A Double Blind Placebo Controlled Study to Evaluate the Effect of Bexagliflozin Tablets on Hemoglobin A1c in Patients With Type 2 Diabetes Mellitus and Moderate Renal Impairment
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Theracos

 
 
Cli ni c al Tri al Pr ot o c ol : T H R- 1 4 4 2- C- 4 4 8 
 
St u d y Title:  
A d o u ble bli n d place b o c o ntr olle d st u d y t o e val u ate t he effect of 
be x a glifl ozi n ta blets o n he m o gl o bi n A 1c i n p atie nts wit h t y pe 2 
dia betes mellit us a n d m o derate re nal i m pair me nt  
St u d y N u m ber:  
T H R -1 4 4 2 -C -4 4 8  
St u d y P h ase:  
3  
Pr o d uct N a me:  
Be x a glifl ozi n Ta blets  
I n dic ati o n: 
T y pe 2 Dia betes M ellit us  
I n vesti g at ors: 
M ulti -ce nter st u d y 
 
 
S p o ns or:  
T herac os S u b, L L C  
S p o ns or C o nt act:  
Tara T h ur ber  
Tra nslati o nal Me dici ne Gr o u p 
Massac h usetts Ge n eral H os pital  
1 8 5 Ca m bri d ge Street, B ost o n, M A 0 2 1 1 4 
P h o ne: 6 1 7- 6 4 3- 0 6 9 9 
Fa x: 6 1 7- 6 4 3- 8 2 0 3 
E- mail: tt h ur ber @cci b. m g h. har var d. e d u 
Me dic al M o nit or:  A n dre w Alle gretti , M. D., M. Sc 
De part me nt of Ne p hr ol o g y 
Massac h usetts Ge n eral H os pital  
1 6 5 Ca m bri d ge Street , S uite 3 2 0, B ost o n, M A 0 2 1 1 4 
P h o ne:  6 1 7- 7 2 4- 8 0 1 8 
Fa x:  6 1 7- 6 4 3- 8 2 0 3 
E- mail:  A A L L E G R E T TI @ P A R T N E R S. O R G   
 
 
Date  
Versi o n 4. 0:  
2 5 Oct o ber  2 0 1 6  
 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n i n t his d oc u me nt is c o nfi de ntial i nf or mati o n of T herac os S u b, L L C 
(“ T her ac os ”) a n d m ust n ot be discl ose d, use d, or c o pie d e x ce pt wit h pri or writte n a p pr o val 
fr o m T her ac os or t o t he e xte nt re q uire d b y a p plica ble l ocal, nati o nal or i nter nati o nal la ws, 
r ules a n d re g ul ati o ns. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 of 7 2  
V 4 ( Gl o bal)  
 
T A B L E O F C O N T E N T S  
S Y N O P SI S  ................................................................................................................................. 7 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  .......................................... 1 1 
1  
I N T R O D U C TI O N ........................................................................................................... 1 3 
1. 1  
Be x a glifl ozi n f or t he Treat me nt of T y pe 2 Dia b etes Mellit us  ............................... 1 4 
1. 1. 1  
S u m mar y of N o n- cli nical Data wit h Be x a glifl ozi n  ..................................... 1 4 
1. 1. 2  
S u m mar y of Cli nical Dat a wit h Be x a glifl ozi n ............................................. 1 4 
2  
S T U D Y O BJ E C TI V E S  .................................................................................................... 1 5 
2. 1  
Pri mar y O bj ecti ve  .................................................................................................. 1 5 
2. 2  
Ke y Sec o n dar y O bjecti ves ..................................................................................... 1 5  
2. 3  
Safet y O bjecti ves  ................................................................................................... 1 5 
2. 4  
Ot her O bjecti ve  ...................................................................................................... 1 5 
3  
I N V E S TI G A TI O N A L P L A N .......................................................................................... 1 6 
3. 1  
O verall St u d y Desi g n a n d Pla n  .............................................................................. 1 6 
3. 2  
Researc h M et h o ds a n d Pr oce d ures  ........................................................................ 1 6 
3. 2. 1  
Scree ni n g Peri o d  .......................................................................................... 1 6 
3. 2. 2  
R u n-i n Peri o d ............................................................................................... 1 6  
3. 2. 3  
Treat me nt Peri o d  .......................................................................................... 1 7 
3. 2. 4  
Gl yce mic C o ntr ol M o nit ori n g...................................................................... 1 8  
3. 2. 5  
O T H E R S A F E T Y M O NI T O RI N G A C TI VI TI E S  ...................................... 1 9 
3. 2. 5. 1  
Re nal F u ncti o n ................................................................................... 1 9  
3. 2. 5. 2  
Dia betic Ket o aci d osis  ........................................................................ 2 0 
3. 2. 5. 3  
Maj or A d vers e Car di o vasc ular E ve nt ( M A C E) ................................. 2 1  
3. 2. 5. 4  
Ot her Ge n eral Safet y M o nit ori n g  ...................................................... 2 1 
3. 2. 6  
D A T A A N D S A F E T Y M O NI T O RI N G B O A R D ( D S M B)  ........................ 2 2 
3. 3  
Rati o nale f or St u d y D esi g n a n d C o ntr ol Gr o u p ..................................................... 2 2  
3. 3. 1  
Rati o nale f or t he St u d y Desi g n  .................................................................... 2 2 
3. 3. 2  
Rati o nale f or t he St u d y P o p ulati o n .............................................................. 2 2  
3. 3. 3  
Rati o nale f or t he D os e Selecti o n .................................................................. 2 3 
3. 4  
St u d y D urati o n a n d Dates  ...................................................................................... 2 4 
4  
S T U D Y P O P U L A TI O N S E L E C TI O N  ........................................................................... 2 5 
4. 1  
St u d y P o p ulati o n .................................................................................................... 2 5  
4. 2  
I n cl usi o n Criteria ................................................................................................... 2 5 
4. 3  
E x cl usi o n Criteria  .................................................................................................. 2 5 
5  
S T U D Y T R E A T M E N T S  ................................................................................................. 2 7 
5. 1  
Descri pti o n of Tr eat me nts ...................................................................................... 2 7 
5. 2  
Treat me nts A d mi nistere d  ....................................................................................... 2 7 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 of 7 2  
V 4 ( Gl o bal)  
 
5. 2. 1  
I n v esti gati o nal Pr od uct ................................................................................ 2 7  
5. 2. 2  
Bac k gr o u n d Or al H y p o gl yce mic A ge nts ( O H As) ....................................... 2 7  
5. 2. 3  
Bac k gr o u n d I ns uli n T hera p y ........................................................................ 2 7  
5. 2. 4  
Resc ue Me dicati o ns f or H y p er gl yce mia  ...................................................... 2 7 
5. 3  
Selecti o n a n d Ti mi n g of D ose f or E ac h Patie nt ..................................................... 2 8  
5. 4  
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps.............................................. 2 9  
5. 5  
Bli n di n g.................................................................................................................. 2 9  
5. 6  
C o nc o mita nt T hera p y............................................................................................. 3 0  
5. 7  
Restricti o ns  ............................................................................................................ 3 0 
5. 7. 1  
Pri or T hera p y  ............................................................................................... 3 0 
5. 7. 2  
Fl ui d a n d F o o d I nta ke .................................................................................. 3 1  
5. 7. 3  
Patie nt Acti vit y Restricti o ns  ........................................................................ 3 1 
5. 8  
Treat me nt C o m plia nce  ........................................................................................... 3 1 
5. 9  
Pac ka gi n g a n d La b eli n g  ......................................................................................... 3 1 
5. 9. 1  
R u n- i n Kit .................................................................................................... 3 1 
5. 9. 2  
I n v esti gati o nal Pr o d uct Kit .......................................................................... 3 2 
5. 1 0  
St ora ge a n d A cc o u nta bilit y .................................................................................... 3 2  
5. 1 1  
I n v esti gati o nal Pr o d uct Rete nti o n at St u d y Site .................................................... 3 2 
6  
S T U D Y P R O C E D U R E S  ................................................................................................. 3 3 
6. 1  
P h o ne I nt er vie w  ..................................................................................................... 3 3 
6. 2  
I nf or me d C o nse nt................................................................................................... 3 3 
6. 3  
Scree ni n g f or I/ E Criteria  ....................................................................................... 3 3 
6. 4  
Me dical Hist or y  ..................................................................................................... 3 3 
6. 4. 1  
Ge ner al De m o gr a p hics a n d C haracteristics  ................................................. 3 3 
6. 4. 2  
Dia betes Hist or y ........................................................................................... 3 4 
6. 4. 3  
Re nal a n d Car di o vas c ular Disease Hist or y  .................................................. 3 4 
6. 4. 4  
Me dicati o n Hist or y  ...................................................................................... 3 4 
6. 5  
Diet a n d E x ercise C o u nseli n g  ................................................................................ 3 4 
6. 6  
P h ysical E x a mi nati o n ............................................................................................. 3 4 
6. 7  
A b bre viate d P h ysical E x a mi nati o n  ........................................................................ 3 5 
6. 8  
B o d y Wei g ht .......................................................................................................... 3 5  
6. 9  
Vital Si g ns  .............................................................................................................. 3 5 
6. 1 0  
Electr ocar di o gra p h y  ............................................................................................... 3 5 
6. 1 1  
Cli nical La b or at or y Tests  ....................................................................................... 3 6 
6. 1 1. 1  
Sa m ple C ollecti o n, St ora ge, a n d S hi p pi n g .................................................. 3 8  
6. 1 1. 1. 1  
He mat ol o g y, Bl o o d C he mistr y, Ser u m Li pi ds, a n d Gl yce mic 
C o ntr ol Assess me nts .......................................................................... 3 8  
6. 1 1. 1. 2  
Uri nal ysis  ........................................................................................... 3 8 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 of 7 2  
V 4 ( Gl o bal)  
 
6. 1 1. 1. 3  
Re nal f u ncti o n testi n g ........................................................................ 3 9  
6. 1 1. 1. 4  
P o p ulati o n P K Sa m pli n g .................................................................... 3 9  
6. 1 2  
Diar y a n d Gl u c o meter R ec or d Re vie w  .................................................................. 3 9 
6. 1 3  
Dis pe nsi n g R u n- i n Dr u g ........................................................................................ 4 0 
6. 1 4  
Ra n d o mizati o n ....................................................................................................... 4 0  
6. 1 5  
Dis pe nsi n g I n v esti gati o nal Pr o d uct ....................................................................... 4 0  
6. 1 6  
A d verse E v e nts Assess me nts  ................................................................................. 4 0 
6. 1 6. 1  
Defi niti o n of A d vers e E v e nts ....................................................................... 4 0 
6. 1 6. 2  
Eliciti n g a n d Re p orti n g A Es  ........................................................................ 4 2 
6. 1 6. 3  
I m me diat el y R e p orta ble A Es ....................................................................... 4 2 
6. 1 6. 4  
Pre g n a nc y  ..................................................................................................... 4 3 
6. 1 6. 5  
Pr oce d ure f or Brea ki n g t he Bli n d ................................................................ 4 4  
6. 1 6. 6  
F oll o w- u p of N o n- Seri o us A Es  ................................................................... 4 4 
6. 1 6. 7  
F oll o w- u p of P ost- St u d y S A Es  .................................................................... 4 4 
6. 1 6. 8  
Uri nar y Tr act I nfecti o ns ( U TIs)  ................................................................... 4 5 
6. 1 6. 9  
Ge nital M yc otic I nfecti o ns ( G MIs)  ............................................................. 4 5 
6. 1 6. 1 0  He pat ot o xicit y  .............................................................................................. 4 5 
6. 1 6. 1 1  H y p o gl yce mia  .............................................................................................. 4 6 
6. 1 6. 1 2  Maj or A d vers e Car di o vasc ular E ve nt ( M A C E) ........................................... 4 8  
6. 1 6. 1 3  Dia betic Ket o aci d osis ( D K A)  ...................................................................... 4 8 
6. 1 6. 1 4  Re nal fail ure e ve nts ...................................................................................... 4 9 
6. 1 6. 1 5  A m p utati o n  .................................................................................................. 4 9 
6. 1 7  
C o nc o mita nt Me dicati o n Assess me nts  .................................................................. 4 9 
6. 1 8  
Re m o val of Patie nts fr o m t he Trial or Disc o nti n u ati o n of I n vesti gati o nal 
Pr o d uct A d mi nistrati o n  .......................................................................................... 5 0 
6. 1 9  
A p pr o priate n ess of Meas ure me nts  ......................................................................... 5 0 
7  
S T U D Y A C TI VI TI E S ..................................................................................................... 5 1  
7. 1  
Scree ni n g ( 3 d a ys t o 3 w ee ks bef ore r u n -i n peri o d, Visit V 1)............................... 5 1 
7. 2  
Visit V 2 ( Start of R u n -i n) ...................................................................................... 5 1 
7. 3  
Visit V 3 ( Ra n d o mizati o n)  ...................................................................................... 5 1 
7. 4  
Visit V 4 ( wee k 2)  ................................................................................................... 5 2 
7. 5  
Visit V 5 ( wee k 6)  ................................................................................................... 5 2 
7. 6  
Visit V 6 ( wee k 1 2) ................................................................................................. 5 2  
7. 7  
Visit V 7 ( wee k 1 8) ................................................................................................. 5 2  
7. 8  
Visit V 8 ( wee k 2 4) ................................................................................................. 5 3  
7. 9  
Visit V 9 ( wee k 2 6) ................................................................................................. 5 3  
7. 1 0  
Earl y Ter mi nati o n Pr oce d ures ............................................................................... 5 3  
8  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  ................................................................. 5 4 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 of 7 2  
V 4 ( Gl o bal)  
 
9  
P L A N N E D S T A TI S TI C A L M E T H O D S  ........................................................................ 5 5 
9. 1  
Ge ner al C o nsi derati o ns .......................................................................................... 5 5  
9. 2  
Deter mi nati o n of Sa m ple Size  ............................................................................... 5 5 
9. 3  
A nal ysis P o p ulati o ns .............................................................................................. 5 6  
9. 3. 1  
I nte nti o n-t o-treat A n al ysis Set ..................................................................... 5 6 
9. 3. 2  
Safet y A nal ysis Set  ...................................................................................... 5 6 
9. 3. 3  
Per Pr ot oc ol A nal ysis Set ............................................................................. 5 6 
9. 4  
De m o gra p hics a n d Baseli ne C haract eristics  .......................................................... 5 6 
9. 5  
A nal ysis of Efficac y  ............................................................................................... 5 6 
9. 5. 1  
A nal ysis of Dr o p o uts Patter n ....................................................................... 5 7  
9. 6  
Sec o n dar y Effic ac y A nal ys es  ................................................................................ 5 7 
9. 7  
Ot her Effi cac y A nal yses  ........................................................................................ 5 8 
9. 8  
A nal ysis of Safet y  .................................................................................................. 5 8 
9. 8. 1  
A d verse E v e nts  ............................................................................................ 5 8 
9. 8. 2  
A d verse E v e nts of S peci al I nt erest  .............................................................. 5 9 
9. 8. 3  
Cli nical a n d La b orat or y E ve nts a n d A nal yses ............................................. 5 9  
9. 8. 4  
P h ysical E x a mi nati o n ................................................................................... 5 9 
9. 9  
I nteri m A nal ysis ..................................................................................................... 5 9 
1 0  A D MI NI S T R A TI V E C O N SI D E R A TI O N S  .................................................................... 6 0 
1 0. 1  
I n v esti gat ors a nd St u d y A d mi nistrati ve Str uct ure  ................................................. 6 0 
1 0. 2  
I nstit uti o nal Re vie w B oar d or I n de p e n de nt Et hics C o m mittee A p pr o val ............. 6 0 
1 0. 3  
Et hical C o n d uct of t he St u d y ................................................................................. 6 0  
1 0. 4  
S u bject I nf or mati o n a n d C o nse nt ........................................................................... 6 1 
1 0. 5  
S u bject C o nf i de ntialit y .......................................................................................... 6 1 
1 0. 6  
St u d y M o nit ori n g ................................................................................................... 6 1  
1 0. 7  
Case Re p ort F or ms a n d St u d y Rec or ds  ................................................................. 6 2 
1 0. 8  
Data a n d Saf et y M o nit ori n g B oar d ........................................................................ 6 2  
1 0. 9  
Pr ot oc ol Vi olati o ns/ De viati o ns  .............................................................................. 6 2 
1 0. 1 0  Access t o S o urce D oc u m e ntati o n  .......................................................................... 6 2 
1 0. 1 1  Rete nti o n of Data ................................................................................................... 6 3  
1 0. 1 2  P u blicati o n a n d Discl os ure P olic y ......................................................................... 6 3  
1 1  R E F E R E N C E LI S T  ......................................................................................................... 6 4 
 
LI S T O F I N -T E X T T A B L E S  
Ta ble  1. 
List of La b orat or y T ests  ............................................................................... 3 7 
Ta ble  2. 
K D O QI C K D  Sta ges  .................................................................................... 6 8 
Ta ble  3. 
Classificati o n/ Sta gi n g S yste m f or Ac ute Ki d ne y I nj ur y  .............................. 6 8 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 of 7 2  
V 4 ( Gl o bal)  
 
LI S T O F I N -T E X T FI G U R E S  
Fi g ure  1. 
Re nal F u ncti o n M o nit ori n g Pla n .................................................................. 2 0  
Fi g ure  2. 
Gl uc os uria i n patie nts wit h n or mal a n d i m paire d re nal f u ncti o n ................. 2 3  
 
LI S T O F A P P E N DI C E S  
A p pe n di x 1  
Sc he d ule of E ve nts ............................................................................. 6 6  
A p pe n di x 2  
Sc he d ule of La b orat or y Tests  ............................................................ 6 7 
A p pe n di x 3  
K D O QI C hr o nic Ki d ne y Disease Classificati o n a n d Ac ute 
Ki d ne y I nj ur y Sta ge D efi niti o n .................................................................................... 6 8  
A p pe n di x 4  
Esti mati n g G F R a n d C orrecti n g Calci u m  .......................................... 6 9 
A p pe n di x 5  
E x a m ples of S G L T 2 I n hi bit ors .......................................................... 7 0  
A p pe n di x 6  
S p o ns or Si g nat ures............................................................................. 7 1  
A p pe n di x 7  
I n v esti gat or’s Si g n at ure ..................................................................... 7 2 
 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 7 of 7 2  
V 4 ( Gl o bal)  
 
S Y N O P SI S 
S p o ns or : 
T herac os S u b, L L C  
N a me of Fi nis he d Pr o d uct:  
Be x a glifl ozi n Ta blets   
N a me of Acti ve I n gre die nt:  
B e x a glifl ozi n  
St u d y  Title : 
A d o u ble bli n d place b o c o ntr olle d st u d y t o e val u ate t he effect of b e x a glifl o zi n ta blets o n 
he m o gl o bi n A 1c i n p atie nts wit h t y p e 2 dia betes mellit us a n d m o derate re nal i m pair me nt   
St u d y N u m ber: T H R -1 4 4 2 -C -4 4 8  
St u d y P h ase:  3  
Pri m ar y O bjecti ve:   
T he pri mar y o bjecti ve of t his st u d y is t o deter mi ne t he efficac y of b e x a glifl ozi n o n l o weri n g 
H b A 1c i n patie nts wit h t y p e 2 di a betes mellit us a n d m o derate re nal i m pair me nt.  
Sec o n d ar y O bjecti ve s: 
T he ke y sec o n dar y efficac y o bj ecti ves are:  
• 
T o assess t he effect of be x a glifl ozi n o n t he c ha n ge i n b o d y wei g ht at w ee k 2 4 i n s u bj ects 
wit h baseli ne B MI ≥ 2 5 k g/ m 2 
• 
T o assess t he effect of be x a glifl ozi n o n t he c ha n ge i n s yst olic bl o o d press ure ( S B P) at 
wee k 2 4 i n s u bjects wit h baseli ne S B P ≥ 1 3 0 m m H g 
• 
C ha n ge i n H b A 1c i n s u bj ects wit h e G F R 4 5 t o 5 9 m L/ mi n/ 1. 7 3 m 2 at wee k 2 4 
• 
C ha n ge i n H b A 1c i n s u bj ects wit h e G F R 3 0 t o 4 4 m L/ mi n/ 1. 7 3 m 2 at wee k 2 4 
 
St u d y Desi g n : 
T H R - 1 4 4 2- C- 4 4 8 is a p h ase 3, m ulti-ce nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, 
parallel - gr o u p st u d y t o e val uate t he efficac y a n d s afet y of oral a d mi nistrati o n of be x a glifl ozi n  
ta blets, 2 0 m g c o m pare d t o place b o i n s u bjects wit h t y pe 2 dia b etes mellit us  ( T 2 D M), 
m o derate r e nal i m pair me nt, a n d i na de q uate gl yce mic c o ntr ol. 
Mai n eli gi bilit y criteria i ncl u de: 1) male or fe mal e s u bjects wit h T 2 D M , 2) scree ni n g H b A 1c 
of 7. 0- 1 0. 5 % (i ncl usi ve), a n d 3) esti mate d gl o mer ular filtrati o n rate (e G F R) base d o n ser u m 
creati ni ne at 2 differ e nt assess me nts ≥ 3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m 2. T he e G F R will be 
calc ulate d b y t he m o difi cati o n of diet i n re nal disease st u d y e q uati o n ( M D R D). At t he ti me of 
scree ni n g, t he d os es a n d fre q ue n c y of all a nti-di a b etic me dicati o ns m ust ha ve bee n sta ble f or 
8 wee ks.   
All eli gi ble s u bjects will c o nti n ue t heir pre -scree ni n g a nti-dia b etic me dicati o ns a n d start a 1-
wee k  place b o r u n-i n peri o d.  S u bjects w h o are c o m plia nt i n ta ki n g r u n-i n me dicati o n 
( missi n g n o m ore t ha n o n e d ose) will be eli gi ble f or ra n d o mizati o n a n d recei ve st u d y dr u g.  
A p pr o xi matel y 3 0 0 s u bj ects of 1 5 0 s u bjects per gr o u p will be ra n d o ml y assi g ne d t o recei v e 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 8 of 7 2  
V 4 ( Gl o bal)  
 
be x a glifl ozi n ta blets, 2 0 m g or place b o , i n e q u al rati o o nce dail y f or 2 4 wee ks i n a n 
o ut patie nt setti n g. Ra n d o mizati o n will be stratifie d b y scree ni n g H b A 1c le vel ( 7. 0 t o 8. 5 % or 
8. 6 t o 1 0. 5 %) , scree ni n g a nti-dia betic treat me nt re gi me n  (i ns uli n treat e d or ot her ) a n d 
scree ni n g e G F R ( 3 0  t o 4 4 m L/ mi n/ 1. 7 3 m 2 or 4 5 t o 5 9 m L/ mi n/ 1. 7 3 m 2). A mi ni mal of 1 3 5 
s u bjects m ust be i n t he e G F R 3 0 t o 4 4 m L/ mi n/ 1. 7 3 m 2 strat u m. 
S u bjects wit h h y per gl yce mia base d o n bl o o d gl u c ose le vels ma y recei ve a p pr o ve d a nti-
dia bet ic me dicati o n. I n a d diti o n, a dj ust me nt b y t h e i n vesti gat or t o t he pres cree ni n g a nti-
dia betic  t hera pi es will be rec o m me n de d if h y p o gl yce mia occ urs. 
St u d y s u bj ects will ha ve sc he d ule d visits at wee ks 2, 6, 1 2, 1 8, a n d 2 4 f or s afet y a n d efficac y 
e val uati o n. At wee ks 2 a n d 1 8, t he visit will be c o n d ucte d a p h o ne i nter vie ws u nless 
cli nicall y necessar y.  A fi nal f oll o w u p visit will be c o n d ucte d at wee k 2 6. 
Meas ure me nt of be x a glifl ozi n plas ma c o nce ntrati o n o ver ti me (s pars el y s a m pl e d) will als o 
be c o n d ucte d fr o m a p pr o xi matel y 1 4 4 st u d y s u bjects as part of a be x a glifl o zi n p o p ulati o n 
p har mac o ki netic ( P K) st u d y. 
St u d y P o p ul ati o n :  
T he st u d y p o p ulati o n will c o nsist of 3 0 0 s u bjects w h o ha ve bee n dia g n ose d wit h s u b-
o pti mall y c o ntr olle d T 2 D M wit h m o derate re n al i m pair m e nt. T he st u d y p o p ulati o n will 
c o m prise:  
 
1.  Me n or n o n- pr e g na nt w o me n ≥ 2 0 years of a ge.  W o me n of c hil d beari n g p ote ntial m ust 
a gree t o us e c o ntrace pti o n d uri n g t he e ntire st u d y t o a v oi d a n y p ossi ble pre g na n c y. 
Fe males w h o ar e s ur gicall y sterile ( h yst erect o m y, o o p h orect o m y) or p ost m e n o pa usal 
(a bse nce of me ns es greater t ha n 1 2 m o nt hs a n d a ge > 4 5 years) are eli gi ble if t he y test 
ne gati ve o n t he uri ne pre g na n c y test. 
2.  S u bjects wit h a dia g n osis of T 2 D M wit h a n H b A 1 c bet wee n 7. 0 a n d 1 0. 5 % (i ncl usi ve) at 
t he ti me of scree ni n g. 
3.  S u bjects w h o are tr eat me nt naï ve or are treate d wit h a sta ble re gi me n of a nti-dia betic 
me dicati o ns  t hat d o n ot pr o vi de a de q u ate gl yce mi c c o ntr ol w he n c o m bi ne d wit h diet a n d 
e x ercise.  At t he ti me of scree ni n g, t he d os es a n d fre q ue n c y of all a n ti-di a b etic 
me dicati o ns m ust ha ve b ee n sta ble f or 8 wee ks . 
4.  S u bjects w h o ha ve a n esti mate d gl o mer ul ar filtrati o n rate (e G F R) ≥ 3 0 a n d 
< 6 0 m L/ mi n/ 1. 7 3 m 2 at 2 ti me p oi nts: scree ni n g ( V 1), a n d 1 a d diti o nal ti me p oi nt 
bet wee n 1 a n d 1 2 m o nt hs of scree ni n g ( t he m ost rece nt hist orical val ue ma y be o btai ne d 
fr o m a vaila ble me dical r ec or ds). T h e e G F R will be calc ul ate d b y t he M D R D e q uati o n.  
5.  S u bjects w h o ha ve a b o d y mass i n de x ( B MI) ≤ 4 5 k g/ m 2 (i ncl usi ve) 
6.  S u bjects w h o ta ki n g sta ble d oses of me dicati o ns f or h y p erte nsi o n or h y p erli pi de mia f or at 
least 3 0 da ys pri or t o ra n d o mizati o n 
7.  S u bjects w h o ha ve sta ble e G F R bet w ee n t he m ost rece nt hist oric v al ue  a n d da y of 
scree ni n g ( n o m ore t ha n 2 0 % c ha n ge i n e G F R). 
 
Test Pr o d uct, D ose , a n d M o de of A d mi nistr ati o n:   
Be x a glifl ozi n ta blets, 2 0 m g  or place b o, o nce dail y b y m o ut h 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 9 of 7 2  
V 4 ( Gl o bal)  
 
D ur ati o n of Tre at me nt:   
2 5 wee ks: 1 wee k r u n-i n, 2 4 wee ks of treat me nt  
Effic ac y Assess me nts:  
Pri mar y efficac y assess me nt:  
• 
C ha n ge of H b A 1 c fr o m b aseli ne t o wee k 2 4  
 
Sec o n dar y efficac y ass ess me nts:  
• 
C ha n ge i n b o d y wei g ht i n s u bjects wit h baseli ne b o d y mass i n de x ( B MI) ≥2 5 k g/ m  
• 
C ha n ges i n s yst olic bl o o d press ure ( S B P) o ver ti me i n s u bjects wit h baseli ne S B P ≥1 3 0 
m m H g  
• 
C ha n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 4 5 t o 5 9 m L/ mi n/ 1. 7 3 m 2 
• 
C ha n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 3 0 t o 4 4 m L/ mi n/ 1. 7 3 m 2 
 
S a m ples f or p o p ulati o n P K a nal ysis will be c ollect e d a n d t he re q uire d plas ma c o nce ntrati o ns 
deter mi ne d.  T he P K p ar a meters will be ass esse d se parat el y as part of t h e p o p ulati o n P K 
a nal ysis.  
S af et y  Assess me nts :  
Safet y will be assesse d b ase d o n a n a n al ysis of t he a d vers e e v e nts rec or d ; of la b orat or y d ata, 
i ncl u di n g he mat ol o g y, ser u m c he mistr y, uri nal ysis, uri nar y electr ol yt es a n d creati ni ne; of 
electr ocar di o gr a m s ( E C Gs), vital si g ns a n d p h ysi cal e x a mi nati o ns ; a n d of c o nc o mita nt 
me dicati o n use.  
St atistic al Met h o ds:   
I n ge ner al, descri pti ve statistics will be prese nte d f or c o nti n u o us varia bl es, a n d fre q u e nc y a n d 
perce nt a ge f or cat e g orical varia bles.  
F or t he pri mar y o bjecti ves, efficac y is defi ne d as l o weri n g of H b A 1 c at w ee k 2 4 fr o m 
baseli ne f or b e x a glifl ozi n w he n c o m pare d t o place b o. F or t he pri mar y e n d p oi nt a nal ysis, t he 
pri mar y a nal ysis will utilize a mi x e d m o del re peate d meas ures ( M M R M) a nal ysis of 
c o varia n ce m o del ( A N C O V A) a p pr oac h, wit h treat me nt, visit, treat me nt - b y-visit i nteracti o n 
a n d ra n d o mizati o n stratifica ti o n fact ors as t he fi x e d effects ter ms a n d bas eli ne H b A 1c as a 
c o variate o n  all a vaila ble data, i nc or p orati n g all visits fr o m eac h patie nt at w hic h H b A 1c w as 
meas ure d i n t he i nte nti o n- t o-treat (I T T) a nal ysis set. All o bser ve d dat a will be a nal yz e d a n d 
data o btai ne d after r esc u e will n ot be e x cl u de d. I n a d diti o n, sa me a nal yses will be c o n d ucte d 
i n per-pr ot oc ol ( P P) a n al ysis set (if it is dee me d differe nt fr o m t he I T T a nal ysis set).  
T he M M R M m o del is o ne a p pr oac h t o o btai n treat me nt effect esti mates i n t he p rese n ce of 
missi n g data. As se nsiti vit y a n al ys es f or missi n g d ata, t he f oll o wi n g will be perf or me d f or t he 
I T T a nal ysis set: 
1.  Missi n g H b A 1c d ata will be i m p ute d via m ulti ple i m p utati o n, f oll o wi n g w hic h t he 
M M R M will be re peate d o n t he c o m plete datas ets wit h  res ults c o m bi ne d acr oss c o m plete 
datasets usi n g sta n d ar d MI tec h ni q ues; H b A 1 c v al ues c ollecte d after t he start of res c ue 
me dicati o n will n ot be e xcl u de d.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 0  of 7 2  
V 4 ( Gl o bal)  
 
2.  Missi n g H b A 1c d ata will be i m p ute d via last o bser vati o n carrie d f or war d (L O C F ), 
f oll o wi n g w hic h t he MM R M will be re peate d; H b A 1c val ues c ollecte d after t he start of 
resc ue m e dicati o n will be c o nsi dere d missi n g. 
3.  H b A 1c val ues c ollecte d after t he start of resc ue m e dicati o n will be c o nsi dere d missi n g, 
a n d t he M M R M a nal yses will be re -perf or me d.  
If t he P P a nalysis set is differe nt fr o m t he I T T a nal ysis set, t he sa me a nal ys es as descri be d 
a b o ve will be c o n d u cte d i n P P a nal ysis set as well.  
T he eff ects of b e x a glifl o zi n o n t he sec o n dar y e n d p oi nts will be teste d i n a hierarc hical testi n g 
strate g y t o preser ve e x peri me nt-wi de t y pe I err or at 0. 0 5:  
1.  S u peri orit y test of t he c h a n ge i n b o d y wei g ht i n s u bjects wit h baseli ne b o d y mass i n de x 
( B MI) ≥ 2 5 k g/ m2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
2.  S u peri orit y test of t he c h a n ge i n s yst olic bl o o d press ure ( S B P) o ver ti me i n s u bjects wit h 
S B P ≥ 1 3 0 m m H g i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
3.  S u peri orit y test of t he c h a n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 4 5 t o 5 9 
m L/ mi n/ 1. 7 3 m 2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
4.  S u peri orit y test of t he c h a n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 3 0 t o 4 4 
m L/ mi n/ 1. 7 3 m 2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
 
