Conditions: AKI
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 152
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of RBT-1 (stannous protoporphyrin \[SnPP\]/iron sucrose \[FeS\]) on preconditioning response biomarkers in subjects who are at risk for AKI following cardiac surgery.

Detailed description:

Arms:
arm 1: Single IV infusion prior to cardiac surgery arm 2: Single IV infusion prior to cardiac surgery arm 3: Single IV infusion prior to cardiac surgery

Interventions: intervention 1: Low Dose RBT-1 intervention 2: High Dose RBT-1 intervention 3: Placebo
Intervention descriptions: intervention 1: intravenous administration intervention 2: intravenous administration intervention 3: intravenous administration

Protocol document:
Prot_000.pdf: 
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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 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
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 
Date:  2 5 A u g  2 0 2 2 
 
    
  
 
C O N FI D E N TI A L   
  
 
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 
Date:  2 5 A u g  2 0 2 2 
 
    
  
  
  
 
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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.  


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 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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C O N FI D E N TI A L   
  
 
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 ]. 


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 4  of 3 6  
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; 


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 2  of 3 6  
•  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 
 
    
  
 
C O N FI D E N TI A L   
  
 
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 
 
    
  
 
C O N FI D E N TI A L   
  
 
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 
 
    
  
 
C O N FI D E N TI A L   
  
 
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 
 
    
  
 
C O N FI D E N TI A L   
  
 
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. 
 
 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
Protocol number: REN-004 
 
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 
 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
21 September 2021 version 1.0 
19 April 2022, version 2.0 
16 November 2022, version 3.0 
 
 
Prepared by: 
Name 
Chao Wang, PhD 
Title 
President and Principal Statistician 
Company 
Pharma Data Associates, LLC 
Street Address 
371 Hoes Lane, Suite 200 
City, State 
Piscataway, NJ 08854 
Phone:  
410-370-9508 
 
 
 
 
 


Rénibus Therapeutics® Inc.
Protocol Number: REN-004
Confidential
16 November 2022 
Page 2 of 41 
Signature Approval Page
By signing below, I indicate that I have reviewed the Statistical Analysis Plan in its entirety and approve its 
contents.
Signature:
Date:
Chao Wang, PhD
Principal Statistician
Pharma Data Associates, LLC
(DD-MMM-YYYY)
Signature:
Date:
Bhupinder Singh, MD, FASN, FNKF
Medical Monitor
Renibus Therapeutics, Inc.
(DD-MMM-YYYY)
Signature:
Date:
Stacey Ruiz, PhD
VP, Drug Development & Medical Affairs
Renibus Therapeutics, Inc.
(DD-MMM-YYYY)
Signature:
Date:
D Jeff Keyser, RPh, JD, PhD
President and Chief Operating Officer
Renibus Therapeutics, Inc.
(DD-MMM-YYYY)
16-Nov-22 | 5:05 PM PST
,
17-Nov-22 | 5:27 PM CST
Renibus Therapeutics, Inc.
17-Nov-22 | 5:57 PM CST
17-Nov-22 | 4:48 PM PST
Renibus Therapeutics, Inc.


Rénibus Therapeutics® Inc. 
Protocol Number: REN-004 
 
Confidential 
16 November 2022 
Page 3 of 41 
Revision History 
 
Version Date 
Author 
Summary of Changes 
1.0 
21 September 2021 
Chao Wang 
First signed off version 
2.0 
12 April 2022 
Chao Wang 
Globally, baseline is changed to Visit 1a. 
Section 7.2 a description for handling missing central 
lab tests or aberrant test results is provided. 
Section 7.3 is updated to be more specific for 
adaptation rule.  
Section 7.5 is updated for the primary and secondary 
endpoints derivation. 
Section 7.6 is added to include additional parameters 
of interest. 
3.0 
01 November 2022 
Chao Wang 
See Section 2.3. 
 
 
 
 
 
 


Rénibus Therapeutics® Inc. 
Protocol Number: REN-004 
 
Confidential 
16 November 2022 
Page 4 of 41 
TABLE OF CONTENTS  
1 
INTRODUCTION ............................................................................................................................................ 7 
2 
STUDY DESCRIPTION ..................................................................................................................................... 7 
2.1 
Study Design .................................................................................................................................................... 7 
2.2 
Study Objectives .............................................................................................................................................. 8 
2.3 
Changes from v2.0 to v3.0 Statistical Analysis Plan ........................................................................................ 9 
3 
ANALYSIS POPULATIONS .............................................................................................................................. 9 
3.1 
Modified Intent-To-Treat (MITT) Population ................................................................................................... 9 
3.2 
Safety Population ............................................................................................................................................ 9 
4 
DEFINITIONS ................................................................................................................................................. 9 
4.1 
Baseline ........................................................................................................................................................... 9 
4.2 
Study Day....................................................................................................................................................... 10 
4.3 
Start/Stop Day ............................................................................................................................................... 10 
5 
EFFICACY ENDPOINTS ................................................................................................................................. 10 
5.1 
Primary Efficacy Endpoint ............................................................................................................................. 10 
5.2 
Secondary Efficacy Endpoints ........................................................................................................................ 11 
5.2.1 
Maximum  PostOp over Baseline in Renal Tubular Injury Biomarkers ................................................ 11 
5.2.2 
Reduction in Urine Output ................................................................................................................... 11 
5.2.3 
Incidence of AKI ................................................................................................................................... 11 
5.3 
Exploratory Efficacy Endpoints ...................................................................................................................... 11 
5.3.1 
Severity of AKI ...................................................................................................................................... 11 
5.3.2 
Mean increase from Baseline in Serum Creatinine.............................................................................. 12 
5.3.3 
Occurrence of MAKE ............................................................................................................................ 12 
5.3.4 
Hospitalization Parameters .................................................................................................................. 12 
5.3.5 
Change in Biomarkers of RBT-1 Activity and/or Kidney Function ........................................................ 13 
6 
SAFETY PARAMETERS ................................................................................................................................. 13 
6.1 
Adverse Events .............................................................................................................................................. 13 
6.2 
Serious Adverse Events .................................................................................................................................. 13 
6.3 
Laboratory Parameters ................................................................................................................................. 14 
6.4 
Other Safety Parameters ............................................................................................................................... 15 
7 
STATISTICAL METHODOLOGY ..................................................................................................................... 15 
7.1 
Determination of Sample Size ....................................................................................................................... 15 
7.2 
General Statistical Considerations ................................................................................................................. 16 
7.3 
Multiple Comparison and Two-Stage Design ................................................................................................ 16 
7.4 
Study Subjects................................................................................................................................................ 18 


Rénibus Therapeutics® Inc. 
Protocol Number: REN-004 
 
Confidential 
16 November 2022 
Page 5 of 41 
7.4.1 
Subject Disposition and Analysis Population ....................................................................................... 18 
7.4.2 
Protocol Deviations .............................................................................................................................. 18 
7.4.3 
Study Populations Analyzed................................................................................................................. 18 
7.4.4 
Demographic and Baseline Characteristics .......................................................................................... 18 
7.4.5 
Study Drug Administration and Surgery .............................................................................................. 18 
7.4.6 
Prior and Concomitant Medication ..................................................................................................... 18 
7.5 
Efficacy Analysis ............................................................................................................................................ 19 
7.5.1 
Primary Efficacy Endpoint Analysis ...................................................................................................... 19 
7.5.2 
Secondary Efficacy Endpoint Analysis .................................................................................................. 19 
7.5.3 
Exploratory Analysis ............................................................................................................................. 20 
7.6 
Safety Analysis ............................................................................................................................................... 22 
7.6.1 
Adverse Events..................................................................................................................................... 22 
7.6.2 
Laboratory Parameters ........................................................................................................................ 22 
7.6.3 
Other Safety Parameters ..................................................................................................................... 22 
8 
SUMMARY TABLES, FIGURES AND LISTINGS ............................................................................................... 23 
9 
APPENDICES ............................................................................................................................................... 26 


Rénibus Therapeutics® Inc. 
Protocol Number: REN-004 
 
Confidential 
16 November 2022 
Page 6 of 41 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AKI 
Acute kidney injury 
ANCOVA 
Analysis of Covariance 
AUC 
Area under the curve 
Avg 
Average 
CABG 
Coronary artery bypass graft 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel χ2 test 
CSR 
Clinical study report 
CysC 
Cystatin C 
eCRF 
Electronic case report form 
Exp 
Exponential 
FeS 
Iron sucrose 
GM 
Geometric mean 
GLSM 
Geometric least squares mean 
HO-1 
Heme oxygenase-1 
ICU 
Intensive Care Unit 
IL-10 
Interleukin-10 
IV 
Intravenous 
KDIGO 
Kidney disease improving global outcomes 
KIM-1 
Kidney injury molecule-1 
LLOQ 
Lower limit of quantification 
Log 
Natural logarithm (base e) 
LSM 
Least Squares Mean 
MAKE 
Major adverse kidney events 
MAKE30 
Major Adverse Kidney Events through Day 30 post-cardiac surgery 
MAKE90 
Major Adverse Kidney Events through Day 90 post-cardiac surgery 
MINP 
Method of inverse normal p-values 
MITT 
Modified intent to treat 
MMRM 
Mixed model for repeated measures 
NGAL 
Neutrophil gelatinase-associated lipocalin 
PostOp 
Post cardiac surgery 
PreOp 
Immediately prior to the cardiac surgery 
RBT-1 
Stannous protoporphyrin and iron sucrose  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SnPP 
Stannous protoporphyrin 
TEAE 
Treatment-emergent adverse event 
 
 
 


Rénibus Therapeutics® Inc. 
Protocol Number: REN-004 
 
Confidential 
16 November 2022 
Page 7 of 41 
1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be used 
for the interim and final analyses of Renibus Therapeutics, Inc. protocol REN-004. This plan also provides 
a description of the tables, figures, and listings that will be included in the final statistical report. It is based 
on the protocol version 5 dated 25 August 2022 and on the annotated electronic case report form (eCRF). 
In case of differences in terms of descriptions or explanations between the SAP and the clinical protocol, 
the SAP will supersede the protocol. Any deviation to this SAP would be reported in the clinical study 
report (CSR). 
 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study to evaluate the effect 
of RBT-1 on preconditioning response biomarkers in subjects who are at risk for acute kidney injury (AKI) 
following cardiac surgery. Eligible subjects will be randomized to receive a single dose of low dose RBT-1 
(45 mg SnPP/240 mg FeS), high dose RBT-1 (90 mg SnPP/240 mg FeS), or placebo (normal saline) via 
intravenous (IV) infusion over a 120-minute period ≥24 but ≤48 hours prior to scheduled cardiac surgery. 
All subjects will be assessed through Day 90 post-cardiac surgery. Subjects will be evaluated at Screening, 
48 and/or 24 hours prior to surgery depending on the time of dosing, on Day 1 (day of surgery), and daily 
through Day 7 or Discharge if earlier, as well as on Days 30, 60, and 90, as described in the Event Schedule 
(see Appendix 1). Assessments include biomarkers of preconditioning response and tubular injury, urine 
output, incidence and severity of AKI, serum creatinine, days on ventilator, days in intensive care unit, 
hospital length of stay, readmission rate, and safety (physical examination, clinical laboratory assessment, 
vital signs, concomitant medications, and adverse events). Evaluations for major adverse kidney events 
(MAKE) (death, need for dialysis, and persistent decrease in kidney function) and safety will be performed 
through Day 90, as described in the Event Schedule (see Appendix 1). 
The duration of the study will be approximately 90 days per subject. A schematic of the study design is 
presented below: 
 


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AKI = acute kidney injury, FeS = iron sucrose, h = hour, SnPP = stannous protoporphyrin 
 
