........................................................................................... 1 5 
9  
S T U D Y P O P U L A TI O N ............................................................................................ 1 6  
9. 1  
I ncl usi o n Criteria ............................................................................................... 1 6 
9. 2  
E xcl usi o n Criteria .............................................................................................. 1 6  
9. 3  
St u d y Desi g n ...................................................................................................... 1 7  
9. 3. 1  
St o p pi n g R ules .......................................................................................... 1 8  
9. 4  
Rec or d kee pi n g a n d M o nit ori n g ......................................................................... 1 8  
9. 5  
I n vesti gati o nal Pr o d uct ...................................................................................... 1 9 
9. 5. 1  
St u d y Dr u g Descri pti o n ............................................................................ 1 9  
9. 5. 2  
Pac ka gi n g .................................................................................................. 1 9  
9. 5. 3  
I n vesti gati o nal Pr o d uct Dis pe nsi n g .......................................................... 1 9 
9. 5. 4  
D osa ge Pre parati o n a n d A d mi nistrati o n ................................................... 1 9  
9. 5. 5  
St ora ge Re q uire me nts ............................................................................... 2 0  
9. 5. 6  
I n vesti gati o nal Pr o d uct Acc o u nta bilit y ..................................................... 2 0 
9. 5. 7  
Retrie val a n d Destr ucti o n ......................................................................... 2 0  
9. 6  
Ra n d o mizati o n a n d Bli n di n g ............................................................................. 2 0  
9. 7  
St u d y Visits ........................................................................................................ 2 0  
9. 7. 1  
Scree ni n g ( Wit hi n 1 Wee k Pri or t o Visit 1) .............................................. 2 0  
9. 7. 2  
Visit 1a ...................................................................................................... 2 1  
9. 7. 3  
Visit 1 b ...................................................................................................... 2 2  
9. 7. 4  
Visit 2 ( Da y 1) .......................................................................................... 2 2  
9. 7. 5  
Visits 3 – 8 ( Da ys 2 – 7) or Disc har ge ...................................................... 2 2  
9. 7. 6  
Visit 9 ( Da y 3 0) ........................................................................................ 2 3  
9. 7. 7  
Visit 1 0 ( Da y 6 0) ...................................................................................... 2 3  
9. 7. 8  
Visit 1 1 ( Da y 9 0)/ Fi nal Visit .................................................................... 2 4  
9. 8  
Cli nical La b orat or y E val uati o ns ........................................................................ 2 4  
9. 9  
Cli nical Pr oce d ures a n d O bser vati o ns ............................................................... 2 4  
9. 9. 1  
Me dical Hist or y ........................................................................................ 2 4  
9. 9. 2  
C o nc o mita nt Me dicati o ns ......................................................................... 2 4  

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 3 of 3 6  
9. 9. 3  
P h ysical E xa mi nati o n ................................................................................ 2 5  
9. 9. 4  
Vital Si g ns ................................................................................................. 2 5  
1 0  A D V E R S E E V E N T R E P O R TI N G ........................................................................... 2 5  
1 0. 1  I n vesti gat or Re p orti n g Re q uire me nts ................................................................ 2 6 
1 0. 2  Assess me nt of Relati o ns hi p t o St u d y Dr u g ....................................................... 2 8  
1 0. 3  Assess me nt of Se verit y ...................................................................................... 2 9  
1 0. 4  Brea ki n g t he Bli n d ............................................................................................. 2 9  
1 1  S T A TI S TI C A L C O N SI D E R A TI O N S ...................................................................... 2 9  
1 1. 1  Criteria f or E val uati o n ....................................................................................... 2 9  
1 1. 2  St u d y P o p ulati o ns .............................................................................................. 3 0  
1 1. 3  Data A nal ysis ..................................................................................................... 3 0  
1 1. 4  Sa m ple Size Calc ulati o ns ................................................................................... 3 1  
1 2  WI T H D R A W A L F R O M S T U D Y ............................................................................ 3 1  
1 3  D A T A M A N A G E M E N T .......................................................................................... 3 1  
1 3. 1  Data base L oc k .................................................................................................... 3 1  
1 4  E T HI C A L C O N SI D E R A TI O N S .............................................................................. 3 2  
1 4. 1  Et hical C o n d uct of t he St u d y ............................................................................. 3 2  
1 4. 2  Re g ulat or y C o nsi derati o ns ................................................................................. 3 2  
1 4. 3  Pr ot oc ol A me n d me nts a n d St u d y Ter mi nati o n .................................................. 3 2  
1 4. 4  Safet y M o nit ori n g .............................................................................................. 3 3  
1 4. 5  Q ualit y C o ntr ol a n d Q ualit y Ass ura nce ............................................................. 3 3  
1 5  G E N E R A L C O N SI D E R A TI O N S ............................................................................. 3 3  
1 5. 1  Disc o nti n uati o n of t he St u d y ............................................................................. 3 3  
1 6  A G R E E M E N T WI T H P R O T O C O L ......................................................................... 3 4  
1 7  R E F E R E N C E S .......................................................................................................... 3 5  
 
 
 
 
 

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Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 5 of 3 6  
3  LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n 
Defi niti o n 
A KI  
ac ute ki d ne y i nj ur y 
C A B G 
c or o nar y arter y b y pass graft 
C F R 
C o de of Fe deral Re g ulati o ns 
C P B 
car di o p ul m o nar y b y pass 
e C R F 
electr o nic case re p ort f or m 
e G F R 
esti mate d gl o mer ular filtrati o n rate 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
Fe S  
ir o n s ucr ose 
G C P 
G o o d Cli nical Practice 
H O - 1 
he me o x y ge nase- 1 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I L- 1 0 
i nterle u ki n- 1 0 
I N D 
I n vesti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
i ntra ve n o us 
I W R S 
K DI G O 
I nteracti ve We b Res p o nse S yste m 
Ki d ne y Disease I m pr o vi n g Gl o bal O utc o mes 
KI M- 1 
ki d ne y i nj ur y m olec ule- 1 
M A K E  
Maj or A d verse Ki d ne y E ve nts 
M A K E 3 0 
Maj or A d verse Ki d ne y E ve nts t hr o u g h Da y 3 0 p ost-
car diac s ur ger y 
M A K E 9 0 
Maj or A d verse Ki d ne y E ve nts t hr o u g h Da y 9 0 p ost-
car diac s ur ger y 
N G A L  
ne utr o p hil gelati nase-ass ociate d li p ocali n 
R B T- 1 
sta n n o us pr ot o p or p h yri n a n d ir o n s ucr ose  
S A P  
S n P P 
statistical a nal ysis pla n 
sta n n o us pr ot o p or p h yri n 
 
A b bre viati o ns use d o nl y i n ta bles a n d fi g ures are defi ne d i n t he ta ble a n d fi g ure f o ot n otes 
a n d are n ot i ncl u de d i n t he List of A b bre viati o ns. 
 
 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 6 of 3 6  
4  S T U D Y S Y N O P SI S  
Re ni b us T her a pe utics, I nc.  
Pr ot oc ol N o. R E N -0 0 4  
N a me of Dr u g:  R B T - 1 
P h ase of De vel o p me nt:  2 
N a me of Acti ve I n gre die nts:  
Sta n n o us pr ot o p or p h yri n ( S n P P) a n d ir o n s ucr ose ( Fe S)  
D ate of St u d y S y n o psis:  
2 5 A u g  2 0 2 2 
Pr ot oc ol Title:  
A P hase 2, D o u ble -Bli n d, Ra n d o mize d, Place b o -C o ntr olle d St u d y t o E val uate t he Effect of R B T -1 o n 
Prec o n diti o ni n g Res p o nse Bi o mar kers i n S u bjects U n der g oi n g C or o nar y Arter y B y pass Graft ( C A B G) 
a n d/ or Car diac Val ve S ur ger y ( T he S T A R T St u d y)  
I n vesti g ati o n al Sites: 
U p t o 2 0 sites i n t he U nite d States, Ca na da, A ustralia, a n d Ne w Zeala n d.  
St u d y O bjecti ves:  
T he o verall o bjecti ve is t o e val uate t he effect of R B T -1 o n prec o n diti o ni n g res p o nse bi o mar kers i n s u bjects 
u n der g oi n g C A B G a n d/ or car diac val ve s ur ger y.  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve is t o e val uate t he efficac y of R B T -1 i n ge nerati n g  a prec o n diti o ni n g res p o nse as 
meas ure d b y plas ma bi o mar kers ( he me o x y ge nase -1 [ H O -1], ferriti n, a n d i nterle u ki n -1 0 [I L -1 0]) fr o m 
Baseli ne ( pre -d ose) t hr o u g h Da y 1 p re-o p.  
Sec o n d ar y O bjecti ves  
T he sec o n dar y o bjecti ves are t o e val uate t he efficac y of R B T -1 o n t he f oll o wi n g:  
•  
C ha n ge i n re nal t u b ular i nj ur y bi o mar kers p ost -car diac s ur ger y t hr o u g h Da y 3.  
•  
Re d ucti o n i n uri ne o ut p ut ( d oc u me nte d oli g uria of < 0. 5 m L/ k g/ h o ur, n ot d ue t o uri nar y tract 
o bstr ucti o n or h y p ote nsi o n) f or m ore t ha n 6 h o urs p ost -car diac s ur ger y t hr o u g h Da y 3.  
•  
I nci de nce of ac ute ki d ne y i nj ur y ( A KI) ( defi ne d usi n g t he m o difie d Ki d ne y Disease I m pr o vi n g 
Gl o bal O utc o mes [ K DI G O] criteria) p ost -car diac s ur ger y t hr o u g h Da y 5.  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bjecti ves are t o e val uate t he f oll o wi n g:  
•  
Se verit y of A KI p ost -car diac s ur ger y t hr o u g h Da y 7.  
•  
Mea n i ncrease i n ser u m creati ni ne p ost -car diac s ur ger y t hr o u g h Da y 7 or u ntil Disc har ge if pri or 
t o Da y 7. 
•  
Occ urre nce of Maj or A d verse Ki d ne y E ve nts ( M A K E) – deat h, nee d f or dial ysi s, a n d persiste nt 
re nal d ysf u ncti o n – p ost -car diac s ur ger y t hr o u g h Da y 3 0 ( M A K E 3 0) a n d Da y 9 0 ( M A K E 9 0) 
p ost -car diac s ur ger y.  
•  
Pr o p orti o n of s u bjects e x perie nci n g M A K E 3 0.  
•  
Pr o p orti o n of s u bjects e x perie nci n g M A K E 9 0.  
•  
Da ys o n ve ntilat or.  
•  
Da ys i n i nte nsi ve care u nit (I C U).  
•  
H os pital le n gt h of sta y.  
•  
Rea d missi o n rate.  
•  
C ha n ges i n bi o mar kers of R B T -1 acti vit y a n d/ or ki d ne y f u ncti o n.  

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 7 of 3 6  
St u d y Desi g n:  
T his is a P hase 2, m ultice nter, d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d st u d y t o e val uate t he effect of 
R B T -1 o n prec o n diti o ni n g res p o nse bi o mar kers i n s u bjects w h o are at ris k f or A KI f oll o wi n g car diac 
s ur ger y. Eli gi ble s u bjects will be ra n d o mize d t o recei ve a si n gle d ose of l o w-d ose R B T -1 ( 4 5 m g S n P P/ 2 4 0 
m g Fe S), hi g h -d ose R B T -1 ( 9 0 m g S n P P/ 2 4 0 m g Fe S), or place b o ( n or mal sali ne) via i ntra ve n o us (I V) 
i nf usi o n o ver a 1 2 0-mi n ute peri o d ≥2 4 b ut ≤4 8 h o urs pri or t o sc he d ule d car diac 
s ur ger y.                                                                                                                                                                                                         
All s u bjects will be assesse d t hr o u g h Da y  9 0 p ost -car diac s ur ger y. S u bjects will be e val uate d at Scree ni n g, 
4 8 a n d/ or 2 4 h o urs pri or t o s ur ger y de pe n di n g o n t he ti me of d osi n g, o n Da y 1 ( da y of s ur ger y), a n d dail y 
t hr o u g h Da y 7 or Disc har ge if earlier, as well as o n Da ys 3 0, 6 0, a n d 9 0, as describe d i n t he E ve nt Sc he d ule 
(see Secti o n 5 ). Assess me nts i ncl u de bi o mar kers of prec o n diti o ni n g res p o nse a n d t u b ular i nj ur y, uri ne 
o ut p ut, i nci de nce a n d se verit y of A KI , ser u m creati ni ne, da ys o n ve ntilat or, da ys i n i nte nsi ve care u nit, 
h os pital le n gt h of sta y, rea d missi o n rate, a n d safet y ( p h ysical e xa mi nati o n, cli nical la b orat or y assess me nt, 
vital si g ns, c o nc o mita nt me dicati o ns, a n d a d verse e ve nts). E val uati o ns f or M A K E ( deat h, nee d f or dial ysis, 
a n d c ha n ge i n ki d ne y f u ncti o n) a n d safet y will be perf or me d t hr o u g h Da y 9 0, as descri be d i n t he E ve nt 
Sc he d ule (see Secti o n 5 ). 
N u m ber of S u bjects t o be E nr olle d:  
A p pr o xi matel y 1 2 6 s u bjects are pla n ne d t o be e nr olle d a n d ra n d o mize d 1: 1: 1 t o l o w d ose R B T -1, hi g h -
d ose R B T -1, a n d place b o ( n = 4 2/ gr o u p).  
I ncl usi o n Criteri a: 
Eli gi ble s u bjects m ust meet all t he f oll o wi n g criteria: 
1.  Male or fe male s u bjects ≥1 8 years of a ge at Scree ni n g.  
2.  A ble a n d willi n g t o c o m pl y wit h all st u d y pr oce d ures.  
3.  Sta ble ki d ne y f u ncti o n per I n vesti gat or assess me nt a n d n o k n o w n e pis o des of A KI d uri n g t he 
prece di n g 4 wee ks.  
4.  Sc he d ule d t o u n der g o n o n -e mer ge nt car diac s ur ger y  re q uiri n g car di o p ul m o nar y b y pass ( C P B), w hic h 
m ust i ncl u de o ne of t he f oll o wi n g : 
•  
C A B G al o ne;  
•  
C o m bi ne d C A B G a n d car diac val ve(s) re place me nt or re pair ; 
•  
Car diac val ve(s) re place me nt or re pair al o ne. 
5.  Fe male a n d male s u bjects of c hil d beari n g p ote ntial m ust a gree t o use 2 f or ms of c o ntrace pti o n, wit h at 
least 1 bei n g a barrier met h o d, or a bstai n fr o m se x ual acti vit y for 3 0 da ys f oll o wi n g st u d y dr u g 
a d mi nistrati o n.  
6.  Male s u bjects m ust a gree n ot t o d o nate or sell s per m f or 3 0 da ys f oll o wi n g st u d y dr u g a d mi nistrati o n.  