A d diti o nal effects of be x a glifl ozi n o n F P G, c ha n ges i n H b A 1c o ver ti me, pr o p orti o n of 
s u bjects w h o reac h a n H b A 1c < 7 %, c ha n ge i n b o d y w ei g ht o v er ti me, c ha n ge i n uri n e 
al b u mi n-t o-creati ni ne rati o (U A C R ) over ti me, a n d t he ge neral safet y of be x a glifl ozi n i n 
s u bjects wit h T 2 D M will be a nal yz e d. N o h y p ot hesis testi n g will be c o n d ucte d a n d will n ot 
be a dj uste d f or m ulti plicit y.  
F or t he pri mar y efficac y e n d p oi nt, sa m ple size calc ulati o n is base d o n a t w o-si de d 
si g nifica n ce at t he 5 % le vel. Ass u mi n g 1. 0 % as t he sta n dar d d e viati o n f or differe n ce i n mea n 
c ha n ges fr o m baseli ne i n H b A 1c bet w ee n be x a glifl ozi n a n d place b o, a n esti mate d sa m ple 
size of 1 3 3 i n eac h ar m will ha ve 9 0 % p o wer t o detect a differe nce i n mea n H b A 1c c ha n ges 
of 0. 4 0 % bet wee n be x a glifl ozi n a n d place b o. T o acc o u nt f or a n esti mate d dr o p o ut rate of 
1 2 %, we pr o p os e ra n d o mizi n g 1 5 0 s u bjects i n eac h st u d y a r m. 
Statistical a nal yses a n d s u m maries will be perf or me d usi n g S A S ®  s oft w are ( S A S I nstit ute, 
Car y, N C).  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 1  of 7 2  
V 4 ( Gl o bal)  
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
A C E  
a n gi ote nsi n -c o n verti n g e nz y m e  
A D A  
A merica n Di a betic Ass o ciati o n  
A E  
ad verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A L P  
al kali ne p h os p hatase  
A N C O V A  
a nal ysis of c o varia nce  
A N O V A  
anal ysis of varia n ce  
A S T  
as partate a mi n otra nsferas e  
A T C  
A nat o mic T hera pe utic C he mical  
B MI  
b o d y mass i n de x  
B U N  
b l o o d urea nitr o ge n  
C F R  
C o de of Fe d er al Re g ul ati o ns  
CI  
c o nfi de nce i nter val 
C K  
creati ni ne k i nas e 
C R F  
case r e p ort f or m 
C R O  
c o ntract r esearc h or ga nizati o n 
C V  
car di o vas c ular  
D P P 4  
di pe pti d yl pe pti dase 4  
D S M B  
Data a n d S af et y M o nit ori n g B oar d  
E C G  
electr ocar di o gra m  
e G F R  
esti mate d gl o mer ular filtrati o n rate  
F A S  
f ull a nal ysis set  
F P G  
fasti n g plas ma gl u c ose  
γ-G T P  
g a m ma -gl uta m yl tra nsferase  
G C P  
G o o d Cli nical Practice  
G L P -1  
gl uca g o n -li ke pe pti de-1  
h  
h o ur  
H b A 1c  
he m o gl o bi n A 1c  
H Bs A g  
he patitis B s urface a nti ge n  
H ct 
h e mat ocrit  
H C V  
he patitis C vir us  
H D P E  
hi g h de nsit y p ol yet h yl e n e  
H F  
heart f ail ure 
H g b  
h e m o gl o bi n  
HI P A A  
Healt h I nf or m ati o n P orta bilit y a n d Acc o u nta bilit y Act  
HI V  
h u ma n i m m u n o deficie nc y vir us 
I C5 0  
i n hi bit or y c o nce ntrati o n 5 0 % 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 2  of 7 2  
V 4 ( Gl o bal)  
 
I E C 
I n d e pe n de nt Et hics C o m mittee  
I N D 
I n v esti gati o nal Ne w Dr u g  
I R A E 
i m me diatel y r e p orta ble a d verse e v e nt 
I R B 
I nstit uti o nal R e vie w B oar d  
I T T 
Inte nt i o n-t o-treat 
I W R S 
Interacti ve We b Res p o nse  S yste m  
K D O QI  
Ki d ne y Disease O utc o mes Q ualif y I nitiati ve  
L C -M S/ M S  
li q ui d c hr o mat o gra p h y c o u ple d wit h ta n d em mass s pectr o metr y  
L D H  
lactic de h y dr o ge nase  
M A C E  
maj or a d vers e car di o vasc ular e ve nt  
M D R D  
m o dificati o n of diet i n re nal disease  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI  
m y ocar dial i nfarcti o n 
M O D Y  
m at urit y– o ns et dia b etes of t he y o u n g  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O H A  
oral h y p o gl yce mia a ge nt  
P D  
p har m aco d y n a mics  
P K  
p har m aco ki netics  
S A E  
seri o us a d vers e e v e nt  
S B P  
s yst olic bl o o d press ure  
S D  
sta n dar d de viati o n  
S G L T 2  
s o di u m gl uc ose c otra ns p orter 2  
S M B G  
self-m o nit ore d bl o o d gl uc ose  
S O P  
sta n dar d o per ati n g pr oce d ure  
T 2 D M  
T y pe 2 di a betes mellit us  
T E A E  
treat me nt e mer ge nt a d verse e ve nt  
TI A  
tra nsie nt isc he mic attac k 
U A C R  
u ri ne alb u mi n -t o-creati ni ne rati o 
U G E  
uri nar y gl uc ose e x creti o n  
U L N  
u p per li mit of n or mal 
U P T  
uri ne pre g n a nc y test  
U TI  
uri nar y tract i nfecti o n 
W O C B P  
w o ma n of c hil d  b eari n g p ote ntial  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 3  of 7 2  
V 4 ( Gl o bal)  
 
1 
I N T R O D U C TI O N 
T y pe 2 di a betes mellit us ( T 2 D M) is o ne of t he l ea di n g ca uses of m or bi dit y a n d m ortalit y 
w orl d wi de, affecti n g a n esti mate d 3 8 7 milli o n pe o ple i n 2 0 1 4 a n d reac hi n g e pi de mic 
pr o p orti o ns i n nearl y all c o u ntries i n t he w orl d.  A p pr o xi matel y 1 7 9 milli o n of t h ose affecte d 
are esti mate d t o b e  u na w are of t h eir c o n diti o n a n d o ver 8 0 % resi de i n l o w- a n d mi d dle-
i nc o me c o u ntries (I nter n ati o nal Dia betes F o u n dati o n, 2 0 1 4).  T 2 D M acc o u nts f or at least 
9 0 % of all dia betes cases. Des pite t he a vaila bilit y of se veral classes of t hera pe utics, t he 
n u m ber of pe o ple wit h T 2 D M is pr ojecte d t o i ncrease b y 5 5 % t o o v er 5 9 0 milli o n a d ults b y 
2 0 3 5. 
C hr o nic gl yce mic c o ntr ol is necessar y t o pre ve nt t he micr o vasc ul ar c o m pli cati o ns of T 2 D M, 
i ncl u di n g ne p hr o p at h y. U p t o o ne-t hir d of patie nts wit h T 2 D M ha ve re n al i m pair me nt (C oll-
de- T uer o et al., 2 0 1 2 ). W hile t he pr o gressi ve n at ure of T 2 D ulti matel y re q uires m ost patie nts 
wit h T 2 D M t o re q uire m ulti ple t hera pies t o mai ntai n n or mal gl u c ose le v els (I nz ucc hi et al., 
2 0 1 2 ; T ur ner et al., 1 9 9 9 ), ma n y of t hese t hera pies are restricte d i n t he c o nte xt of re nal 
i m pair me nt (I nz ucc hi et al., 2 0 1 2). I n a d diti o n, oral h y p o gl yce mic a ge nts ( O H As) c o m m o nl y 
use d, s uc h as s ulf o n yl ureas, are ass ociate d wit h i ncreas e d ris ks of h y p o gl yce mia a n d wei g ht 
gai n p artic ularl y i n patie nts wit h re nal i m pair me nt (Ca va na u g h, 2 0 0 7 ), (I n z ucc hi et al., 
2 0 1 2 ), (1 9 9 8a ). T h us, n o vel eff ecti ve t hera pies t h at ca n be us e d safel y i n p atie nts wit h T 2 D M 
a n d re nal i m pair m e nt are nee de d.  
T he re n al Na +/ gl uc os e tr a ns p ort pr otei n S G L T 2 acti vel y tra ns p orts e xtracell ular gl uc os e i nt o 
cells usi n g t he dri vi n g e n er g y of t he tra ns me m bra ne electr o c he mi cal p ote ntial f or s o di u m 
i o ns. I n di vi d uals wit h disr u pti o ns i n S L C 5 A 2, t he ge n e e n c o di n g S G L T 2, e x hi bit pr o mi ne nt 
gl uc os uri a i n t he a bse n ce of si g nifica nt c o- m or bi dities (Sa nter et al., 2 0 0 3 ; va n de n He u v el et 
al., 2 0 0 2).  T he e x creti o n of gl uc os e i n t he uri ne of dia betic s u bjects i n a m o u nts c o m para ble 
t o or gr eater t ha n t hat see n i n i n di vi d uals har b ori n g l oss of f u n cti o ns m utati o ns i n S L C 5 A 2 
has t he p ote ntial t o i m pr o ve b ot h fasti n g a n d p ost pra n dial h y per gl yce mia wit h o ut i ncreasi n g 
i ns uli n secreti o n, ca usi n g wei g ht gai n, or i n d uci n g h y p o gl yce mia.  Se veral S G L T 2 i n hi bit ors 
ha ve bee n a p pr o v e d as a si n gle a ge nt or i n c o m bi n ati o n wit h ot her h y p o gl yce mic a ge nts  f or 
t he treat me nt of p atie nts wit h T 2 D M (Vi via n, 2 0 1 5 ; W hale n et al., 2 0 1 5 ).  Alt h o u g h t he 
effecti ve ness of S G L T 2 i n hi bit ors, meas ure d b y gl uc os uria, is re d u ce d as t h e gl o mer ular 
filtrati o n rate ( G F R) decr eases, t he dr u gs h a ve b ee n well t olerate d i n ge n eral a n d s u bsta ntial 
a m o u nt of uri nar y gl uc os e is dis p ose d i n dia betic patie nts wit h c hr o nic ki d ne y disease.  T h e 
effecti ve ness of S G L T 2 i n hi bit ors f or H b A 1c re d u cti o n i n patie nts wit h m o derate re nal 
i m pair me nt has bee n d e m o nstrate d i n cli nical trials of ca n a glifl ozi n (Gil bert, 2 0 1 4 ; K o ha n et 
al., 2 0 1 4), da pa glifl ozi n (Yale et al., 2 0 1 3 ), a n d e m pa glifl ozi n ( F DA M e dical re vie w 
e m pa glifl ozi n, refere n ce I D: 3 4 0 2 2 5 7, p a ge 1 0 2/ 3 1 9).  Alt h o u g h t he efficac y v arie d, all 
S G L T 2 i n hi bit ors pr o d uce d H b A 1c re d ucti o ns i n patie nts wit h G F R bet wee n 4 5 a n d 6 0. T he 
cli nical efficac y i n patie nts wit h G F R bet wee n 3 0 a n d 4 5 varie d a m o n g differe nt S G L T 2 
i n hi bit ors (Sc hee n, 2 0 1 5 ). 
I n a trial assessi n g t he car di o vasc ular h azar ds of a d mi nistrati o n of e m pa glifl ozi n ( E M P A-
R E G), dia betic patie nts wit h i ncrease d car di o v as c ular ris k were treate d wit h e m pa glifl ozi n or 
place b o i n c o m bi nati o n wit h sta n dar d of care f or a p pr o xi matel y 3 years.  T he pri mar y 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 4  of 7 2  
V 4 ( Gl o bal)  
 
c o m p osite o utc o me of deat h, MI, a n d str o ke ( M A C E) occ urre d i n 1 0. 5 % of patie nts i n t he 
e m pa glifl ozi n gr o u ps a n d i n 1 2. 1 % of t he patie nts i n t he place b o gr o u p.  T h e M A C E hazar d 
rati o f or patie nts wit h e G F R < 6 0 was 0. 7 8 fa v ori n g e m p a glifl ozi n a n d t here was n o 
statisticall y si g nifica nt differ e nce b et wee n patie nts wit h n or mal a n d i m paire d re nal f u n cti o n 
(Zi n ma n et al., 2 0 1 5 ). 
1. 1   
B e x a glifl o zi n f or t h e Tr e at m e nt of T y p e 2 Di a b et e s M ellit u s 
Be x a glifl ozi n  is a p ote nt a n d hi g hl y s pecific i n hi bit or of t he S G L T 2 wit h a n i n vitr o I C5 0 of 
2 n M or 0. 9 n g/ m L a n d a 2 4 3 5-f ol d selecti vit y f or h u ma n S G L T 2 c o m pare d wit h S G L T 1. 
Be x a glifl ozi n elicits a pr o mi ne nt a n d pre dicta ble gl uc os uri a i n la b orat or y a ni mals a n d h u ma n 
s u bjects.  
1. 1. 1  
S u m m ar y of N o n -cli ni c al D at a wit h B e x a glifl o zi n  
T he p ote ntial a d verse eff ects of be x a glifl ozi n ha ve bee n e val uate d i n st u di es of n o n- cli nical 
safet y p har m ac ol o g y, ac ute a n d c hr o nic ge neral t o xic ol o g y, ge n ot o xicit y, ac ute a n d c hr o nic 
re pr o d ucti ve t o xicit y a n d t w o-year carci n o ge nicit y. Re peat d ose t o xicit y st u dies ha ve f o u n d 
e x acer bati o n of c hr o nic pr o gressi ve ne p hr o pat h y a n d gastri c irritati o n, i ncl u di n g s p ora di c 
ulcerati o n, at t he l o w est o bser va ble d os e le vel i n male rats, as w ell as si g ns of re versi ble 
car diac i nfla m mati o n a n d a b d o mi nal diste nsi o n at a d ose le vel of 2 0 0 m g/ k g i n m o n ke ys.  
Details of t he a d v erse fi n di n gs ar e pr o vi de d i n t he I n v esti gat or’s Br oc h ure. 
1. 1. 2  
S u m m ar y of Cli ni c al D at a wit h B e x a glifl o zi n  
T herac os has c o m plete d ei g ht p has e 1 st u dies t o e val uate safet y, t olera bilit y, 
p har mac o ki netics ( P K), p har mac o d y n a mics ( P D) a n d dr u g meta b olis m i n healt h y s u bjects, 
s u bjects wit h T 2 D M, a n d dia betic s u bjects wit h re nal i m pair me nt. Be x a glifl ozi n was well 
t olerate d b y patie nts wit h n or mal a n d i m paire d re n al f u ncti o n a n d pr o d u ce d cli nicall y 
si g nifica nt uri n ar y gl uc os e e x creti o n ( U G E ), i n patie nts wit h n or mal re nal f u ncti o n a n d i n 
pati e nts wit h mil d a n d m o derate re nal i m pair me nt. Patie nts wit h re nal i m pair me nt  
e x perie nce d s maller i n cr eases i n U G E  v ers us pati e nts wit h n or mal re nal f u ncti o n.  H o we ver, 
t he a m o u nt of gl u c os uria e x perie nce b y patie nts wit h mil d a n d m o derate re n al i m pair me nt is 
a ntici pate d t o pr o vi de t hera pe utic be n efit. Details of t he p har mac ol o g y, efficac y, a n d safet y 
assess me nts are d escri b e d i n t he I n v esti gat or’s Br oc h ure a n d s u m marize d i n t he f oll o wi n g 
secti o ns.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 5  of 7 2  
V 4 ( Gl o bal)  
 
2 
S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bj e cti v e  
T he pri mar y o bjecti ve is  t o deter mi ne t he efficac y of be x a glifl ozi n o n l o weri n g H b A 1 c i n 
patie nts wit h T 2 D M  a n d m o derate re nal i m pair me nt  after 2 4 w ee ks of treat me nt . 
2. 2  
K e y S e c o n d ar y O bj e cti v e s 
T he ke y sec o n dar y o bjecti ves are: 
• 
T o assess t he effect of be x a glifl ozi n o n t he c ha n ge i n b o d y wei g ht at w ee k 2 4 i n s u bjects 
wit h baseli ne B MI ≥2 5 k g/ m 2 
• 
T o assess t he effect of be x a glifl ozi n o n t he c ha n ge i n s yst olic bl o o d press ure ( S B P) at 
wee k 2 4  i n s u bjects wit h baseli ne S B P ≥1 3 0 m m H g 
• 
C ha n ge i n H b A 1c i n s u bj ects wit h e G F R 4 5 t o 5 9 m L/ mi n/ 1. 7 3 m 2 at wee k 2 4 
• 
C ha n ge i n H b A 1c i n s u bj ects wit h e G F R 3 0 t o 4 4 m L/ mi n/ 1. 7 3 m 2 at wee k 2 4 
 
A d diti o nal e x pl orat or y o bjecti ves are:  
• 
C ha n ge i n H b A 1c o v er ti me i n all s u bjects 
• 
Pr o p orti o n of s u bjects w h o reac h t ar get H b A 1c of <  7 % o ver ti me 
• 
C ha n ges i n fasti n g pl as ma gl u c ose ( F P G ) o ver ti me  
• 
Pr o p orti o n of ≥ 5 % re d ucti o n of b o d y w ei g ht i n s u bjects wit h baseli ne B MI ≥ 2 5 k g/ m 2 at 
wee k 2 4  
• 
C ha n ge i n b o d y wei g ht i n all s u bjects o ver ti me 
• 
C ha n ges i n S B P a n d diast olic B P o ver ti me i n all s u bjects 
• 
C ha n ge i n al b u mi n uria ( uri ne al b u mi n creati ni ne rati o  or U A C R ) fr o m b aseli ne t o wee k 
2 4 i n all s u bjects a n d i n s u bjects wit h baseli ne macr oal b u mi n uria ( U A C R ≥ 3 0 0) 
 
2. 3  
S af et y O bj e cti v e s  
T he safet y o bjecti ve is t he e val uati o n of t he s afet y of e x p os ure t o be x a glifl ozi n f or 2 4 wee ks. 
A n a d diti o nal safet y o bjecti ve of t his st u d y is t he c o ntri b uti o n maj or a d vers e car di o v asc ular 
e ve nts ( M A C E) t o a n e ve nt ual meta-a nal ysis t hat is i nte n de d t o e x cl u de e x cessi ve 
car di o vas c ular ris ks f or s u bjects e x p ose d t o be x a glifl ozi n c o m pare d t o s u bjects e x p ose d t o 
place b o d uri n g t he i n vesti gati o nal p has e of be x a glifl ozi n. 
2. 4   
Ot h er O bj e cti v e 
Meas ure me nt  of be x a glifl ozi n  plas ma c o nce ntrati o n as a f u ncti o n of ti me fr o m d osi n g 
(s parsel y sa m ple d) will be c o n d ucte d a n d will i ncl u de a p pr o xi matel y 1 4 4 s u bjects. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 6  of 7 2  
V 4 ( Gl o bal)  
 
3 
I N V E S TI G A TI O N A L P L A N 
3. 1   
O v er all St u d y D e si g n a n d Pl a n 
T H R - 1 4 4 2- C- 4 4 8 is a p h ase 3, m ulti-ce nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, 
parallel - gr o u p st u d y t o e val uate t he efficac y a n d s afet y of oral a d mi nistrati o n of be x a glifl ozi n 
at 2 0 m g vers us place b o i n s u bjects wit h T 2 D M, m o derate re nal i m pair me nt, a n d i na de q uate 
gl yce mic c o ntr ol.  
3. 2   
R e s e ar c h M et h o d s a n d Pr o c e d ur e s 
3. 2. 1  
S cr e e ni n g P eri o d  
All partici pa nts m ust pr o vi de writte n i nf or me d c o nse nt a n d be willi n g a n d a ble t o a d here t o 
t he pr ot oc ol re q uir e me nts. P ote ntial partici pa nts wit h s u b o pti mal gl yce mic c o ntr ol des pite 
diet a n d e x ercise or c o m bi nati o n of diet a n d e x ercise a n d treat me nt as rec o m me n de d i n l ocal 
g ui deli nes a n d wit h m o derate re nal i m pair me nt will e nter a scree ni n g peri o d of bet wee n 3 
a n d 2 1 da ys . T he mai n eli gi bilit y criteria i ncl u de: 1) male or fe male s u bjects wit h T 2 D M, 2) 
scree ni n g H b A 1c of 7. 0 t o 1 0. 5 % (i ncl usi ve), a n d 3) esti mate gl o mer ular filtrati o n rate 
(e G F R) ≥ 3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m 2 base d  o n t he ser u m creati ni ne at t he s cree ni n g visit a n d 
o ne a d diti o nal ti me p oi nt bet wee n 1 a n d 1 2 m o nt hs pri or t o scree ni n g ( ma y be o btai ne d fr o m 
a vaila ble me dical rec or ds) . T he e G F R will be cal c ulate d b y t h e m o dificati o n of diet i n re nal 
disease st u d y e q uati o n ( M D R D). At t he ti me of s cree ni n g, t he d os es a n d fre q ue nc y of all 
a nti-dia betic  me dicati o ns m ust ha ve bee n sta ble f or 8 wee ks.  
3. 2. 2  
R u n -i n P eri o d 
All eli gi ble s u bjects will e nter a o n e- w ee k si n gle bli n d, place b o r u n-i n peri o d t o all o w f or 
dia betes e d ucati o n a n d o pti mizati o n of c o m plia nce wit h diet a n d e x ercise  rec o m me n dati o ns. 
Q ualifie d s u bjects will c o nti n ue t heir pre-s cree ni n g re gi me n f or gl yce mic c o ntr ol (i ncl u di n g 
O H As a n d/ or i ns uli n) a n d will be i nstr ucte d t o ta ke t he r u n-i n me dicati o n o nce dail y f or 7 
a n d u p t o 9 da ys i nte n de d t o fa miliarize s u bjects wit h trial pr oce d ures a n d t o i de ntif y a n d 
reject s u bjects at hi g h ris k f or n o n-c o m plia nce.  D uri n g t he r u n-i n peri o d, s u bjects will 
recei v e diet a n d e x ercis e c o u nseli n g a n d i nstr ucti o ns o n c o ntacti n g t h e cli nic i n t he e ve nt of 
h y p o gl yce mia , h y per glyce mia,  or s y m pt o ms t hat ma y s u g gest ket oaci d osis. S u bjects will be 
trai ne d t o use t he gl uc o m eter a n d rec or d a n y e v e nts i n t he gl yce mic c o ntr ol diar y. 
A dj ust me nt of treat me nt f or h y perte nsi o n or d ysli pi de mia will n ot be per mitte d d uri n g t he 
r u n-i n peri o d. If a c h a n ge i n treat me nt is re q uire d t o a p pr o priatel y ma n a ge d ysli pi de mia 
d uri n g t he s cree ni n g p eri o d, t he s u bject ma y re- e nter t he scree ni n g as a ne w s u bject after t he 
cli nical c o n diti o n a n d treat me nt re gi me n ha v e n ot c ha n ge d f or at least 3 0 da ys. W he n re-
scree ni n g, a ne w s u bject n u m ber will be assi g n e d a n d all scree ni n g acti vities a n d assess me nts 
will be perf or me d . A dj ust me nt f or a nti- dia betic m e dicati o n d uri n g t he scree ni n g a n d r u n-i n 
peri o d is n ot per mitte d.  Re- scree ni n g after a dj ust me nt f or a nti- dia betic m e dicati o n is n ot 
rec o m me n de d as it ta kes 1 2 wee ks t o esta blis h a n H b A 1c sta ble b aseli ne. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 7  of 7 2  
V 4 ( Gl o bal)  
 
3. 2. 3  
Tr e at m e nt P eri o d  
S u bjects w h o are c o m plia nt i n ta ki n g r u n-i n me dicati o n ( missi n g n o m ore t ha n o ne d ose), 
ha ve scree ni n g e G F R ≥ 3 0 a n d < 6 0 m L/ mi n/ 1. 7 3 m2, a n d ha ve sta ble G F R  ( n o m ore t ha n 
2 0 % c ha n ge i n e G F R bet wee n a hist orical val ue a n d t he val ue deter mi ne d at t he scree ni n g 
visit V 1 ) will be eli gi ble f or ra n d o mizati o n a n d recei ve d o u ble bli n d st u d y dr u gs.  
T he treat me nt peri o d f or eac h st u d y s u bject will start at ra n d o mizati o n. A p pr o xi matel y 3 0 0 
eli gi ble s u bjects will be r a n d o mize d at t he e n d of t he r u n-i n peri o d i n a 1: 1 rati o t o recei ve 
o nce dail y be x a glifl ozi n ta blets f or 2 4 w ee ks . Ra n d o mizati o n will be stratifie d b y H b A 1c 
le vel (val ue o n s cree ni n g visit V 1 t o be 7. 0 t o 8. 5 % or 8. 6 t o 1 0. 5 %), scree ni n g a nti-dia b etic  
treat me nt re gi me n (i ns uli n treate d or n ot) a n d e G F R (val ue o n scree ni n g visit V 1 t o be 3 0- 4 4 
or 4 5- 5 9 m L/ mi n/ 1. 7 3 m 2). At least 1 3 5 s u bjects i n eac h of t h e e G F R gr o u ps m ust be 
e nr olle d. 
T he s t u d y s u bjects will be i n c o ntact wit h t he st u d y site at 2, 6, 1 2, 1 8, a n d 2 4 wee ks p ost-
ra n d o mizati o n.  T he i nteracti o ns at wee k 2 a n d wee k 1 8 will be c o n d ucte d b y p h o ne u nl ess a 
cli nic visit is necessar y.  
At t he start of t he treat me nt peri o d eac h s u bject will be pr o vi de d wit h a b ottle of d o u ble bli n d 
i n vesti gati o nal pr o d u ct, d osi n g i nstr ucti o ns, a n d a gl yce mic c o ntr ol diar y i n w hic h t o rec or d 
inf or mati o n relate d t o t he occ urr e nce of h y per gl yc e mic or h y p o gl yce mic e v e nts as well as 
s y m pt o ms t hat ma y s u g gest ket oaci d osis. T he s u bjects will be i nstr ucte d t o ta ke t he 
i n vesti gati o nal pr o d u ct wit h water i n t he m or ni n g pri or t o eati n g. A d diti o nal me dica ti o ns f or 
h y per gl yce mia  (see Secti o n 3. 2. 4 ) a n d f or c o ntr ol of ot her me dical c o n diti o ns will be all o wed 
if dee me d me dicall y n ecessar y b y t he i n vesti gat or, a n d will be rec or de d. 
T he safet y i nf or mati o n  will be dra w n fr o m re vie w of a d vers e e ve nts ( A Es), c o nc o mita nt 
me dicati o n s, vital si g ns, electr ocar di o gra ms ( E C Gs), a n d res ults fr o m p h ysical e x a mi nati o ns 
a n d bl o o d a n d uri ne s peci me n c ollecti o ns. O n t he da y of t he cli nic visit a mi ni m u m fasti n g 
peri o d of 8 h o urs m ust b e c o nfir me d pri or t o bl o o d dra w. At e v er y visit, i ncl u di n g t he p h o n e 
i nter vie ws, partici pa nts will be q uerie d re gar di n g A Es a n d i nf or mati o n o n all e ve nts t hat 
p ote ntiall y re prese nt dia b etic ket oaci d osis ( D K A) or maj or a d verse car di o v asc ular e ve nts 
will be f or war de d t o a car di o vasc ular e n d p oi nt c o m mittee ( C E C) f or bli n de d a dj u dicati o n of 
t he e ve nt. F oll o wi n g t he e xit visit, s u bjects will be a d vise d t o see t heir pri mar y p h ysicia n t o 
u n der g o treat me nt t o c o ntr ol t heir dia betes a n d car di o vasc ular  c o n diti o ns. T he sc he d ule d 
visits a n d pr oce d ures f or eac h visit are pr o vi de d i n A p pe n di x 1 .  
A n assess me nt of be x a glifl ozi n  p o p ulati o n p har mac o ki netics ( P K) will als o be c o n d ucte d t o 
i ncl u de a p pr o xi matel y 1 4 4 s u bjects. Sa m ples will be ta ke n bet w ee n  wee ks 6 a n d 1 2. T he 
p o p ulati o n P K st u d y d esi g n a n d a nal ysis pla n will be descri b e d i n a desi g nate d st u d y 
pr ot oc ol a n d t he a n al ysi s will be re p orte d se p aratel y. 
S u bj ects will ret ur n t o t he cli nic f or a f oll o w -u p e xit visit at W ee k 2 6 or t w o wee k s after last 
d ose  of  st u d y  dr u g  if  t he  s u bject  ter mi nates  pri or  t o  W ee k  2 4.  F oll o wi n g  t he  e xit  visit, 
s u bjects  will  be  a d vise d  t o  see  t heir  pri mar y  p h ysicia n  a n d  res u me  sta n dard  treat me nt  t o 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 1 8  of 7 2  
V 4 ( Gl o bal)  
 
c o ntr ol t heir dia betes.  T he d urati o n of t he o verall st u d y is esti mate d t o be a p pr o xi matel y 3 0 
wee ks.  
N o i nteri m a nal ysis will be perf or me d a n d t he st u d y will n ot be st o p pe d f or f utilit y or 
o ver w hel mi n g be nefit of be x a glifl ozi n  treat me nt.  D u ri n g t h e trial, a D ata a n d Safet y 
M o nit ori n g B o ar d ( D S M B ) will re vie w t he u n bli n de d a g gre gate dat a peri o dicall y a n d ma y 
rec o m me n d a n earl y ter mi nati o n of t he trial f or s afet y reas o ns. 
3. 2. 4  
Gl y c e mi c C o ntr ol M o nit ori n g  
S u bjects wit h h y per gl yce mia base d o n bl o o d g l u c ose le vels d uri n g t he treat me nt peri o d ma y 
recei v e a p pr o v e d a nti-dia betic  me dicati o n. I n a d diti o n, a dj ust me nt b y t he i n vesti gat or t o t he 
pre -scree ni n g a nti-dia betic  t hera pies will be rec o m me n de d if h y p o gl yce mia occ urs. 
P L A C E B O R U N -I N P E RI O D  
D uri n g t h e p lace b o r u n-i n peri o d s u bjects will be i nstr ucte d t o deter mi ne t he S M B G dail y 
after f asti n g o v er ni g ht f or a mi ni m u m of 8 h.  If t he fasti n g bl o o d gl u c ose is ≥ 2 5 0 m g/ d L 
( 1 3. 9 m m ol/ L) t he s u bject s h o ul d c o ntact t he cli nic a n d t he i n vesti gat or will deter mi ne 
w het her t he p artici pa nt s h o ul d atte m pt t o i m pr o ve diet a n d e x ercise t o mai ntai n gl yce mic 
c o ntr ol or if t he partici pa nt m ust disc o nti n ue fr o m t he st u d y a n d i nitiate a m ore i nt e nse 
p har mac ol o gical re gi me n f or gl uc ose c o ntr ol. S u bjects wit h S M B G rea di n gs ≥ 2 5 0 m g/ d L 
( 1 3. 9 m m ol/ L) a n d s e ver e cli nical si g ns or s y m pt o ms of h y per gl yce mia d uri n g t he scree ni n g 
or r u n-i n peri o ds, i ncl u di n g w ei g ht l oss, bl urre d visi o n, i ncrease d t hirst, i ncrease d uri nati o n, 
or fati g ue s h o ul d be e x cl u de d . Patie nts wit h s y m pt o matic  h y p o gl yce mia s h o ul d be wit h dra w n 
fr o m t he st u d y if s y m pt o ms are se vere.  
M AI N T R E A T M E N T P E RI O D  
D uri n g t h e mai n treat me nt peri o d s u bjects will be a d vise d t o c o nti n ue d ail y fasti n g S M B G 
meas ure me nts. I nt e nsificati o n of t he a nti-dia betic  re gi me n s h o ul d a d here t o t he g ui deli nes 
descri be d i n S ecti o n 5. 2. 4  f or “Pres cri pti o n of Resc ue Me di c ati o n ”.  
S t u d y su bj ects s h o ul d c o ntact t he cli nic if a n y fasti n g S M B G is ≥ 2 7 0 m g/ d L ( 1 5 m m ol/ L) 
fr o m wee k 1 t o w ee k 6, ≥ 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) b et wee n  wee k 6 a n d  wee k 1 2, or 
≥ 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) b et wee n  wee k 1 2 a n d  wee k 2 4. Bl o o d gl uc ose val ues c ollecte d 
via S M B G will be re vie we d at st u d y visits b y t he i n vesti gat or. I n a d diti o n, h y per gl yce mia 
will be m o nit ore d b y f asti n g plas ma gl uc os e (F P G ) at eac h cli nical visit  e x ce pt visit V 2 . 
If h y per gl yce mia is i de ntifie d t hr o u g h S M B G or F P G meas ure me nts, t he i n vesti gat or will 
deter mi ne w het h er t he s u bject ha d fast e d f or a mi ni m u m of 8 h o urs pri or t o t he m or ni n g 
bl o o d dra w t o e ns ur e t hat t he gl uc os e val ue is tr ul y fr o m a fasti n g sa m ple. If pr o per fasti n g 
ha d n ot occ urre d, t he s u bject will be as ke d t o ret ur n f or a re peat bl o o d test wit hi n a wee k.  
If a c o n c o mita nt me dicati o n f or h y p er gl yce mia is t o be prescri b e d, a sa m pl e m ust be dra w n 
pri or t o t he a d mi nistrati o n of t he resc u e me dicati o n s o t hat a n H b A 1c v al ue ca n be assesse d . 
Starti n g metf or mi n i n patie nts wit h a n e G F R bet w ee n 3 0 -4 5 m L/ mi n ute/ 1 . 7 3 m2 is n ot 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
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V 4 ( Gl o bal)  
 
