Clinical trial NCT03427125
Conditions: Hyperphosphatemia
Sponsor: Ardelyx
Start date: 2018-01-08; Completion date: 2020-02-27
Enrollment: 1559 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3, 26-week, open label study with a 12-week, placebo-controlled, randomized withdrawal period followed by an open label long term safety extension will evaluate the safety and efficacy of tenapanor to treat hyperphosphatemia in end-stage renal disease (ESRD) on hemodialysis and peritoneal dialysis.

Detailed description:
The study consists of a screening visit, a phosphate binder-free washout period of up to 4 weeks, a 26-week treatment period, an up to 12-week placebo-controlled, randomized withdrawal period, during which patients are randomized 1:1 to either remain on their tenapanor treatment or placebo, followed by an open label safety extension period for a total treatment period of up to 52 weeks. An active control group, for safety analysis only, will receive sevelamer carbonate, open label, for the entire 52-week study period

Depending on increase in serum phosphate (s-P) levels, subjects can be randomized 2 or 3 weeks after being taken off their phosphate lowering medication.

Subjects who qualify to enroll in the study will be randomized 3:1 to either receive tenapanor at a dose of 30 mg bid or sevelamer carbonate.

Arms: arm 1: During the 26-week open label part, all enrolled subjects will receive 30 mg BID doses of tenapanor. Investigators may decrease or increase the dose in 10 mg increments to a minimum of 10 g BIDor a maximum of 30 mg BID arm 2: Placebo arm 3: Subjects randomized into the active control group, for safety analysis, will receive sevelamer carbonate, open label, for the entire 52-week study period. Sevelamer carbonate will be dosed based on package insert instructions (standard of care)
Interventions: intervention 1: Tenapanor intervention 2: Placebo intervention 3: Sevelamer Carbonate
Intervention descriptions: intervention 1: Active Drug intervention 2: Inactive Drug intervention 3: Active control

Protocol documents:
Prot_SAP_000.pdf: 
Cli nic al S t u d y Pr ot oc ol 
A 2 6 - Wee k, P h ase 3, O pe n L a bel St u d y wit h a 1 2- Wee k, Pl ace b o-
C o ntr olle d, R a n d o mize d Wit h dr a w al P eri o d F oll o w e d b y a n O pe n L a bel 
L o n g Ter m S af et y E xte nsi o n t o E v al u ate t he S afet y a n d E ffic ac y of 
Te n a p a n or t o Tre at H y per p h os p h ate mi a i n E n d- St a ge Re n al D ise ase 
P atie nts o n He m o di al ysis a n d Perit o ne al Di al ysis 
Pr ot oc ol N u m ber: T E N- 0 2- 3 0 1 
3 0 Ma y 2 0 1 8
N C T 0 3 4 2 7 1 2 5




Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 2  of 6 6  
T A B L E O F C O N T E N T S  
T A B L E O F C O N T E N T S  ........................................................................................................ 2  
I N-T E X T T A B L E S  .................................................................................................................. 5  
1   
G E N E R A L I N F O R M A TI O N  ................................................................................ 6  
1. 1   
St u d y A d mi nistr ati ve Str uct ure  ..................................................................... 6  
1. 2   
S y n o psis ............................................................................................................. 7  
1. 3   
Sc he d ule of E ve nts  ......................................................................................... 1 5  
1. 4   
List of A b bre vi ati o ns  ..................................................................................... 1 7  
2   
I N T R O D U C TI O N A N D B A C K G R O U N D ......................................................... 1 9  
2. 1   
I ntr o d ucti o n .................................................................................................... 1 9  
2. 2   
Descri pti o n of I n vesti g ati o n al Pr o d uct  ........................................................ 2 0  
2. 3   
Descri pti o n of Acti ve C o ntr ol  ....................................................................... 2 0  
2. 4   
St u d y R ati o n ale  .............................................................................................. 2 0  
2. 5   
Ris k -Be nefit Assess me nt ................................................................................ 2 1  
3   
S T U D Y O B J E C TI V E S  ......................................................................................... 2 3  
3. 1   
Pri m ar y O bjecti v es  ........................................................................................ 2 3  
3. 2   
Sec o n d ar y O bjecti ves  .................................................................................... 2 3  
3. 3   
E x pl or at or y O bjecti ves .................................................................................. 2 4  
4   
S T U D Y D E SI G N  ................................................................................................... 2 5  
4. 1   
Desi g n S u m m ar y  ............................................................................................ 2 5  
4. 1. 1   
Treat me nts A d mi nistere d  ............................................................................ 2 7  
4. 1. 2   
D urati o n of St u d y  ........................................................................................ 2 8  
5   
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S ...................................... 2 9  
5. 1   
I ncl usi o n Criteri a ........................................................................................... 2 9  
5. 2   
E xcl usi o n Criteri a  .......................................................................................... 3 0  
5. 3   
Rescree ni n g Criteri a  ...................................................................................... 3 1  
5. 4   
P atie nt Wit h dr a w al ........................................................................................ 3 1  
5. 5   
E arl y Ter mi n ati o n of St u d y  .......................................................................... 3 2  
5. 6   
Restricti o ns t o P atie nts  .................................................................................. 3 2  
6   
T R E A T M E N T O F P A TI E N T S  ........................................................................... 3 3  
6. 1   
A d mi nistr ati o n of I n vesti g ati o n al Pr o d uct  .................................................. 3 3  
6. 1. 1   
I de ntit y of I n v esti gati o nal Pr o d uct(s) ......................................................... 3 3  
6. 1. 2   
Treat me nts A d mi nistere d  ............................................................................ 3 3  
6. 1. 3   
D ose A dj ust me nts  ....................................................................................... 3 3  
6. 1. 4   
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps  ................................... 3 4  
6. 2   
I n vesti g ati o n al Pr o d uct St or a ge a n d Acc o u nt a bilit y .................................. 3 4  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 3  of 6 6  
6. 2. 1   
St ora ge C o n diti o ns  ...................................................................................... 3 4  
6. 2. 2   
Dr u g Acc o u nta bilit y  .................................................................................... 3 4  
6. 3   
P ac k a gi n g a n d L a beli n g  ................................................................................ 3 5  
6. 3. 1   
St u d y Dr u g  .................................................................................................. 3 5  
6. 3. 2   
Bli n di n g Met h o ds  ........................................................................................ 3 5  
6. 4   
Pr oce d ure f o r Bre a ki n g R a n d o miz ati o n C o de  ............................................ 3 5  
6. 4. 1   
E mer ge n c y U n bli n di n g  ............................................................................... 3 5  
6. 5   
Pri or a n d C o nc o mit a nt T her a p y  .................................................................. 3 5  
6. 5. 1   
Pri or T hera p y  .............................................................................................. 3 5  
6. 5. 2   
C o nc o mit a nt T h era p y  .................................................................................. 3 6  
7   
C O L L E C TI O N O F S T U D Y V A RI A B L E S  ........................................................ 3 7  
7. 1   
Rec or di n g of D at a  .......................................................................................... 3 7  
7. 2   
D a t a C ollecti o n Pri or t o E nr oll me nt ............................................................ 3 7  
7. 3   
S afet y V ari a bles  ............................................................................................. 3 7  
7. 3. 1   
P h ysical E xa mi nati o n  .................................................................................. 3 8  
7. 3. 2   
Vital Si g ns ( bl o o d press ure a n d h eart rate)  ................................................. 3 8  
7. 3. 3   
Electr ocar di o gra ms  ..................................................................................... 3 8  
7. 3. 4   
Cli nic al L a b orat or y Tests  ............................................................................ 3 8  
7. 3. 5   
A nal ysis of Cli nic al L a b orat or y Tests  ........................................................ 3 8  
7. 3. 6   
A d verse E ve nts  ........................................................................................... 4 1  
7. 4   
Effic ac y V ari a bl es  .......................................................................................... 4 5  
7. 5   
E x pl or at or y V ari a bles  ................................................................................... 4 5  
8   
M E T H O D O L O G Y/ S T U D Y VI SI T S  ................................................................... 4 6  
8. 1   
Scree ni n g ( D a y -2 1), Visit 1  ........................................................................... 4 6  
8. 2   
W as h -o ut Peri o d ( D a ys -1 4, -7, a n d -1), Visits 2, 3 a n d 4  ........................... 4 7  
8. 3   
R a n d o miz ati o n ( D a y 1), Visit 5  ..................................................................... 4 7  
8. 4   
Tre at me nt Pe ri o d ( D a ys 8 a n d 1 5 ± 5), Visits 6 a n d 7  ................................ 4 7  
8. 5   
Tre at me nt Pe ri o d ( D a ys 2 9 ± 5 a n d 5 7 ± 7 ), Visits 8 a n d 9 ........................ 4 8  
8. 6   
Tre at me nt Pe ri o d ( D a y 8 5 ± 7 ), Visit 1 0 ...................................................... 4 8  
8. 7   
Tre at me nt Pe ri o d ( D a ys 1 2 0 a n d 1 5 5 ± 7 ), Visits 1 1 a n d 1 2 ...................... 4 8  
8. 8   
E n d of 2 6 -wee k Tre at me nt P eri o d a n d st art of R a n d o mize d 
Wit h dr a w al P eri o d ( D a y 1 8 3 ± 7 ), Visit 1 3 .................................................. 4 9  
8. 9   
R a n d o mize d Wit h dr a w al Pe ri o d ( D a ys 1 9 7, 2 1 1, 2 2 5, 2 3 9 a n d 
2 5 3 ± 7 ), Visits 1 4, 1 5, 1 6, 1 7 a n d 1 8 ............................................................. 4 9  
8. 1 0   
E n d of R a n d o mize d Wit h dr a w al P eri o d a n d st art of S afet y 
E xte nsi o n Peri o d ( D a y 2 6 7 ± 7 ), Visit 1 9 ..................................................... 4 9  
8. 1 1   
S afet y E xte nsi o n Peri o d ( D a ys 2 8 1, 3 0 9, 3 3 7 ± 7 ), Visits 2 0, 2 1, 
2 2  ..................................................................................................................... 5 0  
8. 1 2   
E n d of St u d y ( D a y 3 6 5 ± 7 ), Visit 2 3 ............................................................ 5 0  
8. 1 3   
U nsc he d ule d visits  .......................................................................................... 5 0  
8. 1 4   
Wit h dr a w al P r oce d ures  ................................................................................ 5 1  
8. 1 5   
T ot al Bl o o d V ol u me Re q uire d f or St u d y  ..................................................... 5 1  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4  of 6 6  
8. 1 6   
Pr ot oc ol De vi ati o ns  ........................................................................................ 5 1  
9   
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................ 5 3  
9. 1   
St atistic al A n al ysis Pl a n  ................................................................................ 5 3  
9. 2   
Deter mi n ati o n of S a m ple Size  ....................................................................... 5 3  
9. 3   
A n al ysis Sets  ................................................................................................... 5 3  
9. 4   
St atis tic al Met h o ds ......................................................................................... 5 4  
9. 4. 1   
Ge ner al A p pr oac h  ....................................................................................... 5 4  
9. 4. 2   
Baseli ne Descri pti v e Statistics  .................................................................... 5 5  
9. 4. 3   
Pri mar y Effi cac y A nal ysis  .......................................................................... 5 5  
9. 4. 4   
Sec o n dar y Effi cac y A nal yses ...................................................................... 5 5  
9. 4. 5   
Pr oce d ures f or Ha n dli n g Missi n g Ser u m P h os p h or us Data  ........................ 5 7  
9. 4. 6   
Met h o ds of P o oli n g Data  ............................................................................ 5 7  
9. 4. 7   
Visit Wi n d o ws ............................................................................................. 5 8  
9. 4. 8   
Safet y A nal yses  ........................................................................................... 5 8  
1 0   
A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  ................................................. 5 9  
1 1   
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .................................. 6 0  
1 1. 1   
C o n d uct of St u d y  ........................................................................................... 6 0  
1 1. 2   
Pr ot oc ol A me n d me nts  ................................................................................... 6 0  
1 1. 3   
M o nit ori n g of St u d y ....................................................................................... 6 0  
1 1. 4   
E T HI C S  .......................................................................................................... 6 1  
1 1. 5   
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee 
A p pr o v al  ......................................................................................................... 6 1  
1 1. 5. 1   
Et hics Re vie w Pri or t o St u d y  ...................................................................... 6 1  
1 1. 5. 2   
Et hics Re vie w of ot her D oc u me nts  ............................................................. 6 1  
1 1. 6   
Writte n I nf or me d C o nse nt  ............................................................................ 6 1  
1 2   
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ............................................... 6 2  
1 2. 1   
D at a Re p orti n g a n d C ase Re p ort F or ms  ..................................................... 6 2  
1 2. 1. 1   
Case Re p ort F or ms  ...................................................................................... 6 2  
1 2. 1. 2   
La b orat or y Data  .......................................................................................... 6 2  
1 2. 1. 3   
Rete nti o n of S o urce D oc u m e nts  ................................................................. 6 2  
1 2. 2   
Rete nti o n of Esse nti al D oc u me nts  ................................................................ 6 2  
1 3   
A D MI NI S T R A TI V E I N F O R M A TI O N  .............................................................. 6 3  
1 3. 1   
Fi n a nci n g a n d I ns ur a nce  ............................................................................... 6 3  
1 3. 2   
P u blic ati o n P olic y  .......................................................................................... 6 3  
1 4   
R E F E R E N C E S  ...................................................................................................... 6 4  
1 5   
SI G N A T U R E S  ....................................................................................................... 6 5  
1 5. 1   
I n vesti g at or Si g n at ure ................................................................................... 6 5  
1 5. 2   
S p o ns or Si g n at ure  .......................................................................................... 6 6  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5  of 6 6  
 
I n-Te xt Ta bles  
Ta ble 7 -1  Safet y La b or at or y Tests  ......................................................................................... 4 0  
Ta ble 8 -1  A p pr o xi mate Bl o o d V ol u me p er Pati e nt  ............................................................... 5 1  




Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 7  of 6 6  
1. 2   
S y n o psis  
Pr ot oc ol Title:  
A 2 6 -Wee k, P hase 3, O pe n La bel St u d y wit h a 1 2 -W ee k, Plac e b o -
C o ntr olle d, R a n d o mi ze d Wit h dra wal Peri o d F oll o we d b y a n O pe n La bel 
L o n g Ter m Saf et y E xte nsi o n t o E val uate t h e Safet y a n d Effic ac y of 
Te na pa n or t o Treat H y per p h os p hate mia i n E n d -Sta g e Re nal Dise ase 
Patie nts o n He m o dial ysis a n d Perit o ne al Dial ysis  
S p o ns or:  
Ar del y x, I nc.  
St u d y P h ase:  
P hase 3  
O bjecti ves:  
T he pri m ar y o bje cti ve s of t his st u d y are:  
•  T o e val u ate t he safet y a n d t ol era bilit y of te na p a n or f or t he 
treat me nt of h y p er p h os p hate mia i n E n d-Sta ge R e nal Disease 
Patie nts o n He m o dial ysis ( E S R D -H D) a n d o n Perit o neal Dial ysis 
( E S R D-P D) w he n a d mi nistere d t wi ce dail y f or u p t o 5 2 wee ks.  
•  T o c o m par e t he p h os p h or us l o weri n g eff ect b et wee n  te na pa n or 
a n d plac e b o base d o n  t he c ha n ge i n ser u m p h os p h or us (s-P) fr o m 
t he e n d of t h e 2 6-wee k tre at m e nt p eri o d t o t h e e n d of t he u p t o 1 2-
wee k ra n d o mi ze d wit h dra wal peri o d or t he e n d p oi nt visit f or t his 
peri o d i n t h e res p o n der p o p ul ati o n  (effica c y a nal ysis set). 
T he sec o n da r y o bjecti ves of t his st u d y ar e: 
•  T o c o m par e t he p h os p h or us l o weri n g eff ect b et wee n te na pa n or 
a n d plac e b o base d o n t he c ha n ge i n ser u m p h os p h or us (s -P) fr o m 
t he e n d of t h e 2 6-wee k tre at m e nt peri o d t o t h e e n d of t he 
ra n d o miz e d wit h dra wal peri o d or t h e e n d p oi nt visit f or t his peri o d 
i n t he i nte nt-t o-tre at (I T T) a nal ysis set a n d at i n di vi d ual d oses of 
te na pa n or a n d plac e b o i n b ot h t he effica c y a n d I T T a nal ysis sets . 
•  T o e val u ate t he effe ct of te na pa n or o n t he c h a n ge i n ser u m 
p h os p h or us  le vels fr o m bas eli ne t o t he e n d of 2 6 -we e k treat me nt 
peri o d . 
•  T o e val u ate t he effe ct of t e na pa n or o n t he n u m b er of patie nt s 
reac hi n g ser u m p h os p h or us  g o al le vels defi ne d as < 5. 5 m g/ d L  
d uri n g t he 2 6-wee k treat me nt p eri o d . 
•  T o e val u ate t he effe ct of t e na pa n or o n C alci u m - P h os p h or us 
Pr o d uct (Ca x P ) d uri n g all t hre e st u d y peri o ds  (2 6 -wee k 
treat me nt p eri o d, ra n d o mize d wit h dra wal p eri o d  a n d safet y 
e xte nsi o n peri o d ). 
•  T o e val u ate t he effe ct of t e na pa n or o n i nta ct fi br o blast gr o wt h 
fact or 2 3 (i F G F 2 3) a n d c-t er mi nal F G F 2 3 (c F G F 2 3 ) le vels d uri n g 
all t hr ee st u d y peri o ds  ( 2 6-wee k treat me nt peri o d, r a n d o mize d 
wit h dra wal peri o d a n d safet y e xte nsi o n p eri o d).  
•  T o e val u ate t he effe ct of t e na pa n or o n  t he Ki d ne y Disease Q ualit y 
of Life ( K D Q o L)  s ur ve y d uri n g all t hree st u d y p eri o ds.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 8  of 6 6  
•  T o e val u ate t he effe ct of t e na pa n or o n t he Dial ysis S y m pt o m 
I n de x ( D SI) s ur ve y d uri n g all t hre e st u d y peri o ds  (f or E n glis h 
s pea kers o nl y). 
•  T o c o m par e t he l o n g -ter m saf et y of t e na pa n or t o t he acti v e c o ntr ol 
se vela m er car b o nate. 
T he e x pl or at or y o bj ecti v es of t his st u d y are: 
•  T o c oll ect a n d st ore plas ma/ser u m f or f ut ure e x pl orat or y researc h 
i nt o ser u m/ plas ma bi o mar k ers relat e d t o c ar di o-re n al disease 
a n d/ or b o ne-m eta b olis m or t h at ma y i nfl ue n ce t h e res p o nse (i.e. 
distri b uti o n, saf et y, t olera bilit y, a n d effi cac y) t o te n a pa n or. ( T hese 
data will n ot be p art of t h e st u d y re p ort.)  
N u m b er of Sites:  
7 0  t o 9 5  cli nical sites  i n t he U S 
N u m b er of P atie nt s A p pr o xi matel y 5 6 0  E S R D pati e nts o n he m o - or p erit o neal di al ysis.  
St u d y Desi g n  a n d 
D u r ati o n of 
Tr e at me nt : 
T he st u d y c o nsists of a scre e ni n g visit, a p h os p hate bi n der -free was h-o ut 
peri o d of u p t o f o ur wee ks, a 2 6-wee k treat me nt peri o d, a n u p t o 1 2 -
wee k plac e b o -c o ntr olle d, ra n d o miz e d wit h dra wal peri o d,  d uri n g w hic h 
patie nts are ra n d o mize d 1: 1 t o re mai n o n t he t e na pa n or d ose t he y are 
ta ki n g at t he e n d of t he 2 6-wee k treat me nt or rec ei ve place b o, f oll o we d 
b y a n o pe n la b el safet y e xte nsi o n p eri o d  f or a t otal tr eat m e nt peri o d of 
u p t o 52  wee ks.  A n acti v e c o ntr ol gr o u p, f or safet y a nal ysis , will re cei v e 
se vela m er car b o nate, o pe n la bel, f or t he e ntir e 5 2 -we e k st u d y  peri o d  
(see Secti o n 2. 3 ). 
T he scree ni n g visit ( Visit 1) a n d all ot her visits i n t h e st u d y m ust be 
sc he d ule d after a s h ort di al ysis i nt er val  ( o nl y f or H D patie nts; e. g., 
We d nes da y or Fri da y  f or patie nts o n a M W F sc h e d ul e a n d T h urs da y or  
Sat ur da y  f or patie nts o n a T T h S sc he d ule ). B o d y wei g ht , vital si g ns a n d 
bl o o d c oll ecti o ns f or la b orat or y assess me nts m ust  be perf o me d pre -
dial ysis.  All ot h er assess me nts ma y b e perf o me d pr e -, d uri n g, or p ost-
dial ysis b ut s h o ul d be p erf or me d at t h e sa me ti me at eac h visit. F or P D 
patie nts, visits s h o u l d be perf or me d o n t h e sa me da y eac h wee k, if 
p ossi ble.  
Ser u m p h os p h or us meas ure d at t he scree ni n g visit m ust be ≥4. 0 a n d 
≤8. 0 m g/ d L f or p ati e nt s t o be eli gi ble t o e nter t he was h-o ut peri o d.  
T he was h -o ut peri o d will  be gi n i m me diatel y after t h e scree ni n g v isit.  
Ser u m p h os p h or us  will be me as ure d wee kl y ( pre -dial ysis after a s h ort 
i nter val f or H D patie nts) d uri n g t he was h-o ut peri o d t o deter mi ne if t he 
patie nt  me ets i ncl usi o n criteria f or e nr oll me nt i nt o t h e st u d y.  
T he st u d y visits d uri n g t he was h -o ut peri o d f or H D patie nts s h o ul d be 
sc he d ule d after t he first s h ort i nt er val i n t he we e k t o e ns ure data are 
a vail a ble b ef ore a p ossi ble r a n d o mi zati o n, w hic h c o ul d t he n t a ke pl ace 
after t h e sec o n d s h ort i nter val i n t he we e k . Ot her wis e t he ra n d o miz ati o n 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 9  of 6 6  
vis it will b e sc he d ul e d t he f oll o wi n g wee k after t h e first s h ort dial ysis 
i nter val; t h eref ore, t h e t ot al l e n gt h of ti me off p h os p hate bi n d er 
treat me nt ma y be u p t o 4 wee ks.  
Patie nt s w h o  me et all i n cl usi o n/ e xcl usi o n criteria will be ra n d o mize d 
ce ntrall y 3: 1 t o  eit her rec ei ve te na p a n or  at a d ose of 3 0 m g  bi d  or 
se vela m er car b o nate base d o n p ac ka g e i nsert i nstr ucti o ns  (sta n dar d of 
care) after Visits  2,  3 or 4  (aft er 1, 2 , or 3 wee ks of was h -o ut) if t he y 
ha ve a s -P le vel of at least 6. 0  m g/ d L  a n d n ot m ore t ha n 1 0 .0 m g/ d L  a n d 
ha ve a n i n crease i n s-P of at least 1. 5  m g/ d L v ers us pre was h -o ut ( Visit 
1 , S cree ni n g V isit).  
Patie nt s ra n d o miz e d i nt o t he t e na pa n or gr o u p will re cei ve te na p a n or at a 
d ose of 3 0 m g bi d. Te n a pa n or will be ta k e n t wic e dail y; j ust pri or t o 
brea kfast a n d di n ner. Patie nt s o n H D s h o ul d n ot  ta ke te na pa n or at t h e 
meal i m m e diatel y pr ece di n g dial ysis; i n t his c ase,  patie nt s will ta k e 
te na pa n or pri or t o t h e ne xt m eal after dial ysis. T h ose ra n d o miz e d i nt o 
t he acti ve c o ntr ol gr o u p will ta k e se vel a mer car b o nat e base d o n sta n dar d 
of care usi n g  t h e pac ka g e i nsert f or g ui da nc e f or t he e ntire 5 2-we e k 
st u d y peri o d. Pati e nts w h o are o n a cti ve c o ntr ol will n ot  ha ve Visits 1 4, 
1 6 a n d 1 8.  
I n vesti gat ors m a y decre ase  or i ncr ease t h e d ose of te na pa n or base d o n s -
P le vels a n d/or GI t olera bilit y i n 1 0 m g i ncre m e nts t o a mi ni m u m of 1 0 
m g bi d or a m a xi m u m of 3 0 m g bi d  fr o m e nr oll me nt u ntil Da y 1 8 3 
( Visit 13 ).  T he d ose of se vela mer car b o nate m a y be a dj uste d base d o n 
sta n dar d of care f or t he e ntire 5 2-we e k st u d y peri o d .  
D uri n g t he 2 6 -wee k tr eat m e nt peri o d a n d t h e safet y e xte nsi o n peri o d, 
patie nts o n te na p a n or wit h a s -P ≥ 1 0 m g/ d L at a n y ti me aft er Wee k 2 of 
treat me nt or p ati e nts wit h a s -P ≥ 9 m g/ d L f or t w o c o nsec uti ve visits 
after W ee k 2 will be disc o nti n ue d a n d all visit pr oc e d ures f or Visit 2 3 
will be c o m plete d, if p ossi bl e. Pati e nts i n t h e acti ve c o ntr ol gr o u p, 
recei vi n g se vel a mer c ar b o nat e d o n ot ha v e s pecific disc o nti n uati o n 
criteria; t he y will be tre ate d b ase d o n sta n dar d of c ar e usi n g t he pa c ka ge 
i nsert f or g ui da n ce. 
At t he e n d of t h e 2 6 -wee k tre at m e nt peri o d, patie nts i n t he t e na pa n or 
gr o u p o nl y will be r a n d o mi ze d 1: 1 t o eit her re m ai n o n t he te n a pa n or 
d ose t he y are ta ki n g o n Da y 1 8 3 ( Visit 1 3) or recei ve place b o f or u p t o 
a n a d diti o nal 1 2 we e ks (ra n d o miz e d wit h dra wal peri o d). D uri n g t he 
ra n d o miz e d wit h dra wal peri o d, patie nts wit h a s-P ≥ 9 m g/ d L  will be 
disc o nti n ue d a n d all visit pr o ce d ures f or Visit 2 3  will be c o m plet e d, if 
p ossi ble . Patie nts w h o disc o nti n ue fr o m t he r a n d o mi ze d wit h dra wal 
peri o d wit h s -P ≥ 9 m g/ d L will b e offere d t he o p p ort u nit y t o e nter t h e 
safet y e xt e nsi o n peri o d. I n a d diti o n, pati e nts w h o  ra n d o mize i nt o t h e 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 1 0  of 6 6  
te na pa n or gr o u p a n d c o m plete t he ra n d o miz e d wit h dra wal peri o d are 
eli gi ble t o e nr oll i n t he o p e n la be l safet y e xte nsi o n p eri o d f or a n 
a d diti o n al 1 4 wee ks.  P atie nts w h o  e nr oll i n t o t he o p e n la bel e xt e nsi o n 
peri o d will r ecei ve te n a pa n or.  
La b orat or y effica c y e n d p oi nts will be assesse d at desi g nate d visits 
t hr o u g h o ut t he st u d y; s-P will be m eas ure d at e ver y visit.  
Safet y assess me nts will b e perf or me d d uri n g  t he st u d y a n d will i n cl u de 
p h ysical e x a mi n ati o n s, vital si g ns (bl o o d pr ess ure a n d p ulse ), b o d y 
wei g hts, cli nical la b or at or y e val uati o ns, 1 2 -lea d ele ctr ocar di o gr a ms  
( E C Gs), a n d a d v erse e ve nt ( A E) m o nit ori n g 
Pl a n n e d S a m ple 
Size:  
A p pr o xi matel y 5 6 0  male a n d fe mal e patie nt s wit h e n d sta ge re nal 
d isease ( E S R D) o n c hr o nic mai nte nanc e he m o dial ysis ( H D) 3  ti mes a 
wee k f or a mi ni m u m of 3  m o nt hs  or c hr o nic mai nte n a nce perit o neal 
d ial ysis ( P D) f or a mi ni m u m of 6 m o nt hs are eli gi ble t o parti ci pate . 
Patie nt s will be ra n d o miz e d 3: 1 t o r ecei v e eit her t e na pa n or or acti ve 
c ontr ol.  
P atie nt  Sele cti o n 
Criteri a:  
I ncl usi o n criteri a: 
1.  Si g ne d a n d dat e d i nf or m e d c o nse nt pri or t o a n y st u d y s pecific 
pr oce d ures.  
2.  Males or fe males >  1 8 years  of a ge . 
3.  Fe m ales m ust b e n o n -pre g na nt, n o n -lactati n g a n d f ulfilli n g o n e of 
t he f oll o wi n g: 
a. P ost – me n o pa usal defi ne d as a me n orr hea f or at l east 1 2 m o nt hs 
f oll o wi n g cessati o n of all e x oge n o us h or m o nal tre at me nts a n d 
wit h f olli cle sti m ul ati n g h or m o ne ( F S H) le vels i n t he la b orat or y 
defi ne d p ost -m e n o pa usal ra n g e.  
b.  D oc u me ntati o n of irr e versi ble s ur gi cal st erilizati o n b y 
h ysterect o m y, bil ateral o o p h orect o m y or bilat eral sal pi n gect o m y 
b ut n ot t u bal li g ati o n.  
c. Use of acce pta ble c o ntrac e pti v e met h o d:  I U D wit h s per mici de, a 
fe mal e c o n d o m wit h s per mici de, c o ntrac e pti v e s p o n ge wit h 
s per mici d e, a n i ntra va gi n al s yste m ( e. g., N u va Ri n g ®), a 
dia p hra g m wit h s per mi ci de, a cer vi cal ca p wit h s per mici d e, or 
or al, i m pla nt a ble, tra ns der mal, or i nj ect a ble c o ntra ce pti ves , se x ual 
a bsti ne nc e, or a sterile se x ual part n er. 
4.  Males m ust a gre e t o a v oi d fat heri n g a c hil d ( or d o nati n g s per m), a n d 
t heref ore b e eit h er sterile ( d oc u me nt e d) or a gree t o use, fr o m t he 
ti me of e nr oll me nt u ntil 4 5 d a ys after e n d of st u d y, o ne of t he 
f oll o wi n g a p pr o ve d met h o ds of c o ntrace pti o n: a mal e c o n do m wit h 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 1 1  of 6 6  
s per mici d e, a sterile se x ual part n er , use of a n I U D wit h s per mici de 
b y fe mal e se x ual p art ner, a f e male c o n d o m wit h s per mici d e, 
c o ntrac e pti v e s p o n ge wit h s per mi ci de, a n i ntr a va gi n al s yste m (e. g., 
N u va Ri n g ®), a dia p hra g m wit h s per mi ci de, a cer vic al c a p wit h 
s per mici d e, or oral, i m pl a nta bl e, tra ns der mal, or i nje cta bl e 
c o ntrac e pti v es.  
5.  C hr o nic mai nte n a nce he m o dial ysis 3 x/ wee k f or at le ast 3 m o nt hs  or 
c hr o nic m ai nt e na nce p erit o n eal dial ysis ( P D) f or a mi ni m u m of 6  
m o nt hs.  If m o dalit y of di al ysis has c ha n ge d, patie nt m ust meet o ne 
of t he t w o dial ysis crit eria a b o v e a n d be e n o n t he n e w m o dalit y of 
dial ysis f or a mi ni m u m of o ne m o nt h.  
6.  Sta ble vasc ular a ccess  as assesse d b y I n vesti gat or , if o n H D. 
7.  Kt/ V ≥1. 2  at m ost r ece nt me as ure me nt  pri or t o scre e ni n g . 
8.  Prescri be d a n d t a ki n g a t least 3 d oses of p h os p hat e bi n der  per da y . 
T he  prescri b e d d ose  s h o ul d ha ve be e n u nc ha n g e d d uri n g t he l ast 3 
wee ks pri or t o scree ni n g.  
9.  Ser u m p h os p h or us  le vels m ust  be b et wee n 4. 0  a n d 8. 0 m g/ d L 
(i ncl usi ve) at scree ni n g, a nal yze d at t h e ce ntral la b or at or y use d i n 
t he st u d y. 
1 0.  I nte nti o n all y left bla n k. 
1 1.  F or e nr oll me nt i n t h e st u d y, patie nt s m ust h a ve ser u m p h os p h or us 
le vels of at le ast 6. 0  m g/ d L b ut n ot m ore t ha n 1 0 . 0 m g/ d L a n d ha v e 
ha d a n i ncr ease of at least 1. 5  m g/ d L v ers us pre was h -o ut va l ue after 
1, 2 or  3 wee ks was h -o ut of p h os p hate bi n ders .  
1 2.  A ble t o u n dersta n d a n d c o m pl y wit h t h e pr ot oc ol . 
E xcl usi o n crite ri a:  
 
