Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 312
Healthy volunteers: no

Brief summary:
This was a phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of oral administration of bexagliflozin at 20 mg versus placebo in subjects with T2DM, moderate renal impairment and inadequate glycemic control.

Detailed description:
The phase 3, double-blind, placebo-controlled parallel-group study was conducted at investigative sites in the US, Japan, France and Spain. Approximately 300 subjects were to be randomly assigned to receive bexagliflozin tablets, 20 mg, or placebo in equal ratio for 24 weeks.

The study was to enrolled male and female participants who had T2DM with an HbA1c between 7.0 and 10.5% (inclusive) and stage 3 chronic kidney disease (CKD) as defined by an eGFR of ≥ 30 and\< 60 mL min-1 per 1.73 m2 at the screening visit and one additional time of measurement between 1 and 12 months prior to screening. Subjects were either treatment naïve or were treated with a stable regimen of anti-diabetic medications.

All eligible subjects were to enter a one-week single-blind, placebo run-in period. Subjects who were compliant in taking run-in medication, had screening eGFR ≥ 30 and\< 60 mL min-1 per 1.73 m2, and had stable GFR (no more than 20% change in eGFR between a historical value and the value determined at the screening visit) were eligible for randomization. Randomization was stratified by HbA1c level (7.0 to 8.5% or 8.6 to 10.5%), anti-diabetic treatment regimen and eGFR (30 - 44 mL min-1 per 1.73 m2 or 45 - 59 mL min-1 per 1.73 m2). At least 135 subjects in each of the eGFR groups were planned.

Study subjects were to schedule clinic visits at weeks 2, 6, 12, 18, and 24 for safety and efficacy evaluation. At weeks 2 and 18, the visits were to be conducted via phone interviews unless an in-person visit was considered clinically advisable. A final follow-up visit was to be conducted at week 26 or two weeks after the last dose of investigational product if the subject withdrew prior to week 24.

Arms:
arm 1: Each subject will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. arm 2: Each subject will receive a placebo (inactive) tablet once daily for the duration of the study.

Interventions: intervention 1: Bexagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Bexagliflozin tablet, 20 mg intervention 2: Placebo (inactive) tablet to match the active comparator

Protocol document:
Prot_000.pdf: 
 
 
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 


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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, 


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C o nfi de ntial  
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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  
 


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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)  
 
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 


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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)  
 
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  
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
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Version 1.1 
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1007778 
 
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Sponsor Name: 
Theracos Sub, LLC 
Protocol Number and Title: 
 
THR-1442-C-448 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 
Protocol Version and Date: 
Version 4, 25-Oct-2016 
 
 
INC Research Project Code: 
1007778 
Author(s): 
Fang Zhu, Senior Biostatistician 
SAP Version: 
Version 1.1 
SAP Version Date:  
08-Dec-2017 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Theracos Sub, LLC. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Theracos Sub, LLC.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, INC Research 
should be notified promptly. 


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Revision History 
 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
0.1 
30-Nov-2016 
Fang Zhu 
Initial draft 
0.2 
10-Feb-2017 
Fang Zhu 
Update based on sponsor 
comments 
0.3 
02-Oct-2017 
Fang Zhu 
Update based on sponsor 
comments 
1.0 
26-Oct-2017 
Fang Zhu 
Update per sponsor comments 
1.1 
08-Dec-2017 
Fang Zhu 
Update to include rescue 
medication adjudication 
process 
 
 




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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS .............................................................. 8 
2. 
PURPOSE ................................................................................................... 11 
2.1. 
Responsibilities ............................................................................................................... 11 
2.2. 
Timings of Analyses ....................................................................................................... 11 
3. 
STUDY OBJECTIVES ................................................................................. 12 
3.1. 
Primary Objective ............................................................................................................ 12 
3.2. 
Secondary Objectives ..................................................................................................... 12 
3.3. 
Safety Objectives ............................................................................................................ 12 
3.4. 
Other Objectives .............................................................................................................. 13 
3.5. 
Brief Description ............................................................................................................. 14 
3.6. 
Subject Selection ............................................................................................................ 15 
3.6.1. 
Inclusion Criteria ....................................................................................................... 15 
3.6.2. 
Exclusion Criteria ...................................................................................................... 15 
3.7. 
Determination of Sample Size ........................................................................................ 16 
3.8. 
Treatment Assignment & Blinding ................................................................................ 16 
3.8.1. 
Treatment Assignment ............................................................................................. 16 
3.8.2. 
Blinding ..................................................................................................................... 17 
3.9. 
Administration of Study Medication .............................................................................. 17 
3.10. 
Study Procedures and Flowchart .................................................................................. 18 
4. 
ENDPOINTS ................................................................................................ 20 
4.1. 
Primary Efficacy Endpoint ............................................................................................. 20 
4.2. 
Secondary Efficacy Endpoints ...................................................................................... 20 


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4.3. 
Safety Endpoints ............................................................................................................. 20 
4.4. 
Other Endpoints .............................................................................................................. 21 
5. 
ANALYSIS SETS ........................................................................................ 22 
5.1. 
Screened Analysis Set .................................................................................................... 22 
5.2. 
Safety Analysis Set ......................................................................................................... 22 
5.3. 
Intention-to-Treat Analysis Set ...................................................................................... 22 
5.4. 
Per Protocol Analysis Set .............................................................................................. 22 
5.5. 
Protocol Deviations ......................................................................................................... 22 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ............................. 24 
6.1. 
General Methods ............................................................................................................. 24 
6.2. 
Key Definitions ................................................................................................................ 24 
6.2.1. 
Baseline Values ........................................................................................................ 24 
6.2.2. 
First Dose Date ......................................................................................................... 24 
6.2.3. 
Study Day ................................................................................................................. 25 
6.2.4. 
Duration .................................................................................................................... 25 
6.2.5. 
End of Study ............................................................................................................. 25 
6.2.6. 
Patient Years ............................................................................................................ 25 
6.3. 
Missing Data .................................................................................................................... 25 
6.4. 
Analysis Visit Windows .................................................................................................. 25 
6.5. 
Pooling of Centers .......................................................................................................... 26 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ..................................................................................................... 27 
7.1. 
Subject Disposition and Withdrawals ........................................................................... 27 
7.2. 
Subject Eligiblity and Protocol Deviations ................................................................... 27 
7.3. 
Demographic and Other Baseline Characteristics ...................................................... 27 
7.4. 
Medical History ................................................................................................................ 28 


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7.5. 
Medication ........................................................................................................................ 28 
7.5.1. 
Prior Medication ........................................................................................................ 29 
7.5.2. 
Concomitant Medication ........................................................................................... 29 
7.5.3. 
Rescue  Medication .................................................................................................. 29 
8. 
EFFICACY ................................................................................................... 30 
8.1. 
Primary Efficacy Endpoint and Analysis ...................................................................... 30 
8.1.1. 
Primary Efficacy Analysis ......................................................................................... 30 
8.1.2. 
Sensitivity Analyses .................................................................................................. 31 
8.1.3. 
Subgroups ................................................................................................................ 34 
8.2. 
Secondary Efficacy Endpoint(s) and Analyses ............................................................ 34 
8.2.1. 
Key secondary efficacy endpoints and analyses ...................................................... 35 
8.2.2. 
Exploratory secondary efficacy endpoints and analyses ......................................... 36 
9. 
SAFETY ...................................................................................................... 38 
9.1. 
Extent of Exposure .......................................................................................................... 38 
9.2. 
Treatment Compliance.................................................................................................... 39 
9.3. 
Adverse Events ............................................................................................................... 39 
9.3.1. 
Derived Data ............................................................................................................. 40 
9.3.2. 
Data Summarization ................................................................................................. 40 
9.3.3. 
AE of Special Interest ............................................................................................... 41 
9.4. 
Laboratory Evaluations .................................................................................................. 43 
9.5. 
Vital Signs ........................................................................................................................ 46 
9.6. 
Electrocardiogram ........................................................................................................... 46 
9.7. 
Physical Examination ..................................................................................................... 47 
10. 
ANALYSIS OF PHARMACOKINETICS .................................................. 48 
11. 
INTERIM ANALYSES .............................................................................. 48 
12. 
DATA AND SAFETY MONITORING BOARD ......................................... 48 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ....................... 48 


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14. 
REFERENCE LIST .................................................................................. 49 
15. 
PROGRAMMING CONSIDERATIONS .................................................... 50 
15.1. 
General Considerations .................................................................................................. 51 
15.2. 
Table, Listing, and Figure Format ................................................................................. 51 
15.2.1. 
General ..................................................................................................................... 51 
15.2.2. 
Headers .................................................................................................................... 51 
15.2.3. 
Display Titles ............................................................................................................ 52 
15.2.4. 
Column Headers ....................................................................................................... 52 
15.2.5. 
Body of the Data Display .......................................................................................... 53 
15.2.6. 
Footnotes .................................................................................................................. 55 
16. 
QUALITY CONTROL ............................................................................... 56 
17. 
INDEX OF TABLES ................................................................................. 57 
18. 
INDEX OF FIGURES ............................................................................... 61 
19. 
INDEX OF LISTINGS ............................................................................... 63 
20. 
MOCK-UPS.............................................................................................. 66 
21. 
APPENDIX ............................................................................................... 66 
21.1. 
Adjudication Process...................................................................................................... 66 
21.2. 
SAS Code Used in the Analyses .................................................................................... 66 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass index 
BP 
Blood Pressure 
CEC 
Cardiovascular Endpoint Committee 
CI 
Confidence Interval 
CRF 
Case Report Form 
DKA 
Diabetic Ketoacidosis 
dL  
Deciliter 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimating Glomerular Filtration Rate 
ESA 
Erythropoiesis-stimulating Agent 
FMI 
Fraction of Missing Information 
FPG 
Fasting Plasma Glucose 
GMI 
Genital Mycotic Infection 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HDL-C 
High Density Lipoprotein Cholesterol 
Hgb 
Hemoglobin 
ICH 
International Conference on Harmonization 
IP 
Investigational products 
ITT 
Intention to Treat 
IWRS 
Interactive Web Randomization System 


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Abbreviation 
Description 
LDL-C  
Low Density Lipoprotein Cholesterol  
LOCF  
Last Observation Carried Forward  
MACE  
Major Adverse Cardiovascular Event  
MAR 
Missing at Random 
Max 
Maximum 
MCAR 
Missing Complete at Random 
MCH  
Mean Cell Hemoglobin  
MCHC  
Mean Cell Hematocrit  
MCV  
Mean Cell Volume  
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram  
MI 
Myocardial Infarction  
Min 
Minimum 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
MODY 
Maturity-onset Diabetes of the Young 
N/A 
Not Applicable 
OHA 
Oral Hypoglycemic Agent 
PP 
Per Protocol  
PR 
Time from the beginning of the P wave to the beginning of the 
QRS complex in electrocardiogram 
PT 
Preferred Term 
QRS 
Graphical deflections corresponding to ventricular 
depolarization in a typical electrocardiogram 
RBC 
Red Blood Cell  
RR 
Time between the start of one R wave and the start of the 
next R wave in the ECG 


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Abbreviation 
Description 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SGLT2 
Sodium Glucose Linked Transporter 2 
SI 
Standard International System of Units 
SMBG 
Self-Monitored Blood Glucose 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TLF 
Table, Listing And Figure 
TZD 
Thiazolidinedione 
UACR 
Urine Albumin To Creatinine Ratio  
ULN 
Upper Limit of Normal 
UPT  
Urine Pregnancy Test  
UTI 
Urinary Tract Infection 
WBC 
White Blood Cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding 
the study objectives.   
2.1. 
RESPONSIBILITIES 
Theracos has designed the study protocol and is responsible for the conduct of the 
study.  INC Research is responsible for the development and validation of a clinical 
database using MediData RAVE platform. 
INC Research will perform the statistical analyses and are responsible for the 
production and quality control of all tables, figures and listings. 
Adverse events that have met the seriousness criteria defined in the protocol are 
reported on the serious adverse event (SAE) forms using MediData RAVE platform.  An 
SAE case, consists of the information reported in the SAE forms, subject 
characteristics documented in the case report forms (CRF), and additional source data 
such as a hospital discharge summary, is recorded in a validated ARGUS database 
which is managed by Covance. Any discrepancies in critical data fields of each SAE will 
be reconciled between the AUGUS and THR-1442-C-448 clinical database prior to 
database lock.  The SAE coding, analyses and summaries are based on the final study 
data recorded in the clinical database. Detailed serious adverse event follow-up data 
will be reported from ARGUS database and not included this report. 
Theracos will perform review of all tables, figures and listings before the finalization. 
2.2. 
TIMINGS OF ANALYSES 
The final analysis of safety and efficacy is planned after all patients who complete the 
planned 24 weeks of blinded study treatment and the subsequent follow-up period or 
who have withdrawn from the study.  At this time, the database will be cleaned and 
locked, and the treatment codes will be unblinded.  
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective is to determine the efficacy of bexagliflozin on lowering HbA1c 
in patients with T2DM and moderate renal impairment after 24 weeks of treatment. 
3.2. 
SECONDARY OBJECTIVES 
The key secondary objectives are: 
• 
To assess the effect of bexagliflozin on the change in body weight at week 24 
in subjects with baseline body mass index (BMI) ≥25 kg/m2 
• 
To assess the effect of bexagliflozin on the change in systolic blood pressure 
(SBP) at week 24 in subjects with baseline SBP ≥130 mmHg 
• 
Change in HbA1c in subjects with eGFR 45 to 59 mL/min/1.73 m2 at week 24 
• 
Change in HbA1c in subjects with eGFR 30 to 44 mL/min/1.73 m2 at week 24 
Additional exploratory objectives are: 
• 
Change in HbA1c over time in all subjects 
• 
Proportion of subjects who reach target HbA1c of <7% over time 
• 
Changes in fasting plasma glucose (FPG) over time 
• 
Proportion of ≥ 5% reduction of body weight in subjects with baseline BMI ≥25 
kg/m2 at week 24 
• 
Change in body weight in all subjects over time 
• 
Changes in SBP and diastolic BP over time in all subjects 
• 
Change in albuminuria (urine albumin creatinine ratio [UACR]) from baseline to 
week 24 in all subjects and in subjects with baseline macroalbuminuria (UACR 
≥300) 
3.3. 
SAFETY OBJECTIVES 
The safety objective is the evaluation of the safety of exposure to bexagliflozin for 24 
weeks. 
An additional safety objective of this study is the contribution major adverse 
cardiovascular events (MACE) to an eventual meta-analysis that is intended to exclude 


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excessive cardiovascular risks for subjects exposed to bexagliflozin compared to 
subjects exposed to placebo during the investigational phase of bexagliflozin. 
3.4. 
OTHER OBJECTIVES 
Measurement of bexagliflozin plasma concentration as a function of time from dosing 
(sparsely sampled) will be conducted and will include approximately 144 subjects. 
 
 


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3.5. 
BRIEF DESCRIPTION 
THR-1442-C-448 is a phase 3, multi-center, randomized, double-blind, placebo-
controlled, parallel-group study to evaluate the efficacy and safety of oral 
administration of bexagliflozin at 20 mg versus placebo in subjects with T2DM, 
moderate renal impairment, and inadequate glycemic control. 
Main eligibility criteria include: 1) male or female subjects with T2DM, 2) screening 
HbA1c of 7.0-10.5% (inclusive), and 3) estimated glomerular filtration rate (eGFR) 
based on serum creatinine at 2 different assessments ≥ 30 to < 60 mL/min/1.73 m2 
based on the serum creatinine at the screening visit and one additional time point 
between 1 and 12 months prior to screening (may be obtained from available medical 
records. The eGFR will be calculated by the modification of diet in renal disease study 
equation (MDRD).  At the time of screening, the doses and frequency of all anti-
diabetic medications must have been stable for 8 weeks. 
All eligible subjects will enter a one week single blind, placebo run-in period to allow 
for diabetes education and optimization of compliance with diet and exercise 
recommendations. Subjects who are compliant in taking run-in medication (missing no 
more than one dose), have screening eGFR ≥ 30 to < 60 mL/min/1.73 m2, and have 
stable GFR (no more than 20% change in eGFR between a historical value and the value 
determined at the screening visit V1) will be eligible for randomization and receive 
study drug. 
Approximately 300 subjects will be randomly assigned in equal ratio to receive once 
daily bexagliflozin tablets, 20 mg or placebo, in equal ratio once daily for 24 weeks in 
an outpatient setting.  Randomization will be stratified by screening HbA1c level (7.0 
to 8.5% or 8.6 to 10.5%), screening anti-diabetic treatment regimen (insulin treated or 
other) and screening eGFR (30 - 44 mL/min/1.73 m2 or 45 - 59 mL/min/1.73 m2). At 
least 135 subjects in each of the eGFR groups must be enrolled. 
Study subjects will have scheduled visits at weeks 2, 6, 12, 18, and 24 for safety and 
efficacy evaluation.  At weeks 2 and 18, the visit will be conducted via phone 
interviews unless clinically necessary.  A final follow up visit will be conducted at 
week 26 or two weeks after last dose of study drug if the subject terminates prior to 
Week 24. 
An assessment of bexagliflozin population pharmacokinetics (PK) will also be 
conducted to include approximately 144 subjects. Samples will be taken between 
weeks 6 and 12. The population PK study design and analysis plan will be described in 
a designated study protocol and the analysis will be reported separately. 


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3.6. 
SUBJECT SELECTION 
The study population will include approximately 300 subjects diagnosed with sub-
optimally controlled T2DM who have moderate renal impairment. Eligible subjects who 
must be informed of the nature of the study and the potential risk and consent to 
participate in the study will be enrolled in clinical investigational sites in multiple 
countries. 
3.6.1. 
Inclusion Criteria 
Refer to protocol section 4.2 for inclusion criteria.  
3.6.2. 
Exclusion Criteria 
Refer to protocol section 4.3 for exclusion criteria.  
 
 


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3.7. 
DETERMINATION OF SAMPLE SIZE 
Approximately 300 subjects will be randomized and equally allocated to receive 
bexagliflozin tablets, 20 mg, or placebo. 
The sample size calculation for this study is based on a two group t-test with a two-
sided significance at the 5% level and the following assumptions: 
1) The placebo-corrected population mean change from baseline to Week 24 in HbA1c 
in the dose group of 20 mg will be -0.4%. 
2) The pooled standard deviation for the change from baseline to Week 24 in HbA1c 
for the active and placebo groups will be 1.0%. 
Under the above assumptions, an estimated sample size of 133 evaluable subjects per 
treatment arm yields approximately 90% power to detect a treatment difference 
between bexagliflozin and placebo. A sample size of 150 per arm has been selected to 
account for a potential 12% drop-out and to allow adequate safety evaluation. The 
total sample size for this study will be 300 subjects. 
 
3.8. 
TREATMENT ASSIGNMENT & BLINDING 
3.8.1. 
Treatment Assignment 
The study will be conducted at investigative sites in multiple countries and will likely 
involve variable numbers of subjects at each site. Enrollment will be on a competitive 
basis but each site will be capped at 30 randomized subjects per site. Activation of 
investigational sites in each country will be centrally controlled by an Interactive Web 
Response System (IWRS).   
Eligible subjects who complete the run-in period and meet all study 
inclusion/exclusion requirements will be randomized to receive investigational 
product. The treatment period for each study subject will start at randomization. 
Approximately 300 eligible patients will be randomized at the end of the run-in period 
in a 1:1 ratio to receive once daily bexagliflozin tablets for 24 weeks. Randomization 
will be stratified by HbA1c level (7.0 to 8.5% or 8.6 to 10.5%), screening anti-diabetic 
treatment regimen (insulin treated or not) and screening eGFR (30-44 or 45-59 
mL/min/1.73 m2). 
Subject randomization will be deactivated for all sites when the planned number of 
subjects is met. However, if a potential subject is in run-in period already and wishes 
to continue with the study, the subject will be allowed to continue and, if eligible, to 
be randomized. 


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3.8.2. 
Blinding 
This is a double-blind placebo-controlled study. The sponsor, investigators, study 
coordinators, pharmacists, study subjects, and the cardiovascular adjudication 
committee members will be blinded to the study medication.  Upon randomization, 
each subject will receive a subject randomization number and a drug kit assigned to 
the subject.  To maintain blinding of the individual treatment assignment, the results 
of urinary glucose testing will not be made available to any study personnel or 
subjects. 
If knowledge of the treatment is needed to manage the subject’s condition, the 
investigator will contact the IWRS to obtain the treatment assignment. If unblinding 
occurs for any reason, the time and reason for breaking the blind will be recorded on 
CRF and the sponsor must be notified within 24 h. 
A designated statistician who is not involved with the study operation will hold the 
treatment codes.  The unblinded treatment information can be provided to the DSMB 
to facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted 
to regulatory agencies. 
The treatment assignment will continue to be withheld from the cardiovascular 
adjudication committee members until all global investigational studies are completed 
and a meta-analysis to assess cardiovascular risk is conducted. 
3.9. 
ADMINISTRATION OF STUDY MEDICATION 
The following investigational products (IP) will be used for oral administration: 
• 
Bexagliflozin tablets, 20 mg: tablets containing 20 mg of bexagliflozin 
• 
Bexagliflozin tablets, placebo: tablets containing no bexagliflozin 
Dosing with bexagliflozin tablets, 20 mg or placebo, will be based on randomized 
assignment.  All study subjects will be instructed to self-administer tablets once daily 
in the morning prior to eating or drinking; the medication should be taken with water. 
There will be no change of dose during the treatment period. 
On the day of each scheduled clinic visit, subjects must fast for a minimum of 8 hours 
prior to the collection of blood samples. During the fasting period, only water will be 
permitted. 


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3.10. 
STUDY PROCEDURES AND FLOWCHART 
The activities that must be performed at each clinic visit listed below are presented in 
Table 1.  
Table 1 
Schedule of Events 
Procedure  
Screening  Run-in  
Treatment  
Follow-up
Visit Number  
V1  
V2  
V3  V4  V5  V6  V7  V8  
V9  
Time to Randomization  
3 days -3 
weeks to V2  
-1  
0  
2  
6  
12  
18  
24  
26  
Informed Consent  
X  
 
 
 
 
 
 
 
 
Screening for I/E Criteria  
X  
 
X  
 
 
 
 
 
 
Medical History  
X  
 
 
 
 
 
 
 
 
Diet and Exercise Counseling  
 
X  
 
 
 
 
 
 
 
Physical Examination  
 
 
X  
 
 
 
 
 
 
Abbreviated Physical 
Examination  
X  
 
 
 
 
X  
 
X  
X  
Weight  
X  
 
X  
 
X  
X  
 
X  
X  
Vital Signs  
X  
 
X  
 
X  
X  
 
X  
X  
Electrocardiography  
X  
 
 
 
 
 
 
X  
 
Diary and Glucometer Record 
Review  
 
 
X  
X  
X  
X  
X  
X  
X  
Dispensing Run-in Drug  
 
X  
 
 
 
 
 
 
 
Randomization  
 
 
X  
 
 
 
 
 
 
Dispensing Investigational 
Product  
 
 
X  
 
 
X  
 
 
 
Adverse Events & DKA 
Assessments  
 
X  
X  
X  
X  
X  
X  
X  
X  
Concomitant Medication 
Assessments  
 
X  
X  
X  
X  
X  
X  
X  
X  
Hematology  
X  
 
X  
 
X  
X  
 
X  
X  
Serum Chemistry and 
Electrolytes  
X  
 
X  
 
X  
X  
 
X  
X  
Glycemic Control  
X  
 
X  
 
X  
X  
 
X  
X  
Serum Lipids  
X  
 
X  
 
 
X  
 
X  
X  
Urinalysis  
X  
 
X  
 
X  
X  
 
X  
X  
UACR  
X  
 
X  
 
 
 
 
X  
X  
Urine Pregnancy Test 
(WOCBP)  
X  
 
X  
 
X  
X  
 
X  
X  
Population PK sampling  
 
 
 
 
X  
X  
 
 
 
 
 


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A visit window of ± 3 days is allowed for all visits except Visit 3. V3 is the day of 
randomization and the basis for the visit window. 
The study staff will contact each subject prior to a scheduled clinic visit to confirm 
the time of the visit and to remind the subject of proper fasting practice. A subject 
must be queried to assess compliance with a minimum of 8 hours fast prior to blood 
draw to ensure the FPG and triglycerides values can be accurately determined. If a 
subject has not fasted for a minimal of 8 h, the subject must return as soon as can be 
arranged (within 1 week) to provide a specimen after proper fasting.  
 


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4. 
ENDPOINTS 
4.1. 
PRIMARY EFFICACY ENDPOINT 
• 
Change from baseline to week 24 in HbA1c  
4.2. 
SECONDARY EFFICACY ENDPOINTS 
The key secondary endpoints are: 
• 
Change from baseline to week 24 in body weight in subjects with baseline body 
mass index (BMI) ≥ 25 kg/m2  
• 
Change from baseline to week 24 in SBP in subjects with baseline SBP 
≥ 130 mmHg from baseline  
• 
Change from baseline to week 24 in HbA1c in subjects with eGFR 45 to 
59 mL/min/1.73 m2 
• 
Change from baseline to week 24 in HbA1c in subjects with eGFR 30 to 
44 mL/min/1.73 m2  
Other Efficacy Endpoints 
• 
Change in HbA1c over time in all subjects 
• 
Proportion of subjects who reach target HbA1c of <7% over time 
• 
Changes in FPG over time 
• 
Proportion of ≥ 5% reduction of body weight in subjects with baseline BMI 
≥25 kg/m2 at week 24 
• 
Change in body weight in all subjects over time 
• 
Changes in SBP and diastolic BP over time in all subjects 
• 
Change in albuminuria (urine albumin creatinine ratio or UACR) categories at 
week 24 in all subjects and in subjects with baseline macroalbuminuria (UACR 
≥300) 
 
4.3. 
SAFETY ENDPOINTS  
• 
Adverse events (AE), including AE of special interest (urinary tract infections 
[UTI], genital mycotic infection [GMI], diuretic effects, hepatotoxicity, 
hypoglycemia, MACE, fractures, malignancy, hypersensitivity reactions, 


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hypotensive episodes, acid-base disorders, diabetic ketoacidosis [DKA], renal 
failure events and amputations) 
• 
Laboratory testing, including hematology, serum chemistry, urinalysis, urinary 
electrolytes and creatinine 
• 
12-lead ECG 
• 
Vital signs 
• 
Physical examination 
• Concomitant medication use 
4.4. 
OTHER ENDPOINTS 
• 
Measurement of bexagliflozin plasma concentration as a function of time from 
dosing (sparsely sampled). 
 
 


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5. 
ANALYSIS SETS 
5.1. 
SCREENED ANALYSIS SET 
The Screened Analysis Set will include all subjects who have signed the informed 
consent forms and completed the eligibility screening prior to randomization. The 
screened analysis set will consist of both enrolled subjects and subjects who do not 
meet the eligibility criteria. This set will be used for summaries of subject disposition. 
5.2. 
SAFETY ANALYSIS SET  
All subjects who are randomized and take at least one dose of the double-blind IPs will 
be included in the Safety Analysis Set.  Safety analyses will be based on the treatment 
that a subject takes upon randomization.  The Safety Analysis Set is the primary 
analysis set for safety evaluation. 
5.3. 
INTENTION-TO-TREAT ANALYSIS SET  
All subjects who are randomized will be included in the Intention-to-Treat (ITT) 
Analysis Set.  All analyses of the ITT Analysis Set will be based on each subject’s 
randomized assigned treatment.  The ITT analysis set will serve as the primary set for 
the efficacy analyses. 
5.4. 
PER PROTOCOL ANALYSIS SET  
The Per Protocol (PP) Analysis Set will include all subjects in the ITT Analysis Set who 
meet the study eligibility requirements and have no major protocol deviations that 
affect the validity of the efficacy measurements.  Detailed protocol deviations that 
may result in subject or visit exclusion from the PP Analysis Set are described in 
Section 5.5. The PP Analysis Set will serve as the secondary set for efficacy 
assessment. 
5.5. 
PROTOCOL DEVIATIONS 
Protocol deviations will be captured during the study conduct.  Some of the examples 
of major deviations that may result in subject exclusion from the PP Analysis Set are 
given in Table 2.  The list of deviations will be reviewed before unblinding and major 
protocol deviations that, in the opinion of the medical monitor, could affect the 
primary and secondary variables will be determined.  
 


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Table 2 Some Possible Types of Major Protocol Deviations That Lead to Subject or 
Visit Exclusion from PP analysis set. 
Category  
Criteria 
Exclusion 
Inclusion/Exclusion Criteria  
 
 
Ineligible subject is enrolled  
- Subjects not satisfying HbA1c inclusion criteria  
- Subjects not satisfying eGFR inclusion criteria 
(inclusion #4 and #7) 
- Treated with SGLT2 within 3 months of screening 
 
Subject exclusion 
Prior or Concomitant 
Medication Restrictions  
 
 
Use of another SGLT2 
inhibitor  
Use of an SGLT2 inhibitor as the rescue medication 
for hyperglycemia  
Visit exclusion 
[exclude data post 
SGLT2 starts] 
Use of new Diuretic 
medication 
Initiate of new diuretic medication within 12 weeks
Visit exclusion 
[exclude data post 
initiation of a new 
diuretic] 
 of 
randomization 
Randomization/Blinding  
 
 
Unblinding  
Blind was broken (requested in IWRS)  
Visit exclusion 
[exclude data post 
blind broken] 
Dosing Non-Compliance 
-Subject missed more than 50% of the investigational 
product doses between week 12 and week 24 
Subject exclusion 
 
 
 
 
 
 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
Statistical methodology and analyses are in accordance with the principles outlined by 
the ICH E9 guidelines.  All statistical analyses will be conducted using SAS statistical 
software version 9.3 or higher.  
Tables, listings and figures (TLFs) will be produced in accordance with the principles 
outlined by the ICH E3 guidelines.  For most summary statistics, data will be analyzed 
by the following treatment groups:  Bexagliflozin 20 mg and Placebo.  All available 
data will be presented in the subject listings.    
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], Q1, median, Q3, minimum, and maximum) for continuous variables, 
and frequency and percentage of subjects for categorical and ordinal variables, unless 
otherwise specified.  
Unless otherwise specified, all tests will be two-sided using a 0.05 level of 
significance. All confidence intervals (CIs) will be two-sided 95% CIs.  
The analysis visit window will be assigned to data collection.  One selected data point 
per visit will appear in summary tables and figures.  Refer to section 6.4 for details.  
All visit assessment data will be included in shift tables and will appear in the subject 
listings. 
6.2. 
KEY DEFINITIONS 
6.2.1. 
Baseline Values 
For safety endpoints, baseline is defined as the last non-missing measurement prior to 
the first dose of double-blind IP.  For baseline demographics and efficacy endpoints, 
baseline is defined as the last non-missing value before the randomization date.  
These endpoints include HbA1c values, sitting SBP, height, body weight, BMI, FPG, 
eGFR, and UACR. 
6.2.2. 
First Dose Date 
Two “first dose dates” will be required, one for the Run-In period and one for the 
double-blind treatment period.  The first dose date for the Run-In period will be the 
date of administration of the first dose of single-blind placebo tablets during the 
Run-In period.  The first dose date for the double-blind treatment period will be the 
date that the first dose of randomized, double-blind study drug is administered.  Both 


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first dose dates will be obtained from the CRF.  Study analyses will use the 
double-blind treatment period first dose date.   
6.2.3. 
Study Day 
Study Day is the number of days starting from the first administration of double-blind 
study drug, which is counted as Study Day 1.  If the assessment date is after the date 
of the first double-blind medication, the study day is calculated as date of assessment 
- date of the first dose administration+1.  If the assessment date is prior to the date of 
the first double-blind medication, the study day is calculated as date of assessment - 
date of the first dose administration. 
6.2.4. 
Duration 
Duration of double-blind treatment will be determined as Double-Blind Duration = 
Double-Blind Last Dose Date minus Double-Blind First Dose Date plus 1.  Duration of 
Run-In period will be determined as Last Dose Date in the run-in period minus First 
Dose Date in the run-in period plus 1. 
6.2.5. 
End of Study 
The end of study is defined as the date of final contact as entered on the End-of-Study 
page of the CRF.  Any missing date of last contact on the End-of-Study CRF will be 
imputed as the date of last contact recorded in the database.  
6.2.6. 
Patient Years 
Patient years are calculated as sum of the duration of double-blind treatment / 365.24 
of all subjects in the specified analysis set and treatment arm.  This is used as the 
denominator of the computation of incidence rate. 
6.3. 
MISSING DATA 
The handling of missing or incomplete data is described for each endpoint and data 
type (as needed) in Sections 7 to 10.   
6.4. 
ANALYSIS VISIT WINDOWS 
Table 3 shows how data will be mapped to analysis visits prior to selection of records 
for analysis. All post-baseline visits, including unscheduled and early termination 
visits, will be mapped.  After mapping the data to the analysis visits, the following 
rules will apply unless other handling is specified for a particular analysis.  


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• 
If multiple records are available within a single analysis visit window, the 
record closest to the planned assessment day will be selected for analysis.  
• 
If 2 records are equidistant from the target day, then the later record will be 
selected.  
• 
If a subject has no record in an analysis window, the subject will be considered 
missing at that visit. 
Table 3 
Analysis Visit Windows 
Study Day Window 
Scheduled day   
Scheduled Visit/Week 
Day  1 - 63 
Day 42 
Visit 8/Week 6 
Day 64 – 125 
Day 84 
Visit 9/Week 12 
>= Day 126  
Last Dose Date + 1, or 
Day 168, whichever is 
earlier 
Visit 11/Week 24 
* Week 24 is the end of treatment visit for those subjects completing the study per 
protocol.  For endpoint of lab, vital sign, and ECG, the first collection after assigned 
Week 24 and > 7 days from Week 24 visit will be considered as Week 26 visit. All lab, 
vital sign, and ECG data summary will base on the mapped visit. 
6.5. 
POOLING OF CENTERS 
Subjects will not be pooled based on site size, but rather by region, to ensure a 
sufficient number of subjects per treatment arm in both the ITT and PP sets for 
analysis that contain region as a model effect.  The tables below show which countries 
comprise each of the regions to be used in analysis.   
 
Region 
Country 
Europe 
France 
Spain 
North 
America 
United States 
Asia 
Japan 
 
 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition data will be listed. A disposition table will present, by treatment 
group and overall, the number and/or percentage of subjects who signed the informed 
consent and entered the study (i.e., were screened, screen failed prior to Run-in, 
screen failed during the Run-in, and randomized), complete the study drug, 
discontinued study drug, completed the study, and discontinued from the study after 
randomization.  The reasons for early withdrawal after randomization will be 
summarized.   
Assignment to the analysis sets (Safety, ITT, and PP) will be summarized.  
7.2. 
SUBJECT ELIGIBLITY AND PROTOCOL DEVIATIONS 
All subjects, including screen failure subjects, who violate the Inclusion/ exclusion 
criteria will be listed.  Reason for screen failure will be summarized. 
Deviations that could affect the primary and secondary variables will be considered 
when determining a subject’s eligibility for the PP Analysis Set. The number and 
percent of subjects who had any major deviation and each type of major protocol 
deviation will be tabulated for the ITT Analysis Set.  All deviation term and class will 
be listed. 
7.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics include age, gender, race, ethnicity, and country and 
region of investigational site. Baseline characteristics will include baseline HbA1c 
values, blood pressure, height, body weight, BMI, FPG, eGFR, eGFR baseline groups 
(<45 or ≥45 mL/min/1.73m2), UACR, duration of diabetes from diagnosis to the date of 
informed consent, and prior anti-diabetic treatment status at screening. Baseline will 
be defined as the last non-missing value prior to randomization. Randomization 
stratification related factors will be summarized based on data collected on CRF or by 
lab.  They include screening HbA1c groups (7.0 to 8.5% vs. 8.6 to 10.5%), screening 
anti-diabetic treatment status (insulin treated, other), screening eGFR values, and 
screening eGFR groups (30-44 or 45-59 mL/min/1.73m2). Stratification factors from 
IWRS will be summarized if they are not consistent with CRF or lab values.  Summary 
descriptive statistics by treatment will include counts and percentages for discrete 
variables and estimation of means, standard deviations, medians, inter-quartile range 
(Q1, Q3), minimum, and maximum for continuous variables. Subjects’ baseline 


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demographic and personal baseline characteristics will be summarized by treatment 
group and overall for subjects in the Safety, ITT, and PP Analysis Set. Subject age will 
be the age at date of inform consent collected from CRF. 
Demographics data and randomization stratification factors will be presented in a data 
listing.  Prior treatment will be listed along with all medications. 
7.4. 
MEDICAL HISTORY 
Significant medical and surgical history, including dates of diagnoses and procedures 
and whether the condition is ongoing, if applicable, will be collected. Each condition 
will be recorded as a verbatim term, date of onset, date resolved, and a checkbox 
that indicates ongoing conditions.  Significant surgical and medical history will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.0 or 
higher. 
Medical and surgical history will be summarized for the Safety Analysis Set by 
treatment group, system organ class (SOC), and MedDRA preferred term (PT), overall. 
Subject data will be listed. 
Subject renal, diabetes and cardiovascular diseases history will be summarized for all 
categorical variables by frequency and percentage.  Listing will be provided. 
7.5. 
MEDICATION 
All prescription and over-the-counter medications, including vitamins and herbal 
supplements, that subjects receive during the trial must be documented on the CRF. 
The medication name, dose, frequency, route of administration, date(s) of 
administration and reason for administration must be recorded. This documentation 
should continue through the treatment period and the follow up period.  
All medication will be coded using the World Health Organization Drug Dictionary 
(WHO-DD) version March 2016 or higher.  Preferred drug name, Anatomical/ 
Therapeutic/ Chemical (ATC) class will be reported for inclusion in the database.   
Medication summaries based on ATC level 2 and the preferred drug names will be 
produced for the Safety Analysis Set. The summaries will present, by treatment group, 
the frequency and percentage of subjects who used any medication in an ATC class, or 
any medication based on a single preferred drug name. Medication summaries will be 
sorted by descending total frequency of ATC class and by PT within ATC class. Subjects 
will be counted only once for each medication class and each preferred drug name.  


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For subject listings, medications will be reported based on ATC class and PT; multiple 
medications for an individual subject will be listed by start date and then by stop 
date, from earliest to latest medications.  
7.5.1. 
Prior Medication 
Any medication with a start date prior to or on first dose date for the double-blind 
treatment period will be considered a prior medication.  If the entire start date of a 
given medication is missing, then the medication will be considered as prior 
medication.   
No summary for prior medication will be presented.  Prior and concomitant 
medications will be presented together on a single listing.  The listing will be ordered 
by subject number and medication start/end dates. Prior medication will be flagged.   
7.5.2. 
Concomitant Medication 
A concomitant medication is any medication that starts prior to double-blind 
treatment period and continue into double-blind treatment period, or started after 
the first dose of double-blind treatment. All medications or treatment for controlling 
hyperglycemia will be recorded as concomitant medications in CRF.  In the case of 
completely missing stop date, medication will be assumed to be concomitant. 
Concomitant medications will be presented in a summary table as well as in a subject 
listing.   
7.5.3. 
Rescue  Medication 
Rescue medication is any new anti-hyperglycemic medication that a subject starts 
taking during the double-blind treatment period or an increase in dose of the anti-
hyperglycemic medication that the subject has been taking and continued for more 
than 2 weeks. Rescue medications will be summarized in a separate table and flagged 
in the same listing. 
 
Independent blinded medical reviewers will identify the rescue medication before the 
study is unblinded. Adjudication process and definition of dose intensification and 
relaxation will be specified in a separate adjudication plan (Appendix 21.1). 
 
 


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8. 
EFFICACY 
Efficacy data include HbA1c, FPG, body weight, SBP, DBP, and albuminuria.  
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary efficacy hypothesis is that bexagliflozin reduces HbA1c after 24 weeks of 
treatment when compared to placebo. 
8.1.1. 
Primary Efficacy Analysis 
Let μBexagliflozon and μPBO represent the mean changes from baseline in HbA1c at Week 24 
for bexagliflozin and placebo arms, respectively. The following hypotheses will be 
tested: 
H0: μBexagliflozon = μPBO versus H1: μBexagliflozon ≠ μPBO  
This hypothesis will be tested based on ITT analysis set using all observed data and a 
mixed model repeated measures (MMRM) approach.  Treatment, visit, treatment-by-
visit, region, screening anti-diabetic treatment regimen (insulin treated or other), 
baseline eGFR (<45 or ≥45 mL/min/1.73m2) will be applied as fixed effects.  Baseline 
HbA1c will be used as covariate.  The analysis will evaluate the mean change from 
baseline in HbA1c over the 24-week double-blind treatment period. An unstructured 
covariance will be used to model the within-subject correlation. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. If the model 
with the unstructured covariance structure does not converge, an autoregressive (1) 
covariance structure will be used. HbA1c values obtained after the start of rescue 
medication will not be excluded from the analysis. 
Based on the MMRM model, the treatment and treatment-by-visit interaction terms 
allow for comparisons of the treatment groups at each visit. Least squares (LS) mean 
treatment differences between the bexagliflozin group and the placebo group at week 
24 will be estimated from the model with the corresponding p-values and their 
two-sided 95 % CIs presented. Sample SAS code will be provided in Appendix 21.2. 
Descriptive statistics (n, mean, Q1, median, Q3, SD, minimum, and maximum) will be 
reported by treatment group and visit, along with the least squares means, differences 
between LS means, a 2-sided 95% confidence interval for each difference, p-values 
from the model effects. In addition, the LS means with standard errors of the change 
from baseline over time and difference between treatment groups with 95% will be 
presented graphically for the ITT Analysis Set.   


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For supportive analyses, the primary efficacy endpoint will be analyzed with observed 
available data using the PP analysis set in a similar manner as above.  LS means over 
time will also be presented graphically.  
8.1.2. 
Sensitivity Analyses 
Randomized subjects who withdraw consent to participate in the study will not be 
replaced. The early termination rate is estimated to be 12%.  To the extent possible, 
attempts will be made to minimize the amount of missing data through measures 
planned in the study conduct. 
To investigate the possible implications of missing values in efficacy assessments, the 
number, timing, pattern, and reason for the missing value will be summarized.  If 
there are missing values for the primary analysis, only available data will be analyzed 
and data obtained after rescue will not be excluded.  To account for subjects for 
whom the post-baseline endpoint (ie, at the time when the last post-baseline double-
blind assessment was performed) occurs at a time point before Week 24, a MMRM 
approach will be used as the primary method.  It is assumed that the majority of the 
missing values will be one of the following:  
• 
“Missing Completely at Random (MCAR)” (ie, probability of an observation 
being missing does not depend on observed or unobserved measurements) or 
• 
“Missing at Random (MAR)” (ie, probability of an observation being missing 
depends only on observed measurements) 
In such situations, likelihood-base methods like MMRM are appropriate. 
The dropout patterns will be assessed by a Kaplan-Meier plot of time to 
discontinuation by treatment group to assess whether they differ between treatment 
groups.  
For our primary analysis, it is assumed that a majority of the missing values will be 
MCAR or MAR.  In such situations, likelihood-base methods like MMRM are appropriate 
and widely accepted in superiority trials (Little et al, 2002).  This will be considered 
the primary analysis.  Sensitivity analyses will be performed as: 
1. Missing HbA1c data will be imputed via multiple imputations, following which the 
MMRM will be repeated on the complete datasets with results combined across 
complete datasets using standard MI techniques; HbA1c values collected after the 
start of rescue medication will not be considered missing. 


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2. Missing HbA1c data will be imputed via LOCF, following which the MMRM will be 
repeated; HbA1c values collected after the start of rescue medication will be 
considered missing. 
3. HbA1c values collected after the start of rescue medication will be considered 
missing, and the MMRM analyses will be re-performed. 
4. Missing HbA1c data will be imputed via multiple imputations, following which the 
MMRM will be repeated on the complete datasets with results combined across 
complete datasets using standard MI techniques; HbA1c values collected after the 
start of rescue medication will be considered missing. 
For sensitivity analysis 1 and 4, data will be imputed in the framework of a pattern 
mixture model (PMM) with placebo-based pattern imputation for missing visits.  The 
method described here is based on methodology described by Little and Yau (1996) 
and extended in a PharmaSUG paper by Ratitch and O’Kelly (2011).  The concept for 
the imputation used here is that subjects who drop out of the study from the active 
treated arms will exhibit the same evolution of the disease under study as those 
subjects assigned to the placebo arm.  It is assumed, as well, that subjects who 
discontinue from the placebo arm would have the same evolution of the disease as 
those subjects on the placebo arm who remained in the study.  The three-step 
approach outlined below will be followed (Ratitch B and O’Kelly M, 2011): 
1. 
Non-monotone (intermediate visits) missing data will be imputed first using the 
Monte Carlo Markov Chain method under the MAR assumption in all treatment 
arms (using the MCMC statement in PROC MI). Multiple chains option 
(CHAIN=MULTIPLE option in the MCMC statement of PROC MI) will be used. For the 
non-monotone imputation of the HbA1c missing data, a multivariate normal model 
will be used including variables for the HbA1c at baseline and all post-baseline 
visits within each treatment group.  
2. 
After the non-monotone missing data have been imputed, the remaining 
monotone missing data will be imputed under the Missing Not at Random (MNAR) 
assumption that subjects who withdraw from the bexagliflozin group will have 
correlations with future (post-withdrawal) visits similar to subjects in the placebo 
group, adjusted for baseline covariates and observed outcomes prior to 
withdrawal. Monotone missing data of withdrawn subjects from the placebo group 
will be imputed under the MAR assumption and will follow the pattern of placebo 
completers. In other words, monotone missing values of the HbA1c will be 
imputed for all subjects who withdrew from the study (regardless of treatment 
group) using an imputation model at each time point estimated from subjects 
with available data in the placebo group only.  A regression imputation model for 
the HbA1c at each time point t will include explanatory variables including 


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screening anti-diabetic treatment regimen [insulin treated or other], baseline 
eGFR [<45 or ≥45 mL/min/1.73m2]), region and HbA1c at all previous time points, 
including baseline.  Data from bexagliflozin group with time t data observed will 
not be used to impute time point t.  Imputations will be performed using a 
sequence of regression-based imputations (using PROC MI statement MONOTONE 
REG) for each post-baseline time point as described in (Ratitch B and O’Kelly M, 
2011).  
3. 
Imputed data in each of the multiple imputed datasets will be analyzed using the 
same mixed model for repeated measures as in the primary analysis. The results 
from all imputed datasets will be combined using the Rubin’s combination rule 
(PROC MIANALYZE).  
The sample SAS codes can be found in Appendix 21.2. 
The number of imputation will be determined using the method described by White, 
et.al., 2011.  We will use Bodner’s approximation to estimate the fraction of missing 
information (FMI) as the proportion of the incomplete cases in the data.  Since the 
parameter of interest is the mean changes from baseline in HbA1c at Week 24 for 
bexagliflozin and placebo groups, FMI will be approximated using the proportion of 
subjects missing Week 24 values.  As indicated by Bodner, this is a very conservative 
approach and will work with FMI≤0.5.  The number of imputations m will be 
determined to provide sufficient level of reproducibility using formula: 
m≥100×FMI 
as recommended by White.  The Monte Carlo error of the P-value using m imputation 
datasets will be approximately 0.01 when the true P-value is 0.05, and 0.02 when the 
true P-value is 0.1. 
At least 10 datasets will be imputed.  We will examine the FMI estimated from the 
combined results.  If it is much larger than our initial approximation, a considerable 
volatility is observed from the imputed datasets.  In this case, we will increase the 
number of m using the estimated FMI. 
For sensitivity analysis using LOCF, all observed data and the imputed values will be 
analyzed using MMRM model.  Model will include terms for screening anti-diabetic 
treatment regimen (insulin treated or other), baseline eGFR (<45 or ≥45 
mL/min/1.73m2), region, treatment, visit, treatment-by-visit, and the baseline HbA1c 
value as a fixed effect covariate. LS mean treatment differences between the 
bexagliflozin group and the placebo group will be estimated from the model with the 
corresponding p-values and their two-sided 95 % CIs presented. 


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Sensitivity analysis will be conducted for ITT Analysis Set.  If > 5% subjects in either 
treatment arm had major protocol deviation that cause exclusion from PP analysis set, 
sensitivity analysis will be repeated for PP Analysis Set. 
8.1.3. 
Subgroups 
Both descriptive and model comparison for the primary analysis will be repeated by 
subgroups.  The nominal p-value will be presented without adjustment to the multiple 
comparisons.  They are not used for inferential purpose.  The subgroups include: 
 
• 
Age (<65 years or ≥65 years) 
• 
Gender (male or female) 
• 
Race (3 largest race groups or other) 
• 
Baseline HbA1c (7.0% to 8.5% or 8.6% to 10.5%) 
• 
Screening anti-diabetic treatment regimen (insulin treated or other) 
• 
Baseline eGFR (30-44 mL/min/1.73m2 or 45-59 mL/min/1.73m2) 
• 
Region (North America,  EU, or Asia) 
8.2. 
SECONDARY EFFICACY ENDPOINT(S) AND ANALYSES 
The key secondary efficacy endpoints include: 
• 
Change from baseline to week 24 in body weight in subjects with baseline body 
mass index (BMI) ≥ 25 kg/m2  
• 
Change from baseline to week 24 in SBP in subjects with baseline SBP 
≥ 130 mmHg from baseline  
• 
Change in HbA1c in subjects with eGFR 45 to 59 mL/min/1.73 m2 at week 24 
• 
Change in HbA1c in subjects with eGFR 30 to 44 mL/min/1.73 m2 at week 24 
The exploratory efficacy endpoints include: 
• 
Change in HbA1c over time in all subjects 
• 
Proportion of subjects who reach target HbA1c of <7% over time 
• 
Changes in fasting plasma glucose (FPG) over time 
• 
Proportion of ≥ 5% reduction of body weight in subjects with baseline BMI 
≥25 kg/m2 at week 24 
• 
Change in body weight in all subjects over time 


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• 
Changes in SBP and diastolic BP over time in all subjects 
• 
UACR categories at week 24 in all subjects and in subjects with baseline 
macroalbuminuria (UACR ≥300) 
8.2.1. 
Key secondary efficacy endpoints and analyses 
The primary superiority test on lowering of HbA1c at week 24 from baseline for 
bexagliflozin when compared to placebo will be conducted at 0.05 significance level. 
If it is significant, the hierarchical testing strategy will be followed to preserve 
experiment-wide type I error of 0.05.  The key secondary efficacy end points will be 
tested in the order: 
1. Superiority test of the change in body weight in subjects with baseline BMI 
≥ 25 kg/m2 at week 24 in the bexagliflozin group compared to the placebo 
group 
2. Superiority test of the change in systolic blood pressure (SBP) over time in 
subjects with SBP ≥ 130 mmHg in the bexagliflozin group compared to the 
placebo group 
3. Superiority test of the change in HbA1c at week 24 in subjects with eGFR 45 to 
59 mL/min/1.73m2 in the bexagliflozin group compared to the placebo group 
4. Superiority test of the change in HbA1c at week 24 in subjects with eGFR 30 to 
44 mL/min/1.73m2 in the bexagliflozin group compared to the placebo group 
These key secondary endpoints will only be tested sequentially when significant 
treatment differences are established for the primary efficacy endpoint in the 
comparisons between the bexagliflozin and placebo groups. 
Analysis for key secondary endpoints will be based on the ITT Analysis Set and 
repeated for the PP Analysis Set.   
8.2.1.1. 
Change in body weight from baseline to week 24 in subjects with 
a BMI ≥ 25 kg/m2 
This will be tested if the change from baseline body weight is significantly different 
between bexagliflozin and placebo groups based on ITT analysis set for subject with a 
baseline BMI ≥ 25 kg/m2.  The comparison of change in body weight between 
randomized treatments at week 24 will be carried out using similar MMRM ANCOVA 
model stated in section 8.1.1.  Treatment, visit, treatment-by-visit, region, baseline 
HbA1c level as continuous variable, screening anti-diabetic treatment regimen (insulin 
treated or other), baseline eGFR (<45 or ≥45 mL/min/1.73m2) will be applied as fixed 
effects.  Corresponding baseline weight value will be used as additional covariate. 
Treatment comparison p-values and difference at week 24 will be estimated from the 


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model, with the two-sided 95 % CIs of the treatment difference also presented. If the 
primary hypothesis is not significant, the nominal p-value will not be used for 
inferential purposes.  The most conservative sensitivity analysis, sensitivity analysis #4 
in section 8.1.2, multiple imputations with values after rescue medication considered 
as missing, will be repeated in ITT analysis set.  
8.2.1.2. 
Change in SBP from baseline to week 24 in subjects with 
baseline systolic blood pressure ≥ 130 mmHg 
This will be tested if the primary and the first key secondary efficacy endpoints are 
significant.  Change from baseline in sitting SBP at week 24 will be analyzed using the 
same MMRM ANCOVA model stated in section 8.1.1. The corresponding baseline SBP 
value will be used as additional covariate. Treatment comparison p-values and 
difference at week 24 will be estimated from the model, with the two-sided 95 % CIs 
of the treatment difference also presented.  The most conservative sensitivity 
analysis, sensitivity analysis #4 in section 8.1.2, multiple imputations with values after 
rescue medication considered as missing, will be repeated in ITT analysis set. 
8.2.1.3. 
Change in HbA1c from baseline to week 24 by eGFR status 
They will be tested following the hierarchical order specified in section 8.2.  They will 
be analyzed using the same MMRM ANCOVA model stated in section 8.1.1.  
8.2.2. 
Exploratory secondary efficacy endpoints and analyses 
All endpoints in this section are exploratory.  No sensitivity analyses and adjustment 
for multiple comparisons will be conducted.  Nominal p-values will be used to examine 
any trends in these endpoints.  
8.2.2.1. 
Changes from baseline in HbA1c, body weight, SBP, diastolic BP, 
FPG, and albuminauria over time 
The schedule of HbA1c, body weight, SBP, diastolic BP, and FPG over time can be 
found in Table 1.  The absolute value and change from baseline during the 
double-blind treatment period will be summarized by descriptive statistics at each 
visit.  Change from baseline in HbA1c will be analyzed as part of primary efficacy 
analysis.  The change from baseline in body weight, SBP, and FPG will be analyzed 
using the MMRM ANCOVA model from primary analysis as a template (Section 8.1.1).  
The fixed effect will include region, baseline HbA1c level as continuous variable, 
screening anti-diabetic treatment regimen (insulin treated or other), baseline eGFR 
(<45 or ≥45 mL/min/1.73m2), treatment, visit, and treatment-by-visit.  The 
appropriate baseline values will be used as covariate.  LS means for each treatment 
and the difference between treatments will be estimated at each visit.  The 


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corresponding p-values will also be presented. 
 All values for follow-up visits will be listed.   
8.2.2.2. 
Change in albuminuria from baseline to week 24 
Descriptive statistics for geometric mean, geometric coefficient of variation (gCV), 
median, Q1, Q3, minimum, and maximum of UACR values will be presented at 
baseline, and week 24 for all subjects and for baseline macroalbuminuria subjects 
(>300 mg/g).  UACR data is left-skewed and will be natural log transformed first.  
Change in log transformed UACR from baseline to week 24 will be analyzed by ANCOVA 
model.  The fixed effect will include region, baseline HbA1c level as continuous 
variable, screening anti-diabetic treatment regimen (insulin treated or other), 
baseline eGFR (<45 or ≥45 mL/min/1.73m2), and treatment.  The log transformed 
baseline values will be used as covariate.  Analysis will be repeated for baseline 
macroalbuminuria subjects. LS means for each treatment and the difference between 
treatments will be estimated at week 24. The adjusted geometric mean ratio of 
relative change from baseline in UACR (the ratio of the week 24 geometric mean and 
baseline geometric mean) and the corresponding two sided 95 % CI by treatment group 
will be calculated as the antilog of the LS mean and 95 % CI of log transformed values, 
converted to percentage. The adjusted geometric mean ratios of relative change from 
baseline in UACR for bexagliflozin vs. placebo (ratio of the two ratios obtained from 
previous steps) and their 95% CI will be calculated as the antilog of the LS mean 
differences and their 95% CI.  Sample SAS code will be provided in Appendix 21.2. 
8.2.2.3. 
Proportions of subjects with HbA1c of < 7% over time and 
proportion of ≥ 5% reduction of body weight in subjects with 
baseline BMI≥25 kg/m2 at week 24 
Summary on the proportion of subjects achieving HbA1c < 7% at each visit and the 
proportion of ≥ 5% reduction of body weight during each visit interval will be 
presented over time.  They will be analyzed using generalized estimating equation 
(GEE) logistic regression.  The fixed effect will include region, baseline HbA1c level, 
screening anti-diabetic treatment regimen (insulin treated or other), baseline eGFR 
(<45 or ≥45 mL/min/1.73m2), treatment, visit, and treatment-by-visit.  An 
unstructured correlation structure will be used (or autoregressive [1] if the model with 
the unstructured structure does not converge).  The LS mean proportion for each 
treatment will be estimated at each post-baseline visit.  The odds ratios of 
bexagliflozin group over the placebo group at each visit and across all post-baseline 
time points will be estimated from LS means based on the model with the 
corresponding p-values and their two-sided 95 % CIs presented. Similar method will be 
used for analyzing proportion of subjects with body weight reduction ≥ 5% in subjects 
with baseline BMI≥ 25 mg/m2.  Baseline body weight will be added to the model as a 


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covariate. Sample SAS code will be provided in Appendix. 
9. 
SAFETY 
The analysis population used for safety analyses will be the Safety Analysis Set.  Safety 
data include AEs; physical examination results; vital signs, including blood pressures; 
ECG results; and clinical laboratory results, including serum chemistry, hematology, 
serum lipids, and urinalysis.  
Observed data will be summarized by treatment group as counts and percentages for 
discrete variables and means, SDs, medians, minimum, and maximum for continuous 
variables. All subjects who are randomized and receive at least one dose of 
double-blind study medication will be included in the safety analysis. All safety data 
will be presented in by-subject listings and included in the clinical trial report.  
9.1. 
EXTENT OF EXPOSURE 
Study drug exposure will include: 
• 
Treatment duration by treatment group 
• 
Total dose taken by treatment group 
Treatment duration of tablets (in weeks) is calculated as (the date of the last dose of 
study drug – the date of the first dose of study drug + 1) / 7 and rounded to 1 decimal 
place.  
The specific definitions of the first dose and last dose dates of study drug are given 
below: 
• 
First dose date: The date of the first dose of study treatment during the 
double-blind treatment period obtained from the study drug exposure CRF.  
• 
Last dose date: The date of the last dose of study medication in the 24 
week treatment period for subjects who have completed the study or 
discontinued early.   
Total dose taken will be calculated as number of tablets dispensed – number of tablets 
returned. If any of the bottles dispensed is not returned, it will not be possible to 
compute the total dose received.  In this case, the number of tablets taken will be 
considered as missing.  Summary statistics for total dose taken will be provided by 
treatment group for the double-blind treatment period. 
Summary statistics for treatment duration (in weeks) and a frequency summary of 
treatment duration categories (e.g., >=1 Day, >=6 weeks), will be provided. 


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9.2. 
TREATMENT COMPLIANCE  
Subjects will be provided with dosing instructions each time study medication is 
dispensed. Subjects will also be instructed to bring their medication with them to 
every visit. During the run-in period, subjects will be considered compliant in 
investigational product administration by missing no more than one dose of run-in 
medication. Subjects who are not compliant during the run-in period will be excluded 
from randomization. 
At each visit the study staff will review the self-monitored blood glucose (SMBG) 
control diary, glucometer data and medication use with the subject and record the 
drug consumption in the CRF. Reasons for non-adherence will also be recorded in the 
protocol deviation log if applicable. 
Compliance in the run-in and double-blind phase is calculated for as follows: 
• 
Percent compliance = (number of tablets taken / number of tablets should have 
taken) x 100. 
• 
Number of tablets taken = number of tablets – number of tablets returned. 
• 
Number of tablets should have taken = (number of tablets supposed to take in a 
day) x (number of exposure days). 
• 
Number of exposure days = last dose date – first dose date + 1. 
If any of the bottles dispensed is not returned, it will not be possible to compute the 
compliance.  In this case, the number of tablets taken and compliance will be 
considered as missing.  Summary statistics for tablet or capsule compliance (%) will be 
provided by treatment group for the double-blind treatment period. A frequency 
summary of compliance will also be presented with the following categories: < 75%, 
75% -< 100%, 100%- ≤ 120%, and > 120%. 
9.3. 
ADVERSE EVENTS 
Adverse events will be collected and recorded from the time a subject signs the 
informed consent form (ICF) to the last scheduled contact.  And new SAE reported by 
the subject to the investigator that occur after the last scheduled contact, and are 
determined by the investigator to be reasonably associated with the use of the 
investigational product, should be reported to the sponsor or designated personnel. 
This may include SAEs that are captured on follow-up telephone contact or at any 
other time point after the defined study period (i.e., up to last scheduled contact). 
The investigator should follow SAEs identified after the last scheduled contact until 
the events are resolved, or the subject is lost to follow-up. The investigator should 
continue to report any significant follow-up information to the sponsor until the event 


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has been resolved. This study requires that subjects be actively monitored for SAEs for 
at least 4 weeks after the last treatment.  
For all AEs, preferred AE terms and system organ class (SOC) will be coded using 
terminology from the Medical Dictionary for Regulatory Activities (MedDRA), version 
19.0 or higher. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins after the 
first administration of double-blind study medication or existing AEs that worsen after 
the first dose of double-blind study medication.  All reported AEs will be listed, but 
only TEAEs will be summarized in tables.  
Drug-related AEs will be considered those to be possibly, probably and definitely 
related to IP administration based on the investigators assessment. 
Unless otherwise specified, AEs will be summarized by SOC and PT, with SOCs and PTs 
within SOCs presented in descending order of subject incidence. 
9.3.1. 
Derived Data 
AE onset day is calculated as (date of AE start – date of double-blind first dose + 1) if it 
is after the first dose of study drug. AE onset day is calculated as (date of AE start – 
date of double-blind first dose) if it is before the first dose of study drug.   
9.3.2. 
Data Summarization  
AE summary tables are listed below: 
• 
An overall summary of the number and percentage of subjects reporting any 
TEAEs, serious TEAEs, treatment-related TEAEs, serious treatment-related 
TEAE, any TEAEs leading to treatment discontinuation, any TEAEs leading to 
subject discontinuation and TEAEs leading to death.   
• 
TEAEs overall and by SOC and PT 
• 
TEAEs by severity, overall and by SOC and PT 
• 
Serious TEAEs, overall and by system organ class and preferred term 
• 
TEAEs by relationship to study treatment, overall and by system organ class and 
preferred term 
• 
TEAEs leading to treatment discontinuation, overall and by SOC and PT 


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• 
TEAEs leading to study discontinuation, overall and by SOC and PT 
• 
Most common TEAEs.  Most common TEAEs are defined as TEAEs that occur in 
> 5% of the subjects in either of the treatment groups.  
For summary tables, subjects having more than 1 event with the same PT will be 
counted once for that term.  Subjects having more than 1 event with the same SOC 
will be counted once for each event and once for that SOC.  For tabulations by 
severity, only a subject’s most severe event within the category (e.g. overall, SOC, 
PT) will be counted; similarly, for tabulations by relationship, only a subject’s most 
related event within a category will be counted.  The denominator for percentages 
will be the number of subjects in the Safety Analysis Set for the given treatment group 
(i.e., the N’s for the columns).   
Listings will be provided for all AEs and the following subsets: 
• 
Serious AEs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to death.  
9.3.3. 
AE of Special Interest 
AE of special interest include UTI, GMI, diuretic effects, hepatotoxicity, MACE, 
hypoglycemia, fracture, malignancy, hypersensitivity reactions, hypotensive episodes, 
acid base disorders, DKA, renal failure events, and amputations.  The AEs of special 
interest, except for MACE and amputations, will be prospectively identified based on 
the MedDRA PTs in the AEs log by a medical expert prior to the data base lock and 
unblinding of the individual subject treatment assignment. The list of AEs of special 
interest will be confirmed in a peer review process.  Adjudicated MACE will be 
summarized in the same AE of special interest table. Hypoglycemia events by severity, 
and amputations will be summarized separately.  Additional information will be 
collected for DKA.  These data will be listed if available. 
9.3.3.1. 
AE of special interest identified by PTs 
Cardiovascular events considered as MACE by investigator will be submitted to an 
independent Cardiovascular Endpoint Committee (CEC) for adjudication.  The events 
of interest include cardiovascular mortality, MI, stroke, hospitalization for acute 
coronary syndromes, urgent revascularization procedures, and other possible serious 
cardiovascular events.  Other AE of special interest will be identified from the PTs.  
The number and percentage of subjects experiencing these TEAEs of special interest 
will be summarized for each treatment group by type of event. The incidence rate of 
AE of special interest per 100 patient years will also be summarized. It will be 


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calculated as total number of AEs / total patient years in specific treatment arm (or 
total) * 100. Each category of events will be displayed in a separate listing.   
9.3.3.2. Hypoglycemia Events 
Hypoglycemic event categories include: 
Category 
Description 
Severe 
Assistance required and blood glucose 
≤70 mg/dL
 or no value 
available but responded to glucose treatment 
Documented 
Symptomatic 
Blood glucose ≤70 mg/dL and typical symptoms of hypoglycemia 
Asymptomatic 
Blood glucose ≤70 mg/dL and no typical symptoms of hypoglycemia 
Probable 
Symptomatic 
Typical symptoms of hypoglycemia and no value available but 
responded to glucose treatment 
Relative 
Typical symptoms of hypoglycemia and blood glucose >70 mg/dL 
 
While each event meeting the criteria above will be entered into the hypoglycemia 
log, only critical (severe) hypoglycemia, documented symptomatic hypoglycemia, 
asymptomatic hypoglycemia, and probable hypoglycemia will be entered as AEs.  
The number and percentage will be summarized by treatment for: 
• 
Each category of hypoglycemic events; 
• 
Any severe or documented hypoglycemic events. 
9.3.3.3. 
Revascularization and Amputations 
Revascularization and amputations information are collected in a separate form.  
Frequency and percentage will be summarized for: 
• 
Type of procedures –cardiovascular related or amputation 
• 
Subjects with any amputation 
• 
Conditions that resulted in amputation 
• 
Location of amputation 
Only procedures performed after the first dose of double-blind study drug will be 
summarized. 
9.3.3.4. 
Renal Failure Events 
Frequency and percentage of subjects will be summarized for:  


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• 
Any acute kidney event;  
• 
Acute kidney event by stage of disease.  If a subject has multiple events, the 
highest stage will be summarized.   
All instances of acute kidney event and their stage will be listed.   
9.4. 
LABORATORY EVALUATIONS 
Laboratory tests will include hematology panel, chemistry panel, serum lipids, and 
urinalysis testing. Hematology, chemistry, and urinalysis will be performed at the 
following time points: at the screening visit, on baseline visit (week 0), and at weeks 
12, 24, and 26.  Serum lipids will be performed at the screening visit, on baseline visit 
(week 0), and on weeks 12, 24, and 26. The study staff will contact each subject prior 
to a scheduled clinic visit to confirm the time of the visit and to remind the subject of 
proper fasting practice. A subject must be queried to assess compliance with a 
minimum of 8-hour fast prior to blood draw to ensure the FPG and triglycerides values 
can be accurately determined. If a subject has not fasted for approximately 8 hours, 
the subject must return as soon as can be arranged (within 1 week) to provide a 
specimen after proper fasting. A list of laboratory tests is included in Table 4. 
Low density lipoprotein cholesterol (LDL-C) will be calculated by the Friedewald 
equation. If triglycerides are > 400 mg/dL, the calculated LDL-C value is invalid by this 
equation and will be set as missing. Direct LDL-C will be determined in subjects whose 
triglycerides are > 350 mg/dL at screening visit. All subsequent LDL-C of these subjects 
will be determined by the same direct LDL-C measurements only.  If the triglycerides 
are >350, a reflex test will be performed based on direct LDL measurement.  In that 
case, two values will be reported but only the direct LDL-C will be used for the 
analysis as the screening value.  The following algorithm will be used to obtain LDL-C 
values for the analyses: 
1. Select subjects (based on the SI unit) who had screening triglycerides >3.4 or 
>350 based on the conventional unit 
2. Take the LDL – direct measurement values only, throughout the study visits for 
those subjects 
3. If screening trig > 350 and no direct LDL-C values have been determined, take 
the calculated.   
Among those subjects who have screening triglycerides >350 and have both calculated 
and direct LDL-C values, only take the direct LDL-C. 
Urinalysis microscopy will be conducted if the subject has a positive result on the 
leukocyte esterase or nitrite dipstick tests to clarify the significance of the finding. 
Results of glucose measurement in the urinalysis must be suppressed from the 


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laboratory reports so the sponsor, investigators, study coordinators, pharmacists, 
study subjects, and the CEC members will remain blinded to the dosing assignment.  
The baseline value will be the latest value obtained on or prior to Day 1.  Change from 
baseline for all continuous parameters will be calculated as the post-baseline value 
minus the baseline value.  
Data summaries will use descriptive statistics (number of subjects [n], mean, standard 
deviation [SD], median, minimum and maximum) for continuous variables, and 
frequency and percentage of subjects for categorical and ordinal variables 
Observed values (in SI units) and change from baseline over time will be summarized 
by treatment group.  Laboratory data will be classified as low, normal, or high relative 
to the parameter’s reference range. Laboratory abnormalities for each treatment will 
also be summarized with shift tables for selected parameters.  
All laboratory data will be listed.  For hematology, chemistry, including serum lipids, 
columns will be included for normal ranges and individual abnormal laboratory values 
will be flagged and clinical significance will be indicated.  Listing for urinalysis will 
include the microscopic examination provided for subjects who have a positive result 
from the urinalysis dipstick evaluation.   
 


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Table 4 
List of Laboratory Tests 
Test Name 
 
Blood or Urine 
Vol. (mL) 
Shipment  
Hematology  
-Hematocrit (Hct)  
-Hemoglobin (Hgb)  
-Mean corpuscular hemoglobin 
(MCH) 
-Mean corpuscular hemoglobin 
concentration (MCHC)  
-Platelet count  
-Mean corpuscular volume 
(MCV)  
-Red cell distribution width 
(RDW)  
-Red blood cell (RBC) count  
-White blood cell (WBC) count 
with differential  
2 (blood) 
Ambient 
Serum Chemistry and Electrolytes  
 
10 (serum) 
Ambient 
-Albumin (ALB)  
-Alanine aminotransferase (ALT)  
-Aspartate aminotransferase (AST)  
-Blood urea nitrogen (BUN)  
-Glucose  
-Bicarbonate (HCO3)  
-Creatinine  
-Chloride (Cl)  
-Total protein  
-Calcium (Ca)  
-Magnesium  
-Phosphorus  
-Potassium (K)  
-Sodium (Na)  
-Total bilirubin  
-Direct bilirubin  
-Uric acid  
 
 
Glycemic Control  
-Fasting plasma glucose (FPG)  
-Hemoglobin A1c (HbA1c)  
 
2 (plasma)  
2 (blood) 
Ambient 
Serum Lipids  
-Total cholesterol (TC)  
-High-density lipoprotein cholesterol 
(HDL-C)  
-Triglycerides (TG)  
 
-Low-density lipoprotein 
cholesterol (LDL-C), calculated 
 -LDL-C, direct (if applicable)  
6 (serum) 
Ambient 
Urinalysis  
 
10 (urine) 
Ambient 
-Appearance  
-Bilirubin  
-Color  
-Glucose  
-Ketones  
-Microscopic examination of 
sediment  
-Nitrite  
-Occult blood  
-pH  
-Protein  
-Specific gravity  
-Urobilinogen  
-Leukocyte esterase  
 
 
Urinary Albumin Assessment  
-UACR  
2 (urine) 
Ambient 
Urine pregnancy test (WOCBP)  
2 (urine) 
Local 
Population PK Sampling  
-Bexagliflozin plasma level  
2 (plasma) 
Frozen 
 


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9.5. 
VITAL SIGNS  
Vital signs will be measured at the screening visit, baseline visit (Week 0), and at 
weeks 6, 12, 24, and 26. Measurements of vital signs will include measurement of 
supine, sitting and standing blood pressure (BP) measurements, and heart rate. Only 
the BP measured in the sitting position will be used to determine eligibility.  
Orthostatic systolic and diastolic BP will be calculated as supine measurement – 
standing measurement.  
For BP, pulse rate, and respiration rate, observed values and change from baseline will 
be summarized by treatment group and visit using descriptive statistics (n, mean and 
median, SD, Q1, Q3, minimum, and maximum).  BP summary will include supine, 
sitting, standing and orthostatic BP.  Safety analysis set will be used for table 
summary.  Subjects vital sign measurements, including scheduled and unscheduled 
visits, will be listed.  
9.6. 
ELECTROCARDIOGRAM  
A 12-lead electrocardiogram (ECG) will be conducted at the screening visit and at 
week 24. ECG parameters measured will be the RR interval, PR interval, QRS duration, 
and QT interval. Each ECG should also be assessed by the investigator for signs of 
ischemia, clinically significant hypertrophy, and clinically significant T-wave 
abnormalities or arrhythmia. 
For each abnormal ECG result, the investigator shall ascertain if the observation 
represents a clinically significant change from the screening ECG for that individual 
subject (this determination, however, does not necessarily need to be made the first 
time an abnormal result is observed. The investigator may repeat the ECG to verify 
the results of the original result). If the ECG result is determined to be a clinically 
significant and abnormal change from baseline for that subject, it is considered an AE. 
For the ECG parameters, observed values and change from screening from scheduled 
visits will be summarized with descriptive statistics (n, mean, SD, median, minimum 
and maximum) by treatment group and overall at each visit.  The maximum change 
from baseline from scheduled visits will also be provided for ECG parameters. 
For the ECG overall assessment, the number and percentage of subjects in each 
overall assessment category (normal, abnormal but not clinically significant, abnormal 
and clinically significant, missing) will be presented by treatment group and overall at 
each visit.   


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9.7. 
PHYSICAL EXAMINATION 
A complete physical examination will be conducted at the baseline visit (Week 0). The 
examination will include measurement of body weight, and a general assessment of all 
body systems including the skin, head, eyes, ears, nose, throat, neck, heart, lungs, 
abdomen, lymph nodes, and extremities.  An abbreviated physical examination will be 
conducted at screening visit and at weeks 12, 24, and 26 or clinically indicated.  The 
examination will include body weight and height (height will be measured only at 
screening), and general assessment of the skin, heart, lungs and abdomen. Physical 
examination findings will be presented in a by-subject listing.  
 
 


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10. 
ANALYSIS OF PHARMACOKINETICS 
PK analyses will be included in a separate population PK analysis plan. 
11. 
INTERIM ANALYSES 
No interim analyses are planned. 
12. 
DATA AND SAFETY MONITORING BOARD 
An independent data and safety monitoring board (DSMB) will review descriptive 
summaries of accumulating safety, subject disposition and limited efficacy data every 
6 months, or a frequency recommended by the DSMB.   
A designated statistician who is not involved with the study operation will hold the 
treatment codes. The unblinded treatment information can be provided to the DSMB 
to facilitate the evaluation of any clinically important increase in the rate of a serious 
suspected adverse reaction or to the designated safety contact when the treatment 
information is required to determine if an expedited safety report must be submitted 
to regulatory agencies. The data outputs for this review will be created by an 
unblinded team. Personnel involved in the conduct of the study will not participate in 
the preparation of these outputs, receive the data, or participate in the unblinded 
portions of the DSMB meetings.  More details will be provided for DSMB charter and 
DSMB SAP. 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
In efficacy analysis in section 8, baseline eGFR categories, instead of screening eGFR, 
will be used as covariate and bases of subgroups analysis of key secondary analysis 
HbA1c in each eGFR groups.  Albunimuria will be analyzed categorically, instead of 
change from baseline as continuous variable, due to some large outliers in the dataset. 
 
 


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14. 
REFERENCE LIST 
Bodner TE. What improves with increased missing data imputations?  Structural 
Equation Modeling: A Multidisciplinary Journal 2008; 15: 651—675.  
White IR., Royston P., Wood AM. Multiple imputation using chained equations: Issues 
and guidance for practice.  Statistics in Medicine 2011; 30: 377—399. 
 
 


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15. 
PROGRAMMING CONSIDERATIONS 
The following conventions will hold for programming of outputs: 
• 
SAS® Version 9.3 or higher will be used for programming and production 
• 
The format of the table shells will be followed as closely as possible; however, 
in the course of programming and familiarization with the database, some changes 
may become necessary.  All changes will be documented.  Major changes will be 
documented through a formal amendment to this document.  
• 
Patients in this study will be identified as “Subjects.” 
• 
Descriptive statistics will be displayed in the following order: 
n 
Mean 
SD 
Q1 
Median 
Q3 
Minimum  
Maximum  
• 
Decimal places: For summary statistics, the minimum and maximum will be 
reported with the same number of decimal places as the collected measure, the 
mean, LS mean (if applicable) and median will have 1 more decimal place than the 
measure collected, and the SD and confidence interval (CI) will have 2 more decimal 
places than the collected measure.  For frequency distributions, percentages will be 
reported to 1 decimal place.  For p-values, 4 decimal places will be reported or the 
SAS® p-value format of “< 0.0001” or “> 0.9999” will be reported.  
• 
Unless otherwise noted, the denominator for percentages is the number of 
subjects in the applicable analysis set and treatment group.  
• 
If the frequency for a particular table cell is zero, then “0”, properly aligned, 
will be displayed (i.e. “0 (0.0%)” will not be displayed.) 
• 
Non-numeric values:  Where variables are recorded using < (e.g., “< 10” or “≤ 
10”) the numeric portion of the resultwill be used (e.g., < 10 and ≤ 10 becomes 10) for 
summary; where variables are recorded using > (e.g., “> 10” or “ ≥ 10”) the numeric 
portion of the result will be used (e.g. > 10 and ≥ 10 become 10) for summary; the 
actual recorded results, (e.g. “< 10” or “> 10”) will appear in listings. 


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15.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
 
15.2. 
TABLE, LISTING, AND FIGURE FORMAT 
15.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 9  
• 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
• 
Headers and footers for figures will be in Courier New font, size 9. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, 
such as non-printable control characters, printer-specific, or font-specific 
characters, will not be used. Hexadecimal-derived characters will be used, where 
possible, if they are appropriate to help display math symbols (e.g., μ). Certain 
subscripts and superscripts (e.g., cm2, Cmax) will be employed on a case-by-case 
basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and 
programmer-supplied formats, as appropriate. 
 
15.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
Theracos Sub, LLC 
Protocol Number: THR-1442-C-448       
• 
Draft or Final in top right corner. 
• 
All output should have Page n of N at the top of each page. TLFs should be 
internally paginated in relation to the total length (i.e., the page number should 


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appear sequentially as page n of N, where N is the total number of pages in the 
table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 
15.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 
14.1.1). ICH E3 numbering is strongly recommended but sponsor preferences 
should be obtained prior to final determination. A decimal system (x.y and x.y.z) 
should be used to identify TLFs with related contents. The title is centered. The 
analysis set should be identified on the line immediately following the title. The 
title and table designation are single spaced. A solid line spanning the margins will 
separate the display titles from the column headers. There will be 1 blank line 
between the last title and the solid line. 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
15.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values will be presented in a separate comparison column (if applicable).  
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column 
heading as (N=xx) (or in the row headings if applicable). This is distinct from the 
‘n’ used for the descriptive statistics representing the number of subjects in the 
analysis set. 
• 
The order of treatments in the tables and listings will be active treatment first, 
then placebo, followed by a total column (if applicable). 


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15.2.5. 
Body of the Data Display 
15.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
15.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and 
maximum level for that parameter. For example, the frequency distribution for 
symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for 
Discontinuation from the Study, etc.), then only those categories for which there is 
at least 1 subject represented in 1 or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
• 
Unless otherwise specified in mock-up shell, the estimated mean and median for a 
set of values should be printed out to 1 more significant digit than the original 
values, and standard deviations should be printed out to 2 more significant digits 
than the original values. The minimum and maximum should report the same 
significant digits as the original values. For example, for systolic blood pressure: 
n 
  XX 
Mean 
XXX.X 
SD 
     X.XX 
Q1 
XXX.X 
Median 
XXX.X 
Q3 
XXX.X 


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Minimum 
XXX 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxxx”, where xxxx is the value 
rounded to 4 decimal places. Any p-value less than 0.0001 will be presented as 
<0.0001.  If the p-value is returned as >0.9999 then present as >0.9999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). If the rounded 
percentage is 0.0, display as '<0.1'. Unless otherwise noted, for all percentages, 
the number of subjects in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
• 
Tabular display of data for concomitant and rescue medications should be 
presented by treatment class with the highest occurrence in the total column in 
decreasing order.  Tabular display of data for medical history and adverse event 
data should be presented by the SOC using internationally agreed order.  Within 
the drug class and SOC, medical history (by preferred term), drugs (by ATC2 code), 
and adverse events (by preferred term) should be displayed in decreasing order in 
the total column. If incidence for more than 1 term is identical, they should then 
be sorted alphabetically. Missing descriptive statistics which cannot be estimated 
should be reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number 
of subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject 
can be included in more than one category, describe in a footnote or programming 
note if the subject should be included in the summary statistics for all relevant 
categories or just 1 category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split 
over more than one page, output the subheading followed by “(cont)” at the top of 
each subsequent page.  The overall summary statistics for the subheading should 
only be output on the first relevant page. 
15.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 


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• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output 
as “N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
• 
Units will be included where available 
15.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the 
X-axis and endpoint (e.g., treatment mean change from Baseline) values will be 
displayed on the Y-axis. 
15.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from 
the footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 
3, etc. if a reference footnote. Each new footnote should start on a new line 
where possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data 
will be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates 
the name of the program used to produce the data display, date the program was 
run, and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 
16.x.y.z’). 
 
 


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16. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 03.010 
and 03.013 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
proper clinical trial output by checking for their logic, efficiency and commenting and 
by review of the produced output. 
 
 


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17. 
INDEX OF TABLES 
Number 
Title 
Table 14.1.1.1 
Subject Disposition (Screened Analysis Set) 
Table 14.1.1.2 
Reasons for Screen Failure (Non-randomized Subjects) 
Table 14.1.2 
Summary of Major Protocol Deviations  (Safety Analysis Set) 
Table 14.1.3.1 
Demographics and Baseline Characteristics  (Safety Analysis Set) 
Table 14.1.3.2 
Demographics and Baseline Characteristics  (ITT Analysis Set) 
Table 14.1.3.3 
Demographics and Baseline Characteristics  (PP Analysis Set) 
Table 14.1.4.1 
Summary of Significant Medical and Surgical History by System Organ 
Class and Preferred Term (Safety Analysis Set) 
Table 14.1.4.2 
Summary of Renal Disease History(Safety Analysis Set) 
Table 14.1.4.3 
Summary of Type 2 Diabetes History (Safety Analysis Set) 
Table 14.1.4.4 
Summary of Cardiovascular History  (Safety Analysis Set) 
Table 14.1.5.1  
Summary of Concomitant Medications  (Safety Analysis Set) 
Table 14.1.5.2  
Summary of Hyperglycemia Rescue Medications  (Safety Analysis Set) 
Table 14.1.6 
Study Drug Exposure and Compliance during Double-Blind Treatment 
Period (Safety Analysis Set) 
Table 14.2.1.1 
Analysis of Change from Baseline in HbA1c (%) at Week 24 (ITT 
Analysis Set) 
Table 14.2.1.2 
Analysis of Change from Baseline in HbA1c (%) at Week 24  (PP 
Analysis Set) 
Table 14.2.1.3.1 
Summary of Reason for Missing Values by Visit- Change from Baseline 
in HbA1c (%)  (ITT Analysis Set) 
Table 14.2.1.3.2 
Missing Data Pattern - Change from Baseline in HbA1c (%) (ITT 
Analysis Set) 
Table 14.2.1.4.1 
Sensitivity Analysis 1: Multiple Imputation for Change from Baseline in 
HbA1c (%) Including Observations Obtained After Rescue Medication 
(ITT Analysis Set) 
Table 14.2.1.4.2 
Sensitivity Analysis 2: LOCF for Change from Baseline in HbA1c (%) 
Excluding Observations Obtained After Rescue Medication  (ITT 
Analysis Set) 
Table 14.2.1.4.3 
Sensitivity Analysis 3: Analysis of Change from Baseline in HbA1c (%) 
Excluding Observations Obtained After Rescue Medication  (ITT 
Analysis Set) 


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Number 
Title 
Table 14.2.1.4.4 
Sensitivity Analysis 4: Multiple Imputation for Change from Baseline in 
HbA1c (%) Excluding Observations Obtained After Rescue Medication 
(ITT Analysis Set) 
Table 14.2.1.5 
Analysis of Change from Baseline in HbA1c (%) Over Time  (ITT 
Analysis Set) 
Table 14.2.1.6 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Age  
(ITT Analysis Set) 
Table 14.2.1.7 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Gender  
(ITT Analysis Set) 
Table 14.2.1.8 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Race  
(ITT Analysis Set) 
Table 14.2.1.9 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Baseline 
HbA1c Category  (ITT Analysis Set) 
Table 14.2.1.10 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by 
Background Treatment Status  (ITT Analysis Set) 
Table 14.2.1.11 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by eGFR at 
Screening  (ITT Analysis Set) 
Table 14.2.1.12 
Analysis of Change from Baseline in HbA1c (%) at Week 24 by Region 
(ITT Analysis Set) 
Table 14.2.2.1 
Analysis of Change from Baseline in Body Weight (kg) at Week 24 for 
Subjects with BMI ≥ 25 kg/m2 (ITT Analysis Set) 
Table 14.2.2.2 
Analysis of Change from Baseline in Body Weight (kg) at Week 24 for 
Subjects with BMI ≥ 25 kg/m2 (PP Analysis Set) 
Table 14.2.2.3 
Sensitivity Analysis: Multiple Imputation for Change from Baseline in 
Body Weight (kg) for Subjects with BMI ≥ 25 kg/m2 Excluding 
Observations Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.2.4 
Analysis of Change from Baseline in Body Weight (kg) for Subjects 
with BMI ≥ 25 kg/m2 over Time  
(ITT Analysis Set) 
Table 14.2.3.1 
Analysis of Change from Baseline in SBP (mmHg) at Week 24 for 
Subjects with Baseline SBP ≥ 130 mmHg  (ITT Analysis Set) 
Table 14.2.3.2 
Analysis of Change from Baseline in SBP (mmHg) at Week 24 for 
Subjects with Baseline SBP ≥ 130 mmHg  (PP Analysis Set) 
Table 14.2.3.3 
Sensitivity Analysis: Multiple Imputation for Change from Baseline in 
SBP (mmHg) for Subjects with Baseline SBP ≥ 130 Excluding 
Observations Obtained After Rescue Medication  (ITT Analysis Set) 
Table 14.2.3.4 
Analysis for Change from Baseline in SBP (mmHg) for Subjects with 
Baseline SBP ≥ 130 over Time (ITT Analysis Set) 
Table 14.2.4 
Analysis of Change from Baseline in FPG (mmol/L) Over Time  (ITT 
Analysis Set) 


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Number 
Title 
Table 14.2.5 
Summary of Proportion of Subjects with HbA1c < 7% Over Time  (ITT 
Analysis Set) 
Table 14.2.6 
Summary of Proportion of Subjects with ≥5% Reduction of Body 
Weight with Baseline BMI ≥25 kg/m2 Over Time (ITT Analysis Set) 
Table 14.2.7 
Analysis of Change from Baseline in Body Weight in All Subjects Over 
Time (ITT Analysis Set) 
Table 14.2.8 
Analysis of Change from baseline in SBP (mmHg) in All Subjects Over 
Time (ITT Analysis Set) 
Table 14.2.9 
Summary of DBP (mmHg) in All Subjects Over Time (ITT Analysis Set) 
Table 14.2.10 
Summary of Albuminuria (UACR) in All Subjects and in Baseline 
Macroalbuminura Subjects  
(ITT Analysis Set) 
Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events  (Safety 
Analysis Set) 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term   (Safety Analysis Set) 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity  (Safety Analysis Set) 
Table 14.3.1.4 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Relationship to Study Drug  (Safety Analysis Set) 
Table 14.3.1.5 
Most Common Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.6 
Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term  (Safety Analysis Set) 
Table 14.3.1.7 
Summary of Treatment Emergent Adverse Events Leading to 
Treatment Discontinuation by System Organ Class and Preferred Term  
(Safety Analysis Set) 
Table 14.3.1.8 
Summary of Treatment Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term   (Safety 
Analysis Set) 
Table 14.3.1.9 
 Summary of Treatment Emergent Adverse Events of Interest  (Safety 
Analysis Set) 
Table 14.3.1.10 
Summary of Treatment Emergent Hypoglycemia Events   (Safety 
Analysis Set) 
Table 14.3.1.11 
Summary of Treatment Emergent Acute Kidney Injury Events  (Safety 
Analysis Set) 
Table 14.3.1.12 
Summary of Revascularization and Amputations  (Safety Analysis Set) 
Table 14.3.2.1 
List of Serious Adverse Events  (Safety Analysis Set) 


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Number 
Title 
Table 14.3.2.2 
List of Adverse Events Leading to Treatment Discontinuation  (Safety 
Analysis Set) 
Table 14.3.2.3 
List of Adverse Events Leading to Death  (Safety Analysis Set) 
Table 14.3.4.1 
Summary of Hematology: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.4.2 
Shift in Clinical Laboratory Values: Hematology   (Safety Analysis Set) 
Table 14.3.4.3 
Summary of Serum Chemistry: Results and Change from Baseline by 
Visit (Safety Analysis Set) 
Table 14.3.4.4 
Shift in Clinical Laboratory Values: Serum Chemistry  (Safety Analysis 
Set) 
Table 14.3.4.5 
Summary of Urinalysis: Results and Change from Baseline by Visit – 
Continuous Variables  (Safety Analysis Set) 
Table 14.3.4.6 
Summary of Urinalysis Results by Visit – Categorical Variables  (Safety 
Analysis Set) 
Table 14.3.5  
Summary of Vital Signs: Results and Change from Baseline by Visit  
(Safety Analysis Set) 
Table 14.3.6.1 
Summary of 12-Lead ECG Investigator Overall Assessment by Visit  
(Safety Analysis Set) 
Table 14.3.6.2 
Summary of 12-Lead ECG Parameters by Visit: Results and Change 
from Baseline   (Safety Analysis Set) 
 
 
 


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18. 
INDEX OF FIGURES 
Number 
Title 
Figure 14.1.1 
Kaplan-Meier Plot of Time to Discontinuation by Week 26  (ITT 
Analysis Set) 
Figure 14.2.1.1 
LS Mean (± SE) Change from Baseline in HbA1c (%) (ITT Analysis Set) 
Figure 14.2.1.2 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) 
(ITT Analysis Set) 
Figure 14.2.1.3 
LS Mean (± SE) Change from Baseline in HbA1c (%) (PP Analysis Set) 
Figure 14.2.1.4 
LS Mean Difference (95% CI) in Change from Baseline in HbA1c (%) (PP 
Analysis Set) 
Figure 14.2.1.5 
Sensitivity Analysis 1: Multiple Imputation LS Mean Difference (95% 
CI) in Change from Baseline in HbA1c (%)  Including Observations 
Obtained After Rescue Medication (ITT Analysis Set) 
Figure 14.2.1.6 
Sensitivity Analysis 2: LOCF for LS Mean (95% CI) in Change from 
Baseline in HbA1c (%) Excluding Observations Obtained After Rescue 
Medication (ITT Analysis Set) 
Figure 14.2.1.7 
Sensitivity Analysis 3: LS Mean Difference (95% CI) in Change from 
Baseline in HbA1c (%)  Excluding Observations Obtained After Rescue 
Medication (ITT Analysis Set) 
Figure 14.2.1.8 
Sensitivity Analysis 4: Multiple Imputation LS Mean (95% CI) in Change 
from Baseline in HbA1c (%) Excluding Observations Obtained After 
Rescue Medication (ITT Analysis Set) 
Figure 14.2.2 
 LS Mean (± SE) Change from Baseline in Body Weight (kg) Over Time 
for Subjects with BMI ≥ 25 kg/m2 (ITT Analysis Set) 
Figure 14.2.3 
 LS Mean (± SE) Change from Baseline in SBP (mmHg) Over Time for 
Subjects with Baseline SBP ≥ 130 mmHg (ITT Analysis Set) 
Figure 14.2.4 
LS Mean (± SE) Change from Baseline in HbA1c (%) by eGFR Status (ITT 
Analysis Set) 
Figure 14.2.5 
Proportion of Subjects with HbA1c < 7% Over Time(ITT Analysis Set) 
Figure 14.2.6 
Proportion of Subjects with ≥5% Reduction of Body Weight with 
Baseline BMI ≥25 kg/m2 Over Time (ITT Analysis Set) 
Figure 14.2.7 
LS Mean (95% CI) Change from Baseline in Fasting Plasma Glucose 
(mmol/L) (ITT Analysis Set) 
Figure 14.2.8 
LS Mean (± SE) Change from Baseline in Body Weight for All Subjects  
(ITT Analysis Set) 
Figure 14.2.9 
LS Mean (± SE) Change from Baseline in SBP for All Subjects  (ITT 
Analysis Set)  


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Figure 14.2.10 
LS Mean (± SE) Change from Baseline in DBP for All Subjects  (ITT 
Analysis Set)  
Figure 14.2.11 
Proportion of Albuminuria by Baseline Albuminuria (ITT Analysis Set) 
 
 


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19. 
INDEX OF LISTINGS 
Number 
Title 
Listing 16.2.1.1 
Subject Disposition 
Listing 16.2.1.2 
Subject Discontinuation 
Listing 16.2.2 
Protocol Deviation 
Listing 16.2.3.1 
Analysis Sets (All Randomized Subjects) 
Listing 16.2.3.2 
Subjects Who Did Not Meet Inclusion/Exclusion Criteria 
Listing 16.2.4.1 
Demographics 
Listing 16.2.4.2 
Significant Medical and Surgical History 
Listing 16.2.4.3 
Renal Disease History 
Listing 16.2.4.4 
Type 2 Diabetes History 
Listing 16.2.4.5 
Cardiovascular Disease History 
Listing 16.2.4.6 
Prior and Concomitant Medications  
Listing 16.2.5.1 
Study Drug Accountability  
Listing 16.2.5.2 
Study Drug Exposure and Compliance  
Listing 16.2.6.1 
Glycemic Control Tests: HbA1c (%) 
Listing 16.2.6.2 
Glycemic Control Tests: Fasting Plasma Glucose (mmol/L) 
Listing 16.2.6.3 
Hypoglycemia Events 
Listing 16.2.6.4 
Weight (kg) 
Listing 16.2.6.5 
Albuminuria (mg/g) 
Listing 16.2.7.1  
Adverse Events 


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Number 
Title 
Listing 16.2.7.2.1 
Urinary Tract Infection Adverse Events (Safety Analysis Set)  
Listing 16.2.7.2.2 
Genital Mycotic Infection Adverse Events (Safety Analysis Set)  
Listing 16.2.7.2.3 
Diuretic Effects Adverse Events (Safety Analysis Set)  
Listing 16.2.7.2.4 
Hepatotoxicity Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.5 
Cardiovascular Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.6 
Hypoglycemia Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.7 
Fracture Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.8 
Malignancy Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.9 
Hypersensitivity Reaction Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.10 
Acid-base Disorders Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.11 
Renal Failure Adverse Events (Safety Analysis Set) 
Listing 16.2.7.2.12 
Revascularization and Amputations  (Safety Analysis Set) 
Listing 16.2.7.2.13 
Acute Kidney Injury Events (Safety Analysis Set) 
Listing 16.2.7.3 
Acute Kidney Injury Events  
Listing 16.2.7.4 
Amputation  
Listing 16.2.7.5.1 
DKA Symptoms Assessment 
Listing 16.2.7.5.2 
Suspected DKA Assessment  
Listing 16.2.7.5.3 
Suspected DKA Clinic/Hospital Report 
Listing 16.2.7.5.4 
Suspected DKA Outpatient Clinic  
Listing 16.2.7.5.5 
Suspected DKA Hospitalization  


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Number 
Title 
Listing 16.2.8.1 
Clinical Laboratory Tests: Hematology 
Listing 16.2.8.2 
Clinical Laboratory Tests: Serum Chemistry 
Listing 16.2.8.3 
Clinical Laboratory Tests: Urinalysis 
Listing 16.2.8.4 
Clinical Laboratory Tests: Serum Lipids 
Listing 16.2.8.5 
Urine Pregnancy Test 
Listing 16.2.9.1 
Vital Signs 
Listing 16.2.9.2 
12-Lead Electrocardiogram 
Listing 16.2.9.3 
Physical Examination 
 
 
 


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20. 
MOCK-UPS 
Attachment 1: Planned Table Shells 
Attachment 2: Planned Listing Shells  
Attachment 3: Planned Figure Shells 
 
21. 
APPENDIX 
21.1. 
RESCUE MEDICATION ADJUDICATION PROCESS 
Attachment  5: THR-1442-C-448 SAP rescue med review plan  v1.0 20171115 
21.2. 
SAS CODE USED IN THE ANALYSES 
Attachment 4: SAS Code Used in the Analyses