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
Pa ge 8 of 3 6  
E xcl usi o n Criteri a:  
S u bjects will be i neli gi ble f or st u d y partici pati o n if t he y meet a n y of t he f oll o wi n g criteria: 
1.  Prese nce of A KI at t he ti me of Scree ni n g , as deter mi ne d b y t he I n vesti gat or. 
2.  S ur ger y t o be perf or me d wit h o ut car di o p ul m o nar y b y pass  ( C P B). 
3.  A si g nifica nt p orti o n of t he  sur ger y t o be perf or me d u n der c o n diti o ns of circ ul at or y arrest or 
h y p ot her mia wit h rectal te m perat ure < 2 8 °C ( 8 2. 4 °F) , as deter mi ne d b y t he I n vesti gat or i n c o ns ultati o n 
wit h t he Me dical M o nit or . 
4.  e G F R ≤2 0 m L/ mi n/ 1. 7 3 m 2 or nee d f or  dial ysis.  
5.  S ur ger y f or a ortic dissecti o n or t o c orrect a maj or c o n ge nital heart defect.  
6.  A d mi nistrati o n of i o di nate d c o ntrast me dia wit hi n 2 4 h o urs pri or t o car diac s ur ger y or e vi de nce of 
c o ntrast-i n d uce d ne p hr o pat h y pri or t o car diac s ur ger y. 
7.  Car di o ge nic s h oc k or he m o d y na mic i nsta bilit y wit hi n t he 2 4 h o urs pri or t o s ur ger y a n d re q uire me nt f or 
i n otr o pes or vas o press ors or ot her mec ha nical de vices, s uc h as i ntra-a ortic ball o o n c o u nter -p ulsati o n.  
8.  Re q uire me nt f or a n y of t he f oll o wi n g wit hi n 7 da ys pri or t o car diac s ur ger y : 
•  
Defi brillat or or per ma ne nt pace ma ker;  
•  
Mec ha nical ve ntilati o n;  
•  
I ntra-a ortic ball o o n c o u nter -p ulsati o n;  
•  
Left ve ntric ular assist de vice;  
•  
Ot her f or ms of mec ha nical circ ulat or y s u p p ort.  
9.  K n o w n hist or y of ca ncer wit hi n t he past 2 years, e xce pt f or carci n o ma i n sit u of t he cer vi x or 
a de q uatel y treate d n o n -mela n o ma ca ncer  of t he s ki n.  
1 0.  K n o w n or s us pecte d se psis at ti me of Scree ni n g or c o nfir me d or treate d e n d ocar ditis wit hi n 3 0  da ys 
pri or t o car diac s ur ger y.  
1 1.  Ot her c urre nt acti ve i nfecti o n re q uiri n g s yste mic a nti bi otic treat me nt.  
1 2.  A b n or mal he patic f u ncti o n, defi ne d as t otal bilir u bi n or ala ni ne a mi n otra nsferase or as partate 
a mi n otra nsferase > 2 X t he u p per li mit of n o r mal at ti me of Scree ni n g or C hil d P u g h Class C li ver 
disease or hi g her.  
1 3.  C o n ge nital c oa g ulati o n dis or der  ass ociate d wit h a hi g h ris k of e xcessi ve blee di n g or t hr o m b osis  per 
I n vesti gat or assess me nt . 
1 4.  As ple nia (a nat o mic or f u ncti o nal).  
1 5.  Hist or y of p h ot ose nsiti vit y or acti ve s ki n disease t hat, i n t he o pi ni o n of t he I n vesti gat or, c o ul d be 
w orse ne d b y R B T -1.  
1 6.  K n o w n h y perse nsiti vit y or pre vi o us a na p h yla xis t o S n P P or a n y ti n -base d pr o d uct.  
1 7.  Ser u m ferriti n > 5 0 0 n g/ m L or t h ose w h o ha ve recei ve d I V ir o n wit h i n 1 4  da ys of Scree ni n g.  
1 8.  Pre g na nc y or lactati o n.  
1 9.  Treat me nt wit h a n i n vesti gati o nal dr u g or partici pati o n i n a n i nter ve nti o nal st u d y wit hi n 3 0 da ys pri or 
t o a d mi nistrati o n of st u d y dr u g. 
2 0.  I n t he o pi ni o n of t he I n vesti gat or, a n y disease pr ocesses or c o nf o u ndi n g varia bles t hat w o ul d 
i na p pr o priatel y alter t he o utc o me of t he st u d y. 
2 1.  I na bilit y 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. 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
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Pa ge 9 of 3 6  
Dr u g, D ose a n d M o de of A d mi nistr ati o n:  
R B T -1 will be s u p plie d as a sterile li q ui d (i n se parate vials of S n P P a n d Fe S ) f or I V i njecti o n a n d is 
i nte n de d f or si n gle use. I nstr ucti o ns f or d ose pre parati o n will be s pecifie d i n t he P har mac y Ma n ual. 
C o m merciall y a vaila ble 0. 9 % s o di u m c hl ori de ( n or mal sali ne) f or i njecti o n will be use d f or place b o 
a d mi nistrati o n.  
St u d y dr u g (l o w -d ose R B T -1 [ 4 5 m g S n P P/ 2 4 0 m g Fe S], hi g h -d ose R B T -1 [ 9 0 m g S n P P/ 2 4 0 m g Fe S], or 
place b o [ n or mal sali ne]) will be a d mi nistere d via I V i nf usi o n o ver a 1 2 0 -mi n ute peri o d at ≥2 4 b ut 
≤4 8  h o urs pri or t o sc he d ule d car diac s ur ger y.  
St u d y D ur ati o n:  
St u d y d urati o n is a p pr o xi matel y 9 0 da ys per s u bject.  
Criteri a f or E v al u ati o n:  
Efficac y assess me nts i ncl u de t he f oll o wi n g:  
•  
C ha n ge i n prec o n diti o ni n g plas ma bi o mar kers t hr o u g h Da y 1 p re-o p:  
o  
H O -1, ferriti n, a n d I L -1 0.  
•  
C ha n ge i n re nal t u b ular i nj ur y bi o mar kers p ost -car diac s ur ger y t hr o u g h Da y 3:  
o  
K i d ne y i nj ur y m olec ule-1 ( KI M -1), c ystati n C, a n d ne utr o p hil gelati nase -ass ociate d 
li p ocali n ( N G A L) 
•  
Re d ucti o n i n uri ne o ut p ut ( d oc u me nte d oli g uria of < 0. 5 m L/ k g/ h o ur, n ot d ue t o uri nar y tract 
o bstr ucti o n or h y p ote nsi o n) f or m ore t ha n 6 h o urs p ost -car diac s ur ger y t hr o u g h Da y 3.  
•  
I nci de nce of A KI p ost-car diac s ur ger y t hr o u g h Da y 5, defi ne d as:  
o  
A n a bs ol ute i ncrease i n ser u m creati ni ne b y 0. 5 m g/ d L, w hic h is prese nt o ver 
2 la b orat or y meas ure me nts at least 1 2 h o urs a part; or 
o  
A n i ncrease i n ser u m creati ni ne ³ 1. 5 X Baseli ne.  
•  
Se verit y of A KI p ost -car diac s ur ger y t hr o u g h Da y 7.  
•  
Mea n i ncrease  i n ser u m creati ni ne p ost-car diac s ur ger y t hr o u g h Da y 7 or u ntil Disc har ge if pri or 
t o Da y 7. 
•  
Occ urre nce of M A K E 3 0 a n d M A K E 9 0 p ost -car diac s ur ger y.  
•  
Pr o p orti o n of s u bjects e x perie nci n g M A K E 3 0.  
•  
Pr o p orti o n of s u bjects e x perie nci n g M A K E 9 0.  
•  
Da ys o n ve ntilat or.  
•  
Da ys i n I C U.  
•  
H os pital le n gt h of sta y.  
•  
Rea d missi o n rate.  
•  
C ha n ges i n bi o mar kers of R B T -1 acti vit y a n d/ or ki d ne y f u ncti o n.  
Safet y assess me nts i ncl u de t he f oll o wi n g:  
•  
A d verse e ve nts  
•  
La b orat or y data a n d vital si g ns at re g ular i nter vals.  

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
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Pa ge 1 0  of 3 6  
St atistics: Details of t he efficac y a nal ysis a n d safet y a nal ysis will be defi ne d i n t he statistical a nal ysis pla n 
( S A P). 
A nal ysis P o p ulati o ns : T he efficac y a nal yses will be c o n d ucte d usi n g t he I nte nt -t o-Treat p o p ulati o n (all 
ra n d o mize d s u bjects) a n d Per Pr ot oc ol p o p ulati o n (all ra n d o mize d s u bjects w h o ha d n o maj or pr ot oc ol 
de viati o ns). Safet y a nal yses will be c o n d ucte d usi n g all s u bjects recei vi n g a n y a m o u nt of st u d y dr u g.  
Data A nal ysis : W he n a p pr o priate, s u m mar y statistics will be pr o vi de d ( n u m ber of n o n-missi n g val ues, 
mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles a n d n u m ber a n d 
perce nta ge of s u bjects f or cate g orical varia bles) b y treat me nt gr o u p f or all meas ures, i ncl u di n g 
de m o gra p hic a n d baseli ne assess me nts, safet y, a n d efficac y e n d p oi nts. Baseli ne f or all safet y a n d efficac y 
e n d p oi nts is defi ne d as t he last o bser vati o ns bef ore a d mi nistrati o n of st u d y dr u g.  
S a m ple Size Esti m ate: Ass u mi n g a n i ncrease of 3 0 % i n t he pri mar y bi o mar ker s fr o m baseli ne i n t he R B T-
1 treate d gr o u ps vers us a 1 0 % re d ucti o n i n t he place b o gr o u p a n d a sta n dar d de viati o n of 1 0 %, 6 s u bjects 
per gr o u p w o ul d pr o vi de 8 0 % p o wer t o detect a diff ere nce bet wee n treat me nt a n d place b o gr o u ps wit h a 
si g nifica nce le vel of 0. 0 5. Fr o m a safet y pers pecti ve, 4 0 s u bjects per gr o u p is c o nsiste nt wit h t he sa m ple 
size t y picall y use d i n earl y-sta ge cli nical trials.  

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
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Pa ge 1 1  of 3 6  
5  E V E N T S C H E D U L E  
 
Visit  
Visit 0  
( Scree ni n g) † 
Visit 1 a  
Visit 1 b † †  
Visit 2  
Visit 3  
Visit 4  
Visits 5 - 7 
Visit 8 *  
Visit 9 *  
Visit 1 0 *  
Visit 1 1 */  
Fi n al Visit  
Pr oce d ure  
Ti me p oi nt  
Wit hi n 3 0 
D a ys Pri or t o 
Visit 1  
≥2 4 h b ut 
≤4 8 h 
Pri or t o 
S ur ger y  
2 4 h  (± 4 h)  
Pri or t o 
S ur ger y  
D 1  
Pre -O p  
 
 
D 1  
P ost -O p  
D 2  
D 3  
D 4, 5, 6  
(If  
H os pit alize d)  
D 7  
(± 3 da ys)   
D 3 0  
(± 3 da ys)  
D 6 0  
(± 3 da ys)  
D 9 0  
(± 3 da ys)  
I nf or me d C o nse nt F or m 
X 
 
 
 
 
 
 
 
 
 
 
 
Patie nt Eli gi bilit y  
(I ncl usi o n/ E xcl usi o n  
Criteria)  
X 
X 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X 
 
 
 
 
 
 
 
 
 
 
 
Pri or/ C o nc o mita nt  
Me dicati o n  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P h ysical E xa m  
X 
X 
 
X 
 
X 1 
X 1 
X 1 
X  
X  
 
X  
Wei g ht a n d B MI  
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital Si g ns  
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Ser u m C he mistr y 2 
X 3 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
He mat ol o g y  4 
X  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Uri nal ysis 5 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Uri ne O ut p ut 6 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Bl o o d Bi o mar kers 7 
 
X 
X 
X 8 
 
X 
X 
 
 
 
 
 
Uri nar y  
Bi o mar kers 9 
 
X 
X 
X 8 
 
X 
X 
 
 
 
 
 
Uri ne Pre g na nc y Test 1 0 
X 
 
 
 
 
 
 
 
 
X 
 
 
St u d y Dr u g I nf usi o n 1 1 
 
X 
 
 
 
 
 
 
 
 
 
 
A d verse E ve nts 1 2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B MI = b o d y m ass i n de x; D = D a y; h = h o ur; P ost -O p = p ost -o perati vel y; Pre -O p = pre -o perati vel y  
 
†  Scree ni n g la bs will be a nal yze d at a l ocal la b orat or y; f or s u bjects w h o will be a d mi nistere d st u d y dr u g o n t he sa m e da y of Sc ree ni n g, bl o o d a n d uri ne sa m ples will nee d t o be c ollecte d f or ce ntral 
la b orat or y a nal ysis i n acc or da nce wit h Visit 1a; p h ysical e xa mi nati o ns a n d r o uti ne la bs (ser u m c he mistr y, he mat ol o g y, uri nal ysis) perf or me d as part of sta n dar d of care wit hi n 1 m o nt h of d osi n g 
a d mi nistrati o n ( Visit 1a) ca n be use d f or Scree ni n g assess me nts . 
† †   Visit 1 b will be perf or m e d i n s u bjects w h o recei ve st u d y dr u g wi t hi n 3 6 t o 4 8 h o urs pri or t o s ur ger y. 
*  Visits 8 -1 1 ( D a ys 7, 3 0, 6 0, a n d 9 0) m a y be c o n d ucte d re m otel y as virt ual visits if i n -pers o n visits are n ot p ossi ble; if virt ual visits are c o n d ucte d: 1) bl o o d a n d uri ne sa m ples m a y be c ollecte d b y 
re m ote p hle b ot o my, s uc h as t hr o u g h a m o bile p hle b ot o mist or ot her bl o o d c ollecti o n ce nter a n d 2) p h ysical e xa mi nati o ns ca n be s y m pt o m -directe d.  
 