1.  Se vere h y per p h os p hat e mia d efi ne d as  ser u m p h os p h or us greater t h a n 
1 0 . 0 m g/ d L o n p h os p hat e -bi n ders at a n y ti me p oi nt  d uri n g cli nical 
m o nit ori n g f or t he 3 pre ce di n g m o nt hs  bef ore t h e scr ee ni n g visit. 
2.  Ser u m / plas m a parat h yr oi d h or m o ne > 1 2 0 0 p g/ m L.  T he  m ost rec e nt 
val ue fr o m p ati e nt s’ me dical r ec or ds s h o ul d be use d.  
3.  Cli nic al si g ns of h y p o v ole mia at e nr oll m e nt as j u d ge d b y the 
i n vesti gat or. 
4.  Hist or y of i n fla m mat or y b o wel disease (I B D) or diarr hea 
pre d o mi na nt irrita bl e b o wel s y n dr o me (I B S -D) . 
5.  Sc he d ule d f or li vi n g d o n or ki d n e y tra ns pla nt, pla ns t o c ha n ge t o a 
differe nt met h o d of  dial ysis, h o m e  H D or pla ns t o rel ocate t o a n ot h er 
ce nter d uri n g t he st u d y p eri o d. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 1 2  of 6 6  
6.  A n y e vi de nce of or treat me nt of mali g na nc y wit hi n o ne year, 
e xcl u di n g n o n - mel a n o mat o us mali g na nci es of t he s ki n.  
7.  P ositi ve ser ol o g y ( he p atitis C or B i nfe cti o n, or h u m a n 
i m m u n o defici e nc y vir us) wit h  e vi de n ce of si g nifica nt he patic 
i m pair me nt or W B C el e vati o n acc or di n g t o t h e I n vesti gat or. 
8.  Hist or y of alc o h ol a b use, illicit dr u g use, si g ni fica nt me ntal ill ness, 
or a n y hist or y of dr u g a b use or a d dicti o n wit hi n 1 2 m o nt hs of st u d y 
e nr oll m e nt.  
9.  Li fe e x p ect a nc y <1 2  m o nt hs . 
1 0.  Use of a n i n vesti gati o nal a ge n t wit hi n 3 0 da ys pri or t o Scree ni n g . 
1 1.  Pre vi o us ra n d o miz ati o n i nt o t his st u d y. 
1 2.  Pre vi o us e x p os ure t o te n a pa n or . 
1 3.  I n v ol ve me nt i n t h e pla n ni n g a n d/ or c o n d u ct of t h e st u d y (a p plies t o 
b ot h Ar del y x / C R O staff a n d/ or staff at t he st u d y site). 
1 4.  If, i n t he o pi ni o n of t he I n v esti gat or, t he patie nt  is u n a ble or 
u n willi n g t o f ulfill t he r e q uire me nts of t he pr ot oc ol or has a 
c o n diti o n w hi c h w o ul d re n der t he res ults u ni nter pret a ble.  
St u d y Dr u g:  
Te na pa n or  1 0  m g ta blets a n d m atc h e d pla ce b o  
Acti ve C o ntr ol:  
Se vela m er car b o nate t a blets ( 8 0 0 m g)  
D ose a n d R o ute of 
A d mi nistr ati o n:  
Te na pa n or  will be a d mi nistere d P O at t h e f oll o wi n g d ose le vels:  
•  2 6 -wee k treat me nt peri o d: Titr ati o n sc h e me  (fr o m 
R a n d o miz ati o n ( Visit 5) t o Da y 1 8 3 ( Visit 13 ): starti n g d ose 3 0 
m g bi d, d osi n g ma y b e d o w n -titr ate d or u p-titrate d t o a 
ma xi m u m of 3 0 m g bi d i n a ste p -wise f as hi o n base d o n ser u m 
p h os p h or us le vels  a n d/ or GI t ol era bilit y . D o w n-titrati o n ca n g o 
fr o m 3 0 m g bi d t o 2 0 m g bi d t o 1 0 m g bi d. D ose esc alati o n ca n 
g o i n 1 0 m g bi d i n cre m e nts t o a ma xi m u m  d ose of 3 0 m g bi d.  
•  Ra n d o miz e d wit h dra wal peri o d: Fi xe d d ose base d o n last d ose 
fr o m 2 6 -wee k  treat me nt peri o d. 
•  Safet y e xt e nsi o n peri o d: Starti n g d ose is t he sa me d ose fr o m t he 
e n d of t he 2 6 -wee k treat me nt p eri o d.  Titrati o n is all o we d as 
descri be d f or t h e 2 6 -wee k tre a t m e nt peri o d. 
Se vela m er car b o nate  (acti v e c o ntr ol) will b e a d mi nistere d P O base d o n 
sta n dar d of care d uri n g t he e ntir e 5 2 -wee k st u d y peri o d . 
Place b o  will be a d mi nist ere d P O d uri n g t he ra n d o mi ze d w it h dra wal 
p eri o d o nl y . D uri n g t his peri o d, patie nt s will be ra n d o mize d 1: 1 t o 
recei v e eit her pla ce b o or t e na pa n or.  T he pl ace b o gr o u p will rec ei ve t he 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 1 3  of 6 6  
sa me n u m ber of ta bl ets as t he l ast d ose of te n a pa n or t he y rec ei ve d  
d uri n g t he 2 6 -wee k treat me nt p eri o d.  Patie nts fr o m t he acti ve  c o ntr ol 
gr o u p will n ot e nter t h e ra n d o mize d wit h dr a wal peri o d; t he y will 
c o nti n ue t o rec ei ve se vela m er car b o n ate p er sta n dar d of care f or all 5 2  
wee k s.  
A detail e d descri pti o n of t he d ose a dj ust m e nt pr oc e d ures ca n be f o u n d 
i n Secti o n 6. 1. 3 . 
 
St atistic al 
A n al yses:  
A n al ysis sets:  
S afet y A n al ysis S et ( at e ac h st u d y peri o d):   
All pati e nt s w h o recei ve at least o n e d ose of st u d y dr u g (te na pa n or or 
place b o) or acti ve c o ntr ol f or t he i n di vi d u al st u d y peri o d. T he safet y 
a nal ysis set will be use d f or t h e a nal ysis of all safet y varia bl es.     
I nte nt t o Tre at (I T T) A n al ysis Set ( at e ac h st u d y perio d) : 
All pati e nt s w h o meet t he st u d y e ntr y i n cl usi o n/e x cl usi o n criteria, 
recei v e at least o ne d ose of te nap a n or or pla ce b o , a n d ha ve at least o n e  
p ost -treat me nt ser u m p h os p h or us  f or t he i n di vi d ual st u d y peri o d. T h e 
I T T a nal ysis set will b e use d f or t he a n al ysis of all efficac y v aria bles. 
Effic ac y A n al ysis Set  (1 2 -we e k r a n d o mize d wit h dr a w al pe ri o d ): 
All pati e nt s w h o meet t he st u d y e ntr y i n cl usi o n a n d e xcl usi o n criteri a, 
recei v e at least o ne d ose of  te na p a n or d uri n g t h e 2 6-wee k treat me nt 
peri o d , c o m plet e t he 2 6 -wee k treat me nt peri o d, a n d ac hie v e at least a 
1. 2  m g/ d L re d u cti o n i n ser u m p h os p h or us fr o m baseli ne t o t h e e n d of 
t he 2 6-wee k tr eat me nt. T h e effi cac y a nal ysis set will be use d f or t he 
pri mar y efficac y a nal ysis . 
Per -P r ot oc ol ( P P) A n al ysis Se t ( 1 2-wee k r a n d o mi ze d wit h dr a w al 
peri o d) :  
 
Al l pati e nt s i n t h e I T T a nal ysis set w h o c o m plet e d t h e 1 2 -wee k 
ra n d o miz e d wit h dra wal peri o d as pl a n ne d wit h n o m aj or pr ot oc ol 
de viati o ns t hat i m pa ct t h e pri mar y effic ac y varia bl e .  T he P P a nal ysis 
set will be used f or se nsiti vit y a nal yses t o s u p p ort t h e pri mar y a n d ke y 
sec o n dar y effic ac y a n al yses. 
Effic ac y a n al yses:  
All effic ac y vari a bles will be s u m m ariz e d b y tre at m e nt (i ncl u di n g d ose , 
if a p pli ca bl e) gr o u p, usi n g descri pti ve statisti cs.  All c o nti n u o us 
effica c y v aria bles ( s-P , Ca x P, iF G F 2 3 , c F G F 2 3, K D Q o L a n d D SI) 
will be a n al yz e d usi n g a n a nal ysis of c o vari a nce ( A N C O V A) m o del 
wit h ter ms f or p o ol e d i n vesti gat or site, tre at m e nt  (i n cl u di n g d ose , if 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 1 4  of 6 6  
a p plic a ble), a n d baseli n e as t he c o vari a ble. T he c h a n ge fr o m baseli ne 
will be t h e de pe n d e nt vari a ble. T he l east s q uare s m e a ns ( L S mea ns) will 
be prese nte d f or t he c ha n g e fr o m baseli ne v al ues f or eac h tr eat me nt 
gr o u p  (i ncl u di n g d ose , if a p plica ble) wit h t h e 9 5 % c o nfi de nce i nter v al 
(CI ).  
T he pri m ar y effic ac y varia bl e will b e t he c ha n ge i n ser u m p h os p h or us 
fr o m t he e n d of t he 2 6-wee k tr ea t me nt p eri o d t o t he e n d of t he 1 2-wee k 
ra n d o miz e d wit h dra wal peri o d  or t h e e n d p oi nt visit f or t his peri o d. T h e 
pri mar y efficac y a nal ysis will be base d o n t he diff ere nce bet we e n t he 
te na pa n or treat me nt a n d pla ce b o tr eat me nt gr o u p i n t he res p o n der 
p o p ulati o n  ( effic ac y a nal ysis set). E n d p oi nt f or t his a nal ysis is defi ne d 
as t he last ser u m p h os p h or us la b val u e assess me nt d uri n g a n d u p t o t h e 
e n d of t he 1 2 -wee k ra n d o miz e d wit h dra wal peri o d . 
S ec o n dar y a nal yses are descri b e d i n Secti o n 9  a n d ar e detaile d i n t he 
statisti cal a nal ysis pl a n ( S A P).   
S afet y a n al yses:  
A d verse e ve nts will b e c o de d usi n g t he Me dic al Dicti o nar y f or 
Re g ulat or y Acti vities  (Me d D R A ) a n d will be s u m marize d  b y s yste m 
or ga n class, preferre d ter m, a n d tre at m e nt  (i n cl u di n g d ose , if 
a p plic a ble) gr o u p.  F or a c h a n ge i n st o ol f or m a n d/ or fre q ue nc y t o b e 
c o nsi dere d a n a d verse e ve nt , t he crit eria d etaile d i n Secti o n  7. 3. 6. 1  
m ust be f oll o we d . T hese s u m m aries will be pr o vi de d f or eac h st u d y 
peri o d se paratel y.   
Act ual val ues a n d c ha n g e fr o m baseli ne v al ues f or cli nical la b or at or y 
tests, vital si g ns, b o d y wei g hts, an d E C Gs will b e s u m mari ze d  b y e ac h 
treat me nt (i ncl u di n g d ose , if a p plica ble) gr o u p  f or e a c h visit c olle cte d 
d uri n g t he st u d y. T h e n u m ber a n d perce nta ge of p ati e nt s i n ea c h 
p h ysical e x a mi n ati o n cate g or y will be pr ese nte d f or eac h visit b y 
treat me nt (i ncl u din g  d ose , if a p plicab le) gr o u p. T h ese s u m mari es will 
be pr o vi de d f or e ac h st u d y peri o d se p arat el y.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 1 5  of 6 6  
1. 3   
Sc he d ule of E ve nts  
 
 
Scree ni n g  
 
W as h o ut
h  
 
2 6 -Wee k Tre at m e nt P eri o d  
 
St u d y Da y  
-2 1   
-1 4  
+ 2  
-7  
+ 2  
-1  
+ 2  
1   
8  
+ 5  
1 5  
+ 5  
2 9  
+ 5  
5 7  
+ 7  
8 5  
+ 7  
1 2 0  
+ 7  
1 5 5  
+ 7  
1 8 3  
+ 7  
Visit  
V 1  
V 2  
V 3   
V 4 n  
V 5 n  
V 6   
V 7   
V 8   
V 9   
V 1 0   
V 1 1   
V 1 2   
V 1 3  
I nf or me d c o nse nt 
X  
  
  
  
  
  
  
  
  
  
  
 
 
I ncl usi o n/ E xcl usi o n  
X  
X   
X   
X   
X   
  
  
  
  
  
  
 
 
De m o gra p h ics 
X  
  
  
  
  
  
  
  
  
  
  
 
 
Pre -dial ysis B o d y Wei g ht  
X f 
  
  
  
X   
  
  
  
  
X   
  
  
X  
Kt/ V e 
X   
  
  
  
  
  
  
  
  
  
  
 
 
K D Q o L / D SIj 
X   
  
  
  
  
  
  
  
  
X   
  
  
X  
Me d/ S ur gical H x  
X  
X   
X   
X   
X   
  
  
  
  
  
  
 
 
P h ysical E xa m  
X  
  
  
  
X   
  
  
  
  
  
  
  
X  
Vital si g ns a 
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
E C G e val uati o n  
X  
  
  
  
X   
  
  
  
  
X   
  
  
X  
Cli nical la b orat or y tests b 
X  
  
  
  
X   
  
  
  
  
X   
  
  
X  
F S H test c 
X  
  
  
  
  
  
  
  
  
  
  
 
 
Pre g na nc y test c (ser u m) 
X  
  
  
  
X   
  
  
  
  
X   
  
  
X  
HI V, he patitis B a n d C tests  
X  
  
  
  
  
  
  
  
  
  
  
 
 
Start was h -o ut of p h os p hate bi n ders  
X   
  
  
  
  
  
  
  
  
  
  
 
 
Ra n d o mizati o n # 1 k  
 
  
  
  
X   
  
  
  
  
  
  
 
 
Dr u g dis pe nse  
 
  
  
  
X   
X   
  
X   
X   
X   
X   
X   
 
Dr u g ret ur n  
 
  
  
  
  
X   
  
X   
X   
X   
X   
X   
X  
Dr u g acc o u nta bilit y l 
 
  
  
  
  
X   
  
X   
X   
X   
X   
X   
X  
s-P h os p h or us i 
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Ca x P, F G F 2 3  
X  
  
  
  
X   
  
  
  
  
X   
  
  
X  
E x pl orat or y bi o mar kers  
X  
  
  
  
X   
  
  
  
  
X   
  
  
X  
A E assess me nt d 
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Pri or/ C o n Me ds  
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
 
 
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 1 6  of 6 6  
 
 
 
R a n d o mize d Wit h dr a w al P eri o d g  
 
S af et y E xt e nsi o n P eri o d  
 
St u d y Da y  
 
1 8 3  
+ 7  
 
1 9 7  
+ 7  
 
2 1 1  
+ 7  
 
2 2 5  
+ 7  
 
2 3 9  
+ 7  
 
2 5 3  
+ 7  
 
2 6 7  
+ 7  
 
2 8 1  
+ 7  
 
3 0 9  
+ 7  
 
3 3 7  
+ 7  
 
3 6 5  
+ 7  
 
Visit  
V 1 3  
V 1 4 m  
V 1 5   
V 1 6 m  
V 1 7   
V 1 8 m   
V 1 9   
V 2 0   
V 2 1   
V 2 2   
V 2 3/  
E O T  
Pre -dial ysis B o d y Wei g ht   
 
  
  
  
  
  
X   
  
  
X   
X  
K D Q o L / D SIj 
 
  
  
  
  
  
X   
  
  
  
X  
P h ysical E xa m  
 
  
  
  
  
  
X   
  
  
  
X  
Vital si g ns a 
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
E C G e val uati o n  
 
  
  
  
  
  
X   
  
  
 
X  
Cli nical la b orat or y tests b 
 
  
  
  
  
  
X   
  
  
  
X  
Pre g na nc y test c (ser u m) 
 
  
  
  
  
  
X   
  
  
  
X  
Ra n d o mizati o n  # 2 k  
X  
  
  
  
  
  
  
  
  
 
 
Dr u g dis pe nse  
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
Dr u g ret ur n  
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Dr u g acc o u nta bilit y  
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
s-P h os p h or us i 
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Ca x P, F G F 2 3  
 
  
X   
  
X   
  
X   
  
  
  
X  
E x pl orat or y bi o mar kers  
 
  
X   
  
X   
  
X   
  
  
  