2.2 
Study Objectives 
The overall objective is to evaluate the effect of RBT-1 on preconditioning response biomarkers in subjects 
undergoing CABG and/or cardiac valve surgery. 
The primary objective is to evaluate the efficacy of RBT-1 in generating a preconditioning response as 
measured by a composite of plasma biomarkers (plasma heme oxygenase-1 [HO-1], ferritin, and 
interleukin-10 [IL-10]) from Baseline (pre-dose) through Day 1 PreOp. 
The secondary objectives are to evaluate the efficacy of RBT-1 on the following: 
• 
Change in renal tubular injury biomarkers post-cardiac surgery through Day 3 
• 
Reduction in urine output (documented adverse event [AE] of sustained reduction in urine 
output, oliguria, or anuria) post-cardiac surgery through Day 5 
• 
Incidence of AKI (defined as a ≥1.5X baseline, i.e., a 50% increase from baseline in serum 
creatinine; documented AE of sustained reduction in urine output, oliguria, or anuria; or initiation 
of dialysis) post-cardiac surgery through Day 5 
The exploratory objectives are to evaluate the following: 


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• 
Severity of AKI post-cardiac surgery through Day 7 
• 
Mean increase in serum creatinine post-cardiac surgery through Day 7 or until Discharge if prior 
to Day 7 
• 
Occurrence of MAKE – death, need for dialysis, and persistent renal dysfunction (≥25% decrease 
in estimated glomerular filtration rate [eGFR]) – post-cardiac surgery through Day 30 (MAKE30) 
and Day 90 (MAKE90) post-cardiac surgery 
• 
Proportion of subjects experiencing MAKE30 
• 
Proportion of subjects experiencing MAKE90 
• 
Days on ventilator 
• 
Days in intensive care unit (ICU) 
• 
Hospital length of stay 
• 
Readmission rate 
• 
Changes in biomarkers of RBT-1 activity and/or kidney function 
 
2.3 
Changes from v2.0 to v3.0 Statistical Analysis Plan 
See APPENDIX B for detail. 
 
3 
ANALYSIS POPULATIONS 
The populations of analysis will be confirmed by the Sponsor prior to unblinding. 
3.1 
Intent-To-Treat (ITT) Population 
The ITT population will consist of all randomized subjects who were eligible for the study, received study 
drug, and had biomarker assessments performed at baseline (Visit 1a) and prior to surgery (Visit 1b and/or 
Day 1 PreOp). Subjects in the ITT population will be analyzed as randomized. 
3.2 
Modified Intent-To-Treat (MITT) Population 
The MITT population will consist of all randomized subjects who were eligible for the study, received study 
drug, underwent CABG and/or cardiac valve surgery without delay, and were evaluated through the end 
of index surgery hospitalization. Subjects in the MITT population will be analyzed as randomized.  
3.3 
Safety Population 
The safety population will consist of all subjects who received any amount of study drug. Subjects in the 
Safety population will be analyzed as per actual treatment received. 
4 
DEFINITIONS 
4.1 
Baseline 
Baseline is defined as the last value collected prior to the start of the study drug administration, unless 
specified otherwise. This usually is the value collected at Visit 1a Predose for vital signs, serum chemistry, 
hematology, and blood and urine biomarkers.  If missing, then the value collected at unscheduled visit or 
Visit 0, whichever is available and more recent to study drug administration, will be used.  


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4.2 
Study Day 
To be consistent with the protocol definition, Study Day 1 is the day of the cardiac surgery. Study Days 2, 
3, 4, 5, 6 7, 30, 60 and 90 are the nominal days following Study Day 1.   
 
4.3 
Start/Stop Day 
For adverse events or prior/concomitant medications, unless specified otherwise, the start day and the 
stop day are calculated from the date of the study drug administration. 
Event day = event date – study drug administration date + 1 if the event is on/after study drug date, or  
Event day = event date – study drug administration date if the event is before study drug date. 
 
5 
EFFICACY ENDPOINTS 
5.1 
Primary Efficacy Endpoint 
The primary efficacy composite endpoint is defined as the geometric mean of the ratios of the maximum 
PreOp value (Visit 1b or Day 1 PreOp) over Baseline (Visit 1a) for the 3 preconditioning biomarkers,  
 
𝐸𝐸𝐸𝐸𝐸𝐸൜1
3 ∙൤𝐿𝐿𝐿𝐿𝐿𝐿൬max PreOp HO-1 
Baseline HO-1 ൰+ 𝐿𝐿𝐿𝐿𝐿𝐿൬max PreOp Ferritin
Baseline Ferritin ൰+ 𝐿𝐿𝐿𝐿𝐿𝐿൬max PreOp IL-10
Baseline IL-10 ൰൨ൠ. 
 
For sensitivity analysis, this composite endpoint will also be defined as the geometric mean of the ratios 
of average of Day 1 PostOp through Day 3 over baseline for the 3 preconditioning biomarkers {HO-1, 
Ferritin, and IL-10}, where Avg (average) is calculated as the area under the biomarker-time curve (AUC) 
divided by the duration in the AUC calculation (AUC/D), and 
 
𝐴𝐴𝐴𝐴𝐴𝐴= ൛∑
(
𝑛𝑛
𝑖𝑖=2 𝑣𝑣𝑖𝑖+ 𝑣𝑣(𝑖𝑖−1))(𝑡𝑡𝑖𝑖−𝑡𝑡(𝑖𝑖−1))ൟ/2, 
𝐷𝐷= 𝑡𝑡𝑛𝑛−𝑡𝑡1 
𝑣𝑣1and 𝑣𝑣𝑛𝑛 are the first (Visit 1b or Day 1 for subjects dosed 36 to 48 hours or 24 to <36 hours prior to 
surgery, respectively) and last (Study Day 3) biomarker values after study drug administration, 𝑡𝑡𝑖𝑖 is the 
date and time of the ith biomarker test. 
Baseline for this composite endpoint is calculated as 
(Baseline HO-1 * Baseline ferritin * Baseline IL-10)1/3. 
Because an increase in plasma biomarkers is beneficial and because the ratios are calculated as the follow-
up value over the baseline value, a value >1 for the primary efficacy endpoint would indicate benefit.   
 


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5.2 
Secondary Efficacy Endpoints 
5.2.1 
Maximum  PostOp over Baseline in Renal Tubular Injury Biomarkers 
The secondary efficacy composite endpoint is defined as the geometric mean of the ratios of the 
maximum PostOp value (Day 1, 1 hour post cardiac surgery through Day 3) over Baseline (Visit 1a) for the 
3 tubular injury biomarkers, 
 
Exp[ 1/3 * (  
𝐿𝐿𝐿𝐿𝐿𝐿ቀmax(KIM-1 PostOp through Day 3)
Baseline KIM-1
ቁ +  
𝐿𝐿𝐿𝐿𝐿𝐿ቀmax(CysC PostOp through Day 3)  
Baseline CysC
ቁ +  
𝐿𝐿𝐿𝐿𝐿𝐿ቀmax(NGAL PostOp through Day 3) 
Baseline NGAL
ቁ) ]. 
 
Baseline for this composite endpoint is calculated as 
(Baseline KIM-1 * Baseline CysC * Baseline NGAL)1/3. 
Because a lack of increase in renal tubular injury biomarkers is considered beneficial and because the 
ratios are calculated as the follow-up value over the baseline value, a value >1 would indicate an increased 
risk.   
This endpoint is expected to capture the kidney injury manifested by any of the 3 biomarkers at any time 
in the 3 days following the surgery. 
 
5.2.2 
Reduction in Urine Output 
The reduction in urine output (documented AE of sustained reduction in urine output, oliguria, or anuria) 
post-cardiac surgery through Day 5 will be evaluated by the site and captured as an AE on the AE log eCRF. 
 
5.2.3 
Incidence of AKI  
The incidence of AKI post-cardiac surgery through Day 5 will be defined as: 
o An absolute increase from baseline to ≥1.5 x Baseline at any time; or 
o A documented AE of sustained reduction in urine output, oliguria, or anuria; or  
o Initiation of dialysis 
 
5.3 
Exploratory Efficacy Endpoints 
5.3.1 
Severity of AKI  
Maximum severity of AKI post-cardiac surgery through Day 7 will be a categorical variable.  It is defined 
as the maximum severity over Days 2 through 7 for subject with AKI incidence PostOp through Day 7 
(replacing Day 5 with Day 7 in Section 5.2.3) as follows: 
Stage 1 
if CreatDi- CreatBL >= 0.3 mg/dL, or 


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1.5*CreatBL <= CreatDi < 2*CreatBL (i=2 to 7) 
Stage 2 
if 2*CreatBL <= CreatDi < 3*CreatBL (i=2 to 7) 
Stage 3 
if CreatDi- CreatBL >= 4 mg/dL, or 
3*CreatBL <= CreatDi (i=2 to 7), or 
need for dialysis and date of dialysis < date of surgery +6 
where CreatBL is creatinine at baseline (Day 1 PreOp), CreatDi is creatinine on Day Di (i.e., Days 2, …, 7). 
 
5.3.2 
Mean increase from Baseline in Serum Creatinine 
Mean increase in serum creatinine will be computed as the average of the post-baseline serum creatinine 
through Day 7 or Discharge, whichever is earlier, minus baseline serum creatinine. Baseline is defined as 
the serum creatinine collected at Visit 1a time point. 
 
5.3.3 
Occurrence of MAKE 
Endpoints related to MAKE are as follows: 
o Proportion of subjects experiencing either MAKE30, MAKE60, or MAKE90 
o Proportion of subjects experiencing MAKE30 
o Proportion of subjects experiencing MAKE60 
o Proportion of subjects experiencing MAKE90 
MAKE30 is defined for subjects with AKI incidence PostOp through Day 5 as follows 
o Death (of all cause) and date of death < date of surgery + 30, or 
o Need for dialysis and date of dialysis < date of surgery + 30, or 
o (eGFRD30 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 30 
MAKE60 is defined for subjects with AKI incidence PostOp through Day 5 as follows 
o Death (of all cause) and date of death < date of surgery + 60, or 
o Need for dialysis and date of dialysis < date of surgery + 60, or 
o (eGFRD60 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 60 
MAKE90 is defined for subjects with AKI incidence PostOp through Day 5 as follows 
o Death (of all cause) and date of death < date of surgery + 90, or 
o Need for dialysis and date of dialysis < date of surgery + 90, or 
o eGFRD90 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 90 
where eGFRBL is eGFR at baseline (Day 1 PreOp), eGFR30, eGFR60, and eGFR90 are eGFR on Days 30, 60, and 
90, respectively. Note, eGFR (mL/min/1.73m2) is calculated using 2009 CKD-EPI equation: 
141 × min(Scr/κ, 1)α× max(Scr/κ, 1)-1.209× 0.993Age× 1.018 [if female] × 1.159 [if African American]. 
 
5.3.4 
Hospitalization Parameters 
Parameters related to hospitalization are as follows: 


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o Number of days on ventilator 
o Number of days in intensive care unit (ICU) 
o Hospital length of stay in days 
o Readmission rate, defined as the proportion of subjects who are readmitted to a hospital 
following discharge from the initial hospitalization for CABG and/or cardiac valve surgery 
 
5.3.5 
Change in Biomarkers of RBT-1 Activity and/or Kidney Function 
The change in each exploratory biomarker will be computed for the intervals from baseline (Visit 1A) to 
Day 1 (Visit 2), Day 2 (Visit 3), and Day 3 (Visit 4).  
 
6 
SAFETY PARAMETERS 
Safety will be assessed through adverse events (AEs) and serious adverse events (SAEs), clinical laboratory 
parameters, physical examination, and vital signs. 
 