1 
P h ysical e xa mi nati o n ca n be s y m pt o m -directe d o n D a ys 2 - 6.  

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Pa ge 1 2  of 3 6  
2  
S er u m c he mistr y para m eters i ncl u de t otal pr otei n, al b u mi n, bicar b o nate, bl o o d urea nitr o ge n, ser u m creati ni ne, t otal bilir u bi n , al kali ne p h os p hatase, gl uc ose, s o di u m, p otassi u m, p h os p hate, calci u m, 
m a g nesi u m, ga m m a -gl uta m yl tra nsferase, ala ni ne a mi n otra nsfe rase, as partate a mi n otra nsferase, a n d c ystati n C.  
3 
Ser u m ferriti n is als o t o be assesse d at Scree ni n g if n ot alrea d y i ncl u de d i n l ocal la b orat or y c he mistr y pa nel.  
4 
H e m at ol o g y para m eters i ncl u de re d bl o o d cell c o u nt [ R B C], he m o gl o bi n, he mat ocrit, mea n c or p usc ular v ol u m e [ M C V], m ea n c or p usc ular he m o gl o bi n [ M C H], m ea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n [ M C H C], platelets, m ea n platelet v ol u me [ M P V], re d cell distri b uti o n wi dt h [ R D W], w hite bl o o d cell c o u nt [ W B C],  a n d W B C differe ntial (i ncl u di n g ne utr o p hil s [a bs ol ute a n d 
perce nta ge], l y m p h oc ytes [a bs ol ute a n d perce nta ge], m o n oc ytes [a bs ol ute a n d perce nta ge], e osi n o p hils [a bs ol ute a n d perce nta ge ], a n d bas o p hils [a bs ol ute a n d perce nta ge]). 
5 
Uri nal ysis para m eters i ncl u de gl uc ose, ket o nes, le u k oc ytes, nitrite,  bl o o d, p H, pr otei n, s pecific gra vit y, a n d refle x micr osc o pic.  
6 
Uri ne o ut p ut will be m eas ure d t hr o u g h D a y 3. 
7 
Bl o o d bi o m ar kers i ncl u de prec o n diti o ni n g res p o nse bi o m ar kers ( plas m a he m e o x y ge nase -1 [ H O -1], ferriti n, a n d i nterle u ki n-1 0 [I L -1 0]) a n d ot her bi o m ar kers of R B T -1 acti vit y a n d ki d ne y f u ncti o n.  
8 
Bl o o d a n d uri nar y bi o m ar kers will be c ollecte d wit hi n 4 h o ur s pri or t o car diac s ur ger y.  
9 
Uri nar y bi o m ar kers i ncl u de t u b ular i nj ur y bi o m ar kers ( ki d ne y i nj ur y m olec ule -1 [ KI M-1], c ystati n C, a n d ne utr o p hil gelati nase -ass ociate d li p ocali n [ N G A L]), a n d ot her bi o mar kers of R B T -1 acti vit y 
a n d ki d ne y f u ncti o n.  
1 0 A pre g na nc y test will be perf or m e d i n fe m ale s u bjects of c hil d beari n g p ote ntial.  
1 1 R B T -1 a n d place b o will be a d mi ni stere d via i ntra ve n o us i nf usi o n o ver a 1 2 0-mi n ute peri o d.  
1 2 A d verse e ve nts assess m e nt will i ncl u de p h ot ose nsiti vit y assess me nt.  
 
 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
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Pa ge 1 3  of 3 6  
6  I N T R O D U C TI O N 
6. 1  
B ac k gr o u n d I nf or m ati o n 
I n car diac s ur ger y s u bjects, t he i nci de nce of p ost o perati ve ac ute ki d ne y i nj ur y ( A KI) is 
a p pr o xi matel y 3 0 % a n d si g nifica ntl y i ncreases t he ris k of deat h after car diac s ur ger y 
[R os ner 2 0 0 6 ]. A KI ca n lea d t o a n u m ber of c o m plicati o ns, i ncl u di n g meta b olic aci d osis, 
h y per kale mia, ure mia, c ha n ges i n b o d y fl ui d bala nce, a n d effects o n ot her or ga n s yste ms, 
i ncl u di n g nee d f or dial ysis a n d p ossi bl y deat h [Kell u m 2 0 1 3 ]. Pr o gressi o n t o 
a d va nce d-sta ge c hr o nic ki d ne y disease wit hi n 2 4 m o nt hs occ urs i n a p pr o xi matel y 1 5 % t o 
2 0 % of s u bjects w h o s ur vi ve A KI [ C ha wla 2 0 1 2 ].  
T he dia g n osis of A KI is base d o n t he f oll o wi n g criteria i ntr o d uce d b y t he Ki d ne y Disease 
I m pr o vi n g Gl o bal O utc o mes ( K DI G O) A KI W or k Gr o u p i n 2 0 1 2 [K DI G O 2 0 1 2 ]: 
i ncrease i n ser u m creati ni ne ≥0. 3 m g/ d L wit hi n 4 8 h o urs; i ncrease i n ser u m 
creati ni ne ≥1. 5 X baseli ne, w hic h is k n o w n or pres u me d t o ha ve occ urre d wit hi n t he pri or 
7 da ys; or uri ne v ol u me < 0. 5 m L/ k g/ h o ur f or 6 h o urs. T he ma na ge me nt of A KI is p urel y 
s y m pt o matic, wit h t he ai m of li miti n g da ma ge a n d pre ve nti n g f urt her l oss of f u ncti o n. N o 
p har mac ol o gic t hera p y is a p pr o ve d f or t he treat me nt or pre ve nti o n of A KI. 
It has l o n g bee n rec o g nize d t hat after a n i nitial isc he mic or t o xic i nj ur y, t he ki d ne y 
de vel o ps mar ke d resista nce t o s u bse q ue nt da ma ge [ H o n da 1 9 8 7 , Za ger 1 9 8 4 , 
Za ger 1 9 9 5a , Za ger 1 9 9 5 b , Za ger 1 9 9 5c ]. T his p he n o me n o n, w hic h is me diate d i n part 
b y a n u pre g ulati o n of re nal c yt o pr otecti ve a n d a nti-i nfla m mat or y stress pr otei ns 
(e g, he me o x y ge nase 1 [ H O- 1], ferriti n, ha pt o gl o bi n, he m o pe xi n, he pci di n, al p ha- 1 
a ntitr y psi n, i nterle u ki n- 1 0 [I L- 1 0]), has bee n referre d t o as “isc he mic prec o n diti o ni n g” or 
“ac q uire d c yt oresista nce.” T his p he n o me n o n c o ul d be use d i n a cli nical setti n g t o 
pree m pti vel y pr otect or ga ns, es peciall y w he n a k n o w n i ns ult is a p pr oac hi n g. 
6. 2  
St u d y Dr u g  
A p har mac ol o gical i nter ve nti o n wit h t he a bilit y t o sti m ulate t he ki d ne y’s nat ural 
pr otecti ve pat h wa ys t o pre ve nt A KI w o ul d re prese nt a si g nifica nt me dical a d va nce.  
R B T- 1 is c o m prise d of 2 differe nt c o m p o u n ds, ir o n s ucr ose ( Fe S) a n d sta n n o us 
pr ot o p or p h yri n ( S n P P). Fe S is a n i ntra ve n o us (I V) ir o n re place me nt pr o d uct t hat has bee n 
i n use f or m ore t ha n 6 5 years a n d is c urre ntl y re gistere d i n m ore t ha n 9 0 c o u ntries 
w orl d wi de. I n t he U nite d States, Fe S is a p pr o ve d f or t he treat me nt of ir o n deficie nc y 
a ne mia i n pe diatric a n d a d ult patie nts wit h c hr o nic ki d ne y disease [ Ve n ofer 2 0 1 5 ], wit h 
e x pa n de d i n dicati o ns (ie, nee d f or ra pi d ir o n s u p pl y, patie nts u na ble t o t olerate or c o m pl y 
wit h oral ir o n t hera p y, patie nts wit h i nfla m mat or y b o wel disease i n w h o m oral ir o n 
t hera p y is i neffecti ve) a p pr o ve d f or use o utsi de t he U nite d States [Ve n ofer 2 0 1 6 ]. Ti n 
pr ot o p or p h yri n, a p ote nt c o m petiti ve i n hi bit or of he me o x y ge nase acti vit y, is n ot 
c o m merciall y a vaila ble, b ut has bee n safel y a d mi nistere d t o healt h y v ol u nteers 
[A n ders o n 1 9 8 6 , Ber gl u n d 1 9 8 8 , E mtesta m 1 9 9 3 ], ter m ne w b or ns wit h 
h y per bilir u bi ne mia [ Ka p pas 1 9 8 8 ], a n d a d ult s u bjects wit h he patic d ysf u ncti o n affecti n g 
he me meta b olis m or bilir u bi n c o nj u gati o n [ A n ders o n 1 9 8 6 , Ber gl u n d 1 9 9 0 ] or p or p h yria 
[D o ver 1 9 9 3 , Gal brait h 1 9 8 9 ]. 

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R B T- 1 me diates prec o n diti o ni n g c yt oresista nce i n t he ki d ne y b y acti vati n g t he b o d y’s 
maj or a nti o xi da nt res p o nse pat h wa y, res ulti n g i n t he u pre g ulati o n of c yt o pr otecti ve 
pr otei ns, i ncl u di n g b ut n ot li mite d t o H O- 1, ferriti n, a n d I L- 1 0.  
R B T- 1 is u n der de vel o p me nt as a pr o p h ylactic a ge nt t o i n d uce c yt oresista nce i n or ga ns 
w he n a k n o w n i ns ult is i m mi ne nt. 
6. 3  
Precli nic al E x perie nce 
R B T- 1 has bee n s h o w n t o i n d uce pr of o u n d re nal prec o n diti o ni n g a n d t he e mer ge nce of a 
c yt o pr otecti ve state i n a ni mal m o dels t hat res ulte d i n mar ke d pr otecti o n a gai nst di verse 
f or ms of A KI [Za ger 2 0 1 6 ]. I n c o ntrast t o isc he mic prec o n diti o ni n g, w hic h i n d uces l ocal 
or re m ote isc he mia, t he ac q uire d c yt oresista nce i n d uce d b y R B T- 1 was ac hie ve d wit h o ut 
res ulta nt da ma ge t o t he ki d ne y, li ver, or heart. T h us, t hese data s u g gest t hat R B T- 1 ma y 
pr o vi de a cli nical pr o p h ylactic strate g y f or pr otecti n g a gai nst b ot h re nal a n d e xtrare nal 
i nj uries pri or t o a n i ns ult, s uc h as e x p os ure t o s ur ger y, ball o o n a n gi o plast y, or 
a d mi nistrati o n of a ra di oc o ntrast a ge nt, or ne p hr ot o xic c he m ot hera p y. 
I nitial n o n-cli nical p har mac ol o g y a n d t o xic ol o g y st u dies ha ve bee n c o n d ucte d a n d are 
detaile d i n t he I n vesti gat or’s Br oc h ure. Si n gle- d ose ac ute t o xicit y st u dies of I V R B T- 1 
de m o nstrate d n o-a d verse-effect-le vels of 2 5 m g/ k g Fe S/ 1 0 m g/ k g S n P P i n t he rat a n d 
7. 5 m g/ k g Fe S/ 3 m g/ k g S n P P i n t he d o g. Si n gle-e xte n de d ac ute d ose t o xicit y st u dies of 
I V S n P P de m o nstrate d n o-a d verse-effect-le vels of 1 0 m g/ k g S n P P i n t he rat ( h u ma n 
e q ui vale nt d ose of 9 6 m g) a n d t he d o g ( h u ma n e q ui vale nt d ose of 3 2 4 m g). 
6. 4  
Cli nic al E x perie nce 
P hase 1 st u dies i n healt h y v ol u nteers a n d s u bjects wit h Sta ge 3/ 4 c hr o nic ki d ne y disease 
ha ve de m o nstrate d t hat t he c yt o pr otecti ve pr otei ns (‘res p o nse bi o mar kers’) i n d uce d b y 
R B T- 1 a n d its c o m p o ne nts are u pre g ulate d i n h u ma ns. R B T- 1 is safe a n d well t olerate d 
at t he hi g hest d ose teste d ( 9 0 m g S n P P a n d 2 4 0 m g Fe S). P h ot ose nsiti vit y, w hic h was 
e x pecte d, was t he pri mar y a d verse e ve nt o bser ve d, b ut was n ot d ose-li miti n g. A d verse 
e ve nts were ge nerall y mil d t o m o derate i n se verit y. N o seri o us a d verse e ve nts were 
re p orte d. 
T he c urre nt st u d y is a P hase 2, m ultice nter, d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d 
st u d y t o e val uate t he effect of R B T- 1 o n prec o n diti o ni n g res p o nse bi o mar kers i n s u bjects 
w h o are at ris k f or A KI f oll o wi n g car diac s ur ger y. It is h y p ot hesize d t hat treat me nt wit h 
R B T- 1 pri or t o sc he d ule d car diac s ur ger y will i ncrease res p o nse bi o mar kers, re d uci n g t he 
i nci de nce of A KI p ost-car diac s ur ger y. 
7  S T U D Y O B J E C TI V E S  
T he o verall o bjecti ve is t o e val uate t he effect of R B T- 1 o n prec o n diti o ni n g res p o nse 
bi o mar kers i n s u bjects u n der g oi n g C A B G a n d/ or car diac val ve s ur ger y. 
7. 1  
Pri m ar y O bjecti ve 
T he pri mar y o bjecti ve is t o e val uate t he efficac y of R B T- 1 i n ge nerati n g a 
prec o n diti o ni n g res p o nse as meas ure d b y plas ma bi o mar kers ( H O- 1, ferriti n, a n d I L- 1 0) 
fr o m Baseli ne ( pre- d ose) t hr o u g h Da y 1 pre- o p.  