X  
A E assess me nt d 
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
Pri or/ C o n Me ds  
X  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
a Vital si g ns i ncl u de bl o o d press ure, p ulse a n d m ust be perf or me d pre -dial ysis . 
b  All bl o o d c ollecti o ns are perf or me d pre -dial ysis . 
c F S H test a n d pre g na nc y test are perf or me d o n all fe males at Scree ni n g . After scree ni n g, pre g na nc y tests will o nl y be perf or me d o n fe males of c hil d -beari n g p o te ntial. 
d  A Es a n d S A Es will be c ollecte d fr o m c o nse nti n g t o t he e n d of st u d y . 
e   Kt/ V s h o ul d be t he m ost rece nt hist orical val ue  pri or t o scree ni n g . 
f     Hei g ht will als o be meas ure d at t he scree ni n g visit  
g  I n t he ra n d o mize d w it h dra wal peri o d, patie nt s i n t he te na pa n or gr o u p o nl y  are ra n d o mize d 1: 1 t o eit her sta y o n c urre nt treat me nt  of te na pa n or  or recei ve a matc he d place b o; 
base d o n wit h dra wal criteria , patie nt s ma y e nter t he safet y assess me nt peri o d at a n y visit. 
h     If t he la b orat or y e val uati o ns fr o m t he was h-o ut peri o d dee m t he patie nt i neli gi ble f or t he st u d y, the site m ust i nf or m t he patie nt a n d tell t he m t o ta ke t heir p h os p hate bi n ders . 
i    s-P h os p h or us  sa m ple c ollecte d at visits w he n safet y la bs are n ot c ollecte d.  
j   K D Q o L  (K D Q o L ™-3 6 ), Ki d ne y Disease a n d Q ualit y of L ife s ur ve y.  D SI , Dial ysis S y m pt o m I n de x s ur ve y is f or E n glis h s pea kers o nl y a n d is n ot vali date d i n ot her la n g ua ges. 
k  Ra n d o mizati o n # 1 is 3: 1, te na pa n or: acti ve c o ntr ol.  Ra n d o mizati o n # 2 is 1: 1 fr o m t he te na pa n or gr o u p o nl y t o te na pa n or: place b o . Patie nt s i n t he acti ve co ntr ol  gr o u p will 
recei ve se vela mer car b o nate f or t he e ntire 5 2 -wee k  st u d y peri o d. 
l  Dr u g acc o u nta bilit y will be perf or me d f or b ot h te na pa n or a n d t he acti ve c o ntr ol.  
m Visits 1 4, 1 6 a n d 1 8 are n ot d o ne f or s u bjects ra n d o mize d i nt o t he acti ve c o ntr ol gr o u p.  
n  Patie nts s h o ul d be ra n d o mize d b y t he  wee k after meeti n g s -P was h o ut criteria ;t otal peri o d off bi n der m ust  n ot be greater t ha n 4 wee ks.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 1 7  of 6 6  
1. 4   
List of A b bre vi ati o ns  
A E  
A d vers e e ve nt  
A L T  
Ala ni ne a mi n otra ns a mi nase  
A N O V A  
A nal ysis of varia nce  
A S T  
As partate a mi n otra ns a mi nas e  
BI D  
bis i n die, t wice per da y  
B MI  
B o d y mass i n de x  
C K D  
C hr o nic ki d ne y dis eas e  
eC R F  
Electr o nic c as e re p ort f or m  
C S R  
Cli nical st u d y re p ort  
D B P  
D iast olic bl o o d press ure 
D N A  
De o x yri b o n ucleic aci d  
E C G  
Electr ocar di o gra m  
E S R D  
E n d -sta ge re nal dis ease 
E S R D -P D   
E n d -sta ge re nal dis ease o n perit o neal dial ysis  
F D A  
U S F o o d a n d Dr u g A d mi nistrati o n  
iF G F 2 3  
I ntact Fi br o blast gr o wt h fact or 2 3  
c F G F 2 3  
c-ter mi n us Fi br o blast gr o wt h fact or 2 3 
F S H  
F ollicle -sti m ulati n g h or m o ne le vel 
G C P  
G o o d Cli nical Practice  
GI  
Gastr oi ntesti nal  
H +  
H y dr o ge n  
H D  
He m o dial ysis  
H F  
Heart Fail ure  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
I B 
I n vesti gati o nal Br oc h ure 
I B S 
Irrita ble b o wel s y n dr o me 
I B S-C  
C o nsti pati o n -pre d o mi na nt irrita ble b o wel s y n dr o me  
I B S-D  
Diarr hea -pre d o mi na nt irrita ble b o wel s y n dr o me  
I C5 0 
Half ma xi mal i n hi bit or y c o nce ntrati o n  
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal C o m mittee o n Har m o nizati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 1 8  of 6 6  
I U D 
I ntra uteri ne de vice 
L O C F  
Last o bs er vati o n carrie d f or war d  
L O Q  
Li mit of q ua ntitati o n  
L S mea n  
Least s q uares mea n  
M A D  
M ulti ple as ce n di n g -d ose  
mi n  
Mi ni m u m (e. g., mi n, ma x)  
n,  
N u m ber of o bs er ve d patie nt s 
N  
N u m ber of patie nt s i n t he a p plica ble a nal ysis set 
Na +  
S o di u m  
N H E 3  
Na/ h y dr o ge n a nti p orter  3  
N O A E L  
N o o bs er ve d a d verse effect le vel  
p  
Pr o ba bilit y; p -val ue  
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic  
P O  
Oral a d mi nistrati o n  
P T H  
Parat h yr oi d h or m o ne  
Q D  
q ua q ue die, o nce per da y  
Q R S  
Pri nci pal deflecti o n i n E C G  
Q T  
E C G i nter val  
Q T c 
Q T i nter val w hic h has bee n c orrecte d b y ta ki n g i nt o acc o u nt heart rate  
R A A Si  
R e ni n– a n gi ote nsi n – al d oster o ne s yste m  i n hi bit ors 
R B C  
Re d bl o o d cell  
s- 
s er u m 
S A D  
Si n gle as ce n di n g -d os e  
S A P  
Statistical A nal ysis Pla n  
S A E  
Seri o us a d vers e e ve nt  
S B P  
S yst olic bl o o d press ure  
S D  
Sta n dar d de viati o n  
S O C  
S yste m or ga n class  
S O P  
Sta n dar d o perati n g pr oce d ure  
T E A E  
T E E R  
Treat me nt -e mer ge nt a d vers e e ve nt 
Tra ns e pit helial electr o nic resista nce  
TI D  
ter i n die, t hree ti mes per da y 
W B C  
W hite bl o o d cell  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 1 9  of 6 6  
2   
I N T R O D U C TI O N A N D B A C K G R O U N D 
2. 1   
I ntr o d ucti o n 
C hr o nic ki d ne y disease ( C K D) affects 5 -1 0 % of t h e p o p ulati o n gl o ball y a n d t h e n u m bers of 
patie nts s ufferi n g fr o m e n d -sta g e re nal disease ( E S R D) are i ncreasi n g ( E k n o ya n 2 0 0 4 ). Wit h 
pr o gressi n g i m pair me nt of r e nal f u ncti o n, t h e a bilit y of t he ki d ne ys t o a p pr o priatel y e x cret e 
p h os p hate is re d uc e d a n d h y per p h os p hat e mi a is a ne arl y u ni versal c o m plicati o n of E S R D. 
H y per p h os p hate mi a is als o part of t he C K D B o ne Mi neral Dis or der, w hi c h is ass ociat e d wit h a 
disr u pti o n of n or mal ser u m a n d tiss ue c o nce ntrati o ns of p h os p h or us a n d calci u m, a n d c ha n g es i n 
circ ul ati n g le vels of h or m o nes s uc h as parat h yr oi d h or m o ne ( P T H) a n d vit a mi n D. L eft 
u ntreat e d, h y per p h os p hate mia ca n l ea d t o v asc ular a n d tiss ue cal cifi cati o ns, b o ne pai n, fra ct ures 
a n d w orse ni n g sec o n dar y h y per par at h yr oi dis m a n d is ass ociate d wit h i ncre as e d car di o v asc ular 
m or bi dit y a n d m ort alit y. O bser vati o n al dat a s h o w t hat tre at m e nt wit h p h os p hate bi n ders t o 
re d uce h y per p h os p hate mi a is i n de p e n de ntl y ass ociat e d wit h i m pr o v e d s ur vi val (Wa hee d 2 0 1 3 ), 
a n d a meta-a nal ysis of ra n d o mi ze d cli ni cal trials de m o nst rate t hat n o n-calci u m base d bi n ders 
ha ve  a l o wer m ortalit y as c o m pare d t o calci u m -base d bi n ders (Ja mal et al i n t h e La nc et, 
p u blis he d o nli n e J ul y 1 9, 2 0 1 3). E x peri me ntal st u dies pr o vi de s u p p ort f or t he e pi de mi ol o gi c 
fi n di n gs: p h os p hate e xcess pr o m ot es vascular c alcifi cati o n, i n d uces e n d ot helial d ysf u ncti o n a n d 
ma y c o ntri b ute t o ot her e mer gi n g c hr o nic ki d ne y dis ease -s pecific me c ha nis ms of c ar di o vasc ular 
t o xicit y (Wa h ee d 2 0 1 3). He nce, cli nical tre at m e nt g ui deli n es f or pati e nts wit h a d v a nce d ki d n e y 
disease s u g gest mai ntai ni n g ser u m p h os p h or us  wit hi n 3. 5 t o 5. 5 m g/ d L, w hi c h is cl ose t o t he 
n or mal ra n g e ( K DI G O g ui deli n e 2 0 0 9).  
I n a d diti o n t o dietar y p h os p h or us  restricti o ns a n d dial ysis, 8 0-9 0 % of E S R D patie nts ne e d 
treat me nt wit h oral p h os p hate bi n ders. H o we ver, a si g nifica nt pr o p orti o n of E S R D patie nts still 
d o n’t ac hi e ve a de q u ate p h os p hate c o ntr ol ( D O P P S A n n ual Re p ort 2 0 1 0). A n i m p orta nt barrier 
f or a s uccessf ul treat me nt is t he pill b ur d e n ass ociate d wit h all p h os p hate bi n d ers, w hic h ha ve t o 
be d ose d i n se veral  gra ms per da y a n d ta k e n wit h  e ac h meal t o bi n d di etar y p h os p h or us . T he si d e 
effect pr ofile wit h p o or gastr o -i nt esti nal t ol era bilit y a n d c o ncer ns f or l o n g-ter m ne g ati v e effe cts 
s uc h as tiss ue cal cifi cati o n a n d p ote ntial metal acc u m ulati o n t o xi cit y fr o m cal ci u m-base d a n d 
metal -base d bi n d ers, res pecti v el y, f urt h er i m p air a n effecti ve p h os p h or us  c o ntr ol i n E S R D 
patie nts. T here is , t heref ore, a rati o nal e t o de v el o p or al p h os p hate -l o weri n g dr u gs wit h ne w 
mec ha nis ms of acti o n, a m ore c o n ve ni e nt d osi n g a n d i m pr o ve d ris k -be n efit pr ofile.  
Te na pa n or is a n oral, mi ni mall y a bs or be d c o m p o u n d t hat i n hi bits t h e N H E 3 (s o di u m h y dr o ge n 
e xc ha n ger) tra ns p orter l o call y i n t h e gastr oi ntesti n al tract, w hi c h le a ds t o re d uce d s o di u m (a n d 
fl ui d) a bs or pti o n. Data fr o m pre-cli nical st u dies a n d res ults i n healt h y v ol u nteers s h o w t hat 
te na pa n or als o re d uces t h e u pta k e of p h os p h or us  fr o m t he g ut.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 0  of 6 6  
T e na pa n or r e d uces i nt esti nal p h os p hate a bs or pti o n , pre d o mi na ntl y t hr o u g h r e d ucti o n of passi ve 
paracell ul ar p h os p hate i nfl u x, t he m ost i m p orta nt o v erall mec h a nis m of i ntesti nal p h os p hate 
a bs or pti o n. Te n a pa n or m o d ulates ti g ht j u ncti o ns t o i ncrease T E E R, t h ere b y re d uci n g para cell ular 
p h os p hate per m ea bilit y; t his effe ct is m e diate d e x cl usi vel y via o n -tar get N H E 3 i n hi biti o n.  
Te na pa n or h as bee n a d mi nister e d t o a p pr o xi matel y 3 4 7  healt h y s u bj ects at si n gle d oses u p t o 9 0 0 
m g, a n d i n re p eat e d d oses u p t o 1 8 0 m g/ da y f or 7 d a ys, a n d t o a p pr o xi m atel y 1 0 2 0  I B S-C 
patie nts at d oses u p t o 1 0 0 m g/ da y f or u p t o 1 2 wee ks a n d t o 4 7 7  C K D patie nts ( C K D  sta ges 3 b, 
4 a n d 5 D) f or u p t o 1 2 wee ks at d oses u p t o 1 2 0 m g/ da y.    
2. 2   
Descri pti o n of I n vesti g ati o n al Pr o d uct  
Te na pa n or  is a GI-a cti n g, mi ni mall y s yste mi c, N H E 3 i n hi bit or . Te na p a n or is a d mi nistere d as t he 
h y dr oc hl ori de salt a n d is c he micall y descri b e d as: ( S) -N, N’ -( 1 0, 1 7-di o x o -3, 6, 2 1, 2 4 -tetra o xa-
9, 1 1, 1 6, 1 8 -tetra aza he x ac osa ne-1, 2 6 -di yl) bis( 3 -(( S)-6, 8 -dic hl or o -2 -m et h yl -1, 2, 3, 4 -
tetra h y dr ois o q ui n oli n-4 -yl) be nze n es ulf o na mi de) di h y dr oc hl ori de. Its e m pirical f or m ula is 
C 5 0H 6 8C l6N 8O 1 0S 2. 
 
 
D osi n g c o nsists of o ne t o t hree 1 0 m g ta blets, t a ke n i n c o nj u ncti o n wit h bre a kfast  a n d di n n er .  
 
 
 
 T a blets of te na p a n or s h o ul d be st ore d i n t h e ori gi n al pac k a gi n g 
acc or di n g t o t he la beli n g . 
2. 3   
Descri pti o n of Acti ve C o ntr ol  
T he acti ve c o ntr ol use d i n t his st u d y will  be se vel a m er car b o nate a n d will be s u p pli e d as 
c o m mer ciall y a vaila ble  (2 7 0 t a blet c o u nt b ottl es ) b y t he s p o ns or. Se vela m er car b o nate m ust b e 
st ore d i n t he ori gi nal pac ka gi n g as descri b e d o n t he l a bel.  
T he d ose prescri b e d will be b ase d o n sta n dar d of car e usi n g t he pa c ka ge i nsert  f or g ui da n ce. 
2. 4   
St u d y R ati o n ale  
Re d ucti o n of p h os p h or us  u pta k e is a n est a blis he d tre at me nt a p pr oa c h f or h y per p h os p hate mia i n 
E S R D -H D patie nts a n d a n u m b er of dr u gs t hat bi n d dietar y p h os p h or us  i n t h e g ut l u me n are p art 
of t he sta n dar d of care f or patie nts wit h a d va n ce d ki d ne y disease o n di al ysis. Res ults fr o m b ot h 
P hase 2 b a n d P hase 3 st u dies  i n E S R D-H D patie nts wit h h y per p h os p hate mia, s h o we d t h at 
te na pa n or pr o d u ce d a statisti call y si g nifi ca nt d ecre ase i n ser u m p h os p h or us ; t hese r es ults s u g gest 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 1  of 6 6  
t hat t e na pa n or h as t he p ote ntial t o pr o vi d e p h os p h or us  c o ntr ol c o m p ara bl e t o e xisti n g p h os p hate -
l o weri n g a ge nts a n d i m pr o v e d d osi n g wit h re d uc e d pill b ur de n, w hi c h merits f urt her cli ni cal 
de vel o p m e nt.  
2. 5   
Ris k -Be nefit Assess me nt  
T his ris k-be nefit assess me nt i s base d o n t he n o ncli ni cal t o xic ol o g y, saf et y, a n d p har mac ol o g y 
st u dies as well as t h e 1 9  cli nic al trials  perf or m e d wit h te na pa n or; t he r es ults fr o m t his researc h 
are descri b e d i n t he I n v esti gat or’s Br oc h ure . 
Pre -cli ni cal t o xic ol o gical st u dies u p t o 9 m o nt hs ha v e bee n perf or me d i n r o de nts a n d d o gs. T he 
t o xic ol o gical pr ofil e i ncl u des s oft st o ols a n d/ or di arr hea a n d fi n di n gs sec o n dar y t o de h y dr ati o n; 
t hese fi n di n gs ar e a n e x pe cte d ma nif estati o n of t he c o m p o u n d’s e xa g gerate d p har m ac ol o gic 
acti vit y a n d fi n di n gs  were re versi ble d uri n g t he re c o ver y peri o d wit h o ut dr u g.   A t w o -year 
carci n o g e nicit y st u d y i n S pra g ue -Da wl e y rats  was ne gati ve.  
T he safet y, t oler a bilit y, p har m ac o d y na mics a n d effic ac y of te n a pa n or ha ve b ee n e v al uate d i n 3 4 7  
healt h y s u bj ects at si n gle d oses u p t o 9 0 0 m g, a n d i n re peat e d d oses u p t o 1 8 0 m g/ d a y f or 7 da ys, 
a n d t o 1 0 2 0  I B S-C pati e nts at d oses u p t o 1 0 0 m g/ da y f or u p t o 1 2 wee ks a n d t o 4 7 7  C K D  
patie nts ( C K D sta ges 3 b, 4 a n d 5 D) f or u p t o 1 2 wee ks at d oses u p t o 1 2 0 m g/ da y.  
Te na pa n or h as mi ni mal s yste mic bi oa vaila bilit y. Less t ha n  1 % of plas ma p h ar mac o ki netics 
sa m ples c ollecte d d uri n g h u ma n st u dies ( > 3 0 0 0) h a v e q ua ntifia bl e te na p a n or prese nt i n bl o o d 
ser u m (l o wer li mit of q u a ntificati o n = 0. 5 n g/ m L); all sa m ples wit h te na p a n or were bel o w 1. 5 
n g/ m L .   
T he re d ucti o n i n s o di u m u pta k e res ults i n a n i ncre ase i n net fl ui d v ol u me i n t he i ntesti n al tra ct. 
Base d o n t his me c ha nis m of acti o n, te na p a n or has t h e p ote ntial t o pr o d uce s ofter /l o oser st o ols 
a n d i ncre ase d st o ol fre q u e n c y. T e n a pa n or  has be e n g e nerall y safe a n d well t ol erat e d i n cli ni cal 
st u dies a n d t he saf et y pr ofile wit h s ofte ni n g/l o ose ni n g of st o ol c o nsiste nc y a n d gastr o -i ntesti n al 
a d verse e ve nts ha ve bee n c o nsiste nt wit h its p har mac ol o g y.  
T he t he or eti cal a d v erse effe cts fr o m t e na pa n or treat me nt i n E S R D patie nts w o ul d be d ue t o 
e xa g gerate d p har m ac ol o gical effe cts a n d m a y i ncl u d e ele ctr ol yte dist ur ba n ces, meta b olic 
aci d osis, s oft st o ols/ di arr hea a n d re d uce d bl o o d press ure. W hil e a s ofte ni n g /l o ose ni n g of t he 
st o ol wit h a n i n crease d fl ui d l oss via t he i ntesti ne is a n i nte n d e d a n d desir e d  effect of te n a pa n or 
i n s o me patie nts, se nsiti ve patie nt s s h o ul d be m o nit ore d f or si g ns of de h y drati o n i n case of 
pr ol o n ge d se vere diarr hea. T his st u d y pr ot oc ol i ncl u des cli ni cal la b orat or y tests (i ncl u di n g 
bicar b o nate a n d electr ol yt es) a n d vit al si g ns as well as s pecific disc o nti n u ati o n criteria relat e d t o 
p h os p hate c o ntr ol t o miti g ate ris ks t o st u d y parti ci pa nts as well as t o re d u ce t h e ris k f or se vere 
h y per - or h y p o p h os p hate mia d uri n g the st u d y a n d li mit t h e peri o d wit h ris k f or s u b o pti m al 
p h os p hate c o ntr ol. All patie nt s will re -start t heir pre-st u d y treat me nt wit h p h os p hate bi n ders 
w he n t heir partici pati o n i n t he st u d y e n ds . E S R D-H D  patie nts ar e dial yze d t hr ee ti mes per we e k 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 2  of 6 6  
a n d t heir h ealt h stat us is c h ec ke d at ea c h visit as part of sta n dar d of care. Se e t he I n v esti gat ors 
Br oc h ure f or det ails o n n o n -cli nic al a n d cli nical res ults wit h te n a pa n or. 
Patie nt s will be i nf or me d b ot h v er ball y a n d i n writi n g a b o ut t hese as pects bef ore ta ki n g p art i n 
a n y st u d y -s pecifi c e xa mi nati o n a n d t h e st u d y will b e c o n d ucte d u n d er c o n diti o ns t hat e ns ure a 
hi g h pr o ba bilit y f or t h e ear l y dete cti o n of u nt o war d e ve nts a n d f or a p pr o pri ate i nter ve nti o n. 
I n s u m mar y, t he ris ks t o t he partici pa nts i n t his u p t o o ne year  st u d y ar e c o nsi dere d acc e pta ble 
a n d t he st u d y res ults will be i m p ort a nt f or t h e de vel o p me nt of a p ote ntial n e w dr u g, w hic h c o ul d 
i m pr o ve t h e tre at m e nt of h y per p h os p hat e mi a i n t his patie nt gr o u p. 
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 3  of 6 6  
3   
S T U D Y O B J E C TI V E S  
3. 1   
Pri m ar y O bjecti v e s 
T he pri m ar y o bje cti ve s of t his st u d y are:  
•  T o e val u ate t he safet y a n d t ol era bilit y of te na p a n or f or t he tre at m e nt of 
h y per p h os p hate mia i n E n d -Sta ge Re n al Disease Pati e nts o n He m o dial ysis ( E S R D -H D) 
a n d o n Perit o ne al Dial ysis ( E S R D -P D) w he n a d mi nistere d t wic e dail y f or u p t o 5 2 
wee ks.  
•  T o c o m par e t he p h os p h or us l o weri n g eff ect b et wee n te na pa n or a n d plac e b o base d o n  t h e 
c ha n ge i n ser u m p h os p h or us (s -P) fr o m t he e n d of t h e 2 6 -wee k treat me nt peri o d t o t he 
e n d of t he u p t o 1 2 -we e k  ra n d o mi ze d wit h dr a wal peri o d  or t he e n d p oi nt visit f or t his 
peri o d i n  t h e res p o n der p o p ul ati o n (effica c y a nal ysis set).  
3. 2   
Sec o n d ar y O bjecti ve s 
T he sec o n dar y o bjecti ves of t his st u d y ar e:  
•  T o c o m par e t he p h os p h or us l o weri n g eff ect b et wee n te na pa n or a n d plac e b o base d o n t h e 
c ha n ge i n ser u m p h os p h or us (s -P) fr o m t he e n d of t h e 2 6 -wee k treat me nt peri o d t o t he 
e n d of t he ra n d o miz e d wit h dra wal p eri o d or t h e e n d p oi nt visit f or t his peri o d i n t he 
i nte nt-t o-tre at (I T T) a nal ysis set a n d at i n di vi d u al d oses of te na pa n or a n d place b o i n b ot h 
t he effi cac y  a n d I T T a n al ysis sets . 
•  T o e val u ate t he effe ct of te na pa n or o n t he c h a n ge i n ser u m p h os p h or us  le vels fr o m 
baseli ne  t o t he e n d of 2 6 -wee k tre at m e nt peri o d  
•  T o e val u ate t he effe ct of t e na pa n or o n t he n u m b er of patie nt s reac hi n g ser u m p h os p h or us  
g oal le v el s defi n e d as < 5. 5 m g/ dl  d uri n g t h e 2 6-wee k treat me nt p eri o d . 
•  T o e val u ate t he effe ct of t e na pa n or o n C alci u m - P h os p h or us Pr o d uct (Ca x P ) d uri n g all 
t hree st u d y peri o ds (2 6 -wee k treat me nt peri o d , r a n d o mize d wit h dra wal p eri o d  a n d safet y 
e xte nsi o n peri o d ). 
•  T o e val u ate t he effe ct of t e na pa n or o n i nta ct fi br o blast gr o wt h fact or 2 3 (i F G F 2 3) a n d c-
ter mi n al F G F 2 3  (c F G F 2 3 ) le vels d uri n g all t hre e st u d y peri o ds (2 6 -wee k treat me nt 
peri o d , ra n d o mize d wit h dra wal peri o d  a n d safet y e xt e nsi o n peri o d). 
•  T o e val u at e t he effe ct of t e na pa n or o n t he Ki d ne y Disease Q ualit y of Life ( K D Q o L) 
s ur ve y d uri n g all t hree st u d y p eri o ds.  
•  T o e val u ate t he effe ct of t e na pa n or o n t he Dial ysis S y m pt o m I n de x ( D SI) s ur ve y d uri n g 
all t hr ee st u d y peri o ds  (f or E n glis h s pea kers o nl y). 
•  T o c o m par e t he l o n g -ter m saf et y of t e na pa n or t o t he acti v e c o ntr ol se vela mer c ar b o nat e. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 4  of 6 6  
3. 3   
E x pl or at or y O bjecti ves  
T he e x pl or at or y o bj ecti v es of t his st u d y are:  
•  T o c oll ect a n d st ore plas ma/ser u m f or f ut ure e x pl orat or y researc h i nt o ser u m/ plas ma 
bi o mar kers relat e d t o  car di o-re nal disease a n d/ or b o n e-met a b olis m or t hat ma y i nfl ue nce 
t he res p o nse (i.e. d istri b uti o n, safet y, t olera bilit y, a n d effica c y) t o te n a pa n or. T h ese dat a 
will n ot be p art of t his st u d y re p ort.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 5  of 6 6  
4   
S T U D Y D E SI G N  
4. 1   
Desi g n S u m m ar y  
 
 
    
T he st u d y c o nsists of a scre e ni n g visit, a p h os p hate bi n der -free was h-o ut peri o d of u p t o f o ur 
wee ks, a 2 6 -wee k treat me nt peri o d, a n u p t o 1 2 -wee k place b o -c o ntr olle d, ra n d o mize d 
wit h dra wal  peri o d d uri n g w hic h patie nts are ra n d o mi ze d 1: 1 t o eit h er re mai n o n t he te na pa n or 
d ose t he y are ta ki n g at t he e n d of t he 2 6 -we e k tre at m e nt peri o d or  r ecei v e pla ce b o, f oll o we d b y 
a n o pe n la b el safet y e xte nsi o n p eri o d f or a t otal tre at me nt peri o d of u p t o 5 2 wee ks. A n acti ve 
c o ntr ol gr o u p , f or safet y a nal ysis, will rec ei ve se v ela mer car b o n ate, o pe n la bel, f or t he e ntir e 5 2-
wee k st u d y  peri o d  (see Secti o n 2. 3 ). 
T he scree ni n g visit ( Visit 1) a n d all ot her visits i n t h e st u d y m ust be sc he d ule d after a s h ort 
dial ysis i nt er val ( o nl y f or H D patie nts; e. g., We d n es da y or Fri d a y f or patie nts o n a M W F 
sc he d ule a n d T h urs da y or Sat ur da y f or patie nts o n a T T h S sc he d ule ). B o d y wei g ht , vital si g ns 
a n d bl o o d c ollecti o ns f or la b orat or y as sess me nts m ust  be perf o me d pre -di al ysis.  All ot her 
assess me nts ma y be perf o me d pre -, d uri n g, or p ost-dial ysis b ut s h o ul d be p erf or me d at t h e sa me 
ti me at e ac h visit. F or P D patie nts, vis its s h o ul d be p erf or me d o n t h e sa me da y eac h we e k, if 
p ossi ble. F or a ll patie nts, ser u m p h os p h or us meas ure d at t he scr ee ni n g visit m ust b e ≥4. 0 a n d 
≤8. 0 m g/ d L or p ati e nt s t o be eli gi ble t o e nter t he was h-o ut peri o d.   
T he was h -o ut peri o d  will be gi n i m me diatel y after t h e scree ni n g visit.  Ser u m p h os p h or us  will b e 
meas ure d wee kl y ( pre -dial ysis after a s h ort i nt er val f or H D patie nts) d uri n g t h e was h-o ut peri o d 
t o deter mi ne if t he p atie nt  me ets i ncl usi o n criteri a f or e nr oll m e nt i nt o t he st u d y.   