6.1 
Adverse Events 
Adverse Event means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without 
any judgment about causality. 
All AEs will be recorded on the designated study eCRF for each subject beginning with the administration 
of investigational product and ending with the date of the end of study treatment follow-up (Day 90). AEs 
will be followed by the Investigator until event resolution, the subject is lost to follow-up, or the AE is 
otherwise explained or not considered clinically significant by the Investigator. AEs not resolved by Day 
90 will be considered ongoing. 
When reporting AEs, the Investigator will assess the relationship or association of study drug in causing 
or contributing to the adverse event as well as the intensity of the adverse event. 
Treatment-emergent AEs (TEAEs) will be defined as any AE where the AE start date is on or after the 
infusion start date. AEs related to study treatment will be defined as any AE where the relationship to 
study treatment is considered as “possible” or “related”. 
 
6.2 
Serious Adverse Events 
An adverse event is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 


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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Other medically important event 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
6.3 
Select Adverse Events of Interest 
Following is a list of adverse events of interest by MedDRA preferred term (tentative): 
• 
Atrial fibrillation 
• 
Delirium 
• 
Vasoplegia 
• 
Bleeding 
• 
Myocardial infraction 
• 
Stroke 
• 
Heart failure 
• 
AKI (combined AKI, ARF, AE report of sustained urine reduction) 
• 
Death 
Additionally, photosensitivity AEs will be identified. 
 
6.4 
Laboratory Parameters 
Screening laboratory samples will be processed at a local laboratory. All other laboratory samples will be 
processed at a central laboratory.  For subjects who will be administered study drug on the same day of 
Screening, blood and urine samples will need to be collected for central laboratory analysis in accordance 
with Visit 1a. 
Serum chemistry and hematology will be measured at Screening (Visit 0), Visit 1a, Day 1 PreOp (Visit 2), 
and on Days 2 to 7 (or discharge, whichever is earlier; Visits 3-8), Day 30 (Visit 9), Day 60 (Visit 10), and 
Day 90 (Visit 11).  Serum CysC will only be measured at Visit 1a and on Days 30 (Visit 9) and 90 (Visit 11). 
Serum chemistry parameters include total protein, albumin, bicarbonate, blood urea nitrogen (BUN), 
serum creatinine, total bilirubin, alkaline phosphatase, glucose, sodium, potassium, phosphate, calcium, 
magnesium, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and CysC.   
Hematology parameters include RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, MPV, RDW 
and WBC. 


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Blood and urinary biomarkers will be collected at Visit 1a, 1b, 2 (PreOp, 1h PostOp, 12h PostOp), 3 (Day 
2) and 4 (Day 3). 
Blood biomarkers include preconditioning response biomarkers (plasma HO-1, ferritin, and IL-10) and 
other biomarkers of RBT-1 activity and kidney function. 
Urinary biomarkers include tubular injury biomarkers (KIM-1, CysC, and NGAL) and other biomarkers of 
RBT-1 activity and kidney function, which include but are not limited to urine albumin to creatinine ratio 
(UACR), urine protein to creatinine ratio (UPCR), beta-2-microglobulin, osteopontin, calbindin, clusterin, 
and VEGF. 
Blood and urine samples may be collected by remote phlebotomy, such as through a mobile phlebotomist 
or other blood collection center, for a visit conducted virtually on Day 7, 30, 60, or 90.  
 
6.5 
Other Safety Parameters 
Physical examinations should be performed at Screening, prior to dosing, prior to cardiac surgery on Day 
1, Day 7, Day 30, and Day 90. Symptom-directed physical examinations may be performed on Days 2 – 6. 
Symptom-directed physical examinations may also be performed on Days 7, 30, and 90 if those visits are 
conducted virtually. 
Weight and body mass index will be collected at Screening and on Day 90. 
Vital signs (blood pressure, pulse rate, body temperature) will be collected throughout the study at 
Screening (Visit 0), Visit 1a, Day 1 PreOp (Visit 2), and on Days 2 to 90 (Visit 3 to 11). During hospitalization, 
vital signs will be recorded once per day. 
At each post-cardiac surgery visit, the Investigator/study staff will record whether the subject is in the 
ICU, on a ventilator, has been discharged from the hospital, or readmitted to the hospital. 
 
7 
STATISTICAL METHODOLOGY 
7.1 
Determination of Sample Size 
There will be three treatment groups; the two active (high dose [HD] 90/240 and low dose [LD] 45/240) 
groups will be compared to the control group. Using gatekeeping procedure for multiple comparisons and 
assuming the primary endpoint log composite score derived from this study is comparable to the score 
derived from the REN-003 and REN-001A studies (HD: mean ± SD 1.30±0.56, LD: 1.07±0.52, and placebo: 
0.19±0.19), a sample size of 10 subjects per group will provide >80% power for the between group 
comparisons with two-sided α=0.05 significance level.   
Using the REN-003 Study “FDA Safety Summary-1 Updated Feb2020.docx” non-surgical healthy volunteer 
and CKD patient data mixture, the secondary endpoint log composite score is estimated as 0.41 ± 0.51. 
Thus, with the sample size of 10, 20, and 30 subjects per group, the study will have 40%, 69%, and 86% 
power, respectively, to detect a between active group and placebo group difference in the mean log 
composite score of 0.4, or a between group ratio of 1.5 in the composite score. 


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7.2 
General Statistical Considerations 
Continuous variables will be summarized overall and by treatment group using descriptive statistics (e.g., 
N, mean, median, standard deviation [SD], Q1, Q3, minimum and maximum), while categorical variables 
will be summarized with number and proportion of subjects for each category. 
In addition to the data summary and between group comparison, all data will be presented in the data 
listings with subject ID, treatment group, and other pertinent information. 
For serum creatinine and eGFR, missing or aberrant central lab test results will be replaced by the local 
lab test results if available, or if not available, by linear interpolation by the two data points before and 
after the missing data point (not applicable for Day 7, Day 30, 60, and 90 tests). If Visit 1a is missing, and 
the corresponding local lab is not available, it will be imputed with the screening local lab result. Day 7 
(Visit 8) lab test is collected on the nominal Day 7. If patients are discharged early, their discharge values 
from Days 4, 5, or 6 will be reported as Day 7 values. If Day 7 is missing, and the corresponding local lab 
result is not available, it will be imputed with the last value collected Day 3 through Day 6.  All imputations 
will be documented and signed off prior to the database lock for analysis. Biomarker values below the 
limit of quantification (LLOQ) will be replaced by the LLOQ value divided by 2. Biomarker values above the 
limit of quantification (ULOQ) will be replaced by the ULOQ value.  
Unless specified otherwise, all between group comparisons and confidence intervals will use 2-sided 
a=0.05 significance level. 
Statistical analyses will be performed using SAS version 9.4 or higher. 
 
7.3 
Multiple Comparison and Two-Stage Design  
The gatekeeping procedure will be applied to protect the overall type-I error rate due to the multi-dose 
active treatments vs the placebo comparisons. Specifically, the HD group will be compared to the placebo 
group first for the primary efficacy endpoint with a=0.05. If p-value is <0.05, then the LD group will be 
compared to placebo for the primary efficacy endpoint also with a=0.05.  If the HD group is not statistically 
significant in the first comparison, the LD group will automatically be considered not significant for the 
primary efficacy endpoint. 
The study will potentially be carried out in two stages. The first stage (Stage 1) will enroll approximately 
20 subjects per treatment group for a total of 60 subjects. After these first 60 subjects have completed 
the efficacy assessments through Day 30, an interim analysis will be conducted to compare the primary 
efficacy endpoints between each active dose group against placebo.  
• 
If a significant difference (p≤0.05) in the primary endpoint is observed between the active 
treatment and placebo groups, the study will be stopped unless further enrollment is needed to 
provide additional evidence in support of the secondary endpoints.  


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• 
If a significant difference (p≤0.05) in the primary endpoint is not observed between the active 
treatment and placebo groups, enrollment will proceed to Stage 2 for another 20 patients per 
group   
• 
If one of the active dose groups is dropped, the remaining active dose and placebo groups will 
continue into Stage 2 for another 30 subjects per treatment group.   
• 
The Stage 2 population may be adapted based on the AKI risk factor distribution in the interim 
analysis population, which includes but is not limited to the following:  
• 
Estimated glomerular filtration rate (eGFR) ≥20 and <30 mL/min/1.73m2 ** 
• 
Estimated glomerular filtration rate (eGFR) ≥30 and <60 mL/min/1.73m2  
• 
Age ≥65 years 
• 
Combined valve and coronary surgery 
• 
Previous cardiac surgery with sternotomy 
• 
Documented New York Heart Association Class III or IV within 1 year prior to surgery 
• 
Left ventricular ejection fraction ≤35%  
• 
Congestive heart failure 
• 
Diabetes mellitus requiring insulin 
• 
Type 2 diabetes mellitus with albuminuria (urine albumin >300 mg/g of creatinine as 
documented in medical history) 
• 
Current inpatient status for management of cardiac or pulmonary disease  
• 
Preoperative anemia (hemoglobin <10 g/dL upon Screening) 
** Condition eGFR ≥20 and <30 is taken as 2 counts. All other conditions listed above are taken as 
1 count.  
 
Note that in this study, the composite preconditioning biomarkers are being measured for the first time 
in cardiac surgery patients treated with the study medication. Because of the multi-dimensional data and 
lack of prior knowledge, it is not possible to plan all potential adaptations upfront.  Therefore, the above 
adaptation rule will only serve as a guidance.  As such, no type-I error will be adjusted for the potential 2-
stage design and analysis. 
If enrollment for Stage 2 is adapted based on AKI risk factors, subjects in Stage 2 will be analyzed 
separately from subjects in Stage 1. If so, Stage 1 and Stage 2 can be viewed as two separate studies. 
Hence, the Stage 2 analysis will independently use the gatekeeping procedure with the same 2-sided 
a=0.05.  If there are enough high-risk subjects in Stage 1 (eg, N≥5/group), the high-risk Stage 1 subjects 
may be pooled with Stage 2 subjects as a secondary analysis.  
 


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7.4 
Study Subjects 
 
7.4.1 
Subject Disposition and Analysis Population 
Number of screened subjects, randomized subjects, study drug-treated subjects, and subjects receiving 
surgery will be provided overall and by treatment group. In addition, the number of randomized subjects 
completing the study and the reasons for discontinuation will be summarized overall and by treatment 
group.  
Information on subject disposition will also be listed.  
 
7.4.2 
Protocol Deviations  
Major protocol deviations will be summarized overall and by treatment group for the randomized 
population. A listing will also be provided.  
 
7.4.3 
Study Populations  
The number of subjects in each study population will be summarized overall and by treatment group.  
 
7.4.4 
Demographic and Baseline Characteristics 
Demographic data and baseline characteristics, including a general medical history, will be summarized 
overall and by treatment group for the ITT and MITT populations. 
AKI risk factors will be summarized by number of subjects meeting each risk factor, number of subjects 
meeting categorical and cumulative number of risk factors (eg, 0, 1-2, ≥1, ≥2, and ≥3). 
 
7.4.5 
Study Drug Administration and Surgery 
Time of study drug administration before surgery, duration of infusion, duration of surgery, and time on 
pump will be summarized descriptively with mean and median by treatment group. Subjects with infusion 
interruption and subjects with infusion discontinuation will be summarized with number (n) and percent 
(%) of subjects by treatment group.  
 
7.4.6 
Prior and Concomitant Medication 
All medications taken by subjects from the time of Screening through Day 90 will be recorded. Medications 
will be coded for the therapeutic class and preferred term using the WHO Drug Dictionary (WHODD 
September 2021).   
Subject incidence of prior medications, defined as medications taken prior to the study drug 
administration, will be summarized with number and % of subjects by therapeutic class and preferred 
term, overall and by treatment group, for the Safety and MITT population. Subject incidence of 
concomitant medications, defined as medications taken on/after the day of study drug administration, 
will be summarized similarly.  