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7. 2  
Sec o n d ar y O bjecti ve 
T he sec o n dar y o bjecti ves are t o e val uate t he efficac y of R B T- 1 o n t he f oll o wi n g: 
•  C ha n ge i n re nal t u b ular i nj ur y bi o mar kers p ost-car diac s ur ger y t hr o u g h Da y 3. 
•  Re d ucti o n i n uri ne o ut p ut ( d oc u me nte d oli g uria of < 0. 5 m L/ k g/ h o ur, n ot d ue t o 
uri nar y tract o bstr ucti o n or h y p ote nsi o n) f or m ore t ha n 6 h o urs p ost-car diac 
s ur ger y t hr o u g h Da y 3. 
•  I nci de nce of A KI ( defi ne d usi n g t he m o difie d K DI G O criteria) p ost-car diac 
s ur ger y t hr o u g h Da y 5. 
7. 3  
E x pl or at or y O bjecti ves 
T he e x pl orat or y o bjecti ves are t o e val uate t he f oll o wi n g: 
•  Se verit y of A KI p ost-car diac s ur ger y t hr o u g h Da y 7. 
•  Mea n i ncrease i n ser u m creati ni ne p ost-car diac s ur ger y t hr o u g h Da y 7 or u ntil 
Disc har ge if pri or t o Da y 7. 
•  Occ urre nce of M A K E 3 0 a n d M A K E 9 0 p ost-car diac s ur ger y. 
•  Pr o p orti o n of s u bjects e x perie nci n g M A K E 3 0. 
•  Pr o p orti o n of s u bjects e x perie nci n g M A K E 9 0. 
•  Da ys o n ve ntilat or. 
•  Da ys i n I C U. 
•  H os pital le n gt h of sta y. 
•  Rea d missi o n rate. 
•  C ha n ges i n bi o mar kers of R B T- 1 acti vit y a n d/ or ki d ne y f u ncti o n. 
8  I N F O R M E D C O N S E N T 
T he I n vesti gat or or desi g nee will be res p o nsi ble f or o btai ni n g a si g ne d, writte n i nf or me d 
c o nse nt f or m (I C F) a n d pr o vi di n g a c o p y t o eac h s u bject, le gall y a ut h orize d g uar dia n, or 
a pers o n wit h le gal res p o nsi bilit y f or t he s u bject’s healt h care decisi o ns pri or t o t he 
perf or ma nce of a n y cli nical acti vities or pr oce d ures p urs ua nt t o t his pr ot oc ol. S u bjects 
w h o are visi o n i m paire d ma y ha ve t he I C F rea d t o t he m a n d t heir wit nesse d c o nse nt 
d oc u me nte d. O nl y t he c o nse nt f or m a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d (I R B) or 
I n de pe n de nt Et hics C o m mittee (I E C) will be use d. If E n glis h is N O T t he s u bject’s 
pri mar y la n g ua ge, t he s u bject will be c o nse nte d usi n g a n I R B/I E C-a p pr o ve d I C F i n t he 
re q uisite la n g ua ge. T his c o nse nt will be c o n d ucte d b y a me m ber of t he researc h tea m 
w h o is fl ue nt i n t he la n g ua ge a n d t h us a ble t o a ns wer a n y scie ntific or pr oce d ural 
q uesti o ns raise d b y a n o n- E n glis h s pea ki n g s u bject. 

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9  S T U D Y P O P U L A TI O N  
9. 1  
I ncl usi o n Criteri a  
Eli gi ble s u bjects m ust meet all t he f oll o wi n g criteria: 
1.  Male or fe male s u bjects ≥1 8 years of a ge at Scree ni n g. 
2.  A ble a n d willi n g t o c o m pl y wit h all st u d y pr oce d ures. 
3.  Sta ble ki d ne y f u ncti o n per I n vesti gat or assess me nt a n d n o k n o w n e pis o des of 
A KI d uri n g t he prece di n g 4 wee ks. 
4.  Sc he d ule d t o u n der g o n o n-e mer ge nt car diac s ur ger y re q uiri n g car di o p ul m o nar y 
b y pass ( C P B), w hic h m ust i ncl u de o ne of t he f oll o wi n g: 
•  C A B G al o ne; 
•  C o m bi ne d C A B G a n d car diac val ve(s) re place me nt or re pair; 
•  Car diac val ve(s) re place me nt or re pair al o ne. 
5.  Fe male a n d male s u bjects of c hil d beari n g p ote ntial m ust a gree t o use 2 f or ms of 
c o ntrace pti o n, wit h at least 1 bei n g a barrier met h o d, or a bstai n fr o m se x ual 
acti vit y f or 3 0 da ys f oll o wi n g st u d y dr u g a d mi nistrati o n. 
6.  Male s u bjects m ust a gree n ot t o d o nate or sell s per m f or 3 0 da ys f oll o wi n g st u d y 
dr u g a d mi nistrati o n. 
9. 2  
E xcl usi o n Criteri a  
S u bjects will be i neli gi ble f or st u d y partici pati o n if t he y meet a n y of t he f oll o wi n g 
criteria: 
1.  Prese nce of A KI at t he ti me of Scree ni n g, as deter mi ne d b y t he I n vesti gat or. 
2.  S ur ger y t o be perf or me d wit h o ut car di o p ul m o nar y b y pass ( C P B). 
3.  A si g nifica nt p orti o n of t he s ur ger y t o be perf or me d u n der c o n diti o ns of 
circ ulat or y arrest or h y p ot her mia wit h rectal te m perat ure < 2 8° C ( 8 2. 4° F), as 
deter mi ne d b y t he I n vesti gat or i n c o ns ultati o n wit h t he Me dical M o nit or. 
4.  e G F R ≤2 0 m L/ mi n/ 1. 7 3 m 2 or nee d f or dial ysis. 
5.  S ur ger y f or a ortic dissecti o n or t o c orrect a maj or c o n ge nital heart defect. 
6.  A d mi nistrati o n of i o di nate d c o ntrast me dia wit hi n 2 4 h o urs pri or t o car diac 
s ur ger y or e vi de nce of c o ntrast-i n d uce d ne p hr o pat h y pri or t o car diac s ur ger y. 
7.  Car di o ge nic s h oc k or he m o d y na mic i nsta bilit y wit hi n t he 2 4 h o urs pri or t o 
s ur ger y a n d re q uire me nt f or i n otr o pes or vas o press ors or ot her mec ha nical 
de vices, s uc h as i ntra-a ortic ball o o n c o u nter- p ulsati o n. 
8.  Re q uire me nt f or a n y of t he f oll o wi n g wit hi n 7 da ys pri or t o car diac s ur ger y: 
•  Defi brillat or or per ma ne nt pace ma ker; 
•  Mec h a nical ve ntilati o n; 

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•  I ntra-a ortic ball o o n c o u nter- p ulsati o n; 
•  Left ve ntric ular assist de vice; 
•  Ot her f or ms of mec ha nical circ ulat or y s u p p ort. 
9.  K n o w n hist or y of ca ncer wit hi n t he past 2 years, e xce pt f or carci n o ma i n sit u of 
t he cer vi x or a de q uatel y treate d n o n- mela n o ma ca ncer of t he s ki n. 
1 0.  K n o w n or s us pecte d se psis at ti me of Scree ni n g or c o nfir me d or treate d 
e n d ocar ditis wit hi n 3 0 da ys pri or t o car diac s ur ger y. 
1 1.  Ot her c urre nt acti ve i nfecti o n re q uiri n g s yste mic a nti bi otic treat me nt. 
1 2.  A b n or mal he patic f u ncti o n, defi ne d as t otal bilir u bi n or ala ni ne a mi n otra nsferase 
or as partate a mi n otra nsferase > 2 X t he u p per li mit of n or mal at ti me of Scree ni n g 
or C hil d P u g h Class C li ver disease or hi g her. 
1 3.  C o n ge nital c oa g ulati o n dis or der ass ociate d wit h a hi g h ris k of e xcessi ve blee di n g 
or t hr o m b osis per I n vesti gat or assess me nt. 
1 4.  As ple nia (a nat o mic or f u ncti o nal) 
1 5.  Hist or y of p h ot ose nsiti vit y or acti ve s ki n disease t hat, i n t he o pi ni o n of t he 
I n vesti gat or, c o ul d be w orse ne d b y R B T- 1. 
1 6.  K n o w n h y perse nsiti vit y or pre vi o us a na p h yla xis t o S n P P or a n y ti n- base d 
pr o d uct. 
1 7.  Ser u m ferriti n > 5 0 0 n g/ m L or t h ose w h o ha ve recei ve d I V ir o n wit hi n 1 4 da ys of 
Scree ni n g. 
1 8.  Pre g na nc y or lactati o n. 
1 9.  Treat me nt wit h a n i n vesti gati o nal dr u g or partici pati o n i n a n i nter ve nti o nal st u d y 
wit hi n 3 0 da ys pri or t o a d mi nistrati o n of st u d y dr u g. 
2 0.  I n t he o pi ni o n of t he I n vesti gat or, a n y disease pr ocesses or c o nf o u n di n g varia bles 
t hat w o ul d i na p pr o priatel y alter t he o utc o me of t he st u d y. 
2 1.  I na bilit y 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. 
9. 3  
St u d y Desi g n  
T his is a P hase 2, m ultice nter, d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d st u d y t o 
e val uate t he effect of R B T- 1 o n prec o n diti o ni n g res p o nse bi o mar kers i n s u bjects w h o are 
at ris k f or A KI f oll o wi n g car diac s ur ger y. Eli gi ble s u bjects will be ra n d o mize d t o recei ve 
a si n gle d ose of l o w- d ose R B T- 1 ( 4 5 m g S n P P/ 2 4 0 m g Fe S), hi g h- d ose R B T- 1 ( 9 0 m g 
S n P P/ 2 4 0 m g Fe S), or place b o ( n or mal sali ne) via I V i nf usi o n o ver a 1 2 0- mi n ute peri o d 
≥2 4 b ut ≤4 8 h o urs pri or t o sc he d ule d car diac s ur ger y. 
All s u bjects will be assesse d t hr o u g h Da y 9 0 p ost-car diac s ur ger y. S u bjects will be 
e val uate d at Scree ni n g, 4 8 a n d/ or 2 4 h o urs pri or t o s ur ger y de pe n di n g o n t he ti me of 
d osi n g, o n Da y 1 ( da y of s ur ger y) a n d dail y t hr o u g h Da y 7 or Disc har ge if earlier, as well 
as o n Da ys 3 0, 6 0, a n d 9 0,  as descri be d i n t he E ve nt Sc he d ule (see Secti o n 5 ). 
Assess me nts i ncl u de bi o mar kers of prec o n diti o ni n g res p o nse a n d t u b ular i nj ur y, uri ne 

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o ut p ut, i nci de nce a n d se verit y of A KI, ser u m creati ni ne, da ys o n ve ntilat or, da ys i n I C U, 
h os pital le n gt h of sta y, rea d missi o n rate, a n d safet y ( p h ysical e xa mi nati o n, cli nical 
la b orat or y assess me nt, vital si g ns, c o nc o mita nt me dicati o ns, a n d a d verse e ve nts). 
E val uati o ns f or M A K E ( deat h, nee d f or dial ysis, a n d c ha n ge i n ki d ne y f u ncti o n) a n d 
safet y will be perf or me d t hr o u g h Da y 9 0, as descri be d i n t he E ve nt Sc he d ule (see Secti o n 
5 ). 
T he d urati o n of t he st u d y will be a p pr o xi matel y 9 0 da ys per s u bject. A sc he matic of t he 
st u d y desi g n is prese nte d bel o w: 
 
A KI = ac ute ki d ne y i nj ur y; Fe S = ir o n s ucr ose; h = h o ur; S n P P = sta n n o us pr ot o p or p h yri n  
9. 3. 1  St o p pi n g R ules 
T here are n o pre-esta blis he d st o p pi n g r ules f or t his st u d y. 
9. 4  
Rec or d kee pi n g a n d M o nit ori n g 
All s u bject data will be re p orte d i n t he electr o nic data ca pt ure s yste m, e xce pt f or ce ntral 
la b orat or y re p orts, w hic h will be u pl oa de d b y electr o nic tra nsfer b y t he ce ntral 
la b orat or y. All ori gi nal s o urce d oc u me nts s h o ul d be a vaila ble f or peri o dic m o nit ori n g 
a n d/ or retrie val b y a S p o ns or re prese ntati ve desi g nee. T he I n vesti gat or is res p o nsi ble f or 
t he acc urac y of all data e ntere d i n t he electr o nic case re p ort f or ms (e C R Fs) a n d f or t he 
ti mel y c o m pleti o n of t he e C R Fs. T he s u p p orti n g d oc u me ntati o n will be mai ntai ne d at t he 
site f or a mi ni m u m of eit her: 
1.  T w o ( 2) years f oll o wi n g t he a p pr o val of R B T- 1 f or t his i n dicati o n b y t he F o o d 
a n d Dr u g A d mi nistrati o n ( F D A) 
R B T -1 (L o w D os e) : 
4 5 m g S n P P/ 2 4 0 m g F e S
N = 4 2
R B T -1 ( Hi g h D os e):
9 0 m g S n P P/ 2 4 0 m g F e S
N = 4 2
Pl ac e b o
N = 4 2
T ot al, n = 1 2 6
S af et y Ass ess m e nt
A KI I nci d e nc e/ S e v erit y a n d M aj or A d v ers e Ki d n e y Ev e nts Ass ess m e nt
D ay
-3 0
Scr e e ni n g
- 1
0
D osi n g
( ≥2 4 b ut ≤4 8 h 
pri or t o 
c ar di ac s ur g er y)
1
2
5
6
7
9 0
E n d of 
St u d y
6 0
3 0
3
4
Bi o m ar k er Ass ess m e nt
Disc h ar g e
R a n d o miz ati o n