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 6  of 6 6  
T he st u d y visits d uri n g t he was h -o ut peri o d f or H D patie nts s h o uld  be sc he d ul e d after t he first 
s h ort i nter val i n t h e wee k t o e ns ure d ata is a vaila bl e bef ore a p ossi ble r a n d o miz ati o n, w hi c h 
c o ul d t he n ta ke place after t he sec o n d s h ort i nter v al i n t he wee k . Ot her wise t he ra n d o mizati o n 
visit will b e sc he d ul e d t he f oll o wi n g wee k after t h e first s h ort dial ysis i nter val; t h eref ore, t h e 
t otal le n gt h of p h os p hate bi n d er was h-o ut ma y be u p t o 4 wee ks.  
T he was h o ut peri o d will be a mi ni m u m of 1 wee k  a n d m ust n ot e xc ee d 4 wee ks. Patie nts s h o ul d 
be ra n d o mi ze d b y  o ne wee k after meet i n g s-P was h o ut crit eria  ( after visit 2, 3  or 4 ); t h e t ot al 
was h o ut peri o d m ust  n ot b e greater t ha n 4 we e ks .  
Patie nt s w h o  me et all t h e i ncl usi o n/e xcl usi o n criteri a will be ra n d o miz e d 3: 1 t o eit h er recei ve 
te na pa n or at a d ose of 3 0 m g  bi d  or se vel a mer car bo nate  base d o n p ac ka ge i nsert i nstr u cti o ns 
(sta n dar d of care) after Visits 2, 3 or 4 (after 1, 2 or 3 wee ks of was h -o ut) if t he y  ha ve a s -P le vel 
of at le ast 6. 0  m g/ d L  a n d n ot m ore t ha n 1 0. 0 m g/ d L  a n d ha ve a n i ncrease i n s-P of at le ast 1. 5  
m g/ d L v ers us pre  was h -o ut ( Visit 1 , S cr ee ni n g visit).  
Patie nt s ra n d o miz e d i nt o t he t e na pa n or gr o u p will re cei ve te na p a n or at a d ose of 3 0 m g bi d. 
Te na pa n or will be ta ke n t wi ce dail y; j ust pri or t o br e a kfast a n d di n n er. Pati e nt s o n H D s h o ul d 
n ot  ta ke te n a pa n or at t he m eal i m m e diatel y pr ece di n g dial ysis; i n t his case, p ati e nt s will ta ke 
te na pa n or pri or t o t h e ne xt m eal after dial ysis.  T h os e ra n d o mi ze d i nt o t he a cti v e c o ntr ol gr o u p 
will ta k e se vel a mer c ar b o nat e base d o n sta n d ar d of c are  usi n g  t he p ac ka ge i nsert f or g ui d ance f or 
t he e ntire 5 2-wee k st u d y peri o d . Pati e nts w h o are o n acti v e c o ntr ol  will n ot  ha v e Visits 1 4, 1 6 
a n d 1 8.  
I n vesti gat ors m a y decre ase  or i ncr ease t h e d ose of te na pa n or base d o n s-P le vels a n d / or GI 
t olera bilit y.  T he c ha n ges m ust be ma de i n 1 0 m g i n cre me nts t o a mi ni m u m of 1 0 m g bi d or a 
ma xi m u m of 3 0 m g bi d fr o m e nr oll me nt u ntil Da y 1 8 3 ( Visit 1 3).  T he  d ose of se vela mer 
car b o nat e ma y be a dj uste d b ase d o n sta n dar d of care  f or t he e ntire 5 2-wee k st u d y peri o d .  
D uri n g t he 2 6 -wee k tr eat m e nt  peri o d a n d t h e safet y e xte nsi o n peri o d , patie nt s o n t e na pa n or  wit h 
a s -P ≥ 1 0 m g/ d L at a n y ti me after W ee k 2  of tr eat m e nt  or patie nt s wit h a s-P ≥ 9 m g/ d L f or t w o 
c o nsec uti v e visits  after We e k 2  will b e disc o nti n ue d a n d all visit pr oc e d ures f or Visit 2 3  w ill be 
c o m plete d, if p ossi bl e . Pati e nts i n t h e acti ve c o ntr ol gr o u p, recei vi n g se vela mer c ar b o nat e d o n ot 
ha ve s pecific disc o nti n uati o n criteri a; t h e y will b e tre ate d base d o n st a n dar d of car e usi n g t he 
pac ka ge i nsert f or g ui da n ce.    
At t he e n d of t h e 2 6 -w ee k tre at m e nt peri o d, patie nt s i n t he t e na pa n or gr o u p o nl y will b e 
ra n d o miz e d 1: 1 t o eit h er re mai n o n t he te na p a n or d ose t he y are ta ki n g o n Da y 1 8 3 ( Visit 1 3)  or 
recei v e plac e b o f or u p t o a n a d diti o nal 1 2 we e ks (ra n d o mize d wit h dra wal p eri o d). D uri n g t he 
ran d o miz e d wit h dra wal peri o d, patie nt s wit h a s-P ≥ 9 m g/ d L will be disc o nti n ue d a n d all visit 
pr oce d ures f or Visit 2 3  will be c o m plet e d, if p ossi ble . Patie nt s w h o  disc o nti n ue fr o m t he 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 7  of 6 6  
ra n d o miz e d wit h dra wal peri o d wit h s-P ≥ 9 m g/ d L will be off ere d t h e o p p ort u nit y t o e nt er t he 
safet y e xt e nsi o n peri o d.  
Patie nts w h o ra n d o mize i nt o t h e te na p a n or gr o u p a n d c o m plete t h e ra n d o mize d wit h dr a wal 
peri o d are eli gi ble t o e nr oll i n t he o p e n la b el safet y e xte nsi o n p eri o d f or a n a d diti o nal 1 4 wee ks.   
P atie nts w h o  e nr oll i n t h e o pe n l a bel safet y peri o d will rec ei ve te na pa n or d uri n g t his peri o d. 
La b orat or y effica c y e n d p oi nts will be assesse d at vari o us ti mes t hr o u g h o ut t he st u d y; s -P will be 
meas ure d at e ver y visit.  
Safet y assess me nts will b e perf or me d d uri n g  t he st u d y a n d will i n cl u de p h ysi cal e xa mi nati o n, 
vital si g ns ( B P/ P), b o d y wei g hts, cli ni cal la b orat or y e v al uati o ns, 1 2 -le a d ele ctr oc ar di o gra ms 
(E C Gs), a n d a d v erse e ve nt ( A E) m o nit ori n g.  Bl o o d s a m ples will be c olle cte d a n d st or e d, as 
a p pr o priat e, f or t he p ote nti al e v al uati o n of e x pl orat or y bi o mar kers relat e d t o car di o -re nal disease 
or b o ne met a b olis m or t hat ma y i nfl ue nce t he res p o nse (i.e. distri b uti o n, safet y, t ol era bilit y, a n d 
effica c y) t o te n a pa n or.  
Details of st u d y assess me nts a n d t he sc he d ule of e ve nts f or  t his st u d y are i n Se cti o n 1. 3 . 
4. 1. 1   
Treat me nts A d mi nistere d  
At ra n d o miz ati o n ( Visit 5), patie nts will be ra n d o miz e d t o eit her t e na pa n or or t h e acti ve c o ntr ol 
gr o u p. Patie nts ra n d o miz e d i nt o t he acti ve c o ntr ol gr o u p will rec ei v e se v ele m er car b o n ate f or t he 
e ntire 5 2 -we e k  st u d y peri o d. D ose of se vel a mer will be a dj uste d p er sta n dar d of c are usi n g t h e 
pac ka ge i nsert  f or g ui da n ce. 
Patie nts ra n d o miz e d i nt o t he t e na pa n or gr o u p will re cei ve te na p a n or at a d ose of 3 0 m g bi d. 
Te na pa n or will be ta ke n t wi ce dail y; j ust pri or t o br e a kfast a n d di n n er. Te na p a n or is s u p plie d as 
1 0 m g ta bl ets; e ac h d ose of o ne t o t hree ta bl ets bi d will a c hie v e t ot al dail y d oses of 2 0, 4 0, or 6 0 
m g te na p a n or.   
T he d ose of te n a pa n or ma y b e d o w n titr ate d or u p ti trate d t o a ma x of 3 0 m g bi d i n a ste p-wise 
fas hi o n base d o n ser u m-p h os p h or us le vels a n d/ or GI t olera bilit y  ( det ail e d i n Secti o n 6. 1. 3 ). 
D o w n -titrati o n ca n g o fr o m 3 0 m g bi d t o 2 0 m g bi d a n d 2 0 m g bi d t o 1 0 m g bi d. D ose escalati o n 
ca n g o i n 1 0 m g bi d i ncr e me nts t o a ma xi m u m d ose of 3 0 m g bi d.  
O n dial ysis da ys, pati e nt s o n H D  s h o ul d n ot  ta ke st u d y dr u g at t he meal pri or t o dial ysis a n d 
i nstea d t a ke it bef ore a n ot her m eal.  If a me al is s ki p p e d, t he d ose s h o ul d be ta ke n wit h a n ot her 
meal d uri n g t he d a y or at ar o u n d t he ti me t hat t he m e al w o ul d ha ve b ee n c o ns u me d.  Acti ve 
c o ntr ol (se vela m er car b o nate) will be t a ke n base d o n  sta n dar d of care usi ng t he pa c ka ge i nsert 
f or g ui da nce.  
D uri n g t he ra n d o mize d wit h dra wal peri o d, patie nts i n t he te n a pa n or gr o u p o nl y will be 
ra n d o miz e d t o eit her re mai n o n t heir c urre nt d ose of te na pa n or or r ecei v e pla ce b o i n a 1: 1 rati o. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 8  of 6 6  
Place b o  will be a d mi nist ere d P O d uri n g t he ra n d o mi ze d wit h dra wal peri o d o nl y f or pati e nts 
ra n d o miz e d i nt o place b o fr o m t he te na p a n or gr o u p. T he sa me n u m ber of t a blets as t h e last d ose 
of te na pa n or d uri n g 2 6 -wee k tre at m e nt peri o d will b e a d mi nistere d t o t he place b o gr o u p.  Patie nts 
fr o m t he a cti v e c o ntr ol gr o u p will n ot e nter t he ra n d o mize d wit h dra wal p eri o d; t he y will 
c o nti n ue t o rec ei ve se vela m er car b o n ate p er sta n dar d of care f or t he e ntir e 5 2 -wee k st u d y peri o d.  
D uri n g t he safet y e xte nsi o n p eri o d, patie nts  o n t e na p a n or will c o nti n ue at t h ei r sa me d ose. 
Patie nts o n pl ace b o  will c o nti n ue wit h t he ir sa me d ose fr o m t he e n d of t he 2 6-wee k tr eat me nt 
peri o d.  Titrati o n is all o we d as descri be d f or t he 2 6 -w ee k tre at m e nt peri o d.  
4. 1. 2   
D urati o n of St u d y  
T he e x pe cte d d urati o n of e ac h patie nt’s parti ci pati o n i n  t he st u d y will be u p t o 5 6  we e ks. T he 
scree ni n g peri o d ca n be u p t o 4  wee ks  a n d t h e t ot al of all t hr ee tr eat m e nt peri o ds ca n be u p t o  
5 2 wee ks . 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 2 9  of 6 6  
5   
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
I n vesti gat or(s) will rec or d i n t he patie nt  scree ni n g l o g all patie nt s w h o si g n t he i nf or m e d c o nse nt 
f or m f or e ntr y i nt o t he st u d y. 
Eac h patie nt  s h o ul d me et all of t he i ncl usi o n crit eria a n d n o ne of t he e xcl usi o n criteria f or t his 
st u d y.  
5. 1   
I ncl usi o n Criteri a 
A patie nt will be eli gi ble f or st u d y p art ici pati o n if he/s he meets t he f oll o wi n g criteria: 
1.  Si g ne d a n d dat e d i nf or m e d c o nse nt pri or t o a n y st u d y s pecific pr o ce d ures.  
2.  Males or fe males >  1 8 years  of a ge . 
3.  Fe m ales m ust b e n o n -pre g na nt, n o n -lactati n g a n d f ulfilli n g o n e of t he f oll o wi n g: 
a. P ost – me n o pa usa l defi ne d as a me n orr hea f or at l east 1 2 m o nt hs f oll o wi n g 
cessati o n of all e x o g e n o us h or m o nal tr eat me nts a n d wit h f olli cle sti m ul ati n g 
h or m o ne ( F S H) le v els i n t h e la b or at or y defi n e d p ost -me n o pa usal r a n ge.  
b.  D oc u me ntati o n of irr e versi ble s ur gi cal st erilizati o n b y h ysterect o m y, bil ateral 
o o p h orect o m y or bilateral sal pi n ge ct o m y , b ut n ot t u b al li g ati o n.  
c. Use of acce pta ble c o ntrac e pti v e met h o d:  I U D wit h s per mici de, a f e mal e c o n d o m 
wit h s per mici de, c o ntrace pti ve s p o n ge wit h s per mi ci de, a n i ntr a va gi n al s yste m 
(e. g., N u va Ri n g ®), a dia p hra g m wit h s per mici d e, a c er vical ca p wit h s per mici de, 
or oral, i m pla nt a ble, tra ns der mal, or i nj ect a ble c o ntra ce pti v es , se x ual a bsti ne nce, 
or a steril e se x ual p art ner . 
4.  Males m ust a gre e t o a v oi d fat heri n g a c hil d ( or d o nati n g s per m), a n d t h eref ore be eit h er 
sterile ( d o c u me nte d) or a gre e t o use, fr o m t he ti me of e nr oll m e nt u ntil 4 5 da ys after e n d of 
st u d y, o ne of t he f oll o wi n g a p pr o ve d met h o ds of c o ntrace pti o n: a male c o n d o m wit h 
s per mici d e, a sterile se x ual part n er , use of a n I U D wit h s per mici de  b y fe male se x u al part ner , 
a fe male c o n d o m wit h s per mi ci de, c o ntra ce pti ve s p o n ge wit h s per mi ci de, a n i ntra v a gi nal 
s yste m (e. g., N u va Ri n g ®), a dia p hr a g m wit h s per mi ci de, a cer vic al c a p wit h s per mici d e, or 
oral, i m pla nt a ble, tra ns der mal, or  i nj ect a ble c o ntra ce pti ves. 
5.  C hr o nic mai nte n a nce he m o dial ysis 3 x/ wee k f or at le ast 3  m o nt hs or c hr o ni c mai nte n a nce 
perit o ne al di al ysis ( P D) f or a mi ni m u m of 6  m o nt hs.  If m o dalit y of dial ysis has c ha n ge d 
patie nt m ust m eet o n e of t he t w o dial ysis criteri a a b o ve a n d bee n o n t he ne w m o dalit y of 
dial ysis f or a mi ni m u m of o ne m o nt h.  
6.  Sta ble vasc ular a ccess as assesse d b y I n vesti gat or if o n H D.  
7.  Kt/ V ≥1. 2  at m ost r ece nt me as ure me nt  pri or t o scre e ni n g.  
8.  Prescri be d a n d t a ki n g at least 3 d oses of  p h os p hat e bi n der  per da y. T he  prescri b e d 
d ose  s h o ul d ha ve bee n u n c ha n ge d d uri n g t he l ast 3 wee ks pri or t o scre e ni n g.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 0  of 6 6  
9.  Ser u m p h os p h or us le vels s h o ul d be bet wee n 4. 0 a n d 8. 0 m g/ d L (i n cl usi ve) at scree ni n g 
a nal yz e d at t he ce ntral la b orat or y use d i n t h e st u d y.  
1 0.  I nte nti o n all y left bla n k. 
1 1.  F or e nr oll me nt i n t h e st u d y, patie nt s m ust h a ve ser u m p h os p h or us le vels of at least 6. 0  
m g/ d L b ut n ot m ore t ha n 1 0 . 0 m g/ d L a n d h a ve ha d a n i ncrease of at le ast 1. 5  m g/ d L vers us 
pre was h -o ut val ue  after 1, 2 or 3 wee ks was h -o ut of  p h os p hate bi n ders .  
1 2.   A ble t o u n dersta n d a n d c o m pl y wit h t h e pr ot oc o l. 
5. 2   
E xcl usi o n Criteri a  
A patie nt will n ot b e eli gi bl e f or st u d y parti ci pati o n if he/s he me ets a n y of t h e e xcl usi o n crit eria, 
or will be disc o nti n ue d at t h e discreti o n of t he I n v esti gat or if h e/s he de v el o ps a n y of t he 
f oll o wi n g e xcl usi o n criteri a d uri n g t he st u d y: 
1.  Se vere h y per p h o s p hat e mia d efi ne d as ser u m p h os p h or us greater t h a n 1 0 . 0 m g/ d L o n 
P h os p hate -bi n ders at a n y ti me p oi nt d uri n g cli nic al m o nit ori n g f or t he 3 pre ce di n g m o nt hs  
bef ore t he scre e ni n g visit. 
2.  Ser u m/ plas m a parat h yr oi d h or m o ne > 1 2 0 0 p g/ m L. T he m ost rec e nt val ue fr o m patie nt s’ 
me dic al re c or ds s h o ul d be use d.  
3.  Cli nic al si g ns of h y p o v ole mia at e nr oll m e nt as j u d ge d b y t he In vesti g at or . 
4.  Hist or y of i nfla m mat or y b o wel disease (I B D) or diarr hea pre d o mi na n t irrita ble b o wel 
s y n dr o me (I B S-D) . 
5.  Sc he d ule d f or li vi n g d o n or ki d n e y tra ns pla nt, pla ns t o c ha n ge t o a differe nt met h o d of 
dial ysis , h o me H D or pla ns t o r el oc ate t o a n ot her ce nter d uri n g t h e st u d y peri o d. 
6.  A n y e vi de nce of or treat me nt of mali g na nc y wit hi n o ne year, e x cl u di n g n o n - mela n o mat o us 
mali g n a nci es of t he s ki n.  
7.  P ositi ve ser ol o g y ( he p atitis C or B i nfe cti o n, or h u m a n i m m u n o d eficie nc y vir us) wit h  
e vi de nc e of si g nifi ca nt he p ati c i m p air m e nt or W B C ele vati o n a cc or di n g t o t he I n vesti gat or . 
8.  Hist or y of alc o h o l a b use, illicit dr u g use, si g nifica nt me ntal ill ness, or a n y hist or y of dr u g 
a b use or a d dicti o n wit hi n 1 2 m o nt hs of st u d y e nr oll me nt.  
9.  Life e x p ect a nc y < 1 2  m o nt hs.  
1 0.  Use of a n i n vesti gati o nal a ge nt wit hi n 3 0 da ys pri or t o Scree ni n g . 
1 1.  Pre vi o us ra n d o miz ati o n i nt o t his st u d y. 
1 2.  Pre vi o us e x p os ure t o te n a pa n or  
1 3.  I n v ol ve me nt i n t h e pla n ni n g a n d/ or c o n d u ct of t h e st u d y (a p plies t o b ot h Ar del y x/ C R O staff 
a n d/ or staff at t he st u d y site).  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 1  of 6 6  
1 4.  If, i n t he o pi ni o n of t he I n v esti gat or, t he patie nt  is u n a ble or u n willi n g t o f ulfill t he 
re q uire m e nts of t he pr ot oc ol or has a c o n diti o n w hic h w o ul d re n der t he r es ults 
u ni nter preta bl e.  
5. 3   
Rescree ni n g Criteri a  
Rescree ni n g will o nl y b e all o we d f or s u bjects w h o  scree n fail at Visit 1 d ue t o ser u m p h os p h or us 
le vels o utsi d e of t he pr ot oc ol i ncl usi o n ra n g e ( < 4. 0 or > 8. 0 m g/ d L) a n d b ase d o n t he f oll o wi n g 
criteria:  
•  T he s u bject m ust ha v e hist ori cal ser u m p h os p h or us > 4. 5 m g/ d L a n d < 7 . 5 m g/ d L d uri n g  
t he t w o m o nt hs i m me diat el y pri or t o t he ori gi nal scree ni n g date. 
•  T he s u bject m ust wait a mi ni m u m of o ne wee k pri or t o rescree ni n g t o e ns ure t h at t h e y 
w o ul d n ot be off p h os p hate bi n ders f or a peri o d l o n g er t hat t he was h o ut peri o d descri be d 
i n t he pr ot o c ol. 
Sites m ust o btai n S p o ns or  a p pr o val bef or e rescree ni n g a s u bject.  
5. 4   
P atie nt  Wit h dr a w al  
Patie nt s ar e free t o disc o nti n u e t he st u d y at a n y ti m e, f or a n y reas o n, a n d wit h o ut prej u di ce t o 
f urt her tre at m e nt. T he I n v esti gat or ma y r e m o ve a patie nt  if, i n t he I n v esti gat or’s j u d g me nt, 
c onti n ue d p arti ci pati o n w o ul d p ose u nac ce pt a ble ris k t o t he patie nt  or t o t h e i nt e grit y of t he st u d y 
data. S o me st u d y s pe cifi c disc o nti n uati o n crit eria will als o a p pl y t o st u d y partici p a nts  recei vi n g 
te na pa n or or place b o: 
•  H y p o p h os p h ate mi a:  Ser u m p h os p h or us  ≤ 2. 5 m g/ d L at a n y ti m e. 
•  H y per p h os p h ate mi a:   
o  Ser u m p h os p h or us  ≥ 1 0 . 0 m g/ d L a n y ti m e aft er Wee k 2 of t he 2 6 -wee k tr eat m e nt 
peri o d  
o  Ser u m p h os p h or us ≥ 9 m g/ d L f or t w o c o nse c uti v e visits  after W ee k 2  d uri n g t he 
2 6 -wee k treat me nt or safet y e xte nsi o n peri o d  
o  Ser u m p h os p h or us ≥ 9  m g/ d L d uri n g t he ra n d o miz e d wit h dra wal p eri o d  
Patie nt s disc o nti n ue d fr o m t he r a n d o mi ze d wit h dra w al peri o d will be off ere d t he o p p ort u nit y t o 
e nter t h e o pe n -l a bel safet y assess me nt peri o d or be disc o nti n ue d fr o m t he st u d y a n d ret ur n t o 
sta n dar d of care. 
Patie nts i n t he a cti v e c o ntr ol gr o u p, recei vi n g se vela mer car b o n ate d o n ot ha ve s pecific 
disc o nti n uati o n criteria; t he y will be tre ate d b ase d o n sta n dar d of care usi n g t he pa c ka ge i nsert 
f or g ui da nce.  
A patie nt  w h o  disc o nti n ues will al wa y s be as ke d a b o ut t he re as o n(s) f or disc o nti n uati o n a n d t h e 
prese nce of a n y A Es. T he I n v esti gat or will r ec or d t h e reas o n f or earl y wit h dra wal i n t he e C R F.  
If a pati e nt  disc o nti n ues t h e st u d y, all visit pr oc e d ures f or Visit 2 3  will be c o m plete d, if p ossi bl e . 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 2  of 6 6  
5. 5   
E arl y Ter mi n ati o n of St u d y  
T he st u d y ma y b e ter mi nate d at a n y ti me b y t h e S p o ns or  f or reas o ns i ncl u di n g b ut n ot li mit e d t o 
t he f oll o wi n g (i) if seri o us si de effects oc c ur, (ii) if t he I n vesti gat or d oes n ot a d h ere t o t h e 
pr ot oc ol, (iii) if, i n t he S p o ns or ’s j u d g me nt, t her e are n o f urt her be nefits t o be a c hie v e d fr o m t h e 
st u d y, or (i v) f or a d mi nistrati ve reas o ns. I n t he e ve nt t hat t h e cli nic al de vel o p me nt of t he 
i n vesti gati o nal pr o d uct is disc o nti n u e d, Ar del y x, I nc. s hall i nf or m all I n v esti gat ors / i nstit utio ns 
a n d I R Bs o verseei n g t h e tri al.  
5. 6   
Restricti o ns t o P atie nt s 
•  F or males a n d fertil e fe males :  A d here n ce t o t he pre c a uti o ns ai mi n g at a v oi di n g a pre g na n c y, 
i ncl u di n g mal es n ot d o nati n g s per m, a n d t heref ore us e of c o ntra ce pti ve met h o ds as o utli n e d 
i n t he I ncl usi o n criteri a (Secti o n  5. 1 ). 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 3  of 6 6  
6   
T R E A T M E N T O F P A TI E N T S  
6. 1   
A d mi nistr ati o n of I n vesti g ati o n al Pr o d uct  
6. 1. 1   
I de ntit y of I n v esti gati o nal Pr o d uct(s) 
6. 1. 1. 1   
St u d y dr u g  
Te na pa n or  h y dr o c hl ori de  is a n a m or p h o us, off-w hit e t o w hite p o w der.
 