rec o m me n de d. T he i n vesti gat or s h o ul d assess t he be nefits a n d ris ks of c o nti n ui n g metf or mi n 
treat me nt f or p atie nts w h o ha ve bee n ta ki n g metf or mi n a n d w h ose e G F R falls bel o w 4 5 
m L/ mi n ute/ 1. 7 3 m 2. Metf or mi n t hera p y s h o ul d be disc o nti n ue d if the patie nt’s e G F R  falls 
bel o w 3 0 m L/ mi n ute/ 1. 7 3 m 2. 
S u bjects will be i nstr ucte d t o c o ntact t he cli nic staff f or h y p o gl yce mia, defi ne d as: 1) a n y 
S M B G val ue < 7 0 m g/ d L ( 3. 9 m m ol/ L); or 2) a n y s y m pt o ms of h y p o gl yce mia t hat res ol ve 
wit h f o o d i nta ke, wit h or wit h o ut a n acc o m pa n yi n g S M B G v al ue. H y p o gl yce mia ma y als o be 
detecte d b y F P G val ues, meas ure d b y ce ntral la b orat or y at e v er y cli nic visit, e x ce pt V 2 , 
usi n g t he sa me criteri a as f or S M B G val u es.  
If rec urri n g h y p o gl yce mia (i.e., cli nicall y si g nifica nt h y p o gl yce mia o cc urri n g o n m ulti ple 
differe nt d a ys) is i de ntifie d d uri n g t he mai n treat me nt peri o d, t he d ose a n d fre q ue n c y of 
bac k gr o u n d ( pre- s cree ni n g) me di cal t hera p y f or dia betes s h o ul d be re d u ce d at t he discreti o n 
of t he i n vesti gat or. If t he s u bject is ta ki n g i ns uli n a n d O H A , t he d ose of i ns uli n s h o ul d be 
re d uce d first, a n d, if necessar y t o pre ve nt f urt her h y p o gl yce mia, i ns uli n s h o ul d be 
disc o nti n ue d bef ore oral h y p o gl yce mic a ge nts  are re d uce d. If t he s u bject is ta ki n g o nl y 
O H As or G L P -1 a g o nist , t he d ose or fre q ue n c y of t hese bac k gr o u n d me dicati o ns ca n be 
re d uce d at t he discr eti o n of t he i n vesti gat or. 
3. 2. 5  
O T H E R S A F E T Y M O NI T O RI N G A C TI VI TI E S  
D uri n g t h e c o urs e of t he st u d y i n vesti gat ors will ma na ge bl o o d press ure a n d li pi d val ues 
acc or di n g t o acce pte d sta n dar ds of care f or t he ma na ge me nt of h y perte nsi o n a n d 
d ysli pi de mia.  
3. 2. 5. 1  
R e n al F u n cti o n  
E val uati o n a n d ma na ge me nt of s u bjects wit h a n d at ris k f or ac ute ki d n e y i nj ur y ( A KI) s h o ul d 
be perf or me d d uri n g t he st u d y peri o d b ase d o n t he Ki d ne y Disease: I m pr o vi n g Gl o bal 
O utc o mes ( K DI G O) Cli nical Practice G ui deli ne i n 2 0 1 2 ( K DI G O Cli nical Practice G ui deli ne 
f or A KI, 2 0 1 2).  T he c lassificati o n/sta gi n g S yst e m f or A KI is des cri be d i n A p pe n di x 3 . 
If ser u m creati ni ne i ncreases s u g gesti n g a p ossi ble sta ge 1 A KI, t he i n vesti gat or s h o ul d 
c o nfir m t he i ncr ease i n s er u m cr eati ni ne wit hi n 4 8 h of lear ni n g t he res ult a n d e nter a n A E 
i nt o t he C R F if t he ser u m creati ni ne d o es n ot s p o nta ne o usl y ret ur ns t o < 0. 3 m g/ d L fr o m 
baseli ne. T he i n vesti gat or s h o ul d e nc o ura ge t he s u bjects t o mai ntai n h y drati o n a n d p urs ue 
a n y a d diti o nal cli nicall y rele va nt i n vesti gati o ns t o el uci date t he ca use or p ote ntial 
c o nse q ue nces of t he d ecli ne i n re nal f u n cti o n. St u d y dr u g a d mi nistrati o n ma y b e s us pe n de d if 
cli nicall y i n dicat e d u ntil t he creati ni ne val ue ret ur ns t o < 0. 3 m g/ d L fr o m b aseli ne. Ser u m 
creati ni ne s h o ul d be m o nit ore d base d o n t he i n vesti gat or’s j u d g me nt u ntil creat i ni ne ret ur ns 
t o baseli ne le vel, wit hi n 0. 3 m g/ d L differe n ce.  
If ser u m creati ni ne i ncreases or ot her si g ns s u g gesti n g a p ossi ble sta ge 2 or 3 A KI, t he 
s u bject s h o ul d be m o nit ore d dail y a n d ne p hr ol o g y c o ns ultati o n or h os pitalizati o n wit hi n 2 4 h 
s h o ul d be c o nsi dere d.  St u d y dr u g a d mi nistrati o n s h o ul d be st o p pe d u ntil t he creati ni ne val ue 
ret ur ns t o < 0. 3 m g/ d L fr o m baseli ne. If p ote ntiall y life-t hreat e ni n g c o n diti o ns (i.e., ure mia, 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 0  of 7 2  
V 4 ( Gl o bal)  
 
p ul m o nar y e de ma, arr h yt h mia, disse mi nate d i ntra vasc ular c oa g ulati o n, h y per kale mia, 
meta b olic aci d osis  ) are prese nt occ urri n g i n t he setti n g of a p ossi ble sta ge 2 or 3 A KI e v e nt, 
t he a d mi nistrati o n of st u d y dr u g m ust be st o p pe d a n d t he me dical m o nit or s h o ul d be 
i nf or me d. T he me dical m o nit or will a d vise o n w het her t he st u d y dr u g ca n b e restart e d aft er 
t he res ol uti o n of t he p ote ntiall y life-t hreate ni n g c o n diti o n. L o cal la b orat or y testi n g will be 
acce pta ble w h e n i m me diate la b res ults are necess ar y f or cli nical assess me nt.  
If i nterr u pte d, st u d y dr u g ma y b e rei nitiate d w h e n ser u m creati ni ne ret ur ns t o wit hi n 
0. 3 m g/ d L of t he r a n d o mizati o n val ue or if re nal f u ncti o n re mai ns 0. 5 m g/ d L a b o v e t he 
ra n d o mizati o n val ue b ut a n alter nati ve ca use of t h e w orse n e d re n al f u ncti o n has bee n 
i de ntifie d. D osi n g of st u d y dr u g will be per ma n e ntl y disc o nti n ue d if t he s u bject is t o start 
dial ysis or ot her re nal re place me nt t hera pies.  
T he re n al f u ncti o n m o nit ori n g pla n is s u m marize d i n Fi g ure 1. 
 
Fi g ur e  1. 
R e n al F u n cti o n M o nit ori n g Pl a n  
 
3. 2. 5. 2  
Di a b eti c K et o a ci d o si s  
D K A is a seri o us, ac ute c o m plicati o n of dia betes a n d ca n be life- t hreate ni n g. S u bjects will be 
e d ucate d o n t h e si g ns a n d s y m pt o ms of D K A a n d are re q uire d t o call t he st u d y cli nic a n d 
see k treat me nt s h o ul d s uc h si g ns a n d s y m pt o ms o cc ur.  
D uri n g t h e cli nical  trial p eri o d, p ote ntial D K A will be m o nit ore d b y t he r o uti ne meas ure me nt 
of uri nar y ket o n es a n d assess me nt f or si g ns or s y m pt o ms of aci d osis at e ver y cli nic visit. 
Cli nical prese ntati o ns, s uc h as diffic ult y breat hi n g, a b d o mi nal pai n, na usea, v o miti n g, 
lethar g y, or a fr uit y s mell i n t he breat h, or la b orat or y v al ues t hat s u g gest cli nicall y -si g nifica nt 
aci d osis s h o ul d be d oc u me nte d; treat me nt of D K A s h o ul d be pr o vi de d w h e n a p pr o pri ate.  
If o n g oi n g s y m pt o ms or si g ns s u g gest a p ossi ble D K A, t he i n vesti gat or s h o ul d perf or m 
rele va nt la b orat or y testi n g w hile directi n g a p pr o priate me dical care f or t he s u bject. If D K A is 
s us pecte d, re gar dless of t he bl o o d gl uc os e le vel, t he f oll o wi n g assess me nts s h o ul d be d o ne 
i m me diatel y: p h ysical e x a m a n d ser u m gl uc ose, bi car b o nat e, electr ol yt es, a n d ser u m ket o nes 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 1  of 7 2  
V 4 ( Gl o bal)  
 
meas ure d S T A T at a l ocal la b orat or y. If k et oaci d osis is li kel y, i n vesti gati o n al pr o d uct 
a d mi nistrati o n s h o ul d be disc o nti n ue d a n d i m me diate a p pr o priate me dical t hera p y, i ncl u di n g 
i ns uli n, s h o ul d be i nitiate d. A gl uc os e i nf usi o n ma y be pr o vi de d if necessar y t o a v oi d 
h y p o gl yce mia d uri n g i ns uli n t hera p y. I ns uli n treat me nt s h o ul d c o nti n ue u ntil res ol uti o n of 
t he ket oaci d osis a n d sta bilizati o n of t he s u bject’s cli nical c o n diti o n. I n v esti gati o nal pr o d u ct 
a d mi nistrati o n ma y be res u me d f oll o wi n g sta bilizati o n of t he s u bject’s c o n diti o n. 
I n v esti gat or s h o ul d c ollect t he data necessar y f or t he c o m pleti o n of t he D K A C R F.  
If s y m pt o ms s u g gesti ve of D K A ma y h a ve occ urre d b ut are n ot o n g oi n g, i n vesti gat or s h o ul d 
re vie w a v aila ble dat a i n order t o c o m plete t h e D K A C R F. T he i n vesti gat or ma y als o perf or m 
la b orat or y ass ess me nt usi n g l ocal res o urces if necessar y f or cli nical care.  
3. 2. 5. 3  
M aj or A d v er s e C ar di o v a s c ul ar E v e nt ( M A C E)  
A n i n de pe n de nt car di o vasc ular a dj u dicati o n c o m mittee has bee n  est a blis he d t o re vie w,  u n d er 
bli n d, all p ote ntial car di o vasc ular e ve nts occ urri n g d uri n g t he st u d y. T he e v e nts of i nterest 
i ncl u de car di o v asc ular m ortalit y, m y ocar dial i nfarcti o n, str o ke, h os pitalizati o n f or ac ute 
c or o nar y s y n dr o mes, h os pitalizati o n f or heart fail ure, ur ge nt re vas c ularizati o n pr oce d ures, 
a n d ot her p ossi ble seri o us car di o vasc ul ar e v e nts. T he a dj u dicate d e ve nts will be d oc u me nte d 
a n d arc hi v e d t o all o w a meta -a nal ysis t o be perf or me d at a later ti me.  
3. 2. 5. 4  
Ot h er G e n er al S af et y M o n it ori n g 
T he safet y m o nit ori n g a cti vities will i ncl u de assess me nt of vital si g ns, p h ysical 
e x a mi nati o ns, uri nal ysis, bl o o d c he mistr y, h e mat ol o g y, a d v erse e ve nts, a n d c o nc o mita nt 
me dicati o n use.  T he o cc urre nce of bl o o d, li ver, re nal, or s ki n dis or ders will be m o nit ore d 
t hr o u g h la b orat or y testi n g a n d e val uati o n of a d verse e ve nt d oc u me nt ati o n.   
A d verse e ve nts of s pecial i nterest as  defi ne d i n t h e statistical a nal ysis pla n will i ncl u de a n y 
cli nical si g ns a n d s y m pt o ms t hat i n dicate a d vers e e x perie nce i n t he cate g ories liste d bel o w.  
All s uc h  e ve nts m ust be a p pr o priatel y d o c u me nte d wit hi n s o urce d oc u me ntati o n. 
• 
Ge nital m yc otic i nfecti o ns  
• 
U ri nar y tract i nfecti o ns i ncl u di n g ur os e psis a n d p yel o n e p hritis 
• 
D i uretic effects i ncl u di n g h y p o v ole mia 
• 
H y p ote nsi o n e pis o des  
• 
He pat ot o xicit y  
• 
M A C E  
• 
H y p o gl yce mia  
• 
Fa lls a n d fract ur es 
• 
M ali g na n cies  
• 
H y p erse nsiti vit y r eacti o ns  
• 
Aci d -base dis or d ers  
• 
Re nal fail ure e ve nts  
• 
A m p utati o n  
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 2  of 7 2  
V 4 ( Gl o bal)  
 
3. 2. 6  
D A T A A N D S A F E T Y M O NI T O RI N G B O A R D ( D S M B)  
A n i n de pe n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will m o nit or o verall safet y 
i nf or mati o n d uri n g t he b e x a glifl ozi n de vel o p me nt pr o gra m. T he s afet y re vi e w acti vit y a n d 
p ote ntial ris k be nefit assess me nts utilize d b y t he D S M B are d efi ne d i n its c harter.  
3. 3   
R ati o n al e f or St u d y D e si g n a n d C o ntr ol Gr o u p 
3. 3. 1  
R ati o n al e f or t h e St u d y D e si g n  
Patie nts wit h T 2 D M ha ve i ncrease d ris k of d e vel o pi n g micr o- a n d macr o vasc ular 
c o m plicati o ns. I m pr o v e d c o ntr ol of h y per gl yce mia or bl o o d press ure re d u ces t he ris k of 
dia betic c o m plicati o ns ( U K P D S  (1 9 9 8 b )). A d mi nistrati o n of be x a glifl ozi n, a p ote nt S G L T 2 
i n hi bit or, has bee n s h o w n t o be well t olerate d a n d t o decrease H b A 1 c i n s u bjects wit h T 2 D M 
dra w n fr o m a ge n eral p o p ulati o n.  T H R - 1 4 4 2- C- 4 4 8 is desi g ne d t o e v al uat e t he safet y a n d 
efficac y of b e x a glifl ozi n  i n t he treat me nt of patie nts wit h T 2 D M a n d m o derate re n al 
i m pair me nt.  
A place b o - c o ntr olle d, d o u ble- bli n d, parallel-ar m desi g n w as c h ose n f or t his st u d y. T he 
i ncl usi o n of a place b o gr o u p will all o w me dicati o n effects t o be differe ntiate d fr o m 
i nfl ue nces of c o nf o u n di n g f act ors. T h e s u bjects will c o nti n ue t o recei ve b ac k gr o u n d gl uc ose 
l o weri n g t h era pi es as well as ot her me dicati o ns t o ma na ge c o- m or bi dities t hr o u g h o ut t he 
st u d y. St u d y s u bjects ma y r ecei v e a d diti o nal a p pr o ve d a nti-dia betic  me di cati o ns if t heir 
h y per gl yce mia is n ot c o ntr olle d.  
T he pri mar y e n d p oi nt of re d ucti o n i n H b A 1c directl y reflects i m pr o ve me nt i n gl yce mic 
c o ntr ol a n d is c o nsi der e d a well- vali date d s urr o gat e f or t he l o n g -ter m micr o vasc ular 
c o m plicati o ns of dia betes mellit us.  Res ults fr o m pre vi o us cli nical st u dies d e m o nstrate a 
re d ucti o n i n H b A 1c i n patie nts treate d wit h be x a glifl ozi n as c o m pare d wit h place b o. 
3. 3. 2  
R ati o n al e f or t h e St u d y P o p ul ati o n  
E F FI C A C Y C O N SI D E R A TI O N  
Res ults f r o m p u blis he d data i n i n di vi d uals wit h m utati o ns i n t he ge ne e nc o di n g S G L T 2, i n 
healt h y v ol u nteers a n d p atie nts t hat ha ve bee n treate d wit h ot her S G L T 2 i n hi bit ors, a n d i n 
healt h y v ol u nteers a n d p atie nts t hat ha ve bee n treate d wit h be x a glifl ozi n  at d oses u p t o 1 0 0 
m g i n dicate t h at t he ris k of i n d uce d h y p o gl yce mia as a c o nse q u e nce of t he l oss of S G L T 2 
acti vit y s h o ul d be mi ni mal. Cli nical data i n t he pre vi o us st u dies i n dicate t hat be x a glifl ozi n  
has bee n w ell t olerate d  f or 9 6 wee ks (st u d y T H R- 1 4 4 2- C- 4 1 8). 
T he eff ect of a si n gl e d os e of be x a glifl ozi n  has bee n teste d i n patie nts wit h T 2 D M a n d 
n or mal or i m paire d r e nal f u ncti o n (st u d y T H R- 1 4 4 2- C- 4 2 4). Be x a glifl ozi n  was well 
t olerate d b y patie nts wit h n or mal a n d i m paire d re n al f u ncti o n a n d pr o d uce d cli nicall y 
si g nifica nt U G E i n patie nts wit h n or mal re nal f u n cti o n a n d i n patie nts wit h mil d a n d 
m o derate r e nal i m pair me nt (Fi g ure 2 ). A d mi nistrati o n of be x a glifl ozi n pr o d uce d a mea n 
gl uc os uri a of 4 0 g/ d i n patie nts wit h m o derate re n al i m pair me nt ( G F R 3 0 t o 6 0) c o m pare d t o 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 3  of 7 2  
V 4 ( Gl o bal)  
 
9 9. 6 g/ d i n patie nts wit h n or mal re nal f u n cti o n.  T he decreas e d gl uc os uria is c o nsiste nt wit h a 
re d uce d re n al filtrati o n rate. H o we ver, a n i m pr o ve me nt i n gl yce mic c o ntr ol ca n be pre dicte d 
b y t he U G E of nearl y 4 0 g of gl uc ose per da y. T h e dr u g was als o w ell t olerate d  b y patie nts 
wit h se vere r e nal  i m pair me nt b ut pr o d uce d a U G E  le vel t hat is u nli kel y t o pr o vi de 
t hera pe utic b e nefit. T hes e fi n di n gs pr o vi de rati o n ale f or e x a mi ni n g t he cli nical effi cac y i n 
patie nts wit h T 2 D M a n d m o derate re nal i m pair me nt .  
 
 
Fi g ur e  2.  
Gl u c o s uri a i n p ati e nt s wit h n or m al a n d i m p air e d r e n al f u n cti o n 
 
S A F E T Y C O N SI D E R A TI O N  
Be x a glifl ozi n is pri maril y meta b oli ze d t o i nacti ve gl uc ur o ni d es b y p hase II meta b olis m a n d 
is cleare d t hr o u g h re n al or fecal e x creti o n. P har mac o ki netic ( P K) para meters of be x a glifl ozi n 
a n d its pri nci pal meta b olites were d eter mi ne d i n p atie nts wit h T 2 D M a n d re nal i m pair me nt. 
Re d uce d clear a nce d u e t o  re nal i m pair me nt w as ass ociate d wit h a 3 4 % or 5 4 % hi g h er 
s yste mic e x p os ure i n s u bjects wit h G F R bet wee n 3 0 a n d 6 0 m L/ mi n/ 1. 7 3 m 2 or bel o w 
3 0 m L/ mi n/ 1. 7 3 m 2, res pecti vel y. T he half -life w as e xte n de d fr o m 6. 5 h ( G R F > 9 0) t o 7. 7 h 
( G F R < 3 0) wit h n o acc u m ulati o n of be x a glifl ozi n or its maj or meta b olites.  N o n -cli nical a n d 
cli nical st u dies ha ve de m o nstrate d hi g h m ulti ples of safet y mar gi ns f or be x a glifl ozi n ta blet, 
2 0 m g.   Gi ve n t he m o dest i ncrease i n dr u g e x p os ure, d ose a dj ust me nt i n patie nts wit h 
m o derate r e nal i m pair me nt is n ot necessar y.  A t h or o u g h Q T st u d y h as de m o nstrate d t hat 
1 0 0 m g of b e x a glifl ozi n a d mi nistere d i n a n i m me diate release f or m ulati o n di d n ot pr ol o n g 
t he Q T i nter val or pr o d uce a d vers e c h a n ges i n a n y ot her para meters meas ure d b y E C G. 
3. 3. 3  
R ati o n a l e f or t h e D o s e S el e cti o n 
Be x a glifl ozi n pr o d uces a d ose- de pe n d e nt, sat ura bl e i ncrease i n U G E i n healt h y v ol u nteers 
a n d dia betic s u bjects. N ear - ma xi mal U G E is pr o d uce d b y 2 0 m g of be x a glifl ozi n, w het her 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 4  of 7 2  
V 4 ( Gl o bal)  
 
deli vere d as a n i m me diate release or a n e xte n de d relea se f or m ulati o n. A si n gle d ose of 2 0 m g 
pr o d uces a si g nifica nt re d ucti o n i n fasti n g plas ma gl uc ose ( F P G) a n d a m o dest di uretic 
effect. P o p ulati o n p har mac o d y na mic m o deli n g has i n dicate d t hat be x a glifl ozi n d oses of 2 0 
m g w o ul d r es ult i n 9 0 % of t he ma xi mal U G E , res pecti vel y. I n a l o n g-t er m treat me nt st u d y, 
dail y a d mi nistrati o n of 2 0 m g be x a glifl ozi n was f o u n d t o re d uce H b A 1c b y 0. 7 9 % c o m pare d 
t o place b o at w ee k 2 4. T he treat me nt be n efit was o bser ve d t o i m pr o ve t o 1. 0 2 % at wee k 9 6. 
F P G re d u cti o n, wei g ht l oss, a n d decrease d s yst olic a n d diast olic bl o o d press ure were als o 
o bser ve d f oll o wi n g 9 6 w ee ks of treat me nt. I n a d diti o n, A Es, partic ularl y t h ose i n v ol vi n g U TI 
a n d ge nital m yc otic i nfecti o ns ( G MI), were f o u n d t o be si milar bet wee n place b o a n d acti ve 
a ge nt c o h orts . T o e v al uat e t he saf et y a n d efficac y of be x a glifl ozi n f or t he treat me nt of 
patie nts wit h T 2 D M a n d m o derate re nal i m pair me nt, be x a glifl ozi n ta blets, 2 0 m g, will be 
a d mi nistere d i n t his trial.  
3. 4   
St u d y D ur ati o n a n d D at e s 
I n t he pl a n ne d st u d y, dia betic s u bjects will be scree ne d wit hi n 3 wee ks pri or t o start of t he 
r u n-i n peri o d. Eli gi ble s u bjects w h o si g n t he writte n c o nse nt will start a 1- wee k  r u n-i n peri o d 
pri or t o ra n d o mizati o n t o recei v e st u d y dr u g.  S u bjects will recei ve 2 4 wee ks of treat me nt.  
T he o ver all st u d y d ur ati o n fr o m scree ni n g u ntil f oll o w- u p will be 3 0 wee ks f or st u d y 
s u bjects. F or d etails of t he sc he d ule a n d nat ure of t he i n vesti gati o ns, see t h e Sc he d ule of 
E ve nts i n A p pe n di x 1 . 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 5  of 7 2  
V 4 ( Gl o bal)  
 
4 
S T U D Y P O P U L A TI O N S E L E C TI O N  
4. 1   
St u d y P o p ul ati o n 
T he st u d y p o p ulati o n will i ncl u de a p pr o xi matel y 3 0 0 s u bjects dia g n os e d wit h s u b- o pti mall y 
c o ntr olle d T 2 D M w h o  ha ve m o derate re n al i m pair me nt . Eli gi ble s u bjects w h o m ust be 
i nf or me d of t he nat ure of t he st u d y a n d t he p ot e ntial ris k a n d c o nse nt t o partici pate i n t he 
st u d y will be e nr olle d i n cli nical i n vesti gati o nal sites i n m ulti ple c o u ntries. 
Plas ma sa m ples will be c ollecte d f or p o p ulati o n P K a nal ysis. St u d y s u bjects will be i nf or me d 
of t he p ur p ose of t h e P K st u d y a n d re q ueste d t o c o nse nt t o t he a d diti o nal pr oce d ures a n d 
bl o o d c ollecti o n. 
4. 2   
I n cl u si o n Crit eri a 
T he st u d y p o p ulati o n will i ncl u de: 
1.  Me n or n o n- pr e g na nt w o me n ≥ 2 0 years of a ge.  W o me n of c hil d beari n g p ote ntial m ust 
a gree t o us e c o ntrace pti o n d uri n g t he e ntire st u d y t o a v oi d a n y p ossi ble pre g na n c y. 
Fe males w h o ar e s ur gicall y sterile ( h yst erect o m y, o o p h orect o m y) or p ost m e n o pa usal 
(a bse nce of me ns es greater t ha n 1 2 m o nt hs a n d a ge > 4 5 years) are eli gi ble if t he y test 
ne gati ve o n t he u ri ne pre g na n c y test. 
2.  S u bjects wit h a dia g n osis of T 2 D M wit h a n H b A 1 c bet wee n 7. 0 a n d 1 0. 5 % (i ncl usi ve) at 
t he ti me of scree ni n g. 
3.  S u bjects w h o are tr eat me nt naï ve or are treate d wit h a sta ble re gi me n of a nti -dia betic 
me dicati o ns  t hat d o n ot pr o vi de a de q u ate gl yce mi c c o ntr ol w he n c o m bi ne d wit h diet a n d 
e x ercise. At t he ti me of s cree ni n g, t he d os es a n d fre q ue nc y of all a nti- dia b etic 
me dicati o ns m ust ha ve b ee n sta ble f or 8 wee ks.  
4.  S u bjects w h o ha ve a n esti mate d gl o mer ul ar filtrati o n rate (e G F R) ≥ 3 0 a n d 
< 6 0 m L/ mi n/ 1. 7 3 m 2 at 2 ti me p oi nts: scree ni n g ( V 1), a n d 1 a d diti o nal ti me p oi nt 
bet wee n 1 a n d 1 2 m o nt hs of scree ni n g ( m ost rece nt hist orical val ue ma y be o btai ne d 
fr o m a vaila ble me dical r ec or ds). T h e e G F R will be calc ul ate d b y t he M D R D e q uati o n 
(see A p p e n di x 4 ) 
5.  S u bjects w h o ha ve a b o d y mass i n de x ( B MI) ≤ 4 5 k g/ m 2 (i ncl usi ve) 
6.  S u bjects w h o ta ke sta ble d oses of me dicati o ns f or h y perte nsi o n or h y perli pi de mia f or at 
least 3 0 da ys pri or t o ra n d o mizati o n (if a p plica ble) 
7.  S u bjects w h o ha ve sta ble e G F R bet w ee n t he m ost rece nt hist oric v al ue a n d da y of 
scree ni n g ( n o m ore t ha n 2 0 % c ha n ge i n e G F R bet wee n t he m ost rece nt  hist orical val ue 
a n d t he val ue d eter mi ne d at t he scree ni n g visit V 1 ). 
 