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or 
2.  T w o ( 2) years f oll o wi n g n otificati o n b y t he S p o ns or t o t he F D A of t he 
ter mi nati o n of t he e ntire i n vesti gati o n. 
T he S p o ns or m ust be c o ntacte d a n d gi ve writte n a ut h orizati o n pri or t o a n y st u d y rec or ds 
bei n g destr o ye d at i n vesti gati ve sites. 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h G o o d Cli nical Practice ( G C P), w hic h 
i ncl u des t he S p o ns or- a n d I R B/I E C-a p pr o ve d pr ot oc ol a n d I C F a n d t he F D A a n d 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) re g ulat or y g ui deli nes a n d re q uire me nts. 
N o c ha n ges will be ma de wit h o ut pri or a p pr o val u nless it is i m perati ve f or s u bject safet y. 
A n y s uc h de part ures fr o m t he pr ot oc ol will be re p orte d i m me diatel y t o t he S p o ns or a n d 
rele va nt I R B/I E C. 
All s u bjects’ me dical rec or ds a n d st u d y-relate d d oc u me nts will be ma de a vaila ble t o t he 
S p o ns or f or re g ular m o nit ori n g a n d a u dits, as well as t o t he I R B/I E C a n d F D A or ot her 
g o ver n me ntal a ge nc y wit h o versi g ht or c o m plia nce res p o nsi bilities f or ass uri n g s u bject 
ri g hts a n d welfare. 
9. 5  
I n vesti g ati o n al Pr o d uct  
S u bjects will be ra n d o mize d t o recei ve a si n gle d ose of d o u ble- bli n d R B T- 1 (l o w- d ose 
R B T- 1 [ 4 5 m g S n P P/ 2 4 0 m g Fe S] or hi g h- d ose R B T- 1 [ 9 0 m g S n P P/ 2 4 0 m g Fe S]) or 
place b o ( n or mal sali ne). 
9. 5. 1  St u d y Dr u g Descri pti o n 
T he i n vesti gati o nal pr o d uct ( R B T- 1) is a c o m bi nati o n of S n P P i n a s ol uti o n of s o di u m 
h y dr o xi de a n d of Fe S i n a sali ne s ol uti o n b uffere d wit h s o di u m bicar b o nate. 
C o m merciall y a vaila ble 0. 9 % s o di u m c hl ori de ( n or mal sali ne) f or i njecti o n will be use d 
f or place b o a d mi nistrati o n at st u d y sites.  
9. 5. 2  P ac k a gi n g 
R B T- 1 will be s u p plie d as a sterile li q ui d (i n se parate vials of S n P P a n d Fe S) f or I V 
i njecti o n a n d is i nte n de d f or si n gle use. Glass vials of 5 m L are pl u g ge d wit h 
Tefl o n-c oate d r u b ber st o p pers a n d seale d wit h al u mi n u m seals. 
9. 5. 3  I n vesti g ati o n al Pr o d uct Dis pe nsi n g 
All i n vesti gati o nal pr o d ucts will be dis pe nse d b y desi g nate d a n d trai ne d site p har mac y 
staff.  
9. 5. 4  D os a ge Pre p ar ati o n a n d A d mi nistr ati o n 
Detaile d i nstr ucti o ns f or d ose pre parati o n will be s pecifie d i n t he P har mac y Ma n ual. 
St u d y dr u g ( R B T- 1 or place b o) will be a d mi nistere d via I V i nf usi o n o ver a 1 2 0- mi n ute 
peri o d ≥2 4 b ut ≤4 8 h o urs pri or t o sc he d ule d car diac s ur ger y. St u d y dr u g a d mi nistrati o n 
ma y be perf or me d i n a n o ut patie nt setti n g. 
S u bjects will be o bser ve d f or si g ns a n d s y m pt o ms of h y perse nsiti vit y d uri n g st u d y dr u g 
a d mi nistrati o n a n d f or at least 3 0 mi n utes after a d mi nistrati o n. S u bjects s h o ul d be 

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o bser ve d u ntil t he y are dee me d cli nicall y sta ble. R B T- 1 will o nl y be a d mi nistere d w he n 
pers o n nel a n d t hera pies are a vaila ble f or t he treat me nt of a n y i nf usi o n-relate d reacti o ns. 
9. 5. 5  St or a ge Re q uire me nts 
R B T- 1 s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure c o n diti o ns ( 1 5 - 3 0 °C/ 5 9 - 8 6 °F) 
a n d pr otecte d fr o m li g ht. 
9. 5. 6  I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he I n vesti gat or or desi g nee is res p o nsi ble f or mai ntai ni n g acc urate rec or ds acc o u nti n g 
f or t he recei pt, dis pe nsi n g, a n d fi nal dis p ositi o n of all i n vesti gati o nal pr o d ucts usi n g t he 
a p pr o priate i n vesti gati o nal pr o d uct l o gs pr o vi de d b y t he S p o ns or.  
9. 5. 7  Retrie v al a n d Destr ucti o n 
Peri o dicall y t hr o u g h o ut t he st u d y, sites will perf or m i n vesti gati o nal pr o d uct 
rec o nciliati o n o n a per-s u bject basis. T he S p o ns or’s site m o nit or will re vie w t he l o g a n d 
o nce a n y discre pa ncies ha ve bee n res ol ve d, a ut h orize destr ucti o n/ dis p ositi o n of t he 
s u p plies ass ociate d wit h a gi ve n s u bject b y si g ni n g t he rec o nciliati o n l o g a n d will wit ness 
t he destr ucti o n/ dis p ositi o n. 
9. 6  
R a n d o miz ati o n a n d Bli n di n g 
Eac h s u bject will be assi g ne d a n i de ntificati o n n u m ber b y t he site after t he s u bject 
pr o vi des writte n i nf or me d c o nse nt. 
T he i de ntificati o n n u m ber will c o nsist of a 7- di git n u m ber: 
•  T he first 4 di gits will desi g nate t he site n u m ber as assi g ne d b y t he S p o ns or. 
•  T he last 3 di gits will desi g nate t he or der of t he s u bject at t hat site. 
T he first s u bject w h o si g ns t he I C F at t he site is assi g ne d t he i de ntificati o n n u m ber 0 0 1, 
t he sec o n d s u bject w h o si g ns t he I C F is assi g ne d 0 0 2, t he t hir d is assi g ne d 0 0 3, etc. T he 
s u bject will mai ntai n t he sa me i de ntificati o n n u m ber t hr o u g h o ut t he e ntire st u d y. If a 
s u bject si g ns t he I C F b ut d oes n ot meet t he i ncl usi o n/e xcl usi o n criteria, t he s u bject will 
be mar ke d as a scree n fail ure o n t he Scree ni n g a n d E nr oll me nt L o g pr o vi de d b y t he 
S p o ns or a n d will be e ntere d i n t he electr o nic data ca pt ure s yste m as a scree n fail ure. 
If t he s u bject q ualifies f or st u d y e ntr y after Scree ni n g, t he site staff will use t he 
I nteracti ve We b Res p o nse S yste m (I W R S) t o o btai n t he s u bject’s ra n d o mize d, d o u ble-
bli n de d treat me nt assi g n me nt.  
9. 7  
St u d y Visits 
9. 7. 1  Scree ni n g ( Wit hi n 3 0 D a ys Pri or t o Visit 1) 
St u d y ca n di dates will be e val uate d f or st u d y e ntr y acc or di n g t o t he state d i ncl usi o n a n d 
e xcl usi o n criteria ( Secti o ns 9. 1  a n d 9. 2 , res pecti vel y). T he f oll o wi n g pr oce d ures will be 
perf or me d d uri n g Scree ni n g t o esta blis h eac h ca n di date’s eli gi bilit y f or e nr oll me nt i nt o 
t he st u d y:  
•  O btai n si g ne d, writte n i nf or me d c o nse nt. T he i nf or me d c o nse nt m ust be si g ne d 
bef ore a n y pr oce d ures are perf or me d.  

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•  Rec or d de m o gra p hic i nf or mati o n.  
•  Rec or d me dical hist or y. 
•  Rec or d c o nc o mita nt me dicati o ns.  
•  Perf or m p h ysical e xa mi nati o n, i ncl u di n g wei g ht a n d b o d y mass i n de x. 
•  Rec or d vital si g ns. 
•  O btai n uri ne sa m ple f or pre g na nc y testi n g of fe male s u bjects of c hil d beari n g 
p ote ntial.  
•  O btai n bl o o d sa m ples f or ser u m c he mistr y a n d he mat ol o g y testi n g.  
•  Assess ser u m ferriti n if n ot alrea d y i ncl u de d i n t he l ocal la b orat or y c he mistr y 
pa nel. 
•  O btai n uri ne sa m ple f or uri nal ysis. 
T he I n vesti gat or will e val uate t he res ults of all e xa mi nati o ns, i ncl u di n g cli nical 
la b orat or y tests, a n d deter mi ne eac h ca n di date’s s uita bilit y f or t he st u d y acc or di n g t o t he 
eli gi bilit y criteria.  
Scree ni n g a n d d osi n g ca n occ ur o n t he sa me da y if all pre- d ose assess me nts c o m plete d 
a n d e val uate d pri or t o d osi n g. H o we ver, if Scree ni n g a n d d osi n g occ ur o n t he sa me da y, 
bl o o d a n d uri ne sa m ples will nee d t o be c ollecte d f or ce ntral la b orat or y a nal ysis pri or t o 
d osi n g, as w o ul d be d o ne o n Visit 1a. 
P h ysical e xa mi nati o ns a n d r o uti ne la bs (ser u m c he mistr y, he mat ol o g y, uri nal ysis) 
perf or me d as part of sta n dar d of care wit hi n 1 m o nt h of d osi n g a d mi nistrati o n ( Visit 1a) 
ca n be use d f or Scree ni n g assess me nts. 
9. 7. 2  Visit 1 a 
T he f oll o wi n g pr oce d ures will be perf or me d pri or t o d osi n g:  
•  Re-c o nfir m s u bject’s eli gi bilit y t o partici pate i n t he st u d y.  
•  Rec or d c o nc o mita nt me dicati o ns. 
•  Perf or m p h ysical e xa mi nati o n.  
•  Rec or d vital si g ns. 
•  O btai n bl o o d sa m ples f or ser u m c he mistr y, he mat ol o g y, a n d bl o o d bi o mar ker 
testi n g.  
•  O btai n uri ne sa m ple f or uri nar y bi o mar ker testi n g. 
•  Access t he I W R S t o o btai n t he s u bject’s ra n d o mize d, bli n de d treat me nt 
assi g n me nt (see Secti o n 9. 6 ). 
O nce all pre- d ose pr oce d ures ha ve bee n c o m plete d: 
•  St u d y dr u g ( R B T- 1 or place b o) will be a d mi nistere d via I V i nf usi o n o ver a 
1 2 0- mi n ute peri o d u n der t he s u per visi o n of t he I n vesti gat or/ desi g nee. T he date, 

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rate of i nf usi o n, t otal v ol u me of i nf usi o n, a n d start/st o p ti mes of d osi n g will be 
rec or de d.  
•  S olicit a n y a d verse e ve nts. 
9. 7. 3  Visit 1 b 
Visit 1 b will be c o n d ucte d i n s u bjects w h o are a d mi nistere d st u d y dr u g wit hi n 3 6 t o 4 8 
h o urs pri or t o car diac s ur ger y. T he f oll o wi n g pr oce d ures will be perf or me d: 
•  Rec or d c o nc o mita nt me dicati o ns. 
•  O btai n bl o o d sa m ples f or bl o o d bi o mar ker testi n g.  
•  O btai n uri ne sa m ple f or uri nar y bi o mar ker testi n g. 
•  S olicit a n y a d verse e ve nts. 
9. 7. 4  Visit 2 ( D a y 1)  
9. 7. 4. 1  Pri or t o C ar di ac S ur ger y 
T he f oll o wi n g pr oce d ures will be perf or me d pri or t o t he sc he d ule d car diac s ur ger y o n 
Da y  1:  
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Perf or m p h ysical e xa mi nati o n.  
•  Rec or d vital si g ns. 
•  O btai n bl o o d sa m ples f or ser u m c he mistr y, he mat ol o g y, a n d bl o o d bi o mar ker 
testi n g.  
•  O btai n uri ne sa m ple f or uri nar y bi o mar ker testi n g. 
•  S olicit a n y a d verse e ve nts. 
9. 7. 4. 2  P ost- C ar di ac S ur ger y 
T he f oll o wi n g pr oce d ures will be perf or me d p ost-car diac s ur ger y o n Da y 1:  
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Meas ure uri ne o ut p ut. 
•  S olicit a n y a d verse e ve nts. 
9. 7. 5  Visits 3 – 8 ( D a ys 2 – 7) or Disc h ar ge, If E arlier 
T he f oll o wi n g pr oce d ures will be perf or me d dail y o n Da ys 2 – 7 or disc har ge, if earlier, 
fr o m t he h os pital:  
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Perf or m p h ysical e xa mi nati o n; o n Da ys 2 – 6, p h ysical e xa mi nati o n ca n be 
s y m pt o m- directe d.  
•  Rec or d vital si g ns.  

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•  O btai n bl o o d sa m ples f or ser u m c he mistr y a n d he mat ol o g y. 
•  Meas ure uri ne o ut p ut ( Da ys 2 a n d 3 o nl y). 
•  O btai n bl o o d sa m ples f or bl o o d bi o mar ker testi n g ( Da ys 2 a n d 3 o nl y).  
•  O btai n uri ne sa m ple f or uri nar y bi o mar ker testi n g ( Da ys 2 a n d 3 o nl y). 
•  S olicit a n y a d verse e ve nts. 
N ote t hat t he Da y 7 visit ma y be c o n d ucte d re m otel y as a virt ual visit if a n i n- pers o n visit 
is n ot p ossi ble. If a virt ual visit is c o n d ucte d: 1) bl o o d a n d uri ne sa m ples ma y be 
c ollecte d b y re m ote p hle b ot o m y, s uc h as t hr o u g h a m o bile p hle b ot o mist or ot her bl o o d 
c ollecti o n ce nter, a n d 2) t he p h ysical e xa mi nati o n ca n be s y m pt o m- directe d.  
9. 7. 6  Visit 9 ( D a y 3 0) 
S u bjects will ret ur n t o t he site o n Da y 3 0 f or t he f oll o wi n g pr oce d ures: 
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Perf or m p h ysical e xa mi nati o n.  
•  Rec or d vital si g ns.  
•  O btai n bl o o d sa m ples f or ser u m c he mistr y a n d he mat ol o g y.  
•  O btai n uri ne sa m ple f or uri nal ysis. 
•  O btai n uri ne sa m ple f or pre g na nc y testi n g i n fe male s u bjects of c hil d beari n g 
p ote ntial.  
•  S olicit a n y a d verse e ve nts. 
N ote t hat t he Da y 3 0 visit ma y be c o n d ucte d re m otel y as a virt ual visit if a n i n- pers o n 
visit is n ot p ossi ble. If a virt ual visit is c o n d ucte d: 1) bl o o d a n d uri ne sa m ples ma y be 
c ollecte d b y re m ote p hle b ot o m y, s uc h as t hr o u g h a m o bile p hle b ot o mist or ot her bl o o d 
c ollecti o n ce nter, a n d 2) t he p h ysical e xa mi nati o n ca n be s y m pt o m- directe d. 
9. 7. 7  Visit 1 0 ( D a y 6 0) 
S u bjects will ret ur n t o t he site o n Da y 6 0 f or t he f oll o wi n g pr oce d ures: 
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Rec or d vital si g ns.  
•  O btai n bl o o d sa m ples f or ser u m c he mistr y a n d he mat ol o g y.  
•  S olicit a n y a d verse e ve nts. 
N ote t hat t he Da y 6 0 visit ma y be c o n d ucte d re m otel y as a virt ual visit if a n i n- pers o n 
visit is n ot p ossi ble. If a virt ual visit is c o n d ucte d, bl o o d a n d uri ne sa m ples ma y be 
c ollecte d b y re m ote p hle b ot o m y, s uc h as t hr o u g h a m o bile p hle b ot o mist or ot her bl o o d 
c ollecti o n ce nter. 

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9. 7. 8  Visit 1 1 ( D a y 9 0)/ Fi n al Visit  
S u bjects will ret ur n t o t he site o n Da y 9 0 f or t he f oll o wi n g pr oce d ures: 
•  Rec or d c ha n ges i n c o nc o mita nt me dicati o ns. 
•  Perf or m p h ysical e xa mi nati o n, i ncl u di n g wei g ht a n d b o d y mass i n de x.  
•  Rec or d vital si g ns.  
•  O btai n bl o o d sa m ples f or ser u m c he mistr y a n d he mat ol o g y.  
•  O btai n uri ne sa m ple f or uri nal ysis. 
•  S olicit a n y a d verse e ve nts. 
N ote t hat t he Da y 9 0 visit ma y be c o n d ucte d re m otel y as a virt ual visit if a n i n- pers o n 
visit is n ot p ossi ble. If a virt ual visit is c o n d ucte d: 1) bl o o d a n d uri ne sa m ples ma y be 
c ollecte d b y re m ote p hle b ot o m y, s uc h as t hr o u g h a m o bile p hle b ot o mist or ot her bl o o d 
c ollecti o n ce nter, a n d 2) t he p h ysical e xa mi nati o n ca n be s y m pt o m- directe d. 
9. 8  
Cli nic al L a b or at or y E v al u ati o ns 
Scree ni n g la b orat or y sa m ples will be pr ocesse d at a l ocal la b orat or y. All ot her la b orat or y 
sa m ples will be pr ocesse d at a ce ntral la b orat or y. Eac h of t he la b orat or y para meters t o be 
e val uate d d uri n g t he st u d y a n d c ollecti o n ti mes i ncl u di n g ser u m c he mistr y, he mat ol o g y, 
uri nal ysis, pre g na nc y testi n g, a n d bi o mar kers are detaile d i n t he E ve nt Sc he d ule (see 
Secti o n 5 ). C ystati n C will o nl y be meas ure d at Baseli ne ( Visit 1a) a n d o n Da ys 3 0 ( Visit 
9) a n d 9 0 ( Visit 1 1). 
R o uti ne la bs (ser u m c he mistr y, he mat ol o g y, uri nal ysis) perf or me d as part of sta n dar d of 
care wit hi n 1 m o nt h of d osi n g a d mi nistrati o n ( Visit 1a) ca n be use d f or Scree ni n g 
assess me nts.  
Bl o o d a n d uri ne sa m ples ma y be c ollecte d b y re m ote p hle b ot o m y, s uc h as t hr o u g h a 
m o bile p hle b ot o mist or ot her bl o o d c ollecti o n ce nter, f or a visit c o n d ucte d virt uall y o n 
Da y 7, 3 0, 6 0, or 9 0. Detaile d i nstr ucti o ns re gar di n g sa m ple c ollecti o n a n d pr ocessi n g are 
pr o vi de d i n t he la b orat or y ma n ual.  
9. 9  
Cli nic al Pr oce d ures a n d O bser v ati o ns 
I n vesti gat ors/st u d y staff will re g ularl y m o nit or s u bjects t hr o u g h o ut st u d y partici pati o n. 
At eac h p ost-car diac s ur ger y visit, t he I n vesti gat or/st u d y staff will rec or d w het her or n ot 
t he s u bject is i n t he I C U, o n a ve ntilat or, has bee n disc har ge d fr o m t he h os pital, or 
rea d mitte d t o t he h os pital. 
9. 9. 1  
Me dic al Hist or y 
A c o m plete me dical hist or y will be o btai ne d at Scree ni n g. 
9. 9. 2  
C o nc o mit a nt Me dic ati o ns  
All c o nc o mita nt me dicati o ns ta ke n b y t he s u bject fr o m t he ti me of Scree ni n g t hr o u g h 
Da y 9 0 will be rec or de d.  
C o nc o mita nt me dicati o ns t hat ca n ca use p h ot ose nsiti vit y s h o ul d be a v oi de d, if p ossi ble, 
d uri n g t he st u d y.  

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9. 9. 3  
P h ysic al E x a mi n ati o n 
P h ysical e xa mi nati o ns will be perf or me d b y t he I n vesti gat or or desi g nee w h ose lice nse 
per mits t he perf or mi n g of p h ysical e xa mi nati o ns at t he ti me p oi nts defi ne d i n t he E ve nt 
Sc he d ule (see Secti o n 5 ). P h ysical e xa mi nati o ns s h o ul d be perf or me d at Scree ni n g, pri or 
t o d osi n g, pri or t o car diac s ur ger y o n Da y 1, Da y 7, Da y 3 0, a n d Da y 9 0.  
P h ysical e xa mi nati o ns perf or me d as part of sta n dar d of care wit hi n 1 m o nt h of d osi n g 
a d mi nistrati o n ( Visit 1a) ca n be use d f or Scree ni n g assess me nts.  
S y m pt o m- directe d p h ysical e xa mi nati o ns ma y be perf or me d o n Da ys 2 – 6. S y m pt o m-
directe d p h ysical e xa mi nati o ns ma y als o be perf or me d o n Da ys 7, 3 0, a n d 9 0 if t h ose 
visits are c o n d ucte d virt uall y. 
Wei g ht a n d b o d y mass i n de x will be c ollecte d at Scree ni n g a n d o n Da y 9 0. 
9. 9. 4  Vit al Si g ns 
Vital si g ns ( bl o o d press ure, p ulse rate, b o d y te m perat ure) will be c ollecte d t hr o u g h o ut t he 
st u d y at t he ti me p oi nts defi ne d i n t he E ve nt Sc he d ule (see Secti o n 5 ). D uri n g 
h os pitalizati o n, vital si g ns will be rec or de d o nce per da y.  
1 0  A D V E R S E E V E N T R E P O R TI N G  
All a d verse e ve nts will be rec or de d o n t he desi g nate d st u d y e C R F f or eac h s u bject 
be gi n ni n g wit h t he first a d mi nistrati o n of i n vesti gati o nal pr o d uct a n d e n di n g wit h t he date 
of t he e n d of st u d y treat me nt f oll o w- u p ( Da y 9 0). A d verse e ve nts will be f oll o we d b y t he 
I n vesti gat or u ntil e ve nt res ol uti o n, t he s u bject is l ost t o f oll o w- u p, or t he a d verse e ve nt is 
ot her wise e x plai ne d or n ot c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or. A d verse 
e ve nts n ot res ol ve d b y Da y 9 0 will be c o nsi dere d o n g oi n g. 
A d verse e ve nts assess me nts will i ncl u de p h ot ose nsiti vit y assess me nt. Beca use safet y data 
fr o m I V S n P P a d mi nistrati o n at d oses u p t o 3 m g/ k g has s h o w n p h ot ose nsiti vit y i n 
s u bjects e x p ose d t o s u nli g ht or ultra vi olet- A li g ht f oll o wi n g d osi n g [A n ders o n 1 9 8 6 , 
Ber gl u n d 1 9 9 0 , D o ver 1 9 9 3 , Gal brait h 1 9 8 9 , Ka p pas 1 9 8 8 ], s u bjects will be a d vise d t o 
d o t he f oll o wi n g f or 3 0 da ys f oll o wi n g treat me nt a d mi nistrati o n: 
•  Wear a br oa d-s pectr u m s u nscree n t hat is at least S P F (s u n pr otecti o n fact or) 3 0, 
e ve n o n cl o u d y or c o ol da ys. S u nscree n s h o ul d be a p plie d 3 0 mi n utes bef ore 
g oi n g o utsi de, gi vi n g t he s ki n ti me t o a bs or b it. Beca use s u nscree n te n ds t o be 
br o ke n d o w n o ver ti me b y t he s u n a n d r u b be d or was he d off wit h s weati n g a n d 
water e x p os ure, it s h o ul d be rea p plie d at least e ver y 2 h o urs o ut d o ors a n d 
i m me diatel y after s wi m mi n g or hea v y s weati n g. At least 1 o u nce ( 2 ta bles p o o ns) 
is nee de d t o c o ver t he e ntire b o d y s urface. 
•  A v oi d direct s u nli g ht, es peciall y d uri n g t he ti mes of da y w he n s u n ra ys are 
str o n gest; sit i n t he s ha de. 
•  A v oi d ta n ni n g be ds. 
•  Wear l o n g slee ves, pa nts, or l o n g s kirts w he n i n t he s u n. 
•  Wear a hat wit h a wi de bri m all t he wa y ar o u n d t o s ha de t he face, ears, a n d nec k. 

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•  Wear s u n glasses. 
1 0. 1  
I n vesti g at or Re p orti n g Re q uire me nts 
T he I n vesti gat or m ust i m me diatel y re p ort ( wit hi n 2 4 h o urs b y a writte n re p ort se nt b y fa x 
or e- mail) all seri o us a d verse e ve nts t o t he S p o ns or, re gar dless of w het her t he 
I n vesti gat or belie ves t hat t he y are dr u g-relate d, i ncl u di n g t h ose e ve nts liste d i n t he 
pr ot oc ol as a ntici pate d t o occ ur i n t he st u d y p o p ulati o n i n de pe n de nt of dr u g e x p os ure 
(see Secti o n 1 0. 2 ).  
T hese seri o us a d verse e ve nts m ust be re p orte d t o: 
B h u pi n der Si n g h, M D, F A S N, F N K F, F C R S 
Me dical M o nit or 
Re ni b us T hera pe utics, I nc. 
 
E- mail:  
S A E _ R E N 0 0 4 @re ni b us.c o m 
Fa x:  
1- 8 1 7- 8 8 7- 5 0 4 6  
 
Beca use t he I n vesti gat or is k n o wle d gea ble a b o ut t he h u ma n s u bject (e g, me dical hist or y, 
c o nc o mita nt me dicati o ns), a d mi nisters t he st u d y dr u g, m o nit ors t he s u bject’s res p o nse t o 
t he st u d y dr u g, is a ware of t he s u bject’s cli nical state a n d t h us ma y be se nsiti ve t o 
disti ncti o ns bet wee n e ve nts d ue t o a n u n derl yi n g disease pr ocess vers us e ve nts t hat ma y 
be dr u g-relate d, a n d ma y ha ve o bser ve d t he e ve nt, t he I n vesti gat or m ust i ncl u de a n 
assess me nt of ca usalit y (ie, w het her t here is a reas o na ble p ossi bilit y t hat t he st u d y dr u g 
ca use d t he e ve nt) i n t he re p ort t o t he S p o ns or. C o pies of eac h re p ort t o t he S p o ns or will 
be ke pt i n t he I n vesti gat or’s st u d y file. 
T he I n vesti gat or is res p o nsi ble f or c o m pl yi n g wit h t heir I R B/I E C’s re q uire me nts f or 
re p orti n g seri o us a d verse e ve nts. A n y e x pe dite d safet y re p ort (ie, seri o us u ne x pecte d 
s us pecte d a d verse reacti o n) recei ve d fr o m t he S p o ns or s h o ul d be s u b mitte d t o t he 
I R B/I E C. C o pies of eac h re p ort a n d d oc u me ntati o n of I R B/I E C n otificati o n will be ke pt 
i n t he i n vesti gat or’s st u d y file. 
T he I n vesti gat or m ust rec or d n o n-seri o us a d verse e ve nts i n t he e C R F a n d re p ort t he m t o 
t he S p o ns or acc or di n g t o t he ti meta ble f or re p orti n g (e g, e n d of st u d y).  
Defi niti o ns: 
A d verse E ve nt: A d verse e ve nt mea ns a n y u nt o war d me dical occ urre nce ass ociate d wit h 
t he use of a dr u g i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. A n a d verse e ve nt 
ca n be a n y u nfa v ora ble a n d u ni nte n de d si g n (e g, a n a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a dr u g, wit h o ut a n y j u d g me nt 
a b o ut ca usalit y. 
A d verse Re acti o n:  A d verse reacti o n mea ns a n y a d verse e ve nt defi nitel y ca use d b y t he 
dr u g. 
S us pecte d A d verse Re acti o n:  S us pecte d a d verse reacti o n mea ns a n y a d verse e ve nt f or 
w hic h t here is a “reas o na ble p ossi bilit y” (ie, e vi de nce i n defi nite b ut s u g gests a ca usal 
relati o ns hi p bet wee n t he dr u g a n d t he a d verse e ve nt) t hat t he dr u g ca use d t he a d verse 

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e ve nt. B y defi niti o n, a s us pecte d a d verse reacti o n is i de ntical t o t he defi niti o n of a d verse 
dr u g reacti o n per I C H E 2 A. 
E xa m ples t hat w o ul d s u g gest a ca usal relati o ns hi p: 
• A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be str o n gl y 
ass ociate d wit h dr u g e x p os ure (e g, a n gi oe de ma, he patic i nj ur y, Ste ve ns-J o h ns o n 
S y n dr o me) 
• O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b ut is ot her wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he dr u g 
(e g, te n d o n r u pt ure) 
•  A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical st u d y (e g, k n o w n 
c o nse q ue nces of t he u n derl yi n g disease or c o n diti o n u n der i n vesti gati o n or ot her 
e ve nts t hat c o m m o nl y occ ur i n t he st u d y p o p ulati o n i n de pe n de nt of dr u g t hera p y) 
t hat i n dicates t h ose e ve nts occ ur m ore fre q ue ntl y i n t he dr u g treat me nt gr o u p t ha n 
i n a c o nc urre nt or hist orical c o ntr ol gr o u p. 
U ne x pecte d A d verse E ve nt or U ne x pecte d A d verse Re acti o n:  A n a d verse e ve nt or 
a d verse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he I n vesti gat or’s 
Br oc h ure or is n ot liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d. 
A d verse e ve nts or a d verse reacti o ns t hat are me nti o ne d as occ urri n g wit h a class of dr u gs 
or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g will be c o nsi dere d 
“ u ne x pecte d” if t he y are n ot s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g 
u n der i n vesti gati o n. 
U ntil t he I n vesti gat or’s Br oc h ure is u p date d t o i ncl u de a ne w seri o us s us pecte d a d verse 
reacti o n, s u bse q ue nt occ urre nces of si milar seri o us s us pecte d a d verse reacti o ns m ust be 
s u b mitte d e x pe diti o usl y t o F D A i n I n vesti gati o nal Ne w Dr u g (I N D) Safet y Re p orts a n d 
t o ot her a p pr o priate re g ulat or y a ut h orities i n c o u ntries ot her t ha n t he U nite d States i n a n 
I n di vi d ual Case Safet y Re p ort or usi n g a C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces I f or m, as a p pr o priate. 
Seri o us A d verse E ve nt or Seri o us A d verse Re acti o n:  A n a d verse e ve nt or a d verse 
reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her t he I n vesti gat or or S p o ns or, it 
res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h. 
•  A life-t hreate ni n g a d verse e ve nt. 
•  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. 
•  A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns. 
•  A c o n ge nital a n o mal y/ birt h defect. 
I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. 

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If eit her t he I n vesti gat or or S p o ns or belie ves t hat t he e ve nt is seri o us, it m ust be e val uate d 
b y t he S p o ns or f or e x pe dite d re p orti n g t o re g ulat or y a ut h orities. 
Life- T hreate ni n g A d verse E ve nt or Life- T hreate ni n g A d verse Reacti o n:  A n a d verse 
e ve nt or s us pecte d a d verse reacti o n is c o nsi dere d “life-t hreate ni n g” if, i n t he vie w of 
eit her t he I n vesti gat or or t he S p o ns or, its occ urre nce places t he s u bject at i m me diate ris k 
of deat h. 
Seri o us U ne x pecte d S us pecte d A d verse Re acti o n:  A n a d verse e ve nt f or w hic h t here is 
a reas o na ble p ossi bilit y t hat t he dr u g ca use d t he a d verse e ve nt, a n d it is n ot liste d i n t he 
I n vesti gat or’s Br oc h ure or is n ot liste d at t he s pecificit y or se verit y t hat has bee n 
o bser ve d, a n d it res ults i n a n y of t he seri o us o utc o mes liste d a b o ve. T his criteri o n is 
c o nsiste nt wit h t he c o nce pts of F D A 2 1 C o de of Fe deral Re g ulati o n ( C F R) 3 1 2 a n d t he 
I C H E 2 A G ui deli ne f or e x pe dite d safet y re p orts. 
T he S p o ns or m ust n otif y t he a p pr o priate re g ulat or y a ut h orit y(ies) a n d all partici pati n g 
I n vesti gat ors i n a n e x pe dite d safet y re p ort (e g, I N D Safet y Re p ort or I n di vi d ual Case 
Safet y Re p ort) of p ote ntiall y seri o us ris ks fr o m cli nical st u dies or a n y ot her s o urce (ie, a 
seri o us u ne x pecte d s us pecte d a d verse reacti o n), as s o o n as p ossi ble, b ut n o later t ha n 
1 5 cale n dar da ys after t he S p o ns or recei ves t he safet y i nf or mati o n a n d deter mi nes t hat t he 
i nf or mati o n q ualifies f or re p orti n g. 
D uri n g t he c o urse of dr u g de vel o p me nt, t he S p o ns or ma y bec o me a ware of ne w safet y 
i nf or mati o n fr o m a variet y of s o urces a n d will deci de if a n i n di vi d ual case of a seri o us 
a n d u ne x pecte d a d verse e ve nt meets t he criteria f or re p orti n g t o re g ulat or y a ut h orities. 
If t he a d verse e ve nt d oes n ot meet all criteria (ie, reas o na ble p ossi bilit y of ca usalit y, 
seri o us a n d u ne x pecte d), it s h o ul d n ot be s u b mitte d as a n e x pe dite d safet y re p ort. 
A n y u ne x pecte d fatal or life-t hreate ni n g s us pecte d a d verse reacti o n m ust be re p orte d t o 
re g ulat or y a ut h orities n o later t ha n 7 cale n dar da ys after t he S p o ns or recei ves t he safet y 
i nf or mati o n. 
1 0. 2  Assess me nt of Rel ati o ns hi p t o St u d y Dr u g 
T he f oll o wi n g criteria m ust be use d t o b y t he I n vesti gat or t o c haracterize t he relati o ns hi p 
or ass ociati o n of 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 d verse e ve nt: 
U nrel ate d:  Relati o ns hi p s u g gests n o ass ociati o n of t he e ve nt t o st u d y dr u g; t he e ve nt is 
relate d t o ot her eti ol o gies, s uc h as t he s u bject’s cli nical state or c o nc o mita nt me dicati o ns 
U nli kel y:  Relati o ns hi p s u g gests a n u nli kel y ass ociati o n of t he e ve nt t o st u d y dr u g gi ve n 
t he s u bject’s c urre nt disease state 
P ossi ble:  Relati o ns hi p s u g gests treat me nt wit h st u d y dr u g ca use d or c o ntri b ute d t o t he 
e ve nt; t he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of st u d y 
dr u g a n d/ or f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g; t he e ve nt mi g ht ha ve 
bee n pr o d uce d b y ot her fact ors (e g, t he s u bject’s cli nical state or ot her m o des of t hera p y 
a d mi nistere d t o t he s u bject)  

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Rel ate d:  Relati o ns hi p s u g gests a defi nite ca usal relati o ns hi p t o st u d y dr u g; t he e ve nt 
f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g a n d ca n n ot be reas o na bl y e x plai ne d 
b y t he k n o w n c haracteristics of t he s u bject’s cli nical state or ot her m o des of t hera p y 
a d mi nistere d t o t he s u bject 
1 0. 3  Assess me nt of Se verit y 
T he f oll o wi n g criteria m ust be use d b y t he I n vesti gat or t o rate t he i nte nsit y of t he a d verse 
e ve nt: 
Mil d:  A ware ness of si g ns or s y m pt o ms, b ut easil y t olerate d a n d are of mi n or irrita nt t y pe 
ca usi n g n o l oss of ti me fr o m n or mal acti vities; s y m pt o ms d o n ot re q uire t hera p y or a 
me dical e val uati o n; si g ns a n d s y m pt o ms are tra nsie nt  
M o der ate:  E ve nts i ntr o d uce a l o w le vel of i nc o n ve nie nce or c o ncer n t o t he s u bject a n d 
ma y i nterfere wit h dail y acti vities, b ut are us uall y i m pr o ve d b y si m ple t hera pe utic 
meas ures; m o derate e x perie nces ma y ca use s o me i nterfere nce wit h f u ncti o ni n g 
Se vere:  E ve nts i nterr u pt t he s u bject’s n or mal dail y acti vities a n d ge nerall y re q uire 
s yste mic dr u g t hera p y or ot her treat me nt; t he y are us uall y i nca pacitati n g 
1 0. 4  
Bre a ki n g t he Bli n d 
T his is a d o u ble- bli n d st u d y. Brea ki n g t he bli n d i n a cli nical trial o n a n e mer ge nc y basis 
s h o ul d o nl y occ ur w he n k n o wle d ge of t he treat me nt t o w hic h a s u bject was all ocate d 
w o ul d ha ve i m plicati o ns f or t he e mer ge nc y me dical ma na ge me nt of t he s u bject or if 
re q uire d f or re g ulat or y re p orti n g. If necessar y, e mer ge nc y brea ki n g of t he bli n d ca n be 
c o n d ucte d t hr o u g h t he I nteracti ve We b Res p o nse S yste m b y t he Me dical M o nit or. T he 
reas o n f or u n bli n di n g, pers o n c o n d ucti n g t he u n bli n di n g, pers o n(s) w h o k n o w t he 
u n bli n de d treat me nt, a n d date/ti me of u n bli n di n g will be rec or de d. 
1 1   S T A TI S TI C A L C O N SI D E R A TI O N S  
T his secti o n o utli nes t he statistical c o nsi derati o ns t o be use d i n t he a nal ysis of data fr o m 
t he st u d y. A se parate S A P will descri be data ha n dli n g a n d statistical tec h ni q ues. 
1 1. 1  
Criteri a f or E v al u ati o n 
Efficac y assess me nts i ncl u de t he f oll o wi n g: 
•  C ha n ge i n prec o n diti o ni n g plas ma bi o mar kers fr o m Baseli ne ( pre- d ose) t hr o u g h 
Da y 1 pre- o p: 
o  H O - 1, ferriti n, a n d I L- 1 0  
•  C ha n ge i n re nal t u b ular i nj ur y bi o mar kers p ost- cardiac s ur ger y t hr o u g h Da y 3: 
o  KI M- 1, c ystati n C, a n d N G A L 

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•  Re d ucti o n i n uri ne o ut p ut ( d oc u me nte d oli g uria of < 0. 5 m L/ k g/ h o ur, n ot d ue t o 
uri nar y tract o bstr ucti o n) f or m ore t ha n 6 h o urs p ost-car diac s ur ger y t hr o u g h Da y 
3. 
•  I nci de nce of A KI p ost-car diac s ur ger y t hr o u g h Da y 5, defi ne d as: 
o  A n a bs ol ute i ncrease i n ser u m creati ni ne b y 0. 5 m g/ d L, w hic h is prese nt 
o ver 2 la b orat or y meas ure me nts at least 1 2 h o urs a part; or 
o  A n i ncrease i n ser u m creati ni ne ≥1. 5 X Baseli ne. 
•  Se verit y of A KI p ost-car diac s ur ger y t hr o u g h Da y 7. 
•  A vera ge i ncrease i n ser u m creati ni ne p ost-car diac s ur ger y t hr o u g h Da y 7 or u ntil 
Disc har ge if pri or t o Da y 7. 
•  Occ urre nce of M A K E 3 0 a n d M A K E 9 0 p ost-car diac s ur ger y. 
•  Pr o p orti o n of s u bjects e x perie nci n g M A K E 3 0. 
•  Pr o p orti o n of s u bjects e x perie nci n g M A K E 9 0. 
•  Da ys o n ve ntilat or. 
•  Da ys i n i nte nsi ve care u nit.  
•  H os pital le n gt h of sta y. 
•  Rea d missi o n rate. 
•  C ha n ges i n bi o mar kers of R B T- 1 acti vit y a n d/ or ki d ne y f u ncti o n. 
Safet y assess me nts i ncl u de t he f oll o wi n g: 
•  A d verse e ve nts. 
•  La b orat or y data a n d vital si g ns at re g ular i nter vals. 
1 1. 2  
St u d y P o p ul ati o ns 
T he efficac y a nal yses will be c o n d ucte d usi n g t he I nte nt- t o- Treat p o p ulati o n (all 
ra n d o mize d s u bjects) a n d Per Pr ot oc ol p o p ulati o n (all ra n d o mize d s u bjects w h o ha d n o 
maj or pr ot oc ol de viati o ns). Safet y a nal yses will be c o n d ucte d usi n g all s u bjects recei vi n g 
a n y a m o u nt of st u d y dr u g. 
1 1. 3  
D at a A n al ysis 
Details of t he efficac y a nal ysis a n d safet y a nal ysis will be defi ne d i n t he S A P. W he n 
a p pr o priate, s u m mar y statistics will be pr o vi de d ( n u m ber of n o n- missi n g val ues, mea n, 
me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bles a n d 
n u m ber a n d perce nta ge of s u bjects f or cate g orical varia bles) b y treat me nt gr o u p f or all 
meas ures, i ncl u di n g de m o gra p hic a n d baseli ne assess me nts, safet y, a n d efficac y 
e n d p oi nts. Baseli ne f or all safet y a n d efficac y e n d p oi nts is defi ne d as t he last 
o bser vati o ns bef ore a d mi nistrati o n of st u d y dr u g. 

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1 1. 4  
S a m ple Size C alc ul ati o ns 
Ass u mi n g a n i ncrease of 3 0 % i n t he pri mar y bi o mar kers fr o m baseli ne i n t he R B T- 1 
treate d gr o u ps vers us a 1 0 % re d ucti o n i n t he place b o gr o u p a n d a sta n dar d de viati o n of 
1 0 %, 6 s u bjects per gr o u p w o ul d pr o vi de 8 0 % p o wer t o detect a differe nce bet wee n 
treat me nt a n d place b o gr o u ps wit h a si g nifica nce le vel of 0. 0 5. Fr o m a safet y pers pecti ve, 
4 0 s u bjects per gr o u p is c o nsiste nt wit h t he sa m ple size t y picall y use d i n earl y-sta ge 
cli nical trials.   
1 2  WI T H D R A W A L F R O M S T U D Y  
E ver y reas o na ble eff ort s h o ul d be ma de t o mai ntai n pr ot oc ol c o m plia nce a n d 
partici pati o n i n t he st u d y. S h o ul d a s u bject wit h dra w or be pre mat urel y ter mi nate d fr o m 
t he st u d y f or a n y reas o n, t he reas o n f or earl y st u d y wit h dra wal will be rec or de d. If 
wit h dra wal is t he res ult of a seri o us a d verse reacti o n, t he s u bject will be f oll o we d u ntil 
t he c o n diti o n has res ol ve d, as deter mi ne d b y t he I n vesti gat or. 
T he I n vesti gat or or S p o ns or ma y wit h dra w a n y s u bject at a n y ti me f or me dical reas o ns or 
f or a d mi nistrati ve reas o ns (ie, s u bjects u na ble or u n willi n g t o c o m pl y wit h t he pr ot oc ol). 
If s o, t he s u bject will be ce ns ore d at ti me of wit h dra wal a n d, if p ossi ble, a fi nal 
e val uati o n (e n d- of-st u d y pr oce d ures) will be ma de. All treate d s u bjects will be i ncl u de d 
i n t he safet y a nal yses. 
I n t he u nli kel y e ve nt t he S p o ns or or F D A s h o ul d deter mi ne it is a p pr o priate t o ter mi nate 
t he st u d y earl y, e ver y eff ort will be ma de f or tra nsiti o ni n g s u bjects wit h mi ni mal 
disr u pti o n t o t he s u bject a n d I n vesti gat or. T he I R B/I E C will be n otifie d of ter mi nati o n 
a n d reas o n(s). Pr oce d ures f or f oll o w- u p of researc h s u bjects will be de vel o pe d b y t he 
st u d y p h ysicia n i n c o ns ultati o n wit h t he S p o ns or a n d I R B/I E C. 
1 3   D A T A M A N A G E M E N T  
T he sta n dar d pr oce d ures f or ha n dli n g a n d pr ocessi n g rec or ds will be f oll o we d as per 
G C P a n d t he data ma na ge me nt sta n dar d o perati n g pr oce d ures of t he c o ntract researc h 
or ga nizati o n. A c o m pre he nsi ve Data Ma na ge me nt Pla n will be de vel o pe d a n d a p pr o ve d 
b y a re prese ntati ve of t he Data Ma na ge me nt c o ntract researc h or ga nizati o n a n d t he 
S p o ns or. 
1 3. 1  
D at a b ase L oc k 
T he data base will be l oc ke d i n or der t o pr otect write access after t he f oll o wi n g 
prec o n diti o ns are f ulfille d: 
•  All data are e ntere d i n t he data base; 
•  All a d verse e ve nts are rec or de d t o t he satisfacti o n of t he C hief Me dical Officer;  
•  All data q ueries ha ve bee n res ol ve d t o t he satisfacti o n of t he Lea d Bi ostatisticia n; 
•  All decisi o ns ha ve bee n ma de re gar di n g all pr ot oc ol vi olat ors a n d p o p ulati o n 
e xcl usi o ns; 

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•  Writte n a ut h orizati o ns t o l oc k t he data base are o btai ne d fr o m Cli nical Data 
Ma na ge me nt a n d t he C hief Me dical Officer. 
1 4  E T HI C A L C O N SI D E R A TI O N S  
1 4. 1  
Et hic al C o n d uct of t he St u d y 
T he st u d y will be c o n d ucte d i n acc or da nce wit h U S Title 2 1 C F R a n d t he I C H E 6 ( R 2) 
G o o d Cli nical Practice: I nte grate d A d de n d u m t o I C H E 6( R 1) G ui da nce f or I n d ustr y. T he 
Declarati o n of Helsi n ki a n d its m ost rece nt u p dates ( F ortaleza, Brazil; 2 0 1 3) will be 
o bser ve d. 
T he I n vesti gat or will pr o vi de t he S p o ns or/ desi g nee wit h d oc u me ntati o n of I R B/I E C 
a p pr o val of t he pr ot oc ol a n d t he sa m ple i nf or me d c o nse nt d oc u me nt bef ore t he st u d y ma y 
be gi n at t he i n vesti gati ve site. T he I R B/I E C will re vie w t he pr ot oc ol as re q uire d. 
T he I n vesti gat or will s u p pl y t he f oll o wi n g t o t he I R B/I E C: 
•  T he c urre nt I n vesti gat or’s Br oc h ure a n d u p dates 
•  St u d y pr ot oc ol a n d a me n d me nts 
•  I nf or me d c o nse nt a n d asse nt d oc u me nt a n d u p dates 
•  Rele va nt c urric ula vitae 
•  Safet y alerts 
•  Seri o us a d verse reacti o n re p orts 
T he I n vesti gat or m ust pr o vi de t he f oll o wi n g d oc u me ntati o n t o t he S p o ns or or desi g nee: 
•  T he I R B/I E C ori gi nal a p pr o val of t he pr ot oc ol a n d t he i nf or me d c o nse nt, a n d 
re-a p pr o val of t he st u d y (a n n ual or se mi-a n n ual, per I R B/I E C g ui deli nes) 
•  T he I R B/I E C a p pr o vals of a n y re visi o ns t o t he i nf or me d c o nse nt d oc u me nt or 
a me n d me nts t o t he pr ot oc ol 
•  All ot her d oc u me nts t hat are re q uire d b y l ocal re g ulat or y a ut h orities 
1 4. 2  
Re g ul at or y C o nsi der ati o ns 
After rea di n g t he pr ot oc ol, eac h I n vesti gat or/s u b-I n vesti gat or will si g n a pr ot oc ol 
si g nat ure pa ge a n d ret ur n a c o p y of t he si g ne d pa ge t o t he S p o ns or/ desi g nee, w hile 
mai ntai ni n g t he ori gi nal at t he site. 
1 4. 3  
Pr ot oc ol A me n d me nts a n d St u d y Ter mi n ati o n 
T he I R B/I E C m ust be i nf or me d a n d gi ve a p pr o val f or a n y a me n d me nts li kel y t o affect 
t he safet y of t he s u bjects or t he c o n d uct of t he st u d y. 
T he I R B/I E C m ust be a d vise d i n writi n g of t he st u d y’s c o m pleti o n or earl y ter mi nati o n 
a n d a c o p y of t he n otificati o n m ust be pr o vi de d t o t he S p o ns or. 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
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Pa ge 3 3  of 3 6  
1 4. 4  
S afet y M o nit ori n g 
T he S p o ns or’s Me dical M o nit or will m o nit or safet y data t hr o u g h o ut t he c o urse of t he 
st u d y. T he S p o ns or’s Dr u g Safet y De part me nt, or t heir desi g nee, will e x pe dite t o t he 
re g ulat or y a ut h orities o nl y t he s us pecte d a d verse reacti o ns t hat are pr o d uct-relate d a n d 
u ne x pecte d i n acc or da nce wit h F D A 2 1 C F R 3 1 2, F D A G ui da nce o n Safet y Re p orti n g 
Re q uire me nts f or I N Ds, a n d t he I C H E 2 A g ui deli ne. 
1 4. 5  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce 
B y si g ni n g t his pr ot oc ol, t he S p o ns or a grees t o be res p o nsi ble f or i m ple me nti n g a n d 
mai ntai ni n g q ualit y c o ntr ol a n d q ualit y ass ura nce s yste ms wit h writte n sta n dar d o perati n g 
pr oce d ures t o e ns ure t hat t he st u d y is c o n d ucte d a n d data are ge nerate d, d oc u me nte d, a n d 
re p orte d i n c o m plia nce wit h t he pr ot oc ol, acce pte d sta n dar ds of G C Ps, a n d all a p plica ble 
fe deral, state, a n d l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he cli nical 
st u d y. 
B y si g ni n g t his pr ot oc ol, t he I n vesti gat or a grees t o c o n d uct t he st u d y i n a n efficie nt a n d 
dili ge nt ma n ner a n d i n c o nf or ma nce wit h t his pr ot oc ol, ge nerall y acce pte d sta n dar ds of 
G C P, a n d all a p plica ble fe deral, state, a n d l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he 
c o n d uct of t he cli nical st u d y. 
T he I n vesti gat or als o a grees t o all o w m o nit ori n g, a u dits, I R B/I E C re vie w a n d re g ulat or y 
a ge nc y i ns pecti o n of st u d y-relate d d oc u me nts a n d pr oce d ures a n d pr o vi de f or direct 
access t o all st u d y-relate d s o urce data a n d d oc u me nts. I n vesti gat ors will be gi ve n n otice 
bef ore a q ualit y ass ura nce a u dit occ urs. 
T he I n vesti gat or s hall pre pare a n d mai ntai n c o m plete a n d acc urate st u d y d oc u me ntati o n 
i n c o m plia nce wit h G C P sta n dar ds a n d a p plica ble fe deral, state, a n d l ocal la ws, r ules a n d 
re g ulati o ns, a n d pr o m ptl y s u b mit t o t he S p o ns or all f or ms a n d re p orts re q uire d b y t his 
pr ot oc ol f oll o wi n g c o m pleti o n or ter mi nati o n of t he cli nical st u d y or as ot her wise 
re q uire d d ue t o a n y a gree me nt wit h t he S p o ns or. 
1 5  G E N E R A L C O N SI D E R A TI O N S  
1 5. 1  
Disc o nti n u ati o n of t he St u d y 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t his st u d y or t he I n vesti gat or’s partici pati o n 
i n t his st u d y f or safet y or a d mi nistrati ve reas o ns at a n y ti me. 
 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
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Pa ge 3 4  of 3 6  
1 6  A G R E E M E N T WI T H P R O T O C O L  
I ha ve rea d t his pr ot oc ol a n d a gree t o c o n d uct t his cli nical st u d y as o utli ne d herei n. I will 
e ns ure t hat all s u b-I n vesti gat ors a n d ot her st u d y staff me m bers ha ve rea d a n d u n dersta n d 
all as pects of t his pr ot oc ol. I a gree t o c o o perate f ull y wit h Re ni b us T hera pe utics, I nc. a n d 
its a p p oi nte d Cli nical Researc h Or ga nizati o n d uri n g t he st u d y. I will a d here t o all F D A, 
I C H, re vise d Declarati o n of Helsi n ki ( 2 0 1 3) a n d ot her a p plica ble re g ulati o ns a n d 
g ui deli nes re gar di n g cli nical trials o n a st u d y dr u g d uri n g a n d after st u d y c o m pleti o n. 
Pri nci p al I n vesti g at or: 
Pri nte d Na me:  
 
Si g nat ure:  
 
Date:  
 
Pr ot oc ol R E N- 0 0 4 
A P hase 2, D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d St u d y t o E val uate t he Effect 
of R B T- 1 o n Prec o n diti o ni n g Res p o nse Bi o mar kers i n S u bjects U n der g oi n g C or o nar y 
Arter y B y pass Graft ( C A B G) a n d/ or Car diac Val ve S ur ger y ( T he S T A R T St u d y) 
Pr ot oc ol – Versi o n 5:  2 5 A u g 2 0 2 2 
 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
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Pa ge 3 5  of 3 6  
1 7  R E F E R E N C E S  
A n ders o n K E, Si mi o natt o C S, Dr u m m o n d G S, Ka p pas A. Dis p ositi o n of 
ti n- pr ot o p or p h yri n a n d s u p pressi o n of h y per bilir u bi ne mia i n h u ma ns. Cli n P h ar m ac ol 
T her . 1 9 8 6; 3 9( 5): 5 1 0- 2 0. 
Ber gl u n d L, A n geli n B, Bl o mstra n d R, Dr u m m o n d G, Ka p pas A. S n- pr ot o p or p h yri n 
l o wers ser u m bilir u bi n le vels, decreases biliar y bilir u bi n o ut p ut, e n ha nces biliar y he me 
e xcreti o n a n d p ote ntl y i n hi bits he patic he me o x y ge nase acti vit y i n n or mal h u ma n 
s u bjects. He p at ol o gy . 1 9 8 8; 8( 3): 6 2 5- 3 1. 
Ber gl u n d L, A n geli n B, H ultcra ntz R, et al. St u dies wit h t he he me o x y ge nase i n hi bit or 
S n - pr ot o p or p h yri n i n s u bjects wit h pri mar y biliar y cirr h osis a n d i di o pat hic 
hae m oc hr o mat osis. G ut . 1 9 9 0; 3 1( 8): 8 9 9- 9 0 4. 
C ha wla L, Ki m mel P. Ac ute ki d ne y i nj ur y a n d c hr o nic ki d ne y disease: a n i nte grate d 
cli nical s y n dr o me. Ki d ney I nt . 2 0 1 2; 8 2( 5): 5 1 6- 2 4. 
D o ver S B, M o ore M R, Fitzsi m m o ns EJ, Gra ha m A, Mc C oll K E. Ti n pr ot o p or p h yri n 
pr ol o n gs t he bi oc he mical re missi o n pr o d uce d b y he me ar gi nate i n ac ute he patic 
p or p h yria. G astr oe nter ol o gy . 1 9 9 3; 1 0 5( 2): 5 0 0- 6. 
E mtesta m L, A n geli n B, Ber gl u n d L, Dr u m m o n d G S, Ka p pas A. P h ot o d y na mic 
pr o perties of S n- pr ot o p or p h yri n: cli nical i n vesti gati o ns a n d p h ot otesti n g i n h u ma n 
s u bjects. Act a Der m Ve nere ol . 1 9 9 3; 7 3( 1): 2 6- 3 0. 
Gal brait h R A, Ka p pas A. P har mac o ki netics of ti n- mes o p or p h yri n i n ma n a n d t he effects 
of ti n-c helate d p or p h yri ns o n h y pere xcreti o n of he me pat h wa y prec urs ors i n s u bjects wit h 
ac ute i n d uci ble p or p h yria. He p at ol o gy . 1 9 8 9( 9): 8 8 2- 8. 
H o n da I K, His hi da A, I k u ma K, Y o ne m ura K. Ac q uire d resista nce t o ac ute re nal fail ure: 
e dit orial re vie w. Ki d ney I nt.  1 9 8 7; 3 1( 6): 1 2 3 3- 8. 
Ka p pas A, Dr u m m o n d G S, Ma n ola T, Pet meza ki S, Valaes T. S n- pr ot o p or p h yri n use i n 
t he ma na ge me nt of h y per bilir u bi ne mia i n ter m ne w b or ns wit h direct C o o m bs- p ositi ve 
A B O i nc o m pati bilit y. Pe di atrics . 1 9 8 8; 8 1( 4): 4 8 5- 9 7. 
K DI G O A KI W or k Gr o u p. K DI G O cli nical practice g ui deli ne f or ac ute ki d ne y i nj ur y. 
Ki d ney I nt S u p p . 2 0 1 2; 1 7: 1- 1 3 8. 
Kell u m J, La meire N. Dia g n osis, e val uati o n, a n d ma na ge me nt of ac ute ki d ne y i nj ur y: A 
KI D G O s u m mar y ( part 1). Crit C are . 2 0 1 3; 1 7( 1): 2 0 4. 
R os ner M H, O k usa M D. Ac ute ki d ne y i nj ur y ass ociate d wit h car diac s ur ger y. Cli n J A m 
S oc Ne p hr ol . 2 0 0 6; 1( 1): 1 9- 3 2. 
Ve n ofer ® [ pac ka ge i nsert]. A merica n Re ge nt, I nc., S hirle y, N Y; A u g ust 2 0 1 5. 
Ve n ofer ® [s u m mar y of pr o d uct c haracteristics]. Vif or P har ma U K Li mite d, S urre y, U K; 
N o ve m ber 2 0 1 6. 
Za ger R A, Baltes L A, S har ma H M, J ur k o witz M S. Res p o nses of t he isc he mic ac ute re nal 
fail ure ki d ne y t o a d diti o nal isc he mic e ve nts. Ki d ney I nt.  1 9 8 4; 2 6( 5): 6 8 9- 7 0 0. 

Pr ot oc ol N u m ber: R E N -0 0 4 – Versi o n 5 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
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Pa ge 3 6  of 3 6  
Za ger R A, B ur k hart K M, G m ur DJ. P ostisc he mic pr o xi mal t u b ular resista nce t o o xi da nt 
stress a n d Ca 2 + i o n o p h o ne-i n d uce d attac k. I m plicati o ns f or re perf usi o n i nj ur y. L a b 
I nvest. 1 9 9 5a; 7 2( 5): 5 9 2- 6 0 0. 
Za ger R A. He me pr otei n-i n d uce d t u b ular c yt oresista nce: e x pressi o n at t he plas ma 
me m bra ne le vel. Ki d ney I nt.  1 9 9 5 b; 4 7( 5): 1 3 3 6- 4 5. 
Za ger R A. O bstr ucti o n of pr o xi mal t u b ules i nitiates c yt oresista nce a gai nst h y p o xic 
da ma ge. Ki d ney I nt.  1 9 9 5c; 4 7( 2): 6 2 8- 3 7. 
Za ger R A, J o h ns o n A C, Fr osta d K B. C o m bi ne d ir o n s ucr ose a n d pr ot o p or p h yri n 
treat me nt pr otects a gai nst isc he mic a n d t o xi n- me diate d ac ute re nal fail ure. Ki d ney I nt. 
2 0 1 6; 9 0( 1): 6 7- 7 6.