  
   
A matc hi n g plac e b o will b e i de nticall y s u p pli e d i n H D P E b ottles.  
6. 1. 1. 2   
Acti ve c o ntr o l 
Se vela m er  car b o nate will be s u p pli e d, as c o m merciall y a vaila bl e.  Eac h b ottle  c o nt ai ns t w o-
h u n dre d se ve nt y  (2 7 0 ) 8 0 0 m g ta bl ets.  
6. 1. 2   
Treat me nts A d mi nistere d  
T a blets  c o ntai ni n g 1 0  m g of te na pa n or  or c orres p o n di n g plac e b o will b e ta k e n t wice d ail y P O 
j ust prior t o bre a kfast a n d di n ner .  O n dial ysis da ys, patie nt s o n H D  s h o ul d n ot  ta ke st u d y dr u g at 
t he me al pri or t o dial ysis a n d i nste a d ta ke it bef or e a n ot her me al. E ac h d ose of o ne t o t hree 
ta blets will a c hie v e t ot al dail y d oses of 2 0 , 4 0, or 6 0  m g te na p a n or.  If a me al is s ki p pe d, t he d ose 
s h o ul d be ta ke n wit h a n ot h er meal d uri n g t h e da y or at ar o u n d t h e ti me t h at t h e me al w o ul d ha ve 
bee n c o ns u me d.   
D uri n g t he ra n d o mize d wit h dra wal peri o d , patie nt s i n t he te n a pa n or gr o u p will be ra n d o mize d t o 
either r e mai n o n t heir c urre nt d ose of te na p a n or or s witc he d t o plac e b o i n a 1: 1 rati o.  
D uri n g t he safet y e xte nsi o n p eri o d, patie nt s will c o nti n ue wit h t h e sa me d ose fr o m t he e n d of t he 
2 6 -wee k  treat me nt peri o d. Titrati o n is all o we d as des cri be d f or t h e 2 6 -w ee k tre at m e nt peri o d.  
Patie nt s i n t he a cti v e c ontr ol  gr o u p will re cei v e se vel a mer c ar b o nate f or t he e ntire 5 2 we e k  st u d y 
peri o d . 
6. 1. 3   
D ose A dj ust me nts  
All pati e nt s i n t h e te n a pa n or gr o u p will start at a d os e of 3 0  m g bi d .  After r a n d o mi zati o n ( Visit 
5) t o Da y 1 8 3 ( Visit 13 ), d oses ca n be a dj uste d i n 1 0 m g i ncre me nts base d o n ser u m p h os p h or us 
le vels a n d/ or GI t oler a bilit y . D o w n -titrati o n c a n g o fr o m 3 0 m g bi d t o 2 0 m g bi d a n d 2 0 m g bi d 
t o 1 0 m g bi d. D ose escalati o n ca n g o fr o m 1 0 m g bi d t o 2 0 m g bi d , a n d 2 0 m g bi d t o 3 0 m g bi d.   
6. 1. 3. 1   
Disc o nti n uati o n criteri a  
See Secti o n 5. 4  P ati e nt Wit h dr a w al  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 4  of 6 6  
6. 1. 4   
Met h o d of Assi g ni n g Patie nt s t o Treat me nt Gr o u ps 
T he C R O or desi g nat e d statisticia n will pre pare t he r a n d o miz ati o n sc h e me i n acc or d a nce wit h its 
sta n dar d o perati n g pr oce d ures ( S O Ps) a n d t he ra n d o mizati o n pl a n, w hic h reflect G o o d Cli nic al 
Practic e ( G C P) sta n d ar ds.  
After o btai ni n g i nf or m e d c o nse nt, patie nt s will be all ocate d se q u e nti al e nr oll me nt n u m bers i n 
t heir or der of c o m pl eti n g Scre e ni n g  assess me nts.  
Patie nt s will be ra n d o miz e d after t he was h o ut peri o d 3: 1 t o rec ei ve te na pa n or or t he a cti v e 
c ontr ol , se vela m er car b o nate.  Patie nt s i n t he t e na pa n or gr o u p will be ra n d o miz e d a sec o n d ti me 
at t he e n d of t he 2 6 -wee k  treat me nt peri o d t o e nt er i nt o t he ra n d o miz e d wit h dra wal p eri o d  ( Visit 
1 3)  t o eit h er re m ai n o n t heir c urre nt d ose of te n a pa n or  or a mat c he d pl ace b o i n a 1: 1 rati o. 
Ra n d o miz ati o n c o des will b e assi g ne d via a n I nter acti ve Res p o nse Te c h n ol o g y  (I RT ). 
T he I R T will all ocate t he treat me nt a n d pr o vi d e t he r a n d o miz ati o n n u m ber f or b ot h t he 2 6-wee k 
treat me nt p eri o d a n d t he ra n d o mize d wit h dra wal p eri o d.  T he I R T will pr o vi de  t he a p pr o pri ate 
b ottle  I D c h ose n fr o m t h ose b ottle I Ds a vaila bl e at t h e st u d y site  f or t e na pa n or a n d plac e b o o nl y. 
T he ra n d o mizati o n is carrie d o ut at st u d y l e vel a n d t he assi g ne d ra n d o mizati o n n u m bers a n d t he 
ass ociate d b o ttl e I Ds will n ot be se q ue ntial wit hi n a st u d y site. T h e acti ve c o ntr ol will n ot ha v e 
u ni q ue b ottle I D #s.   
If a pati e nt wit h dr a ws fr o m participati o n i n t h e st u d y, t he n his/ her e nr oll me nt / ra n d o mizati o n 
c o de ca n n ot be re use d.  
6. 2   
I n vesti g ati o n al Pr o d uct St or a ge a n d Acc o u nt a bilit y 
6. 2. 1   
St ora ge C o n diti o ns  
T he I n vesti g at or will  e ns ure t hat all t he st u d y dr u g a n d acti v e c o ntr ol  are st ore d a n d dis pe nse d i n 
accor da n ce wit h F o o d a n d Dr u g A d mi nistr ati o n ( F D A) re g ulati o ns c o n cer ni n g t he st ora ge a n d 
a d mi nistr ati o n of i n vesti g ati o n al dr u gs.  
Ta blets of te na p a n or a n d pla ce b o s h o ul d be st or e d i n t he ori gi n al pa c ka gi n g a cc or di n g t o t he 
la beli n g. T he a cti ve c o ntr ol s h o ul d als o be st or e d i n t he ori gi nal pac k a gi n g ac c or di n g t o t he 
la beli n g. 
6. 2. 2   
Dr u g Acc o u nta bilit y  
T he I n vesti g at or m ust e ns ure t hat all dr u g s u p plies ar e ke pt i n a sec ure l oc ke d ar ea wit h acc ess 
li mite d t o t h ose a ut h orize d b y t he I n vesti g at or. T h e I n vesti gat or or t he I n vesti gat or’s desi g ne e 
m ust mai ntai n acc ur ate re c or ds of t he re cei pt of all st u d y dr u g a n d acti ve c o ntr ol s hi p pe d b y t h e 
S p o ns or  or its re prese ntati ve, i n cl u di n g b ut n ot li mit e d t o t he d ate r ecei v e d, l ot n u m ber, a m o u nt 
recei v e d, a n d t he dis p ositio n of all st u d y dr u g. C urre nt dis pe nsi n g rec or ds will als o be 
mai nt ai ne d i ncl u di n g t he d ate a n d a m o u nt of st u d y dr u g a n d acti ve c o ntr ol dis pe nse d a n d t he 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 5  of 6 6  
patie nt  rec ei vi n g t he dr u g. All re mai ni n g st u d y dr u g n ot re q uire d b y r e g ulati o ns t o be hel d b y t he 
clini cal f acilit y m ust be ret ur n e d t o S p o ns or  or its re prese ntati ve i m me diatel y aft er t he st u d y is 
c o m plete d  usi n g t h e st u d y dr u g ret ur n f or m pr o vi de d . 
6. 3   
P ac k a gi n g a n d L a beli n g  
6. 3. 1   
St u d y Dr u g  
 
T a blets of st u d y dr u g s h o ul d be st ore d i n t h e ori gi n al 
pac ka gi n g acc or di n g t o t he la beli n g . 
6. 3. 2   
Bli n di n g Met h o ds  
T he 2 6 -wee k tr eat m e nt peri o d a n d t h e safet y e xte nsi o n peri o d are o p e n la bele d peri o ds a n d st u d y 
dr u g will n ot be bli n de d.  
I n t he ra n d o mize d wit h dra wal peri o d, the treat me nt will be a d mi nist ere d i n a d o u ble -bli n d 
fas hi o n.  T he a cti v e a n d pla ce b o t a blets are i d e nti cal i n a p peara nce (s ha pe, c ol or, siz e, et c.). 
O nl y t he part y r es p o nsi ble f or l a beli n g, war e h o usi n g a n d s hi p pi n g dr u g s u p pl y, t he st u d y 
statisti cia n, r es p o nsi ble f or pre pari n g t he r a n d o mi zati o n list, a n d t he I R T ma na g er res p o nsi ble 
e ns uri n g dr u g is a vaila bl e at sites will ha v e k n o wle d ge of t he tr eat me nts assi g ne d d uri n g t he 
ra n d o miz e d wit h dra wal peri o d. 
T he a cti ve c ontr ol , se vela m er car b o n ate, will be a d mi nistere d as c o m m erciall y pa c ka ge d a n d 
use d f or  t he e ntire 5 2 -wee k  st u d y peri o d  f or patie nt s ra n d o miz e d i nt o t hat gr o u p. 
6. 4   
Pr oce d ure f o r Bre a ki n g R a n d o miz ati o n C o de  
6. 4. 1   
E mer ge n c y U n bli n di n g  
D uri n g t he c o urse of t h e ra n d o mi ze d wit h dr a wal peri o d, t he bli n d is t o be br o ke n o nl y w he n t he 
safet y of t he p ati e nt  is at ris k a n d kn o wle d ge of t he tr eat m e nt is esse ntial t o t he cli nical 
ma na ge me nt of t he patie nt . A de cisi o n t o u n bli n d a p atie nt  m ust be ma de i n c o ncert wit h t h e 
Me dical M o nit or  a n d t h e S p o ns o r, e xce pt i n a n e m er ge nc y sit uati o n w he n t h e bli n d m ust be 
br o ke n t o det er mi n e treat me nt f or t he p ati e nt . If a p atie nt  is u n bli n de d, t h e dat e a n d reas o n f or 
t he u n bli n di n g m ust be r ec or de d o n t he s o urce d oc u me nts. Please r efer t o Secti o n 7. 3. 6  f or 
re p orti n g re q uire m e nts.  
6. 5   
Pri or a n d C o nc o mit a nt T her a p y  
6. 5. 1   
Pri or T hera p y  
T his is a st u d y i n E S R D -H D  a n d E S R D -P D  patie nts wit h h y per p h os p hate mia . Patie nts wit h pri or 
t hera p y s pecifie d i n t he e x cl usi o n criteria (Secti o n  5. 2 ) will n ot be eli gi ble f or e ntr y i nt o t he 
st u d y. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 6  of 6 6  
6. 5. 2   
C o nc o mit a nt T h era p y  
T he use of c o nc o mit a nt me dicati o ns d uri n g t h e st u d y , u nless nee de d t o treat a n A E, s h o ul d be t h e 
sa me as t he me di cati o ns use d a n d rec or de d at scre e ni n g a n d d uri n g t he was h o ut  p eri o d.  
All pre vi o us me dicati o n ( prescri pti o n a n d o v er -t he-c o u nter), vit a mi n a n d mi n eral s u p ple me nts, 
a n d her bs ta ke n b y t he partici p a nt i n t he past 3 0 d a ys will be re c or de d i n t he me dical hist or y 
secti o n of t h e patie nt ’s eC R F a n d will i n cl u de start a n d st o p date,  d ose a n d r o ute of 
a d mi nistr ati o n, fr e q ue nc y , a n d i n dic ati o n. Me dicati o ns ta ke n f or a pr oce d ur e s h o ul d als o be 
i ncl u de d. 
6. 5. 2. 1   
Pr o hi bite d M e di cati o ns  
T he use of p h os p hate bi n ders ot her t h a n se vel a mer c ar b o nate use d i n t he acti v e c o ntr ol gr o u p are 
pr o hi bite d.  P h os p hat e bi n ders i n cl u de b ut are n ot li mite d t o t he f oll o wi n g: 
•  Se vela m er car b o nate a n d h y dr o c hl ori d e ( Re n vela ® , Re na gel® ) 
•  La nt ha n u m car b o n ate ( F osre n ol ® ) 
•  S ucr oferric o x y h y dr o xi d e ( Vel p h or o ® ) 
•  Ferri c citrat e ( A ur y xia ® ) 
•  Calci u m car b o n ate ( T u ms ® ) 
•  Calci u m ac etat e ( P h os L o ® ) 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 7  of 6 6  
7   
C O L L E C TI O N O F S T U D Y V A RI A B L E S  
7. 1   
Rec or di n g of D at a  
T he I n vesti g at or will e ns ure t hat dat a are r ec or de d i n t he el ectr o nic Case Re p ort F or m (e C R F) 
f or t his st u d y. T he I n vesti gat or e ns ures acc ura c y, c o m plet e ness, a n d ti meli ness of t he data 
rec or de d an d of t he pr o visi o n of a ns wers t o data q ueries.  T he I n vesti gat or will si g n t h e 
c o m plete d e C R F a n d a c o p y of t he c o m pl ete d e C R F will be ar c hi ve d.  
7. 2   
D at a C ollecti o n Pri or t o  E nr oll me nt  
D uri n g Scree ni n g  a n d t he W as h-o ut  Peri o d , e. g., after si g ni n g t he i nf or me d c o nse nt b ut pri or t o 
e nr oll m e nt, t h e f oll o wi n g i nf or mati o n will be c ollect e d fr o m e ver y p ote ntial patie nt  f or baseli ne 
de m o gra p hi cs as well as t o assess eac h pati e nt ’s s uit a bilit y t o partici pat e  i n t his st u d y pr ot oc ol: 
•  Asse ss me nt of t he disease stat us o utli n e d i n t h e i ncl usi o n/e xcl usi o n crit eria  
•  Date of birt h, g e n der,  a n d ra ce  
•  Wei g ht ( pr e-dial ysis) a n d hei g ht ( k g a n d c m, r es pecti vel y)  
•  Kt/ V  –  m ost rece nt val u e  pri or t o scre e ni n g  
•  K D Q o L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y)  
•  Me dical a n d s ur gical hist or y  
•  P h os p hate bi n der c urr e ntl y use d a n d d ose  
•  P h ysical e xa mi nati o n  
•  Vital si g ns  ( pre-di al ysis)  
•  Electr ocar di o gra m ( E C G) e v al uati o n  
•  Bl o o d sa m ple f or cli nical la b orat or y  c he mistr y a n d h e mat ol o g y  tests, a n d vir ol o g y l a b orat or y 
tests ( pre-dial ysis)  
•  F S H a n d pre g na nc y test, if a p pli ca ble  
•  Bl o o d sa m ple f or C a x P pr o d uct , F G F 2 3 a n d e x pl or at or y bi o m ar kers 
•  C o nc o mit a nt m e dic ati o ns  
7. 3   
S afet y V ari a bles  
Safet y assess me nts will b e perf or me d d uri n g  t he st u d y a n d will i n cl u de p h ysi cal e xa mi nati o n s, 
vital si g ns, b o d y wei g ht s, cli nical la b or at or y tests, el ectr oc ar di o gra ms, a n d a d verse e v e nt 
rec or di n g. B o d y wei g ht , vit al si g ns a n d bl o o d c oll ecti o ns f or la b orat or y assess me nts m ust  be 
perf o me d pre dial ysis.  All ot her assess me nts ma y b e perf o me d pre -, d uri n g, or p ost-dial ysis b ut 
s h o ul d be perf or me d at t h e sa me ti me at e ac h visit.  See Secti o n 8  (Met h o d ol o g y/ St u d y Visits ) 
f or a detaile d sc he d ule of pr oc e d ures.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 8  of 6 6  
7. 3. 1   
P h ysical E xa mi nati o n  
T he p h ysical e xa mi nati o n will i ncl u d e a n assess me nt of t he f oll o wi n g ite ms:  ge ner al 
a p peara n ce, s ki n (i ncl u di n g a n y pitti n g e de ma i n l o wer le gs / fe et), car di o vasc ul ar, res pirat or y, 
a b d o me n. A n y fi n di n gs or a bse n ce of fi n di n gs relati ve t o ea c h patie nt ’s ph ysical e xa mi nati o n 
will be c aref ull y d oc u me nte d i n t he patie nt ’s e C R F. 
7. 3. 2   
Vital Si g ns ( bl o o d p ress ure a n d h eart rate)  
Bl o o d press ure a n d heart rate will be o btai n e d at all patie nt  visits  ( pre-dial ysis) . Bl o o d pr ess ure , 
sitti n g s yst oli c a n d di ast oli c bl o o d press ure ( S S B P a n d S D B P) will be meas ure d after t h e pati e nt  
has bee n sitti n g f or a p pr o xi matel y  5  mi n utes . All  m e as ure me nts will be re c or de d o n t he s o urc e 
d oc u me nt a n d in t h e eC R F.  
7. 3. 3   
Electr ocar di o gra ms  
A 1 2 -lea d el ectr oc ar di o gra m ( E C G) will b e perf or m e d i n t he sitti n g or s u pi n e p ositi o n (f or at 
least 5 mi n utes). T h e  E C G m ust be tra ns mitte d t o t he ce ntral E C G site ( Me d p ace C ore La b) .  
T he f oll o wi n g E C G p ara m eters will b e rec or d e d:  he art rat e, P R -i nter v al, Q R S ( pri nci pal 
deflecti o n i n E C G) -d ur ati o n, Q T -i nter val (u nc orre cte d), Q Tc -i nter v al (c orre cte d), R R-i nter v al.  
T he I n vesti g at or will assess a n y a b n or maliti es u p o n recei vi n g a n e mail alert fr o m Me d pa ce C ore 
La b ; a b n or maliti es will be classifie d  as  cli nicall y si g nifica nt a n d n ot cli nicall y si g nifica nt. 
Electr ocar di o gra p hic i nter v als a n d I n vesti gat or assess me nt of all a b n or m al E C Gs will b e 
rec or de d o n t h e e C R F. 
A d diti o nal E C Gs m a y be o bt ai ne d if cli nicall y i n dicate d.   
7. 3. 4   
Cli nic al L a b orat or y Tests  
Sa m ple s m ust  be o btai n e d , pre-di al ysis,  f or t he cli ni cal l a b orat or y tests i de ntifie d i n Ta ble 7 -1 . A 
c oa g ulati o n pr ofile  will o nl y be perf or me d o n patie nt s ta ki n g warfari n .  
Ot her e val u ati o ns a n d tests perf or me d d uri n g Scree ni n g  a n d ot her ti m e p oi nts, s pecifie d i n t he 
Sc he d ule of E v e nts  (Secti o n 1. 3 ) will i ncl u de:  
•  Se r ol o g y scree n, i. e., H Bs A g, H C V, a n d HI V 
•  F S H test will b e perf or m e d o n all fe males at Scr ee ni n g  
•  Pre g na nc y test, if a p plica bl e  
7. 3. 5   
A nal ysis of Cli nic al L a b orat or y Tests  
A certifi e d la b orat or y will b e use d t o pr oc ess a n d pr o vi de res ults f or t h e cli nical la b or at or y t ests. 
T he baseli ne l a b orat or y t est res ults f or cli ni cal assess me nt f or a p arti c ular t est will b e defi n e d as 
t he last meas ure me nt pri or t o t he i nitial d ose of st u d y dr u g or acti v e c o ntr ol . 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L   
Pa ge 3 9  of 6 6  
F or a n y l a b orat or y test val ue o utsi de t he ref ere nc e ra n ge t hat t he I n vesti gat or c o nsi ders cli nicall y 
si g nifica nt, t he I n v esti gat or will:  
•  Re peat t he t est t o verif y t he o ut -of -r a n ge val ue. 
•  F oll o w t h e o ut -of -ra n g e val u e t o a satisfact or y cli nic al res ol uti o n.  
•  Rec or d as a n A E a n y la b orat or y test val ue t h at ( 1) is c o nfir me d a n d t he I n vesti gat or 
c o nsi ders cli nicall y si g nifica nt, or ( 2) t hat r e q uires a patie nt  t o be disc o nti n u e d fr o m t h e 
st u d y, or ( 3) t hat re q uires a patie nt  t o rec ei ve treat me nt, or ( 4) f ulfills o ne or m ore S A E 
criteria.  
 