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7.5 
Efficacy Analysis 
Primary endpoint will be analysed using both the ITT and MITT populations.  All other efficacy endpoints 
will be analyzed using the MITT population.  
Surgery type and time on pump may be used as covariates in ANCOVA or MMRM, or as stratification factor 
in Cochran-Mantel-Haenszel (CMH) χ2 test. When used as stratification factor, time on pump will be 
trichotomized by the approximate tertile (≤90, >90 to 120, >120 minutes) of the distribution in the MITT 
population. Other variables (eg, AKI risk factor and investigator site) may also be considered as covariates 
or stratification factors. The decision for including/excluding these variables as covariates or stratification 
factors will be based on the blinded review prior to any unblinded analysis. 
 
7.5.1 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint (geometric mean of the ratios of maximum PreOp over baseline in 
preconditioning biomarkers, Section 5.1) will be summarized using descriptive statistics (N, mean, median, 
standard deviation, minimum, and maximum) in the log scale and presented after the anti-log 
(exponential) transformation for each group separately. 
An analysis of covariance (ANCOVA) model will be applied to the log-transformed primary efficacy 
endpoint.  The model will include treatment group as main effect, and surgery type and time on-pump as 
covariates.  Least squares mean (LSM) and the 95% confidence interval (CI) will be calculated for each 
treatment group and for the between active treatment and placebo difference.  The LSM (95% CI) will be 
anti-log transformed and presented as the geometric LSM (GLSM) and 95% CI for each treatment group, 
and GLSM ratio (and 95% CIs) for each active treatment over placebo. 
A sensitivity analysis will be carried out by the Cochran-Mantel-Haenszel (CMH) χ2 test for the row mean 
score difference between active treatment and placebo stratified by the surgery type and time on pump. 
A modified ridit score will be used in the calculation of the CMH test statistic. As a supplementary analysis 
for the primary endpoint, each component of the composite endpoint  
• 
max PreOp HO-1 
Baseline HO-1    
• 
max PreOp ferritin  
Baseline ferritin  
• 
max PreOp IL-10 
Baseline IL-10  
will be analyzed in the same way as for the primary efficacy endpoint. 
 
7.5.2 
Secondary Efficacy Endpoint Analysis 
7.5.2.1 
Max PostOp over baseline in the composite of renal tubular injury biomarkers 
The secondary endpoint (geometric mean of the ratios of maximum PostOp over baseline in renal tubular 
injury biomarkers, Section 5.2.1) will be summarized and analyzed similarly to the primary endpoint.   


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Likewise, each component of the composite endpoint 
• 
max KIM-1 PostOp through Day 3)
Baseline KIM-1
  
• 
max(CysC PostOp through Day 3)
Baseline CysC
 
• 
max(NGAL over PostOp through Day 3)
Baseline NGAL 
 
will be analyzed similarly to the composite endpoint. 
A sensitivity analysis will be conducted for the maximum of the ratios of maximum PostOp over 
baseline in renal tubular injury biomarkers (see Section 5.2.1). 
 
7.5.2.2 
Reduction in Urine Output 
The proportion of subjects with reduction in urine output (ie, subjects with a documented AE of sustained 
reduction in urine output, oliguria, or anuria) through Day 5 will be presented for each treatment group. 
Reduction in urine output (yes/no) will also be analyzed using the Fisher’s exact test for the comparison 
between each active treatment group and the placebo group.   
 
7.5.2.3 
Incidence of AKI  
Incidence of AKI through Day 5 defined in Section 5.2.3 will be presented using proportions and analyzed 
using the Fisher’s exact test as described above for reduction in urine output. 
As a sensitivity analysis, subject incidence of ≥0.3 mg/dL and ≥0.5 mg/dL increase from baseline over 2 
consecutive measurements at least 12 hours apart in serum creatinine from post-cardiac surgery through 
Day 5 will be analyzed similarly. 
 
7.5.3 
Exploratory Analysis 
7.5.3.1 
Severity of AKI  
Maximum severity of AKI through Day 7 will be summarized by presenting the proportion of subjects in 
each severity stage in each treatment group. CMH test for the row mean score difference will be used for 
the between active treatment and placebo difference stratified by the surgery type and time on pump. A 
modified ridit score will be used in the CMH test. 
 
7.5.3.2 
Mean increase from baseline in serum creatinine  
Mean changes and % mean changes from baseline (defined as Visit 1a) to the mean of creatinine PostOp 
through Day 7 (or discharge if earlier) will be summarized by treatment group. The between active 
treatment and placebo difference in mean change and % mean change will be analyzed using ANCOVA 
with treatment as main effect and baseline as a covariate. LSM difference and the associated 95% CI will 
be presented. 


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Additionally, the CMH test stratified by the baseline creatinine in approximately tertile (≤0.9, >0.9 to 1.2, 
>1.2 mg/dL) will be carried out as a sensitivity analysis. 
Analysis of change and % change from baseline to each post-dose visit through Day 90 (i.e., Days 1, 2, 3, 
4, 5, 6, 7, 30, 60, and 90) will be analyzed using the mixed effects model for repeated measures (MMRM), 
which includes treatment, visit, and treatment-by-visit interaction as factors, baseline as a covariate, and 
subject as repeated measure unit. The LSM and 95% CI will be presented for each treatment group at each 
time point.  In the computation, the variance-covariance matrix will be assumed AR(1) structure and the 
denominator degrees-of-freedom will be estimated using the improved Kenward-Rodger method. LSM 
and 95% for the between active dose and placebo group difference will also be presented at each time 
point.  
 
7.5.3.3 
Mean reduction from Baseline in estimated glomerular filtration rate (eGFR) 
Mean change and % mean change from baseline (defined as Visit 1a) in eGFR (mL/min/1.73m2) will be 
summarized and analyzed similarly to that for the serum creatinine. 
 
7.5.3.4 
Occurrence of MAKE 
Proportions of subjects with (1) either MAKE30, MAKE60, or MAKE90, (2) MAKE30, (3) MAKE60, and 
(4) MAKE90 will be calculated and analyzed using the Fisher’s exact test as described for the reduction in 
urine output.  
 
7.5.3.5 
Hospitalization parameters 
Number of days on ventilator, number of days in intensive care unit and length of hospital stay will be 
summarized by treatment group with descriptive statistics of mean, median, and SD.  Appropriate 
statistical tests will be applied for the between treatment comparison.  Exploratory analysis may be 
carried out using the Kaplan-Meier survival method.  The between treatment difference will be tested 
using the log-rank test.  Proportion of subjects who are re-admitted to the hospital after the initial hospital 
stay for the cardiac surgery will be calculated for Days 30, 60, and 90 and analyzed using the Fisher’s exact 
test.  
Additionally, the association between hospital parameters and the primary efficacy endpoint (as well as 
HO-1, IL-10, and ferritin) will be explored graphically by X-Y scatter plot and curve fitting for each 
treatment group. 
As an exploratory analysis, numbers of days on ventilator, in ICU, and in the initial hospitalization, and 
hospital readmission rate will be summarized by the below subgroup. 
• 
Type of surgery (CABG vs valve vs CABG and valve combined) 
• 
Inpatient vs outpatient for the initial hospitalization 
• 
CKD vs non-CKD 
• 
Number of risk factors at baseline (≤2 vs >2, and 0, 1-2, ≥3) 
 


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7.6 
Safety Analysis 
The safety analyses described in this section will be conducted on the safety population.  
 
7.6.1 
Adverse Events  
AEs will be coded by system organ class (SOC) and preferred term according to the MedDRA dictionary 
(version 24.1).   
TEAEs will be summarized for subject incidence rate. An overall summary of TEAEs that includes the total 
number of TEAEs reported, the number and proportion of subjects experiencing at least one TEAE, at least 
one severe TEAE, at least one treatment-related TEAE, at least one serious TEAE, at least one TEAE leading 
to study discontinuation, and at least one TEAE resulting in death will be displayed by treatment group. 
The number and proportion of subjects experiencing a TEAE will also be presented by SOC and PT by 
treatment group. 
Overall and by PT incidence rate will be summarized for subjects with TEAE of interest (Section 6.3) for 
each treatment group.  Overall subject incidence rate for photosensitivity TEAEs will also be summarized 
for each treatment group. 
A listing of all AEs will be provided. Separate listings will be created for all serious AEs, AEs leading to study 
discontinuation, and deaths. 
 
7.6.2 
Laboratory Parameters 
Screening laboratory samples for chemistry, hematology and urinalysis will be processed at a local 
laboratory. All other laboratory samples will be processed at a central laboratory. For chemistry and 
hematology parameters, results at each visit will be summarized by treatment group. In addition, shift 
tables will also be presented within treatment groups.  
All laboratory results will be listed.  
 
7.6.3 
Other Safety Parameters 
Weight, body mass index, and vital signs (blood pressure, pulse rate, body temperature) at each scheduled 
visit and change from baseline at each visit will be summarized by treatment group. Physical examination 
results will be listed. Details of hospitalization(s) will be listed. 


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8 
SUMMARY TABLES, FIGURES, AND LISTINGS 
LIST OF TABLES 
Disposition 
Table 14.1-1 Summary of Subject Disposition - Safety Population 
Demographics and Baseline Characteristics 
Table 14.1-2 Summary of Subject Demographics - Safety Population 
Table 14.1-3 Summary of Subject Baseline Characteristics - Safety Population 
Table 14.1-4 Summary Subject General Medical History - Safety Population 
Table 14.1-5 Summary of Subject Acute Kidney Injury Risk Factor Evaluation at Baseline - Safety Population 
Study Drug, Surgery, Concomitant Medications, and Important Protocol Deviations 
Table 14.1-6 Summary of Study Drug Administration - Safety Population 
Table 14.1-7 Summary of Surgery Type, Duration, and Time on Pump - Safety Population 
Table 14.1-8.1 Subject Incidence of Prior Medications - Safety Population 
Table 14.1-8.2 Subject Incidence of Concomitant Medications - Safety Population 
Table 14.1-9 Summary of Important Protocol Deviations – Safety Population 
Efficacy Endpoints 
Table 14.2-1.1.1 Analysis of Primary Efficacy Endpoint (Geometric Mean of the Ratios of Max PreOp over Baseline in 
Preconditioning Biomarkers) - ITT Population 
Table 14.2-1.1.2 Analysis of Primary Efficacy Endpoint (Geometric Mean of the Ratios of Max PreOp over Baseline in 
Preconditioning Biomarkers) - MITT Population 
Table 14.2-1.1.3 Analysis of Primary Efficacy Endpoint (Geometric Mean of the Ratios of Average PostOp over Baseline in 
Preconditioning Biomarkers) - MITT Population 
Table 14.2-1.2.1 Analysis of the HO-1 Component of the Primary Efficacy Endpoint (Ratio of Max PreOp over Baseline) - MITT 
Population 
Table 14.2-1.2.2 Analysis of the Ferritin Component of the Primary Efficacy Endpoint (Ratio of Max PreOp over Baseline) - 
MITT Population 
Table 14.2-1.2.3 Analysis of the IL-10 Component of the Primary Efficacy Endpoint (Ratio of Max PreOp over Baseline) - MITT 
Population 
Table 14.2-2.1.1 Analysis of Secondary Efficacy Endpoint (Geometric Mean of the Ratios of Max PostOp over Baseline in 
Tubular Injury Biomarkers) - MITT Population 
Table 14.2-2.1.2 Analysis of Secondary Efficacy Endpoint (Max of Max PostOps over Baseline in Tubular Injury Biomarkers) - 
MITT Population 
Table 14.2-2.2.1 Analysis of the Ratio of Max PostOp over Baseline in KIM-1 - MITT Population 
Table 14.2-2.2.2 Analysis of the Ratio of Max PostOp over Baseline in Cystatin-C - MITT Population 
Table 14.2-2.2.3 Analysis of the Ratio of Max PostOp over Baseline in NGAL - MITT Population 
Table 14.2-3.2 Subject Incidence of Sustained Urine Reduction Reported as an AE - MITT Population 
Table 14.2-4.2 Subject Incidence of Revised Acute Kidney Injury (AKI) - MITT Population 
Table 14.2-5.1 Analysis of Mean Change and Percent Mean Change from Baseline to PostOp Through Day 7 (or Early 
Discharge) in Serum Creatinine (mg/dL) - MITT Population 
Table 14.2-5.2 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Serum Creatinine (mg/dL) MITT 
Population 
Table 14.2-6.1 Analysis of Mean Change and Percent Mean Change from Baseline to PostOp Through Day 7 (or Early 
Discharge) in eGFR (mL/min/1.73m2)- MITT Population 
Table 14.2-6.2 Analysis of Change and Percent Change from Baseline at Each Visit in eGFR (mL/min/1.73m2) - MITT 
Population 
Table 14.2-7.1 Subject Incidence of Major Adverse Kidney Events (MAKE) Post Surgery - MITT Population 
Table 14.2-8.1 Analysis of Post Surgery Hospitalization Parameters - MITT Population 
Table 14.2-8.2 Analysis of Post Surgery Hospitalization Parameters (High Dose and Low Dose are Combined) - MITT 
Population 
Table 14.2-8.1 Analysis of Post Surgery Hospitalization Parameters by Surgery Type - MITT Population 
Table 14.2-8.2 Analysis of Post Surgery Hospitalization Parameters by In/Outpatient Surgery Status - MITT Population 
Table 14.2-8.3 Analysis of Post Surgery Hospitalization Parameters by CKD/Non-CKD Status - MITT Population 