4. 3   
E x cl u si o n Crit eri a 
Patie nt s w h o e x hi bit a n y of t he f oll o wi n g c haracteristics  will be e x cl u de d fr o m t he st u d y. 
1.  D ia g n osis of t y p e 1 dia betes mellit us or mat urit y– o nset dia betes of t he y o u n g ( M O D Y) 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 6  of 7 2  
V 4 ( Gl o bal)  
 
2.  He m o gl o bi n o pat h y t hat affects H b A 1c meas ure me nt  
3.  F re q u e nt s y m pt o matic h y p o gl yce mia ( greater t h a n o ne e pis o de per wee k o n a vera ge) 
4.  Ge nit o uri nar y tract i nfecti o n wit hi n 6 wee ks of scree ni n g or hist or y of ≥ 3 ge nit o uri nar y 
i nfecti o ns re q uiri n g treat me nt wit hi n t he last 6 m o nt hs 
5.  Ca ncer, acti ve or i n r e missi o n f or < 3 yea rs ( N o n-mela n o ma s ki n ca ncer or basal cell 
carci n o ma or carci n o ma i n sit u of t he cer vi x will n ot be gr o u n ds f or e x cl usi o n) 
6.  Hist or y of alc o h ol or illicit dr u g a b us e i n t he past 2 years 
7.  E vi de nce of a b n or mal li v er f u ncti o n tests (t otal bilir u bi n or al kali ne p h os p h atase > 1. 5 x 
u p per li mit of n or mal ( U L N) wit h t he e x ce pti o n of is olate d Gil bert's s y n dr o me); or 
ala ni ne a mi n otra nsf eras e ( A L T) or as partat e a mi n otra nsferase ( A S T) > 2. 5 x U L N  
8.  Hist or y of MI, str o ke or h os pitalizati o n f or heart fail ure, or h os pitalizati o n f or u nsta ble 
a n gi n a i n t he pri or 3 m o nt hs 
9.  E vi de nce of N Y H A class I V heart fail ure at scree ni n g or ra n d o mizati o n  
1 0.  C urre ntl y or wit hi n 3 m o nt hs of ta ki n g a n S G L T 2 i n hi bit or fr o m scree ni n g (A p pe n di x 5 ) 
1 1.  A n y c o n diti o n, disease, dis or der, or cli nicall y rele va nt la b orat or y a b n or malit y t hat, i n t he 
o pi ni o n of t he PI, w o ul d je o par dize t he s u bject's a p pr o priate partici pati o n i n t his st u d y or 
o bsc ure t he eff ects of treat me nt  
1 2.  W o me n w h o are pr e g na nt or breastf ee di n g  
1 3.  Patie nts w h o are r ecei vi n g r e nal re place me nt t hera p y ( p erit o neal or h e m o dial ysis) or w h o 
ha ve u n der g o ne r e nal tra ns pla ntati o n 
1 4.  C orrecte d s er u m cal ci u m <  8 m g/ d L ( A p pe n di x 4 ) at scree ni n g ( V 1) or ra n d o mizati o n 
( V 3) 
1 5.  U nc o ntr olle d h y pert e nsi o n (s yst olic bl o o d press ure > 1 7 0 or diast olic bl o o d press ure 
> 1 1 0) 
1 6.  C urre ntl y p artici pati n g i n a n ot her i nter v e nti o nal trial  or recei vi n g t reat me nt wit h a n 
i n vesti gati o nal dr u g wit hi n 3 0 da ys or 7 h alf-li ves of scree ni n g, w hic he v er is l o n ger  
1 7.  Pre vi o us treat me nt wit h be x a glifl ozi n  or E G T 0 0 0 1 4 7 4 
1 8.  Missi n g m ore t ha n 1 d os e of t he st u d y dr u g d uri n g t he r u n-i n peri o d 
1 9.  Fasti n g bl o o d gl uc os e val ue d uri n g t he r u n-i n peri o d ≥ 2 5 0 m g/ d L  ( 1 3. 9 m m ol/ L) 
ass ociate d wit h  se vere cli nical si g ns or s y m pt o ms of h y p er gl yce mia  
2 0.  A n y e pis o de of s y m pt o matic h y p o gl yce mia d uri n g t he r u n-i n peri o d i n w hic h s y m pt o ms 
are se v ere  
2 1.  S u bjects w h o are u n a ble t o rea d a n d write i n t heir nati ve la n g ua ge 
2 2.  S u bjects w h o are u n a ble t o c o m pre he n d a n d willi n g t o pr o vi de writte n i nf or me d c o nse nt 
i n acc or d a nce wit h i nstit uti o nal a n d re g ulat or y g ui deli nes 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 7  of 7 2  
V 4 ( Gl o bal)  
 
5 
S T U D Y T R E A T M E N T S 
5. 1   
D e s cri pti o n of Tr e at m e nt s 
Be x a glifl ozi n ta blets, 2 0 m g, a n d place b o, are bl u e ca plet-s h a pe d, fil m- c oate d ta blets t hat are 
i nte n de d f or use i n i n vesti gati o nal st u dies i n h u ma ns. T he ta blets c o ntai n e x ci pie nts desi g n e d 
t o pr o m ote e xte n de d release t hr o u g h a gastr orete nti ve mec ha nis m. T he dr u g pr o d u cts e x hi bit 
a great er t ha n 7 5 % releas e of dr u g s u bsta nce b y 8 h i n si m ulate d gastric fl ui d i n vitr o. The 
f oll o wi n g i n vesti gati o nal dr u gs will be us e d f or oral a d mi nistrati o n: 
• 
Be x a glifl ozi n ta blets, 2 0 m g: ta blets c o ntai ni n g 2 0 m g of be x a glifl ozi n  
• 
Be x a glifl ozi n ta blets, place b o: ta blets c o ntai ni n g n o be x a glifl ozi n  
 
5. 2  
Tr e at m e nt s A d mi ni st er e d  
5. 2. 1  
I n v e sti g ati o n al Pr o d u ct 
Be x a glifl ozi n  ta blets, 2 0 m g or place b o, s h o ul d be ta ke n i n t he m or ni n g pri or t o eati n g or 
dri n ki n g. T he t a blets  s h o ul d be ta ke n wit h 2 5 0 m L of water.  
5. 2. 2  
B a c k gr o u n d Or al H y p o gl y c e mi c A g e nt s ( O H A s)  
S u bjects will c o nti n ue O H As t hat were pres cri be d pri or t o scree ni n g. T h e d ose, fre q u e nc y, 
a n d ti me of a d mi nistrati o n of t hese me dicati o ns s h o ul d re mai n sta ble t hr o u g h o ut t he st u d y 
u nless t he i n vesti gat or d ee ms a dj ust me nt necessar y f or t he me dical well - bei n g of t he s u bject. 
C ha n ges t o t he d os e or fr e q ue nc y of oral a nti -dia b etic me dicati o ns will be rec or de d i n t he 
c o nc o mita nt me dicati o ns l o g.  
5. 2. 3  
B a c k gr o u n d I n s uli n T h er a p y  
S u bjects w h o are prescri be d i ns uli n pri or t o scree ni n g will c o nti n ue t he d ose, fre q u e nc y, a n d 
ti me of i ns uli n a d mi nistrati o n t hr o u g h o ut t he st u d y. T he d os e, fre q ue n c y, a n d ti me of i ns uli n 
i njecti o ns s h o ul d re mai n sta ble u nless t he i n vesti gat or dee ms a dj ust me nt ( d ecrease or 
i ncreas e) necessar y f or t h e me dical w ell- bei n g of t he s u bject. C ha n ges t o t h e d ose, fre q ue nc y, 
or ti me of a d mi nistrati o n of i n s uli n will be rec or de d i n t he c o nc o mita nt me dicati o ns l o g.  
5. 2. 4  
R e s c u e M e di c ati o n s f or H y p er gl y c e mi a  
If h y per gl yce mia is i de ntifie d t hr o u g h S M B G or F P G meas ure me nts, t he i n vesti gat or will 
deter mi ne w het h er t he s u bject ha s faste d f or a mi ni m u m of 8 h o urs pri or t o t he m or ni n g 
bl o o d dra w t o e ns ur e t hat t he F P G va l ue is tr ul y a fasti n g sa m ple. If pr o p er fasti n g h as n ot 
occ urr e d, t he s u bject will be as ke d t o ret ur n f or a re peat bl o o d test wit hi n a wee k.  
T he i n vesti gat or ma y pr escri be res c ue me di cati o n f or h y per gl yc e mia at a n y ti me it is dee me d 
necessar y f or t he well - bei n g of t he s u bject. A re vi e w of diet a n d e x ercise c o u nseli n g is 
s u g geste d pri or t o pres cri pti o n of resc ue me di cati o n i n t he a bse nce of s pecific me dical 
i n dicati o ns f or resc u e me dicati o n. Resc ue me dicati o n is s u g geste d if:  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 8  of 7 2  
V 4 ( Gl o bal)  
 
1.  m ore t ha n 3 c o nsec uti ve, dail y, fasti n g S M B G meas ures are ≥ 2 7 0 m g/ d L ( 1 5 m m ol/ L) 
fr o m wee k 1 t o w ee k 6, ≥ 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) fr o m wee k 6 t o wee k 1 2, or 
≥ 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) fr o m wee k 1 2 t o wee k 2 4, or 
2. fasti n g S M B G val ues are ≥ 2 5 0 m g/ d L ( 1 3. 9 m m ol/ L,), ass o ciate d wit h cli nical si g ns or 
s y m pt o ms of h y per gl yce mia (e. g. wei g ht l oss, bl urre d visi o n, i ncrease d t hirst, or 
i ncreas e d uri nati o n, or f ati g ue), a n d t he si g ns or s y m pt o ms are s e vere. 
 
A me dicati o n gi ve n t o treat h y p er gl yce mia will be c o nsi dere d a res c ue t hera p y f or 
h y per gl yce mia o nl y if it is c o nti n ue d f or 2 w ee ks or l o n ger. D ose or fre q ue nc y i n creases i n 
O H A or i ns uli n re gi me ns prescri be d pri or t o scree ni n g will be c o nsi dere d resc ue me dicati o n. 
D uri n g t h e treat me nt p eri o d, i ncre me nts or decre me nts i n t he d oses of O H A or i ns uli n m ust 
be d oc u me nte d i n t he c o nc o mita nt me dicati o ns C R F. 
T he i n vesti gat or ma y pr o vi de resc u e treat me nt wit h a n y a p pr o ve d me dicati o n f or dia betes 
t hat is n ot ot her wise c o ntrai n dicate d, wit h t he e x ce pti o n of a n S G L T 2 i n hi bit or, as st u d y 
s u bjects ma y alrea d y be t a ki n g a dr u g i n t hat class as a c o nse q u e nce of bei n g ra n d o mize d t o 
recei v e be x a glifl ozi n. Starti n g metf or mi n i n patie nts wit h a n e G F R bet w ee n 3 0 - 4 5 
m L/ mi n ute/ 1. 7 3 m 2 is n ot rec o m me nde d. T h e i n vesti gat or s h o ul d assess t he be nefits a n d 
ris ks of c o nti n ui n g metf or mi n treat me nt f or p atie nts w h o ha ve bee n ta ki n g metf or mi n a n d 
w h ose e G F R falls bel o w 4 5 m L/ mi n ute/ 1. 7 3 m 2. Metf or mi n treat me nt s h o ul d be 
disc o nti n ue d if the patie nt’s e G F R  falls bel o w 3 0 m L/ mi n ute/ 1. 7 3 m2. 
S u bjects w h o recei ve res c ue me dicati o n d ue t o i na de q uate gl yce mic c o ntr ol will c o nti n ue t o 
recei v e i n vesti gati o nal pr o d uct a n d sta n dar d of care per i n vesti gat or d ecisi o n, acc or di n g t o 
c urre nt tr eat me nt g ui deli nes. F oll o wi n g t he  e xit visit s u bjects will be a d vise d t o see t heir 
pri mar y p h ysicia n t o u n d er g o treat me nt t o c o ntr ol t heir dia betes. 
If h y p o gl yce mia o cc urs i n a n y s u bj ect pres cri be d resc ue m e dicati o n f or h y per gl yce mia 
d uri n g t he st u d y, t he t otal dail y d ose of t h e res c ue me dicati o n s h o ul d be re d uce d at t he 
discreti o n of t he i n vesti gat or. 
If a r esc ue m e dicati o n f or h y p er gl yce mia is t o be prescri be d, a bl o o d sa m ple m ust be dra w n 
pri or t o t he a d mi nistrati o n of t he resc u e me dicati o n s o t hat a fi nal H b A 1c v al ue ca n b e 
deter mi ne d f or t h e H b A 1 c effi cac y a nal yses.  
5. 3   
S el e cti o n a n d Ti mi n g of D o s e f or E a c h P ati e nt 
D osi n g wit h be x a glifl ozi n ta blets, 2 0 m g or place b o, will be base d o n ra n d o mize d 
assi g n me nt. All st u d y s u bjects will be i nstr ucte d t o self -a d mi nister ta blets o nce dail y i n t he 
m or ni n g pri or t o eati n g or dri n ki n g; t he me di cati o n s h o ul d be ta ke n wit h w ater. T here will be 
n o c ha n ge of d ose d uri n g t he treat me nt peri o d. 
O n t he da y of eac h s c he d ule d cli nic visit, s u bjects m ust fast f or a mi ni m u m of 8 h o urs pri or 
t o t he c ollecti o n of bl o o d sa m ples. D uri n g t he fasti n g peri o d, o nl y w ater will be per mitte d. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 2 9  of 7 2  
V 4 ( Gl o bal)  
 
5. 4   
M et h o d of A s si g ni n g P ati e nt s t o Tr e at m e nt Gr o u p s 
T he st u d y will be c o n d ucte d at i n vesti gati ve sites i n m ulti ple c o u ntries a n d will li kel y i n v ol ve 
varia ble n u m bers of s u bjects at eac h site. E nr oll me nt will be o n a c o m petiti ve basis b ut eac h 
site will be ca p pe d at 3 0 ra n d o mize d s u bjects per site. Acti vati o n of i n vesti gati o nal sites i n 
eac h c o u ntr y will be ce ntrall y c o ntr olle d b y a ce ntrall y ma n a ge d I nteracti ve We b Res p o nse 
S yste m (I W R S). 
Eli gi ble s u bjects w h o c o m plete t he r u n -i n peri o d a n d meet all st u d y i n cl usi o n/e x cl usi o n 
re q uire me nts will be r a n d o mize d t o recei ve i n vesti gati o nal pr o d uct.  T h e treat me nt peri o d f or 
eac h st u d y s u bject will start at ra n d o mizati o n. A p pr o xi matel y 3 0 0 eli gi ble patie nts will be 
ra n d o mize d at t he e n d of t he r u n-i n peri o d i n a 1: 1 rati o t o recei ve o nce d ail y be x a glifl ozi n 
ta blets f or 2 4 wee ks. Ra n d o mizati o n will be stratifie d b y H b A 1c le v el ( 7. 0 t o 8. 5 % or 8. 6 t o 
1 0. 5 %), scr ee ni n g a nti-di a betic  treat me nt re gi me n (i ns uli n treate d or n ot) a n d scree ni n g 
e G F R ( 3 0 - 4 4 or 4 5- 5 9 m L/ mi n/ 1. 7 3 m2). 
S u bject ra n d o mizati o n will be deacti vate d f or all sites w he n t he pla n ne d n u m ber of s u bjects 
is met.  H o we ver, if a p ote ntial s u bject is  i n r u n-i n peri o d alrea d y a n d wis h es t o c o nti n ue 
wit h t he st u d y, t he s u bject will be all o we d t o c o nti n ue a n d, if eli gi ble, t o be ra n d o mize d.  
5. 5   
Bli n di n g 
T his is a d o u ble- bli n d place b o-c o ntr olle d st u d y. T he s p o ns or, i n vesti gat ors, st u d y 
c o or di nat ors, p har macists, st u d y s u bjects, a n d t he car di o vas c ular a dj u dicati o n c o m mittee 
me m bers  will be bli n de d t o t he st u d y me dicati o n . U p o n ra n d o mizati o n, eac h s u bject will 
recei v e a s u bject ra n d o mizati o n n u m ber a n d a dr u g kit assi g ne d t o t he s u bj ect. T o mai ntai n 
bli n di n g of t he i n di vi d ual treat me nt assi g n me nt, t he res ults of uri nar y gl uc ose testi n g will n ot 
be ma de a v aila ble t o  a n y st u d y pers o n n el or s u bjects.  
If k n o wle d ge of t he treat me nt is nee de d t o ma na ge t he s u bject’s c o n diti o n, t he i n vesti gat or 
will c o ntact t he I W R S t o o btai n t he treat me nt assi g n me nt.  If u n bli n di n g occ urs f or a n y 
reas o n, t he ti me a n d reas o n f or brea ki n g t he bli n d will be rec or d e d o n t he case re p ort f or m 
( C R F) a n d t he s p o ns or m ust be n otifie d wit hi n 2 4 h.  
A desi g n ate d statisticia n w h o is n ot i n v ol ve d wit h t he st u d y o perati o n will h ol d t he treat me nt 
c o des. T he u n bli n de d tr eat me nt i nf or mati o n ca n b e pr o vi de d t o t he D S M B t o facilitate t he 
e val uati o n of a n y cli nicall y i m p orta nt i ncrease i n t he rate of a seri o us s us pecte d a d verse 
reacti o n or t o t he d esi g n ate d safet y c o nt act w he n t he treat me nt i nf or m ati o n is re quire d t o 
deter mi ne if a n e x pe dite d safet y re p ort m ust be s u b mitte d t o re g ulat or y a ge ncies.   
T he treat me nt assi g n me nt will c o nti n ue t o be wit h hel d fr o m t he car di o vasc ular a dj u dicati o n 
c o m mittee me m bers u ntil all gl o bal i n vesti gati o nal st u dies are c o m plete d  a n d a meta-a n al ysis 
t o assess car di o v asc ular ris k is c o n d ucte d. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 0  of 7 2  
V 4 ( Gl o bal)  
 
5. 6   
C o n c o mit a nt T h er a p y 
D uri n g t h e c o urs e of t he st u d y i n vesti gat ors will ma na ge gl uc ose, bl o o d press ure, li pi d le vels, 
a n d a ne mia acc or di n g t o l ocal or re gi o n al sta n dar d of care g ui da nce d oc u m e n ts f or t he 
ma na ge me nt of T 2 D M a n d ot her c o m or bi dit y or disease as iss ue d b y t he rele va nt 
pr ofessi o nal b o dies ( e. g. A D A, t he Nati o nal Ki d n e y F o u n dati o n, et c.). S u bjects s h o ul d be 
pr o vi de d access t o all a d diti o nal t hera pies a n d i nter ve nti o ns d uri n g t he c o urs e of t he st u d y if 
t hese ar e cli nicall y i n dicate d a n d a p pr o v e d b y l ocal c o m pete nt a ut h orities. 
S u bjects will be all o we d t o ta ke me dicati o ns or m e dici nal s u p ple me nts prescri be d t o ma na ge 
n o n- dia betic me dical c o n diti o ns d uri n g t he st u d y. A n y c o nc urre nt me dicati o n or 
s u p ple me ntal treat me nt of ot her, n o n- dia b etes me dical c o n diti o ns s h o ul d be c o nti n ue d at a 
sta ble d ose a n d fre q ue n c y f or t he e ntire st u d y d urati o n u nless t here is cli nical reas o n t o 
c ha n ge t he d os e or fre q u e nc y.  
Bl o o d press ur e me dicati o ns s h o ul d n ot be altere d d uri n g t he s cree ni n g p eri o d a n d t he first 1 2 
wee ks of t he m ai n treat m e nt peri o d u nless it is me dicall y n ecess ar y t o d o s o. If a c h a n ge i n 
treat me nt is re q uir e d t o a p pr o priatel y ma na ge a n e mia, or d ysli pi de mia d uri n g t he scree ni n g 
peri o d, t he s u bject ma y r e -e nter t he scree ni n g after t he cli nical c o n diti o n a n d treat me nt 
re gi me n ha ve n ot c ha n ge d f or at least 3 0 da ys . If it is me dicall y necessar y t o alter bl o o d 
press ure me di cati o ns d uri n g t he first 1 2 w ee ks of t he treat me nt peri o d t o miti gate 
s y m pt o matic h y p ote nsi o n, ne w di uretic me dicati o ns s h o ul d n ot be i nitiate d a n d t he d ose a n d 
fre q ue n c y of e xisti n g di uretic me dicati o ns s h o ul d n ot be i ncreas e d. C ha n ges t o t he d ose or 
fre q ue n c y of a nti- h y p erte nsi ve a n d di uretic me dicati o ns m ust be rec or d e d i n t he c o nc o mita nt 
me dicati o ns l o g.  
S u bjects w h o d o n ot meet pr ot oc ol- s pecifie d gl yce mic tar gets at s pecifie d ti me p oi nts d uri n g 
t he st u d y ma y  r ecei ve res c ue me dicati o n at t he discreti o n of t he i n vesti gat or d uri n g t h e st u d y. 
A nti -dia betic t her a pies pr escri be d t o s u bjects f or t he p ur p ose of treati n g h y per gl yce mia f or 
m ore t ha n 2 wee ks will be c o nsi der e d res c ue me di cati o ns ( Secti o n 5. 2. 4 Resc ue Me dicati o n s 
f or H y per gl yce mia).  
S u bjects ma y r ecei ve a n y me dicati o ns f or A Es t hat are necessar y i n t he i n vesti gat ors’ 
j u d g me nts. A n y me dicati o n prescri be d t o a s u bject after e nr oll me nt a n d pri or t o 
ra n d o mizati o n, i ncl u di n g c o ntrace pti ves, m ust be rec or d e d i n t he C R F. T he me dicati o n 
na me, d ose, fr e q ue n c y, r o ute of a d mi nistrati o n, date(s) of a d mi nistrati o n a n d reas o n f or 
a d mi nistrati o n m ust be rec or de d. T his d oc u me nt ati o n s h o ul d c o nti n ue t hr o u g h t he treat me nt 
a n d f oll o w u p peri o ds.  
5. 7   
R e stri cti o n s 
5. 7. 1  
Pri or T h er a p y  
All s u bjects will c o nti n ue re gi me ns f or me dical c o n diti o ns d uri n g t he st u d y as i n dicate d 
a b o ve. N o s u bject s hall ha ve bee n treat e d wit h a n i n vesti gati o nal dr u g wit hi n 3 0 da ys of 
scree ni n g or wit hi n a peri o d e q ual t o less t ha n 7 half-li ves of t he i n vesti gati o nal dr u g, 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 1  of 7 2  
V 4 ( Gl o bal)  
 
w hic he ver is l o n ger. N o s u bject s hall ha ve bee n treate d wit h a n S G L T 2 i n hi bit or wit hi n 3 
m o nt hs of scree ni n g.  
5. 7. 2  
Fl ui d a n d F o o d I nt a k e  
D uri n g t h e st u d y, s u bjects will be c o u nsele d t o re mai n a de q uatel y h y drate d at all ti mes.  I n 
a d diti o n, s u bjects will recei ve c o u ns eli n g re gar di n g a n a p pr o pri ate diet t o ac hie ve gl yce mic 
c o ntr ol base d o n sta n dar ds of me dical care i n dia betes. S u bjects will fast f or a mi ni m u m of 
8 h pri or t o t he sc he d ule d bl o o d sa m ple dra ws. D uri n g fasti n g, o nl y w ater will be per mitte d.  
5. 7. 3  
P ati e nt  A cti vit y R e stri cti o n s  
T hr o u g h o ut t he st u d y peri o d, s u bjects will  be c o u nsele d a n d e n c o ura ge d t o e n ga ge i n a l e vel 
of p h ysical acti vit y t hat is a p pr o priate f or t heir p h ysical c o n diti o n.  F or t h ose wit h o ut s pecific 
restricti o ns or li mitati o ns, at least 1 5 0 mi n/ wee k of m o derate acti vit y is a d vise d b y t he 
A merica n Di a betes Ass o ciati o n (A merica n Dia b etes, 2 0 1 4 ). Alter n ati vel y, l ocal g ui deli nes 
ma y b e use d.  
5. 8   
Tr e at m e nt C o m pli a n c e 
S u bjects will be pr o vi de d wit h d osi n g i nstr ucti o ns eac h ti me t hat st u d y me dicati o n is 
dis pe nse d. S u bjects will als o be i nstr ucte d t o bri n g t heir me di cati o n wit h t he m at e ver y visit. 
S u bjects will be e x cl u de d fr o m ra n d o mizati o n if m ore t ha n o ne d ose of t he r u n-i n me dicati o n 
has bee n misse d . 
At eac h visit t he st u d y st aff will re vie w t he S M B G diar y, gl uc o meter rec or d, a n d me dicati o n 
use wit h t he s u bject a n d r ec or d t he dr u g c o ns u m pti o n i n t he C R F. Reas o ns f or n o n- a d here nce 
will als o be rec or d e d i n t he pr ot oc ol de viati o n l o g if a p plica ble. 
5. 9   
P a c k a gi n g a n d L a b eli n g 
I n v esti gati o nal pr o d uct will be pr o vi de d t o t he p har macist or desi g nate d site pers o n nel i n 
b ottles of 9 0 ta blets e ncl ose d wit h a c hil d- resista nt ca p. B ottles of 1 5 place b o ta blets will be 
pr o vi de d f or t he 1- wee k r u n-i n p orti o n of t he st u d y. All  i n vesti gatio nal pr o d uct s u p plies will 
be pre pare d a n d la bele d acc or di n g t o t he re q uire m e nts of l ocal la ws a n d re g ulati o ns. T he 
p har macist or desi g n ate d site pers o n nel will dis pe nse t he i n vesti gati o nal pr o d ucts f or eac h 
s u bject acc or di n g t o ra n d o mizati o n assi g n me nt made i n t he I nteracti ve We b Res p o nse 
S yste m  (I W R S). D uri n g t he treat me nt peri o d, s u bjects will be pr o vi de d wit h a ne w b ottle 
e ver y 1 2 w ee ks. T h ere will be n o i ntra- s u bject d os e escal ati o n or bac k-titrati o n. 
T here are t w o t y pes of i n vesti gati o nal pr o d u ct kits . 
5. 9. 1  
R u n -i n Kit 
Eac h kit c o ntai ns o ne b ottle of 1 5 ta blets of be x a glifl ozi n ta blets, place b o. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 2  of 7 2  
V 4 ( Gl o bal)  
 
T he la bel attac he d t o eac h r u n -i n kit will c o ntai n t he pr ot oc ol n u m ber, pr o d uct i de ntificati o n, 
l ot n u m ber, s u bject n u m ber, st ora ge c o n diti o n, t he s p o ns or’s na me a n d a d dress, e x pirati o n 
date, t he i n vesti gati o nal dr u g ca uti o n state me nt, a n d a n y ot h er re q uire d st u d y dr u g 
i nf or mati o n. 
5. 9. 2  
I n v e sti g ati o n al Pr o d u ct Kit 
Eac h kit c o ntai ns 1 b ottle of 9 0 ta blets of be x a glifl ozi n ta blets, 2 0 m g or place b o. 
T he la bels attac h e d t o ea c h st u d y kit will c o ntai n s o me or all of t he f oll o wi n g i nf or m ati o n: 
t he kit n u m ber, pr ot oc ol n u m ber, pr o d uct i de ntificati o n, bli n de d batc h n u m ber, a desi g n ate d 
s pace f or s u bject n u m ber, st ora ge c o n diti o ns, s p o ns or’s na me, ma n ufact urer's na m e a n d 
a d dress, i n vesti gat or’s n a me, e x pirati o n date, t he i n vesti gati o nal dr u g ca uti o n state me nt,  a n d 
a n y ot h er r e q uire d st u d y dr u g i nf or mati o n. 
5. 1 0  St or a g e a n d A c c o u nt a bilit y  
Be x a glifl ozi n  ta blets will be st ore d i n a sec ure area wit h li mite d access at c o ntr olle d r o o m 
te m peratur es of 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F) u ntil rea d y f or dis p e nsi n g t o st u d y s u bjects. T he 
s p o ns or will n otif y t he sites of t he pr ocess f or ret ur ni n g u n use d dr u g. 
5. 1 1   I n v e sti g ati o n al Pr o d u ct R et e nti o n at St u d y Sit e 
T he trial staff m ust rec or d t he a m o u nt of i n vesti g ati o nal pr o d uct dis pe nse d t o eac h s u bject i n 
t he d osi n g r ec or d. T o e ns ure a de q u ate rec or d k ee pi n g, s u bjects m ust bri n g all i n vesti gati o nal 
pr o d ucts t o eac h cli nic visit . T he re mai ni n g t a blets will be acc o u nte d f or i n t he C R F a n d dr u g 
c o ns u m pti o n f or ms. T he pr oce d ur es f or o bt ai ni n g dr u g res u p pl y will be pr o vi de d b y t he 
s p o ns or. At t he last da y of d osi n g ( V 8 visit ), t he st u d y dr u g b ottle a n d a n y re mai ni n g ta bl ets 
will be c ollecte d fr o m t he patie nt a n d st ore d at t he site u ntil t he cl ose - o ut visit. All  u n use d 
dr u g m ust be ret ur ne d t o a s p o ns or-desi g nat e d de p ot after t he s p o ns or or its desi g nee verifies 
dr u g acc o u nti n g . 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 3  of 7 2 
V 4 ( Gl o bal)  
 
6 
S T U D Y P R O C E D U R E S  
6. 1   
P h o n e I nt er vi e w 
S o me sc he d ule d visits will be c o n d ucte d b y p h o ne.  D uri n g a p h o ne i nter vi e w, t he 
i n vesti gat or or d esi g nee will re vie w t he dail y S M B G a n d  gl yce mic c o ntr ol rec or d wit h t he 
s u bject. P ote ntial A Es a n d c ha n ge i n me dicati o n use s h o ul d be q uerie d. A n a d diti o nal cli nic 
visit ma y b e sc h e d ule d if cli nicall y necessar y. 
6. 2   
I nf or m e d C o n s e nt  
Bef ore eac h s u bject is e nr olle d  i n t he cli nical st u d y, writte n i nf or me d c o ns e nt will be 
o btai ne d acc or di n g t o t he re g ulat or y a n d l e gal re q uire me nts of t he partici pati n g c o u ntr y. As 
part of t his pr oce d ure, t h e i n vesti gat or m ust e x plai n orall y a n d i n writi n g t he nat ure, d urati o n, 
a n d p ur p ose of t h e st u d y, a n d t he acti o n of t he dr u g i n s uc h a ma n ner t h at t he st u d y s u bject is 
a war e of t he p ote ntial ris ks, i nc o n ve nie nces, or A Es t hat ma y o cc ur. T h e i n vesti gat or s h o ul d 
e d ucate p ot e ntial s u bjects a b o ut t he scie ntific i m p orta nce of t heir data a n d t he vital r ole t hat 
t heir partici pati o n has f or t he o utc o me of t he e ntire st u d y. T h e s u bject m ust be i nf or me d t hat 
he/s he is free t o wit h dra w fr o m t he st u d y at a n y ti me. He or s he will recei ve all i nf or mati o n 
t hat is re q uire d b y nati o n al re g ulati o ns a n d G o o d Cli nical Practice ( G C P)  g ui deli nes.  
T he i nf or me d c o ns e nt d o c u me nt m ust be si g ne d a n d date d; o ne c o p y will b e gi v e n t o t he 
patie nt, a n d t he i n vesti gat or will retai n a c o p y as part of t he cli nical st u d y rec or ds. T he 
i n vesti gat or will n ot u n d erta ke a n y i n vesti gati o n s pecificall y re q uire d f or t he cli nical st u d y 
u ntil writte n c o nse nt has bee n o btai ne d. T h e ter ms of t he c o nse nt a n d w he n it was o btai ne d 
m ust als o be d oc u me nte d. 
6. 3   
S cr e e ni n g f or I/ E Crit eri a  
At t he i nitial scree ni n g, t he i n vesti gat or s h o ul d re vie w t he i ncl usi o n a n d e x cl usi o n criteria 
base d o n t he i nf or mati o n c ollecte d at t he s cree ni n g visit. He or s he s h o ul d e val uate a n y 
c ha n ge t o stat us affecti n g c o nf or ma n ce t o i ncl usi o n a n d e x cl usi o n criteria at s u bse q ue nt visits 
pri or t o ra n d o mizati o n. At ra n d o mizati o n, t he i n vesti gat or s h o ul d c o nfir m t he r u n-i n dr u g 
c o m plia nce.  
6. 4   
M e di c al Hi st or y  
T he f oll o wi n g i nf or mati o n will be c ollecte d at t he scree ni n g visit:  
6. 4. 1  
G e n er al D e m o gr a p hi c s a n d C h ar a ct eri sti c s  
1.  Date of birt h, a ge, se x, a n d race, a n d w het h er a fe mal e s u bject is of c hil d beari n g p ot e ntial 
or n ot. 
2.  Si g nifica nt me dical a n d s ur gical hist or y, i n cl u di n g dates of dia g n oses a n d pr oce d ures a n d 
w het her t he c o n diti o n is o n g oi n g, if a p plica ble. 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 4  of 7 2  
V 4 ( Gl o bal)  
 
6. 4. 2  
Di a b et e s Hi st or y  
1.  Hist or y of all me dicati o ns use d t o treat dia betes ( t o be rec or de d i n t he c o nc o mita nt 
me dicati o n f or m), i ncl u di n g start dat e, d urati o n of use, a n d st o p date, if a p plica ble. 
2.  Hist or y of c o m plicati o ns d ue t o dia betes, i ncl u di n g ne p hr o pat h y, reti n o pat h y, 
ne ur o pat h y, n o n-tr a u matic a m p utati o ns, a n d dia betic ket oaci d osis, i ncl u di n g date of 
dia g n osis 
3.  Fre q u e nc y of h y p o gl yce mic e ve nts ( per wee k) t h at are s y m pt o matic or re q uire assista nce.  
 
6. 4. 3  
R e n al a n d C ar di o v a s c ul ar Di s e a s e Hi st or y  
1.  C hr o nic ki d ne y disease sta ge, base d o n K O QI C K D cla ssificati o n a n d d urati o n 
(A p pe n di x 3 ) 
2.  C urre ntl y recei vi n g er yt hr o p oiesis -sti m ulati n g a ge nt ( E S A) f or a n e mia a n d ti me of 
starti n g E S A 
3.  Hist or y of b o n e diseas e 
4.  Hist or y of dis or d ers of calci u m a n d p h os p h or us meta b olis m or h y p er parat h yr oi dis m 
5.  Hist or y of n e ur o pat h y 
6.  Hist or y of car di o v asc ular disease i ncl u di n g pres e n ce of a n gi n a, c o n gesti ve heart fail ure 
(i ncl u di n g N Y H A cl assificati o n), k n o w n at her oscl er otic car di o vasc ular disease, pri or MI, 
tra nsie nt isc he mic attac k or str o ke, a n d pri or car diac or peri p heral re-v asc ul arizati o n 
pr oce d ur es. T he hist or y s h o ul d i ncl u de t he date of dia g n osis a n d t he c urre nt stat us of 
dia g n osis (r es ol ve d or o n g oi n g). 
 
6. 4. 4  
M e di c ati o n Hi st or y  
1.  Use of pr escri be d or n o n- prescri be d m e dicati o ns, i ncl u di n g na m e of me dicati o n, 
i n dicati o ns f or usa ge, start a n d st o p dates, d ose, a n d fre q ue n c y 
2.  Use of s u p ple me nts, i ncl u di n g o ver t he c o u nter dr u gs, ir o n s u p ple me nt, vit a mi ns, her bal 
pre par ati o ns, a n d dietar y s u p ple me nts wit hi n t he past 3 0 da ys pri or t o scree ni n g. Eac h 
me dicati o n hist o r y will i ncl u de t he a ge nt use d, i n dicati o n f or usa ge, st art a n d st o p dates, 
d ose, a n d fr e q ue n c y. 
 