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y 2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 0  of 6 6  
T a ble 7 -1   
Cli nic al L a b or at or y T ests  
He m at ol o g y a 
C he mistr y b 
C o a g ul ati o n Pr ofile c , d 
Ser ol o g y c 
Ot her e 
He mat ocrit  
He m o gl o bi n  
Re d bl o o d cell ( R B C) c o u nt 
W hite bl o o d cell ( W B C) c o u nt  
Ne utr o p hils ( %)  
L y m p h oc ytes ( %)  
M o n oc ytes ( %)  
Bas o p hils ( %)  
E osi n o p hils ( %)  
Platelet c o u nt  
Al b u mi n  
Ala ni ne a mi n otra nsa mi nase ( A L T)  
As partate a mi n otra nsa mi nase ( A S T)  Al kali ne 
p h os p hatase  
Bilir u bi n, t otal  
Bicar b o nate  
Bl o o d urea nitr o ge n ( B U N)  
Calci u m , t otal 
C hl ori de  
Creati ni ne  
Creati ne ki nase  
Gl uc ose  
Ma g nesi u m  
P h os p h or us fj 
P ota ssi u m 
Ca x P j 
S o di u m  
Pr ot hr o m bi n ti me  
Acti vate d partial 
t hr o m b o plasti n ti me 
He patitis B i nfecti o n  
He patitis C i nfecti o n  
H u ma n i m m u n o deficie nc y vir us 
F S H b g 
Ser u m  
pre g na nc y g  
F G F -2 3 c hj  
Parat h yr oi d 
H or m o ne ( P T H) c 
a  W h ole bl o o d.  
b  Ser u m.  
c  Plas ma .  
d  O nl y i n pe o ple treate d wit h Warfari n . 
e   N ot part of sta n dar d cli nical la b orat or y tests, m ust be s pecifie d; perf or me d at s pecifie d ti me p oi nts. 
f   Ser u m p h os p h or us  is als o perf or me d s e paratel y fr o m sta n dar d cli nical la b orat or y tests at pr ot oc ol s pecifie d ti me p oi nts. 
g  F S H a n d s er u m pre g na nc y tests are perf or me d o n all fe males  at Scree ni n g . After s cree ni n g, pre g na nc y tests  will o nl y be perf or me d o n fe males of c hil d -beari n g 
p ote ntial u nless F S H at s cree ni n g i n dicates p ost -me n o pa us al stat us.  
h  B ot h i ntact a n d c -ter mi n us F G F-2 3 will be meas ure d.  
j  Use d i n efficac y a nal yses  
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 1  of 6 6  
7. 3. 6   
A d verse E ve nts  
T he I n vesti g at or is res p o nsi bl e f or e ns uri n g t hat all staff i n v ol v e d i n t h e st u d y are fa miliar 
wit h t he c o nte nt of t his secti o n.  
A n A E is defi ne d as a n y u nt o war d me dic al oc c urre n ce i n a p ati e nt  a d mi nist ere d  a 
p har mac e uti cal pr o d uct d uri n g t h e c o urse of a cli nical i n vesti g ati o n. A n A E c a n t heref or e be 
a n y u nfa v ora bl e a n d u ni nte n de d si g n, s y m pt o m, or disease te m p orall y ass ociat e d wit h t h e use 
of a n i n vesti g ati o n al pr o d uct, w het her or n ot t h o u g ht t o be rel ate d t o t he i n vesti gati o nal 
pr o d uct.  
Patie nt s will be m o nit ore d t hr o u g h o ut t h e st u d y f or A Es, fr o m t he scree ni n g visit t hr o u g h t he 
o pe n la bel e xt e nsi o n  peri o d o n Da y 3 6 5 . All A Es s p o nta ne o usl y re p orte d b y t h e pati e nt  or 
re p orte d i n r es p o nse t o t he o pe n q u esti o n fr o m t he st u d y pers o n nel:  “ Ha v e y o u ha d a n y 
healt h pr o ble ms si nc e t he pre vi o us visit? ”, or re ve ale d b y o bser vati o n will be c olle cte d a n d 
rec or de d i n t he e C R F. W h e n c oll ecti n g A Es, t he re c or di n g of dia g n oses is preferre d ( w he n 
p ossi ble) t o rec or di n g a list of si g ns a n d s y m pt o ms. I n i nsta nces of well -rec o g ni ze d 
s y m pt o ms, t he y c a n be re c or de d as t he c o m m o nl y use d dia g n osis (e. g., fe v er, r u n n y n ose, a n d 
c o u g h ca n be r ec or de d as “fl u”). H o we ver, if a dia g n osis is k n o w n , b ut t here are ot her si g ns 
or s y m pt o ms t hat are n ot g e nerall y part of t he di a g n osis, t he dia g n osis a n d e ac h si g n or 
s y m pt o m s h o ul d be re c or de d se paratel y.  
A d verse e ve nts t hat are i d e ntifie d at t he last assess m e nt V isit 2 3  ( or t h e earl y ter mi nati o n 
visi t) as s pecifie d i n t he pr ot o c ol m ust b e rec or de d o n t he A E eC R F wit h t h e stat us of t h e A E 
n ote d, a n d t h e A E m ust be f oll o we d u ntil A E is res ol ve d or sta ble. All e ve nts t hat ar e 
o n g oi n g at t his ti m e will b e rec or d e d as o n g oi n g o n t he eC R F. T he pr oc e d ures s p ecifi e d i n 
Secti o n  7. 3. 6. 8  ar e t o be f oll o we d f or re p orti n g S A Es.  
7. 3. 6. 1   
A d verse E ve nts Ass ociate d wit h C ha n ge i n St o ol F or m a n d/ or Fre q ue n c y  
Base d o n te na p a n or’s a bilit y t o i n hi bit t he a bs or pti o n of dietar y s o di u m, it is k n o w n t o alt er 
st o ol f or m a n d fre q u e nc y i n s o m e pati e nt s.  F or a c ha n ge i n st o ol f or m a n d/ or fre q u e nc y t o be 
c o nsi dere d a n a d verse e ve nt t he p ati e nt  m ust c o nsi der t he b o wel m o v e me nts t o be 
“ b ot hers o me.”  
7. 3. 6. 2   
Rec or di n g A d verse E v e nts  
A d verse e ve nts are t o b e rec or d e d o n t he A E p a ge of t he eC R F. Se verit y will b e gra de d 
acc or di n g t o t he f oll o wi n g defi niti o ns:  
•  Mil d :  T he p ati e nt  e x p erie nc es a ware ness of s y m pt o ms b ut t hese ar e easil y t ol erate d or 
ma na ge d wit h o ut s pecific treat me nt  
•  M o derate :  T he patie nt  e x peri e nces disc o mf ort e n o u g h t o ca use i nterfere n ce wit h us ual 
acti vit y, a n d/ or t he c o n diti o n re q uires s pecific treat m e nt  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 2  of 6 6  
•  Se vere :  T h e patie nt  is i nca pa cit ate d wit h i na bilit y t o w or k or d o us ual acti vit y, a n d/ or t he 
e ve nt re q uires si g nifi ca nt tr eat me nt meas ures.  
Acti o n ta k e n will b e cate g oriz e d as d ose n ot c h a n ge d, d ose re d uce d, dr u g i nterr u pte d, dr u g 
wit h dra w n, re q uire d c o nc o mita nt  me di cati o n, re q uir e d c o nc o mita nt pr oce d ure a n d/ or ot h er.  
E ve nt o ut c o me at res ol uti o n or ti me of l ast f oll o w -u p will be re c or de d as n ot re c o vere d/ n ot 
res ol ve d, rec o v ere d/res ol v e d, rec o v ere d/r es ol ve d wit h se q uelae, r ec o veri n g/res ol vi n g, f atal or 
u n k n o w n.  
7. 3. 6. 3   
Assess me nt of A d verse E ve nts  
T he rel ati o ns hi p of t he e ve nt t o t h e st u d y dr u g or acti ve c o ntr ol s h o ul d b e det er mi ne d b y t he 
I n vesti gat or acc or di n g t o t he f oll o wi n g criteria:  
•  N ot relat e d:  T h e e ve nt is m ost li kel y pr o d uc e d b y ot her fact ors s uc h as t he p ati e n t’s 
cli ni cal c o n diti o n, i nt erc urre nt ill n ess, or c o nc o mita nt dr u gs, a n d d oes n ot f oll o w a k n o w n 
res p o nse patter n t o t he st u d y dr u g/acti ve c o ntr ol, or t he te m p or al relati o ns hi p of t he e v e nt 
t o st u d y dr u g/acti ve c o ntr ol a d mi nistrati o n ma kes a c a usal rel ati o n s hi p u nli kel y 
•  P ossi bl y relate d: T he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nc e fr o m t he ti m e of dr u g 
a d mi nistr ati o n, a n d is p ossi bl y d ue t o dr u g a d mi nistr ati o n a n d ca n n ot b e reas o na bl y 
e x plai n e d b y ot her f act ors s uc h as t he p ati e nt ’s cli nic al c o n diti o n, i nterc urre nt ill ness, or 
c o nc o mita nt dr u gs.  
•  R elat e d:  T h e e ve nt f oll o ws a reas o na ble t e m p oral se q ue nce fr o m t he ti me of dr u g 
a d mi nistr ati o n, a n d/ or f oll o ws a k n o w n res p o nse patt er n t o t he st u d y dr u g /acti ve c o ntr ol, 
a n d ca n n ot b e reas o na bl y e x plai ne d b y ot h er fact ors s uc h as t he patie nt ’s cli ni cal 
c o n diti o n, i nter c urre nt ill n ess, or c o nc o mit a nt dr u gs.  
7. 3. 6. 4   
F oll o wi n g A d verse E ve nts  
All ( b ot h seri o us a n d n o n -seri o us) A Es m ust be f oll o we d u ntil t h e y are r es ol ve d or sta biliz e d, 
or u ntil all atte m pts t o deter mi ne res o l uti o n of t he e v e nt are e x ha uste d. T h e I n vesti g at or 
s h o ul d use his/ her discreti o n i n or d eri n g a d diti o nal tests as necessar y t o m o nit or t he 
res ol uti o n of s uc h e v e nts. 
7. 3. 6. 5   
Disc o nti n uati o n d ue t o A d verse E ve nts  
A n y patie nt  w h o e x p erie nc es a n A E ma y b e wit h dra w n a t a n y ti me fr o m t he st u d y at t he 
discreti o n of t he I n vesti gat or. Patie nt s wit h dra w n fr o m t he st u d y d ue t o a n A E, w het h er 
seri o us or n o n-seri o us, m ust be f oll o we d b y t he I n vesti gat or u ntil t h e cli nic al o ut c o me of t h e 
A E is deter mi ne d. T h e A E(s) s h o ul d be n o te d o n t h e a p pr o priat e C R Fs a n d t he patie nt ’s 
pr o gress s h o ul d be f oll o we d u ntil t he A E is res ol ve d. A decisi o n t o disc o nti n ue a patie nt  d ue 
t o a n A E s h o ul d be disc usse d wit h t he Me di cal M o nit or. If t he A E m a y relate t o o v er d ose of 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 3  of 6 6  
st u d y treat me nt, t he I B sh o ul d be c o ns ulte d  f or details re gar di n g a n y s pecific a cti o ns t o b e 
ta ke n. 
7. 3. 6. 6   
Pre g na nc y  
Fe m ale p ati e nt s m ust be i nstr uct e d t o disc o nti n ue all st u d y dr u gs a n d i nf or m t he st u d y 
I n vesti gat or i m m e diatel y if t he y be c o me pr e g na nt d uri n g t he st u d y. 
T he I n vesti g at or m ust r e p ort a n y pre g n a nc y t o 
 wit hi n 1 b usi n ess 
da y of bec o mi n g a ware of it. T he p ati e nt  m ust b e i m me diatel y disc o nti n u e d fr o m f urt her 
treat me nt wit h st u d y dr u g. A n u nc o m plicate d pre g na nc y will n ot b e c o nsi der e d a n A E or 
S A E, b ut all pre g n a nci es will be f oll o we d t hr o u g h birt h.  
Pre g na ncies ar e ca pt ur e d if t h e y occ ur i n fe m ale p ati e nt s or i n t he se x u al part ners of mal e 
patie nt s fr o m t he ti m e t he p atie nt  is first e x pose d t o t he i n vesti g ati o n al pr o d uct u ntil 3 0  da ys 
after l ast e x p os ure t o t he i n vesti gati o nal pr o d u ct . 
A n y c o n ge nital a b n or m alities i n t he offs pri n g of a patie nt  w h o re cei v e d st u d y dr u g will be 
re p orte d as a n S A E. T h e o utc o m e of a n y pre g n a nc y a n d t he prese nce or a bse nc e of a n y 
c o n ge nit al a b n or malit y will be rec or d e d i n t h e s o urc e d oc u me ntati o n a n d re p ort e d t o  
 
7. 3. 6. 7   
Seri o us A d verse E ve nts  
A n S A E is a n y A E occ urri n g fr o m Scree ni n g  t hr o u g h fi nal st u d y visit ( Da y 3 6 5 ), at a n y d ose 
t hat res ults i n a n y of t h e f oll o wi n g o utc o m es: 
•  Deat h  
•  A life -t hre ate ni n g a d verse dr u g e x p erie n ce 
•  I npatie nt  h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitali zati o n  
•  A persiste nt or si g nifi ca nt disa bilit y/i nca pa cit y  
•  A c o n ge nital a n o m al y/ birt h defe ct  
I m p orta nt me di cal 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 pitali zati o n ma y b e c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate m e dical j u d g m e nt, 
t he y ma y je o par dize t h e patie nt  a n d ma y r e q uire me dical or s ur gi cal i nter ve nti o n t o pr e ve nt 
a n y of t he o ut c o mes liste d i n t his defi niti o n. E xa m pl es of s uc h me dic al e ve nts i ncl u d e 
aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e m er ge nc y r o o m or at h o m e, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i np ati e nt  h os pitalizati o n, or t h e de v el o p me nt of 
dr u g de pe n de nc y or dr u g a b use.  
N ote:  S A Es re q uire i m me diat e re p orti n g t o 
. See “ Re p orti n g Seri o us 
A d verse E ve nts” bel o w f or details.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 4  of 6 6  
7. 3. 6. 8   
Re p orti n g Seri o us A d verse E v e nts  
I n t he e ve nt of a n y S A E re p orte d or o bser v e d d uri n g t he st u d y, w het her or n ot attri b ut a ble t o 
t he st u d y dr u g, site p ers o n nel will re p ort it t o 
 wit hi n 2 4 h o urs of t he 
k n o wle d ge of t he o cc urre nc e.  
T o re p ort t h e S A E, c o m pl ete t he S A E f or m el ectr o ni call y i n t he ele ctr o nic d ata ca pt ur e 
( E D C) s yste m f or t he st u d y. W h e n t he f or m is c o m pl ete d, 
 p ers o n nel 
will be n otifie d ele ctr o nic all y a n d will r etri e ve t h e f or m. If t he e v e nt m eets seri o us criteri a 
a n d it is n ot p ossi bl e t o a ccess t he i nter net, se n d a n e mail t o 
 at 
 or call t h e 
 ( p h o ne n u m ber 
liste d bel o w), a n d fa x/ e mail t he c o m pl ete d p a per ba c k-u p S A E f or m t o   
 ( c o ntact 
i nf or mati o n list e d bel o w) wit hi n 2 4 h o urs of a ware n ess. W he n t he E D C s yste m b ec o m es 
a vail a ble, t he S A E i nf or mati o n m ust be e nt ere d wit hi n 2 4 h o urs of t he s yste m be c o mi n g 
a vail a ble. I n c o mi n g re p orts are re vie we d d uri n g n or mal b usi ness h o urs.  
Safet y C o nta ct I nf or m ati o n:  
 
 
 
 
 
T he I n vesti g at or is re q uire d t o s u b mit S A E re p orts t o t he I nstit uti o nal Re vi e w B o ar d 
(I R B)/I n de pe n de nt Et hics C o m mitt ee (I E C) i n acc or da nce wit h l ocal re q uire me nts. All 
i n vesti gat ors i n v ol ve d i n tri als usi n g t he sa me i n v esti gati o nal pr o d uct will re cei ve a n y safet y 
alert n otifi cati o ns f or o n war d s u b missi o n t o t heir l oc al I R B/I E C as re q u ire d. All re p orts se nt 
t o i n vesti g at ors will b e bli n d e d. 
F oll o w -U p Re p orts  
T he I n vesti g at or m ust c o nti n u e t o f oll o w t he patie nt  u ntil t h e S A E has res ol ve d or u ntil t h e 
c o n diti o n b ec o m es c hr o nic i n nat ure, st a bilizes (i n t h e case of persist e nt i m pair m e nt) o r t h e 
patie nt  dies.  
Wit hi n 2 4 h o urs of re cei pt of f oll o w -u p i nf or m ati o n, t he I n vesti g at or m ust u p d ate t he S A E 
f or m ele ctr o ni call y i n t he E D C s yste m f or t he st u d y a n d s u b mit a n y s u p p orti n g 
d oc u me nt ati o n ( e. g., patie nt  disc har ge s u m m ar y or a ut o ps y re p orts) t o 
 
 pers o n nel via fa x or e-mail. If it is n ot p ossi bl e t o ac cess t he E D C s yste m, ref er t o t h e 
pr oce d ures o utli ne d a b o ve f or i nitial r e p orti n g of S A Es.   