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LIST OF TABLES 
Table 14.2-8.4 Analysis of Post Surgery Hospitalization Parameters by No. of Baseline Risk Factors - MITT Population 
Table 14.2-8.5 Analysis of Post Surgery Hospitalization Parameters by The Tertile of Baseline EUROSCORE - MITT Population 
Table 14.2-8.6 Analysis of Post Surgery Hospitalization Parameters by The Tertile of Baseline STS Score - MITT Population 
Table 14.2-8.7 Correlation Analysis between Hospital Parameters and Primary Composite and Component Endpoints – MITT 
Population 
Table 14.2-8.8 Analysis of the Composite Score of Ventilator Days, ICU Days, and Hospital Days – MITT Population 
Adverse Events 
Table 14.3-1.1 Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Population 
Table 14.3-1.2.1 Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by Preferred Term - Safety Population 
Table 14.3-1.2.2 Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred 
Term - Safety Population 
Table 14.3-1.3 Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term, 
and Worst Severity - Safety Population 
Table 14.3-1.4 Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term, 
and Strongest Relationship to Study Drug - Safety Population 
Table 14.3-1.5 Subject Incidence of Treatment-Emergent Serious Adverse Events (TESAEs) by System Organ Class and 
Preferred Term - Safety Population 
Table 14.3-1.6 Subject Incidence TESAEs Leading to Study Discontinuation by System Organ Class and Preferred Term - Safety 
Population 
Table 14.3-1.7 Subject Incidence of TESAEs with Outcome of Death by System Organ Class and Preferred Term - Safety 
Population 
Table 14.3-1.8 Select TEAEs of Interest, Overall and by Preferred Term – Safety Population 
Table 14.3-1.9 Photosensitivity TEAEs, Overall and by Preferred Term – Safety Population 
Clinial Laboratory Parameters 
Table 14.3-2.1 Summary of Hematology Test Results by Visit - Safety Population 
Table 14.3-2.2 Summary of Chemistry Test Results by Visit - Safety Population 
Table 14.3-2.3 Summary of Urinary Tubular Injury Biomarkers - MITT Population 
Table 14.3-3.1.1 Subject Incidence of Hematology Test Result Shift from Baseline to the Highest Post Baseline - Safety 
Population 
Table 14.3-3.1.2 Subject Incidence of Hematology Test Result Shift from Baseline to the Lowest Post Baseline - Safety 
Population 
Table 14.3-3.2.1 Subject Incidence of Chemistry Test Result Shift from Baseline to the Highest Post Baseline - Safety 
Population 
Table 14.3-3.2.2 Subject Incidence of Shift from Baseline to the Lowest Post Baseline Chemistry Parameters - Safety 
Population 
Vital Signs 
Table 14.3-4.1 Summary of Vital Signs by Visit - Safety Population 
Table 14.3-4.2 Summary of Body Weight (kg) and BMI (kg/m2) at Baseline and End of Study - Safety Population 
 
 
LIST OF LISTINGS 
Listing 16.1-7 Subject Randomization Schedule - All Randomized Subjects 
Listing 16.2-1.1 Subject Study Enrollment and Disposition - All Screened Subjects 
Listing 16.2-1.2 Subject Demographics - Safety Population 
Listing 16.2-1.3 Subject Baseline Characteristics - Safety Population 
Listing 16.2-1.4.1 Subject Medical History - Safety Population 
Listing 16.2-1.4.2 Subject COVID-19 Infection and Vaccination History - Safety Population 
Listing 16.2-1.5.1 Acute Kidney Injury Risk Factor Definitions  
Listing 16.2-1.5.2 Subject Acute Kidney Injury Risk Factors - MITT Population 
Listing 16.2-1.7 Subject Cardiac Surgical Characteristics - MITT Population 
Listing 16.2-1.8 Subject Prior and Concomitant Medications - MITT Population 


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LIST OF LISTINGS 
Listing 16.2-2.1.1 Subject Preconditioning Response Biomarker Individual Test Results by Visit - MITT Population 
Listing 16.2-2.1.2 Subject Preconditioning Response Biomarker Composite Score (Max PreOp/Baseline) - MITT Population 
Listing 16.2-2.2.1 Subject Kidney Tubular Injury Biomarker Individual Test Results by Visit - MITT Population 
Listing 16.2-2.2.2 Subject Kidney Tubular Injury Biomarker Composite Score (Max PostOp/Baseline) - MITT Population 
Listing 16.2-2.3.2 Subject Sustained Urinary Retention During the First 5 Days Post Surgery Based on AE Report - MITT 
Population 
Listing 16.2-2.4 Subject Serum Creatinine and eGFR Assessments by Visit - MITT Population 
Listing 16.2-2.5.1 Subject Incidence of Acute Kidney Injury PostOp Through Day 5 - MITT Population 
Listing 16.2-2.5.2 Subject Incidence and Severity of Acute Kidney Injury PostOp Through Day 7 - MITT Population 
Listing 16.2-2.6 Subject Major Kidney Events Derivation - MITT Population 
Listing 16.2-2.7 Subject Post Surgery Hospitalization Parameters - MITT Population 
Listing 16.2-3.1 All Adverse Event Reports - Safety Population 
Listing 16.2-3.2 Serious Treatment-Emergent Adverse Events - Safety Population 
Listing 16.2-3.3 Treatment-Emergent Adverse Events Leading to Study Discontinuation - Safety Population 
Listing 16.2-3.4 Treatment-Emergent Adverse Events with Outcome of Death - Safety Population 
Listing 16.2-3.5.1 Subject Hematology Test Results by Visit - Safety Population 
Listing 16.2-3.5.2 Subject Chemistry Test Results by Visit - Safety Population 
Listing 16.2-3.5.3 Subject Urinalysis Test Results by Visit - Safety Population 
Listing 16.2-3.5 Treatment-Emergent Adverse Events Drug Related - Safety Population 
Listing 16.2-3.6 Subject Vital Signs by Visit - Safety Population 
Listing 16.2-3.7 Subject Body Weight, Height, and BMI at Screening and End of Study - Safety Population 
 
 
LIST OF FIGURES 
Figure 14.2-2.1 Kaplan-Meier Plot for Duration of Hospital Stay for the Initial Hospitalization - MITT Population 
Figure 14.2-2.2 Kaplan-Meier Plot for Duration of ICU for the Initial Hospitalization - MITT Population 
Figure 14.2-2.3 Kaplan-Meier Plot for Days on Ventilator for the Initial Hospitalization - MITT Population 
Figure 14.2-2.4 Kaplan-Meier Plot for Time to First Hospital Readmission - MITT Population 
Figure 14.2-2.5 Kaplan-Meier Plot for Duration of First Hospital Readmission - MITT Population with Hospital Readmission 
Figure 14.2-3.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 
Figure 14.2-3.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 
Figure 14.2-3.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 
Figure 14.2-4.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over Max PreOp/Baseline in Serum HO-1 by 
Treatment Group 
Figure 14.2-4.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over Max PreOp/Baseline in Serum HO-1 by Treatment 
Group 
Figure 14.2-4.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over Max PreOp/Baseline in Serum HO-1 by 
Treatment Group 
Figure 14.2-5.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over Max PreOp/Baseline in Serum IL-10 by 
Treatment Group 
Figure 14.2-5.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over Max PreOp/Baseline in Serum IL-10 by Treatment 
Group 
Figure 14.2-5.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over Max PreOp/Baseline in IL-10 by Treatment 
Group 
 


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9 
APPENDICES 
 
APPENDIX A  – Schedule of Visits 
 
Visit 
Visit 0 
(Screening)† 
Visit 1a 
Visit 1b†† 
Visit 2 
Visit 3 
Visit 4 
Visits 5-7 
Visit 8* 
Visit 9* 
Visit 
10* 
Visit 11*/ 
Final Visit 
Procedure 
Time point 
Within 30 
Days Prior to 
Visit 1 
≥24 h but 
≤48 h 
Prior to 
Surgery 
24 h (± 4 
h) Prior to 
Surgery 
D1 
Pre-Op 
 
 
D1 
Post-Op 
D2 
D3 
D4, 5, 6 
(If  
Hospitalized) 
D7 
(± 3 days)  
D30 
(± 3 days) 
D60 
(± 3 days) 
D90 
(± 3 days) 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient Eligibility  
(Inclusion/Exclusion  
Criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant  
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam  
X 
X 
 
X 
 
X 1 
X 1 
X 1 
X  
X  
 
X  
Weight and BMI 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs  
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry 2 
X 3 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 4 
X  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 5 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine Output 6 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Blood Biomarkers 7 
 
X 
X 
X 8 
 
X 
X 
 
 
 
 
 
Urinary  
Biomarkers 9 
 
X 
X 
X 8 
 
X 
X 
 
 
 
 
 
Urine Pregnancy Test 10 
X 
 
 
 
 
 
 
 
 
X 
 
 
Study Drug Infusion 11 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Events 12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BMI = body mass index; D = Day; h = hour; PostOp = post-operatively; PreOp = pre-operatively 
 
†  Screening labs will be analyzed at a local laboratory; for subjects who will be administered study drug on the same day of Screening, blood and urine samples will need to be collected for central 
laboratory analysis in accordance with Visit 1a; physical examinations and routine labs (serum chemistry, hematology, urinalysis) performed as part of standard of care within 1 month of dosing 
administration (Visit 1a) can be used for Screening assessments. 
††  Visit 1b will be performed in subjects who receive study drug within 36 to 48 hours prior to surgery. 


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*  
Visits 8-11 (Days 7, 30, 60, and 90) may be conducted remotely as virtual visits if in-person visits are not possible; if virtual visits are conducted: 1) blood and urine samples may be collected by 
remote phlebotomy, such as through a mobile phlebotomist or other blood collection center and 2) physical examinations can be symptom-directed. 
 
1 
Physical examination can be symptom-directed on Days 2-6.  
2 
Serum chemistry parameters include total protein, albumin, bicarbonate, blood urea nitrogen, serum creatinine, total bilirubin, alkaline phosphatase, glucose, sodium, potassium, phosphate, 
calcium, magnesium, gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and cystatin C.  
3 
Serum ferritin is also to be assessed at Screening if not already included in local laboratory chemistry panel.  
4 
Hematology parameters include red blood cell count [RBC], hemoglobin, hematocrit, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin 
concentration [MCHC], platelets, mean platelet volume [MPV], red cell distribution width [RDW], white blood cell count [WBC], and WBC differential (including neutrophils [absolute and 
percentage], lymphocytes [absolute and percentage], monocytes [absolute and percentage], eosinophils [absolute and percentage], and basophils [absolute and percentage]). 
5 
Urinalysis parameters include glucose, ketones, leukocytes, nitrite, blood, pH, protein, specific gravity, and reflex microscopic. 
6 
Urine output will be measured through Day 3. 
7 
Blood biomarkers include preconditioning response biomarkers (plasma heme oxygenase-1 [HO-1], ferritin, and interleukin-10 [IL-10]) and other biomarkers of RBT-1 activity and kidney 
function. 
8 
Blood and urinary biomarkers will be collected within 4 hours prior to cardiac surgery. 
9 
Urinary biomarkers include tubular injury biomarkers (kidney injury molecule-1 [KIM-1], cystatin C, and neutrophil gelatinase-associated lipocalin [NGAL]), and other biomarkers of RBT-1 
activity and kidney function. 
10 A pregnancy test will be performed in female subjects of childbearing potential. 
11 RBT-1 and placebo will be administered via intravenous infusion over a 120-minute period. 
12 Adverse events assessment will include photosensitivity assessment.  
 


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APPENDIX B – Change from Version 2.0 SAP to this Version 3.0 SAP 
Section 2.2 The secondary objectives are to evaluate the efficacy of RBT-1 on the following: 
v2.0 
• 
Reduction in urine output (documented oliguria of <0.5 mL/kg/hour, not due to urinary tract 
obstruction or hypotension) for more than 6 hours post-cardiac surgery through Day 3 
• 
Incidence of AKI (defined using the modified Kidney Disease Improving Global Outcomes [KDIGO] 
criteria) post-cardiac surgery through Day 5 
v3.0 
• 
Reduction in urine output (documented adverse event [AE] of sustained reduction in urine 
output, oliguria, or anuria) post-cardiac surgery through Day 5 
• 
Incidence of AKI (defined as a ≥1.5X baseline, i.e., a 50% increase from baseline in serum 
creatinine; documented AE of sustained reduction in urine output, oliguria, or anuria; or initiation 
of dialysis) post-cardiac surgery through Day 5 
 
Section 3.1 Modified Intent-to-Treat (MITT) Population 
v2.0 
• 
None  
v3.0 
• 
The ITT population will consist of all randomized subjects who were eligible for the study, received 
study drug, and had biomarker assessments performed at baseline (Visit 1a) and prior to surgery 
(Visit 1b and/or Day 1 PreOp). Subjects in the ITT population will be analyzed as randomized. 
 
Section 3.2 Modified Intent-to-Treat (MITT) Population 
v2.0 
• 
The MITT population will consist of all randomized subjects who were eligible for the study, 
received study drug, underwent CABG and/or cardiac valve surgery without delay, and have 
at least one post baseline primary efficacy assessment. Subjects in the MITT population will 
be analyzed as randomized.  
v3.0 
• 
The MITT population will consist of all randomized subjects who were eligible for the study, 
received study drug, underwent CABG and/or cardiac valve surgery without delay, and were 
evaluated through the end of index surgery hospitalization. Subjects in the MITT population 
will be analyzed as randomized. 
 


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Section 3.3 Per Protocol Population 
v2.0 
The per-protocol population will consist of subjects from the MITT population who had primary efficacy 
assessments through Day 3 and had no major protocol violations. Subjects with major protocol deviations 
will be identified using the eCRF Form Protocol Deviation ([“Any protocol deviation” = “Yes”] and 
[“Deviation Impact” is not reported as “Minor”]). Subjects in the Per Protocol population will be analyzed 
as treated. 
v3.0 
This section is removed. 
 
Section 5.2.2 Reduction in Urine Output 
v2.0 
• 
The reduction in urine output (documented oliguria of <0.5 mL/kg/hour, not due to urinary 
tract obstruction or hypotension) for 6 or more consecutive hourly assessments post-cardiac 
surgery through Day 3 will be evaluated by the site and captured as a (Yes/No) binary variable 
on the daily eCRF. 
v3.0 
• 
The reduction in urine output (documented AE of sustained reduction in urine output, 
oliguria, or anuria) post-cardiac surgery through Day 5 will be evaluated by the site and 
captured as an AE on the AE log eCRF. 
 
Section 5.2.3 Incidence of AKI 
The incidence of AKI post-cardiac surgery through Day 5 will be defined as: 
v2.0 
• 
An absolute increase from baseline in serum creatinine by 0.5 mg/dL, which is present over 2 
consecutive laboratory measurements at least 12 hours apart; or 
• 
An increase in serum creatinine ≥1.5 x Baseline at any time 
This secondary efficacy endpoint will be a binary variable and will be derived as presented in 
Appendix 2. 
v3.0 
• 
An absolute increase from baseline to ≥1.5 x Baseline at any time; or 
• 
A documented AE of sustained reduction in urine output, oliguria, or anuria; or  
• 
Initiation of dialysis 


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Section 5.3.1 Severity of AKI 
v2.0 
Maximum severity of AKI post-cardiac surgery through Day 7 will be a categorical variable (stage 1, stage 
2, and stage 3) and will be as presented in Appendix 2. 
v3.0 
Maximum severity of AKI post-cardiac surgery through Day 7 will be a categorical variable.  It is defined 
as the maximum severity over Days 2 through 7 for subject with AKI incidence PostOp through Day 7 
(replacing Day 5 with Day 7 in Section 5.2.3) as follows: 
Stage 1 
if CreatDi- CreatBL >= 0.3 mg/dL, or 
 
1.5*CreatBL <= CreatDi < 2*CreatBL (i=2 to 7) 
Stage 2 
if 2*CreatBL <= CreatDi < 3*CreatBL (i=2 to 7) 
Stage 3 
if CreatDi- CreatBL >= 4 mg/dL, or 
3*CreatBL <= CreatDi (i=2 to 7), or 
need for dialysis and date of dialysis < date of surgery + 7 
where CreatBL is creatinine at baseline (Day 1 PreOp), CreatDi is creatinine on Day Di (i.e., Days 2, …, 7). 
 
Section 5.3.3 Occurrence of MAKE 
v2.0 
Endpoints related to MAKE are as follows: 
o Proportion of subjects experiencing either MAKE30 or MAKE90 post-cardiac surgery 
o Proportion of subjects experiencing MAKE30 
o Proportion of subjects experiencing MAKE90 
These efficacy endpoints will be binary variables and will be derived as presented in Appendix 3. 
v3.0 
Endpoints related to MAKE are as follows: 
o Proportion of subjects experiencing either MAKE30, MAKE60, or MAKE90 
o Proportion of subjects experiencing MAKE30 
o Proportion of subjects experiencing MAKE60 
o Proportion of subjects experiencing MAKE90 
MAKE30 is defined for subjects with AKI incidence PostOp through Day 5 as follows 
o Death (of all cause) and date of death < date of surgery + 30, or 
o Need for dialysis and date of dialysis < date of surgery + 30, or 
o (eGFRD30 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 30 
MAKE60 is defined for subjects with AKI incidence PostOp through Day 5 as follows 


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o Death (of all cause) and date of death < date of surgery + 60, or 
o Need for dialysis and date of dialysis < date of surgery + 60, or 
o (eGFRD60 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 30 
MAKE90 is defined for subjects with AKI incidence PostOp through Day 5 as follows 
o Death (of all cause) and date of death < date of surgery + 90, or 
o Need for dialysis and date of dialysis < date of surgery + 90, or 
o eGFRD90 - eGFRBL)/eGFRBL <= -0.25 PostOp through Day 30 
where eGFRBL is eGFR at baseline (Day 1 PreOp), eGFR30, eGFR60, and eGFR90 are eGFR on Days 30, 60, and 
90, respectively. Note, eGFR (mL/min/1.73m2) is calculated using 2009 CKD-EPI equation: 
141 × min(Scr/κ, 1)α× max(Scr/κ, 1)-1.209× 0.993Age× 1.018 [if female] × 1.159 [if African American]. 
 
Section 6.3 Select Adverse Events of Interest 
v2.0 
This section is inserted in v3.0. 
v3.0 
Following is a list of adverse events of interest by MedDRA preferred term (tentative): 
• 
Atrial fibrillation 
• 
Delirium 
• 
Vasoplegia 
• 
Bleeding 
• 
Myocardial infraction 
• 
Stroke 
• 
Heart failure 
• 
AKI (combined AKI, ARF, AE report of sustained urine reduction) 
• 
Death 
 
Section 7.4.4 Demographic and Baseline Characteristics 
v2.0 
• 
AKI risk factors will be summarized by number of subjects meeting each risk factor, and number 
of subjects meeting cumulative number of risk factors (eg, ≥1, ≥2). 
v3.0 
• 
AKI risk factors will be summarized by number of subjects meeting each risk factor, number of 
subjects meeting categorical and cumulative number of risk factors (eg, 0, 1-2, ≥1, ≥2, and ≥3). 
Additionally, photosensitivity AEs will be identified. 


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Section 7.5 Efficacy Analysis 
v2.0 
All efficacy analyses will be conducted on the MITT population. The primary efficacy endpoint analysis will 
be repeated for the PP population. 
When used as stratification factor, time on pump will be trichotomized by the tertile of the distribution in 
the MITT population. 
v3.0 
Primary endpoint will be analysed using both the ITT and MITT populations.  All other efficacy endpoints 
will be analyzed using the MITT population.  
When used as stratification factor, time on pump will be trichotomized by the approximate tertile (≤90, 
>90 to 120, >120 minutes) of the distribution in the MITT population. 
 
Section 7.5.2.2 Reduction in Urine Output 
v2.0 
• 
The proportion of subjects with reduction in urine output for ≥6 hours through Day 3 will be 
presented for each treatment group. 
v3.0 
• 
The proportion of subjects with reduction in urine output (ie, subjects with a documented AE of 
sustained reduction in urine output, oliguria, or anuria; or initiation of dialysis) through Day 5 will 
be presented for each treatment group. 
 
Section 7.5.2.3 Incidence of AKI  
v2.0 
• 
As a sensitivity analysis, subject incidence of ≥0.3 mg/dL increase from baseline … will be analyzed 
similarly. 
v3.0 
• 
As a sensitivity analysis, subject incidence of ≥0.3 mg/dL and ≥0.5 mg/dL increase from baseline 
… will be analyzed similarly. 
 
Section 7.5.3.2 Mean increase from baseline in serum creatinine 
v2.0 
• 
Additionally, the CMH test stratified by the baseline creatinine in tertile will be carried out as a 
sensitivity analysis. 


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• 
Analysis of change and % change from baseline to each PostOp visit through Day 7 (i.e., Days 1, 2, 
3, 4, 5, 6, and 7) will be analyzed using … 
v3.0 
• 
Additionally, the CMH test stratified by the baseline creatinine in approximately tertile (≤0.9, >0.9 
to 1.2, >1.2 mg/dL) will be carried out as a sensitivity analysis. 
• 
Analysis of change and % change from baseline to each post-dose visit through Day 7 (i.e., Days 
1, 2, 3, 4, 5, 6, and 7) will be analyzed using … 
 
Section 7.5.3.4 Occurrence of MAKE 
v2.0 
Proportions of subjects with (1) either MAKE30 or MAKE90, (2) MAKE30, and (3) MAKE90 will be 
calculated and analyzed using the Fisher’s exact test as described for the reduction in urine output. This 
summary will be presented for subjects who develop AKI incidence (see Table 2.2 in Appendix 2) during 
hospitalization, subjects who do not develop AKI incidence during hospitalization, and all subjects. 
v3.0 
Proportions of subjects with (1) either MAKE30, MAKE60, or MAKE90, (2) MAKE30, (3) MAKE60, and 
(4) MAKE90 will be calculated and analyzed using the Fisher’s exact test as described for the reduction in 
urine output.  
 
Section 7.5.3.5 Hospital parameters 
v2.0 
Number of days on ventilator, number of days in intensive care unit and length of hospital stay will be 
summarized by treatment group. Proportion of subjects who are re-admitted to the hospital after the 
initial hospital stay for the cardiac surgery will be calculated.  
v3.0 
Number of days on ventilator, number of days in intensive care unit and length of hospital stay will be 
summarized by treatment group with descriptive statistics of mean, median, and SD.  Appropriate 
statistical tests will be applied for the between treatment comparison.  Additional analysis may be carried 
out using the Kaplan-Meier survival method.  The between treatment difference will be tested using the 
log-rank test.  Proportion of subjects who are re-admitted to the hospital after the initial hospital stay for 
the cardiac surgery will be calculated for Days 30, 60, and 90 and analyzed using the Fisher’s exact test.  
Additionally, the association between hospital parameters and the primary efficacy endpoint (as well as 
HO-1, IL-10, and ferritin) will be explored graphically by X-Y scatter plot and curve fitting for each 
treatment group. 


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As an exploratory analysis, numbers of days on ventilator, in ICU, and in the initial hospitalization, and 
hospital readmission rate will be summarized by the below subgroup. 
• 
Type of surgery (CABG vs valve vs CABG and valve combined) 
• 
Inpatient vs outpatient for the initial hospitalization 
• 
CKD vs non-CKD 
• 
Number of risk factors at baseline (≤2 vs >2, and 0, 1-2, ≥3) 
• 
Baseline EUROSCORE tertile 
• 
Baseline STS score tertile 
Also as an exploratory analysis, composite score constructed by the weighted sum of the ventilator days, 
ICU days, and initial hospital days will be derived.  The weight will be derived based on the resource 
utilization for each of these 3 parameters. 
 
Section 7.5.3.6 Change in Biomarkers of RBT-1 Activity and/or Kidney function 
V2.0  
Change and % change from baseline (Visit 1a) to the Day 1 – 7 average biomarker values will be 
summarized by treatment group. The active treatment and placebo difference will be analyzed similar to 
that for the mean change in creatinine using the MMRM method. 
V3.0 
This section is removed. 
 
Section 7.6. Additional Parameters for Analysis 
v2.0 
Variables of interest: 
1. Single incidence of ≥50% increase from baseline in serum creatinine. 
2. Single incidence of ≥50% increase from baseline in serum creatinine AND sustained serum 
creatinine increase through Day 30, 60, and/or 90  
3. Persistent AKI, defined as serum creatinine increase from baseline for ≥ 48 hours and ≥ 72 hours 
by 
• 
≥ 0.3 mg/dL 
• 
≥ 0.5 mg/dL 
• 
≥ 50% 
4. Persistent AKI during the initial hospitalization, as defined in #3 above, AND sustained serum 
creatinine increase through Day 30, 60, and/or 90  
5. Persistent AKI during the initial hospitalization, as defined in #3 above, AND eGFR decrease of 
≥25%, ≥30%, and ≥50% on Day 30, 60, and/or 90 
6. eGFR decrease by 
• 
≥ 25% 
• 
≥ 30% 


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• 
≥ 50%  
from baseline during initial hospitalization for  
• 
≥ 48 hours 
• 
≥ 72 hours  
7. eGFR decrease as defined in #6 above AND sustained through Day 30, 60, and/or 90 
8. Worsening proteinuria at Day 30 and/or 90 compared with baseline 
9. Worsening albuminuria at Day 30 and/or 90 compared with baseline 
10. MAKE outcomes and the association with the parameters defined in #1-#9 above, including 
percent of subjects meeting each criterion who have MAKE 
11. Days on ventilator and the association with the parameters defined in #1-#9 above 
12. Days in intensive care unit (ICU) and the association with the parameters defined in #1-#9 above 
13. Hospital length of stay and the association with the parameters defined in #1-#9 above 
14. Readmission rate and the association with the parameters defined in #1-#9 above 
v3.0 
This section is completely removed. 
 
Section 7.6.1 Adverse Events 
v2.0 
This paragraph is newly added to v3.0. 
v3.0 
Overall and by PT incidence rate will be summarized for subjects with TEAE of interest (Section 6.3) for 
each treatment group.  Overall subject incidence rate for photosensitivity TEAEs will also be summarized 
for each treatment group. 
 
Appendix 1 Schedule of Visits 
v3.0  
• 
V2.0 Schedules for “D1 1h Post-Op” is replaced with “D1 Post-Op” and v2.0 “D1 12h Post-Op” is 
removed. 
Footnote  
v2.0 
6 Urine output will be measured until Discharge. 
8 Blood and urinary biomarkers will be collected within 1 hour prior to cardiac surgery. 
v3.0 
6 Urine output will be measured through Day 3. 
8 Blood and urinary biomarkers will be collected within 4 hours prior to cardiac surgery. 
 


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Appendix 2 Derivation of occurrence and severity of AKI 
v2.0 
The data that will be used to derive occurrence and severity of AKI post-cardiac surgery through Day 7 is 
schematically presented in the table below. 
 
Table 2.1 - Format of the data to derive occurrence of AKI 
Visit 
CreatDi 
(mg/dL) 
Change 
from 
Baseline 
(Visit 1A) 
Change 
from BL >= 
0.5 mg/dL 
CreatDi >= 
1.5*CreatBL 
Severity of 
AKI 
(GFRDi – 
GFRBL)/GFRBL <= 
-0.25 
Baseline (Visit 
1A) 
(before dosing) 
CreatBL 
0 
N/A 
N/A 
N/A 
N/A 
D1 PreOp (after 
dosing but prior 
surgery) 
Creatpreop 
Creatpreop- 
CreatBL 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
D2 
CreatD2 
CreatD2- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3 
no need to 
calculate 
D3 
CreatD3 
CreatD3- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3 
no need to 
calculate 
D4 
CreatD4 
CreatD4- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3  
no need to 
calculate 
D5 
CreatD5 
CreatD5- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3 
no need to 
calculate 
D6 
CreatD6 
CreatD6- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3 
no need to 
calculate 
D7 
CreatD7 
CreatD7- 
CreatBL 
Yes or No 
Yes or No 
NA, stage 1, 
stage 2 
or stage 3 
no need to 
calculate 
D30 
CreatD30 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
Yes or No 
D60 
CreatD60 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
Yes or No 
D90 
CreatD90 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
no need to 
calculate 
Yes or No 
 
In the table above, eGFR (mL/min/1.73m2) is calculated using 2009 CKD-EPI equation: 
 
141 × min(Scr/κ, 1)α× max(Scr/κ, 1)-1.209× 0.993Age× 1.018 [if female] × 1.159 [if African American] 
 
where: Scris serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and 
-0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1 
 


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If a patient is considered to have an AKI incidence, then the severity of AKI, defined as stage, is derived 
as follows: 
 
Stage 1  
if CreatDi- CreatBL >= 0.3 mg/dL OR  1.5*CreatBL <= CreatDi < 2*CreatBL (i=2 to 7) 
Stage 2  
if 2*CreatBL <= CreatDi < 3*CreatBL (i=2 to 7) 
Stage 3  
if CreatDi- CreatBL >= 4 mg/dL  OR  3*CreatBL <= CreatDi (i=2 to 7)  OR  need for 
dialysis and date of dialysis < date of  
 
 
surgery + 7 
Occurrence and severity of AKI will be derived as presented in the tables below. 
 
Table 2.2 – Derivation of occurrence of AKI (subject level) 
Incidence of AKI post-cardiac surgery 
through Day 7 (subject level) 
Derivation 
Yes 
If there are two consecutive “Yes” for Change from baseline (visit 1a) 
>= 0.5 mg/dL from D2 to D5 
OR 
If there is one “Yes” for CreatDi >= 1.5*CreatBL from D2 to D5 
No 
Otherwise 
 
 
Table 2.3 – Derivation of severity of AKI (subject level) 
Severity of AKI post-cardiac 
surgery through Day 7 
(subject level) 
Derivation 
Stage 1 
  
If Incidence of AKI post-cardiac surgery through Day 7 =’Yes’ 
AND 
Maximum severity of AKI from D2 to D7 = ‘Stage 1’  
Stage 2 
  
If Incidence of AKI post-cardiac surgery through Day 7 =’Yes’ 
AND 
Maximum severity of AKI from D2 to D7 = ‘Stage 2’ 
Stage 3 
  
If Incidence of AKI post-cardiac surgery through Day 7 =’Yes’ 
AND 
Maximum severity of AKI from D2 to D7 = ‘Stage 3’ 
 
OR 
 
If Incidence of AKI post-cardiac surgery through Day 7 =’Yes’ 
AND 
Need for dialysis and the date of dialysis < date of surgery + 7 
 
v3.0 
This appendix is completely removed. 
 
Appendix 3 – Derivation of occurrence of MAKE 
v2.0 
Table 3.1 - Derivation of severity of MAKE 30 (subject level) 


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Occurrence of 
MAKE30 
Derivation 
Yes 
If death (all-cause mortality) and date of death < date of surgery + 30 
OR 
if need for dialysis and the date of dialysis < date of surgery + 30 
OR 
If subject has incidence of AKI post-cardiac surgery through Day 5 AND (eGFRD30 - 
eGFRBL)/eGFRBL <= -0.25 
No 
Otherwise 
 
Table 3.2 - Derivation of severity of MAKE 90 (subject level) 
Occurrence of 
MAKE90 
Derivation 
Yes 
If death (all-cause mortality) and date of death < data of surgery + 90 
OR 
if need for dialysis and the date of dialysis < date of surgery + 90 
OR 
If subject has incidence of AKI post-cardiac surgery through Day 5 AND (eGFRDi - 
eGFRBL)/eGFRBL <= -0.25 on D30, D60 and D90 
No 
Otherwise 
 
v3.0 
This appendix is completely removed. 
 
Section 8 Summary Tables, Figures, and Listings 
v2.0  
Below tables, listings, and figures are removed from v3.0 as a result of the SAP update. 
Table 14.2-3.1 Subject Incidence of Reduction in Urine Output Post Surgery Through Day 3 (per the Urine Output eCRF) - 
MITT Population 
Table 14.2-4.1 Subject Incidence and Max Severity of Acute Kidney Injury (AKI) - MITT Population 
Table 14.2-7.2 Subject Incidence of Post Surgery Major Adverse Kidney Event (MAKE) Collected on the AE CRF - MITT 
Population 
Table 14.2-9.1 Subject Incidence of PostOp Creatinine Increase - Part 1 - MITT Population 
Table 14.2-9.2 Subject Incidence of PostOp Creatinine Increase - Part 2 - MITT Population 
Table 14.2-9.3 Subject Incidence of PostOp Creatinine Increase - Part 3 - MITT Population 
Table 14.2-9.4 Subject Incidence of PostOp Creatinine Increase - Part 4 - MITT Population 
Table 14.2-9.5 Subject Incidence of PostOp eGFR Decrease - Part 1 - MITT Population 
Table 14.2-9.6 Subject Incidence of PostOp eGFR Decrease - Part 2 - MITT Population 
Table 14.2-10.1 Analysis PostOp Proteinuria and Albuminuria - MITT Population 
Table 14.2-10.2 Analysis PostOp Urine Albumin/Creatinine and Protein/Creatinine Ratios - MITT Population 
Table 14.2-11 Subject Incidence of PostOp Creatinine Increase by 0.3 mg/dL, 0.5 mg/dL, 50% Increase from Baseline During 
Hospitalization - MITT Population 
Table 14.2-12.1 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Urine Albumin Creatinine Ratio 
(UACR, mg/g) - MITT Population 
Table 14.2-12.2 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Urine Protein Creatinine Ratio 
(UPCR, g/g) - MITT Population 


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Table 14.2-13.1.1 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Kidney Injury Molecule-1 
(ng/mL) - MITT Population 
Table 14.2-13.1.2 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Urine Creatinine-Normalized 
Kidney Injury Molecule-1 (ng/mg) - MITT Population 
Table 14.2-13.1.3 Frequency Counts for Subjects Whose uCr-Normalized Kidney Injury Molecule-1 (ng/mg) > 2.38 - MITT 
Population 
Table 14.2-13.2.1 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Cystatin C (ng/mL) - MITT 
Population 
Table 14.2-13.2.2 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Urine Creatinine-Normalized 
Cystatin C (ng/mg) - MITT Population 
Table 14.2-13.2.3 Frequency Counts for Subjects Whose uCr-Normalized Cystatin C (ng/mg) > 48.0 - MITT Population 
Table 14.2-13.3.1 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Neutrophil Gelatinase Lipocal 
(ng/mL) - MITT Population 
Table 14.2-13.3.2 Analysis of Change and Percent Change from Baseline to Each PostOp Visit in Urine Creatinine-Normalized 
Neutrophil Gelatinase Lipocal (ng/mg) - MITT Population 
Table 14.2-13.3.3 Frequency Counts for Subjects Whose uCr-Normalized NGAL (ng/mg) > 94.4 - MITT Population 
Table 14.2-14.1 Subject Counts by CKD and AKI Risk Factors- MITT Population 
Table 14.2-14.2 Summary of Day 30 eGFR and Hospital Parameters by CKD - MITT Population 
Table 14.2-14.3 Frequency Counts for Subjects who had 0.3mg/dL, 0.5mg/dL or 50% Increase in sCr by CKD - MITT 
Population 
Table 14.2-14.4 Summary of Day 30 eGFR and Hospital Parameters by AKI Risk Factor - MITT Population 
Table 14.2-14.5 Frequency Counts for Subjects who had 0.3, 0.5 or 50% increase in sCr by AKI Risk Factor - MITT Population 
Table 14.2-15.1 Subject Incidence of AKI by No. of Baseline Risk Factors - Version 1 - MITT Population 
Table 14.2-15.2 Subject Incidence of AKI by No. of Baseline Risk Factors - Version 2 - MITT Population 
Table 14.2-15.3 Subject Incidence of AKI by No. of Baseline Risk Factors - Version 3 - MITT Population 
Table 14.2-15.4 Composite of Single sCr >=0.3, 0.5 mg/dL or 50% Increase with Days on Ventilator >1, Days in ICU >X, Days in 
Hospital >Y - MITT Population 
Listing 16.2-2.1.3 Subject Preconditioning Response Biomarker Composite Score (Avg Post Dose/Baseline) - MITT Population 
Listing 16.2-2.3.1 Subject Sustained Urinary Retention During the First 3 Days Post Surgery Based on Urine Output - MITT 
Population 
Listing 16.2-2.5.3 Subject Acute Kidney Injury Incidence and Severity - MITT Population 
Listing 16.2-8.1 Patients with 50% Increase in Serum Creatinine in Hospital and Sustained Through Day 30 and, Day 60 or Day 
90 - MITT Population 
Listing 16.2-8.2 Patients with Serum Creatinine Increase in Hospital for 48 and 72 Hours - MITT Population 
Listing 16.2-8.3 Patients with Serum Creatinine Increase in Hospital for 48 and 72 Hours and Sustained Through Day 30, and 
60 or 90 - MITT Population 
Listing 16.2-8.4 Patients with Serum Creatinine Increase in Hospital for 48 and 72 Hours, and eGFR Decrease at Day 30, and 
60 or 90 - MITT Population 
Listing 16.2-8.5 Patients with eGFR Decrease in Hospital for 48 and 72 Hours - MITT Population 
Listing 16.2-8.6 Patients with eGFR Decrease in Hospital for 48 and 72 Hours, and Sustained at Day 30, and 60 or 90 - MITT 
Population 
Listing 16.2-9.1 Patients with 15% Increase in PostOp Urine Protein or Albumin - MITT Population 
Listing 16.2-9.2 Patients with 15% Increase in PostOp Urine Albumin/Creatinine and Protein/Creatinine Ratios - MITT 
Population 
Figure 14.2-1.1 Spaghetti Plot of Creatinine (mg/dL) Over Time - MITT Population 
Figure 14.2-1.2 Spaghetti Plot of eGFR (mL/min/1.73 m2) Over Time - MITT Population 
Figure 14.2-1.3 Spaghetti Plot of KIM-1 (ng/mL) Over Time - MITT Population 
Figure 14.2-1.4 Spaghetti Plot of NGAL (ng/mL) Over Time - MITT Population 
Figure 14.2-1.5 Spaghetti Plot of Cystatin C (ng/mL) Over Time - MITT Population 
Figure 14.2-3.1 Scatter Plot Matrix of Total No. of AKI Risk Factors, 0.3 mg/dL Increase in sCr for 48 Hours, Day 30 eGFR,Days 
on Ventilator, Days in Hospital, and Days in ICU - MITT Population 


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Figure 14.2-3.2 Scatter Plot with LOESS Curve of 0.3 mg/dL Increase in sCr any Time in Hospital over Total No. of AKI Risk 
Factors - MITT Population 
Figure 14.2-3.3 Scatter Plot with LOESS Curve of 0.3 mg/dL Increase in sCr for 48 Hours in Hospital over Total No. of AKI Risk 
Factors - MITT Population 
Figure 14.2-3.4 Scatter Plot with LOESS Curve of 0.5 mg/dL Increase in sCr any Time in Hospital over Total No. of AKI Risk 
Factors - MITT Population 
Figure 14.2-3.5 Scatter Plot with LOESS Curve of 0.5 mg/dL Increase in sCr for 48 Hours in Hospital over Total No. of AKI Risk 
Factors - MITT Population 
Figure 14.2-3.6 Scatter Plot with LOESS Curve of Day 30 eGFR over Total No. of AKI Risk Factors any Time in Hospital - MITT 
Population 
Figure 14.2-3.7 Scatter Plot with LOESS Curve of Day 30 eGFR over 0.3 mg/dL Increase in sCr any Time in Hospital - MITT 
Population 
Figure 14.2-3.8 Scatter Plot with LOESS Curve of Day 30 eGFR over 0.3 mg/dL Increase in sCr for 48 Hours in Hospital - MITT 
Population 
Figure 14.2-3.9 Scatter Plot with LOESS Curve of Day 30 eGFR over 0.5 mg/dL Increase in sCr any Time in Hospital - MITT 
Population 
Figure 14.2-3.10 Scatter Plot with LOESS Curve of Day 30 eGFR over 0.5 mg/dL Increase in sCr for 48 Hours in Hospital - MITT 
Population 
Figure 14.2-3.11 Scatter Plot with LOESS Curve of Day 30 eGFR over Days in Hospital - MITT Population 
Figure 14.2-3.12 Scatter Plot with LOESS Curve of Day 30 eGFR over Days on Ventilator - MITT Population 
Figure 14.2-3.13 Scatter Plot with LOESS Curve of Day 30 eGFR over Days in ICU - MITT Population 
Figure 14.2-4.1 Scatter Plot of PostOp Max(sCr) over PostOp Max(KIM-1) on Log2 Scale 
Figure 14.2-4.2 Scatter Plot of PostOp Max(sCr) over PostOp Max(Cystatin C) on Log2 Scale 
Figure 14.2-4.3 Scatter Plot of PostOp Max(sCr) over PostOp Max(NGAL) on Log2 Scale 
 
v3.0 
Below tables, listings, and figures are added or modified for v3.0 as a result of SAP update. 
Table 14.1-9 Summary of Important Protocol Deviations – Safety Population 
Table 14.2-4.2 Subject Incidence of Revised Acute Kidney Injury (AKI) - MITT Population 
Table 14.2-7.1 Subject Incidence of Major Adverse Kidney Events (MAKE) Post Surgery - MITT Population 
Table 14.2-8.1 Analysis of Post Surgery Hospitalization Parameters by Surgery Type - MITT Population 
Table 14.2-8.2 Analysis of Post Surgery Hospitalization Parameters by In/Outpatient Surgery Status - MITT Population 
Table 14.2-8.3 Analysis of Post Surgery Hospitalization Parameters by CKD/Non-CKD Status - MITT Population 
Table 14.2-8.4 Analysis of Post Surgery Hospitalization Parameters by No. of Baseline Risk Factors - MITT Population 
Table 14.2-8.5 Analysis of Post Surgery Hospitalization Parameters by The Tertile of Baseline EUROSCORE - MITT Population 
Table 14.2-8.6 Analysis of Post Surgery Hospitalization Parameters by The Tertile of Baseline STS Score - MITT Population 
Table 14.2-8.7 Correlation Analysis between Hospital Parameters and Primary Composite and Component Endpoints – MITT 
Population 
Table 14.2-8.8 Analysis of the Composite Score of Ventilator Days, ICU Days, and Hospital Days – MITT Population 
Table 14.3-1.8 Select TEAEs of Interest, Overall and by Preferred Term – Safety Population 
Table 14.3-1.9 Photosensitivity TEAEs, Overall and by Preferred Term – Safety Population 
Listing 16.2-2.3.2 Subject Sustained Urinary Retention During the First 5 Days Post Surgery Based on AE Report - MITT 
Population 
Listing 16.2-2.4 Subject Serum Creatinine and eGFR Assessments by Visit - MITT Population 
Listing 16.2-2.5.1 Subject Incidence of Acute Kidney Injury PostOp Through Day 5 - MITT Population 
Listing 16.2-2.5.2 Subject Incidence and Severity of Acute Kidney Injury PostOp Through Day 7 - MITT Population 
Figure 14.2-3.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 
Figure 14.2-3.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 


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Figure 14.2-3.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over GM of Max PreOp/Baseline Preconditioning 
Biomarkers by Treatment Group 
Figure 14.2-4.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over Max PreOp/Baseline in Serum HO-1 by 
Treatment Group 
Figure 14.2-4.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over Max PreOp/Baseline in Serum HO-1 by Treatment 
Group 
Figure 14.2-4.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over Max PreOp/Baseline in Serum HO-1 by 
Treatment Group 
Figure 14.2-5.1 Scatter Plot with LOESS Curve Fitting for Days on Ventilator Over Max PreOp/Baseline in Serum IL-10 by 
Treatment Group 
Figure 14.2-5.2 Scatter Plot with LOESS Curve Fitting for Days in ICU Over Max PreOp/Baseline in Serum IL-10 by Treatment 
Group 
Figure 14.2-5.3 Scatter Plot with LOESS Curve Fitting for Days in Hospital Over Max PreOp/Baseline in IL-10 by Treatment 
Group