6. 5  
Di et a n d E x er ci s e C o u n s eli n g  
S u bjects will recei ve c o u nseli n g r e gar di n g a n a p pr o priate diet a n d e x ercis e t o ai d i n gl yce mic 
c o ntr ol base d o n sta n dar ds of me dical care i n dia betes t hr o u g h o ut t he st u d y. I n a d diti o n, all 
s u bjects are e nc o ur a ge d t o c o ns u me e n o u g h li q ui d t o mai ntai n a de q uate h y drati o n. 
6. 6   
P h y si c al E x a mi n ati o n  
A c o m plete p h ysical e x a mi nati o n will be perf or m e d b y t h e i n vesti gat or at t he ti me p oi nts 
i n dicate d i n t he Sc he d ule of E ve nts (A p pe n di x 1 ). T he e x a mi nati o n will i ncl u de a ge neral 
assess me nt of all b o d y s yste ms i ncl u di n g t he s ki n, hea d, e yes, ears, n ose, t hr oat, nec k, heart, 
l u n gs, a b d o me n, l y m p h n o des, a n d e xtre mities. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 5  of 7 2  
V 4 ( Gl o bal)  
 
6. 7   
A b br e vi at e d P h y si c al E x a mi n ati o n  
A n a b bre viat e d p h ysical e x a mi nati o n will i ncl u de meas ure me nt of  h ei g ht at scree ni n g  V 1  
o nl y a n d a ge neral assess me nt of t he s ki n, heart, l u n gs a n d a b d o me n. T he i n vesti gat or will 
perf or m a b b re viat e d p h ysical e x a mi nati o ns at t he ti me p oi nts i n dicate d i n t he Sc he d ule of 
E ve nts ( A p pe n di x 1 ), u nless cli nicall y i n dicate d. 
6. 8   
B o d y W ei g ht 
T otal b o d y w ei g ht will b e deter mi ne d i n e v er y cli nical vi sit e x ce pt visit V 2. T he wei g ht m ust 
be deter mi ne d usi n g a s cale t hat is cali brate d. E ver y eff ort s h o ul d be ma de t o use t he sa me 
scale t hr o u g h o ut t he st u d y d ur ati o n. 
6. 9   
Vit al Si g n s  
Vital si g ns will be meas ure d at t he ti me p oi nts i n dicate d i n t he Sc he d ule of E ve nts ( A p pe n di x 
1 ) a n d will i ncl u de s u pi ne, sitti n g a n d sta n di n g B P meas ure me nts, a n d heart rate. O nl y t he 
B P meas ur e d i n t he sitti n g p ositi o n will be use d t o deter mi ne eli gi bilit y.  
De vices desi g n e d t o meas ure B P fr o m t he fi n ger or wrist ma y n ot be use d. T he left ar m a n d 
sa me c uff sizes s h o ul d be use d f or eac h meas ure m e nt at all visits. If t he left ar m ca n n ot be 
use d at t he scr ee ni n g visit or d uri n g t he st u d y f or B P meas ure me nts, t he reas o n s h o ul d b e 
d oc u me nte d, a n d t he ri g ht ar m s h o ul d be use d f or B P meas ure me nts f or all s u bse q ue nt visits. 
At eac h visit, B P meas ur e me nts will be o btai ne d usi n g a cali brate d s p h y g m o ma n o meter 
w hile t he s u bject is i n sitti n g, s u pi ne, a n d sta n di n g p ositi o ns. A si n gle hear t rate meas ure me nt 
s h o ul d be ta ke n j ust pri or t o t he B P e val uati o n i n t he sitti n g, s u pi ne, a n d sta n di n g p ositi o ns.  
All rea di n gs ar e t o be e nt ere d i nt o t he s o urce d oc u me nt a n d C R F f or all s u bjects. T he date 
a n d ti me of B P meas ure me nts s h o ul d be ca pt ure d i n t he s o urce d oc u m e nt a n d C R F. B P will 
be assesse d first i n t he sitti n g p ositi o n. Sitti n g B P a n d heart rate will be meas ure d after t he 
s u bject has been sitti n g f or at least 5 mi n  wit h feet o n t he fl o or a n d ar m s u p p orte d at heart 
le vel. 
After sitti n g B P meas ur e me nt has bee n c o m plet e d, s u pi ne a n d sta n di n g B P will be meas ure d 
t o e val uate ort h ostatic vit al si g ns. S u pi ne a n d sta n di n g bl o o d press ure meas ures will n ot be 
use d t o deter mi ne eli gi bilit y f or t he st u d y. First, t he s u bject will lie flat f or 5 mi n  a n d ha ve 
heart r ate a n d s u pi ne bl o o d press ure meas ure d usi n g t he sa m e e q ui p me nt a n d ar m as 
descri be d f or sitti n g B P. O nce t he s u pi ne B P meas ure me nt is c o m plete, t he s u bject will 
sta n d. Sta n di n g B P a n d h eart r ate will be meas ure d after 2 mi n  of sta n di n g. F or sta n di n g B P 
meas ure me nts, t he ar m s h o ul d be s u p p orte d a n d e xte n de d s uc h t hat t he c uff is at heart le v el.  
6. 1 0   El e ctr o c ar di o gr a p h y  
A 1 2 -lea d el ectr o car di o gra m ( E C G) will be c o n d u cte d at t he ti me p oi nts i n dicate d i n t he 
Sc he d ule of E ve nts i n A p pe n di x 1  a n d w he ne ver cli nicall y i n dicate d. T his pr oce d ure s h o ul d 
be perf or me d i n t he s u pi ne p ositi o n after at least 1 0 mi n of rest. E C G para meters meas ure d 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 6  of 7 2  
V 4 ( Gl o bal)  
 
will be t he R R i nter val, P R i nter val, Q R S d urati o n, a n d Q T i nter val. E ac h E C G s h o ul d als o 
be assesse d b y t he i n v esti gat or f or si g ns of isc h e mia, cli nicall y si g nifica nt h y p ertr o p h y, a n d 
cli nicall y si g nifica nt T -w a ve a b n or m alities or arr h yt h mia.  
It is t he i n vesti gat or’s res p o nsi bilit y t o re vi e w t he res ults of t he E C G as t he y bec o me 
a vaila ble. F or eac h a b n or mal E C G res ult, t he i n vesti gat or s hall as certai n if t he o bser vati o n 
re pres e nts a cli nicall y si g nifica nt c ha n ge fr o m t he scree ni n g E C G f or t hat i n di vi d ual 
s u bject.  T his deter mi nati o n  d oes n ot necess aril y n ee d t o be ma d e t he first ti me a n a b n or mal 
res ult is o bser ve d. T he i n vesti gat or m a y re p eat t he E C G t o verif y t he ori gi n al res ult. If t he 
E C G res ult is deter mi ne d t o be a cli nicall y si g nifi ca nt a n d a b n or mal c ha n ge fr o m baseli ne f or 
t hat s u bject, it is c o nsi dere d t o reflect a n A E.  
6. 1 1  Cli ni c al L a b or at or y T e st s  
Cli nical la b orat or y test para meters  are liste d i n Ta ble 1.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 7  of 7 2  
V 4 ( Gl o bal)  
 
T a bl e  1 . 
Li st of L a b or at or y T e st s  
Test N a me  
  
Bl o o d or Uri ne V ol. 
( m L) 
S hi p me nt  
He m at ol o g y  
2 ( bl o o d)  
A m bie nt  
- He mat ocrit ( Hct)  
- He m o gl o bi n ( H g b)  
- Mea n c or p usc ular he m o gl o bi n 
( M C H) 
- Mea n c or p usc ular he m o gl o bi n 
c o nce ntrati o n ( M C H C)  
- Platelet c o u nt  
- Mea n c or p usc ular  v ol u me 
( M C V) 
- Re d cell distri b uti o n wi dt h 
( R D W) 
- 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 wit h differe ntial  
  
  
Ser u m C he mistr y a n d Electr ol ytes    
1 0 (ser u m)  
A m bie nt  
- Al b u mi n ( A L B)  
- Ala ni ne a mi n otra nsferase ( A L T)  
- As partate a mi n otra nsferase ( A S T)  
- Bl o o d urea nitr o ge n ( B U N)  
- Gl uc ose  
- Bicar b o nate ( H C O 3) 
- Creati ni ne  
- C hl ori de ( Cl)  
- T otal pr otei n  
- Calci u m ( Ca)  
- Ma g nesi u m  
- P h os p h or us  
- P otassi u m ( K)  
- S o di u m ( Na)  
- T otal bilir u bi n  
- Direct bilir u bi n  
- Uric aci d  
  
  
Gl yce mic C o ntr ol  
  
  
A m bie nt  
- Fasti n g plas ma gl uc ose ( F P G)  
- He m o gl o bi n A 1c ( H b A 1c)  
  
2 ( plas ma)  
2 ( bl o o d)  
  
Ser u m Li pi ds  
  
6 (ser u m)  
A m bie nt  
- T otal c h olester ol ( T C)  
- Hi g h -de nsit y li p o pr otei n 
c h olester ol ( H D L -C)  
- Tri gl yceri des ( T G)  
- L o w -de nsit y li p o pr otei n 
c h olester ol ( L D L -C), 
calc ulate d  
- L D L -C, direct (if a p plica ble)  
  
  
  
Uri n al ysis  
  
1 0 ( uri ne)  
A m bie nt  
- A p peara nce  
- Bilir u bi n  
- C ol or  
- Gl uc ose  
- Ket o nes  
- Micr osc o pic e xa mi nati o n of 
se di me nt  
- Nitrite  
- Occ ult bl o o d  
- p H  
- Pr otei n  
- S pecific gra vit y  
- Ur o bili n o ge n  
- Le u k oc yte esterase  
  
  
Uri n ar y Al b u mi n Assess me nt  
- U A C R  
 
2 ( uri ne ) 
A m bie nt  
Uri ne pre g n a nc y test ( W O C B P)  
  
2 ( uri ne)  
L ocal  
P o p ul ati o n P K S a m pli n g  
- B e xa glifl ozi n plas ma le vel  
  
2 ( plas ma)  
Fr oze n  
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 8  of 7 2  
V 4 ( Gl o bal)  
 
6. 1 1. 1  
S a m pl e C oll e cti o n, St or a g e, a n d S hi p pi n g  
6. 1 1. 1. 1  
H e m at ol o g y, Bl o o d C h e mi str y, S er u m Li pi d s, a n d Gl y c e mi c C o ntr ol 
A s s e s s m e nt s  
Bl o o d sa m ples f or h e mat ol o g y, c h e mistr y, ser u m li pi ds a n d gl yce mic c o ntr ol assess me nts 
will be c ollecte d. S u bjects will be i n a seate d or s u pi ne p ositi o n d uri n g bl o o d c ollecti o n. 
Sa m ples will be c ollecte d at t he ti me p oi nts i n dicate d i n t he sc he d ule of e v e nts i n A p pe n di x 1  
a n d A p pe n di x 2 . 
T he st u d y staff will c o ntact eac h s u bject pri or t o a sc he d ule d cli nic visit t o c o nfir m t he ti me 
of t he visit a n d t o re mi n d t he s u bject of pr o per fasti n g practice. A s u bj ect m ust be q uerie d t o 
assess c o m plia nce wit h a  mi ni mal of 8 h fast pri or t o bl o o d dra w t o e ns ure t he F P G a n d 
tri gl yceri des val ues ca n b e acc uratel y d eter mi ne d. If a s u bject h as n ot faste d f or a mi ni mal of 
8 h, t he s u bject m ust ret ur n as s o o n as ca n be arra n ge d ( wit hi n 1 wee k) t o pr o vi de a s peci me n 
after pr o p er f asti n g.  
L D L -C will be calc ul ate d b y  t he Frie d e wal d e q u ati o n. If tri gl yceri des are > 4 0 0 m g/ d L, t he 
calc ulate d L D L-C val ue is i n vali d b y t his e q uati o n a n d will be set as missi n g. Direct L D L -C 
will be deter mi ne d i n s u b jects w h ose tri gl yceri des are >3 5 0 m g/ d L at scree ni n g visit. All 
s u bse q ue nt L D L -C of t hese s u bjects will be deter mi ne d b y t he sa m e direct L D L -C 
meas ure me nts o nl y.  
A n i n vesti gat or ca n p erf or m a d diti o nal la b orat or y testi n g t o dia g n ose or t o f oll o w u p a n 
a d verse e ve nt pr o gressi o n or res ol uti o n. Cli nical sa m ples s h o ul d be a nal yz e d i n a l ocal 
la b orat or y if a fast t ur nar o u n d ti me is necessar y t o deter mi ne treat me nt pla n.  
6. 1 1. 1. 2  
Uri n al y si s  
Uri ne sa m ples will be c ollecte d r o uti nel y at desi g n ate d cli nic visits fr o m a clea n cat c h 
sa m ple. Uri nal ysis will be perf or me d at t he ti me p oi nts i n dicate d i n t he sc he d ule of e v e nts 
(A p pe n d i x 1 a n d A p pe n di x 2 ). I n v esti gat or or staff s h o ul d d oc u me nt if pre- me n o pa usal 
fe male s u bjects are me nstr uati n g a n d n ot e it i n t he s o urce d oc u m e nts si nce he mat uria is 
li kel y t o be i de ntifie d o n di pstic k uri nal ysis. 
Uri ne sa m ples will be tra ns p orte d t o t he ce ntral la b orat or y f or uri nal ysis. Micr osc o p y will be 
c o n d ucte d if t he s u bject has a p ositi ve res ult o n t he le u k oc yte esteras e or nitrite di pstic k tests 
t o clarif y t he si g nifica n ce of t he fi n di n g. Res ults of gl uc ose m eas ure me nt i n t he uri nal ysis 
m ust be s u p presse d fr o m t he la b orat or y re p orts s o t he s p o ns or, i n vesti gat ors, st u d y 
c o or di nat ors, p har macists, st u d y s u bjects, a n d t he C E C me m bers will re mai n bli n de d t o t he 
d osi n g assi g n me nt. 
I n a d diti o n, stri ps t o assess le u k oc yt e esterase a n d nitrite b ut n ot gl uc ose will be pr o vi de d f or 
i m me diate assess me nt at t he cli nical sites. If m ore t ha n traces of p ositi ve res ults are s h o w n i n 
t he le u k oc yte esterase a n d / or nitrite testi n g, a uri n e c ult ure s h o ul d be p erf or me d i n 
a desi g n ate d la b orat or y r e gar dless of p atie nt re p orte d si g ns or s y m pt o ms. Res ults of t he 
uri nal ysis a n d p ossi ble uri ne c ult ure will be d oc u m e nte d i n t he C R Fs. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 3 9  of 7 2  
V 4 ( Gl o bal)  
 
6. 1 1. 1. 3  
R e n al f u n cti o n t e sti n g  
Ser u m creati ni ne will be meas ure d as part of t he s er u m c he mi str y at t he s c he d ule d cli nical 
visits.  U A C R will be deter mi ne d at  ti me p oi nts s pecifie d i n t he sc h e d ule of la borat or y tests 
(A p pe n di x 2 ).  
At t he scree ni n g a n d ra n d o mizati o n visits ( V 1 a n d V 3), se r u m sa m ples m ust be s u b mitte d t o 
t he ce ntral la b orat or y f or ser u m creati ni ne testi n g. T he ser u m creati ni ne v al ue deter mi ne d  at 
t he scree ni n g visit b y t he ce ntral la b orat or y will b e t he val ue f or assessi n g eli gi bilit y, 
assi g ni n g strat u m at r a n d o mizati o n, a n d t he ce ntral la b ser u m creati ni ne val ue deter mi ne d at 
t he ra n d o mizati o n ( V 3) will be t he baseli ne val ue f or t he data a nal yses.  
D uri n g t h e st u d y p eri o d, if a ra pi d t ur nar o u n d ti me is necessar y f or cli nical assess me nt of a 
p ote ntial ki d ne y i nj ur y, t esti n g fr o m l ocal la b orat ories s h o ul d be use d. 
6. 1 1. 1. 4  
P o p ul ati o n P K S a m pli n g  
Bl o o d sa m ples f or t he p o p ulati o n P K a nal ysis will be dra w n w he n t he s u bjects ret ur n t o t he 
cli nic bet wee n wee k s 6 a n d 1 2 fr o m 1 4 4 s u bjects w h o c o nse nt t o partici pati n g i n t he P K 
st u d y i n parti ci pati n g trial ce nters. O n e bl o o d sa m ple will be dra w n at eac h of t he 3 ti me 
p oi nts fr o m eac h s u bject f or a t otal of 3 p ost- d ose sa m ples per s u bject. A p pr o xi matel y 7 2 
s u bjects will be sa m ple d at 0. 2 5 t o 1 h, 7 t o 1 0 h, a n d 2 0 t o 2 4 h p ost d ose (r o uti ne 1). 
A n ot her 7 2 s u bjects will be sa m ple d at 1. 5 t o 3 h, 3. 5 t o 6. 5 h a n d 7 t o 1 0 h p ost- d ose 
(r o uti ne 2). T he s a m pli n g ti me s h o ul d ta ke i nt o c o nsi derati o n t he st u d y s u bject a vaila bilit y 
a n d ca n b e o n a n y of t he da ys d uri n g t h e wee k of t he s pecifie d cli nical vi sits. T he d ose d oes 
n ot nee d t o be ta ke n at t he cli nic h o we v er t he precise d osi n g ti me a n d sa m ple dra w ti me m ust 
be rec or de d  i n t he C R F. 
T w o m L ( 2 m L) of w h ol e ve n o us bl o o d will be c ollecte d fr o m a p eri p heral vei n. Sa m ples 
will be place d i n t u bes c o ntai ni n g K 2E D T A, st ore d o n ice, a n d ce ntrif u ge d u n der 
refri gerati o n f or at least t e n mi n utes at 3, 0 0 0 r p m. After ce ntrif u gati o n, plas ma will be 
re m o ve d a n d st or e d fr oze n i n 3 ali q u ots of 2 0 0 µ L at or bel o w - 2 0 o C at t he site. Pr ocesse d 
fr oze n plas ma sa m ples will be tra nsferre d o n dr y i ce t o t he ce ntral la b orat or y at s pecifie d 
s hi p me nt i nter vals a n d will be st ore d at or bel o w - 2 0 o C u ntil a nal ysis.  
Plas ma c o nce ntr ati o ns of be x a glifl ozi n will be deter mi ne d b y a vali dat e d L C -M S/ M S 
met h o d. A p pr o xi matel y 2 1 6 meas ure me nts of b e x a glifl ozi n plas ma c o nce ntrati o ns will be 
c ollecte d fr o m a n esti mat e d 7 2 s u bjects w h o will ha ve recei ve d acti ve dr u g i n t his st u d y. 
6. 1 2   Di ar y a n d Gl u c o m et er R e c or d R e vi e w  
Re vie w gl yce mic c o ntr ol  diar y, gl u c o meter  rec or d, a n d s y m pt o ms t hat ma y i ndicat e p ote ntial 
D K A wit h t he s u bject a n d rec or d  t h e fi n di n gs i n t he C R F . 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 0  of 7 2  
V 4 ( Gl o bal)  
 
6. 1 3   Di s p e n si n g R u n-i n Dr u g  
Eac h eli gi ble st u d y s u bject will recei ve o n e b ottle of r u n -i n dr u g bas e d o n t he sc he d ule d visit 
o utli ne d i n A p pe n di x 1 . 
Patie nts s h o ul d self-a d mi nister first d ose of r u n-i n dr u g wit h 2 5 0 m L of wat er u n der 
o bser vati o n d uri n g t he sc he d ule d visit.  
6. 1 4   R a n d o mi z ati o n 
S u bjects  w h o ha ve met all t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria at t he e n d 
of t he r u n-i n peri o d will be ra n d o mize d t o recei ve i n vesti gati o nal pr o d u ct usi n g t he I W R S. A 
ra n d o mizati o n n u m ber a n d a dr u g kit n u m ber will be assi g n e d t o t he s u bject. T he s u bject 
s h o ul d be i nstr ucte d t o refrai n fr o m ta ki n g t he r u n-i n me dicati o n o n t he da y of 
ra n d o mizati o n. T he date a n d ti me of t he last d ose of r u n-i n dr u g s h o ul d be rec or d e d. Su bject 
will ta ke t he first d ose of t he d o u ble- bli n d st u d y dr u g at t he cli nic. 
6. 1 5   Di s p e n si n g I n v e sti g ati o n al Pr o d u ct  
At ra n d o mizati o n a n d at wee k 1 2, eac h st u d y s u bj ect will recei ve o ne b ottl e of t he 
i n vesti gati o nal pr o d u ct base d o n t he kit n u m ber assi g ne d t o t he s u bject b y t he I W R S. O ne 
b ottle of t he i n vesti gati o nal pr o d uct will pr o vi de dail y d osi n g f or 1 2 wee ks. 
Patie nts s h o ul d self- a d mi nister first d ose of i n vesti gati o nal p r o d u ct wit h 2 5 0 m L of w ater 
u n der o bser v ati o n d uri n g t he sc he d ule d visits, if t he y h a ve n ot alrea d y ta k e n i n vesti gati o nal 
pr o d uct t hat da y.  
6. 1 6  A d v er s e E v e nt s A s s e s s m e nt s  
6. 1 6. 1  
D efi niti o n of A d v er s e E v e nt s  
A d verse e v e nt ( A E ): A n y u nt o war d me dical o cc urre nce i n a s u bject a d mi nistere d a 
p har mace utical pr o d uct t hat d oes n ot necess aril y ha ve a ca usal relati o ns hi p wit h t he 
treat me nt.  
A n A E ca n t h eref ore b e a n y u nf a v ora bl e a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociat e d wit h t he use of a me dici n al 
pr o d uct, w het her or n ot it is c o nsi dere d relate d t o t he me dici nal pr o d uct us e. 
Seri o us a d verse e ve nt ( S A E): A seri o us a d verse e ve nt (e x perie n ce) or reacti o n is a n y 
u nt o war d me dical o cc urr e nce t hat at a n y d ose:  
• 
res ults i n deat h,  
• 
is life-t hreate ni n g, ( N O T E: T he ter m "life -t hreat e ni n g" i n t his c o nte xt refers t o a n e ve nt 
i n w hic h t he s u bject was at ris k of deat h at t he ti m e of t he e v e nt; it d oes n ot refer t o a n 
e ve nt w hic h h y p ot heticall y mi g ht h a ve ca use d deat h if it were m ore s e vere.)  
• 
re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 1  of 7 2  
V 4 ( Gl o bal)  
 
• 
res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y, 
• 
is a c o n ge nital a n o mal y/ birt h defect, or  
• 
is a me dicall y i m p ortant e ve nt or reacti o n. Me dical a n d scie ntific j u d g me nt s h o ul d be 
e x ercise d i n deci di n g w h et her ot her sit uati o ns s h o ul d be c o nsi dere d s eri o us s uc h as 
i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y life-t hreate ni n g or res ult i n deat h 
or h os pitalizati o n b ut ma y je o p ar dize t he s u bject or ma y re q uire i nter ve nti o n t o pre ve nt 
o ne of t he ot her o ut c o mes liste d i n t he defi niti o n a b o ve. T hese s h o ul d als o us uall y be 
c o nsi dere d seri o us. E x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge n c y 
r o o m or at h o me f or aller gic br o n c h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n h os pitalizati o n; or de vel o p me nt of dr u g d e pe n de n c y or dr u g a b use.  
 
A d verse R e acti o n: A n a d verse r eacti o n mea ns a n y a d v erse e ve nt ca use d b y a dr u g. A d verse 
reacti o ns are a s u bs et of all s us pecte d a d v erse e ve nts i n w hic h t here is a reas o n t o c o ncl u de 
t hat t he dr u g ca us e d t he e ve nt. 
U ne x pecte d A d verse Dr u g Re acti o n ( U A D R): A n a d verse reacti o n, t he nat ure or se verit y 
of w hic h is n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e. g., I n v esti gat or’s 
Br oc h ure f or a n u n a p pr o ve d i n vesti gati o nal me di ci nal pr o d uct). 
Seri o us a n d U ne x pecte d S us pecte d A d verse R e acti o n ( S U S A R): T h e s p o ns or m ust re p ort 
i n a n I N D safet y re p ort a n y s us pecte d a d v erse reacti o n t o st u d y treat me nt (i.e., i ncl u di n g 
acti ve c o m parat ors) t h at is b ot h seri o us a n d u ne x pecte d ( 2 1 C F R 3 1 2. 3 2(c)( 1)(i)). Bef ore 
s u b mitti n g a n I N D safet y re p ort, t he s p o ns or n ee ds t o e ns ure t hat t he e v e nt meets all t hree of 
t he defi niti o ns:  
• 
S us pecte d a d verse r eacti o n  
• 
Seri o us  
• 
U ne x pecte d  
 
Se verit y: A Es will be gr a de d o n a 3- p oi nt scale a n d re p orte d as i n dicate d i n t he C R F. T he 
i nte nsit y of a n a d vers e e x perie nce is defi ne d as f oll o ws: 
1 = Mil d: e ve nt is me dicall y si g nifica nt b ut pr o d u ces n o disr u pti o n t o dail y acti vit y; 
2 = M o derat e: e ve nt is me dicall y si g nifi ca nt a n d re d uces or affects n or mal dail y acti vit y;  
3 = Se ver e: e ve nt is me di call y si g nifica nt a n d res ults i n i na bilit y t o w or k or perf or m 
n or mal dail y acti vit y.  
 
I n vesti g ati o n al Pr o d uct C a us alit y: A n assi g n me nt ma de b y t h e i n vesti ga t or base d o n t he 
circ u msta nces of t he e v e nt a n d its a nal ysis. Cases wit h ca usal rel ati o ns hi p classifie d as 
p ossi ble, pr o ba ble or defi nite are defi ne d as relate d. Cases wit h ca usal relati o ns hi p 
cate g orize d as n ot li kel y or u nrelate d are d efi ne d as n ot relate d.  Relati o ns hi p of a n A E t o 
d osi n g will be assess e d as f oll o ws: 
Defi nite:  T he e ve nt r es p o n ds t o wit h dra wal of t he i n vesti gati o nal pr o d u ct ( dec halle n ge), 
a n d rec urs wit h rec halle n ge b y a d mi nistrati o n of t he i n vesti gati o nal pr o d uct.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 2  of 7 2  
V 4 ( Gl o bal)  
 
Pr o b a ble:  T h ere is a reas o na ble ca us al relati o ns hi p bet wee n t he i n vesti gati o nal pr o d uct 
a n d t he A E. T he e ve nt r es p o n ds t o dec halle n ge. R ec halle n ge is n ot re q uire d. 
P ossi ble:  T here is a r eas o na ble ca us al relati o ns hi p bet wee n t he i n v esti gati o nal pr o d uct 
a n d t he A E. D ec halle n ge is lac ki n g or d ec h alle n ge res p o nse is u nclear.  
N ot Li kel y : T here is a te m p oral relati o ns hi p t o i n vesti gati o nal pr o d u ct a d mi nistrati o n, b ut 
t here is n ot a reas o na ble ca usal relati o ns hi p bet wee n t he i n vesti gati o nal pr o d uct a n d t he 
e ve nt.  
U nrel ate d : T h ere is n ot a te m p oral or ca usal relati o ns hi p t o i n vesti gati o nal pr o d uct 
a d mi nistrati o n.  
 
6. 1 6. 2  
Eli citi n g a n d R e p orti n g A E s  
T he i n vesti gat or will peri o dicall y assess s u bjects f or t he occ urre n ce of A Es after a s u bject 
c o nse nts t o partici pati o n i n t he st u d y. T o a v oi d bias i n c ollecti n g i nf or m ati o n a b o ut A Es, t he 
i n vesti gat or s h o ul d as k s u bjects t he f oll o wi n g q u esti o n: " H o w ha ve y o u felt si nce y o u were 
last c hec ke d?" All A Es (seri o us a n d n o n-seri o us) re p orte d b y t he s u bject m ust be rec or d e d o n 
t he s o urce d o c u me nts a n d C R Fs pr o vi de d b y t h e s p o ns or. 
It is t he i n vesti gat ors r es p o nsi bilit y t o re vi e w t he res ults of all la b orat or y t ests as t he y 
bec o me a v aila ble. F or eac h a b n or mal la b orat or y t est res ult t he i n vesti gat or nee ds t o ascertai n 
if t his is a cli nicall y si g nifica nt c ha n ge fr o m b aseli ne f or t hat i n di vi d ual s u bject (t his 
deter mi nati o n, h o we ver, d oes n ot necess aril y n ee d t o be ma de t he first ti me a n a b n or mal 
val ue is o bser ve d. T h e i n vesti gat or m a y re p eat t he la b orat or y test or re q uest a d diti o nal tests 
t o verif y t he res ults of t h e ori gi n al la b orat or y t ests). If t he la b orat or y val u e is deter mi ne d t o 
be a cli nicall y si g nifica nt a n d a b n or mal c h a n ge fr o m baseli ne f or t hat s u bject, t his is 
c o nsi dere d a la b orat or y A E.  
H y p o gl yce mia is defi ne d as a n y F P G or S M B G val ue < 7 0 m g/ d L a n d d oc u me nte d as 
descri be d i n Secti o n 6 . 1 6. 1 1. 
A n y i ncreas e i n li ver f u n cti o n tests ( A S T, A L T, or bilir u bi n) greater t ha n 3 ti mes t he U L N 
f or t he la b or at or y utilize d will be c o nsi dere d a la b orat or y A E. 
I n a d diti o n, t he s p o ns ors Me dical M o nit or or its desi g nat e d pers o n n el m ust be n otifie d 
i m me diatel y b y tele p h o n e, e mail, or fa x of a n y i m me diatel y re p orta ble A Es (I R A E) 
acc or di n g t o t he pr oce d ure o utli ne d bel o w. S pecial atte nti o n s h o ul d be pai d t o rec or di n g 
h os pitalizati o n a n d c o nc o mita nt me dicati o ns.  
6. 1 6. 3  
I m m e di at el y R e p ort a bl e A E s  
T he i n vesti gat or m ust re p ort a n y S A E t o t he s p o ns or or its re pres e ntati ve i m me diatel y after 
t he i n vesti gat or b ec o mes a war e of t he e ve nt. A n S A E f or m s h o ul d be c o m plete d a n d se nt t o 
t he s p o ns or wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt. 
N o n -seri o us e v e nts t hat r e q uire disc o nti n uati o n of i n vesti gati o nal pr o d u ct (i ncl u di n g 
la b orat or y a b n or malities) s h o ul d be re p orte d t o t he s p o ns or wit hi n 3 w or ki n g da ys. T h e C R F 
A E f or m s h o ul d be c o m plete d a n d se nt t o t he s p o ns or. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 3  of 7 2  
V 4 ( Gl o bal)  
 
S u bjects e x perie nci n g a n S A E s h o ul d be f oll o we d cli nicall y u ntil t heir healt h has ret ur ne d t o 
baseli ne stat us or n o f urt her i m pr o ve me nt i n c o n diti o n ca n be e x pecte d wit h f urt her care. It is 
e x pecte d t hat t he i n vesti gat or will pr o v i de or arra n ge a p pr o pri ate s u p p orti ve care f or t he 
s u bject. 
6. 1 6. 4  
Pr e g n a n c y  
W O C B P w h o are se x uall y acti ve m ust use a n effecti ve met h o d of birt h c o ntr ol d uri n g t he 
c o urse of t he st u d y, i n a ma n ner s uc h t hat ris k of fail ure is mi ni mize d. Acce pta ble birt h 
c o ntr ol met h o ds i ncl u de, b ut are n ot li mite d t o, oral c o ntrace pti ves, i ntra uteri ne de vices, 
De p o -Pr o vera ® , N or pla nt® , h or m o nal c o ntrace pti ve i m pla nts, bilateral t u bal li gati o n, part ner 
wit h vasect o m y, c o n d o m or dia p hra g m pl us c o ntrace pti ve s p o n ge, f oa m, or jell y, a n d 
a bsti ne nce.  
 
Bef ore e nr olli n g W O C B P i n t his cli nical trial, i n vesti gat ors m ust re vi e w g ui deli nes a b o ut 
st u d y partici p ati o n f or W O C B P. T he t o pics s h o ul d ge n erall y i ncl u de: 
• 
Ge ner al i nf or mati o n  
• 
I nf or me d c o ns e nt f or m 
• 
Pre g n a nc y pr e ve nti o n i nf or mati o n 
• 
Dr u g i nteracti o ns wit h h or m o nal c o ntrace pti ves. 
• 
C o ntrace pti ves i n c urre nt use. 
• 
G ui deli nes f or t he f oll o w- u p of a re p orte d pre g na n c y. 
 
Pri or t o st u d y e nr oll me nt, W O C B P m ust be a d vise d of t he i m p orta nce of a v oi di n g pre g n a nc y 
d uri n g trial p artici pati o n a n d t he p ote ntial ris k fact ors f or a n u ni nte nti o nal pre g na nc y. T he 
s u bject m ust si g n a n i nf or me d c o nse nt f or m stati n g t he a b o ve- me nti o ne d ris k fact ors a n d t h at 
t he c o nse q ue n ces w ere disc usse d wit h her. 
D uri n g t h e st u d y, all W O C B P s h o ul d be i nstr ucte d t o c o ntact t h e i n vesti gat or i m me diatel y if 
t he y s us pect t he y mi g ht b e pre g na nt (e. g. misse d or late me nstr ual c ycle). 
If a s u bject or i n vesti gat or s us pects t hat t he s u bject ma y b e pre g n a nt pri or t o i n vesti gati o nal 
pr o d uct a d mi nistrati o n, t he i n vesti gati o nal pr o d uct a d m i nistrati o n m ust be wit h hel d u ntil t he 
res ults of ser u m pr e g na n c y t ests are a vaila ble. If t he pre g na n c y is c o nfir m e d, t he s u bject m ust 
n ot recei ve t h e i n vesti gati o nal pr o d uct a n d m ust n ot be e nr olle d or re mai n i n t he st u d y. If 
pre g na nc y is s us pecte d w hile t he s u bject is recei vi n g st u d y treat me nt, t he i n vesti gati o nal 
pr o d uct m ust be wit h hel d i m me diatel y u ntil t he res ult of t he pre g na n c y test is k n o w n. If 
pre g na nc y is c o nfir me d, t he i n vesti gati o nal pr o d uct will be per ma ne ntl y disc o nti n ue d a n d t he 
s u bject will be wit h dra w n fr o m t he trial. ( E x ce pti o ns t o st u d y dis c o nti n uati o n ma y be 
c o nsi dere d f or life -t hr eat e ni n g c o n diti o ns o nl y aft er c o ns ultati o ns wit h a s p o ns or Me dical 
M o nit or or desi g n ate d pers o n nel.) T he i n vesti gat or m ust n otif y t he Me dical M o nit or wit hi n 3 
w or ki n g d a ys of a n y fe m ale s u bject w h o bec o mes pre g na nt. T his re p orti n g re q uire me nt will 
c o nti n ue u ntil 4 wee ks after t he last i n vesti gati o nal pr o d uct e x p os ure.  
T he i n vesti gat or m ust rec or d t he e ve nt o n t he Pre g na nc y S ur veilla nce F or m a n d f or w ar d it t o 
s p o ns or’s cli nical or desi g nat e d pers o n n el. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 4  of 7 2  
V 4 ( Gl o bal)  
 
Pr ot oc ol re q uire d pr o ce d ures f or st u d y disc o nti n u ati o n a n d f oll o w- u p m ust be perf or me d o n 
t he s u bject u nless c o ntrai n dicate d b y pre g n a nc y (e. g., x-ra y st u dies). Ot h er a p pr o priate 
pre g na nc y f oll o w - u p pr o ce d ures s h o ul d b e c o nsi d ere d if i n dicate d. I n a d diti o n, t he 
i n vesti gat or m ust re p ort t o t he s p o ns or, o n t he a p pr o priate Pre g n a nc y S ur veilla nce F or m, a n y 
f oll o w- u p i nf or mati o n re gar di n g t h e c o urs e of t he pre g na nc y, i n cl u di n g p eri natal a n d 
ne o natal o utc o me. I nfa nts will be f oll o we d f or a mi ni m u m of si x m o nt hs. 
6. 1 6. 5  
Pr o c e d ur e f or Br e a ki n g t h e Bli n d  
As i n dicate d i n Secti o n 5. 5  a b o ve, t he s p o ns or, me dical m o nit or, st u d y c o or di nat ors, 
p har macists, st u d y s u bjects, a n d t he C E C me m bers will be bli n de d t o t he treat me nt 
assi g n me nt d uri n g t he st u d y peri o d. T he i n vesti gat or s h o ul d als o re mai n bli n de d t o t he 
s u bject treat me nt d uri n g t he e ntire st u d y u nless k n o wle d ge of t he s u bject’s treat me nt is 
re q uire d f or cli nical car e a n d safet y. T h e E mer ge n c y C o de Brea k m o d ule i n t he I W R S is 
use d f or s uc h sit uati o ns. T he i n vesti gat or m ust c o nfir m t he i nte nti o n t o u n bli n d t he s u bject’s 
treat me nt t o o btai n t he d ose i nf or mati o n i n I W R S. U p o n c o m pleti o n of t he u n bli n di n g, t he 
s yste m will se n d a n al ert t o desi g nate d st u d y tea m me m bers t hat a n u n bli n di n g e v e nt has 
occ urr e d. D oc u m e ntati o n of brea ki n g t he bli n d s h o ul d be rec or de d i n t he s u bject’s me dical 
rec or d wit h t he date a n d ti me t he bli n d was br o ke n, a n d t he na mes of t h e pers o n nel 
re q uesti n g a n d a ut h orizi n g u n bli n di n g. T h e treat me nt assi g n me nt will c o nti n ue t o be 
wit h hel d fr o m t he C E C me m bers u ntil all p hase 3 st u dies are c o m plete d.  
6. 1 6. 6  
F oll o w -u p of N o n -S eri o u s A E s  
N o n -seri o us A Es t hat are i de ntifie d o n t he last sc h e d ule d c o ntact m ust be rec or de d i n t he A E 
C R F wit h t he  c urre nt stat us n ote d. All n o n-seri o us e ve nts t hat are o n g oi n g at t he ti me will be 
rec or d e d as o n g oi n g i n t he C R F. 
6. 1 6. 7  
F oll o w -u p of P o st -St u d y S A E s  
S A Es t hat are i de ntifie d o n t he last sc he d ule d c o ntact m ust be rec or de d o n t he A E C R F pa ge 
a n d re p ort e d t o t he s p o ns or acc or di n g t o t he re p orti n g pr oce d ures o utli ne d i n Secti o n 6. 1 6. 3 . 
T hese ma y i ncl u de u nres ol ve d pre vi o usl y re p ort e d S A Es, or ne w S A Es. T he i n vesti gat or 
s h o ul d f oll o w t hese S A Es u ntil t he e ve nts are res ol ve d, or t he s u bject is l ost t o f oll o w- u p. 
Res ol uti o n mea ns t he s u bject has ret ur n e d t o t he baseli ne state of h ealt h, or t he i n vesti gat or 
d oes n ot e x pect a n y f urt h er i m pr o ve me nt or w orse ni n g of t he s u bject’s c o n diti o n. T he 
i n vesti gat or s h o ul d c o nti n ue t o re p ort a n y si g nifica nt f oll o w- u p i nf or mati o n t o t he s p o ns or 
u ntil t he e ve nt has bee n r es ol ve d.  
A n y n e w S A Es re p orte d b y t he s u bject t o t he i n vesti gat or t hat occ ur after t he last sc he d ule d 
c o ntact, a n d are d eter mi n e d b y t h e i n vesti gat or t o be reas o n a bl y ass ociat e d wit h t he use of 
t he i n vesti gati o nal pr o d u ct, s h o ul d be re p orte d t o t he s p o ns or or desi g nat e d pers o n nel. T his 
ma y i ncl u d e S A Es t hat ar e ca pt ur e d o n f oll o w- u p t ele p h o ne c o nt act or at a n y ot her ti me p oi nt 
after t he d efi ne d st u d y peri o d (i.e., u p t o last sc he d ule d c o ntact). T h e i n vesti gat or s h o ul d 
f oll o w S A Es i de ntifie d after t he last sc h e d ule d c o ntact u ntil t he e ve nts are res ol ve d, or t he 
s u bject is l ost t o f oll o w- u p. T he i n vesti gat or s h o ul d c o nti n ue t o re p ort a n y si g nifica nt f oll o w-

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 5  of 7 2  
V 4 ( Gl o bal)  
 
u p i nf or mati o n t o t he s p o ns or u ntil t he e ve nt has b ee n res ol v e d. T his st u d y re q uires t hat 
s u bjects be acti vel y m o nit ore d f or S A Es f or at least 4 wee ks aft er t he last treat me nt.  
6. 1 6. 8  
Uri n ar y Tr a ct I nf e cti o n s ( U TI s)  
E ve nts p ote ntiall y r e pres e nti n g U TIs, i ncl u di n g c ystitis, uret hritis, p yel o n e p hritis, or 
ur ose psis, s h o ul d be car ef ull y e v al uate d a n d d o c u me ntati o n of si g ns, s y m pt o ms, c ult ure 
res ults f or i nfecti o us a ge nt, a n d treat me nt s h o ul d be u n derta k e n w he n a p pr o priate.  
T he i n vesti gat or s h o ul d q uer y t he s u bject at e ver y visit f or s y m pt o ms t hat ma y b e relat e d t o a 
U TI a n d, if a p pr o priate, d oc u me nt t hese e v e nts as s y m pt o matic U TI i n t he C R F u nless a n 
alter nati ve dia g n osis is prese nt. I n a d diti o n, a clea n catc h uri ne s a m ple will be o btai ne d a n d a 
uri nal ysis will be perf or me d  o n t hat sa m ple at e v er y cli nical visit  e x ce pt t he visit V 2 . A 
p ositi ve uri nal ysis will be defi ne d as o ne wit h det ecta ble le u k o c yt e esteras e a n d/ or nitrites. If 
t he s u bject re p orts s y m pt o ms c o nsiste nt wit h a U TI or t he uri nal ysis at t he cli nical site is 
p ositi ve, a uri ne c ult ure will be perf or me d at t he ce ntral la b orat or y. A p ositi ve uri ne c ult ure 
will be defi ne d as o n e wit h 1 0 5 C F U of a n y s p ecies. T he i n vesti gat or ma y als o perf or m a 
uri ne c ult ure usi n g l ocal res o urces if necessar y f or cli nical care.  
6. 1 6. 9  
G e nit al M y c oti c I nf e cti o n s ( G MI s)  
T he i n vesti gat or will q uer y t he s u bj ects f or si g ns or s y m pt o ms t hat ma y re prese nt a G MI at 
all cli nic visits. G MIs will be dia g n os e d base d o n s y m pt o ms a n d, if a p pr o pri ate, p h ysi cal 
e x a m a n d la b orat or y fi n di n gs. I n vesti gat ors m ust e x cl u de t he p ossi bilit y of se x uall y 
tra ns mitte d i nfecti o ns bef ore dia g n osi n g G MI. Dia g n osis of G MIs m ust be d oc u me nte d i n 
t he C R F. 
6. 1 6. 1 0  H e p at ot o xi cit y  
If plas ma A S T a n d/ or A L T c o nce ntrati o ns > 3 x U L N are detecte d, t he i n vesti gat or will 
rec or d i n t he s o urce d o c u me nts t he date c orres p o n di n g t o t he date of t he la b orat or y 
a b n or malit y; t he t y pe, fre q ue nc y, a n d d os e of a n y c o nc urre nt me dicati o ns or s u p ple me nts 
ta ke n b y t he s u bject wit hi n t he 1 4 da ys of t he detecte d a b n or malit y; a n d a n y s y m pt o ms or 
c ha n ge i n p h ysical e x a m t hat ha ve occ urre d si nce t he pri or assess me nt. T h e i n vesti gat or 
s h o ul d perf or m a d diti o nal la b orat or y a n d i ma gi n g tests t o atte m pt t o esta blis h t he ca use of 
t he A S T a n d A L T ele v ati o ns, i ncl u di n g r uli n g o ut a n y p ot e ntial c o ntri b uti o n fr o m b o ne or 
m uscle eti ol o gies.  
A n y cli nicall y si g nifica nt i ncreas e i n he patic e nz y mes a n d s pecificall y a n y A L T or A S T > 3 
x U L N re q uir es i m me diate re peat test wit hi n 4 8 t o 7 2 h o ur t o c o nfir m t he h e patic e nz y m e 
ele vati o n a n d s h o ul d be r e peate d b ase d o n t he cli nical sit uati o n at least e ver y 9 6 h o ur ( 4 
da ys) u ntil A L T a n d A S T ret ur n t o < 2. 5 x U L N. St u d y m e dicati o n s h o ul d be st o p pe d a n d t he 
e ve nt s h o ul d be re p orte d as a la b or at or y A E wit hi n t he C R F if t he e nz y me ele vati o n is 
c o nfir me d or w orse ni n g.  
He pat ot o xicit y will be d ia g n os e d a n d e ntere d as a n A E s h o ul d a n y of t he f oll o wi n g occ ur: 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 6  of 7 2  
V 4 ( Gl o bal)  
 
• 
A L T or A S T > 8 x U L N;  
• 
A L T or A S T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N or I N R > 1. 5 
• 
A L T or A S T > 3 x U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).  
 
I n t he e ve nt of h e pat ot o xicit y, i n vesti gati o nal pr o d uct s h o ul d be per ma n e ntl y disc o nti n ue d. 
T he i n vesti gat or is e nc o ura ge d t o c o ns ult wit h t he Me dical M o nit or re gar di n g dia g n ostic 
e val uati o n f or t he h e patic e nz y me el e vati o ns. C o ns ultati o n wit h a he pat ol o gist ma y als o be 
a p pr o priate i n s o me circ u msta nces.  
6. 1 6. 1 1  H y p o gl y c e mi a  
E ve nts of h y p o gl yce mia or p ote ntiall y re pres e nti n g h y p o gl yce mia s h o ul d be caref ull y 
e val uate d.  
All s u bjects will be pr o vi de d wit h a gl uc o mete r a n d diar y f or rec or di n g bl o o d gl uc os e 
meas ure me nts a n d si g ns a n d s y m pt o ms of h y p o gl yce mia. D uri n g t he st u d y t he s u bject is 
e x pecte d t o rec or d dail y S M B G rea di n gs a n d all si g ns a n d s y m pt o ms t hat ma y p ote ntiall y 
reflect h y p o gl yce mia. I n t he e ve nt of s uc h si g ns or s y m pt o ms, t he s u bject is e x pecte d t o 
c hec k t he bl o o d gl uc os e if it is reas o na bl y safe t o d o s o, a n d c o ns u me car b o h y drates, if 
a p pr o priate, t o tr eat h y p o gl yce mia.  
T he s u bject will be e x pecte d t o rec or d i n t he gl yce mic c o ntr ol diar y t he f oll o wi n g 
i nf or mati o n f or eac h h y p o gl yce mic e ve nt: 
1.  Si g ns a n d s y m pt o ms attri b ute d t o h y p o gl yce mia a n d t he ti me a n d date o n w hic h t he y 
occ urr e d  
2.  S M B G rea di n g at t he ti me of t he si g ns a n d s y m pt o ms attri b ute d t o h y p o gl yce mia  
3.  Ti me ela pse d fr o m t he m ost rece nt meal t o t he o nset of si g ns a n d s y m pt o ms 
4.  T y pe of treat me nt use d ( e. g., j uice, crac k ers) f or t he si g ns a n d s y m pt o ms a n d w het her 
assista nce was re q uir e d fr o m a n ot her pers o n t o a d mi nister t he treat me nt  
5.  S M B G rea di n g 1 5 mi n ut es after treat me nt wit h car b o h y drate a n d t he ti me at w hic h 
t his was meas ure d 
6.  W het her or n ot t he si g ns a n d s y m pt o ms attri b ute d t o h y p o gl yce mia res ol ve d after 
bl o o d gl uc ose ret ur ne d t o n or mal. 
 
S u bjects are e n c o ura ge d t o call t he st u d y cli nic s h o ul d si g ns a n d s y m pt o ms p ote ntiall y 
relate d t o h y p o gl yce mia occur.  
At eac h st u d y visit, t he i n vesti gat or is e x pecte d t o re vie w t he gl uc o m eter a n d gl yce mic 
c o ntr ol diar y wit h partic ular atte nti o n t o a n y S M B G val ue < 7 0 m g/ d L a n d a n y rec or de d si g ns 
or s y m pt o ms p ote ntiall y relate d t o h y p o gl yce mia. I n a d diti o n, t he i n vesti gat or s h o ul d q uer y 
t he s u bject wit h re gar d t o t he occ urre nce of si g ns a n d s y m pt o ms p ote ntiall y relate d t o 
h y p o gl yce mia e ve n if n o ne are rec or de d i n t he diar y.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 7  of 7 2  
V 4 ( Gl o bal)  
 
I n t he e ve nt of a bl o o d gl uc ose val ue < 7 0 m g/ d L or si g ns a n d s y m pt o ms p ote ntiall y rel ate d 
t o h y p o gl yce mia, t h e i n vesti gat or s h o ul d c o m plet e t he s u p ple me ntal C R F t hat  will i ncl u de 
data fr o m t he gl yce mic c o ntr ol diar y a n d acti o n ite ms t o re d uce f ut ure h y p o gl yce mia 
e pis o des.  
H y p o gl yce mia e v e nts will be rec or de d i n t he h y p o gl yce mia l o g u n d er 5 cat e g ories:  
1.  Se vere h y p o gl yce mia: a n e ve nt re q uiri n g assista nce b y a n ot her p ers o n t o acti vel y 
a d mi nister car b o h y drate, gl uca g o n, or ot her res uscitati ve acti o ns. T hese e pis o des ma y 
be ass ociate d wit h s uffici e nt  ne ur o gl yc o pe ni a t o i n d uce seiz ure or c o ma. Plas ma 
gl uc ose m eas ur e me nts ma y n ot b e a vaila bl e d uri n g s uc h a n e ve nt, b ut ne ur ol o gical 
rec o ver y attri b uta ble t o t he rest orati o n of pl as ma gl uc ose t o n or mal is c o nsi dere d 
s ufficie nt e vi de n ce t hat t he e ve nt w as i nd uce d b y a l o w plas ma gl uc ose c o nce ntrati o n. 
All s uc h e ve nts s h o ul d be rec or de d as S A Es i n t he C R F. 
2.  D oc u me nte d s y m pt o matic h y p o gl yce mia: a n e ve nt d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl yce mia ar e acc o m pa nie d b y a meas ure d plas ma gl uc os e c o nce ntrati o n < 
7 0 m g/ d L ( 3. 9 m m ol/ L).  
3.  As y m pt o matic h y p o gl yce mia: a n e ve nt n ot acc o m pa nie d b y t y pi cal s y m pt o ms of 
h y p o gl yce mia b ut wit h a meas ure d bl o o d gl uc ose c o nce ntrati o n < 7 0 m g/ d L 
( 3. 9 m m ol/ L).  
4.  Pr o ba ble s y m pt o matic h y p o gl yce mia: a n e v e nt d uri n g w hic h s y m pt o ms of 
h y p o gl yce mia ar e n ot acc o m pa nie d b y a bl o o d gl uc ose deter mi nati o n b ut t hat is 
pres u ma bl y ca us e d b y a bl o o d gl uc ose c o nce ntrati o n < 7 0 m g/ d L ( 3. 9 m m ol/ L). 
5.  Relati ve h y p o gl yce mia: A n e ve nt d uri n g w hic h t h e pers o n wit h dia bet es re p orts a n y 
of t he t y pical s y m pt o ms of h y p o gl yce mia, a n d i nt er prets t h ose as i n dicati ve of 
h y p o gl yce mia, b ut wit h a meas ure d plas ma gl u c os e c o nce ntrati o n > 7 0 m g/ d L 
( 3. 9 m m ol/ L).  
 
W hile eac h e ve nt meeti n g t he criteria a b o ve will be e ntere d i nt o t he h y p o gl yce mia l o g, o nl y 
critical h y p o gl yce mia, d o c u me nte d s y m pt o matic h y p o gl yce mia, as y m pt o matic 
h y p o gl yce mia, a n d pr o b a ble h y p o gl yce mia will be e ntere d as A Es.  
I n t he e ve nt of as y m pt o m atic h y p o gl yce mia, t he i n vesti gat or s h o ul d re vie w t he si g ns a n d 
s y m pt o ms of h y p o gl yce mia wit h t he s u bject t o elicit a c o m plete descri pti o n a n d s h o ul d 
re vie w pr o p er gl uc o met er tec h ni q ue t o e ns ure t hat t he l o w gl uc os e val ue is n ot d ue t o 
i m pr o per use of t he gl u c o meter. 
T he i n vesti gat or s h o ul d be alerte d t o t he li keli h o o d of i m pr o per gl uc ose m eas ure me nt 
tec h ni q ue if a stu d y s u bject re p orts a n S M B G val u e < 5 5 m g/ d L t h at is n ot ass ociate d wit h 
a n y si g ns or s y m pt o ms of h y p o gl yce mia a n d is n ot treate d b y s o me f or m of gl uc ose 
a d mi nistrati o n.  
I n t he e ve nt of pr o ba ble s y m pt o matic h y p o gl yce mia, t he i n vesti gat or s h o ul d e nc o ura ge t he 
s u bject t o o btai n gl uc os e val ues, w he n p ossi ble, i n t he c o nte xt of si g ns a n d s y m pt o ms of 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 8  of 7 2  
V 4 ( Gl o bal)  
 
h y p o gl yce mia, e ve n if t h e gl u c ose val ue is meas ure d after treat me nt f or t he s y m pt o ms is 
a d mi nistere d.  
If h y p o gl yce mia o cc urs i n a n y s u bj ect pres cri be d resc ue m e dicati o n f or h y per gl yce mia 
d uri n g t he st u d y, t he t otal dail y d ose of t h e res c ue me dicati o n s h o ul d be re d uce d 5 0 % or 
m ore at t he discr eti o n of t he i n vesti gat or . 
6. 1 6. 1 2  M aj or A d v er s e C ar di o v a s c ul ar E v e nt ( M A C E)  
E val uati o n of M A C E will be u n derta ke n acr oss t he de vel o p me nt pr o gra m f or be x a glifl ozi n. 
All M A C E re p orts s h o ul d als o be ca pt ure d as S A Es a n d e ver y eff ort will be ma de t o e ns ure 
t hat e ve nts rec or de d as M A C E are c o d e d i n a si milar ma n ner wit hi n t he safet y data b ase. T h e 
S A E listi n g will als o be re vie we d p eri o dicall y b y t he C E C me m bers t o i de ntif y p ote ntial 
M A C E t hat ma y n ot ha v e bee n r e p orte d b y t h e site i n vesti gat ors. I n vesti gat ors will f oll o w all 
s u bjects f or M A C E f or t h e d urati on of t he st u d y e v e n if st u d y me di cati o n has bee n 
per ma ne ntl y wit h dra w n. 
T he i n de pe n de nt C E C will recei ve a n d a dj u dicat e t he f oll o wi n g e v e nts.  
• 
All deat hs  
• 
S us pecte d n o n- f atal m y o car dial i nfarcti o n ( MI) 
• 
S us pecte d h os pitalizati o n f or u nsta ble a n gi na ( H U A) 
• 
S us pecte d tra nsie nt isc he mic attac k ( TI A) a n d str o ke  
• 
S us pecte d h os pitalizati o n f or heart fail ure ( H F) 
• 
Re p orte d c or o n ar y r e vas c ularizati o n pr oce d ure 
 
6. 1 6. 1 3  Di a b eti c K et o a ci d o si s ( D K A)  
D K A is a seri o us, ac ute c o m plicati o n of dia betes a n d ca n be life-t hreate ni n g. S u b jects will be 
e d ucate d o n t h e si g ns a n d s y m pt o ms of D K A a n d are re q uire d t o call t he st u d y cli nic a n d 
see k treat me nt s h o ul d s uc h si g ns a n d s y m pt o ms o cc ur.  
D uri n g t h e cli nical trial p eri o d, p ote ntial D K A will be m o nit ore d b y t he r o uti ne meas ure me nt 
of uri n ar y ket o n es a n d assess me nt f or si g ns or s y m pt o ms of aci d osis at e ver y cli nic visit. 
Cli nical prese ntati o ns, s uc h as diffic ult y breat hi n g, a b d o mi nal pai n, na usea, v o miti n g, 
let har g y, or a fr uit y s mell i n t he breat h, or la b orat or y v al ues t hat s u g gest cli nicall y-si g nifica nt 
aci d osis s h o ul d be d oc u me nte d; treat me nt of D K A s h o ul d be pr o vi de d w h e n a p pr o pri ate.  
If o n g oi n g s y m pt o ms or si g ns s u g gest a p ossi ble D K A, t he i n vesti gat or s h o ul d perf or m 
rele va nt la b orat or y testi n g w hile directi n g a p pr o priate me dical care f or t he s u bject. If D K A is 
s us pecte d, re gar dless of t he bl o o d gl uc os e le vel, t he f oll o wi n g assess me nts s h o ul d be d o ne 
i m me diatel y: p h ysical e x a m a n d ser u m gl uc ose, bi car b o nat e, electr ol yt es, a n d ser u m ket o nes 
meas ure d S T A T at a l ocal la b orat or y. If k et oaci d osis is li kel y, i n vesti gati o n al pr o d uct 
a d mi nistrati o n s h o ul d be disc o nti n ue d a n d i m me diate a p pr o priate me dical t hera p y, i ncl u di n g 
i ns uli n, s h o ul d be i nitiate d. A gl uc os e i nf usi o n ma y be pr o vi de d if necessar y t o a v oi d 
h y p o gl yce mia d uri n g i ns uli n t hera p y. I ns uli n treat me nt s h o ul d c o nti n ue u ntil res ol uti o n of 
t he ket oaci d osis a n d sta bilizati o n of t he s u bject’s cli nical c o n diti o n. I n v esti gati o nal pr o d u ct 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 4 9  of 7 2  
V 4 ( Gl o bal)  
 
a d mi nistrati o n ma y be res u me d f oll o wi n g sta bilizati o n of t he s u bject’s c o n diti o n. 
I n v esti gat or s h o ul d c ollect t he data necessar y f or t he c o m pleti o n of t he D K A C R F.  
If s y m pt o ms s u g gesti ve of D K A ma y h a ve occ urre d b ut are n ot o n g oi n g, i n vesti gat or s h o ul d 
re vie w a v aila ble dat a i n or der t o c o m plete t h e D K A C R F. T he i n vesti gat or ma y als o perf or m 
la b orat or y ass ess me nt usi n g l ocal res o urces if necessar y f or cli nical care.  
6. 1 6. 1 4  R e n al f ail ur e e v e nt s  
Re nal f u ncti o n a n d p ote ntial A KI will be m o nit ore d cl osel y as descri be d i n Secti o n 3. 2. 5. 1 .  
E ve nts p ote ntiall y r e pres e nti n g r e nal fail ure e v e nts, i ncl u di n g re v ersi ble a n d irre versi ble 
A KI, oli g uria , a n d us e of re nal r e place me nt t hera p y, et c. s h o ul d be e val u ate d wit h 
d oc u me ntati o n of si g ns, s y m pt o ms, la b orat or y res ults, a n d treat me nt. 
6. 1 6. 1 5  A m p ut ati o n  
A m p utati o n a n d relate d a d verse e v e n ts will be rec or de d i n a de dicate d case re p ort f or m. 
D uri n g eac h st u d y visit, t he i n vesti gat or s h o ul d q uer y t he s u bject f or a n y a m p utati o n a n d 
relate d a d v erse e ve nts a n d pr oce d ures. I n vesti gat ors are re mi n de d t o c o u ns el a p pr o priat e f o ot 
care t o a v oi d c uts or s ores a n d t o treat e v e n mi n or c uts or s ores t o pre v e nt i nfecti o n a n d 
ulcerati o n. Patie nts w h o ha ve ha d a pre vi o us a m p utati o n s h o ul d be cl osel y m o nit ore d. 
S pecial atte nti o n ma y b e a p pr o priate f or patie nts w h o are als o recei vi n g t hiazi de di uretics as 
t hese ha ve b ee n s h o w n t o i ncreas e t he ris k of a m p utati o n i n dia betics.  
6. 1 7   C o n c o mit a nt M e di c ati o n A s s e s s m e nt s  
A c o nc o mita nt me dicati o n is a n y me dicati o n t hat t he s u bject has bee n ta ki n g pri or t o 
e nr oll me nt a n d t hat t he s u bject is e x pecte d t o c o nti n ue t o ta ke f or s o me p orti o n of t he trial, as 
well as a n y me dicati o n ot her t ha n t he i n vesti gati o n al pr o d uct t hat t he s u bject ta kes d uri n g t h e 
c o urse of t he trial.  
T he me dicati o ns or tr eat me nt f or c o ntr olli n g h y p o gl yce mia m ust be rec or de d as c o nc o mita nt 
me dicati o ns i n t he C R F. A n y me di cati o n gi ve n t o treat h y per gl yce mia a n d c o nti n ue d f or 
m ore t ha n 2 wee ks is c o nsi dere d a r esc u e t hera p y a n d s h o ul d be rec or de d i n t he c o nc o mita nt 
me dicati o n l o g.  
C ha n ges fr o m bas eli ne a nti- h y perte nsi ve t hera p y a n d t heir rati o nale m ust be rec or de d i n t he 
C R F.  
All prescri pti o n a n d o ver-t he-c o u nter me dicati o ns, i ncl u di n g vita mi ns a n d h er bal 
s u p ple me nts, t hat s u bjects recei v e d uri n g t he trial m ust be d oc u me nte d o n t he C R F. T his 
d oc u me ntati o n s h o ul d c o nti n ue u ntil t he s u bjects c o m plete t he st u d y.  
I ns uli n a n d its r o ute of a d mi nistrati o n will be rec or de d as t otal dail y d ose. 
C o nc o mita nt me dicati o ns will be c o de d usi n g t h e W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O - D D). A ta ble of c o n c o mita nt me dicati o ns base d o n t he A nat o mic 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 0  of 7 2  
V 4 ( Gl o bal)  
 
T hera p e utic C he mical ( A T C) classificati o n c o d e a n d preferre d n a me will b e pr o d uce d. A 
listi n g of c o nc o mita nt me dicati o ns will i ncl u de all me dicati o ns ta ke n b y a n y s u bjects d uri n g 
t he c o urse of t h e st u d y. 
6. 1 8   R e m o v al of P ati e nt s fr o m t h e Tri al or Di s c o nti n u ati o n of 
I n v e sti g ati o n al Pr o d u ct A d mi ni str ati o n 
T he i n vesti gat or m ust e m p hasize t o p ote ntial s u bjects t he i m p orta nce of c o nti n ue d 
partici pati o n f or t he f ull d urati o n of t he trial d uri n g t he i nf or me d c o nse nt pr ocess. P ote ntial 
s u bjects s h o ul d be i nf or me d t hat the trial pr oce d ures will all o w a d diti o nal me dicati o ns t o 
c o ntr ol h y p er gl yce mia or ot her a d verse c o n diti o ns. It is als o i m p orta nt t o e m p hasize t hat 
missi n g data a n d misse d visits c o ul d affect  t he e ntire trial. If s u bjects are dissatisfie d wit h t he 
c o n d uct of t he trial b ut h a ve n ot wit h dra w n, t he i n vesti gat or s h o ul d ma k e a n eff ort t o a d dress 
t heir c o ncer ns a n d r etai n t he m i n t he trial if p ossi ble. I n d oi n g s o, i n vesti gat ors m ust be 
caref ul t hat t he eff orts d o n ot cr oss o ver i nt o c oerci o n . I n v esti g at or s h o ul d e nc o ur a g e a 
s u bj ect t o r e m ai n i n t h e st u d y e v e n if t h e i n v esti g ati o n al pr o d uct a d mi nistr ati o n is 
st o p p e d s o t h at s af et y i nf or m ati o n c a n b e c oll ect e d.  
Partici pati o n i n a cli nical trial is v ol u ntar y. A s u bj ect ca n wit h dr a w fr o m t he st u d y at a n y 
ti me. T he s p o ns or or i n vesti gat or m a y ter mi nate t he st u d y f or me dical or a d mi nistrati ve 
reas o ns. If a decisi o n is ma de t o wit h dra w a s u bj ect fr o m t he st u d y, n o f urt her i n vesti gati o nal 
pr o d uct s h o ul d be a d mi nistere d. E ve n if t h e s u bject disc o nti n ues st u d y m e dicati o n, e v er y 
atte m pt s h o ul d be ma de t o c o m plete all re q uire d st u d y e v al uati o ns a n d pr o ce d ures.  Reas o ns 
f or all wit h dra w als s h o ul d be rec or de d o n t he C R F. E x a m ples of reas o ns f or wit h dra wal 
i ncl u de:   
1.  A pr ot oc ol vi olati o n has occ urre d , 
2.  A seri o us or i nt olera ble a d ve rse e v e nt has occ urre d, 
3.  A cli nicall y si g nifica nt c ha n ge i n a la b orat or y para meter has o cc urre d ,  
4.  T he s p o ns or or i n vesti gat or ter mi nates t he st u d y, or 
5.  T he patie nt re q u ests t o be wit h dra w n  fr o m t he st u d y. 
 
S u bjects w h o d o n ot c o m plete t he st u d y b ut w h o h a ve recei ve d i n v esti gati o nal pr o d uct 
s h o ul d ha ve a f oll o w- u p e x a mi nati o n, i ncl u di n g a p h ysical e x a mi nati o n, vital si g ns, E C G a n d 
cli nical la b orat or y tests acc or di n g t o  Secti o n 7 . 
S u bjects w h o wit h dra w fr o m t he st u d y will n ot be re place d. 
6. 1 9   A p pr o pri at e n e s s of M e a s ur e m e nt s  
H b A 1c is a wi del y use d meas ure of c hr o nic gl yce mia, reflecti n g a v era ge bl o o d gl uc os e le vels 
o ver a n a p pr o xi matel y 3- m o nt h peri o d of ti me. It is a n acce pte d s urr o gate mar ker f or ris k of 
micr o vasc ular c o m plicati o ns a n d is wi del y us e d as a meas ure me nt f or t he a de q uac y of 
gl yce mic ma na ge m e nt. Ot her st u d y pr oce d ures a n d meas ure me nts i n t his pr ot oc ol are wi del y 
use d a n d ge nerall y rec o g nize d as relia ble, acc urate, a n d rel e va nt f or s u bj ects wit h  T 2 D M.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 1  of 7 2  
V 4 ( Gl o bal)  
 
7 
S T U D Y A C TI VI TI E S  
T he st u d y acti vities at eac h cli nic visit liste d bel o w are prese nte d i n A p pe n di x 1 . T he 
re q uire d la b orat or y tests sc he d ule d at eac h visit are liste d i n A p pe n di x 2 . Detaile d st u d y 
pr oce d ur es ar e descri be d i n Secti o n 6 .  
A visit wi n d o w of ± 3 da ys is all o we d f or all visits e x ce pt visit V 3 . Visit 3 is t he da y of 
ra n d o mizati o n a n d t he basis f or t he visit wi n d o w.  
7. 1   
S cr e e ni n g (3 d a y s t o 3 w e e k s b ef or e r u n -i n p eri o d, Vi sit V1)  
• 
E x plai n t he c o nte nt of t he i nf or me d c o ns e nt materials t o t he s u bject a n d c ollect si g ne d 
i nf or me d c o nse nt 
• 
C ollect nee de d i nf or m ati o n a n d e val uat e c o nf or ma nce t o  i ncl usi o n a n d e x cl usi o n criteria 
• 
O btai n me dical hist or y a n d de m o gra p hic i nf or m ati o n 
• 
Perf or m a n a b bre viat e d p h ysical e x a mi nati o n  
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
Perf or m a 1 2 -l ea d E C G meas ure me nt 
• 
Dra w bl o o d if a mi ni m u m 8- h fast has bee n c o m plete d b y t h e s u bject as d escri be d i n 
Secti o n 6. 1 1. 1 . T he s pecific la b orat or y t ests sc he d ule d f or t his visit are liste d i n A p pe n di x 
2  
• 
C ollect a clea n -catc h, mi d-strea m uri ne s a m ple 
 
7. 2   
Vi sit V 2 ( St art of R u n-i n) 
• 
C o u nsel s u bject o n a p pr o priate diet a n d e x ercis e 
• 
Dis pe nse r u n- i n kit f or r u n-i n peri o d 
• 
Assess a d vers e e ve nts a n d D K A assess me nt  
• 
Rec or d me dicati o ns use d 
 
7. 3   
Vi sit V 3 ( R a n d o mi z ati o n) 
• 
Perf or m a c o m plet e p h ysical e x a mi nati o n  
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
Dra w bl o o d if a mi ni m u m 8  h o ur fast has bee n c o m plete d b y t he s u bject as descri be d i n 
Secti o n 6. 1 1. 1 . T he s pecific la b orat or y t ests sc he d ule d f or t his visit are liste d i n A p pe n di x 
2  
• 
C ollect a clea n -catc h, mi d -strea m uri ne s a m ple 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
C o nfir m t he eli gi bilit y a n d perf or m t he ra n d o mizati o n pr oce d ures 
• 
Rec or d dr u g acc o u nta bilit y, c ollect r u n-i n b ottle a n d dis pe nse i n vesti gati o n al pr o d uct 
base d o n ra n d o mizati o n 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 2  of 7 2  
V 4 ( Gl o bal)  
 
 
7. 4   
Vi sit V 4 (w e e k 2 ) 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
Rec or d dr u g acc o u nta bilit y 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d 
• 
T his is a p h o ne visit. A site visit ma y be sc h e d ule d if cli nicall y n ee de d . 
 
7. 5   
Vi sit V 5 ( w e e k 6) 
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
Dra w bl o o d if a mi ni m u m 8 -h fast has bee n c o m plete d b y t h e s u bject as d escri be d 
i n Secti o n 6. 1 1. 1 . T he s pecific la b orat or y tests sc h e d ule d f or t his visit are liste d 
i n A p pe n di x 2  
• 
C ollect a clea n -catc h, mi d-strea m uri ne s a m ple 
• 
C ollect bl o o d s peci me ns f or s pars e P K sa m pli n g fr o m selecte d s u bjects i n partici pati n g 
ce nters. Alter nati vel y, bl o o d sa m ples ca n be o n a n y of t he da ys d uri n g t he wee k of t he 
cli nical visit  
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
Rec or d dr u g acc o u nta bilit y 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d 
 
7. 6   
 Vi sit V 6 ( we e k 1 2 ) 
• 
Perf or m a n a b bre viat e d p h ysical e x a mi nati o n  
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
 Dra w bl o o d if a mi ni m u m 8- h fast has bee n c o m plete d b y t h e s u bject as d escri be d 
i n Secti o n 6. 1 1. 1 . T he s pecific la b orat or y tests sc h e d ule d f or t his visit are liste d 
i n A p pe n di x 2  
• 
C ollect a clea n -catc h, mi d-strea m uri ne s a m ple 
• 
C ollect bl o o d s peci me ns f or s pars e P K sa m pli n g fr o m selecte d s u bjects i n partici pati n g 
ce nters . Alter nati vel y, bl o o d sa m ples ca n be o n a n y of t he da ys d uri n g t he wee k of t he 
cli nical visit. 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
Rec or d dr u g acc o u nta bilit y, c ollect pre vi o us i n vesti gati o nal pr o d uct b ottle a n d d is pe nse 
ne w b ottle of i n vesti gati o nal pr o d uct base d o n ra n d o mizati o n 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d 
 
7. 7   
Vi sit V 7 ( w e e k 1 8) 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 3  of 7 2  
V 4 ( Gl o bal)  
 
• 
Rec or d dr u g acc o u nta bilit y 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d 
• 
T his is a p h o ne visit. A site visit ma y be sc h e d ule d if cli nicall y n ee de d.  
 
7. 8   
Vi sit V 8 ( w e e k 2 4 ) 
• 
Perf or m a n a b bre viat e d p h ysical e x a mi nati o n  
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
 Dra w bl o o d if a mi ni m u m 8- h fast has bee n c o m plete d b y t h e s u bject as d escri be d 
i n Secti o n 6. 1 1. 1 . T he s pecific la b orat or y tests sc h e d ule d f or t his vi sit are liste d 
i n A p pe n di x 2  
• 
C ollect a clea n - catc h, mi d-strea m uri ne s a m ple 
• 
Perf or m a 1 2 -l ea d E C G meas ure me nt 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
Rec or d dr u g acc o u nta bilit y a n d c ollect pre vi o us i n vesti gati o nal pr o d u ct b ottle 
• 
A d verse e ve nts & D K A Assess me nts  
• 
Rec or d me dicati o ns use d  
 
7. 9   
Vi sit V 9 ( w e e k 2 6) 
• 
Perf or m a n a b bre viat e d p h ysical e x a mi nati o n  
• 
Meas ure b o d y wei g ht  
• 
Meas ure vital si g ns, i ncl u di n g bl o o d press ures a n d heart rate 
• 
 Dra w bl o o d if a mi ni m u m 8- h fast has bee n c o m plete d b y t h e s u bject as d escri be d 
i n Secti o n 6. 1 1. 1 . T he s pecific la b orat or y tests sc h e d ule d f or t his visit are liste d 
i n A p pe n di x 2  
• 
C ollect a clea n -catc h, mi d-strea m uri ne s a m ple 
• 
Re vie w S M B G a n d gl yc e mic c o ntr ol rec or d  
• 
A d verse e ve nts & D K A assess me nts 
• 
Rec or d me dicati o ns use d 
 
7. 1 0   E arl y T er mi n ati o n Pr o c e d ur e s 
S u bjects re m o ve d fr o m t he st u d y d u e t o dr u g relat e d t o xicit y will be f oll o w e d u ntil res ol uti o n 
or sta bilizati o n of t he a d verse e v e nt. S p o ns or m ust be n otifie d i n t he e ve nt t hat a s u bject 
wit h dra ws or is wit h dra w n fr o m t he st u d y.  
S u bjects w h o wit h dra w c o nse nt a n d ha ve recei ve d st u d y dr u g will ha ve a f oll o w- u p 
e x a mi nati o n , t w o wee ks after t he l ast d ose of st u d y dr u g, f oll o wi n g t he s c h e d ule of e v e nts as 
o utli ne d i n vis it V 8. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 4  of 7 2  
V 4 ( Gl o bal)  
 
8 
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  
T he cli nical res ear c h f acilit y will be m o nit ore d b y t he st u d y m o nit or t o e ns ure c orrect 
perf or ma n ce of t he st u d y pr oce d ur es a n d t o e ns ure t hat t he st u d y is c o n d uct e d acc or di n g t o 
t he pr ot oc ol a n d r ele va nt re g ulat or y re q uire me nts. C R F e ntries will be verifi e d wit h t he 
s o urce d oc u m e ntati o n. 
Q ualit y c o ntr ol pri nci ples will be a p plie d t hr o u g h o ut t he perf or ma n ce of t his st u d y b y 
f oll o wi n g t he S O Ps of t h e C R O a n d t he s p o ns or.  Re vie w pr oce d ures will be i m ple me nte d at 
t he C R O f or all d oc u me nts t hat are ge n erate d in relati o n t o t he st u d y. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 5  of 7 2  
V 4 ( Gl o bal)  
 
9 
P L A N N E D S T A TI S TI C A L M E T H O D S  
9. 1   
G e n er al C o n si d er ati o n s 
T he f oll o wi n g s ecti o ns pr o vi de a s u m mar y of t h e pla n ne d a nal ysis of t he trial b ut a c o m plete 
statistical a nal ysis pla n will be de vel o pe d as a s e parate d oc u me nt a n d will be t he fi nal pla n. 
All statistical a nal yses will be perf or me d usi n g V ersi o n 9. 2 or later of Statistical A nal ysis 
S oft ware ( S A S ® ). 
I n ge ner al, descri pti ve statistics ( n u m ber of s u bjects [ n], mea n, sta n dar d d e viati o n [ S D], Q 1, 
me dia n, Q 3, 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 varia bles, a n d 
fre q ue n c y a n d p erce nta ge f or cate g orical varia bl es.  
U nless ot her wise s pecifie d, all tests will be t w o -si de d usi n g a 0. 0 5 le vel of si g nifica n ce. All 
c o nfi de nce i nter vals ( CIs) will be t w o -si de d 9 5 % c o nfi de nce i nter vals.  
T he pri mar y s u peri orit y t est o n l o weri n g of H b A 1 c at wee k 2 4 fr o m bas eli ne f or 
be x a glifl ozi n w he n c o m pare d t o place b o will be c o n d ucte d at 0. 0 5 le vel of si g nifica n ce. If it 
is s uccessf ul, t he f oll o wi n g hier ar c hical testi n g strate g y will be f oll o we d i n testi n g sec o n d ar y 
efficac y e n d p oi nts i n or d er t o preser ve e x peri me nt- wi de t y p e I err or at 0. 0 5:  
1.  S u peri orit y test of t he c h a n ge i n b o d y wei g ht i n s u bjects wit h baseli ne b o d y mass i n de x 
( B MI) ≥ 2 5 k g/ m2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p  
2.  S u peri orit y test of t he c h a n ge i n s yst olic bl o o d press ure ( S B P) o ver ti me i n s u bjects wit h 
S B P ≥ 1 3 0 m m H g i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
3.  S u peri orit y test of t he c h a n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 4 5 t o 
5 9 m L/ mi n/ 1. 7 3 m 2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
4.  S u peri orit y test of t he c h a n ge i n H b A 1c o v er ti me i n s u bjects wit h e G F R 3 0 t o 
4 4 m L/ mi n/ 1. 7 3 m 2 i n t he be x a glifl ozi n gr o u p c o m pare d t o t he place b o gr o u p 
 
9. 2   
D et er mi n ati o n of S a m pl e Si z e 
A p pr o xi matel y 3 0 0 s u bj ects will be ra n d o mize d a n d e q uall y all ocate d t o recei ve 
be x a glifl ozi n ta blets, 2 0 m g, or place b o.   
T he s a m ple size calc ulati o n f or t his st u d y is base d o n a t w o gr o u p t- test wit h a t w o-si de d 
si g nifica n ce at t he 5 % le vel a n d t he f oll o wi n g assu m pti o ns:  
1)  T he place b o -c orrecte d p o p ulati o n mea n c ha n ge fr o m baseli ne t o Wee k 2 4 i n H b A 1c 
i n t he d ose gr o u p of 2 0 m g wi ll be - 0. 4 %.  
2)  T he p o ole d sta n dar d d e vi ati o n f or t he c h a n ge fr o m baseli ne t o Wee k 2 4 i n H b A 1c f or 
t he acti ve a n d place b o gr o u ps will  be 1. 0%.  
 
U n der t he a b o ve ass u m pti o ns, a n esti mate d sa m ple size of 1 3 3 e val ua ble s u bjects per 
treatme nt ar m yiel ds a p pr o xi matel y 9 0 % p o wer t o detect a treat me nt differe nce b et wee n 
be x a glifl ozi n a n d place b o. A sa m ple size of 1 5 0 per ar m h as bee n s electe d t o acc ou nt f or a 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 6  of 7 2  
V 4 ( Gl o bal)  
 
p ote ntial 1 2 % dr o p- o ut a n d t o all o w a de q uate s afet y e v al uati o n.  T he t otal sa m ple size f or 
t his st u d y will be 3 0 0 s u bjects. 
T his st u d y will be c o n d u cte d at m ulti ple i n vesti gati ve sites a n d will li kel y i n v ol ve varia ble 
n u m bers of s u bjects at eac h site.  E nr oll me nt will be o n a c o m petiti ve basis b ut will be 
ca p pe d at 3 0 s u bjects fr o m eac h site.  
9. 3   
A n al y si s P o p ul ati o n s  
9. 3. 1  
I nt e nti o n-t o-tr e at A n al y si s S et 
All s u bjects w h o are ra n d o mize d will be i ncl u de d i n t he I nt e nti o n- t o-treat (I T T) A nal ysis Set.  
All a nal ys es of t he I T T a nal ysis set will be bas e d o n eac h s u bject’s ra n d o mize d assi g ne d 
treat me nt. T he I T T a nal ysis set will ser ve as t he pri mar y s et f or t he efficac y a nal ys es. 
9. 3. 2  
S af et y A n al y si s S et  
All s u bjects w h o are ra n d o mize d a n d ta ke at least o ne d ose of d o u ble- bli n d st u d y me dicati o n 
will be i ncl u de d i n t he Safet y A nal ysis Set. Safet y a nal ys es will be base d o n t he me dicati o n 
t hat a s u bject was act uall y ta k e n. T he Safet y A nal ysis Set  is t he pri mar y a n al ysis set f or 
safet y e v al uati o n . 
9. 3. 3  
P er Pr ot o c ol A n al y si s S et  
T he Per Pr ot oc ol ( P P) A nal ysis Set will i ncl u de all s u bjects i n t he I T T a nal ysis set w h o meet 
t he st u d y eli gi bilit y re q uire me nts a n d ha v e n o maj or pr ot oc ol de viati o ns t hat affect t he 
vali dit y of t he efficac y m eas ure m e nts.  Pr ot oc ol de viati o ns t hat ma y res ult i n s u bject 
e x cl usi o n fr o m t he P P A nal ysis Set will be detaile d i n t he Statistical A nal ysis Pla n.  
9. 4   
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s 
De m o gra p hic a n d  baseli n e c har acteristics will be s u m marize d descri pti vel y base d o n t he I T T 
a n d P P (if a p plica ble) a n al ysis sets f or eac h treat me nt gr o u p as well as f or all s u bjects 
c o m bi ne d. Ke y varia bles i ncl u de a ge, ge n der, race, et h nicit y, bas eli ne H b A 1 c val ues, bl o o d 
press ure, b o d y w ei g ht, b o d y mass i n de x ( B MI i n k g/ m 2), fasti n g pl as ma gl uc ose le vel, e G F R, 
a n d a nti-dia betic tr eat me nt stat us at scree ni n g (i ncl u di n g t y p e of t hera p y us e d [treat me nt 
naï ve, metf or mi n, s ulf o n yl urea, D P P- 4 i n hi bit or, al p ha- gl uc osi dase i n hi bit or, G L P- 1 a g o nist, 
i ns uli n). I n ge n eral, b aseli ne meas ure m e nt is defi n e d as t he last meas ure me nt pri or t o t he first 
d ose of d o u ble- bli n d me dicati o n. 
9. 5   
A n al y si s of Effi c a c y 
All efficac y a n al ys es will be perf or me d bas e d o n t he I T T a n al ysis set. T h e pri mar y e n d p oi nt 
a nal ysis will als o be c o n d ucte d usi n g t he P P A nal ysis Set (if dee me d differe nt fr o m I T T 
a nal ysis s et).  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 7  of 7 2  
V 4 ( Gl o bal)  
 
F or t he pri mar y e n d p oi nt of H b A 1c c ha n ge fr o m baseli ne o ver 2 4 wee ks of treat me nt , t he 
M M R M a nal ysis of c o v aria nce m o del ( A N C O V A) wit h baseli ne H b A 1 c as a c o vari ate will 
be fitte d t o  t he a vaila ble data, i nc or p orati n g all visits at w hic h H b A 1c w as meas ure d f or eac h 
s u bject i ncl u di n g t he s c h e d ule d a n d t he u nsc h e d ul e d visits f or meas ure m e nt of H b A 1c 
(Nati o nal Researc h C o u ncil, 2 0 1 0 ). Treat me nt, visit , treat me nt-b y -visit,  a n d stratificati o n 
fact ors f or ra n d o mizati o n ( H b A 1c le v el [ 7. 0 t o 8. 5 % or 8. 6 t o 1 0. 5 %), scree ni n g a nti-dia b etic 
treat me nt re gi me n [i ns uli n treate d, ot her], e G F R [ 3 0- 4 4 or 4 5- 5 9 m L/ mi n/ 1. 7 3 m2] will be 
a p plie d as fi x e d eff ects. Fr o m t h is m o del, a n esti mate of t he treat me nt differe nce at w ee k 2 4 
will be ge n erat e d, as will a n assess me nt of w h et her t his esti mate is si g nifica ntl y differe nt 
w he n c o m pari n g at a t w o -si de d 0. 0 5 le vel of si g nifica nce. A n u nstr uct ure d wit hi n-patie nt 
c o varia n ce str uct ure will be ass u me d. If t h e m o del wit h t he u nstr uct ure d c o varia nce str uct ure 
d oes n ot c o n ver ge, a n a ut ore gressi ve( 1) c o v aria n ce str uct ure will be us e d. H b A 1c val ues 
o btai ne d after t he start of resc ue m e dicati o n will n ot be e x cl u de d fr o m t his pri mar y a n al ysis.  
T he M M R M m o del is o ne a p pr oac h t o o btai n treat me nt effect esti mates i n t he prese n ce of 
missi n g data. As se nsiti vit y a n al ys es f or missi n g d ata, t he f oll o wi n g will be perf or me d:  
1)  Missi n g H b A 1c d ata will be i m p ute d via m ulti ple i m p utati o n ( MI), f oll o w i n g w hic h 
t he M M R M will be re peate d o n t he c o m plete datas ets wit h res ults c o m bi ne d acr oss 
c o m plete datasets usi n g sta n dar d MI tec h ni q ues; H b A 1c val ues c ollecte d after t he 
start of resc u e me dicati o n will n ot be c o nsi dere d missi n g. 
2)  Missi n g H b A 1c d ata will be  i m p ute d via L O C F, f oll o wi n g w hic h t he M M R M will be 
re peat e d; H b A 1c v al ues c ollecte d after t he start of resc ue m e dicati o n will be 
c o nsi dere d missi n g. 
3)  H b A 1c val ues c ollecte d after t he start of resc ue m e dicati o n will be c o nsi dere d 
missi n g , a n d t he M M R M a nal ys es will be re -perf or me d.  
 
If it is dee me d t hat t he P P a nal ysis set is differe nt fr o m t he I T T a n al ysis set, sa me a nal yses as 
descri be d a b o ve will be c o n d ucte d i n P P a nal ysis s et as well. 
9. 5. 1  
A n al y si s of  Dr o p o ut s P att er n  
T he earl y t er mi nati o n rat e is esti mate d t o be 1 2 %. T o t he e xte nt p ossi ble, atte m pts will be 
ma de t o mi ni mize t he a m o u nt of missi n g data t hr o u g h meas ures pla n n e d i n t he st u d y 
c o n d uct. 
T he n u m ber, ti mi n g, p atter n, reas o n f or a n d p ossi ble i m plicati o ns of missi n g val u es i n 
efficac y ass ess me nts will be i n vesti gat e d. T he dr o p o ut patter ns will be assesse d b y K a pla n-
Meier pl ots if a p plica ble t o assess w het her t h e y differ b et wee n treat me nt gr o u ps.  
9. 6  
S e c o n d ar y Effi c a c y A n al y s e s  
T o assess t he treat me nt effect o n t he c ha n ge of b o d y w ei g ht i n s u bjects wit h  baseli ne B MI ≥ 
2 5 k g/ m 2 at wee k 2 4, a n a nal ysis of c o varia nce m o del ( A N C O V A) will be i m ple me nte d 
usi n g all a vaila bl e data at wee k 2 4 ( v al ues o btai ne d after t he start of resc ue me dicati o n will 
n ot be e x cl u de d i n t he a n al ysis). M M R M m o deli n g a p pr oac h will b e utilize d. T he m o del will 
i ncl u de treat me nt, visit, treat me nt-b y -visit, r a n d o mizati o n stratificati o n fact ors, a n d t he 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 8  of 7 2  
V 4 ( Gl o bal)  
 
baseli ne wei g ht val ue as fi x e d effects/c o v ariates. Least s q uares mea n treat me nt differe n ces 
bet wee n t he b e x a glifl ozi n a n d place b o will be esti mate d fr o m t he m o del. T he c orres p o n di n g 
9 5 % CI a n d p- val u e will be pr o vi de d. 
T he c ha n ge i n s yst olic bl o o d press ure ( S B P) i n s u bjects wit h baseli ne S B P ≥ 1 3 0 m m H g i n 
t he be x a glifl ozi n gr o u p c o m pare d wit h place b o at wee k 2 4 will be a n al yze d usi n g t he similar 
met h o d wit h baseli ne S B P meas ure as a c o variate. T he sa me a n al ysis met h o d a p plies f or t he 
testi n g of c h a n ges i n H b A 1c at wee k 2 4 f or s u bj ects wit h baseli ne e G F R 4 5-
5 9 m L/ mi n/ 1. 7 3 m 2, a n d f or s u bjects wit h baseli ne e G F R 3 0- 4 4 m L/ mi n/ 1. 7 3 m2. 
All a nal ys es will be c o n d ucte d i n I T T a n al ysis set. A hierarc hical testi n g pr oce d ure will be 
a p plie d t o a b o ve f o ur e n d p oi nts i n t he se q ue nce pr o vi de d i n Secti o n 9. 1 . 
9. 7   
Ot h er Effi c a c y A n al y s e s  
C ha n ges i n H b A 1c, F P G, S B P/ D B P, b o d y wei g ht, a n d al b u mi n le vel i n uri ne f or all s u bjects 
d uri n g t he tr eat me nt peri o d will be s u m marize d descri pti vel y b y eac h ti me p oi nt (i.e., Wee ks 
6, 1 2, 2 4). I n a d diti o n, t hese e n d p oi nts ma y be a nal yz e d usi n g a si milar M M R M  m o del as 
use d f or t he pri mar y a nal ysis of H b A 1 c t o c o m pare be x a glifl ozi n wit h place b o.  
C u m ulati ve s u m mar y o n t he pr o p orti o n of s u bjects ac hie vi n g H b A 1 c  < 7 %, a n d t he 
pr o p orti o n of s u bjects ac hie vi n g b o d y w ei g ht re d ucti o n of at least 5 % will als o be prese nte d.  
A nal ys es will be c o n d uct e d usi n g I T T a nal ysis set. 
9. 8  
A n al y si s of S af et y  
All safet y a nal yses will be c o n d ucte d b ase d o n t he Safet y A nal ysis Set.  
Safet y d ata will i ncl u de A Es, p h ysical e x a m res ults, vital si g ns, E C G res ults, a n d cli nical la b 
meas ure me nts of  s er u m c he mistr y, he m at ol o g y, ser u m li pi ds, gl yce mic c o ntr ol para met ers 
a n d uri ne s peci me ns.  O bser ve d dat a will be s u m marize d usi n g des cri pti ve statistics b y 
treat me nt gr o u p bas e d o n t he Safet y A nal ysis Set . 
9. 8. 1  
A d v er s e E v e nt s  
A d verse e ve nts wi ll be ma p pe d t o preferre d ter m a n d b o d y s yste m usi n g t he Me dical 
Dicti o nar y f or Re g ul at or y A cti vities ( Me d D R A). A E rec or ds t hat be gi n at or after t h e first 
a d mi nistrati o n of i n vesti gati o nal pr o d u cts are c o nsi dere d treat me nt e mer ge nt A Es ( T E A Es). 
T he n u m ber a n d p erce nta ge of s u bjects re p orti n g T E A Es will be s u m marize d f or eac h 
treat me nt gr o u p b y Me d D R A s yste m or ga n class a n d preferre d ter m. F urt h er s u m maries b y 
se verit y, a n d b y r elati o ns hi p t o st u d y treat me nt will als o be pr o vi de d. Dr u g-relate d A Es will 
be c o nsi der e d t h ose t o be at least p ossi bl y relate d t o i n vesti gati o nal pr o d u ct base d o n t he 
i n vesti gat or’s assess me nt. T he n u m ber a n d p erce nta ge of s u bjects re p orti n g seri o us A Es, a n d 
t he n u m ber a n d perce nta ge of s u bjects re p orti n g A Es lea di n g t o treat me nt disc o nti n uati o n 
will als o be s u m marize d f or eac h treat me nt gr o u p b y Me d D R A s yste m or ga n class a n d 
preferre d t er m.  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 5 9  of 7 2  
V 4 ( Gl o bal)  
 
9. 8. 2  
A d v er s e E v e nt s of S p e ci al I nt er e st  
A d verse e ve nts of s pecial i nterest i ncl u de U TI, G MI, di uretic effects, h e pat ot o xicit y, 
h y p o gl yce mia, M A C E, fr act ure, mali g na n c y, h y perse nsiti vit y reacti o ns, h y p ote nsi ve 
e pis o des, aci d bas e dis or ders, D K A, re nal fail ure a n d a m p utati o n . T hese will be 
pr os pecti vel y i de ntifie d b ase d o n t he Me d D R A preferre d ter ms i n t he a d v ers e e ve nt l o g b y a 
me dical e x pert pri or t o t he data bas e l oc k a n d u n bli n di n g of t he i n di vi d ual s u bject treat me nt 
assi g n me nt. T he list of a d verse e v e nts of s pecial i nterest will be c o nfir m e d i n a peer re vie w 
pr ocess.  
T he n u m ber a n d p erce nta ge of s u bjects e x perie n ce d T E A E of s pecial i nterest will be 
s u m marize d f or eac h treat me nt gr o u p b y t y pes of e ve nts. T he i nci de n ce rat e of a d verse 
e ve nts of s peci al i nterest per 1 0 0 patie nt years will als o be s u m marize d. A d diti o nal a nal yses 
will be s pecifie d i n t he st atistical a nal ysis pla n t o e val uate ot her e ve nt a ss ociate d safet y 
para meters a n d p ote ntial ris ks i n s u b p o p ulati o ns base d o n a ge, ge n der, or ot her baseli ne 
c haracteristics (if s a m ple size all o ws) . 
9. 8. 3  
Cli ni c al a n d L a b or at or y E v e nt s a n d A n al y s e s  
Cli nical a n d la b orat or y p ara meters  will be  meas ure d at baseli ne , d uri n g t h e treat me nt peri o d  
a n d at f oll o w- u p.  T hes e varia bles i ncl u de vital si g ns ( bl o o d press ure, p uls e, res pirati o n rate, 
a n d te m perat ure), cli nical la b orat or y o utc o mes a n d E C G data . T he y will be s u m marize d as 
act ual val ues a n d c ha n ges fr o m baseli ne b y treat me nt f or eac h visit f or selecte d para meters. 
La b orat or y d ata will be classifie d as l o w, n or mal or hi g h relati ve t o t h e para meter’s refere n ce 
ra n ge. La b orat or y a b n or malities f or eac h treat me nt will als o be s u m marize d wit h s hift ta bles  
f or select e d par a meters. 
9. 8. 4  
P h y si c al E x a mi n ati o n  
A b n or mal fi n di n gs will be prese nt e d i n a b y s u bject listi n g . 
9. 9  
I nt eri m A n al y si s 
T here will be n o i nteri m a nal ysis. T h e fi nal a n al ysis will be perf or me d after all s u bjects ha ve 
c o m plete d t he f oll o w u p assess me nts a n d all s u bject data ha v e bee n clea n e d a n d l oc ke d  i n t he 
st u d y data b ase. 
A n i n de pe n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will m o nit or t he safet y of t h e 
s u bjects i n t his st u d y.  T h e o bjecti ves of t he D S M B are t o assess dr u g s afet y a n d t o all o w f or 
pr ot oc ol m o dificati o n or earl y st o p pi n g d u e t o safet y c o ncer ns. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 0  of 7 2  
V 4 ( Gl o bal)  
 
1 0  A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
1 0. 1   I n v e sti g at or s a n d St u d y A d mi ni str ati v e Str u ct ur e 
I nf or mati o n re gar di n g ke y pers o n nel i n v ol ve d i n t he c o n d uct of t he st u d y, i ncl u di n g na m es 
a n d c o ntact d etails of partici pati n g i n ve sti gat ors, m o nit ors, cli nical la b orat ories, a n d tec h ni cal 
de part me nts a n d/ or i nstit uti o ns, as well as i nf or mati o n o n me m bers of a d diti o nal st u d y 
c o m mittees, will be f o u n d i n t he st u d y files of t he i n vesti gati o nal site . 
1 0. 2   I n stit uti o n al R e vi e w B o ar d or I n d e p e n d e nt Et hi c s C o m mitt e e 
A p pr o v al  
T he st u d y pr ot oc ol, i nf or me d c o nse nt d oc u me nt, rele va nt s u p p orti n g i nf or mati o n, a n d all 
t y pes of s u bj ect recr uit me nt or a d vertise me nt i nf or mati o n m ust be s u b mitte d t o t he 
I nstit uti o nal Re vie w B oar d (I R B) or I n d e pe n de nt Et hics C o m mittee (I E C) f or re vie w a n d 
m ust be a p pr o ve d b y t he s p o ns or a n d t he I R B /I E C bef ore t h e st u d y is i nitiate d. A n y 
a me n d me nts or a d d e n da t o t he pr ot oc ol m ust als o be a p pr o ve d b y t h e I R B /I E C pri or t o 
i m ple me nti n g c ha n ges i n t he st u d y. T he i n v esti gat or is re s p o nsi ble f or k ee pi n g t he I R B/I E C 
i nf or me d of t he pr o gress of t he st u d y a n d of a n y c ha n ges ma de t o t he pr ot oc ol as dee me d 
a p pr o priate, b ut i n a n y case at least o nce a year. T he i n vesti gat or m ust als o kee p t he I R B /I E C 
i nf or me d of a n y S A Es o cc urri n g t o s u bjects u n der t heir s u per visi o n. 
1 0. 3   Et hi c al C o n d u ct of t h e St u d y 
T he pr oce d ures set o ut i n t his pr ot oc ol pertai ni n g t o t he c o n d uct, e v al uati o n, a n d 
d oc u me ntati o n of t his st u d y are desi g n e d t o e ns ure t hat t he s p o ns or a n d i n vesti gat or f oll o w 
I nter nati o nal C o nfere nce of Har m o nisati o n G C P G ui deli nes ( E 6) a n d t he g ui di n g pri nci ples 
detaile d i n t he Declarati o n of Helsi n ki.  T he st u d y will als o be carri e d o ut i n kee pi n g wit h 
a p plica ble l ocal la ws a n d re g ulati o ns.  A n i ns pecti o n b y t he s p o ns or re prese ntati ves a n d/ or 
t heir desi g n ee a n d/ or  ot her a ut h orize d re g ul at or y a ut h orities re prese ntati ves ma y occ ur at a n y 
ti me. T he i n vesti gat or m ust a gr ee t o t he i ns pecti o n of st u d y-relate d rec or ds b y t he re g ulat or y 
a ut h orit y/s p o ns or r e pres e ntati ves, a n d m ust all o w direct access t o s o urce d o c u me nts t o t he 
re g ulat or y a ut h orit y/s p o ns or re pr ese ntati ves. 
T he i n vesti gat or is res p o nsi ble f or c o m pl yi n g wit h t he pr ot oc ol a n d all a p pr o priate 
re g ulati o ns a n d g ui deli nes g o ver ni n g gl o b al cli nical researc h. A d diti o nall y, he/s he is 
res p o nsi ble f or e ns uri n g t hat all partici pati n g staff me m bers are a de q u atel y trai ne d a n d 
c o m pete nt t o perf or m his/ her assi g ne d tas ks. 
M o dificati o ns t o t he st u d y pr ot oc ol will n ot be i m ple me nte d b y eit her t he s p o ns or or t he 
i n vesti gat or wit h o ut a gr ee me nt b y b ot h p arties. H o we ver, t he i n v esti gat or ma y i m ple me nt a 
de viati o n fr o m or a c ha n ge of t he pr ot oc ol t o eli mi nate a n y i m me diate hazar ds t o t he trial 
s u bjects wit h o ut pri or I R B/I E C or s p o ns or a p pr o v al/fa v ora bl e o pi ni o n. As s o o n as p ossi ble, 
t he i m ple me nte d de viati o n or c ha n ge, t h e reas o ns f or it, a n d if a p pr o pri ate, t he pr o p ose d 
pr ot oc ol a me n d me nt s h o ul d be s u b mitte d t o t he I R B/I E C a n d s p o ns or. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 1  of 7 2  
V 4 ( Gl o bal)  
 
A n y d e viati o ns fr o m t he pr ot oc ol m ust be f ull y e x plai ne d a n d d oc u me nt e d b y t he 
i n vesti gat or. T h e cir c u msta nces, acti o n ta ke n, a n d i m pact of t he de viati o n o n t he trial m ust be 
c o m m u nicate d b y t he pri nci pal i n vesti gat or t o t he desi g nat e d me dical m o nit or. A n y 
s u bse q ue nt acti o ns will be assesse d b y t he d esi g nate d me dical m o nit or a n d d oc u me nte d. 
1 0. 4   S u bj e ct I nf or m ati o n a n d C o n s e nt 
Pri or t o t he be gi n ni n g of t he st u d y, t he i n vesti gat or m ust ha ve recei ve d fr o m t he I E C or I R B 
t he writte n a p pr o v al or fa v ora ble o pi ni o n of t he i nf or me d-c o nse nt f or m a n d a n y ot h er writte n 
i nf or matio n t o be pr o vi de d t o s u bjects. T he writte n a p pr o val of t he I R B /I E C t o get her with 
t he a p pr o ve d s u bject i nf or mati o n/ i nf or me d c o nse nt f or ms m ust be file d.  T he i nf or me d 
c o nse nt f or m m ust c o ntai n all ele me nts re q uire d b y a ut h orize d re g ulat or y a ut h orities a n d I C H 
G C P g ui deli nes. 
Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y st u d y- s p ecific pr oce d ure ta kes place.  
Partici pati o n i n t he st u d y a n d date of i nf or me d c o nse nt gi ve n b y t he s u bj ect s h o ul d be 
d oc u me nte d a p pr o p riatel y i n t he s u bject’s files. A c o p y of t he si g ne d i nf or me d c o nse nt f or m 
m ust be pr o vi de d t o t he s u bject. If a p plica ble, it will be pr o vi de d i n a certifie d tra nslati o n i n 
t he la n g u a ge u n d erst o o d b y t he s u bject, if n ot E n glis h.  Si g ne d c o nse nt f or ms m ust re mai n i n 
eac h s u bject’s st u d y file a n d m ust be a vaila ble f or verificati o n b y st u d y m o nit ors at a n y ti me.  
1 0. 5  S u bj e ct C o nfi d e nti alit y 
T he i nf or mati o n o btai ne d d uri n g t he c o n d uct of t his cli nical st u d y is c o nfi d e ntial, a n d 
discl os ure t o t hir d parties ot her t ha n t h ose n ote d b el o w is pr o hi bite d. I nf or mati o n o btai ne d 
d uri n g t he c o n d uct of t his st u d y will be use d b y t h e s p o ns or i n c o n necti o n wit h t he 
de vel o p me nt of t he i n vesti gati o nal pr o d uct. T h e st u d y i n vesti gat or is o bli ge d t o pr o vi de t he 
s p o ns or wit h c o m plete test res ults a n d all data de v el o pe d i n t his st u d y. S u bject -s pecific 
i nf or mati o n ma y b e pr o vi de d t o ot her a p pr o pri ate me dical pers o n n el o nl y wit h t he s u bject’s 
per missi o n. T o e ns ure c o m plia nce wit h c urre nt I C H g ui deli nes, d ata ge n erate d b y t his st u d y 
m ust be a vaila ble f or i ns pecti o n u p o n re q uest b y re prese nt ati ves of nati o nal a n d l ocal healt h 
a ut h orities, t he s p o ns or, a n d t he I R B/I E C f or eac h st u d y site. St u d y i nf or m ati o n fr o m t his 
pr ot oc ol will be p oste d o n cli nicaltrials. g o v a n d a n y l ocal re g ulat or y re gistr y we bsites, as 
re q uire d b y r e g ulati o n. 
S u bject na mes a n d ot her i de ntifiers, s uc h as p h ot o gra p hs, a u di o, or vi de ota pes, ma y n ot be 
discl ose d i n a n y p u blicati o n wit h o ut pri or writte n a ut h orizati o n fr o m t he s u bject. 
1 0. 6   St u d y M o nit ori n g 
A n a ut h orize d s p o ns or re prese ntati ve will c o n d u ct site visits t o i ns pect st u d y dat a, s u bjects’ 
me dical rec or ds, a n d C R Fs i n acc or da n ce wit h I C H g u i deli nes, G C Ps, a n d t he res pecti ve 
nati o nal a n d l ocal g o ver n me nt re g ulati o ns a n d g ui deli nes. 
T he i n vesti gat or will per mit a ut h orize d re prese ntati ves of t he s p o ns or a n d t he res pecti ve 
nati o nal or l ocal healt h a ut h orities , ot her a ut h orize d re g ulat or y a ut h orities, a n d I R B/I E C t o 
i ns pect facilities a n d r ec or ds rele va nt t o t his st u d y. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 2  of 7 2  
V 4 ( Gl o bal)  
 
1 0. 7   C a s e R e p ort F or m s a n d St u d y R e c or d s 
F or eac h s u bject c o nse nt e d, a case re p ort f or m ( C R F), i n electr o ni c f or mat, will be s u p plie d 
a n d mai ntai ne d b y t he C R O staff a n d si g ne d b y t he i n vesti gat or or a ut h ori ze d desi g nee t o 
i n dicate t hat he/s he has r e vie we d a n d a grees wit h t he e ntere d d ata. T his als o a p plies t o t h ose 
s u bjects w h o fail t o c o m plete t he trial. T he reas o n f or s u bject wit h dra wal m ust be rec or d e d i n 
t he case re p ort f or m. 
E ntrie s ma de i n t he C R F m ust be verifia ble a gai nst s o urce d oc u me nts. S o urce d oc u me nts are 
defi ne d as all me dical rec or ds, me dical n otes, la b orat or y res ults, E C G traces a n d a n y 
a d diti o nal d oc u me nt ot her t ha n t he C R F t hat has ori gi nal s u bject i nf or mati o n c o ntai ne d 
wit hi n it.  
All C R Fs a n d s o urce d o c u me nts s h o ul d be c o m plete d f oll o wi n g G C P a n d t he C R O’s 
sta n dar d o per ati n g pr oce d ures. 
1 0. 8   D at a a n d S af et y M o nit ori n g B o ar d 
A n i n de pe n de nt D ata a n d Safet y M o nit ori n g B oar d ( D S M B) will m o nit or o verall safet y 
i nf or mati o n d uri n g t he b e x a glifl ozi n de vel o p me nt pr o gra m. T he s afet y re vi e w acti vit y a n d 
p ote ntial ris k be nefit assess me nts utilize d b y t he D S M B will be defi ne d i n its c harter.  
1 0. 9   Pr ot o c ol Vi ol ati o n s/ D e vi ati o n s 
It is i m p orta nt t o c o n d uct t he st u d y acc or di n g t o t h e pr ot oc ol.  Pr ot oc ol de vi ati o n wai vers  
will n ot be pr os pecti vel y gr a nte d b y t he s p o ns or. If mi n or pr ot oc ol de viati o ns occ ur, t he 
i n vesti gat or m ust deci d e t he m ost a p pr o priate w a y t o pr ocee d wit h st u d y acti vities a n d 
s h o ul d c o ns ult t he st u d y re pres e ntati ve f or assista nce. If m aj or pr ot oc ol de viati o ns occ ur, t he 
s p o ns or’s me dical m o nit or m ust be n otifie d i m me diatel y s o t hat a d ecisi o n a b o ut w het her t o 
kee p t he s u bject i n t he st u d y ca n be ma d e.  
O nl y if a n e mer ge nc y o cc urs t hat re q uires a de p art ure fr o m t he pr ot o c ol f or a n i n di vi d ual 
s u bject ca n t here be a de part ure wit h o ut t he s p o ns or’s pre-a p pr o v al. T he nat ure a n d reas o ns 
f or t he pr ot oc ol de vi ati o n will be rec or d e d i n t he s u bject’s C R F, a n d t he pri nci pal 
i n vesti gat or m ust n otif y t he S p o ns or. 
Pr ot oc ol vi olati o ns/ de viati o ns m ust be re p orte d i n t he fi nal st u d y re p ort. 
1 0. 1 0  A c c e s s t o S o ur c e D o c u m e nt ati o n 
A ut h orize d s p o ns or re prese ntati ves will c o n d uct site visits t o i ns pect st u d y data, s u bjects’ 
me dical rec or ds, a n d C R Fs i n acc or da n ce wit h I C H g ui deli nes, G C Ps, a n d t he res pecti ve 
l ocal a n d nati o nal g o ver n me nt re g ulati o ns a n d g ui deli nes. 
T he i n vesti gat or will per mit a ut h orize d re prese ntati ves of t he s p o ns or a n d t he res pecti ve 
nati o nal or l ocal healt h a ut h orities, ot her a ut h orize d re g ulat or y a ut h orities, a n d I R B/I E C t o 
i ns pect facilities a n d r ec or ds rele va nt t o t his st u d y. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 3  of 7 2  
V 4 ( Gl o bal)  
 
Eac h ce nter will be visite d at re g ular i nter vals b y a m o nit or t o e ns ure c o m plia nce wit h t he 
st u d y pr ot oc ol, G C P, a n d le gal as pects. T his will i ncl u de o n-site c h ec ki n g of t he C R Fs f or 
c o m plete ness a n d clarit y, cr oss -c h ec ki n g wit h s o urce d oc u m e nts, a n d clarificati o n of 
a d mi nistrati ve matters.  
All C R F data will be e nt ere d i nt o a cli nical data b ase. F oll o wi n g t he c orrecti o n of a n y err ors, 
t he cli nical data bas e will be l oc ke d. 
1 0. 1 1  R et e nti o n of D at a 
T he st u d y file a n d all s o urce  dat a s h o ul d be ret ai ne d u ntil n otificati o n is gi ve n b y t h e s p o ns or 
f or destr ucti o n. 
If t he i n vesti gat or wit h dr a ws fr o m t he trial a n d reli n q uis hes his/ her res p o nsi bilit y f or t he 
mai nte na nce a n d ret e nti o n of rec or ds, he/s he m ust n otif y t he s p o ns or i n writi n g s o t hat 
arra n ge me nts ca n b e ma d e t o pr o perl y st ore t h e trial materials.  
1 0. 1 2  P u bli c ati o n a n d Di s cl o s ur e P oli c y 
All data a n d res ults a n d all i ntellect ual - pr o pert y ri g hts i n t he data a n d res ults deri ve d fr o m 
t he st u d y will be t he pr o p ert y of t he s p o ns or, w h o ma y utilize t he data i n vari o us wa ys, s uc h 
as f or s u b missi o n t o g o ver n me nt re g ulat or y a ut h orities or discl os ure t o ot her i n vesti gat ors. 
N o p u blicati o n or discl os ure of st u d y res ults will be per mitte d e x ce pt as s pecifie d i n a 
se parat e, writte n a gree m e nt bet wee n T h erac os S u b, L L C  a n d t he i n v esti gat or.  If res ults of 
t his st u d y are re p orte d i n me dical j o ur nals or at meeti n gs, all s u bjects’ i d e ntities will re mai n 
c o nfi de ntial. 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 4  of 7 2  
V 4 ( Gl o bal)  
 
1 1  R E F E R E N C E LI S T  
( 1 9 9 8a). I nte nsi v e bl o o d- gl uc ose c o ntr ol wit h s ul p h o n yl ureas or i ns uli n c o m pare d wit h 
c o n ve nti o nal treat me nt a n d ris k of c o m plicati o ns i n patie nts wit h t y pe 2 dia betes ( U K P D S 
3 3). T he La n cet  3 5 2, 8 3 7- 8 5 3. 
( 1 9 9 8 b). Ti g ht bl o o d press ure c o ntr ol a n d ris k of macr o vas c ular a n d micr o vasc ular 
c o m plicati o ns i n t y pe 2 dia betes: U K P D S 3 8. U K Pr os pecti ve Dia bet es St u d y Gr o u p. B mj  
3 1 7 , 7 0 3- 7 1 3. 
A merica n Di a betes, A. ( 2 0 1 4). Sta n dar ds of me di cal care i n dia bet es --2 0 1 4. Dia betes Care  
3 7 S u p pl 1 , S 1 4- 8 0. 
Ca va na u g h, K. ( 2 0 0 7). Dia betes ma na ge me nt iss ues f or patie nts wit h c hr o nic ki d ne y disease. 
Cli n Dia betes, 9 0- 9 7. 
C oll- de- T uer o, G., M ata- Cases, M., R o dri g uez- P o ncelas, A., Pe pi o, J. M., R o ura, P., Be nit o, 
B., Fra nc h- Na d al, J., a n d Saez, M. ( 2 0 1 2). C hr o nic ki d ne y disease i n t he t y pe 2 dia betic 
patie nts: pre vale n ce a n d a ss ociate d varia bles i n a ra n d o m sa m ple of 2 6 4 2 p atie nts of a 
Me diterra n ea n area. B M C ne p hr ol o g y  1 3, 8 7. 
Gil bert, R. E. ( 2 0 1 4). S o di u m- gl uc ose li n ke d tra ns p orter- 2 i n hi bit ors: p ote ntial f or 
re n o pr otecti o n be y o n d bl o o d gl uc os e l o weri n g? Ki d ne y i nter n ati o nal 8 6, 6 9 3- 7 0 0. 
I nz ucc hi, S. E., Ber ge nstal, R. M., B use, J. B., Dia ma nt, M., Ferra n ni ni, E., N a uc k, M., Peters, 
A. L., Ts a pas, A., We n der, R., Matt he ws, D. R. , et al. ( 2 0 1 2). Ma na ge me nt of h y p er gl yce mia 
i n t y pe 2 dia b etes: a patie nt-ce ntere d a p pr o ac h: p ositi o n state me nt of t he A merica n Dia b etes 
Ass ociati o n ( A D A) a n d t he E ur o pea n Ass ociati o n f or t he St u d y of Dia betes ( E A S D). 
Dia betes care  3 5, 1 3 6 4- 1 3 7 9. 
K o ha n, D. E., Fi orett o, P., Ta n g, W., a n d List, J. F. ( 2 0 1 4). L o n g- ter m st u d y of patie nts wit h 
t y pe 2 dia b etes a n d mo derate r e nal i m pair me nt s h o ws t hat da pa glifl ozi n re d uces wei g ht a n d 
bl o o d press ure b ut d oes n ot i m pr o ve gl yce mic c o ntr ol. Ki d ne y i nter nati o nal  8 5, 9 6 2- 9 7 1. 
Nati o nal Resear c h C o u ncil ( 2 0 1 0). T he Pre v e nti o n a n d Treat me nt of Missi n g D ata i n Cli nical 
Trials. I n  9 7 8- 0- 3 0 9- 1 5 8 1 4- 5, N. R. C o u ncil, e d., p p. 1 6 2. 
Sa nter, R., Ki n ner, M., Lasse n, C. L., Sc h n e p pe n h ei m, R., E g gert, P., Bal d, M., Br o de hl, J., 
Dasc h ner, M., E hric h, J. H., Ke m per, M. , et al. ( 2 0 0 3). M olec ular a nal ysis of t he S G L T 2 ge ne 
i n patie nts wit h re nal gl uc os uria. J A m S oc Ne p hr ol 1 4, 2 8 7 3- 2 8 8 2. 
Sc hee n, A.J. ( 2 0 1 5). P har mac o ki netics, P har mac o d y na mics a n d Cli nical Use of S G L T 2 
I n hi bit ors i n Patie nts wit h T y pe 2 Dia betes M ellit us a n d C hr o nic Ki d ne y Disease. Cli nical 
p har mac o ki netics  5 4, 6 9 1- 7 0 8. 
T ur ner, R. C., C ull, C. A., Fri g hi, V., a n d H ol ma n, R. R. ( 1 9 9 9). Gl yce mic c o ntr ol wit h diet, 
s ulf o n yl ur ea, metf or mi n, or i ns uli n i n patie nts wit h t y pe 2 dia b etes mellit us: pr o gressi ve 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 5  of 7 2 
V 4 ( Gl o bal)  
 
re q uire me nt f or m ulti ple t hera pies ( U K P D S 4 9). U K Pr os pecti ve Dia b etes St u d y ( U K P D S) 
Gr o u p. J A M A  2 8 1, 2 0 0 5- 2 0 1 2. 
va n de n He u v el, L. P., Assi n k, K., Wille mse n, M., a n d M o n ne ns, L. ( 2 0 0 2). A ut os o mal 
recessi ve re n al gl u c os uri a attri b uta ble t o a m utati o n i n t he s o di u m gl uc ose c otra ns p orter 
( S G L T 2). H u ma n ge n etics 1 1 1, 5 4 4- 5 4 7. 
Vi via n, E. ( 2 0 1 5). S o di u m- Gl uc ose C otra ns p orter 2 I n hi bit ors i n t he Treat me nt of T y p e 2 
Dia betes Mellit us. T he Dia betes e d ucat or.  
W hale n, K., Miller, S., a n d O n ge, E. S. ( 2 0 1 5). T h e R ole of S o di u m- Gl uc ose C o -Tra ns p ort er 
2 I n hi bit ors i n t he Tr eat me nt of T y p e 2 Dia b etes. Cli nical t hera pe utics  3 7, 1 1 5 0- 1 1 6 6. 
Yale, J. F., Ba kris, G., Cari o u, B., Y ue, D., Da vi d- Net o, E., Xi, L., Fi g uer oa, K., Wajs, E., 
Usis ki n, K., a n d Mei ni n ger, G. ( 2 0 1 3). Efficac y a n d safet y o f ca na glifl ozi n i n s u bjects wit h 
t y pe 2 dia b etes a n d c hr o nic ki d ne y disease. Di a bet es, o besit y & meta b olis m 1 5, 4 6 3- 4 7 3. 
Zi n ma n, B., Wa n ner, C., Lac hi n, J. M., Fitc hett, D., Bl u h m ki, E., Ha ntel, S., Matt he us, M., 
De vi ns, T., J o ha nse n, O. E., W oerle, H.J. , et al. ( 2 0 1 5). E m pa glifl ozi n, Car di o vasc ular 
O utc o mes, a n d M ortalit y i n T y pe 2 Dia betes. T h e Ne w E n gla n d j o ur n al of me dici ne  3 7 3, 
2 1 1 7- 2 1 2 8. 
 
 
 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 6  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 1   
S c h e d ul e of E v e nt s 
Pr oce d ure  
Scree ni n g  
R u n -i n 
Tre at me nt  
F oll o w -u p  
Visit N u m b er  
V 1  
V 2  
V 3  V 4  V 5  V 6  V 7  V 8  
V 9  
Ti me t o R a n d o miz ati o n  
3 d a ys - 3 
w ee ks  t o V 2 
- 1 
0 
2 
6 
1 2  
1 8  
2 4  
2 6  
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
Scree ni n g f or I/ E Criteria  
X  
 
X  
 
 
 
 
 
 
Me dical Hist or y  
X  
 
 
 
 
 
 
 
 
Diet a n d E xercise C o u nseli n g  
 
X  
 
 
 
 
 
 
 
P h ysical E xa mi nati o n  
 
 
X  
 
 
 
 
 
 
A b bre viate d P h ysical E xa mi nati o n  
X  
 
 
 
 
X  
 
X  
X  
W ei g ht  
X  
 
X  
 
X  
X  
 
X  
X  
Vital Si g ns  
X  
 
X  
 
X  
X  
 
X  
X  
Electr ocar di o gra p h y  
X  
 
 
 
 
 
 
X  
 
Cli nical La b orat or y T ests  
X  
 
X  
 
X  
X  
 
X  
X  
Uri nal ysis  
X  
 
X  
 
X  
X  
 
X  
X  
P o p ulati o n P K Sa m pli n g  
 
 
 
 
X  
X  
 
 
 
Diar y a n d Gl uc o meter Rec or d Re vie w  
 
 
X  
X  
X  
X  
X  
X  
X  
Dis pe nsi n g R u n -i n Dr u g 
 
X  
 
 
 
 
 
 
 
Ra n d o mizati o n  
 
 
X  
 
 
 
 
 
 
Dis pe nsi n g I n vesti gati o nal Pr o d uct  
 
 
X  
 
 
X  
 
 
 
A d verse E ve nts & D K A Assess me nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt Me dicati o n Assess me nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 7  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 2   
S c h e d ul e of L a b or at or y T e st s 
Pr oce d ure  
Scree ni n g  
R u n -i n 
Tre at me nt  
F oll o w -
u p  
Visit n u m ber  
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7  
V 8  
V 9  
Ti me t o Ra n d o mizati o n Visit ( wee ks)  
3 da ys - 
3 wee ks  t o 
V 2  
- 1 
0 
2 
6 
1 2  
1 8  
2 4  
2 6  
He mat ol o g y  
X  
 
X  
 
X  
X  
 
X  
X  
Ser u m C he mistr y a n d Electr ol ytes  
X  
 
X  
 
X  
X  
 
X  
X  
Gl yce mic C o ntr ol  
X  
 
X  
 
X  
X  
 
X  
X  
Ser u m Li pi ds  
X  
 
X  
 
 
X  
 
X  
X  
Uri nal ysis  
X  
 
X  
 
X  
X  
 
X  
X  
U A C R  
X  
 
X  
 
 
 
 
X  
X  
Uri ne Pre g na nc y T est ( W O C B P)  
X  
 
X  
 
X  
X  
 
X  
X  
P o p ulati o n P K sa m pli n g  
 
 
 
 
X  
X  
 
 
 
 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 8  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 3   
K D O QI C hr o ni c Ki d n e y Di s e a s e Cl a s sifi c ati o n a n d 
A c ut e Ki d n e y I nj ur y St a g e D efi niti o n 
C hr o nic ki d ne y disease ( C K D) is defi ne d as eit her ki d ne y d a ma ge or G F R < 6 0 
m L/ mi n/ 1. 7 3 m 3 f or ≥3 m o nt hs.  Ki d ne y da ma ge is defi ne d as pat h ol o gic a b n or malities or 
mar kers of d a ma ge, i n cl u di n g a b n or malities i n bl o o d or uri ne tests or i ma gi n g st u dies ( N F K 
K D O Q g ui deli nes ). 
Sta ges of C K D ar e  o utli ne d i n Ta ble 2.  
T a bl e  2 . 
K D O QI C K D St a g e s  
St a ge  
Descri pti o n  
G F R ( m L/ mi n/ 1. 7 3 m 2) 
1  
Ki d ne y da ma ge wit h  n or mal or ↑↓G F R  
≥ 9 0  
2  
Ki d ne y da ma ge wit h mil d ↓G F R  
6 0 -8 9  
3  
M o derate ↓G F R  
3 0 -5 9  
4  
Se vere ↓G F R  
1 5 -2 9  
5  
Ki d ne y fail ure  
<  1 5 ( or dial ysis)  
 
Ac ute ki d ne y i nj ur y sta ges base d o n t he D efi niti o n b y t he A c ute Ki d ne y I nj ur y N et w or k 
( A KI N) ar e o utli ne d i n Ta ble 3 (K DI G O Cli nical Practice G ui deli ne f or A KI, 2 0 1 2 ). 
T a bl e  3 . 
Cl a s sifi c ati o n/ St a gi n g S y st e m f or A c ut e Ki d n e y I nj ur y  
St a ge  
Ser u m cre ati ni ne criteri a  
Uri ne o ut p ut criteri a  
1  
1. 5 t o 1. 9 ti mes baseli ne or ≥ 0. 3 m g/ d L ( ≥ 2 6. 5  µ m ol/ L) i ncrease fr o m 
baseli ne  
< 0. 5 m L/ k g / h f or 6 t o 1 2 h  
2  
2. 0 t o 2. 9 ti mes baseli ne  
<  0. 5 m L/ k g / h f or ≥ 1 2 h  
3  
3. 0 ti mes baseli ne , or 
I ncrease i n ser u m creati ni ne t o ≥4. 0 m g/ d L ( ≥ 3 5 3. 6 µ m ol/ L) , or 
I nitiati o n of re nal re place me nt t hera p y, or 
I n patie nts <  1 8 years, decreas e i n e G F R t o <  3 5 m L / mi n per 1. 7 3 m2 
<  0. 3 m L/ k g / h f or ≥ 2 4 h 
or a n uria f or ≥ 1 2 h  
 
 

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 6 9  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 4   
E sti m ati n g G F R a n d C orr e cti n g C al ci u m  
e G F R  
T he e q uati o n f or esti mati n g gl o mer ular filtrati o n rate ( G F R) fr o m ser u m creati ni ne is t he 
is ot o pe dil uti o n mass s pectr o metr y (I D M S)-tracea ble M o dificati o n of Diet i n Re nal Disease 
( M D R D) st u d y e q uati o n. T his e G F R calc ulat or a p plies ser u m crea ti ni ne ( Scr) re p orte d i n 
m g/ d L.  
T he e G F R s h o ul d be calc ulate d base d o n f oll o wi n g e q u ati o n  
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 x ( Scr)-1. 1 5 4 × ( A ge) -0. 2 0 3 x ( 0. 7 4 2 if fe male) x ( 1. 2 1 2 if 
Africa n A merica n)  
T he e G F R  f or J a pa nese s u bjects s h o ul d be calc ul ate d base d o n f oll o wi n g e q uati o n (Mats u o et 
al., 2 0 0 9) : 
e G F R ( m L/ mi n/ 1. 7 3 m2) = 1 9 4 × ( Scr )-1. 0 9 4 × ( A ge) -0. 2 8 7× ( 0. 7 3 9 if f e male)  
C orrecte d Ser u m C alci u m  
C orrecte d s er u m cal ci u m = 0. 8 * [ 4 g/ d L – meas ure d ser u m al b u mi n [i n g/ d L]) + meas ure d 
calci u m [i n m g/ d L]  

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 7 0  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 5   
E x a m pl e s of S G L T 2 I n hi bit or s 
T he f oll o wi n g m e dicati o ns are pr o hi bite d d uri n g t he st u d y. Ot h er S G L T 2 i n hi bit ors t hat ma y 
be a p pr o ve d f or t he tr eat me nt of T 2 D M d uri n g t he T H R- 1 4 4 2- C- 4 4 8 st u d y will als o be 
pr o hi bite d as a c o n c o mita nt me dicati o n i n t his pr ot oc ol. 
Ge neric N a me  
Tr a de N a me  
ca na glifl ozi n  
I n v o k a na™ 
ca na glifl ozi n pl us metf or mi n  
I n v o k a met™ 
da pa glifl ozi n  
Far xi ga ™ or F or xi ga ™ 
e m pa glifl ozi n 
J ar dia nce®  
e m pa glifl ozi n pl us li na gli pti n 
Gl y x a m bi ®  
e m pa glifl ozi n/ metf or mi n H Cl  
S y njar d y  
da pa glifl ozi n/ metf or mi n H Cl 
e xte n de d releas e ta blet  
Xi g d u o X R  

	  
1 0/ 2 7/ 2 0 1 6
	  
10/27/2016

B e xa glifl ozi n T a blets  
 
T herac os S u b, L L C  
Cli nical Trial Pr ot oc ol : T H R -1 4 4 2 - C-4 4 8  
 
2 5 Oct o ber 2 0 1 6   
 
 
 
 
C o nfi de ntial  
P a ge 7 2  of 7 2  
V 4 ( Gl o bal)  
 
A p p e n di x 7   
I n v e sti g at or’ s Si g n at ur e 
St u d y  Title:  
A d o u ble bli n d place b o c o ntr olle d st u d y t o e val u ate t he effect of 
be x a glifl ozi n ta blets o n he m o gl o bi n A 1c i n p atie nts wit h t y pe 2 
dia betes mellit us a n d m o derate re nal i m pair me nt  
St u d y  N u m ber:  
T H R -1 4 4 2 -C -4 4 8  
Fi n al  D ate:  
2 5 Oct o ber  2 0 1 6  
I h a ve r ea d t he pr ot oc ol descri be d a b o ve. I a gree t o c o m pl y wit h t he I nter n ati o nal C o nfere n ce 
o n Har m o nisati o n (I C H) Tri partite g ui deli ne o n G o o d Cli nical Practice ( G C P) a n d all 
a p plica ble r e g ulati o ns a n d t o c o n d uct t he st u d y as descri be d i n t he pr ot o c ol.  
I a gree t o e ns ur e t hat Fi n a ncial Discl os ure State m e nts will be c o m plete d b y m yself a n d m y 
s u bi n vesti gat ors at t he st art of t he st u d y a n d f or u p t o 1 year after t he st u d y is c o m plete d, if 
t here are c h a n ges t hat aff ect m y fi na ncial discl os ure stat us. 
I a gree t o e ns ur e t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot be 
use d f or a n y p ur p ose ot h er t ha n t he e v al uati o n or c o n d uct of t he cli nical i n vesti gati o n wit h o ut 
t he pri or writte n c o ns e nt of T herac os S u b, L L C.  
  
 
 
Si g ne d:  
 
 
Date:    
 
Pri nci pal I n vesti gat or