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 5  of 6 6  
7. 4   
Effic ac y V ari a bl e s 
Ser u m p h os p h or us  will be me as ure d at all st u d y visits. T he pri mar y effica c y vari a bl e will be 
t he c ha n g e i n s-P fr o m t he e n d of t he 2 6 -wee k treat m e nt peri o d  ( Visit 1 3) t o t h e e n d of t he 
ra n d o miz e d wit h dra wal peri o d or t h e e n d p oi nt visit f or t his peri o d. T h e pri m ar y effic ac y 
a nal ysis will b e base d o n t h e differe n ce bet wee n t h e te na pa n or tr eat me nt a n d pla ce b o 
treat me nt gr o u p i n t he res p o n der p o p ulati o n.  A res p o n der is a patie nt  t hat h a d a ser u m 
p h os p h or us decrease of ≥ 1. 2 m g/ d L fr o m e nr oll m e nt ( Da y 1) t o t he e n d of t he 2 6 -wee k 
treat me nt p eri o d ( Visit 1 3). 
T he f oll o wi n g are t h e sec o n dar y varia bl es: 
•  Patie nt s re ac hi n g ser u m p h os p h or us g oal le vels defi n e d as < 5. 5 m g/ d L  d uri n g t he 2 6 -
wee k treat me nt peri o d  
•  Ca x P pr o d uct  
•  i F G F 2 3 (i nta ct) a n d c F G F 2 3 (c -t er mi n us) 
•  Ki d ne y Disease a n d Q ualit y of Life s ur ve y ( K D Q OL ) 
o  Ki d ne y Disease a n d Q ualit y of Life ™ ( K D Q O L™-3 6) ( C o p yri g ht © 2 0 0 0 b y 
R A N D a n d t he U ni versit y of Ariz o na)  
•  Dial ysis S y m pt o m I n de x s ur ve y ( D SI) 
o  T he U ni versit y  of Pitts b ur g h Me dic al Ce nter, V A Pitts b ur g h Healt hc are 
S yste m ( Weis b or d et al. J Pai n S y m pt o m Ma na g e, 2 0 0 4: 2 7, 2 2 6 -4 0.)  
7. 5   
E x pl or at or y V ari a bles  
T he f oll o wi n g e x pl orat or y varia bles will b e c ollecte d at s pecifie d ti mes t o i n vesti g ate t h e 
relati o ns hi p wit h dr u g efficac y .  
•  E x pl orat or y bi o mar k er a nal yses ( p ot e nti all y i n f ut ure)  
Plas ma  a n d ser u m f or f ut ure e x pl or at or y rese arc h i nt o bi o mar kers relat e d t o t he car di o-r e nal 
disease are a a n d/ or relat e d t o t h e res p o nse (i.e. distri b uti o n, safet y, t oler a bilit y a n d effica c y) 
t o te na p a n or. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 6  of 6 6  
8   
M E T H O D O L O G Y/ S T U D Y VI SI T S  
8. 1   
Scree ni n g ( D a y -2 1), Visit 1   
At t he Scree ni n g  visit,  the I n vesti gat or will i nf or m e ac h pr os pecti ve patie nt  of t he nat ure of 
t he st u d y, e x pl ai n t h e p ote ntial ris ks, a n d o btai n writt e n i nf or me d c o nse nt fr o m t he patie nt  
pri or t o perf or mi n g a n y st u d y -relate d pr o ce d ures.  
Scree ni n g e v al uat i o ns will c o nsist of t he f oll o wi n g: 
•  I nf or me d c o nse nt ( ma y be c o m plete d da y(s) bef or e Scree ni n g  visit, if n ee de d)  
•  I ncl usi o n a n d e x cl usi o n criteri a (Secti o n  5 ) 
•  De m o gra p hics  
•  Hei g ht a n d wei g ht ( pre -dial ysis)  
•  M e dical /s ur gical hist or y  
•  P h os p ha te bi n der use d a n d d ose  
•  K D Q O L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y) 
•  Kt/ V ( m ost rece nt me as ure me nt pri or t o scre e ni n g) 
•  P h ysical e xa mi nati o n ( Secti o n  7. 3. 1 ) 
•  Vital si g ns  ( pre-di al ysis) (Secti o n 7. 3. 2 )  
•  E C G  e v al uati o n (Secti o n  7. 3. 3 ) 
•  Cli nic al l a b orat or y tests ( pre-dial ysis)  (Secti o n 7. 3. 4 ) 
o  Ser u m c he mistr y  
o  He mat ol o g y  
o  C oa g ulati o n pr ofil e (if a p plica ble)  
•  F S H test a n d ser u m pr e g na nc y test will be perf or m e d o n all fe mal es   
•  HI V, he patitis B a n d C tests   
• 
F G F -2 3 , Ca x P pr o d uct  a n d e x pl orat or y bi o mar k er sa m ple  (pre -di al ysis)  
•  Be gi n c ollecti n g a d v erse e ve nts  
•  Start was h o ut of p h os p hate bi n ders  
•  Pri or/c o nc urre nt me dicati o ns  
Patie nt s will be i nstr u cte d n ot t o c h a n ge a n y c o n c o mita nt me di cati o ns wit h o ut t h e a p pr o val 
of t he I n vesti g at or. T h e res ults of t he scr ee ni n g e val u ati o ns (a vaila ble at t hat ti m e) m ust m eet 
t he i ncl usi o n/e x cl usi o n criteria f or t he p ati e nt  t o c o nti n ue t o t h e was h -o ut  peri o d .  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 7  of 6 6  
Rescree ni n g will be all o we d f or s u bje cts w h o scree n fail at Visit 1 d ue t o ser u m p h os p h or us 
le vels o utsi d e of t he pr ot oc ol i ncl usi o n ra n g e ( < 4. 0 or > 8. 0 m g / d L) a n d b ase d o n t he crit eria 
i n Secti o n 5. 3 . 
8. 2   
W as h -o ut  Peri o d ( D a y s -1 4 , -7, a n d -1 ), Visit s 2 , 3 a n d 4  
T he  peri o d w hi c h patie nts are off bi n ders ca n last u p t o 4  wee ks . If at Visit 2 , 3 or 4   
( Da ys -1 4 , -7 or -1 ) a patie nt ’s ser u m p h os p h or us  is ≥ 6. 0  m g/ d L  a n d n ot m or e t ha n 1 0 . 0 
m g/ d L  a n d t here h as bee n a ≥ 1. 5  m g/ d L i ncre ase si n ce t he scr ee ni n g visi t ( Visit 1) t he y ca n 
pr ocee d t o Visit 5 f or e nr oll me nt ; ot her wise p ati e nt s s h o ul d pr ocee d t o t he ne xt visit.  At 
Visit  4 , if a patie nt ’s ser u m p h os p h or us  d oes n ot meet t he a b o v e i ncl usi o n criteria,  t he patie nt  
is scree n faile d. 
T he f oll o wi n g pr o ce d ures s h o ul d occ ur at was h o ut visits  
•  Re vie w of i ncl usi o n /e x cl usi o n criteri a  
•  C ha n ges t o m e dical/s ur gic al hist or y  
•  C ha n ges t o Pri or/c o n c urre nt me dic ati o ns  
•  Vital si g ns  ( pre-di al ysis)  
•  Ser u m p h os p h or us  ( pre-dial ysis)  
•  A d verse e ve nt  re p orti n g 
8. 3   
R a n d o miz ati o n (D a y 1 ), Visit 5  
•  C o nfir m eli gi bilit y b y r e vie wi n g incl usi o n /excl usi o n criteria  (Secti o n  5 ) 
•  B o d y wei g ht  ( pre-di al ysis)  
•  C ha n ges t o m e dical/s ur gic al hist or y  
•  P h ysical e xa m i nati o n 
•  V ital si g ns ( pre-di al ysis)  
•  E C G e v al uati o n  
•  Cli nic al l a b orat or y tests ( pre-dial ysis)  
•  Ser u m pre g na nc y test, if a p plic a ble  
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( pr e-dial ysis)  
•  Dis pe nse st u d y dr u g or acti v e c o ntr ol  
•  A d verse e ve nt re p orti n g  
•  Re vie w pri or/ c o nc urre nt me di cati o ns  
8. 4   
Tre at me nt Pe ri o d  ( D a ys 8  a n d 1 5  ±  5 ), Visits  6 a n d 7  
•  V ital si g ns ( pre-di al ysis)  
•  Ser u m p h os p h or us  ( pre-dial ysis)  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 8  of 6 6  
•  A d verse e ve nt re p orti n g 
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g or acti ve c o ntr ol ( Da y 8, Visit 6 o nl y) 
•  Dis pe nse st u d y dr u g ( Da y 8, Visit 6 o nl y), if a p plic a ble 
•  Re vie w c o nc urr e nt me dicati o ns  
8. 5   
Tre at me nt P e ri o d ( D a ys 2 9 ±  5 a n d 5 7  ±  7 ), Visits 8 a n d 9 
•  V ital si g ns ( pre-di al ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol , if a p plica ble 
•  Ser u m p h os p h or us  ( pre-dial ysis)  
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 6   
Tre at me nt Pe ri o d ( D a y 8 5  ±  7 ), Visit 1 0 
•  B o d y wei g ht  ( pre-di al ysis)  
•  K D Q O L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y) 
•  V ital si g ns ( pre-di al ysis)  
•  E C G e v al uati o n  
•  Cli nic al l a b orat or y tests  ( pre-dial ysis)  
•  Ser u m pre g na nc y test, if a p plic a ble  
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( pr e-dial ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol , if a p plica ble 
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 7   
Tre at me nt Pe ri o d ( D a ys 1 2 0 a n d 1 5 5  ±  7 ), Visits 1 1 a n d 1 2 
•  V ital si g ns ( pre-di al ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol , if a p plica ble 
•  Ser u m p h os p h or us  ( pre-dial ysis)  
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 4 9  of 6 6  
8. 8   
E n d of 2 6 -wee k T re at me nt P eri o d a n d st art of R a n d o mize d Wit h dr a w al 
Peri o d ( D a y 1 8 3 ±  7 ), Visit 1 3 
•  Ra n d o m iz ati o n  # 2  
•  B o d y wei g ht  ( pre-di al ysis)  
•  K D Q O L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y) 
•  P h ysical E xa mi nati o n  
•  V ital si g ns ( pre-di al ysis)  
•  E C G e v al uati o n  
•  Cli nic al l a b orat or y tests  ( pre-dial ysis)  
•  Ser u m pre g na nc y test, if a p plic a ble  
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( pr e-dial ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol, if a p plica ble 
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 9   
R a n d o mize d Wit h dr a w al Pe ri o d ( D a ys 1 9 7, 2 1 1, 2 2 5 , 2 3 9 a n d 2 5 3  ±  7 ), Visits 
1 4, 1 5, 1 6, 1 7 a n d 1 8  
S u bjects i n t he acti ve c o ntr ol gr o u p d o n ot h a ve Visits 1 4, 1 6 a n d 1 8.  
•  V ital si g ns ( pre-di al ysis)  
•  Ser u m p h os p h or us  ( pre-dial ysis)   
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( Da ys 2 1 1 a n d 2 3 9 ±  5 , Visits 
1 5 a n d 1 7 o nl y)  
•  Dis pe nse st u d y dr u g or acti v e c o ntr ol at Visits 1 5 a n d 1 7 o nl y , if a p plica ble 
•  Ret ur n/a cc o u nt a bi lit y of st u d y dr u g or acti ve c o ntr ol  
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 1 0   
E n d of R a n d o mize d Wit h dr a w al P eri o d a n d st art of S afet y E xte nsi o n Peri o d 
( D a y 2 6 7  ±  7 ), Visit 1 9  
•  B o d y wei g ht  ( pre-di al ysis)  
•  K D Q O L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y)  
•  P h ysical E xa mi nati o n  
•  V ital si g ns ( pre-di al ysis)  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 0  of 6 6  
•  E C G e v al uati o n  
•  Cli nic al l a b orat or y tests  ( pre-dial ysis)  
•  Ser u m pre g na nc y test, if a p plic a ble  
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( pr e-dial ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol , if a p plica ble 
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 1 1   
S afet y E xte nsi o n Peri o d ( D a ys 2 8 1 , 3 0 9, 3 3 7  ±  7 ), Visits 2 0, 2 1, 2 2  
•  Pre -dial ysis b o d y wei g ht  ( Da y 3 3 7, Visit 2 2 o nl y)  
•  V ital si g ns ( pre-di al ysis)  
•  Ser u m p h os p h or us  ( pre-dial ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  Dis pe nse st u d y dr u g  or acti v e c o ntr ol , if a p plica ble 
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 1 2   
E n d of St u d y  ( D a y 3 6 5  ±  7 ), Visit 2 3  
•  B o d y wei g ht  ( pre-di al ysis)  
•  K D Q O L  s ur ve y 
•  D SI  s ur ve y (f or E n glis h s pea kers o nl y) 
•  P h ysical E xa mi nati o n  
•  V ital si g ns ( pre-di al ysis)  
•  E C G e v al uati o n  
•  Cli nic al l a b orat or y tests  ( pre-dial ysis)  
•  Ser u m pre g na nc y test, if a p plic a ble  
•  F G F -2 3, Ca x P pr o d uct a n d e x pl orat or y bi o mar k er sa m ple  ( pr e-dial ysis)  
•  Ret ur n/a cc o u nt a bilit y of st u d y dr u g  or acti ve c o ntr ol  
•  A d verse e ve nt re p orti n g  
•  Re vie w c o nc urr e nt me dicati o ns  
8. 1 3   
U nsc he d ule d visits  
U nsc he d ule d visits , f or misse d sc he d ule d visits or safet y or t ol era bilit y  r elat e d reas o ns are 
all o we d.  Pr oce d ur es perf or me d ar e at t he discr eti o n of t he I n vesti g at or.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 1  of 6 6  
8. 1 4   
Wit h dr a w al P r oce d ures  
I n t he e ve nt of a patie nt ’s wit h dr a wal, t h e I n vesti g at or will ma k e e ver y eff ort t o c o m plete all 
assess me nts perf or me d at E n d -of -tre at m e nt visit o n Da y 3 6 5  ( Visit 2 3 ). Wit h dr a w n pati e nt s 
will be f oll o we d u ntil res ol uti o n of a n y A Es or u ntil t he u nres ol ve d A Es ar e j u d ge d b y t h e 
I n vesti gat or t o ha ve st a bilize d. 
F or t he wit h dra wal crit eria see Se cti o n  5. 4 . 
8. 1 5   
T ot al Bl o o d V ol u me Re q uire d f or St u d y  
T a ble 8 -1   
A p pr o xi m ate Bl o o d V ol u me per C o m plete d P atie nt  
Test  
N u m ber of 
S a m ples  
V ol u m e ( m L)   
T ot al ( m L)  
Ser ol o g y a n d F S H test (s er u m)  
1  
5  
5  
He mat ol o g y ( bl o o d)  
6  
3  
1 8  
C he mistr y (s er u m)  (i ncl u des s er u m pre g na nc y test) 
6  
7  
4 2  
P h os p h or us  / Calci u m (s er u m)#  
1 7  
7  
1 1 9  
P T H ( plas ma)  
8  
4  
3 2  
F G F -2 3  (plas ma ) 
8  
8  
6 4  
E x pl orat or y bi o mar ker s a m ple (s er u m  a n d plas ma)  
8  
1 3  
1 0 4  
T ot al  v ol u m e  
-- 
-- 
3 8 4  
#Se parate s a m ple is o nl y ta ke n at s pecifie d ti mes w he n n o c he mistr y s a m ple is ta ke n 
8. 1 6   
Pr ot oc ol De vi ati o ns  
Patie nt s m ust f ull y m eet t he f oll o wi n g criteria i n or d er t o e nr oll i n t h e st u d y. I n kee pi n g wit h 
re g ulat or y r e q uire me nts, Ar del y x  d oes n ot gr a nt pr ot oc ol wai vers t o i ncl usi o n/e xcl usi o n 
criteria.  
A pr ot oc ol de vi ati o n is defi ne d as a n y i nte nti o nal or u ni nte nti o nal c ha n ge t o, or 
n o nc o m pli a nce wit h, t he a p pr o ve d pr ot oc ol pr oce d ur es or re q uire m e nts. De viati o ns ma y 
res ult fr o m t h e acti o n or i na cti o n of t he patie nt , I n vesti gat or, or sit e staff. E x a m pl es of 
de viati o ns i ncl u d e, b ut ar e n ot li mite d t o : 
•  Fail ure t o a d here t o st u d y e xcl usi o n a n d i ncl usi o n criteria 
•  Fail ure t o c o m pl y wit h dis pe nsi n g or d osi n g re q uire me nts  
•  Misse d or o ut -of -wi n d o w visits  
•  Fail ure t o a d here t o test re q uire m e nts, i ncl u di n g vital si g ns, la b orat or y t ests, p h ysi cal 
e xa mi n ati o ns , m e dic al hist or y; eit her tests n ot d o n e, i nc orrect tests d o ne, or n ot d o ne 
wit hi n t he ti m e fra m e s pecifi e d i n t h e pr ot oc ol  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 2  of 6 6  
•  Pr oce d ural de viati o ns s uc h as i nc orrect st ora ge of st u d y dr u g, fail ure t o u p dat e t he I C F 
w he n ne w ris ks bec o me k n o w n, fail ur e t o o bt ai n I nstit uti o n al Re vie w B o ar d (I R B) 
a p pr o vals f or t he pr ot oc ol a n d I C F re visi o ns  
A  pr ocess f or defi ni n g a n d ha n dli n g pr ot oc ol de vi ati o ns will be esta blis he d. Pr ot oc ol 
de viati o ns t hat effect t he safet y of a patie nt  re q uires  i m me di ate n otifi cati o n of  t he Me di cal 
M o nit or  a n d S p o ns or . T he I n vesti g at or is res p o nsi bl e f or seei n g t hat a n y k n o w n pr ot oc ol 
de viati o ns are rec or d e d a n d ha n dle d as a gr ee d. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 3  of 6 6  
9   
S T A TI S TI C A L C O N SI D E R A TI O N S   
9. 1   
St atistic al A n al ysis  Pl a n  
A f or mal statistic al a n al ysis pla n ( S A P) is pr o vi de d s e parat el y. N o c ha n ges ar e e x pe cte d f or 
t he pri m ar y a n d sec o n dary a nal yses . If t h e la n g u a ge i n t his pr ot oc ol a n d t he la n g ua g e i n t he 
S A P differ, t he S A P g o ver ns. If a d diti o nal a nal yses are perf or me d or c h a n ges are ma de t o t he 
pla n ne d a n al yses after u n bli n di n g of t he st u d y data, s uc h de viati o ns will b e d oc u m e nte d i n 
t he cli nic al st u d y re p ort. 
9. 2   
Deter mi n ati o n of S a m ple Size  
A p pr o xi matel y fi ve h u n dr e d si xt y (5 6 0) male a n d f e male p ati e nt s wit h e n d st a ge re nal 
d isease ( E S R D) o n c hr o nic mai nte na nc e he m o dial ysis ( H D) 3 ti mes a wee k f or a mi ni m u m 
of 3 m o nt hs  or perit o n eal dial ysis ( P D) f or a mi ni m u m of 6 m o nt hs will b e e nr olle d i n t his 
st u d y. Patie nt s will be ra n do miz e d i n a 3: 1 rati o t o re cei ve eit h er te na p a n or ( ~ 4 2 0 patie nt s) or 
acti v e c o ntr ol ( ~ 1 4 0 pati e nt s). T h ose patie nt s i n t he t e na pa n or gr o u p will be ra n d o mize d at 
t he e n d of t h e 2 6 -wee k tre at me nt peri o d t o e nter i nt o t he r a n d o mize d wit h dra wal peri o d t o 
eit her r e mai n o n t heir c urre nt d ose of te na p a n or or pl ace b o i n a 1: 1 rati o.  
F or t he pri mar y effica c y a nal ysis, a sa m pl e size of 1 4 6  patie nt s (7 3  pati e nt s/ gr o u p) i n t he 1 2-
wee k ra n d o mi ze d wit h dra wal peri o d is e x pecte d t o pr o vi de m ore t ha n 9 5 % p o wer t o detect a 
differe nc e bet wee n te na p a n or a n d pl ace b o treat me nt i n t he c h a n ge i n ser u m p h os p h or us fr o m 
t he e n d of t h e 2 6 -wee k tre at m e nt peri o d t o t h e e n d of t he 1 2 -wee k ra n d o mize d wit h dra wal 
peri o d or t he e n d p oi nt visit f or t his peri o d, bet wee n t he te na p a n or treat me nt a n d pl ace b o. 
T his cal c ulati o n is base d o n  a t w o-sa m ple t-test wit h a t w o-si de d si g nifi ca nc e le vel of 
α = 0. 0 5, a n ass u me d tre at m e nt diff ere nc e of 1. 0 m g/ d L a n d a c o m m o n sta n d ar d de viati o n of 
1. 6 m g/ d L. T his sa m ple si ze ( 5 6 0 ) all o ws f or a 3 0 % dr o p o ut rate, mea ni n g 30 % of pati e nt s 
will n ot c o m plete t h e 2 6 -wee k tre at m e nt peri o d. T his sa m ple siz e als o ass u mes at least 5 0 % 
of patie nt s i n t he te na p a n or gr o u p will be c o nsi dere d res p o n ders i n t he 2 6 -wee k treat me nt 
peri o d, i.e., p ati e nt s w h o ac hie v es at l east a 1. 2 m g/ d L re d ucti o n f r o m baseli ne t o t he e n d of 
t he 2 6-wee k  tr eat me nt peri o d. 
9. 3   
A n al ysis Sets  
F o ur a nal ysis sets are defi ne d f or t his st u d y: safet y a nal ysis set, i nt e nt t o treat (I T T) a n al ysis 
set, effic ac y a nal ysis set a n d per-pr ot oc ol ( P P) a nal ysis set.  T hese a nal ysis sets will be 
deter mi ne d  f or ea c h st u d y peri o d se p arat el y (if a p pli ca ble). T he safet y a nal ysis set will be 
defi ne d base d o n all p atie nt s e nr oll e d i n t his st u d y. All ot her t hree a nal ysis sets will be 
defi ne d base d o n t h ose patie nt s w h o are ra n d o miz e d t o recei ve t e na pa n or i n t he 2 6 -wee k 
treat me nt p eri o d. 
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 4  of 6 6  
S afet y A n al ysis Set:  
All pati e nt s w h o recei ve at least o n e d ose of st u d y dr u g (te na pa n or or place b o) or acti ve 
c o ntr ol f or t h e i n di vi d ual st u d y p eri o d will  be i ncl u d e d i n t he saf et y a n al ysis set.  S uc h 
patie nt s will be a nal y ze d ac cor di n g t o t he tr eat me nt act uall y re cei ve d.  
I nte nt t o Tre at (I T T) A n al ysis Set: 
All pati e nt s w h o meet t he st u d y e ntr y i n cl usi o n/e x cl usi o n criteria, re cei ve at l east o ne d ose of 
te na pa n or or place b o , a n d ha ve at l east o ne p ost treat me nt ser u m p h os p h or us  assess me nt  f or 
t he i n di vi d ual st u d y p eri o d will be i n cl u de d i n t he I T T a nal ysis set. F or t h e 1 2 -wee k 
ra n d o miz e d wit h dra wal peri o d, patie nt s will be a nal y ze d ac c or di n g t o t he tre at m e nt gr o u p 
i nt o w hic h t h e y were ra n d o mize d.  T he I T T a nal ysis set will be us e d f or t he a n al ysis of all 
effica c y varia bles.  
Effic ac y A n al ysis Set:  
All pati e nt s w h o meet t he st u d y e ntr y i n cl usi o n a n d e xcl usi o n criteri a, recei ve at le ast o ne 
d ose of te na pa n or d uri n g t he 2 6-wee k treat me nt peri o d,  c o m plete t h e 2 6 -w ee k tre at m e nt 
peri o d,  a n d a c hie ve at l east a 1. 2 m g/ d L r e d ucti o n i n ser u m p h os p h or us fr o m baseli ne t o t he 
e n d of t he 2 6 -wee k treat me nt p eri o d will be i n cl u de d i n t he effica c y a nal ysis set. T he effica c y 
a nal ysis set will be use d  f or t h e pri mar y effic ac y a n al ysis . 
Per -P r ot oc ol A n al ysis Set:  
Al l pati e nt s i n t h e I T T a nal ysis set w h o c o m plet e t he 1 2 -wee k ra n d o mi ze d wit h dra wal peri o d 
as pla n ne d wit h n o maj or pr ot oc ol de viati o ns t hat i m pa ct t h e pri m ar y effic ac y varia bl e . T he 
p er-p r ot oc ol ( P P) a nal ysis set will b e use d f or se nsiti vit y a nal yses t o s u p p ort t he pri mar y a n d 
ke y sec o n dar y effi cac y a nal yses. Patie nt s i n t he P P a nal ysis set will b e det er mi n e d pri or t o 
t he dat a base l o c k or u n bli n di n g of t he st u d y data.  
9. 4   
St atistic al Met h o ds  
9. 4. 1   
Ge ner al A p pr oac h  
Descri pti ve st atistics i ncl u di n g t h e n u m ber of o bser v ati o ns, me a n, sta n dar d d e viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d f or c o nti n u o us vari a bles. Fre q ue nc y a n d 
perce nt a ge of patie nt s will be prese nte d f or c ate g oric al vari a bles. C o nti n u o us var ia bles will 
be a nal y ze d usi n g a nal ysis of varia n ce ( A N O V A) or a nal ysis of c o varia nce ( A N C O V A) . 
Cate g ori cal v aria bl es will be a nal y ze d usi n g a C o c hr a n -Ma ntel -Ha e nszel ( C M H) test or a 
Pears o n’s C hi -s q uare test. 
Safet y a nal yses will be p erf or me d o n all patie n ts e nr olle d i n t his st u d y, w hile effic ac y 
a nal yses will b e perf or me d o nl y o n t h ose  patie nt s w h o are ra n d o mize d t o recei ve t e na pa n or 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 5  of 6 6  
i n t he 2 6-wee k treat me nt p eri o d  (i. e., patie nt s tr eat e d wit h acti ve c o ntr ol will n ot be i ncl u de d 
i n a n y effi cac y a n al yses). 
9. 4. 2  Baseli ne Descri pti v e Statistics  
Baseli ne c haracteristics, i ncl u di n g de m o gra p hi cs, disease c hara cteristics, pri or/c o nc o mit a nt 
me dic ati o ns, a n d me di cal/s ur gical hist or y will b e s u m mari ze d b y tr eat me nt (i n cl u di n g d ose , 
if a p pli ca bl e) gr o u p a n d o verall f or e ac h a n al ysis set. T hese s u m maries will b e pr o vi de d f or 
eac h st u d y peri o d se parat el y. 
9. 4. 3   Pri mar y Effi cac y A nal ys is 
T he pri m ar y effic ac y varia bl e is t he c ha n ge i n s-P fr o m t he e n d of t he 2 6 -wee k treat me nt 
peri o d ( Visit 1 3) t o t he e n d of t he 1 2 -wee k ra n d o miz e d wit h dra wal p eri o d ( Visit 1 9) or t he 
e n d p oi nt visit f or t his peri o d. A n e n d p oi nt visit is defi ne d as t he last visit wit h a n s -P 
assess me nt d uri n g t he r a n d o mi ze d wit h dra wal peri o d. T he pri m ar y i nt erest of t his st u d y is t he 
differe nc e bet wee n t he t e na pa n or treat me nt a n d pla c e b o treat me nt gr o u p i n t h e mea n c ha n ge 
( w.r.t. t he pri m ar y effic ac y varia bl e) i n t h e res p o n der p o p ulati o n (t he efficac y a nal ysis set). A 
res p o n der is a patie nt  t hat ha d a ser u m p h os p h or us decrease of ≥ 1. 2 m g/ d L fr o m e nr oll me nt 
( Da y 1) t o t he e n d of t he 2 6 -wee k tr eat me nt p eri o d ( Visit 1 3). T he pri mar y efficac y v aria ble 
will be a n al yz e d usi n g a n A N C O V A m o del. T he m o del i ncl u des fi xe d  effects f or tr eat me nt, 
p o ole d i n vesti gat or site, a n d t he baseli ne s -P val ue as a c o nti n u o us c o v ariate. T he b aseli n e f or 
t his a nal ysis is defi ne d as t h e s-P val ue at t he e n d of 2 6 -wee k treat me nt peri o d. Wit hi n t he 
fra me w or k of t his m o d el, t h e differe n ce bet wee n t h e te na pa n or treat me nt a n d pla ce b o 
treat me nt i n t he mea n c h a n ge fr o m t he e n d of t he 2 6-wee k treat me nt peri o d t o t he e n d of t he 
1 2 -wee k ra n d o mi ze d wit h dra wal peri o d ( or t he e n d p oi nt visit f or t his peri o d) will be 
esti mate d. T h e c orres p o n di n g t w o -si ded 9 5 % CI a n d t he p -val u e f or t he treat me nt differe n ce 
will als o be pr ese nte d. St atistical si g nific a nce will be declar e d if t h e esti m ate d differe n ce 
bet wee n t h e te n a pa n or tre at m e nt a n d plac e b o tre at me nt i n t he mea n c ha n ge is ne gati v e (i.e., < 
0) a n d t he c or r es p o n di n g t w o-si de d p-val u e is ≤ 0. 0 5.   
9. 4. 4   
Sec o n dar y Effi cac y A nal yses  
9. 4. 4. 1   
Ke y Sec o n dar y Effic ac y A nal yses  
T he a nal ysis met h o d d escri be d f or t h e pri m ar y effi ca c y varia ble i n Se cti o n 9. 4. 3  will be 
perf or me d as f oll o ws:  
•  i n t he I T T a nal ysis set  
•  t o c o m par e t he i n di vi d u al d oses of te na p a n or a n d pl a ce b o i n t h e I T T a nal ysis set –  
fr o m hi g h d ose t o l o w d ose  
•  t o c o m par e t he i n di vi d u al d oses of te na p a n or a n d pl a ce b o i n t h e effi cacy a n al ysis 
set –  fr o m hi g h d ose t o l o w d ose 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 6  of 6 6  
A se q ue ntial testi n g pr o ce d ure will be use d t o c o ntr ol t he fa mil y -wise t y pe I err or rate 
ass ociate d wit h t he k e y sec o n dar y effica c y a nal yses. S pecific all y, t he pri mar y effi cac y 
a nal ysis will b e perf or m e d at t h e 5 % si g nifi ca nc e le v el. If statistic al si g nifica nc e is declare d 
f or t his a nal ysis, t h e n t he first ke y sec o n dar y effic ac y a nal ysis  list e d i n t his secti o n will be 
perf or me d at t he 5 % le vel. If st atistical si g nifi ca nc e is declare d f or t his a nal ysis, t he n t he n e xt 
ke y sec o n dar y effi cac y a nal ysis will be perf or me d at t he 5 % le v el. T his pr oce d ure c o nti n ues 
u ntil o ne of t he ke y se c o n dar y effi cac y a nal ysis i n t h e list res ults i n a p -val ue > 5 %. Statisti cal 
si g nifica n ce will be declare d f or se c o n dar y efficac y a nal yses u p t o t his p oi nt i n t he list.  
9. 4. 4. 2   
Ot her Sec o n dar y Efficac y A nal yses  
T he c ha n g e i n s -P fr o m baseli ne t o t h e e n d of 2 6 -we e k treat me nt peri o d will be a n al yz e d 
usi n g a n A N C O V A m o del wit h effects f or p o ole d i n vesti gat or site, a n d t he baseli ne s -P val ue 
as a c o nti n u o us c o v ariate.  T he L S -mea n of t he c h a n g e  will be pr ese nte d wit h t he 
c orres p o n di n g t w o -si de d 9 5 % CI a n d p-val ue .  
T he pr o p orti o n of p ati e nt s reac hi n g ser u m p h os p h or us g oal le vels of < 5. 5 m g/ dl at e ac h visit 
d uri n g t he 2 6 -wee k treat me nt p eri o d will be esti mate d wit h  as y m pt otic 9 5 % CI . 
A N C O V A will be perf or me d f or t he c ha n g e fr o m baseli ne at ea c h visit f or t he f oll o wi n g 
varia bl es:  
•  Ca x P pr o d uct  
•  i F G F 2 3 (i nta ct) a n d c F G F 2 3 (c-t er mi n us), b ot h o n a l o garit h mic sc ale 
•  Ki d ne y Disease Q ualit y of Life s ur ve y ( K D Q o L) 
•  Dial ysis S y m pt o m I n de x  s ur ve y ( D SI) 
T he A N C O V A m o del i ncl u des fi x e d effects f or treat me nt ( i n cl u di n g d ose , if a p plica ble) 
gr o u p, p o ole d i n vesti gat or site, a n d t he baseli ne val u e ( defi ne d f or t he i n di vi d ual st u d y 
peri o d) as a c o nti n u o us c o vari ate. S pe cifi call y,   
•  f or t he 2 6 -wee k tre at m e nt peri o d a n d safet y e xt e nsi o n peri o d, t he L S -mea n of t he 
c ha n ge will be prese nte d wit h t h e c orres p o n di n g t w o -si de d 9 5 % CI a n d p-val u e. F or 
i F G F 2 3 a n d c F G F 2 3, t h e bac k-tra nsf or me d p oi nt esti mate a n d  9 5 % CI will b e 
pr o vi de d.  
•  f or t he ra n d o mize d wit h dra wal peri o d, t he treat me nt gr o u p differe nce b et wee n 
te na pa n or a n d plac e b o i n t h e me a n c ha n g e will b e esti mate d wit h t he c orr es p o n di n g 
t w o-si de d 9 5 % CI a n d p-val u e. F or i F G F 2 3 a n d c F G F 2 3,  t he b ac k-tr a nsf or me d p oi nt 
esti mate a n d  9 5 % CI will be pr o vi de d.  
All sec o n dar y efficac y a nal yses descri be d i n t his sec ti o n will be d escri pti ve a n d n o 
m ulti plicit y a dj ust me nt will b e ma d e f or t hese a n al ys es.   


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 7  of 6 6  
9. 4. 5   
Pr oce d ures f or Ha n dli n g Missi n g Ser u m P h os p h or us Data  
I n t he c o m plet e d cli nical st u d y T E N-0 2 -2 0 1 ( wit h si milar st u d y d esi g n a n d pri mar y effi cac y 
varia bl e b ut diff ere nt tr eat me nt d ur ati o ns) c o n d u cte d b y Ar del y x, t he rate of missi n g s -P data 
was 6. 2 5 % ( 5/ 8 0) at b ot h wee k -2 a n d we e k -4 d uri n g t he 4 -wee k ra n d o mize d wit h dra wal 
peri o d. T he r ate of missi n g s -P data d uri n g t h e ra n d o mize d wit h dra wal p eri o d i n t he c urre nt 
st u d y is e x pect e d t o be i n t he si mil ar ra n ge f or t h e first 4 wee ks a n d hi g her t h a n 6. 2 5 % 
t hereafter (i.e., fr o m wee k-4 t o we e k -1 2, n o i n f or m ati o n a b o ut s uc h data fr o m lit erat ure or 
ot her si milar cli ni cal trials). Si nc e t he last o bser vati o n carrie d f or war d ( L O C F) met h o d 
(state d bel o w) will be use d f or t he pri m ar y effi cac y a nal ysis, t he missi n g s-P data d uri n g t h e 
ra n d o miz e d wit h dra wal peri od is e x p ect e d t o ha v e v er y li mite d i m pa ct o n t h e p o wer of t he 
a nal ysis f or t he c urre nt st u d y.  
A n e n d p oi nt visit f or t he pri mar y effi cac y a nal ysis is defi ne d as t h e last visit wit h a n s -P 
assess me nt d uri n g t he r a n d o mi ze d wit h dra wal peri o d, w hic h a m o u nts t o  i m p uti n g t he 
missi n g s -P data at Wee k -1 2 of t he ra n d o mize d wit h dra wal peri o d usi n g t he L O C F met h o d 
s uc h t hat e ac h patie nt’s s-P val ue at t h e e n d p oi nt visit re prese nts t h e patie nt’s last e x peri e nce 
w hile rec ei vi n g st u d y treat me nt. Ass u mi n g t hat m or e place b o p ati e nts will dr o p o ut earl y 
beca use of a lac k of effica c y d uri n g t h e ra n d o mize d wit h dra wal peri o d, a n d as s uc h, L O C F 
will te n d t o u n deresti mate t h e tr ue eff ect of t he dr u g relati ve t o place b o pr o vi di n g a 
c o nser vati v e esti mate of t he dr u g’s effe ct.  
T o s u p p ort t he pri mar y efficac y a nal ysis ( L O C F met h o d), a se nsiti vit y a nal ysis will be 
perf or me d usi n g a mi xe d -eff ects m o d el f or re p eat e d meas ures ( M M R M). S pecificall y, t h e 
de pe n de nt v aria ble f or t he M M R M m o del will be t he c ha n ge i n s-P fr o m t h e e n d of t he 2 6 -
w ee k treat me nt peri o d ( Visit 1 3) t o ea c h visit d uri n g t he 1 2 -wee k ra n d o mize d wit h dra wal 
peri o d , a n d t h e M M R M m o del i ncl u des fi xe d eff ects of treat me nt, p o ole d i n v esti gat or site , 
visit ( Visit 1 4 t hr o u g h Visit 1 9), tre at m e nt -b y -visit i nteracti o n, a n d t he base li ne s-P val ue as a 
c o nti n u o us c o variat e. T he baseli ne is defi ne d as t he s-P val ue at t he e n d of 2 6 -wee k treat me nt 
peri o d. T he c o varia n ce m atri x f or t he re p eat e d meas ures will be ass u me d t o be u nstr uct ure d. 
Wit hi n t he fra me w or k of t his m o del, t he differe n c e b et wee n t h e te n a pa n or tre at m e nt a n d 
place b o treat me nt i n t he mea n c ha n ge fr o m t he e n d of t he 2 6 -wee k tr eat m e nt peri o d t o w ee k-
1 2 of t he 1 2 -wee k ra n d o mize d wit h dra wal p eri o d will be esti mat e d. T he c orres p o n di n g t w o -
si de d 9 5 % CI a n d t he p-v al ue f or t h e tre at m e nt diff er e nce will als o be pr ese nte d.  
A n e n d p oi nt visit (t he L O C F met h o d)  will als o be us e d f or ot her efficac y a nal yses , if 
a p plic a ble. All ot her effica c y a nal yses will be p erf or me d base d o n t h e o bser ve d dat a.   
9. 4. 6   
Met h o ds of P o oli n g Data  
F or t he p ur p ose of a dj usti n g f or i n vesti g at or effe cts i n statisti cal m o dels, i n v esti gat or sites 
will be p o ol e d i nt o gr o u ps base d o n g e o gra p hic r e gi o n a n d n u m ber of patie nt s e nr olle d wit h 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 8  of 6 6  
a n ai m f or c o m para ble sa m ple siz es a m o n g p o ol e d i n vesti gat or sites. T he g o al of t h e p o oli n g 
strate g y will be t o a v oi d l ess t ha n a mi ni m u m n u m ber of patie nt s per p o ole d i n vesti gat or site.  
T he size of a p o ole d i n vesti gat or site w o ul d g e nerall y de pe n d o n t he e nr oll me nt si ze f or ea c h 
i n di vi d ual i n vesti gat or site. T h e p o ole d i n vesti gat or sites will b e use d i n all a p plic a ble 
a nal yses w here a dj ust me nt f or i n vesti g at or eff ect is desire d.  
9. 4. 7   
Visit Wi n d o ws  
N o a nal ysis visit wi n d o ws will be f or mall y defi n e d. T he sc he d ul e of e ve nts i n  Secti o n 1. 3  
details t he i nte n de d c oll ecti o n of st u d y v aria bles at s pecifi e d visits. S h o ul d a d diti o n al data be 
c olle cte d b et wee n sc he d ule d visits, t hese data will be i ncl u de d i n t he p ati e nt  data listi n gs b ut 
i g n ore d f or a nal yses p ur p oses, u nless t he a d diti o nal data is t h e last d ata c olle cte d d uri n g ea c h 
st u d y peri o d . 
9. 4. 8  Safet y A nal yses  
Safet y a nal yses i ncl u d e s u m mari es f or a d verse e v e nts, safet y la b orat or y tests, vital si g ns, 
b o d y wei g hts, 1 2 -lea d E C Gs, a n d p h ysi cal e xa mi n ati o ns. T hese s u m mari es will be pr o vi de d 
f or eac h st u d y peri o d se parat el y.  
A d verse e ve nts will b e c o de d usi n g t he Me dic al Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A). S u m mar y ta bles a n d listi n gs will be pr o vi de d b y s yste m or ga n class a n d 
preferre d ter m f or ea c h tre at m e nt (i n cl u di n g d ose , if a p plic a ble) gr o u p f or treat me nt -
e mer ge nt a d verse e v e nts ( T E A Es). Act u al val ues  a n d c ha n ge fr o m b aseli ne v al ues f or 
cli ni cal la b orat or y tests, vital si g ns, b o d y wei g hts, a n d E C Gs will b e s u m marize d b y 
treat me nt (i ncl u di n g d ose , if a p plica ble) gr o u p f or e a c h visit. T h e n u m ber a n d perce nta ge of 
patie nt s i n ea c h p h ysical e xa mi nati o n cate g or y will b e prese nte d b y treat me nt (i ncl u di n g  
d ose , if a p pli ca bl e) gr o u p f or eac h visit.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 5 9  of 6 6  
1 0  
A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
T he I n vesti g at or will pr o vi de direct acc ess t o s o urce data a n d d o c u me nts f or t he S p o ns or  or 
its desi g nee c o n d ucti n g st u d y -relate d m onit ori n g a n d/ or a u dits, I R B/ I n d e pe n de nt Et hics 
C o m mittee (I E C) re vi e w, a n d re g ulat or y re vi e w. T he p ur p ose of a n a u dit or i ns pecti o n is t o 
s yste mati call y a n d i n d e pe n de ntl y e xa mi ne all st u d y-r elat e d acti vities a n d d oc u me nts, t o 
deter mi ne w het h er t hese a cti v iti es were c o n d ucte d, a n d data were re c or de d, a n al yz e d, a n d 
acc uratel y re p orte d a cc or di n g t o t he pr ot oc ol, G C P ( G o o d Cli nical Practice), g ui deli nes of 
t he I nter n ati o n al C o nfere n ce o n Har m o nizati o n (I C H), a n d a n y a p plicati o n re g ul at or y 
re q uire m e nts. T he I n vesti gat or  will c o ntact t he S p o ns or i m me di atel y if c o ntacte d b y a 
re g ulat or y a ge nc y a b o ut a n i ns pe cti o n at a n y cli nical site . 
T he I n vesti g at or m ust i nf or m t h e st u d y patie nt  t h at his/ her st u d y-rel ate d r ec or ds ma y be 
re vie we d b y t h e a b o ve i n di vi d uals wit h o ut vi olati n g t he patie nt ’s pri v ac y of pers o nal h ealt h 
i nf or mati o n i n c o m pli a nce wit h re g ulati o ns of t he He alt h I ns ura nc e P orta bilit y a n d 
Acc o u nta bilit y Act of 1 9 9 6  ( HI P A A). 
A tte nti o n is dra w n t o t he r e g ulati o ns pr o m ul g ate d b y t he F D A u n der t h e Fr ee d o m of 
I nf or mati o n Act pr o vi di n g, i n part, t hat i nf or mati o n f ur nis he d t o cli nic al I n vesti gat ors a n d 
I R Bs will be ke pt c o nfi de ntial b y t he F D A o nl y if m ai ntai ne d i n c o nfi de nc e b y t he 
I n vesti gat or a n d I R B. B y si g ni n g t his pr ot oc ol, t he I n vesti gat or affir ms t o t he S p o ns or  t hat 
t he I n vesti g at or will mai ntai n, i n c o nfi d e nce, i nf or m ati o n f ur nis he d t o hi m or h er b y t he 
S p o ns or  a n d will di v ul ge s uc h i nf or mati o n t o t he I R B u n der a n a p pr o pri ate  u n derst a n di n g of 
c o nfi de ntialit y wit h s uc h b o ar d.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 0  of 6 6  
1 1  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T he S p o ns or or its desi g nee  will i m ple me nt a n d mai ntai n q ualit y c o ntr ol a n d q ualit y 
ass ura nce pr oce d ures wit h writte n S O Ps t o e ns ure t h e st u d y is c o n d uct e d a n d data ar e 
ge nerat e d, d oc u me nte d, a n d r e p orte d i n c o m plia n ce wit h t he pr ot o c ol, G C P, a n d a p pl ica ble 
re g ulat or y r e q uire me nts. 
1 1. 1   
C o n d uct of St u d y  
T his st u d y will be c o n d uct e d i n a cc or da nc e wit h t h e pr o visi o ns of t he Decl arati o n of Helsi n ki 
a n d all r e visi o ns t her e of ( T o k y o  2 0 0 4) , a n d i n acc or d a nce wit h t he F D A C o de of Fe d eral 
Re g ulati o ns ( 2 1 C F R Parts 1 1, 5 0, 5 4, 5 6, 3 1 2 ) a n d t he I nter nati o nal C o nfere nc e o n 
Har m o niz ati o n (I C H) G ui deli nes o n g o o d cli nical pr acti ce ( I C H E 6 R 2 ). S pecificall y, t his 
st u d y is base d o n a de q uatel y p erf or me d l a b orat or y a n d a ni mal e x peri me ntati o n; t he st u d y 
will be c o n d u cte d u n d er a pr ot oc ol re vi e we d b y a n I R B or I E C; t he st u d y will be c o n d uct e d 
b y scie ntificall y a n d me dic all y q u alifie d pers o ns; t h e be nefits of t h e st u d y are i n pr o p orti o n t o 
t he ris ks; t he ri g hts a n d welf are of t he p ati e nt s will b e res pect e d; t h e p h ysicia ns c o n d u cti n g 
t he st u d y d o n ot fi n d t he ha zar ds t o o ut wei g h t he p ot e ntial be nefits; a n d eac h patie nt  will gi ve 
his or her writte n, i nf or me d c o nse nt bef ore a n y pr ot o c ol -dri ve n tests or e val uati o ns ar e 
perf or me d.  
T he I n vesti g at or m a y n ot de viate fr o m t he pr ot oc ol wit h o ut a f or m al pr ot o c ol a me n d me nt 
ha vi n g bee n esta blis he d a n d a p pr o ve d b y a n a p pr o pri ate I R B, e x ce pt w he n ne cessar y t o 
eli mi nat e i m me di ate ha zar ds t o t h e patie nt . A n y de vi at i o n m a y res ult i n t he p ati e nt  ha vi n g t o 
be wit h dra w n fr o m t h e st u d y, a n d m a y re n der t h at  patie nt  n o n -e val u a ble.  
1 1. 2   
Pr ot oc ol A me n d me nts  
O nl y t he S p o ns or  ma y m o dif y t he pr ot o c ol. All a me n d me nts t hat ha ve a n i m p act o n patie nt  
ris k or t he st u d y o bje cti v es, or re q uire re visi o n of t he I C F, m ust re cei v e a p pr o val fr o m t he 
I R B pri or t o t heir im ple m e ntati o n.  S h o ul d t h e pr ot oc ol c ha n ges be si g nific a nt i.e., w her e 
there ar e c ha n ges i n t he e xisti n g pr ot o c ol t h at si g nifi ca ntl y affect safet y of patie nt s, sc o pe of 
t he i n vesti gati o n, or scie ntifi c q ualit y of t he st u d y, t h e S p o ns or m ust s u b mit t he pr ot oc ol t o 
t he F D A pri or t o t he pr ot o c ol a me n d me nt bei n g i m pl e me nt e d.  
1 1. 3   
M o ni t ori n g of St u d y 
T he I n vesti g at or will per mit t h e site m o nit or t o r e vie w st u d y data as fre q ue ntl y as is dee me d 
necessar y t o e ns ure data ar e bei n g r ec or de d i n a n a de q uate m a n ner a n d pr ot oc ol a d h ere nc e is 
satisfact or y. 
T he I n vesti g at or will pr o vi de a ccess t o t h e s o urce d o c u me nts or pr o vi d e certifie d c o pies of 
t he me dical rec or ds f or t he m o nit or t o verif y eC R F e ntries. T he I n v esti gat or is e x pecte d t o 
c o o perat e wit h t h e S p o ns or / desi g nee i n e ns uri n g t he st ud y a d heres t o G C P re q uire me nts.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 1  of 6 6  
T he I n vesti g at or m a y n ot recr uit patie nt s i nt o t h e st u d y u ntil S p o ns or  or its desi g ne e has 
c o n d ucte d a det aile d r e vie w of t h e pr ot oc ol a n d eC R F  wit h t h e site st aff . Wit h a gree me nt of 
S p o ns or , atte n da nc e at a n I n vesti gat or me eti n g ma y f ulfill t his re q uir e me nt.  
1 1. 4   
E T HI C S  
1 1. 5   
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee A p pr o v al  
1 1. 5. 1   
Et hics Re vie w Pri or t o St u d y  
T he I n vesti g at or will e ns ure t hat t he pr ot oc ol a n d c o nse nt f or m are r e vie we d a n d a p pr o ve d b y 
t he a p pr o pri ate I R B pri or t o t he start of a n y st u d y pr oce d ures. T he I R B will be a p pr o priat el y 
c o nstit ut e d a n d will perf or m its f u ncti o ns i n acc or d a nce wit h F D A re g ulati o ns, I C H G C P 
g ui deli n es, a n d l oc al re q uire me nts as a p pli ca bl e.  
1 1. 5. 2   
Et hics Re vie w of ot her D oc u me nts  
I n a d diti o n, t he I R B will a p pr o ve all pr ot oc ol a me n d me nts (e xc e pt f or S p o ns or -a p pr o ve d 
l o gistic al or a d mi nistr ati v e c ha n ges), writte n i nf or me d c o nse nt d oc u m e nts a n d d oc u me nt 
u p dates, patie nt  r ecr uit me nt pr o ce d ures, writte n i nf or mati o n t o be pr o vi d e d t o t h e patie nt s, 
a vail a ble saf et y i nf or m ati o n, i nf or mati o n a b o ut pa y me nt a n d c o m p e nsati o n a vaila ble t o 
patie nt s, t he I n vesti gat or’s c urri c ul u m vita e a n d/ or ot her e vi de n ce of q ualific ati o ns, a n d a n y 
ot her d oc u m e nts re q uest e d b y t he I R B a n d r e g ulat or y a ut h orit y as a p pli ca bl e.  
1 1. 6   
Writte n I nf or me d C o nse nt  
T he nat ur e a n d p ur p ose of t he st u d y w ill be f ull y e x plai ne d t o ea c h patie nt  ( or t h e patie nt ’s 
le gall y res p o nsi ble g u ar dia n). T h e patie nt s m ust b e gi ve n a m ple ti me a n d o p p ort u nit y t o 
i n q uire a b o ut det ails of t h e trial, t o ha v e q uesti o ns a ns were d t o t heir satisfacti o n, a n d t o 
deci de w het her t o partici pat e. Writte n i nf or me d c o nse nt m ust be o btai n e d fr o m ea c h patie nt  
( or g uar dia n) pri or t o a n y stu d y pr oce d ur es bei n g perf or me d.  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 2  of 6 6  
1 2  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 2. 1   
D at a Re p orti n g a n d C ase Re p ort F or ms  
1 2. 1. 1   
Case Re p ort F or ms  
T he I n vesti g at or will be pr o vi de d wit h eC R Fs, a n d will e ns ure all d ata fr o m pati e nt  visits are 
pr o m ptl y e ntere d i nt o t h e eC R Fs i n ac c or da nce wit h t he s pecific i nstr u cti o ns gi v e n. T he 
I n vesti gat or m ust si g n t he eC R Fs t o v erif y t h e i nt e grit y of t he d ata r ec or de d. 
1 2. 1. 2   
La b orat or y Data  
A list of t he n or m al ra n g es f or all l a b orat or y tests t o be u n derta k e n f or ms part of t h e 
d oc u me nt ati o n t o be c ollate d pri or t o trial start. If a c e ntral la b orat or y has bee n sel ect e d t o 
c o n d uct a n y or all tests, it is esse ntial all sa m ples be a nal yz e d at t hat la b orat or y. T he 
I n vesti gat or m ust mai ntai n s o urce d oc u m e nts  s uc h as la b orat or y re p orts a n d c o m plete hist or y 
a n d p h ysical e xa mi nati o n re p orts.  
1 2. 1. 3   
Rete nti o n of S o urce D oc u m e nts  
T he I n vesti g at or m ust mai ntai n s o urce d o c u me nts s uc h as la b orat or y re p orts, x -ra ys, E C Gs, 
c o ns ultati o n re p orts, a n d c o m pl ete hist or y a n d p h ysi c al e x a mi n ati o n re p orts.  
1 2. 2   
Rete nti o n of Esse nti al D oc u me nts  
Esse ntial d o c u me nts s h o ul d be mai ntai ne d f or at least 1 1 years base d u p o n t h e S p o ns or’s 
re q uire m e nts a n d m a y be re q uir e d t o be mai ntai n e d l o n ger base d u p o n a p plica ble re gi o n al 
re g ulat or y r e q uire me nts. T he I n v esti gat or/i nstit uti o n s h o ul d ta ke m eas ures t o pre ve nt 
acci d e ntal or pre mat ure destr u cti o n of t hese d oc u me nts.  S h o ul d t he I n vesti g at or/i nstit uti o n 
n ot be a bl e t o m ai nt ai n t h e rec or ds f or t his peri o d of ti me, t he I n vesti gat or /i nstit uti o n m ust 
i nf or m t he S p o ns or i n writi n g, via certifie d mail, at l east 9 0 da ys pri or t o t he destr u cti o n of 
a n y st u d y d oc u me nts, s o t hat t h e S p o ns or has t he o pti o n, at t h e S p o ns or’s e x pe nse, t o ha ve 
t he rec or ds st ore d f or a l o n ger peri o d of ti me. It is t h e res p o nsi bilit y of S p o ns or t o i nf or m t h e 
I n vesti gat or/i nstit uti o n as t o w he n t hese d o c u me nts n o l o n ger nee d t o be retai ne d. 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 3  of 6 6  
1 3  
A D MI NI S T R A TI V E I N F O R M A TI O N  
 
 
 
 
 
 
 
 


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 4  of 6 6  
1 4  
R E F E R E N C E S  
A T S C o m mitt ee o n Pr oficie nc y St a n dar ds f or Cli nic al P ul m o nar y F u ncti o n L a b o rat ories. 
A T S state me nt: g ui d eli n es f or t he si x -mi n ute wal k test. A m J Res pir Crit Care Me d. 
2 0 0 2; 1 6 6: 1 1 1 – 1 1 7.  
Ca m pa nelli P C, Marti n E A, R ot h ge b J M. T he use of res p o n de nt a n d i nter vi e wer de briefi n g 
st u dies as a wa y t o st u d y res p o nse err or i n s ur ve y d at a. The Statisti cia n. 1 9 9 1; 4 0 :2 5 3 – 2 6 4.  
Ericss o n K A, Si m o n H A. Ver bal re p orts as da ta. Ps y c h ol o gic al Re vie w. 1 9 8 0;8 7 :2 1 5 – 2 5 0.  
Le wis SJ, Heat o n K W. St o ol f or m scale as a usef ul g ui de t o i ntesti n al tr a nsit ti me. Sc a n d  J 
Gastr oe nter ol. 1 9 9 7; 3 2 :9 2 0 – 9 2 4.  
Li n dsa y R M, Hei de n hei m P A, Nesralla h G, Gar g A X, S uri R.  Mi n u tes t o rec o ver y after a 
he m o dial ysis sessi o n:  a si m pl e healt h -relate d q u alit y of life q uesti o n t hat is relia bl e, vali d, 
a n d se nsiti ve t o c ha n g e . Cli n J A m S oc Ne p hr ol . 2 0 0 6; 1 :9 5 2 – 9 5 9 . 
Weis b or d S D, Frie d L F, Ar n ol d R M, R ot o n di AJ, Fi ne MJ, Le ve ns o n DJ, S witzer G E. 
De vel o p me nt of a s y m pt o m assess me nt i nstr u me nt f or c hr o nic he m o dial ysis pati e nts:  t h e 
dial ysis s y m pt o m i n de x . J Pai n S y m p Ma na g e. 2 0 0 4; 2 7 :2 2 6 – 2 4 0 . 
E k n o ya n G, La m eire N, Bars o u m R, Ec kar dt K U, Le vi n A, L e vi n N, L oc atelli F, Mac Le o d 
A, Va n h ol der R, Wal k er R, Wa n g H. T he b ur d e n of ki d ne y disease: i m pr o vi n g gl o bal 
o utc o m es. Ki d ne y I nt. 2 0 0 4; 6 6( 4): 1 3 1 0 – 1 3 1 4.  
Wa hee d A A, Pe draza F, L e nz O, Isa k o va T ( 2 0 1 3) P h os p hate c o nt r ol i n e n d-st a ge re nal 
disease: barriers a n d o p p ort u nities. Ne p hr ol o g y, Di al ysis, Tra ns pla ntati o n 2 0 1 3; 0: 1 -8.  
K DI G O, Cli nical Practice G ui deli ne f or t he Dia g n osis, E val uati o n, Pre ve nti o n, a n d 
Treat me nt of  C hr o nic Ki d ne y Disease -Mi n eral a n d B o ne Dis or der ( C K D -M B D). Ki d ne y 
I nter nati o nal 2 0 0 9; 7 6( S u p pl 1 1 3): S 1 -S 1 3 0  
d D O P P S A n n ual Re p ort of t he Dial ysis O utc o mes a n d Practic e Patt er ns St u d y: He m o di al ysis 
Data  1 9 9 9 -2 0 0 8. Ar b or Researc h C olla b orati ve f or Healt h, A n n Ar b or, MI. A vaila ble fr o m:  
htt p:// w w w. d o p ps. or g/a n n ualre p ort/arc hi v es/ D O P P S A R 2 0 1 0/i n de x. ht m  


Ar del y x, I nc.  
Pr ot oc ol N u m ber:  T E N -0 2 -3 0 1  
E diti o n N o. 4  
 
3 0 M a y  2 0 1 8  
C O N FI D E N TI A L  
Pa ge 6 5  of 6 6  
1 5  
SI G N A T U R E S  
1 5. 1   
I n vesti g at or Si g n at ure 
I a gree t o c o n d uct t he st u d y o utli ne d a b o v e ac c or di n g t o t he t er ms a n d c o n diti o ns of t h e 
pr ot oc ol, G C P g ui deli nes, a n d wit h a p pli ca bl e re g ulat or y re q uire me nts. All i nf or mati o n 
pertai ni n g t o t h e st u d y will b e tre ate d i n a c o nfi d e nti al ma n n er.  
 
 
 
I n vesti gat or’s Si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
I n vesti gat or's Pri nte d Na me 
 
I n vesti gati o nal Site or Na m e of I nstit uti o n  
 
 
 
Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _