A 26 Week, Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel Group, Phase 3 Trial With a 26 Week Safety Extension Period Evaluating the Safety and Efficacy of Dapagliflozin 5 and 10 mg, and Saxagliptin 2.5 and 5 mg in Pediatric Patients With Type 2 Diabetes Mellitus Who Are Between 10 and Below 18 Years of Age
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: AstraZeneca

Pr ot oc ol N u m b er: D 1 6 8 0 C 0 0 0 1 9  
Offici al Tit l e: A 2 6 W e e k, M ultic e nt er, R a n d o miz e d, Pl ac e b o -C o ntr oll e d, D o u bl e -Bli n d,  P ar all el 
Gr o u p, P h as e 3 Tri al wit h a 2 6 W e e k S af et y E xt e nsi o n P eri o d  E v al u ati n g t h e S af et y a n d Effic ac y of 
D a p a glifl ozi n 5 a n d 1 0 m g, a n d  S a x a gli pti n 2. 5 a n d 5 m g i n P e di atric P ati e nts wit h T y p e 2 Di a b et es  
M ellit us w h o ar e b et w e e n 1 0 a n d b el o w 1 8 y e ars of a g e  
N C T N u m b er : N C T 0 3 1 9 9 0 5 3  
D oc u m e nt D at e: 0 7  F e br u ar y  2 0 2 2  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
2 
wit hi n y o ur or g a niz ati o n or t o y o ur i n de pe n de nt et hics c o m mittee(s). A n y ot her use, c o p yi n g, 
discl os ure  or  disse mi n ati o n  of  t his  i nf or m at i o n  is  strictl y  pr o hi bite d  u nless  e x pressl y  
a ut h orize d i n writi n g b y B M S. A n y s u p ple me n t al i nf or m ati o n (e g, a me n d me nts) t h at m a y 
be a d de d t o t his d oc u me nt is als o c o nfi de nti al  a n d pr o priet ar y t o B M S a n d m ust be ke pt i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt. A n y pers o n w h o recei ves 
t his d oc u me nt wit h o ut d ue a ut h oriz ati o n fr o m B M S is re q ueste d t o ret ur n it t o B M S or 
pr o m ptl y destr o y it. All ot her ri g hts reser ve d. Refere nces t o B M S i n t his pr ot oc ol m a y a p pl y 
t o p art ners t o w hic h B M S h as tr a nsferre d o blig ati o ns, e g, a C o ntr act Rese arc h Or g a niz ati o n 
( C R O). 
T his s u b missi o n d oc u me nt c o ntai ns c o nfi de ntial c o m mercial i nf or mati o n, discl os ure of w hic h is 
pr o hi bite d wit h o ut pr o vi di n g a d va nce n otice t o  Astra Ze neca a n d o p p ort u nit y t o o bject. 
T his Cli nical St u d y Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca Sta n dar d 
pr oce d ures. T he cli nical st u d y pr ot oc ol is p u blicl y re gistere d a n d t he res ults are discl ose d a n d/ or 
p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P o lic y o n Bi oet hics a n d i n c o m plia nce wit h all 
pre vaili n g la ws a n d re g ulati o ns. 
Re place all pre vi o us versi o n(s) of t he pr ot oc ol wit h t his re vise d prot oc ol a n d please pr o vi de a c o p y 
of t his re vise d pr ot oc ol t o all st u d y pers o n nel u n der y o ur s u per visi o n, a n d arc hi ve t he pre vi o us 
versi o ns. 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 
D O C U M E N T HI S T O R Y 
D oc u me nt  
D ate of Iss ue 
S u m m ar y of C h a n ge 
Re vise d 
Pr ot oc ol 0 6 
0 7- Fe b- 2 0 2 2  
I nc or p orates Gl o bal A me n d me nt 0 6 
A me n d me nt 0 6  
0 7- Fe b- 2 0 2 2 
T he f oll o wi n g re visi o ns were ma de t o t he pr ot oc ol: 
T o all o w f or fle xi bilit y i n sc he d uli n g, t he wi n d o w peri o d f or Wee k 1 0 4 
p ost- d ose visit was m o difie d fr o m “ ± 7 da ys” t o “- 2 8 da ys t o + 7 da ys” 
fr o m t he ori gi nal sc he d ule d date. 
 
Base d o n disc ussi o ns wit h F D A, t he pri mar y o bjecti ve was m o difie d t o 
assess t he effect of all d oses a n d re gi me ns c o m bi ne d f or eac h dr u g vers us 
place b o.  
I n li ne wit h t his, t he pri mar y a n d sec o n dar y o bjecti ves were re or dere d 
a n d u p date d. T he re or deri n g was d o ne t o ma ke o verall a nal ysis (all d oses 
f or eac h treat me nt) as t he pri mar y o bjecti ve.  
T he pri mar y o bjecti ve was u p date d as f oll o ws:  
T o deter mi ne if t here will be a great er mea n re d ucti o n fr o m baseli ne i n 
H b A 1c ac hie ve d after 2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of 
da pa glifl ozi n ( 5 m g or 1 0 m g [all d oses a n d re gi me ns c o m bi ne d]) or 
sa xa gli pti n ( 2. 5 m g or 5 m g [all d oses a n d re gi me ns c o m bi ne d]) 
c o m pare d wit h place b o. 
 
T he sec o n dar y o bjecti ves were u p date d t o f oll o w t he or der/ hierarc h y of 
o verall, f oll o we d b y l o w- d ose/ hi g h- d ose re gi me n testi n g, f oll o we d b y 
l o w- d ose re gi me n testi n g. 
 
C orres p o n di n g t o t he c ha n ge i n pri m ar y o bjecti ve, t he pri mar y a nal ysis 
was u p date d as: 
T he pri mar y efficac y a nal ysis will be perf or me d usi n g a n a nal ysis of 
c o varia nce ( A N C O V A).  
 
Ot her ke y c ha n ges i ncl u de: 
Base d o n disc ussi o ns wit h t he F D A, t he a nal yses were u p date d t o use a 
f ull al p ha of 0. 0 5 t o test eac h dr u g vers us place b o rat her t ha n c urre nt 
s plit i nt o 0. 0 2 5. 
U p date d te xt: 
“ F or eac h dr u g, t he c o m paris o n vs place b o will be teste d at a 2-si de d 
al p ha le vel of 0. 0 5.” 
F or p o wer a nal ysis, t he as s u m pti o n of a n effect size of 0. 7 5 % rat her t ha n 
0. 5 % was use d. Acc or di n gl y sa m ple size secti o n was u p date d t o i ncl u de 
t he f oll o wi n g c ha n ges:  
 
Te xt delete d:  
T he B o nferr o ni met h o d t o c o ntr ol t he t y pe 1 err or rate acr oss t w o 
c o m paris o ns wit h res pect t o t he t w o gr o u ps of researc h h y p ot heses 
( da pa glifl ozi n vs place b o a n d sa xa gli pti n vs place b o) will be use d. 
Ass u mi n g a sta n dar d de viati o n of 0. 9 % f or c ha n ge fr o m baseli ne H b A 1c 
at Week  2 6, a n d 5 0 % of s u bjects will u n der g o t he sec o n d ra n d o mizati o n, 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 
D oc u me nt  
D ate of Iss ue 
S u m m ar y of C h a n ge 
a t otal of 2 3 7 pe diatric s u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 
recei ve da pa glifl ozi n 5 m g ( 7 9 s u bjects), sa xa gli pti n 2. 5 m g 
( 7 9 s u bjects), or place b o ( 79 s u bjects) res pecti vel y. Ass u mi n g t hat 2 % of 
s u bjects d o n ot ha ve a pri mar y e n d p oi nt, a t otal of a p pr o xi matel y 
2 4 3  s u bjects will be ra n d o mize d. 
 
Re vise d te xt i ncl u de d:  
“If 2 4 3 pe diatric s u bjects are ra n d o mize d a n d a nal yze d, a n d eac h 
treat me nt c o m pare d t o place b o at a 2-si de d al p ha = 0. 0 5 le vel, t his will 
pr o vi de a p pr o xi matel y 8 0 % p o wer f o r eac h c o m paris o n t o detect a 
0. 7 5 % re d ucti o n i n H b A 1c c ha n ge fr o m baseli ne ass u mi n g a sta n dar d 
de viati o n of 1. 7 %.” 
 
Te xt delete d:  
T he a ntici pate d differe nce of 0. 5 % bet wee n eac h st u d y dr u g (sa xa gli pti n 
a n d da pa glifl ozi n)  a n d place b o use d i n sa m ple size esti mati o n is 
c o nsiste nt wit h esti mates t hat were o b tai ne d i n a d ult cli nical trials wit h 
sa xa gli pti n or da pa glifl ozi n as a d d- o n t o a nti- dia betic me dicati o n w here 
t he pri mar y e n d p oi nt was i m pr o ve me nt i n H b A 1c after 2 4 wee ks 
treat me nt. 
T he sta n dar d de viati o n esti mate of 0. 9 % is c o nsiste nt wit h esti mates 
o btai ne d i n t hese a d ult st u dies as well as wit h p u blis he d esti mates fr o m 
pe diatric trials of ot her a nti- dia betic me dicati o ns. 
 
Re vise d te xt i ncl u de d: 
“ T he sta n dar d de viati o n esti mate of 1. 7 % is base d o n a bli n de d re vie w of 
t he o n g oi n g st u d y data.” 
 
Ot her u p dates t o t he te xt f or c o nsiste nc y a n d mi n or clarificati o ns. 
Re vise d 
Pr ot oc ol 0 5 
2 4- Se p- 2 0 2 0  
I nc or p orates Gl o bal A me n d me nt 0 5 
A me n d me nt 0 5  
2 4- Se p- 2 0 2 0  
T he pr ot oc ol was re vise d t o s pecif y t hat visits s h o ul d be dela ye d t o 
mai ntai n a n i nter val of at least 1 2 wee ks bet wee n t he Wee k 1 4 a n d 
Wee k 2 6 visits a n d bet wee n t he t hir d ra n d o mizati o n visit (f or s u bjects 
u n der g oi n g t hir d ra n d o mizati o n) a n d t he Wee k 5 2 visit i n case t he 
Wee k 1 4 or t hir d ra n d o mizati o n visit is dela ye d. T his c ha n ge was 
i nstit ute d beca use H b A 1c is deri ve d fr o m t he a vera ge of t he bl o o d 
gl uc ose fl uct uati o n i n t he prece di n g 3 m o nt hs a n d t heref ore, 
a p pr o xi matel y 1 2 wee ks of e x p os ure t o a ne w d ose is nee de d t o 
de m o nstrate efficac y. 
S h ort- a n d l o n g-ter m peri o d st u d y visits ca n be dela ye d b y a ma xi m u m 
of 1 1 m o nt hs i n t otal. If t he d urati o n of i n vesti gati o nal pr o d uct 
a d mi nistrati o n is l o n ger t ha n 5 2 ( + 1) wee ks, t he safet y f oll o w- u p peri o d 
s h o ul d be s h orte ne d s uc h t hat t he c o m plete st u d y d urati o n d oes n ot 
e xcee d 1 0 4 wee ks. T he Wee k- 1 0 4 visit s h o ul d n ot be dela ye d. 
If m ore t ha n 1 2 wee ks ela pse bet ween t he H b A 1c c ollecti o n at Wee k 2 6 
a n d t he t hir d ra n d o mizati o n at Wee k  3 2, or t he H b A 1c c ollecti o n at 
Wee k 3 2 a n d t he t hir d ra n d o mizati o n at Wee k 4 0, t he s u bject s h o ul d n ot 
g o t hr o u g h t his ra n d o mizati o n as t he H b A 1c val ue w o ul d n o l o n ger be 
relia ble t o ascertai n eli gi bilit y f or t he t hir d ra n d o mizati o n.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 
D oc u me nt  
D ate of Iss ue 
S u m m ar y of C h a n ge 
Ot her u p dates i ncl u de g ui da nce o n c ha n ges nee de d t o t he cli nical 
c o n d uct d ue t o t he c or o na vir us disease 2 0 1 9 ( C O VI D- 1 9) pa n de mic 
(e. g., se n di n g t he i n vesti gati o nal pr o d uct directl y t o s u bjects’ h o mes, 
h o me visits b y st u d y site pers o n nel/ ve n d or, all o wi n g off-site m o nit ori n g 
visits); u p dates t o t he te xt f or c o nsiste nc y wit h t he latest Astra Ze neca 
te m plate; a n d mi n or clarificati o ns. 
Re vise d 
Pr ot oc ol 0 4 
2 7-J u n- 2 0 1 9  
I nc or p orates Gl o bal A me n d me nt 0 4 
A me n d me nt 0 4  
2 7-J u n- 2 0 1 9 
T he pr ot oc ol has bee n re vise d t o reflect m o dificati o ns t o t he st u d y 
desi g n, i.e., t he e xte nsi o n of t he sc ree ni n g peri o d a n d c ha n ge of t he 
scree ni n g/retesti n g desi g n, t he u p date of safet y c o ncer ns a n d m o nit ori n g 
of a d verse e ve nts of i nterest, t he re visi o n of fasti n g bl o o d gl uc ose, 
gr o wt h, b o ne a n d mat urati o ns mar kers meas ure me nts, as well as Ta n ner 
sta gi n g sc he d ules i n s u bjects w h o disc o nti n ue d t he i n vesti gati o nal 
pr o d uct earl y, a n d t he clarificati o n of  i nitiati o n or u p-titrati o n of i ns uli n 
at t he Resc ue Visit  a n d a d verse e ve nts/seri o us a d verse e ve nts c ollecti o n 
u ntil st u d y c o m pleti o n. I n a d diti o n, t he c orrecti o n of t he i n vesti gati o nal 
pr o d uct dis pe nsati o n sc he d ule is i nc or p orate d, a n d s o me c o m m o n 
la n g ua ge is a d de d/re vise d i n se veral secti o ns f or har m o nizati o n acr oss all 
Astra Ze neca cli nical st u d y pr ot oc ols. 
Re vise d 
Pr ot oc ol 0 3 
0 4- Oct- 2 0 1 8  
I nc or p orates Gl o bal A me n d me nt 0 3 
A me n d me nt 0 3  
0 4- Oct- 2 0 1 8 
Base d o n rec o m me n dati o ns pr o vi de d b y t he F o o d a n d Dr u g 
A d mi nistrati o n ( F D A), t he pr ot oc ol has bee n re vise d t o reflect 
m o dificati o ns i n t he st u d y desi g n, i.e., t he a d diti o n of a ra n d o mize d 
wit h dra wal of bac k gr o u n d me dicati o n i n a s u bset of eli gi ble s u bjects 
fr o m t he acti ve treat me nt ar ms, a n d ra n d o mize d wit h dra wal of 
bac k gr o u n d me dicati o n/s witc h t o acti ve treat me nt i n a s u bset of eli gi ble 
s u bjects i n t he place b o ar m.  
C ollecti o n of vital stat us has bee n re m o ve d. 
Re vise d 
Pr ot oc ol 0 2 
0 4- A pr- 2 0 1 7  
I nc or p orates Gl o bal A me n d me nt 0 2 
A me n d me nt 0 2  
0 4- A pr- 2 0 1 7 
T he pr ot oc ol has bee n re vise d t o reflect t he cessati o n of 
Brist ol- M yers S q ui b b’s r ole i n t h e st u d y a n d t he s pecifie d preferre d 
o bjecti ves a n d pr oce d ures f oll o wi n g E ur o pea n Me dici nes A ge nc y 
( E M A) a n d U nite d States F D A re vie w. A p ost-st u d y visit has als o bee n 
a d de d at Wee k 1 0 4.  
Re vise d 
Pr ot oc ol 0 1 
1 1- Oct- 2 0 1 6  
I nc or p orates Gl o bal A me n d me nt 0 1 
A me n d me nt 0 1  
1 1- Oct- 2 0 1 6 
S u bse q ue nt t o rece nt Healt h A ut h orit y fee d bac k, t he ori gi nal st u d y 
desi g n has bee n e ntirel y re vise d i n  acc or da nce wit h t he F D A-s pecifie d 
preferre d st u d y o bjecti ves a n d desi g n. 
Ori gi nal 
Pr ot oc ol 
0 2- Mar- 2 0 1 6
 N ot
 
a p plica ble
 
 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
6 
T A B L E O F C O N T E N T S 
TI T L E P A G E .................................................................................................................... ........... 1  
D O C U M E N T HI S T O R Y ............................................................................................................ 3  
T A B L E O F C O N T E N T S ............................................................................................................ 6  
S Y N O P SI S ...................................................................................................................... .............. 9 
1   I N T R O D U C TI O N A N D S T U D Y R A TI O N A L E .............................................................. 2 4 
1. 1   St u d y Rati o nale .................................................................................................................. 2 5  
1. 2   Researc h H y p ot heses ......................................................................................................... 2 6  
1. 3   O bjecti ves .................................................................................................................... ....... 2 6 
1. 3. 1   Pri m ary O bjective ....................................................................................................... 2 6  
1. 3. 2   Sec o n d ary O bjectives .................................................................................................. 2 6  
1. 3. 3   S afety O bjectives ......................................................................................................... 2 8  
1. 3. 4   Ex pl or at ory O bjectives ............................................................................................... 2 8  
1. 3. 5   P h ar m ac oki netic/ P h ar m ac o dy n a mic O bjective .......................................................... 2 9  
1. 4   Pr o d uct De vel o p me nt Bac k gr o u n d .................................................................................... 2 9  
1. 5   O verall Ris k/ Be nefit Assess me nt ....................................................................................... 3 0  
2   E T HI C A L C O N SI D E R A TI O N S ........................................................................................ 3 1  
2. 1   G o o d Cli nical Practice ....................................................................................................... 3 1  
2. 2   I nstit uti o nal Re vie w B oar d/In de pe n de nt Et hics C o m mittee .............................................. 3 2  
2. 3   I nf or me d C o nse nt ............................................................................................................... 3 2 
2. 4   Ha n dli n g of H u ma n Bi ol o gical Sa m ples ........................................................................... 3 4  
3   I N V E S TI G A TI O N A L P L A N ............................................................................................. 3 4 
3. 1   St u d y Desi g n a n d D urati o n ................................................................................................ 3 4  
3. 2   P ost- St u d y Access t o T hera p y ........................................................................................... 4 1  
3. 3   St u d y P o p ulati o n ................................................................................................................ 4 1  
3. 3. 1   I ncl usi o n Criteri a ........................................................................................................ 4 1 
3. 3. 2   Excl usi o n Criteri a ....................................................................................................... 4 4  
3. 3. 3   W o me n of C hil d be ari n g P ote nti al............................................................................... 4 7  
3. 4   Scree n Fail ures ................................................................................................................... 4 7  
3. 5   C o nc o mita nt Treat me nts .................................................................................................... 4 7  
3. 5. 1   Pr o hi bite d a n d/ or Restricte d Tre at me nts .................................................................... 4 7  
3. 5. 2   Ot her Restricti o ns a n d Prec a uti o ns ............................................................................ 4 7  
3. 6   Disc o nti n uati o n of t he St u d y .............................................................................................. 4 8  
3. 7   Disc o nti n uati o n of I n vesti gati o nal Pr o d uct F oll o wi n g A n y Treat me nt wit h St u d y Dr u g . 4 8  
3. 7. 1   Pr oce d ures f or H a n dli n g P atie nts I n c orrectly E nr olle d or R a n d o mize d ................... 5 0  
3. 7. 2   Resc ue G ui deli nes f or S u bjects wit h Pr ot oc ol- Defi ne d L ack of Glyce mic C o ntr ol .... 5 0  
3. 7. 3   Disc o nti n u ati o n G ui deli nes D ue t o Pr ot oc ol- Defi ne d Hy p o glyce mi a E pis o des ........ 5 2  
3. 7. 4   Disc o nti n u ati o n G ui deli nes D ue t o Di a betic Ket o aci d osis ........................................ 5 2 
3. 8   P ost- St u d y Dr u g F oll o w- u p ............................................................................................... 5 3  
3. 8. 1   Wit h dr a w al of C o nse nt................................................................................................ 5 3  
3. 8. 2   L ost t o F oll o w- u p ........................................................................................................ 5 4  
4   S T U D Y D R U G ..................................................................................................................... 5 5  
4. 1   I n vesti gati o nal Pr o d uct ...................................................................................................... 57  
4. 2   N o n-I n vesti gati o nal Pr o d uct .............................................................................................. 5 7  
4. 3   St ora ge a n d Dis pe nsi n g ...................................................................................................... 5 7  
4. 4   Met h o d of Assi g ni n g S u bj ect I de ntificati o n ...................................................................... 5 8  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
7 
4. 5   Selecti o n a n d Ti mi n g of D o se f or Eac h S u bject ................................................................ 6 0 
4. 6   Bli n di n g/ U n bli n di n g .......................................................................................................... 6 1  
4. 7   Treat me nt C o m plia nce ....................................................................................................... 6 2  
4. 8   Destr ucti o n of St u d y Dr u g ................................................................................................. 6 2  
4. 9   Ret ur n of I n vesti gati o nal Pr o d uct ...................................................................................... 6 3  
4. 1 0  Retai ne d Sa m ples f or Bi oa va ila bilit y/ Bi oeq ui vale nce ...................................................... 6 3  
5   S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .............................................................. 6 4  
5. 1   Fl o w C hart/ Ti me a n d E ve nts Sc he d ule .............................................................................. 6 5  
5. 1. 1   Retesti n g/ Re assess me nt D uri n g Sc ree ni n g or Le a d-I n Peri o d ................................... 7 7 
5. 2   St u d y Materials .................................................................................................................. 7 7  
5. 3   Safet y Assess me nts ............................................................................................................ 7 8  
5. 3. 1   Self- M o nit ori n g Bl o o d Gl uc ose a n d G ui d a nce o n M a n a ge me nt a n d Re p orti n g of 
Hy p o glyce mi a E pis o des .............................................................................................. 7 8  
5. 3. 2   Self- M o nit ori n g Bl o o d Ket o ne Testi n g a n d G ui d a nce o n M a n a ge me nt a n d Re p orti n g 
of Di a betic Ket o ac i d osis E pis o des .............................................................................. 7 9 
5. 3. 3   G ui d a nce o n Assess me nt of Uri n ar y I nfecti o ns a n d He m at uri a ................................. 8 0  
5. 3. 4   G ui d a nce o n Assess me nt of C ar di ov asc ul ar Eve nts ................................................... 8 1  
5. 3. 5   G ui d a nce o n Assess me nt of He p atic L a b or at ory A b n or m alities ................................ 8 1  
5. 3. 6   P hysic al Ex a mi n ati o n ................................................................................................. 8 2  
5. 3. 7   Me as ures of Gr o wt h a n d M at urity .............................................................................. 8 2  
5. 3. 8   Bl o o d Press ure, Ort h ost atic Bl o o d Press ure a n d He art R ate .................................... 8 3  
5. 3. 9   G ui d a nce o n V ol u me De pleti o n .................................................................................. 8 3  
5. 3. 1 0  S u p ple me nt al Visits ..................................................................................................... 8 4  
5. 3. 1 1  I m a gi n g Assess me nt f or t he St u dy ............................................................................... 8 4 
5. 4   Efficac y Assess me nts ......................................................................................................... 8 4  
5. 5   P har mac o ki netic/ P har m ac o d y na mic Assess me nts............................................................. 8 5  
5. 6   Bi o mar ker Assess me nts ..................................................................................................... 8 6  
5. 7   O utc o mes Researc h Assess me nts ...................................................................................... 8 6  
5. 8   Ot her Assess me nts ............................................................................................................. 8 6  
5. 8. 1   Diet a n d Exercise C o u nseli n g ..................................................................................... 8 6  
5. 8. 2   Wei g ht, Hei g ht, a n d B MI ............................................................................................ 8 6  
5. 9   Res ults of Ce ntral Assess me nts ......................................................................................... 8 7  
6   A D V E R S E E V E N T S ........................................................................................................... 8 7  
6. 1   Seri o us A d verse E ve nts ..................................................................................................... 8 8  
6. 1. 1   Seri o us A dverse Eve nt C ollecti o n a n d Re p orti n g ....................................................... 8 9  
6. 2   N o nseri o us A d verse E ve nts ............................................................................................... 9 0  
6. 2. 1   N o nseri o us A dverse Eve nt C ollecti o n a n d Re p orti n g ................................................. 9 1  
6. 3   La b orat or y Test Res u lt A b n or malities ............................................................................... 9 1 
6. 4   Pre g na nc y ..................................................................................................................... ...... 9 2 
6. 5   O ver d ose ...................................................................................................................... ...... 9 2 
6. 6   P ote ntial Dr u g-I n d uce d Li ver I nj ur y .................................................................................. 9 2  
6. 7   Me dicati o n Err or .............................................................................................................. .. 9 2 
6. 8   Ot her Safet y C o nsi derati o ns .............................................................................................. 9 3  
6. 8. 1   A dverse Eve nts of I nterest ........................................................................................... 9 3  
7   D A T A M O NI T O RI N G C O M MI T T E E A N D O T H E R E X T E R N A L 
C O M MI T T E E S ................................................................................................................... 9 4  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
8 
7. 1   Data M o nit ori n g C o m mittee .............................................................................................. 9 4  
7. 2   Car di o vasc ular A dj u dicati o n C o m mittee ........................................................................... 9 4  
7. 3   He patic A dj u dicati o n C o m mittee ....................................................................................... 9 4  
7. 4   Dia betic Ket oaci d osis A dj u dicati o n C o m mittee ................................................................ 9 5  
8   S T A TI S TI C A L C O N SI D E R A TI O N S ............................................................................... 9 5  
8. 1   Sa m ple Size Deter mi nati o n ................................................................................................ 9 5  
8. 2   P o p ulati o ns f or A nal yses ................................................................................................... 9 5  
8. 3   E n d p oi nts ..................................................................................................................... ...... 9 6 
8. 3. 1   Pri m ary E n d p oi nt ........................................................................................................ 9 6  
8. 3. 2   Sec o n d ary E n d p oi nts................................................................................................... 9 6  
8. 3. 3   Ex pl or at ory E n d p oi nts ................................................................................................ 9 6  
8. 4   A nal yses ...................................................................................................................... ....... 9 7 
8. 4. 1   De m o gr a p hics a n d B aseli ne C h ar acteristics .............................................................. 9 8  
8. 4. 2   Effic acy A n alyses ........................................................................................................ 9 8  
8. 4. 3   S afety A n alyses .......................................................................................................... 1 0 4  
8. 4. 4   P h ar m ac oki netic A n alyses ........................................................................................ 1 0 6  
8. 4. 5   P h ar m ac o dy n a mic A n alyses ..................................................................................... 1 0 6  
8. 4. 6   Bi o m arker A n alyses .................................................................................................. 1 0 6  
8. 4. 7   O utc o mes Rese arc h A n alyses.................................................................................... 1 0 6  
8. 4. 8   Ot her A n alyses .......................................................................................................... 1 0 7  
8. 5   I nteri m A nal yses .............................................................................................................. 1 0 7 
9   S T U D Y M A N A G E M E N T ................................................................................................. 1 0 7  
9. 1   C o m plia nce .................................................................................................................... .. 1 0 7 
9. 1. 1   C o m pli a nce wit h t he Pr ot oc ol  a n d Pr ot oc ol Revisi o ns ............................................ 1 0 7 
9. 1. 2   M o nit ori n g ................................................................................................................ 1 0 8  
9. 1. 3   I nvesti g ati o n al Site Tr ai ni n g ..................................................................................... 1 0 9 
9. 2   Rec or ds ....................................................................................................................... ...... 1 0 9 
9. 2. 1   Rec or ds Rete nti o n ..................................................................................................... 1 0 9  
9. 2. 2   St u dy Dr u g Rec or ds .................................................................................................. 1 0 9  
9. 2. 3   C ase Re p ort F or ms ................................................................................................... 1 1 0  
9. 3   Cli nical St u d y Re p ort a n d P u blicati o ns ........................................................................... 1 1 0  
1 0  G L O S S A R Y O F T E R M S .................................................................................................. 1 1 2  
1 1  LI S T O F A B B R E VI A TI O N S ........................................................................................... 1 1 3  
1 2  R E F E R E N C E S ................................................................................................................... 1 1 6  
A P P E N DI X 1  
C E N T R A L L A B O R A T O R Y A S S E S S M E N T S ....................................... 1 1 8  
A P P E N DI X 2  
S U S T AI N E D E L E V A T E D LI V E R S A F E T Y A B N O R M A LI TI E S 
F L O W C H A R T .................................................................................................................. 1 2 3  
A P P E N DI X 3  
T A N N E R A S S E S S M E N T S C A L E ............................................................ 1 2 4  
A P P E N DI X 4  
D E FI NI TI O N O F M E DI C A TI O N E R R O R ............................................ 1 2 6  
 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
9 
S Y N O P SI S 
Cli nic al Pr ot oc ol C V 1 8 1 3 7 5 ( A Z st u d y n u m ber: D 1 6 8 0 C 0 0 0 1 9) 
Pr ot oc ol Title: A 2 6- Wee k, M ultice nter, Ra n d o mize d, Place b o- C o ntr olle d, D o u ble- Bli n d, Parallel Gr o u p, P hase 3 
Trial wit h a 2 6- Wee k Safet y E xte nsi o n Peri o d E val uati n g t he Safet y a n d Efficac y of Da pa glifl ozi n 5 a n d 1 0 m g, a n d 
Sa xa gli pti n 2. 5 a n d 5 m g i n Pe diatric Patie nts wit h T y pe 2 Dia betes Mellit us W h o Are Bet wee n 1 0 a n d Bel o w 
1 8 Years of A ge.  
I n vesti g ati o n al Pr o d uct(s), D ose a n d M o de of A d mi nistr ati o n, D ur ati o n of Tre at me nt wit h I n vesti g ati o n al 
Pr o d uct(s): Da pa glifl ozi n 5 m g, da pa glifl ozi n 1 0 m g, sa xa gli pti n 2. 5 m g, sa xa gli pti n 5 m g ta blets a d mi nistere d orall y 
o nce dail y f or t he 2 6- wee k d o u ble- bli n de d treat me nt peri o d a n d t he 2 6- wee k site a n d s u bject- bli n de d l o n g-ter m ( L T) 
e xte nsi o n. 
T hr o u g h o ut t his pr ot oc ol, refere nce t o  2 6 wee ks of treat me nt s h o ul d be i nter prete d as treat me nt recei ve d u ntil t he 
Wee k 2 6 visit. Li ke wise, 5 2 wee ks of treat me nt s h o ul d be i nter prete d as treat me nt recei ve d u ntil t he Wee k 5 2 visit.  
St u d y P h ase: 3 b  
Rese arc h H y p ot hesis:  
I n pe diatric T y pe 2 Dia betes Mellit us ( T 2 D M) s u bjects o n diet a n d e xercise a n d metf or mi n, or i ns uli n, or metf or mi n 
a n d i ns uli n: 
T he pri mar y researc h h y p ot hesis f or da pa glifl ozi n is w het her t he a d diti o n of da pa glifl ozi n res ults i n a greater mea n 
re d ucti o n fr o m baseli ne i n gl yc os ylate d he m o gl o bi n ( H b A 1c) as c o m pare d t o place b o w he n eac h are a d mi nistere d 
o ver 2 6 wee ks of oral d o u ble- bli n d a d d- o n treat me nt. 
T he pri mar y researc h h y p ot hesis f or sa xa gli pti n is w het he r t he a d diti o n of sa xa gli pti n res ults i n a greater mea n 
re d ucti o n fr o m baseli ne i n H b A 1c as c om pare d t o place b o w he n eac h are a d mi nist ere d o ver 2 6 wee ks of oral d o u ble-
bli n d a d d- o n treat me nt.  
O bjecti ves:  
Pri m ar y O bjecti ve: 
T o deter mi ne if t here will be a greater  mea n re d ucti o n fr o m baseli ne i n H b A 1c ac hie ve d after 2 6 wee ks of oral 
d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 1 0 m g [all d oses a n d re gi me ns c o m bi ne d]) or sa xa gli pti n 
( 2. 5 m g or 5 m g [all d oses a n d re gi me ns c o m bi ne d])  c o m pare d t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c 
le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (i m me diate release [I R] or e xte n de d release [ X R]), i ns uli n, 
or metf or mi n (I R or X R) pl us i ns uli n. 
Sec o n d ar y O bjecti ves: 
a) T o deter mi ne if t here will be a great er mea n re d ucti o n fr o m baseli ne H b A 1c ac hie ve d after 2 6 wee ks of oral 
d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g ( wit h titrati o n t o t he hi g h- d ose f or t h ose 
w h o d o n ot ac hie ve t he gl yce mic tar get of H b A 1c < 7 % at 1 2 wee ks) c o m pare d t o place b o i n pe diatric T 2 D M 
s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n. 
b)  T o deter mi ne if t here will be a great er mea n re d ucti o n fr o m baseli ne H b A 1c ac hie ve d after 2 6 wee ks of oral 
d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g c o m pare d t o place b o i n pe diatric T 2 D M 
s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n. 
c) T o c o m pare mea n re d ucti o n fr o m base li ne of H b A 1c at Wee k 2 6 ac hie ve d w hile re mai ni n g o n t he l o w- d ose dr u g 
( da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g) vers us u p-titrati o n t o t he hi g h- d ose ( da pa glifl ozi n 1 0 m g or sa xa gli pti n 
5 m g) a m o n gst pe diatric T 2 D M s u bjects o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2. 
d)  T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne Fasti n g Plas ma Gl uc ose ( F P G) ac hie ve d 
after 2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 1 0 m g [all d oses a n d re gi me ns 
c o m bi ne d]) or of sa xa gli pti n ( 2. 5 m g or 5 m g [all d oses a n d re gi me ns c o m bi ne d]) c o m pare d t o place b o i n 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 0 
pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), 
i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
e) T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne i n F P G ac hie ve d after 2 6 wee ks of oral 
d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g ( wit h titrati o n t o t he hi g h- d ose f or t h ose 
w h o d o n ot ac hie ve t he gl yce mic tar g et of H b A 1c < 7 % at 1 2 wee ks) c o m p are d t o place b o i n pe diatric T 2 D M 
s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R 
or X R) pl us i ns uli n.  
f) 
T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne F P G ac hie ve d after 2 6 wee ks of oral 
d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g c o m pare d t o place b o i n pe diatric T 2 D M 
s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n. 
g)  T o c o m pare mea n re d ucti o n fr o m baseli ne of F P G at Wee k  2 6 ac hie ve d w hile re mai ni n g o n t he l o w- d ose dr u g 
( da pa glifl ozi n  5  m g  or  sa xa gli pti n  2. 5  m g)  vers us  u p-titrati o n  t o  t he  hi g h- d ose  ( da pa glifl ozi n  1 0  m g  or  
sa xa gli pti n 5 m g) a m o n gst pe diatric T 2 D M s u bjects o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or 
metf or mi n (I R or X R) pl us i ns uli n w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2. 
h)  T o c o m pare t he perce nta ge of  s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 1 0 m g [all d oses a n d re gi me ns c o m bi ne d]) 
or of sa xa gli pti n ( 2. 5 m g or 5 m g [all d oses a n d re gi me ns c o m bi ne d]) c o m pare d t o place b o i n pe diatric T 2 D M 
s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n. 
i) 
T o c o m pare t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glif l ozi n 5 m g or sa xa gli pti n 2. 5 m g ( wit h titrati o n t o t he 
hi g h- d ose f or t h ose w h o d o n ot ac hie ve t he gl yce mic ta r get of H b A 1c < 7 % at 1 2 wee ks) vers us place b o i n 
pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or 
metf or mi n (I R or X R) pl us i ns uli n. 
j) 
T o c o m pare t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n  t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g vers us place b o i n 
pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), 
i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
k)  T o c o m pare t he perce nta ge of pe diatri c T 2 D M s u bjects o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, 
or metf or mi n (I R or X R) pl us i ns uli n wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at Wee k 2 6 
w hile re mai ni n g o n t he l o w- d ose dr u g ( da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g) vers us u p-titrati o n t o t he 
hi g h- d ose ( da pa glifl ozi n 1 0 m g or sa xa gli pti n 5 m g) a m o n gst s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at 
Wee k 1 2. 
Of n ote sec o n dar y o bjecti ves will be pr ese nte d i n hierarc hical testi n g or der a n d la bele d n u mericall y i n Secti o n  8. 4. 2. 2  
a n d t he statistical a nal ysis pla n.  
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 1 
Fi g ure 1:  
Sc he m atic of gr o u p c o m p aris o ns i n st u d y Pri m ar y & Sec o n d ar y 
O bjecti ves 
 
 
At t he e n d of 2 6 wee ks of i n vesti gati o nal pr o d uct (I P) a d mi nistrati o n, st u d y partici pa nts will bel o n g t o o ne of f o ur 
s u b gr o u ps (I-I V); t he pri mar y o bjecti ve a n d sec o n dar y o bjecti ves a t o k will e nc o m pass c o m paris o ns of res ults fr o m 
m ulti ple c o m bi nati o ns of t hese s u b gr o u ps, as sc he matize d a b o ve. 
 
 
S afet y O bjecti ves: 
 
T o assess t he safet y a n d t olera bilit y, i ncl u di n g t he i nci de nce of a d verse e ve nts ( A Es) a n d e ve nts of h y p o gl yce mia, 
of da pa glifl ozi n a n d sa xa gli pti n as a d d- o n t o diet a n d e xercise a n d metf or mi n (I R or X R), or i ns uli n, or metf or mi n 
(I R or X R) pl us i ns uli n i n pe diatric T 2 D M s u bjects w he n a d mi nistere d f or u p t o 2 6 wee ks of s h ort-ter m ( S T) 
d o u ble- bli n d treat me nt, a n d, se paratel y, u p t o 5 2 wee ks of t otal treat me nt. 
 
T o assess t he i nci de nce of dia betic ket oaci d osis ( D K A) wit h da pa glifl ozi n a n d sa xa gli pti n as a d d- o n t o diet a n d 
e xercise a n d metf or mi n (I R or X R), or i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n i n pe diatric T 2 D M s u bjects 
w he n a d mi nistere d f or u p t o 2 6 wee ks of S T d o u ble- bli n d treat me nt, a n d, se paratel y, u p t o 5 2 wee ks of t otal 
treat me nt. 
 
T o assess meas ures of gr o wt h a n d mat urit y a n d Ta n ner sta gi n g a n d mar kers of b o ne healt h i n pe diatric T 2 D M 
s u bjects w he n a d mi nistere d da pa glifl ozi n or sa xa gli pti n as a d d- o n t o diet a n d e xercise a n d metf or mi n (I R or X R), 
or i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n f or u p t o  2 6 wee ks of S T d o u ble- bli n d treat me nt, a n d, se paratel y, 
f or u p t o 5 2 wee ks of t otal treat me nt, a n d f or a n a d diti o nal 5 2 wee ks after t he st u d y has bee n c o m plete d a n d 
st u d y-relate d treat me nt has bee n disc o nti n ue d. 
 
T o assess t he safet y a n d t olera bilit y of da pa glifl ozi n ( o r sa xa gli pti n) m o n ot hera p y i n pe diatric s u bjects w h o are 
ra n d o mize d t o wit h dra w bac k gr o u n d metf or mi n. 
E x pl or at or y O bjecti ves: 
 
T o c o m pare t he perce nta ge of s u bjects re q uiri n g gl yce mic resc ue me dicati o n or disc o nti n ui n g st u d y me dicati o n 
d ue t o lac k of efficac y wit h da pa glifl ozi n or sa xa gli pti n a gai nst t he perce nta ge wit h place b o d uri n g 2 6 wee ks of 
oral d o u ble- bli n d a d d- o n treat me nt i n pe diatric T 2 D M s u bj ects wit h H b A 1c of 6. 5 t o 1 0 . 5 % o n diet a n d e xercise 
a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
 
T o assess ti me t o i nitiati o n of gl yce mic resc ue me dicati o n or disc o nti n uati o n of st u d y me dicati o n d ue t o lac k of 
efficac y wit h da pa glifl ozi n, sa xa gli p ti n or place b o d uri n g t he 2 6- wee k S T treat me nt peri o d a n d d uri n g t he 
5 2- wee k S T + L T treat me nt peri o d i n pe diatric T 2 D M s u bjec ts wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise 
a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n.  
 
T o assess t he mea n c ha n ge fr o m baseli ne i n H b A 1c ac hi e ve d wit h da pa glifl ozi n t h era p y vers us place b o, a n d 
se paratel y, ac hie ve d wit h sa xa gli pti n t hera p y vers us placeb o after 5 2 wee ks of oral bli n de d a d d- o n treat me nt i n 
pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or 
metf or mi n (I R or X R) pl us i ns uli n.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 2 
 
T o assess t he mea n c ha n ge fr o m baseli ne i n F P G ac hie ve d wit h da pa glifl ozi n t hera p y vers us place b o, a n d 
se paratel y, ac hie ve d wit h sa xa gli pti n t hera p y vers us place b o after 5 2 wee ks of oral bli n de d a d d- o n treat me nt i n 
pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or 
metf or mi n (I R or X R) pl us i ns uli n. 
 
T o assess t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % after 
5 2 wee ks of oral bli n de d a d d- o n t hera p y wit h da pa g lifl ozi n vers us place b o or saxa gli pti n vers us place b o i n 
pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or 
metf or mi n (I R or X R) pl us i ns uli n. 
 
T o assess t he effect of m o n ot hera p y of da pa glifl ozi n t hera p y (a n d se paratel y sa xa gli pti n t hera p y) f or s u bjects 
ra n d o mize d  t o  wit h dra w  bac k gr o u n d  metf or mi n  relati ve  t o  da pa glifl ozi n + metf or mi n  (a n d  se paratel y  
sa xa gli pti n + metf or mi n)  a n d  relati ve  t o  place b o + metf or min  d uri n g  t he  ra n d o mize d  wit h dra wal  peri o d  usi n g  
c ha n ge i n H b A 1c, c ha n ge i n F P G, ac hie ve me nt of t h era pe utic gl yce mic res p o nse ( H b A 1c < 7 %) a n d ti me t o 
resc ue or disc o nti n uati o n d ue t o lac k of gl yce mic c o ntr ol. 
P h ar m ac o ki netic/ P h ar m ac o d y n a mic O bjecti ve: 
 
T o  e x pl ore  t he  p har mac o ki netic  ( P K)  a n d  e x p os ure-res p o nse  relati o ns hi p  of  da pa glifl ozi n  a n d,  se paratel y,  
sa xa gli pti n, a n d its meta b olite 5- h y dr o x y-sa xa gli pti n ( 5- O H-sa xa gli pti n), i n s u bjects a ge d 1 0 t o bel o w 1 8 years 
wit h T 2 D M base d o n t he c ollecti o n of p o p ulati o n P K sa m ples. 
St u d y Desi g n: T he pr o p ose d st u d y is a 2 6- wee k P hase 3 b, m ultice nter, ra n d o mize d, place b o-c o ntr olle d, d o u ble- bli n d, 
parallel- gr o u p st u d y wit h a 2 6- wee k safet y e xte nsi o n peri o d t o  e val uate t he safet y a n d efficac y of da pa glifl ozi n ( 5 m g 
a n d 1 0 m g), a n d, se paratel y, sa xa gli pti n ( 2. 5 m g a n d 5 m g) i n pe diatric s u bjects wit h T 2 D M, a n d a n a d diti o nal 
p ost-st u d y visit at Wee k 1 0 4 f or assess me nt of meas ures of gr o wt h a n d mat urit y. A p pr o xi matel y 2 4 3 pe diatric s u bjects 
will  be  ra n d o mize d  i n  a  1: 1: 1  rati o  t o  recei ve  da pa glifl ozi n  5  m g,  sa xa gli p ti n 2. 5 m g,  or  place b o. 
A p pr o xi matel y 8 1 s u bjects will be ra n d o mize d t o eac h treat me nt ar m.  
T he pri mar y efficac y e n d p oi nt will be assesse d at t he e n d of  t he i nitial 2 6- wee k d o u ble- bli nd treat me nt peri o d (referre d 
t o as t he S T peri o d [fr o m Da y 1 t o e n d of Wee k 2 6]). T he S T peri o d will be f oll o we d b y a 2 6- wee k, d o u ble- bli n d 
safet y e xte nsi o n peri o d (t he L T treat me nt peri o d [fr o m Wee k 2 7 t o e n d of Wee k 5 2]). Da pa glifl ozi n a n d, se paratel y, 
sa xa gli pti n will be c o m pare d a gai nst t he si n gle s hare d place b o c o m parat or.  
Safet y m o nit ori n g will c o nti n ue f oll o wi n g t he Wee k 5 2 e n d- of-treat me nt visit u ntil t he Wee k 1 0 4 p ost-st u d y visit. 
Meas ures of gr o wt h a n d mat urit y will be as sesse d at t he Wee k 1 0 4 p ost-st u d y visit. 
Scree ni n g pr oce d ures are e x pecte d t o last 6 t o 8 wee ks. If, h o we ver, at i nitial scree ni n g, o ne or m ore la b orat or y val ues 
are n ot i n t he eli gi bilit y ra n ge, b ut t he I n vesti gat ors deter m i ne t he y are a me na ble t o c orrecti o n wit hi n a reas o na ble 
ti me fra me, t he scree ni n g peri o d ca n be e xte n de d t o a ma xi m u m of 6 m o nt hs. At scree ni n g, all pr oce d ures a n d 
assess me nts s h o ul d be c o m plete d a n d re vie we d b y t he I n vesti gat ors. Retesti n g/reassess me nt of faile d varia bles ca n be 
perf or me d  as  deter mi ne d  b y  t he  I n vesti gat ors  d uri n g  t he  6- m o nt h  scree ni n g  peri o d.  Retesti n g/reassess me nt  
fre q ue ncies are at t he discreti o n of t he I n vesti gat ors, b ut s h o ul d occ ur at least o nce e ver y 3 m o nt hs. I n cases w he n a 
s u bject d oes n ot meet o ne or m ore criteria t he first ti me a n d is later reassesse d t o see if he/s he will meet t hat criteria, 
t he I n vesti gat or s h o ul d e ns ure t hat other criteria are still met (a n d ha ve n ot bec o me dis q ualif yi n g d uri n g t he i nteri m 
ti me peri o d) bef ore acce pti n g t hat t he s u bject meets all eli gi bilit y criteria. S u bjects w h o fail t o meet t he eli gi bilit y 
criteria after t he 6- m o nt h scree ni n g peri o d s h o ul d be c o nsi dere d as scree n fail ures a n d wit h dra w n fr o m t he st u d y. 
Scree n-faile d s u bjects, h o we ver, ca n be re-scree ne d a ma xi m u m of t w o m ore ti mes at a later ti me. F or re-scree ni n g, 
s u bjects m ust be re-c o nse nte d a n d all t he scree ni n g pr oce dures a n d assess me nts m ust be re peate d. S u bjects are n ot 
a ble t o be re-scree ne d if t he y t ur n 1 8 years of a ge d uri n g t he scree ni n g peri o d. 
Pri or t o ra n d o mizati o n o n Da y 1, s u bjects will be re q uire d t o  ha ve bee n treate d wit h diet a n d e xercise a n d a sta ble 
d ose of at least 1 0 0 0 m g metf or mi n (I R or X R) f or a mi ni m u m of 8 wee ks, or a sta ble baseli ne d ose of i ns uli n f or a 
mi ni m u m of 8 wee ks, or a sta ble c o m bi nati o n of at least 1 0 0 0 m g metf or mi n a n d i ns uli n f or a mi ni m u m of 8 wee ks. 
At least 5 0 % of s u bjects will be o n a sta ble baseli ne d ose of  metf or mi n, wit h or wit h o ut c o nc urre nt i ns uli n t hera p y. 
At least 3 0 % of t otal s u bjects will be bet wee n t he a ges of 1 0 a n d 1 4 years a n d at least o ne t hir d, b ut n o m ore t ha n t w o 
t hir ds, fe male s u bjects. 
D uri n g t he 2- wee k lea d-i n peri o d, s u bject s will be i nstr ucte d o n a diet a n d e xercise pr o gra m (i n acc or da nce wit h t he 
A merica n Dia betes Ass ociati o n [ A D A] or si milar l ocal g ui d eli nes) t o be f oll o we d f or t he st u d y d urati o n. S u bjects will 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 3 
mai ntai n t heir baseli ne t y pes a n d/ or d oses of a nti dia betic  t hera p y t hr o u g h o ut t he st u d y ( 2- wee k lea d-i n, 2 6- wee k 
d o u ble- bli n d S T treat me nt peri o d, a n d t he 2 6- wee k bli n de d safet y e xte nsi o n L T treat me nt peri o d), u nless t he y are 
ra n d o mize d t o wit h dra w bac k gr o u n d me dicati o n wit h metf or mi n at Wee k 3 2 or Wee k 4 0, u ntil Wee k 5 2. If a p plica ble, 
i n vesti gat ors will e nc o ura ge s u bjects t o kee p t heir i ns uli n d oses sta ble. D o w n-titrati o n of i ns uli n will be all o we d o nl y 
as necessar y t o pre ve nt h y p o gl yce mia a n d will be at t he disc reti o n of t he I n vesti gat or. I ns uli n will be u p-titrate d or 
a d de d as resc ue as warra nte d b y a h y per gl yce mic state. H o me gl uc ose meters t o m o nit or gl uc ose c o ntr ol will be 
dis pe nse d t o s u bjects a n d self- bl o o d gl uc ose m o nit ori n g re q u ire me nts a n d pr oce d ures will be e x plai ne d. S u bjects will 
als o be i nstr ucte d o n t he use of t he s u bject diar y t o rec or d self- m o nit ori n g gl uc ose le vels a n d dail y i ns uli n d ose, if 
a p plica ble. S u bjects will als o recei ve a bl o o d ke t o ne meter f or testi n g w he n D K A is s us pecte d. 
After t he lea d-i n peri o d, eli gi ble s u bjects wit h H b A 1c of 6. 5 % t o 1 0. 5 % at scree ni n g will be ra n d o mize d 1: 1: 1 t o 
recei ve  oral,  d o u ble- bli n d,  dapa glifl ozi n  5  m g  (a p pr o xi matel y  8 1  s u bj ects),  sa xa gli pti n  2. 5  m g  (a p pr o xi matel y  
8 1 s u bjects), or place b o (a p pr o xi matel y 8 1 s u bjects). Da y 1 Ra n d o mizati o n will be stratifie d base d o n baseli ne 
a nti- dia betes treat me nt re gi me n (sta ble baseli ne d ose of metf or mi n (I R or X R), a sta ble baseli ne d ose of i ns uli n, or a 
sta ble baseli ne c o m bi nati o n of metf or mi n a n d i ns uli n), ge n der, a n d a ge at ra n d o mizati o n ( 1 0 t o bel o w 1 5 years of a ge, 
1 5 t o bel o w 1 8 years of a ge).  
Sa m ples f or a nal ysis of plas ma le vels of da pa glifl ozi n, sa xa gli pti n a n d its meta b olite 5- O H-sa xa gli pti n will be 
c ollecte d u p t o 1 h o ur pre- d ose a n d a p pr o xi matel y 2 h o urs p ost- d ose (  1 h o ur) d uri n g t he Wee k 6, 1 2, 2 0, a n d 
2 6 visits.  
Sa m ples f or a nal ysis of F P G will be c ollecte d u p t o 1 h o ur pre- d ose d uri n g t he Da y 1 visit, a n d u p t o 1 h o ur pre- d ose 
a n d a p pr o xi matel y 2 h o urs p ost- d ose (  1 h o ur) d uri n g t he Wee k 6, 1 2, 2 0, a n d 2 6 visits. 
Plas ma sa m ples f or a nal ysis of di pe pti d yl- pe pti dase- 4 ( D P P- 4) acti vit y  will be c ollecte d u p t o 1 h o ur pre- d ose d uri n g 
t he Da y 1 visit, a n d at 2 h o urs p ost- d ose ( 1 hr) d uri n g t he Wee k 6, 1 2, 2 0, a n d 2 6 visits.  
All plas ma sa m ples will be dra w n i n t he fasti n g c o n diti o n. 
H b A 1c res ults will be bli n de d f oll o wi n g I P a d mi nistrati o n o n Da y 1 u ntil after st u d y c o m pleti o n. A bli n de d H b A 1c 
assess me nt will be perf or me d at Wee k 1 2 f or all s u bjects. A sec o n d ra n d o mizati o n will be perf or me d at t he Wee k 1 4 
visit, base d o n t he Wee k 1 2 H b A 1c a ssess me nt. All s u bjects wit h Wee k 1 2 H b A 1c val ues < 7 % will re mai n o n 
pre vi o usl y assi g ne d l o w- d ose ra n d o mize d treat me nt ( da pa glif l ozi n 5 m g, or sa xa gli pti n 2.5 m g, or place b o) after t he 
Wee k 1 2 assess me nt. S u bjects assi g ne d t o t he da pa glifl ozi n treat me nt ar m at Da y 1 Ra n d o mizati o n wit h Wee k 1 2 
H b A 1c val ues  7 % will be re-ra n d o mize d i n a 1: 1 rati o t o c o nti nue o n t he l o w- d ose treat me nt ( da pa glifl ozi n 5 m g) 
or t o u p-titrate t o t he hi g h- d ose treat me nt ( da pa glifl ozi n 1 0 m g) after t he Wee k 1 2 assess me nt. Si milarl y, s u bjects 
assi g ne d t o t he sa xa gli pti n  treat me nt ar m at Da y 1 Ra n d o mizati o n wit h Wee k 1 2 H b A 1c val ues  7 % will be 
re-ra n d o mize d i n a 1: 1 rati o t o c o nti n ue o n t he l o w- d ose tr eat me nt (sa xa gli pti n 2. 5 m g) or t o u p-titrate t o t he hi g h- d ose 
treat me nt (sa xa gli pti n 5 m g) after t he Wee k 1 2 assess me nt. S u bjects assi g ne d t o t he place b o treat me nt ar m at 
Da y 1 Ra n d o mizati o n wit h Wee k 1 2 H b A 1c val ues  7 % will c o nti n ue o n place b o treat me nt. T o mai ntai n t he bli n di n g 
of treat me nts as well as H b A 1c res ults, all place b o s u bjects a n d all s u bjects ta ki n g sa xa gli pti n or da pa glifl ozi n wit h 
a n H b A 1c < 7 % at wee k 1 2 will g o t hr o u g h a d u m m y sec o n d ra n d o mizati o n pr ocess t hat will be i n disti n g uis ha ble (f or 
t he s u bjects a n d site pers o n nel) fr o m t he act ual sec o n d ra n d o mizati o n. D uri n g t he Wee k 1 4 visit, bli n de d st u d y dr u g 
will be dis pe nse d t o all s u bjects i n ac c or da nce wit h t he treat me nt assi g n me nts base d o n Wee k 1 2 H b A 1c assess me nts.  
After c o m pleti o n of t he S T tr eat me nt peri o d, all s u bjects will e nter t he L T treat me nt peri o d. S u bjects w h o are recei vi n g 
bac k gr o u n d me dicati o n wit h i ns uli n o nl y, or i ns uli n + metf or m i n (a n d w h o are t heref ore n ot eli gi ble f or t he t hir d 
ra n d o mizati o n) will c o nti n ue wit h t heir ra n d o mize d st u d y me dicati o n assi g ne d after t he Wee k 1 2 assess me nt i n t he 
d o u ble- bli n d L T treat me nt peri o d. 
After c o m pleti o n of assess me nts at Wee k 2 6, a s u bset of  eli gi ble s u bjects w h o are recei vi n g bac k gr o u n d me dicati o n 
wit h metf or mi n o nl y will u n der g o a t hir d ra n d o mizati o n (ra n d o mize d wit h dra wal of bac k gr o u n d me dicati o n) at eit her 
Wee k 3 2 or Wee k 4 0. Eli gi bilit y f or ra n d o mize d wit h dra wal fr o m bac k gr o u n d me dicati o n will be restricte d t o s u bjects 
w h o are recei vi n g bac k gr o u n d treat me nt wit h metf or mi n o nl y, a n d w h o ha ve H b A 1c < 7. 5 % at Wee k 2 6 or Wee k 3 2 
pr o vi de d t he y ha ve n ot i nitiate d resc ue gl yce mic c o ntr ol t hera p y or bee n wit h dra w n fro m st u d y dr u g. S u bjects w h o 
are recei vi n g bac k gr o u n d me dicati o n w it h metf or mi n o nl y, w h o d o n ot q ualif y f or t he  t hir d ra n d o mizati o n at Wee k 3 2 
d ue t o a n H b A 1c ≥ 7. 5 % at Wee k 2 6, ma y q ualif y f or t he t hir d ra n d o mizati o n at Wee k 4 0 if H b A 1c < 7. 5 % at 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 4 
Wee k 3 2. S u bjects w h o ha ve passe d Wee k 4 0 will n ot be i ncl u de d i n t he ra n d o mize d wit h dra wal of bac k gr o u n d 
me dicati o n. D uri n g t he t hir d ra n d o mizati o n:  
 
Eli gi ble s u bjects w h o are recei vi n g ac ti ve treat me nt will be gr o u pe d i nt o t w o se parate strata f or sa xa gli pti n a n d 
da pa glifl ozi n, a n d t he n ra n d o mize d 1: 1 wit hi n eac h stra ta t o eit her disc o nti n ue bac k gr o u n d me dicati o n wit h 
metf or mi n or t o c o nti n ue bac k gr o u n d me dicati o n wit h metf or mi n. F or s u bjects o n acti ve treat me nt w h o are 
ra n d o mize d t o wit h dra w bac k gro u n d treat me nt wit h metf or mi n, t h ose w h o are c urre ntl y recei vi n g hi g h d oses of 
sa xa gli pti n ( 5 m g) or da pa glifl ozi n ( 1 0 m g) will c o nti n ue t o recei ve t he hi g h d oses, w hereas s u bjects w h o are 
c urre ntl y recei vi n g l o w d oses of sa xa g li pti n ( 2. 5 m g) or da pa glifl ozi n ( 5 m g) will ha ve t heir d oses u p-titrate d t o 
t he  hi g h  d oses  (sa xa gli pti n  5  m g  or  da pa glifl ozi n  1 0  m g).  S u bjects  i n  t he  acti ve  treat me nt  ar ms  w h o  are  
ra n d o mize d t o c o nti n ue bac k gr o u n d me dicati o n wit h metf ormi n will c o nti n ue wit h t heir c urre nt d ose of eit her 
sa xa gli pti n or da pa glifl ozi n. 
 
Eli gi ble s u bjects w h o are recei vi n g place b o will be ra n do mize d 1: 1: 1 t o eit her w it h dra w bac k gr o u n d me dicati o n 
wit h metf or mi n a n d s witc h t o acti ve treat me nt wit h eit her sa xa gli pti n 5 m g or da pa glifl ozi n 1 0 m g or t o re mai n 
o n bac k gr o u n d me dicati o n wit h metf or mi n a n d c o nti n ue wit h place b o.  
Disc o nti n uati o n of bac k gr o u n d metf or mi n will occ ur i n a n u n bli n de d ma n ner. E x p os ure t o m o n ot hera p y i n s u bjects 
u n der g oi n g ra n d o mize d wit h dra wal of metf or mi n will last fr o m t he start of metf or mi n wit h dra wal f or t hat s u bject 
(f oll o wi n g ra n d o mizati o n at Wee k 3 2 or Wee k 4 0) u ntil t he e n d of Wee k 5 2, w he n all s u bjects will disc o nti n ue st u d y 
me dicati o ns. After Wee k 5 2, all s u bjects will ta ke t he m ost  a p pr o priate me dicati o n at t he discreti o n of t he treati n g 
p h ysicia n. 
Resc ue d s u bjects a n d s u bjects w h o disc o nti n ue I P will n o t be eli gi ble f or ra n d o mize d wit h dra wal of bac k gr o u n d 
me dicati o n at Wee k 3 2 or Wee k 4 0. 
S u bjects wit h H b A 1c ≥ 7. 5 % at Wee k 2 6 a n d Wee k 3 2 a n d s u bjects w h o are recei vi n g back gr o u n d treat me nt wit h 
eit her  i ns uli n  o nl y,  or  i n s uli n + metf or mi n,  i ncl u di n g  t h ose  ra n d o mize d t o  recei ve  place b o,  will  c o nti n ue  t heir  
ra n d o mize d st u d y me dicati o n (assi g ne d after t he Wee k 1 2 assess me nt) i n t he d o u ble- bli n d L T treat me nt peri o d.  
A d verse e ve nts a n d seri o us a d verse e ve nts ( S A Es) will be assesse d d uri n g a Wee k 5 6 p h o ne visit. 
I n case a visit is dela ye d f or a n y reas o n, s u bse q ue nt visits s h o ul d be sc he d ule d s uc h t hat a n i nter val of at least 1 2 wee ks 
is mai ntai ne d bet wee n t he: 
 
Wee k- 1 4 visit a n d t he Wee k- 2 6 visit. 
 
T hir d ra n d o mizati o n (f or s u bjects u n der g oi n g t hir d ra n d o mizati o n; occ urri n g at t he Wee k- 3 2 or t he Wee k- 4 0 
visit) a n d t he Wee k- 5 2 visit. 
If m ore t ha n 1 2 wee ks ela pse bet wee n t he H b A 1c c ollecti o n at Wee k 2 6 a n d t he t hir d ra n d o mizati o n at Wee k 3 2, or 
t he H b A 1c c ollecti o n at Wee k 3 2 a n d t he t hir d ra n d o mizati o n at Wee k 4 0, t he s u bject s h o ul d n ot g o t hr o u g h t his 
ra n d o mizati o n, as t he H b A 1c val ue w o ul d n o l o n ger be relia ble t o ascertai n eli gi bilit y f or t he t hir d ra n d o mizati o n. 
S h ort- a n d l o n g-ter m peri o d st u d y visits ca n be dela ye d b y a ma xi m u m of 1 1 m o nt hs i n t otal. If t he d urati o n of I P 
a d mi nistrati o n is l o n ger t ha n 5 2 ( + 1) wee ks, t he safet y f oll o w- u p peri o d s h o ul d be s h orte ne d s uc h t hat t he c o m plete 
st u d y d urati o n d oes n ot e xcee d 1 0 4 wee ks ( + 7 da ys). A wi n d o w peri o d of - 2 8 da ys t o + 7 da ys fr o m t he ori gi nal 
sc he d ule d date will be all o we d f or t he Wee k- 1 0 4 visit. 
S u bjects w h o disc o nti n ue st u d y dr u g bef ore t he e n d of t he st u d y treat me nt peri o d will e nter a n o n-treat me nt, f oll o w- u p 
p hase, i n w hic h s u bjects will f oll o w t heir visit sc he d ules wi t h m o difie d assess me nts u ntil st u d y c o m pleti o n. S u bjects 
will atte n d a p ost-st u d y visit at Wee k 1 0 4, f or assess me nt of meas ures of gr o wt h a n d mat urit y. T his visit s h o ul d be 
c o m plete d wit h o ut dela y at 1 0 4 wee ks ( + 7 da ys) fr o m Da y 1, re gar dless of w het her a n y ot her st u d y visits were 
dela ye d. 
All s u bjects wit h H b A 1c > 8. 0 % at a n d after Wee k 2 6 will be resc ue d. 
Disc o nti n ue d s u bjects will still be e val uate d f or resc ue a n d will n ot be re place d. 
T he I n vesti gat or, S p o ns or, site a n d s u bject will be bli n de d t o t he s u bjects’ H b A 1c res ults f oll o wi n g a d mi nistrati o n of 
I P o n Da y 1 u ntil after st u d y c o m pleti o n. I n t he e ve nt of a n H b A 1c res ult > 8. 0 % d uri n g t he L T treat me nt peri o d 
( w he n t hese val ues re q uire s u bject resc ue), t he i n vesti gator will be i nf or me d via a n H b A 1c alert fr o m t he ce ntral 
la b orat or y b ut will re mai n bli n de d t o t he H b A 1c res ult. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 5 
D uri n g t he c o urse of t he trial, s u bjects ma y be eli gi ble f or t he a d diti o n of o pe n-la bel resc ue me dicati o n t o t heir bli n de d 
treat me nt re gi me n i n or der t o treat o n g oi n g h y per gl yce mia. I ns uli n ma y be use d as resc ue, at t he I n vesti gat or’s 
discreti o n. A n y per ma ne nt c ha n ges i n d ose of basal i ns uli n s h o ul d be d o ne after e val uati o n of resc ue criteria, i ncl u di n g 
b ot h self- m o nit ori n g bl o o d gl uc ose ( S M B G) a n d ce ntral la b orat or y F P G val ues.  
Pre-s pecifie d gl yce mic criteria (see Ta ble 1 bel o w), base d u p o n S M B G, F P G, or si n gle ce ntral la b orat or y F P G a n d 
re peat c o nfir mat or y F P G ha ve bee n esta blis he d d uri n g t he treat me nt peri o d, starti n g at Wee k 6, a n d u p t o b ut n ot 
i ncl u di n g t he Wee k 5 2 visit, t o deter mi ne eli gi bilit y f or o pe n-la bel resc ue me dicati o n. 
 
T a ble 1: 
L ac k of Gl yce mic C o ntr ol Criteri a f or I niti ati o n of Resc ue Me dic ati o n 
St u d y wee k 
Resc ue criteri o n 
Wee k 6 visit u p t o a n d n ot 
i ncl u di n g Wee k 2 6 visit 
F P G > 1 3. 3 m m ol/ L ( 2 4 0 m g/ dl) base d o n 3 c o nsec uti ve fasti n g S M B G val ues 
f oll o we d b y a c o nfir mat or y ce ntral la b orat or y F P G 
or 
Si n gle ce ntral la b orat or y F P G f oll o we d b y a c o nfir mat or y ce ntral la b orat or y F P G 
Wee k 2 6 visit u p t o a n d n ot 
i ncl u di n g Wee k 5 2 visit 
F P G > 1 0 m m ol/ L ( 1 8 0 m g/ dl) base d o n S M B G f or 3 c o nsec uti ve da ys f oll o we d b y 
a c o nfir mat or y ce ntral la b orat or y F P G 
or 
Si n gle ce ntral la b orat or y F P G f oll o we d b y a c o nfir mat or y ce ntral la b orat or y F P G 
or 
H b A 1c > 8. 0 % ( w hile H b A 1c val ues will re mai n bli n de d t hr o u g h o ut t he st u d y, 
sites will be n otifie d t o all o w resc ue if val ues e xcee d t his t hres h ol d) 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 8 
St u d y P o p ul ati o n:  
F or e ntr y i nt o t he st u d y, t he f oll o wi n g ke y i ncl usi o n criteri a M U S T be met. T he f ull i ncl usi o n/e xcl usi o n criteria are 
f o u n d i n Secti o n 3. 3 of t he pr ot oc ol. 
I ncl usi o n Criteri a: 
1)  Tar get P o p ulati o n 
a) Pre vi o usl y dia g n ose d wit h T 2 D M b y W orl d Healt h Or ga nizati o n/ A D A criteria 
b)  H b A 1c  6. 5 % a n d  1 0. 5 % o btai ne d d uri n g t he 6- m o nt h scree ni n g peri o d 
c) C urre ntl y o n diet a n d e xercise a n d sta ble d ose of at  least 1 0 0 0 m g metf or mi n (I R or X R) f or a mi ni m u m of 
8 wee ks, or sta ble d ose of i ns uli n f or a mi ni m u m of 8 wee ks, or a sta ble c o m bi nati o n of at least 1 0 0 0 m g 
metf or mi n (I R or X R) a n d i ns uli n f or a mi ni m u m of 8 wee ks pri or t o Da y 1 Ra n d o mizati o n 
d)  Male a n d fe male s u bjects eli gi ble if reac he d 1 0 years of a ge at scree ni n g, a n d u p t o b ut n ot i ncl u di n g 1 8 years 
of a ge at ra n d o mizati o n. At least 3 0 % of t otal s u bject s will be bet wee n t he a ges of 1 0 a n d 1 4 years a n d at 
least o ne t hir d b ut n o m ore t ha n t w o t hir ds, fe male s u bjects. 
E xcl usi o n Criteri a:  
1)  Tar get Disease E xce pti o ns 
a) Prese nce of T y pe 1 dia betes, as de m o nstrate d b y: 
 Pree xisti n g dia g n osis of T y pe 1 dia betes,  
O R 
 P ositi vit y at scree ni n g of eit her a nti b o dies t o gl uta mic aci d decar b o x ylase ( G A D) or pr otei n t yr osi ne 
p h os p hatase-li ke pr otei n a nti b o dies (I A- 2) A N D a b n or mall y l o w le vels of C- pe pti de. G A D a n d I A- 2 
a nti b o d y  testi n g  will  be  perf or me d  i n  all  scree ne d  s u bjects,  C- pe pti de  o nl y  i n  ot her wise  eli gi ble,  
a nti b o d y- p ositi ve s u bjects. All i nsta nces of a nti b o d y- p o siti ve s u bjects wit h n or mal or ele vate d C- pe pti de 
val ues will be disc usse d b y t he I n vesti gat or wit h t h e st u d y me dical m o nit ors a n d S p o ns or’s st u d y direct or 
t o c o nfir m st u d y eli gi bilit y. 
b) Pre vi o us dia g n osis of m o n o ge nic eti ol o g y of T y pe 2 dia betes s uc h as mat urit y o nset dia betes of t he y o u n g 
( M O D Y), ge netic dis or ders wit h str o n g ass ociati o ns wit h i ns uli n resista nce/ dia betes a n d/ or o besit y s uc h as 
T ur ner’s S y n dr o me a n d Pra der- Willi, or  sec o n dar y dia betes (ster oi d use, C us hi n g’s disease, acr o me gal y), 
sec o n dar y dia betes mellit us, or dia betes i nsi pi d us. 
c) Dia betes ket oaci d osis wit h i n 6 m o nt hs of scree ni n g 
d) C urre nt use of t he f oll o wi n g me dicati o ns f or t he treat me nt of dia betes, or use wit hi n t he s pecifie d ti mefra me 
pri or t o scree ni n g f or t he mai n st u d y: 
i. 
Ei g ht wee ks: s ulf o n yl ureas, al p ha gl uc osi dase i n hi bit ors, meti gli ni de, oral or i njecta ble i ncreti ns or 
i ncreti n mi metics, ot her a nti- dia betes me dicati o ns n ot ot her wise s pecifie d 
ii. 
Si xtee n wee ks: t hiaz oli di ne di o nes. D P P- 4 i n hi b it ors ( wit h n o re p orte d me dicati o n relate d A Es 
relate d t o D P P- 4 i n hi bit ors), s o di u m gl uc ose c otra ns p orter- 2 ( S G L T- 2) i n hi bit ors ( wit h n o re p orte d 
me dicati o n relate d A Es relate d t o S G L T- 2 i n hi bit ors) 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
1 9 
St u d y Dr u g: i ncl u des b ot h I n vesti g ati o n al [ Me dici n al] Pr o d ucts (I P/I M P) a n d N o n-i n vesti g ati o n al [ Me dici n al] 
Pr o d ucts ( N o n-I P/ N o n-I M P) as liste d: 
T a ble 2:  
St u d y Dr u g f or B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
Me dic ati o n
 P ote nc y
 
I P/ N o n-I P
Sa xa gli pti n
 2. 5
 
m g
 
I P
Sa xa gli pti n
 5
 
m g
 
I P
Da pa glifl ozi n
 5
 
m g
 
I P
Da pa glifl ozi n
 1 0
 
m g
 
I P
Place b o Matc hi n g Sa xa gli pti n  2. 5 m g/ 5 m g 
0 m g 
I P 
Place b o Matc hi n g Da pa glifl ozi n 5 m g 
0 m g 
I P 
Place b o Matc hi n g Da pa glifl ozi n 1 0 m g 
0 m g 
I P 
 
St atistic al C o nsi der ati o ns: 
S a m ple Size: 
T he sa m ple size f or t his st u d y was selecte d t o be c o nsiste nt wit h t he researc h h y p ot heses. 
Da pa glifl ozi n a n d sa xa gli pti n will be c o m pare d wit h place b o se paratel y. N o c o m paris o ns bet wee n da pa glifl ozi n a n d 
sa xa gli pti n will be perf or me d.  
T he sa m ple size f or t his st u d y is base d o n t he a bilit y t o detect a 0. 7 5 % i m pr o ve me nt o ver pl ace b o f or da pa glifl ozi n or 
sa xa gli pti n i n c ha n ge fr o m baseli ne i n H b A 1c at Wee k 2 6 ( S T) wit h a p pr o xi matel y 8 0% p o wer f or eac h c o m paris o n 
at a 2-si de d al p ha le vel of 0. 0 5.If 2 4 3  pe diatric s u bjects are ran d o mize d a n d a nal yze d, a n d eac h treat me nt c o m pare d 
t o place b o at a 2-si de d al p ha = 0. 0 5 le vel, t his will pr o vi de a p pr o xi matel y 8 0 % p o wer f or eac h c o m paris o n t o detect a 
0. 7 5 % re d ucti o n i n H b A 1c c ha n ge fr o m baseli ne vers us place b o ass u mi n g a sta n dar d de viati o n of 1. 7 %. 
Da y 1 Ra n d o mizati o n will be stratifie d base d o n t he baseli ne a n ti- dia betic treat me nt re gi me n (sta ble baseli ne d ose of 
metf or mi n [I R or X R]), a sta ble baseli ne d ose of i ns uli n, or a sta ble c o m bi nati o n of metf or mi n [I R or X R] a n d i ns uli n), 
ge n der, a n d a ge ( 1 0 t o bel o w 1 5 years of a ge, 1 5 t o bel o w 1 8 years of a ge). 
T he sta n dar d de viati o n esti mate of 1. 7 % is base d o n a bli n de d re vie w of t he o n g oi n g st u d y data. 
E n d p oi nts: 
Pri m ar y E n d p oi nt: 
C ha n ge fr o m baseli ne i n H b A 1c at Wee k 2 6 
Sec o n d ar y E n d p oi nts: 
 
C ha n ge fr o m baseli ne i n F P G at Wee k 2 6 
 
Perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at Wee k 2 6 
E x pl or at or y E n d p oi nts: 
E x pl or at ory effic acy e n d p oi nts f or s h ort-ter m assess me nt of s a x a gli pti n a n d d a p a glifl ozi n 
 
Perce nta ge of s u bjects w h o re q uire gl yce mic resc ue me di cati o n or disc o nti n ue t he st u d y me dicati o n d ue t o lac k 
of efficac y d uri n g t he 2 6 - wee k treat me nt peri o d 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 0 
 
Ti me t o i nitiati o n of gl yce mic resc ue me dicati o n or di sc o nti n uati o n of st u d y me dicati on d ue t o lac k of efficac y 
d uri n g t he 2 6- wee k treat me nt peri o d 
E x pl or at ory effic acy e n d p oi nts f or l o n g-ter m assess me nt of s a x a gli pti n a n d d a p a glifl ozi n:  
 
C ha n ge fr o m baseli ne i n H b A 1c at Wee k 5 2 
 
C ha n ge fr o m baseli ne i n F P G at Wee k 5 2 
 
Perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7 % at Wee k 5 2 
 
Ti me t o i nitiati o n of gl yce mic resc ue me dicati o n or di sc o nti n uati o n of st u d y me dicati on d ue t o lac k of efficac y 
d uri n g t he 5 2- wee k treat me nt peri o d 
E x pl or at ory effic acy e n d p oi nts f or m o n ot her a py assess me nt of s a x a gli pti n a n d d a p a glifl ozi n:  
 
C ha n ge i n H b A 1c d uri n g t he ra n d o mize d wit h dra wal peri o d 
 
C ha n ge i n F P G d uri n g t he ra n d o mize d wit h dra wal peri o d 
 
Perce nta ge of s u bjects w h o ac hie ve or mai ntai n a H b A 1c le vel < 7. 0 % at t he e n d of t he ra n d o mize d wit h dra wal 
peri o d 
 
Ti me t o i nitiati o n of gl yce mic resc ue me dicati o n or di sc o nti n uati o n of st u d y me dicati on d ue t o lac k of efficac y 
usi n g t he start ti me of ra n d o mize d wit h dra wal as t he refere nce p oi nt 
S afet y E n d p oi nts: 
Safet y e n d p oi nts c o nsist of t he i nci de nce of A Es, S A Es, h y p o gl yce mic e ve nts, disc o nti n uati o ns d ue t o A Es, mar ke d 
a b n or malities i n cli nical la b orat or y tests, vital si g ns, Ta n ner  sta gi n g, meas ures of gr o wt h a n d mat urati o n, D K A e ve nts, 
a n d safet y la b orat or y tests. 
A n al yses: 
Da pa glifl ozi n a n d sa xa gli pti n will be s u m marize d se paratel y. A c o m m o n place b o gr o u p will be i ncl u de d i n eac h 
s u m mar y. 
I n a d diti o n, wit hi n t he a nal yses of da pa glifl ozi n a n d sa xa gli pti n, t he o verall (c o m bi ne d l o w- d ose a n d hi g h- d ose) 
efficac y a n d safet y a nal yses will be re peate d f or t he s u b g r o u p of s u bjects o n a sta ble baseli ne d ose of metf or mi n (I R 
or X R) ( wit h or wit h o ut i ns uli n). F or t hese a nal yses, t he da pa glifl ozi n a n d sa xa gli pti n re gi me ns wit hi n eac h treat me nt 
will be c o m bi ne d i nt o o ne s u b gr o u p a n d c o m pare d t o t he c orres p o n di n g (c o m m o n) place b o su b gr o u p. P- val ues 
c orres p o n di n g t o s u b gr o u p c o m paris o ns will be re p orte d f or t he pr i mar y a n d sec o n dar y efficac y e n d p oi nts, a n d will 
be re p orte d at t he n o mi nal si g nifica nce le vel. 
All efficac y a nal yses will be perf or me d usi n g t he Ra n d o miz e d S u bjects Data Set (all ra n d o mize d s u bjects w h o recei ve 
at least o ne d ose of st u d y me dicati o n d uri n g t he treat me nt peri o d) u nless ot her wise s pecifie d. F urt her m ore, t o acc o u nt 
f or ra n d o mizati o n wit h dra wal, a nal yses de dicate d t o m o n ot hera p y assess me nt will be perf or me d o n t he Ra n d o mize d 
Wit h dra wal S u bjects Data Set. 
T he f oll o wi n g treat me nt re gi me ns are c o nsi dere d f or a nal ysis: 
 
L o w- d ose/ hi g h- d ose: I nitial treat me nt of t he l o w- d ose f oll o we d b y u p-titrati n g t o t he hi g h- d ose f or t h ose w h o d o 
n ot ac hie ve t he gl yce mic tar get of H b A 1c < 7 % at Wee k 1 2 a n d c o nti n ui n g treat me nt wit h t he l o w- d ose f or t h ose 
ac hie vi n g t he gl yce mic tar get of H b A 1c < 7 % at Wee k 1 2 
 
L o w- d ose: I nitial treat me nt of t he l o w- d ose f oll o we d b y c o nti n ui n g treat me nt o n t he l o w- d ose dr u g f or t h ose w h o 
d o n ot ac hie ve t he gl yce mic tar get of H b A 1c < 7 % at We e k 1 2 a n d c o nti n ui n g treat me nt wit h t he l o w- d ose f or 
t h ose ac hie vi n g t he gl yce mic tar get of H b A 1c < 7 % at Wee k 1 2 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 1 
F oll o wi n g t he t hir d ra n d o mizati o n: 
 
S u bjects i nitiall y ra n d o mize d t o da pa glifl ozi n ( or sa xa g li pti n) wit h metf or mi n as bac k gr o u n d t hera p y will be 
re-ra n d o mize d i n a 1: 1 rati o t o eit her da pa glifl ozi n ( or saxa gli pti n) al o ne or t o da pa glifl ozi n ( or sa xa gli pti n) wit h 
metf or mi n as bac k gr o u n d t hera p y  
 
S u bjects i nitiall y ra n d o mize d t o place b o wit h metf or mi n as bac k gr o u n d t hera p y will be re-ra n d o mize d i n a 1: 1: 1 
rati o t o da pa glifl ozi n al o ne or sa xa gli pti n al o ne or place b o wit h metf or mi n as bac k gr o u n d t hera p y 
F or eac h dr u g, t he c o m paris o n vs place b o will be teste d at a t w o-si de d al p ha le vel of 0. 0 5.  
T he pri mar y efficac y a nal ysis will be pe rf or me d usi n g a n  a nal ysis of c o varia nce ( A N C O V A). F or t his a nal ysis, all 
d ose le vels f or a treat me nt will be c o m bi ne d i nt o o ne treat me nt gr o u p f or eac h dr u g. Se parate m o dels will be use d f or 
sa xa gli pti n a n d da pa glifl ozi n a nal yses, a n d eac h a nal ysis will i ncl u de t he (c o m m o n) place b o c o ntr ol. Eac h m o del will 
ha ve ter ms f or baseli ne val ue, treat me nt gr o u p, a n d ra n d o mi zati o n strata. P oi nt esti mates a n d 9 5 % c o nfi de nce i nter vals 
will be calc ulate d base d o n ma xi m u m li keli h o o d f or t he a dj u ste d mea n c ha n ges wit hi n eac h treat me nt gr o u p as well 
as f or t he differe nces i n a dj uste d me a n c ha n ges bet wee n treat me nt gr o u ps. 
T he i nte nt-t o-treat esti ma n d ( w hic h will be esti mate d usi n g all a vaila ble data re gar dless of pre mat ure treat me nt 
disc o nti n uati o n a n d re gar dless of resc ue t hera p y i nitiati o n) will be e val uate d as t he pri m ar y esti ma n d. Missi n g val ues 
f or Wee k 2 6 will be i m p ute d usi n g a m ulti ple i m p utati o n met h o d ass u mi n g t he data are n ot missi n g at ra n d o m. 
M ulti ple i m p utati o n usi n g retrie ve d dr o p- o uts will be use d if t here is s ufficie nt data fr o m ‘retrie ve d dr o p- o uts’, defi ne d 
as s u bjects w h o disc o nti n ue d t he treat me nt ( b ut n ot t he st u d y) a n d ha d a Wee k 2 6 H b A 1c val ue. T he details of t he 
i m p utati o n met h o ds will be prese nte d i n t he statistical a nal ysis pla n.  
T o assess t he r o b ust ness of t he pri mar y efficac y a nal ysis f o r t he c ha n ge i n H b A 1c fr o m baseli ne t o Wee k 2 6, a d diti o nal 
se nsiti vit y a nal ysis ma y be perf or me d usi n g t he E val ua ble Su bjects Data Set if > 1 0 % of t he s u bjects i n a n y treat me nt 
gr o u p i n t he Ra n d o mize d S u bjects Data Set ha ve rele va nt pr ot oc ol de viati o ns. 
T he  pri mar y  e n d p oi nt  will  als o  be  c o m pare d  bet wee n  t he  l o w- d ose/ hi g h- d ose  treat me nt  re gi me n  a n d  place b o,  
se paratel y f or b ot h da pa glifl ozi n a n d sa xa gli pti n. I n a d ditio n, u p-titrati n g t o hi g h- d ose a n d c o nti n ui n g o n l o w- d ose 
will be c o m pare d i n t he s u bset of da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d H b A 1c  7 % at Wee k 1 2. T hese 
a nal yses are descri be d u n der sec o n dar y efficac y a nal yses. 
Sec o n dar y efficac y a nal yses will als o be perf or me d se parate l y f or eac h dr u g ( da pa glifl ozin a n d sa xa gli pti n). F or eac h 
dr u g, t he f oll o wi n g se q ue ntial testi n g or der will be e m pl o ye d t o c o ntr ol m ulti plicit y of testi n g f or t he sec o n dar y 
o bjecti ves. 
1.  C o m paris o n of mea n re d ucti o n i n H b A 1c fr o m baseli ne at Wee k 2 6 bet wee n  t he l o w- d ose/ hi g h- d ose treat me nt 
re gi me n a n d place b o 
2.  C o m paris o n of mea n re d ucti o n i n H b A 1c fr o m baseli ne at Wee k 2 6 bet wee n t he l o w- d ose treat me nt re gi me n a n d 
place b o 
3.  C o m paris o n of mea n re d ucti o n i n F P G fr o m baseli ne at Wee k 2 6 bet wee n o verall dr u g treat me nt (all d oses a n d 
re gi me ns c o m bi ne d) a n d place b o 
4.  C o m paris o n of mea n re d ucti o n i n F P G fr o m baseli ne at  Wee k 2 6 bet wee n t he l o w-d ose/ hi g h- d ose treat me nt 
re gi me n a n d place b o  
5.  C o m paris o n of mea n re d ucti o n i n F P G fr o m baseli ne at Wee k 2 6 bet wee n t he l o w- d ose treat me nt re gi me n a n d 
place b o 
6.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at 
Wee k 2 6 bet wee n o verall dr u g treat me nt (all d oses a n d re gi me ns c o m bi ne d) a n d place b o 
7.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at 
Wee k 2 6 bet wee n t he l o w- d ose/ hi g h - d ose treat me nt re gi me n a n d place b o 
8.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at 
Wee k 2 6 bet wee n t he l o w- d ose treat me nt regi me n a n d place b o 
9.  C o m paris o n of mea n re d ucti o n i n H b A 1 c fr o m baseli ne at Wee k 2 6 bet wee n t he hi g h- d ose a n d t he l o w- d ose i n 
s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 2 
1 0.  C o m paris o n of mea n re d ucti o n i n F P G fr o m baseli ne at  Wee k 2 6 bet wee n t he hi g h- d ose a n d t he l o w- d ose i n 
s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2 
1 1.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7. 0 % at 
Wee k 2 6 bet wee n t he hi g h- d ose a n d t he l o w- d ose i n s u bjects w h o d o n ot ac hie ve a n  H b A 1c < 7 % at Wee k 1 2 
 
F or eac h dr u g, a wei g hte d A N C O V A will be perf or me d f or t he c ha n ge fr o m baseli n e i n H b A 1c at Wee k 2 6 t o c o m pare 
t he place b o a n d t he l o w- d ose/ hi g h- d ose treat me nt re gi me n. F or t his a nal ysis, all da pa glifl ozi n a n d sa xa gli pti n s u bjects 
w h o ha d H b A 1c < 7 % at Wee k 1 2 a n d re mai ne d o n t he l o w- d ose will get a wei g ht of o ne. T he da pa glifl ozi n a n d 
sa xa gli pti n s u bjects w h o ha d H b A 1c  7 % at Wee k 1 2 a n d c o nti n ue d o n t he l o w- d ose will get a wei g ht of 0. T he 
da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d H b A 1c  7 % at Wee k 1 2 a n d recei ve d t he hi g h- d ose will get a wei g ht 
of 2. All s u bjects w h o d o n ot u n der g o t he sec o n d ra n d o mizati o n a n d all place bo s u bjects will get a wei g ht of o ne. 
F or eac h dr u g, a wei g hte d A N C O V A will be perf or me d f or t he c ha n ge fr o m baseli n e i n H b A 1c at Wee k 2 6 t o c o m pare 
t he place b o a n d t he l o w- d ose treat me nt re gi me n. F or t his a nal ysis, all da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d 
H b A 1c < 7 % at Wee k 1 2 a n d re mai ne d o n t he l o w- d ose will be get a wei g ht of o ne. T he da pa glifl ozi n a n d sa xa gli pti n 
s u bjects w h o ha d H b A 1c  7 % at Wee k 1 2 a n d c o nti n ue d o n t he l o w- d ose will get a wei g ht of 2. T he da pa glifl ozi n 
a n d sa xa gli pti n s u bjects w h o ha d H b A 1c  7 % at Wee k 1 2 a n d recei ve d t he hi g h- d ose will get a wei g ht of 0. All 
s u bjects w h o d o n ot u n der g o t he sec o n d ra n d o mizati on a n d all place b o s u bjects will get a wei g ht of o ne. 
F or s u bjects o n da pa glifl ozi n a n d sa xa gli pti n w h o ha d H b A 1c  7 % at Wee k 1 2, t he c ha n ge fr o m baseli ne H b A 1c at 
Wee k 2 6 ( S T) will be c o m pare d bet wee n t he s u bjects re-ra n d o mize d t o re mai n o n t he l o w- d ose a n d t he s u bjects w h o 
are re-ra n d o mize d t o t he hi g h- d ose us i n g a n A N C O V A. T his a nal ysis will be base d o n t he U p-titrati o n Ra n d o mize d 
S u bjects Data Set. 
 
C ha n ge fr o m baseli ne at Wee k 2 6 ( S T) i n F P G will be a nal yze d si milarl y as t he a nal yses of c ha n ge fr o m baseli ne i n 
H b A 1c at Wee k 2 6. 
T he pr o p orti o n of s u bjects ac hie vi n g H b A 1c < 7. 0 % at Wee k  2 6 ( S T) will be a nal yze d usi n g wei g hte d l o gistic 
re gressi o n wit h a dj ust me nt f or t he baseli ne H b A 1c measure me nt a n d t he ra n d o mizati o n strata. Wei g hti n g f or t he 
s u bjects will be a p plie d si milarl y t o a wei g hti n g i n t he a nalysis of c ha n ge fr o m baseli ne i n H b A 1c. S u bjects wit h 
missi n g a res p o nse at Wee k 2 6 will be i m p ute d b y dic h ot o mizi n g t he i m p ute d val ues of H b A 1c at Wee k 2 6. 
T he assess me nt of safet y will be base d o n t he a nal yses of A Es, vital si g ns, p h ysical e xa mi nati o ns, electr ocar di o gra ms, 
h y p o gl yce mia e ve nts, D K A e ve nts, safet y la b orat or y e val uati o ns, a n d meas ures of gr o wt h a n d mat urit y. Da pa glifl ozi n 
a n d sa xa gli pti n will be s u m marize d se paratel y. B ot h l o w- d ose a n d hi g h- d ose sa xa gli pti n a n d da pa glifl ozi n gr o u ps, 
res pecti vel y, will be c o m bi ne d f or sa xa gli pti n a n d da pa glifl ozi n t o pr o vi de t he safet y s u m mar y f or o verall sa xa gli pti n 
a n d o verall da pa glifl ozi n c o m pare d t o place b o. A c o m m o n place b o gr o u p will be i ncl u de d i n eac h s u m mar y.  
Meas ures of gr o wt h, b o ne, a n d mat urati o n mar kers will be  s u m marize d f or S T a n d t he c o m bi ne d S T + L T treat me nt 
peri o ds. E x pl orat or y a nal yses will be perf or me d f or o vera ll sa xa gli pti n a n d o verall da pa glifl ozi n se paratel y, b y 
c o m bi ni n g  all l o w- d ose  a n d  hi g h- d ose  treat me nt  gr o u ps  as  a p pr o priate.  All  a nal yses  will  be  c o n d ucte d  o n  t he  
Ra n d o mize d S u bjects Data Set. 
E x pl orat or y a nal yses f or t he m o n ot hera p y peri o d will i ncl u de o nl y s u bjects w h o are o n bac k gr o u n d me dicati o n wit h 
metf or mi n a n d ha ve H b A 1c meas ure me nt < 7. 5 % at Wee k 2 6 or Wee k 3 2.  
T he  m o n ot hera p y  safet y  assess me nt  will  i ncl u de  sta n dar d  safet y  assess me nts  occ urri n g  d uri n g  t he  ra n d o mize d  
wit h dra wal peri o d. T hese a nal yses will be c o n d ucte d d uri n g t he ra n d o mize d wit h dra wal peri o d usi n g t he Ra n d o mize d 
Wit h dra wal S u bject Data Set. E x pl orat or y efficac y a n d safet y a nal yses will i ncl u de s h ort a n d l o n g-ter m assess me nt 
of sa xa gli pti n a n d da pa glifl ozi n, a n d m o n ot hera p y assess me nt.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 3 
Fi g ure 4:  
S u b gr o u ps f oll o wi n g t he t hir d r a n d o miz ati o n at Wee k 3 2 or Wee k 4 0 
 
a S u bjects w h o fail t o q ualif y f or t he t hir d ra n d o mizati o n d ue t o H b A 1c ≥ 7. 5 % at Wee k 2 6 ma y q ualif y at Wee k 3 2 
if H b A 1c < 7. 5 % at Wee k 3 2. 
b S u bjects w h o meet t he eli gi bilit y criteria at Wee k 2 6 will u n der g o t he t hir d ra n d o mizati o n at Wee k 3 2, a n d 
s u bjects w h o meet t he eli gi bilit y criteria at Wee k 3 2 will u n der g o t he t hir d ra n d o mizati o n at Wee k 4 0. S u bjects w h o 
ha ve passe d Wee k 4 0 of t he st u d y will n ot be eli gi ble f or t he t hir d ra n d o mizati o n.  
 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 4 
1  I N T R O D U C TI O N A N D S T U D Y R A TI O N A L E 
T y pe  2  dia betes  is  a  c o m ple x  a n d  m ultifact oria l  meta b olic  dis or der  wit h  c o ntri b uti o ns  fr o m  
ge netic, be ha vi oral, a n d e n vir o n me ntal ris k fact or s. Des pite a wealt h of i nf or mati o n c o ncer ni n g 
T y pe 2 dia betes i n a d ults, data  u ni q ue t o t he pe diatric a ge gr ou p re gar di n g t he pat h o p h ysi ol o g y of 
a n d t hera p y f or T y pe 2 dia betes are li mite d .1 
As i n a d ults, T y pe 2 dia betes i n c hil dre n is c h aracterize d b y h y per gl yce mia ass ociate d wit h i nitial 
relati ve i ns ufficie nc y of i ns uli n secreti o n a n d i ncrease d i ns uli n resista nce, a n d is ulti matel y ofte n 
f oll o we d b y pa ncreatic β -cell fail ure.2, 3, 4 A p ote ntiall y i m p orta nt differe nce bet wee n a d ults a n d 
pe diatric patie nts wit h T y pe 2 dia betes is t hat i n t he nat ural c o urse of T y pe 2 dia betes i n pe diatric 
patie nts, t he gl uc ose d ysre g ulati o n ma y de vel o p o ver a m uc h m ore ra pi d ti me fra me t ha n is see n 
i n a d ults.5 T his ma y be a c o ntri b uti n g fact or t o t he te n de nc y f or p o orer pr o g n osis f or micr o vasc ular 
a n d macr o vasc ular dia betic c o m plicati o ns f or pe di atric patie nts wit h T y pe 2 dia betes, as t he y 
bec o me a d ults .6 A n a d diti o nal fact or u ni q ue t o t he de vel o p m e nt of T y pe 2 dia betes i n t he pe diatric 
a ge ra n ge is t he p ote ntial a d diti ve c o ntri b uti o n a n d i m pact of t h e i ns uli n resista nce of p u bert y, 
w hic h,  alt h o u g h  a  nat ural  p he n o me n o n  d uri n g  p u bert al  de vel o p me nt,  ma y  ha ve  a  ne gati ve  
i nfl ue nce o n a n d p ote ntiall y e xacer bate gl yce mic d ysre g ulati o n i n s usce pti ble c hil dre n.5  
As wit h a d ults, it is e x pecte d t hat c hil dre n a n d a d olesce nts wit h T y pe 2 dia betes are at ris k f or 
e ve nt uall y  de vel o pi n g  dia betes-relate d  micr o-  a n d  macr o vasc ular  c o m plic ati o ns  wit h  hi g her  
gl yce mic le vels .1 Data fr o m a n u m ber of s mall st u dies c o n d ucte d i n li mite d et h nic gr o u ps ha ve 
c o nfir me d  a n  i ncrease d  ris k  of  micr o vasc ular  c o m plicati o ns 1, 7 i n  pe diatric  patie nts  wit h  
T y pe  2  dia betes  c o m pare d  wit h  c hil dre n  a n d  a d olesce nts  wit h o ut  dia betes.  F or  e xa m ple,  
micr oal b u mi n uria,  macr oa l b u mi n uria,  a n d  h y perc h olester ole mia ha ve  all  s h o w n  a n  i ncrease d  
te n de nc y t o de vel o p i n Pi ma I ndia n c hil dre n wit h T y pe 2 dia b etes. A m o n g Ja pa nese pe diatric 
patie nts, reti n o pat h y has bee n o bser ve d at a si milar rate i n t h ose w it h T y pe 1 a n d T y pe 2 dia betes, 
alt h o u g h  it  a p pears  t o  be  less  c o m m o n  i n  pe diatric  patie nts  c o m pare d  wit h  a d ults  wit h  
T y pe 2 dia betes. A st u d y i n A ustralia f o u n d t hat pe diatric patie nts wit h T y pe 2 dia betes ha ve 
si g nifica ntl y hi g her rates of microal b u mi n uria a n d h y perte nsi o n t ha n  t h ose wit h T y pe 1 dia betes, 
des pite s h orter d urati o n of disease a n d l o wer gl yc os ylate d he m o gl o bi n ( H b A 1c).8 A d diti o nal s mall 
st u dies ha ve s h o w n a n i ncrease d occ urre nce of renal disease (Ja pa nese), n o n-alc o h olic fatt y li ver 
disease  (t he  Ma nit o ba  Cree),  a n d  car di o vasc ular  m ortalit y  ass ociate d  wit h  h y perte nsi o n  a n d  
d ysli pi de mia i n pe diatric patie nts wit h T y pe 2 dia betes .9 
T here is e vi de nce i n a d ults fr o m t he U K Pr os pec ti ve Dia betes St u d y ( U K P D S) t hat n or malizati o n 
of bl o o d gl uc ose s u bsta ntiall y decr eases t he fre q ue nc y of micr o vasc ular c o m plicati o ns of T y pe 2 
dia betes ( U K P D S Gr o u p 1 9 9 8), c o nsiste nt wit h w hat has bee n n ote d wit h T y pe 1 dia betes .1 0 It is 
ass u me d t hat a ma na ge me nt re gi me n base d o n a de q uate gl yce mic c o ntr ol, via lifest yle c ha n ges 
wit h m o dificati o n of diet a n d p h y sical acti vit y a n d, as a p pr o priate, me dical treat me nt, s h o ul d hel p 
t o re d uce t he ris k of c o m plicati o ns i n y o u n ger pers o ns as well as a d ults wit h t he disease. 
C urre nt t hera pe utic a ge nts ha ve li mite d efficac y a n d are ass ociate d wit h si de effects i ncl u di n g 
h y p o gl yce mia,  wei g ht  gai n,  e de ma  a n d  gastr oi ntesti nal  effects.  W hile  t here  are  se veral  oral  
gl uc ose-l o weri n g  me dicati o ns  a p pr o ve d  f or  a d u lts  wit h  T y pe  2  dia betes,  t he  o nl y  oral  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 5 
gl uc ose-l o weri n g me dicati o n a p pr o ve d  f or use i n pe diatric patie nts a ge 1 0 a n d ol der is metf or mi n. 
A ge nts wit h ne w mec ha nis ms of acti o n f or t he tr eat me nt of T y pe 2 dia b etes are bei n g st u die d. 
Gi ve n t he nee d f or a d diti o nal oral gl uc ose-l o we ri n g t hera p y o pti o ns f or pe diatric patie nts wit h 
T y pe  2  dia betes,  it  is  a p pr o priate  t o  test  t h e  h y p ot hesis  t hat  sa xa gli pti n,  a n  orall y  acti ve  
di pe pti d yl- pe pti dase- 4  ( D P P- 4)  i n hi bit or,  a n d  da pa glifl ozi n,  a n  orall y  acti ve  s o di u m  gl uc ose  
c otra ns p orter- 2  ( S G L T- 2)  i n hi b it or,  will  c o nfer  t he  t hera pe utic  be nefit  of  gl uc ose-l o weri n g,  
wit h o ut a d di n g t he ris k of h y p o gl yce mia, i n t his p o p ulati o n. I n a d diti o n, t he ris k of wei g ht gai n is 
n ot e x pecte d wit h sa xa gli pti n, w hile da pa glifl ozi n is e x pecte d t o c o nfer s o me wei g ht l oss. T his 
pr o gra m will i n vesti gate t he p har m ac o ki netics ( P K), efficac y, safet y, a n d t olera bilit y of sa xa gli pti n 
vers us place b o, a n d se paratel y, da pa glifl ozi n vers us place b o f or t he treat me nt of T y pe 2 dia betes 
i n pe diatric patie nts a ge d fr o m 1 0 t o < 1 8 years. 
1. 1  St u d y  R ati o n al e  
T his is a P hase 3 b st u d y perf or me d as part of  t he de vel o p me nt pr o gra ms f or sa xa gli pti n a n d 
da pa glifl ozi n t o i m pr o ve gl yce mic c o ntr ol as a n a dj u nct t o diet a n d e xercise a n d treat me nt wit h 
metf or mi n i m me diate release (I R) or e xte n de d release ( X R), i ns uli n, or metf or mi n (I R or X R) a n d 
i ns uli n. T his pr ot oc ol will be perf or me d t o meet t he pe diatric p ost- ma r keti n g re q uire me nts f or 
O n gl yza, K o m bi gl yze X R, Far xi ga,  a n d Xi g d u o X R as re q uire d b y t he Pe diatric Researc h E q uit y 
Act ( P R E A), a n d O n gl yza Pe di atric I n vesti gati o nal Pla n. 
Sa xa gli pti n  a n d  da pa glifl ozi n  ha ve  de m o nstrate d,  b ot h  i n di vi d ua ll y  a n d  i n  c o m bi nati o n  wit h  
i ns uli n or metf or mi n, a fa v ora ble safet y a n d t olerabilit y pr ofile i n t he a d ult de vel o p me nt pr o gra ms. 
T he y  ha ve  de m o nstrate d  a  l o w  pr o pe nsit y  f o r  h y p o gl yce mia,  a n d  b ot h  dr u gs  ha ve  eit her  
de m o nstrate d wei g ht ne utralit y (sa xa gli pti n) or m o dest wei g ht re d ucti o n ( da pa glifl ozi n). B ot h 
da pa glifl ozi n a n d sa xa gli pti n ha ve als o de m o nstrat e d persiste nt effects o n  H b A 1c o ver 2 years of 
t hera p y. Gi ve n t he nee d f or a d ditio nal oral gl uc ose-l o weri n g t hera p y o pti o ns f or pe diatric patie nts 
wit h T y pe 2 dia betes, it is a p pr o priate t o test t he h y p ot hesis t hat sa xa gli p ti n, a n orall y acti ve 
D P P- 4 i n hi bit or, a n d da pa glifl ozi n, a n orall y acti ve S G L T- 2 i n hi bit or, will  c o nfer t he t hera pe utic 
be nefit of gl uc ose-l o weri n g i n t his p o p ulati o n. 
T he a d diti o nal ra n d o mize d wit h dra wal of bac k gr o u n d me dicati o n i n a s u bset of eli gi ble patie nts 
fr o m t he treat me nt ar ms base d o n H b A 1c < 7. 5 % at Wee k 2 6 or Wee k 3 2, a n d t he s witc h t o acti ve 
treat me nt i n a s u bset of eli gi ble patie nts fr o m t he place b o ar m starti n g at Wee k 3 2 or Wee k 4 0 will 
pr o vi de i nf or mati o n o n patie nts be i n g treate d wit h m o n ot hera p y. T he H b A 1c criteria f or patie nts 
t o be i ncl u de d i n t he ra n d o mize d wit h dra wal gr o u p ( H b A 1c < 7. 5 %) is t he c urre nt H b A 1c g oal 
rec o m me n de d  b y  t he  A merica n  Dia betes  Ass ociati o n  ( A D A)  i n  dia betic  patie nts  acr oss  all  
pe diatric a ges ( A D A S O C 2 0 1 8) 1 1.  
T hr o u g h o ut t his pr ot oc ol, refere nce t o 2 6 wee ks of  treat me nt s h o ul d be i nter prete d as treat me nt 
recei ve d  u ntil  t he  Wee k  2 6  visit.  Li ke wise,  5 2  wee ks  of  treat me nt  s h o ul d  be  i nter prete d  as  
treat me nt recei ve d u ntil t he Wee k 5 2 visit. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 6 
1. 2  R e s e ar c h H y p ot h e s e s  
I n pe diatric T y pe 2 Dia betes Mellit us ( T 2 D M) s u bjects o n diet a n d e xercise a n d metf or mi n (I R or 
X R), or i ns uli n, or metf or mi n (I R or X R) a n d i ns uli n: 
 T he pri mar y researc h h y p ot hesis f or da pa glifl ozi n is w het her ad diti o n of da pa glifl ozi n res ults 
i n a greater mea n re d ucti o n fr o m baseli ne i n H bA 1c as c o m pare d t o place b o w he n eac h are 
a d mi nistere d o ver 2 6 wee ks of or al d o u ble- bli n d a d d- o n treat me nt. 
 T he pri mar y researc h h y p ot hesis f o r sa xa gli pti n is w het her a d ditio n of sa xa gli pti n res ults i n a 
greater  mea n  re d ucti o n  fr o m  base li ne  i n  H b A 1c  as  c o m pare d  t o  place b o  w he n  eac h  are  
a d mi nistere d o ver 2 6 wee ks of or al d o u ble- bli n d a d d- o n treat me nt. 
1. 3  O bj e cti v e s  
1. 3. 1  Pri m ar y  O bj e cti v e  
T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne i n H b A 1c ac hie ve d after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 1 0 m g [all d oses a n d 
re gi me ns c o m bi ne d]) or saxa gli pti n ( 2. 5 m g or 5 m g [all d oses  a n d re gi me ns c om bi ne d]) c o m pare d 
t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d 
metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
1. 3. 2  S e c o n d ar y  O bj e cti v e s  
a) T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne H b A 1c ac hie ve d after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of  da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g 
( wit h titrati o n t o t he hi g h- d ose f or t h ose w h o d o n ot ac hie ve t he gl yce mic tar get of H b A 1c 
< 7 % at 1 2 wee ks) c o m pare d t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 
6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) 
pl us i ns uli n.  
b)  T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne H b A 1c ac hie ve d after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of  da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g 
c o m pare d t o place b o i n pe diatric T 2 D M s u bjec ts wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns u li n, or metf or mi n (I R or X R) pl us i ns uli n. 
c) T o c o m pare mea n re d ucti o n fr o m baseli ne of H b A 1c at Wee k 2 6 ac hie ve d w hile re mai ni n g o n 
t he  l o w- d ose  dr u g  ( da pa glifl ozi n  5  m g  or  sa xa gli pti n  2. 5  m g)  vers us  u p-titrati o n  t o  t he  
hi g h- d ose ( da pa glifl ozi n 1 0 m g or  sa xa gli pti n 5 m g) a m o n gst pe diatric T 2 D M s u bjects o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns uli n , or metf or mi n (I R or X R) pl us i ns uli n w h o d o 
n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2. 
d)  T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m ba seli ne Fasti n g Plas ma Gl uc ose 
( F P G) ac hie ve d after 2 6 wee ks of oral d o u ble- blin d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 
1 0 m g [all d oses a n d re gi me ns c o m bi ne d]) or of sa xa gli pti n ( 2. 5 m g or 5 m g [all d oses a n d 
re gi me ns c o m bi ne d]) c o m pare d t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 
6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) 
pl us i ns uli n. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 7 
e) T o deter mi ne if t here will be a greater mea n re d ucti o n fr o m baseli ne i n F P G ac hie ve d after 2 6 
wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g ( wit h 
titrati o n t o t he hi g h- d ose f or t h ose w h o d o n ot ac hie ve t he gl yce m ic tar get of H b A 1c < 7 % at 
1 2 wee ks) c o m pare d t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n 
diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf ormi n (I R or X R) pl us i ns uli n.  
f) T o deter mi ne if t here will be a greater m ea n re d ucti o n fr o m baseli ne F P G ac hie ve d after 
2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of  da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g 
c o m pare d t o place b o i n pe diat ric T 2 D M s u bjects wit h H b A 1c le vels of 6. 5 t o 1 0. 5 % o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns u li n, or metf or mi n (I R or X R) pl us i ns uli n. 
g)  T o c o m pare mea n re d ucti o n fr o m baseli ne of F P G at Wee k 2 6 ac hie ve d w hile re mai ni n g o n 
t he  l o w- d ose  dr u g  ( da pa glifl ozi n  5  m g  or  sa xa gli pti n  2. 5  m g)  vers us  u p-titrati o n  t o  t he  
hi g h- d ose ( da pa glifl ozi n 1 0 m g or  sa xa gli pti n 5 m g) a m o n gst pe diatric T 2 D M s u bjects o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns uli n , or metf or mi n (I R or X R) pl us i ns uli n w h o d o 
n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2. 
h)  T o c o m pare t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % after 2 6 wee ks of oral d o u ble- bli n d a d d- o n t hera p y of da pa glifl ozi n ( 5 m g or 
1 0 m g [all d oses a n d re gi me ns c o m bi ne d]) or of sa xa gli pti n ( 2. 5 m g or 5 m g [all d oses a n d 
re gi me ns c o m bi ne d]) c o m pare d t o place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c le vels of 
6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) 
pl us i ns uli n. 
i) T o c o m pare t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % after 2 6 wee ks of oral d o u ble- bli nd a d d- o n t hera p y of da pa glifl ozi n 5 m g or 
sa xa gli pti n 2. 5 m g ( wit h titrati o n t o t he hi g h- d ose f or t h ose w h o d o n ot ac hie ve t he gl yce mic 
tar get of H b A 1c < 7 % at 1 2 wee ks) vers us place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c of 
6. 5 t o 1 0. 5 % o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) 
pl us i ns uli n. 
j) T o c o m pare t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % after 2 6 wee ks of oral d o u ble- blin d a d d- o n t hera p y of da pa glifl ozi n 5 m g or 
sa xa gli pti n 2. 5 m g vers us placeb o i n pe diatric T 2 D M s u bjects wi t h H b A 1c le vels of 6. 5 t o 
1 0. 5 % o n diet a n d e xercise a n d me tf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us 
i ns uli n. 
k)  T o c o m pare t he perce nta ge of pe diatric T 2 D M  s u bjects o n diet a n d e xercise a n d metf or mi n 
(I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n wit h baseli ne H b A 1c ≥ 7 %  w h o 
ac hie ve  a n  H b A 1c  le vel  <  7. 0 %  at  Wee k  2 6  w hile  re mai n i n g  o n  t he  l o w- d ose  dr u g  
( da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g) versus u p-titrati o n t o t he hi g h- d ose ( da pa glifl ozi n 
1 0 m g or sa xa gli pti n 5 m g) a m o n gst s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2. 
 
Of  n ote  sec o n dar y  o bjecti ves  wi ll  be  prese nte d  i n  hierarc hical  testi n g  or der  a n d  la bele d  
n u mericall y i n Secti o n  8. 4. 2. 2  a n d t he statistical a nal ysis pla n.  
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 8 
Fi g ure 1. 3. 2- 1:  
Sc he m atic of gr o u p c o m p aris o ns i n st u d y Pri m ar y & Sec o n d ar y 
O bjecti ves 
 
 
At t he e n d of 2 6 wee ks of i n vesti gati o nal pr o d uct (I P) a d mi nistrati o n,  st u d y partici pa nts will 
bel o n g t o o ne of f o ur s u b gr o u ps (I-I V); t he pri m ar y o bjecti ve a n d sec o n dar y o bjecti ves a t o k will 
e nc o m pass c o m paris o ns of res ults fr o m m ulti ple c o m bi nati o ns of t hese s u b gr o u ps, as sc he matize d 
a b o ve.  
1. 3. 3  S af et y  O bj e cti v e s  
 T o assess t he safet y a n d t olera bilit y, i ncl u di n g t he i nci de nce of a d verse e ve nts ( A Es) a n d 
e ve nts of h y p o gl yce mia, of da pa glifl ozi n a n d sa xa gli pti n as a d d- o n t o diet a n d e xercise a n d 
metf or mi n (I R or X R), or i ns u li n, or metf or mi n (I R or X R) pl us i ns uli n i n pe diatric T 2 D M 
s u bjects w he n a d mi nistere d f or u p t o 2 6 wee ks of s h ort-ter m ( S T) d o u ble- bli n d treat me nt, a n d, 
se paratel y, u p t o 5 2 wee ks of t otal treat me nt. 
 T o assess t he i nci de nce of dia b etic ket oaci d osis ( D K A) wit h da pa glifl ozi n a n d sa xa gli pti n as 
a d d- o n t o diet a n d e xercise a n d metf or mi n (I R or X R), or i ns uli n, or  metf or mi n (I R or X R) 
pl us i ns uli n i n pe diatric T 2 D M s u bjects w he n  a d mi nistere d f or u p t o 2 6 wee ks of S T d o u ble-
bli n d treat me nt, a n d, se paratel y, u p t o 5 2 wee ks of t otal treat me nt. 
 T o assess meas ures of gr o wt h a n d mat urit y a n d Ta n ner sta gi n g a n d mar k ers of b o ne healt h i n 
pe diatric T 2 D M s u bjects w he n a d mi nistere d da pa gl ifl ozi n or sa xa gli pti n as a d d- o n t o diet a n d 
e xercise a n d metf or mi n (I R or X R), or i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n f or u p t o 
2 6 wee ks of S T d o u ble- bli n d treat me n t, a n d, se paratel y, f or u p t o 5 2 wee ks of t otal treat me nt, 
a n d f or a n a d diti o nal 5 2 wee ks after t he st u d y has bee n c o m plete d a n d st u d y-relate d treat me nt 
has bee n disc o nti n ue d. 
 T o assess t he safet y a n d t olera bilit y of da pa glifl ozi n ( or sa xa gli pti n) m o n ot hera p y i n 
pe diatric s u bjects w h o are ra n d o mize d t o wit h dra w bac k gr o u n d metf or mi n.     
1. 3. 4  E x pl or at or y  O bj e cti v e s  
 T o c o m pare t he perce nta ge of s u bjects re q uiri n g gl yce mic resc ue me dicati o n or disc o nti n ui n g 
st u d y  me dicati o n  d ue  t o  lac k  of  efficac y  wit h da pa glifl ozi n  or  sa xa gli pti n  a gai nst  t he  
perce nta ge wit h place b o d uri n g 2 6 wee ks of or al d o u ble- bli n d a d d- o n treat me nt i n pe diatric 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
2 9 
T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet  a n d e xercise a n d metf or mi n (I R or X R), 
i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
 T o  assess  ti me  t o  i nitiati o n  of  gl yce mic  re sc ue  me dicati o n  or  disc o nti n uati o n  of  st u d y  
me dicati o n d ue t o lac k of effi cac y wit h da pa glifl ozi n, sa xa gli pti n, or place b o d uri n g t he 
2 6- wee k S T treat me nt peri o d a n d d uri n g t he 5 2 - wee k S T + L T treat me nt peri o d i n pe diatric 
T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet  a n d e xercise a n d metf or mi n (I R or X R), 
i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n.  
 T o assess t he mea n c ha n ge fr o m baseli ne i n H b A 1 c ac hie ve d wit h da pa glifl ozi n t hera p y vers us 
place b o, a n d se paratel y, ac hie ve d wit h sa xa gli pti n  t hera p y vers us place b o after 5 2 wee ks of 
oral bli n de d a d d- o n treat me nt i n  pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns u li n, or metf or mi n (I R or X R) pl us i ns uli n.  
 T o assess t he mea n c ha n ge fr o m baseli ne i n F P G  ac hie ve d wit h da pa glifl ozi n t hera p y vers us 
place b o, a n d se paratel y, ac hie ve d wit h sa xa gli pti n t hera p y vers us place b o after 5 2 wee ks of 
oral bli n de d a d d- o n treat me nt i n  pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % o n diet 
a n d e xercise a n d metf or mi n (I R or X R), i ns u li n, or metf or mi n (I R or X R) pl us i ns uli n. 
 T o  assess  t he  perce nta ge  of  s u bjects  wit h  baseli ne  H b A 1c  ≥ 7 %  w h o  ac hie ve  a n  
H b A 1c le vel < 7. 0 % after 5 2 wee ks of oral bli n de d a d d- o n t hera p y wit h da pa glifl ozi n vers us 
place b o, or sa xa gli pti n vers us place b o i n pe diatric T 2 D M s u bjects wit h H b A 1c of 6. 5 t o 1 0. 5 % 
o n diet a n d e xercise a n d metf or mi n (I R or X R), i ns uli n, or metf or mi n (I R or X R) pl us i ns uli n. 
 T o  assess  t he  effect  of  m o n ot hera p y  of  da pa g lifl ozi n  t hera p y  (a n d  separatel y  sa xa gli pti n  
t hera p y)  f or  s u bjects  ra n d o mize d  t o  wit h dra w  bac k gr o u n d  metfor mi n  relati ve  t o  
da pa glifl ozi n + metf or mi n
 (a n d
 se paratel y
 sa xa gli pti n + metf or mi n)
 a n d
 relati ve
 t o
 
place b o + metf or mi n d uri n g t he ra n d o mize d wit h dra wal peri o d usi n g c ha n ge i n H b A 1c, c ha n ge 
i n F P G, ac hie ve me nt of t hera pe utic gl yce mic res p o nse ( H b A 1c < 7 %), a n d ti me t o resc ue or 
disc o nti n uati o n d ue t o lac k of  gl yce mic c o ntr ol.     
1. 3. 5  P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c O bj e cti v e 
 T o  e x pl ore  t he  P K  a n d  e x p os ure-res p o nse  rela ti o ns hi p  of  da pa glifl ozi n  a n d,  se paratel y,  
sa xa gli pti n a n d its metab olite 5- h y dr o x y-sa xa gli pti n ( 5- O H-sa xa gli pti n), i n s u bjects a ge d 1 0 
t o bel o w 1 8 years wit h T 2 D M base d o n t he c ollecti o n of p o p ulati o n P K sa m ples. 
1. 4  Pr o d u ct D e v el o p m e nt B a c k gr o u n d 
Sa xa gli pti n  ( B M S- 4 7 7 1 1 8)  is  a  hi g hl y  p ote nt,  selecti ve,  re versi b le,  a n d  c o m petiti ve  
D P P- 4 i n hi bit or.  Di pe pti d yl- pe p ti dase- 4  is  t he  e nz y me  res p o nsi ble  f or  t he  i nacti vati o n  of  
gl uca g o n-li ke pe pti de- 1 ( G L P- 1) a n d gl uc ose- de pe n de nt i ns uli n otr o pic p ol y pe p ti de. B y i n hi biti n g 
t he e nz y me D P P- 4, sa xa gli pti n p ote ntiates acti ve e n d o ge n o us G L P- 1 c o nce ntrati o ns, a u g me nti n g 
t he  p h ysi ol o gical  mec ha nis m  of  i ns uli n  secreti o n  a n d  s u p pressin g  gl uca g o n  release,  t here b y  
re d uci n g p ost pra n dial a n d fasti n g gl uc ose le vels i n patie nts wit h T 2 D M. 
T he  res ults  fr o m  t he  a d ult  sa xa gli pti n  de ve l o p me nt  pr o gra m  s u p p ort  t he  oral  d ose  of  
sa xa gli pti n 5 m g o nce dail y i n a wi de ra n ge of patie nts wit h T 2 D M, as eit her m o n ot hera p y, a d d- o n 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 0 
c o m bi nati o n t hera p y wit h metf or mi n, a t hiaz oli di ne di o ne, a s ulf o n yl urea ( S U), i ns uli n, or i nitial 
c o m bi nati o n  t hera p y  wit h  metf or mi n.  T he  res ults  fr o m  t he  a d ult  P has e  3  st u dies  c o nfir me d  
cli nicall y mea ni n gf ul be nefits of sa xa gli pti n 5 m g o n H b A 1c, as well as F P G, p ost pra n dial gl uc ose 
( P P G), i ns uli n, C- pe pti de, a n d gl uca g o n le vels. I n a n e xte nsi ve P hase 2 b/ 3 pr o gra m, m ost re p orte d 
A Es were n o n-seri o us a n d di d n o t re q uire disc o nti n uati o n of treat me nt. T he safet y pr ofile was 
c o m para ble t o place b o a n d ge nera ll y c o nsiste nt w he n sa xa gli pti n was gi ve n as m o n ot hera p y, as 
a d d- o n c o m bi nati o n treat me nt t o metf or mi n, t o i ns uli n ( wit h or  wit h o ut bac k gr o u n d metf or mi n), 
a n d as i nitial t hera p y i n c o m bi nati o n wit h metf or mi n. Treat me nt wit h sa xa gli pti n le d t o rates of 
h y p o gl yce mia t hat were ge nerall y si milar c o m pare d t o place b o, e xce pt i n c o m bi nati o n wit h i ns uli n 
or a n S U.  
Da pa glifl ozi n is a rati o nall y desi g ne d, sta ble, c o m p etiti ve, re versi ble, hi g hl y selecti ve a n d orall y 
acti ve i n hi bit or of S G L T- 2, t he maj or tra ns p orter res p o nsi ble f or re nal gl uc ose rea bs or pti o n. 
Da pa glifl ozi n i n hi bits h u ma n S G L T- 2 ( Ki = 0. 5 5 n M) selecti vel y ( 1 4 0 0- f ol d selecti ve), a n d is als o 
hi g hl y selecti ve vers us ot her faci litati ve gl uc ose tra ns p orters. Da paglifl ozi n’s mec ha nis m of acti o n 
is differe nt a n d c o m ple me ntar y t o t he mec ha nis ms of c urre ntl y a vaila ble a nti dia betic me dici nes, 
res ulti n g i n t he direct a n d i ns uli n-i n de pe n de nt eli mi nati o n of gl uc ose b y t he ki d ne y. F urt her, as 
S G L T- 2 is al m ost e xcl usi vel y e x presse d i n t he ki d ne y, t he hi g hl y selecti ve nat ure of da pa glifl ozi n 
mi ni mizes  t he  ris k  of  off  tar get  (i.e.,  n o n- ki d ne y )  effects.  As  s uc h,  da pa glifl ozi n  offers  a n  
i m p orta nt a d diti o nal strate g y f or i m pr o vi n g gl yce mic c o ntr ol i n patie nts wit h T 2 D M. 
Da pa glifl ozi n has bee n s h o w n t o be effecti ve i n l o weri n g H b A 1c i n a d ult patie nts wit h T 2 D M, 
w he n st u die d as m o n ot hera p y a n d i n c o m bi nati o n wit h i ns uli n or oral a nti dia betic me dicati o ns. 
Res ults fr o m sec o n dar y gl yce mic efficac y e n d p oi nts (i ncl u di n g F P G, 2- h o ur P P G, a n d c ha n ge i n 
H b A 1c i n patie nts wit h baseli ne H b A 1c  9. 0 %) are c o nsiste nt wit h t he mai n H b A 1c res ults a n d 
f urt her s u p p ort t he r ole of da pa glifl ozi n as a gl uc ose-l o weri n g a ge nt. I m p orta ntl y, da pa glifl ozi n 
has  bee n  s h o w n  t o  i m pr o ve  gl yce mic  c o ntr ol  wit h  a  l o w  i ntri nsic  ris k  f or  h y p o gl yce mia.  
F urt her m ore, t he stea d y e xcreti o n of gl uc ose d ue t o S G L T- 2 i n hi biti o n res ults i n a c o nti n ual l oss 
of cal ories t hat ulti matel y lea d s t o a decrease i n wei g ht a n d a di p osit y. T he i n hi biti o n of s o di u m 
a n d gl uc ose tra ns p ort i n t he pr o xi mal t u b ule als o ca us es a mil d di uretic effe ct, lea di n g t o a m o dest 
l o weri n g of bl o o d press ure ( B P). O verall, da pa glifl ozi n has bee n s h o w n t o i m pr o ve H b A 1c wit h a 
l o w ris k of h y p o gl yce mia, w hile als o de m o nstrati n g p ositi ve tre n ds f or c o m m o n c o m or bi dities 
( wei g ht gai n a n d s yst olic h y perte nsi o n) ass ociate d wit h i ncrease d car di o vasc ular ris k i n T 2 D M 
a d ult patie nts. 
1. 5  O v er all  Ri s k/ B e n efit  A s s e s s m e nt  
Da pa glifl ozi n a n d sa xa gli pti n, ha ve bee n a p pr o ve d as a nti dia betic a ge nts i n ma n y c o u ntries, 
i ncl u di n g t he U nite d States ( U S) a n d t he E ur o pea n U ni o n f or use i n a d ults a n d c hil dre n wit h 
T 2 D M. 
E val uati o n of t he cli nical safet y a n d efficac y da ta acc u m ulate d i n dicates a p ositi ve ris k/ be nefit 
pr ofile f or da pa glifl o zi n a n d sa xa gli pti n. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 1 
S a x a gli pti n 
Pri or t o a p pr o val, sa xa gli pti n was e val uate d i n 6 c ore P hase 3, ra n d o mize d, d o u ble- bli n d c o ntr olle d 
trials. C o m pare d t o c o ntr ol, treat me nt wit h sa xa gli pti n at d oses of 2. 5 m g t o 1 0 m g res ulte d i n 
cli nicall y rele va nt a n d statisticall y si g nifica nt i m pr o ve me nts i n H b A 1c, F P G, a n d 2 h o ur P P G. 
Re d ucti o ns i n H b A 1c were see n acr oss s u b gr o u ps i ncl u di n g a ge, ge n der, race a n d baseli ne b o d y 
mass i n de x ( B MI). 
O verall, sa xa gli pti n has bee n well t olerate d i n cl i nical st u dies. T he maj orit y of A Es re p orte d i n 
cli nical st u dies ha ve bee n of mil d i nte nsit y a n d fe w ha ve re q uire d tr eat me nt disc o nti n uati o n. 
F or a n o verall ris k/ be nefit assess me nt of sa xa gl i pti n, see t he I n vesti gator’s Br oc h ure/ pac ka ge 
leaflet. 
D a p a glifl ozi n 
Pri or t o a p pr o val, da pa glifl ozi n was e val uate d i n  5 c ore P hase 2 b st u dies, 1 6 c ore P hase 3 st u dies, 
a n d 3 re gi o nal P hase 3 st u dies. T hese st u dies esta b lis he d t hat da pa glifl ozi n is effecti ve i n re d uci n g 
H b A 1c i n a br oa d ra n ge of s u bjects, re gar dless of  disease pr o gressi o n/ d urati o n or c o nc o mita nt use 
of  a nti dia betic  t hera pies.  Da pa glifl ozi n  c o nsiste ntl y  de m o nstrate d  statisticall y  a n d  cli nicall y  
si g nifica nt mea n re d ucti o ns i n H b A 1c vers us place b o a m o n g t he t hree d oses t y picall y st u die d 
( 2. 5 m g, 5, m g a n d 1 0 m g). O verall, t he d ose of 1 0 m g pr o vi de d better efficac y t ha n t he t w o l o wer 
d oses. Effects o n sec o n dar y gl y ce mic efficac y para meters, i n cl u di n g F P G a n d P P G, s u p p ort t he 
pri mar y H b A 1c efficac y fi n di n gs. Da pa glifl ozi n als o res ulte d i n a m o dest re d ucti o n i n t otal b o d y 
wei g ht relati ve t o place b o or c o m parat or, lar gel y attri b uta ble t o  a decrease i n b o d y fat mass, as 
well as re d ucti o ns i n s yst olic B P. Place b o-c o ntr o lle d data f or u p t o 2 years i n dicate t hat t he 
be neficial effects o n gl yce mic a n d n o n- gl yce mic para meters were mai ntai ne d. 
O verall, da pa glifl ozi n has bee n well t olerate d i n cli nical st u dies. 
F or a n o verall ris k/ be nefit assess me nt of da pa glifl ozi n, see t he I n vesti gat or’s Br oc h ure/ pac ka ge 
leaflet. 
2
 E T HI C A L
 C O N SI D E R A TI O N S
 
2. 1  G o o d Cli ni c al Pr a cti c e 
T his st u d y will be c o n d ucte d i n acc or da nce wit h G o o d Cli nical Practice ( G C P), as defi ne d b y t he 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) a n d i n acc or da nce wit h t he et hical pri nci ples 
u n derl yi n g  E ur o pea n  U ni o n  Directi ve  2 0 0 1/ 2 0/ E C  a n d  t he  U nite d  States  C o de  of  Fe deral  
Re g ulati o ns, Title 2 1, Part 5 0 ( 2 1 C F R 5 0). 
T he st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol. T he pr ot oc ol a n d a n y a me n d me nts 
a n d t he s u bject i nf or me d c o nse nt will recei ve I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics 
C o m mittee (I R B/I E C) a p pr o val/fa v ora ble o pi ni o n pri or t o i nitiati o n of t he st u d y. 
All p ote ntial seri o us breac hes m u st be re p orte d t o t he S p o ns or/ desi g nee i m me diatel y. A seri o us 
breac h is a breac h of t he c o n diti o ns a n d pri nci ples of G C P i n c o n necti o n wit h t he st u d y or t he 
pr ot oc ol, w hic h is li kel y t o affect , t o a si g nifica nt de gree, t he safet y or p h ysical or me ntal i nte grit y 
of t he s u bjects of t he st u d y or t he scie ntific val ue of t he st u d y. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 2 
Pers o n nel  i n v ol ve d  i n  c o n d ucti n g  t his  st u d y  will  be  q ualifie d  b y  e d ucati o n,  trai ni n g,  a n d  
e x perie nce t o perf or m t heir res pecti ve tas ks. 
T his st u d y will n ot use t he ser vices of st u d y pers o n nel w here sa ncti o ns ha ve bee n i n v o ke d or w here 
t here has bee n scie ntific misco n d uct or fra u d (e. g., l oss of me dical lice ns ure, de bar me nt).  
2. 2  I n stit uti o n al  R e vi e w  B o ar d/I n d e p e n d e nt Et hi c s C o m mitt e e  
Bef ore st u d y i nitiati o n, t he I n vesti gat or m ust ha ve writte n a n d date d a p pr o val/fa v ora ble o pi ni o n 
fr o m  t he  I R B/I E C  f or  t he  pr ot oc ol,  c o nse nt  f or m,  s u bject  recr uit me nt  materials  
(e. g.,  a d vertise me nts),  a n d  a n y  ot her  writte n  i nf or mati o n  t o  be  pr o vi de d  t o  s u bjects.  T he  
I n vesti gat or or S p o ns or/ desi g nee s h o ul d als o pr o vi de t he I R B/I E C wit h a c o p y of t he I n vesti gat or 
Br oc h ure or pr o d uct la beli n g i n f or mati o n t o be pr o vi de d t o s u bjects a n d a n y u p dates. 
T he I n vesti gat or or S p o ns or/ de si g nee s h o ul d pr o vi de t he I R B/I E C wit h re p orts, u p dates a n d ot her 
i nf or mati o n (e. g., e x pe dite d safet y re p orts, a me n d me nts, a n d a d mi nistrati ve letters) acc or di n g t o 
re g ulat or y re q uire me nts or i nstit uti o n pr oce d ures. 
2. 3  I nf or m e d  C o n s e nt  
I n vesti gat ors m ust e ns ure t hat s u bjects are clearl y a n d f ull y i nf or me d ab o ut t he p ur p ose, p ote ntial 
ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hich t he y v ol u nteer t o partici pate. 
I n sit uati o ns w here c o nse nt ca n n ot be gi ve n t o su bjects, t heir le gall y acce pta ble re prese ntati ves (as 
per c o u ntr y g ui deli nes) are clearl y  a n d f ull y i nf or me d a b o ut t he p urp ose, p ote ntial ris ks, a n d ot her 
critical iss ues re gar di n g cli nical st u dies i n w hic h t he s u bject v ol u nt eers t o partici pate. 
T he S p o ns or/ desi g nee will pr o vi de t he I n vesti gat or wit h a n a p pr o priate (i.e., Gl o bal or L ocal) 
sa m ple  i nf or me d  c o nse nt  f or m  w hic h  will  i ncl u de  all  ele me nts  re q uire d  b y  I C H,  G C P  a n d  
a p plica ble re g ulat or y re q uire me nts. T he sa m ple i n f or me d c o nse nt f or m will a d here t o t he et hical 
pri nci ples t hat ha ve t heir ori gi n  i n t he Declarati o n of Helsi n ki. 
I n vesti gat ors m ust: 
1)  Pr o vi de a c o p y of t he c o nse nt f or m  a n d writte n i nf or mati o n a b o ut t he st u d y i n t he la n g ua ge i n 
w hic h t he s u bject is pr oficie nt  pri or t o cli nical st u d y partici pati o n. T he la n g ua ge m ust be 
n o n-tec h nical a n d easil y u n derst o o d.  
2)  All o w ti me necessar y f or s u bject or s u bject’s le gall y acce pta ble re prese ntati ve t o i n q uire a b o ut 
t he details of t he st u d y. 
3)  O btai n a n i nf or me d c o nse nt si g ne d a n d pers o nall y date d b y t he s u bject or t he s u bject’s le gall y 
acce pta ble re prese ntati ve a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. 
4)  O btai n t he I R B/I E C’s writte n a p pr o val/fa v ora ble  o pi ni o n of t he writte n i nf or me d c o nse nt f or m 
a n d a n y ot her i nf or mati o n t o be pr o vi de d t o t h e s u bjects, pri or t o t he be gi n ni n g of t he st u d y, 
a n d after a n y re visi o ns are c o m plete d f or ne w i nf or mati o n. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 3 
5)  If i nf or me d c o nse nt is i nitiall y gi ve n b y a s u bject’s le gall y acce pta ble re prese ntati ve or le gal 
g uar dia n, a n d t he s u bject s u bse q ue ntl y bec o me s ca pa ble of ma ki n g an d c o m m u nicati n g his or 
her i nf or me d c o nse nt d uri n g t he st u d y, c o nse nt m ust a d diti o nall y be o btai ne d fr o m t he s u bject. 
6)  Re vise t he i nf or me d c o nse nt w he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat is 
rele va nt t o t he s u bject’s c o nse nt. T he I n vesti gat or, or a perso n desi g nate d b y t he I n vesti gat or, 
s h o ul d f ull y i nf or m t he s u bject or t he s u bject’s le gall y acce pta ble re prese ntati ve or le gal 
g uar dia n of all perti ne nt as pect s of t he st u d y a n d of a n y ne w i nf or mati o n rele va nt t o t he 
s u bject’s willi n g ness t o c o ntin ue partici pati o n i n t he st u d y. T his c o m m u nicati o n s h o ul d be 
d oc u me nte d. 
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y s u bjects m ust be pr otecte d, res pecti n g t he pri vac y 
a n d c o nfi de ntialit y r ules a p plica ble t o re g ulat or y re q uire me nts, t he s u bject’s si g ne d i nf or me d 
c o nse nt  f or m  a n d  w here  a p plica ble  t he  s u bject’s  si g ne d  Healt h  I ns ura nce  P orta bilit y  a n d  
Acc o u nta bilit y Act of 1 9 9 6 ( HI P A A) A ut h orizati o n. S u bjects will be  assi g ne d a u ni q ue i de ntifier 
b y t he S p o ns or. A n y s u bject rec or ds or datasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n t he 
i de ntifier o nl y; s u bject na mes or a n y i nf or mati on w hic h w o ul d ma ke t he s u bject i de ntifia ble will 
n ot be tra nsferre d. T he s u bject m u st be i nf or me d t hat his/ her pers o nal st u d y-relate d data will be 
use d b y t he S p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure a n d use 
of t heir data m ust als o be e x plai ne d t o t he s u bj ect i n t he i nf or me d c o nse nt f or m. T he s u bject m ust 
be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y Cli nical Q ualit y Ass ura nce a u dit ors 
or ot her a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y a p pr o priate I R B/I E C me m bers, a n d b y 
i ns pect ors fr o m Re g ulat or y A ut h orities. T he c o nse nt f or m m ust als o i ncl u de a state me nt t hat t he 
S p o ns or/ desi g nee a n d Re g ulat or y A ut h orities ha ve direct access t o  s u bject rec or ds. 
F or mi n ors, acc or di n g t o l ocal le gisl ati o n, o ne or b ot h pare nts or a le gall y acce pta ble re prese ntati ve 
m ust be i nf or me d of t he st u d y pr oce d ures a n d m u st si g n t he i nf or me d c o nse nt f or m a p pr o ve d f or 
t he st u d y pri or t o cli nical st u d y partici pati o n. T he e x plicit wis h of a mi n or, w h o is ca pa ble of 
f or mi n g a n o pi ni o n a n d assessi n g t his i nf or mati o n t o ref use partici pati o n i n, or t o be wit h dra w n 
fr o m, t he cli nical st u d y at a n y ti me sh o ul d be c o nsi dere d b y t he I n vesti gat or. 
Mi n ors w h o are j u d ge d t o be of a n a ge of re as o n m ust als o gi ve t heir writte n asse nt. 
S u bjects u na ble t o gi ve t h eir writte n c o nse nt ma y o nl y be e nr olle d i n t he st u d y wit h t he c o nse nt of 
a le gall y acce pta ble re prese ntati ve. T he s u bject m ust als o be i nf or m e d a b o ut t he nat ure of t he st u d y 
t o t he e xte nt c o m pati ble wit h his or her u n dersta n di n g, a n d s h o ul d t his s u bject bec o me ca pa ble, he 
or s he s h o ul d pers o nall y si g n a n d da te t he c o nse nt f or m as s o o n as p ossi ble. T he e x plicit wis h of 
a s u bject w h o is u na ble t o gi ve his or her writte n c o nse nt, b ut w h o is ca pa ble of f or mi n g a n o pi ni o n 
a n d assessi n g i nf or mati o n t o ref use  partici pati o n i n, or t o be with dra w n fr o m, t he cli nical st u d y at 
a n y ti me s h o ul d be c o nsi dere d b y t he I n vesti gat or. 
S u bjects w h o are re-scree ne d are re q uire d t o si g n a ne w i nf or me d c o nse nt f or m. 
T he ri g hts, safet y, a n d well bei n g of t he st u d y s u bjects are t he m ost i m p orta nt c o nsi derati o ns a n d 
s h o ul d pre vail o ver i nterests of scie nce a n d s ociet y. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 4 
2. 4  H a n dli n g of H u m a n Bi ol o gi c al S a m pl e s 
A f ull c hai n of c ust o d y is mai ntai ne d f or all sa m p les t hr o u g h o ut t heir lifec ycle. T he i n vesti gat or 
at eac h site kee ps f ull tracea bilit y of c ollecte d bi ol o gical sa m ples fr o m t he s u bjects w hile i n st ora ge 
at  t he  site  u ntil  s hi p me nt  or  dis p osal/ destr ucti o n  ( w here  a p pr o priate)  a n d  rec or ds  rele va nt  
pr ocessi n g i nf or mati o n relate d t o t he sa m ples w hilst at site.  
T he sa m ple recei ver kee ps f ull tracea bilit y of t he sa m ples w hile i n st ora ge a n d d uri n g use u ntil 
use d or dis p ose d/ destr o ye d of or u ntil f urt her s h i p me nt a n d kee ps rec or d of recei pt of arri val a n d 
o n war d  s hi p me nt  or  dis p osal/ destr o ye d.  Astra Ze neca  or  dele gate d  re prese ntati ves  will  kee p  
o versi g ht of t he e ntire life c ycle t hr o u g h i nter nal pr oce d ures, m o nit ori n g of st u d y sites, a u diti n g or 
pr ocess c hec ks, a n d c o ntract ual re q uire me nts of e xter nal la b orat or y pr o vi ders. Sa m ples retai ne d 
f or f urt her use will be st ore d i n t he Astra Ze neca-assi g ne d bi o ba n ks or ot her sa m ple arc hi ve 
facilities a n d will be trac ke d b y t he a p pr o priate Astra Ze neca Tea m d uri n g f or t he re mai n der of t he 
sa m ple life c ycle. 
3
 I N V E S TI G A TI O N A L
 P L A N
 
3. 1  St u d y D e si g n a n d D ur ati o n 
T he st u d y start date is t he date o n  w hic h t he cli nical st u d y will be o pe n f or recr uit me nt of s u bjects. 
T he first act of recr uit me nt is t he first site o pe n a n d will be t he st u d y start date. T hr o u g h o ut t his 
pr ot oc ol, refere nce t o 2 6 wee ks of treat me nt s h o ul d be i nter pre te d as treat me nt recei ve d u ntil t he 
Wee k 2 6 visit. Li ke wise, 5 2 wee ks of treat me nt s h o ul d be i nter prete d as treat me nt recei ve d u ntil 
t he Wee k 5 2 visit. 
T he  pr o p ose d  st u d y  is  a  2 6- wee k  P hase  3 b,  m u ltice nter,  ra n d o mize d,  place b o-c o ntr olle d,  
d o u ble- bli n d, parallel- gr o u p, st u d y wit h a 2 6- wee k safet y e xte nsi o n peri o d t o e val uate t he safet y 
a n d efficac y of da pa glifl ozi n ( 5  m g a n d 1 0 m g), a n d, se paratel y, sa xa gli pti n ( 2. 5 m g a n d 5 m g) i n 
pe diatric s u bjects wit h T 2 D M a n d a n a d diti o na l p ost-st u d y visit at Wee k 1 0 4 f or assess me nt of 
meas ures of gr o wt h a n d mat urit y. A p pr o xi matel y  2 4 3 pe diatric s u bjects will be ra n d o mize d i n 
a
 
1: 1: 1
 rati o
 t o
 recei ve
 da pa glifl ozi n
 5
 m g,
 sa xa gli pti n
 2. 5
 m g,
 or
 place b o.
 
A p pr o xi matel y 8 1 s u bjects will be ra n d o mize d t o eac h treat me nt ar m. 
T he pri mar y efficac y e n d p oi nt will be assesse d at t he e n d of t he i nitial 2 6- wee k, d o u ble- bli n d, 
treat me nt peri o d (referre d t o as t he s h ort-ter m [ S T] peri o d [fr o m Da y 1 t o e n d of Wee k 2 6]). T he 
S T peri o d will be f oll o we d b y a 2 6- wee k, d o u ble- bli n d safet y e xte nsi o n peri o d (t he l o n g-ter m [ L T] 
peri o d [fr o m Wee k 2 7 t o e n d of Wee k 5 2]). Da pa glifl ozi n a n d, se paratel y, sa xa gli pti n, will be 
c o m pare d a gai nst t he si n gle s hare d place b o c o m par at or. Safet y m o nit ori n g will c o nti n ue f oll o wi n g 
t he Wee k 5 2 e n d- of-treat me nt visit u ntil t he Wee k 1 0 4 p ost-st u d y visit.  
Meas ures of gr o wt h a n d mat urit y will be  assesse d at t he Wee k 1 0 4 p ost-st u d y visit.  
Scree ni n g pr oce d ures are e x pecte d t o last 6 t o 8 wee ks. If, h o we ver, at i nitial scree ni n g, o ne or 
m ore la b orat or y val ues are n ot i n t he eli gi bilit y ra n ge, b ut t he I n vesti gat ors deter mi ne t he y are 
a me na ble t o c orrecti o n wit hi n a reas o na ble ti me fra me, t he scree ni n g peri o d ca n be e xte n de d t o a 
ma xi m u m  of  6  m o nt hs.  At  scree ni n g,  all  scre e ni n g  pr oce d ures  a n d  assess me nts  s h o ul d  be  
c o m plete d a n d re vie we d b y t he I n vesti gat ors. Re testi n g/reassess me nt of faile d varia bles ca n be 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 5 
perf or me d  as  deter mi ne d  b y  t he  I n vesti gat ors  d uri n g  t he  6- m o nt h  scree ni n g  peri o d.  
Retesti n g/reassess me nt fre q ue ncies are at t he discreti o n of t he I n ve sti gat ors, b ut s h o ul d occ ur at 
least o nce e ver y 3 m o nt hs. I n cases w he n a s u bject d oes n ot meet o ne or m ore criteria t he first ti me 
a n d is later reassesse d t o see if he/s he will meet t h at criteria, t he I n vesti gat or s h o ul d e ns ure t hat 
ot her criteria are still met (a n d ha ve n ot bec o me dis q ualif yi n g d uri n g t he i nteri m ti me peri o d) 
bef ore  acce pti n g  t hat  t he  s u bjec t  meets  all  eli gi bilit y  criteria.  S u bjects  w h o  fail  t o  meet  t he 
eli gi bilit y criteria after t he 6- m o nt h scree ni n g peri o d s h o ul d be c o nsi dere d as scree n fail ures a n d 
wit h dra w n fr o m t he st u d y. Scree n-faile d s u bjects , h o we ver, ca n be re-scree ne d a ma xi m u m of t w o 
m ore ti mes at a later ti me. F or re-scree ni n g, s u bject s m ust be re-c o nse nte d a n d all t he scree ni n g 
pr oce d ures m ust be re peate d. S u bj ects are n ot a ble t o be re-scree n e d if t he y t ur n 1 8 years of a ge 
d uri n g t he scree ni n g peri o d.  
Pri or t o ra n d o mizati o n o n Da y 1, s u bjects will be re q uire d t o ha ve  bee n treate d wit h diet a n d 
e xercise a n d sta ble d ose of at least 1 0 0 0 m g metf or mi n (I R or X R) f or a mi ni m u m of 8 wee ks, or 
a sta ble baseli ne d ose of i ns uli n f or a mi ni m u m of 8 wee ks, or a sta ble c o m bi nati o n of at least 
1 0 0 0 m g metf or mi n (I R or X R) a n d i ns uli n f or a mi n i m u m of 8 wee ks. At least 5 0 % of s u bjects 
will be o n a sta ble baseli ne d ose of  metf or mi n, wit h or wit h o ut c o ncurre nt i ns uli n t hera p y. At least 
3 0 % of t otal s u bjects will be be t wee n t he a ges of 1 0 a n d 1 4 years a n d at least o ne t hir d, b ut n o 
m ore t ha n t w o t hir ds, fe male s u bjects. 
D uri n g t he 2- wee k lea d-i n peri o d, s u bjects will be i nstr ucte d o n a diet a n d e xercise pr o gra m 
(i n acc or da nce wit h t he A D A or si milar l ocal g ui deli nes) t o be f oll o we d f or t he st u d y d urati o n. 
S u bjects will mai ntai n t heir ba seli ne t y pes a n d/ or d oses of a nti dia betic t hera p y t hr o u g h o ut t he 
st u d y ( 2- wee k lea d-i n, 2 6- wee k d o u ble- bli n d S T treat me nt peri o d, a n d t he 2 6- wee k bli n de d safet y 
e xte nsi o n L T treat me nt peri o d), u nless t he y are ra n d o mize d t o wit h dra w bac k gr o u n d me dicati o n 
wit h metf or mi n at Wee k 3 2 or Wee k 4 0, u ntil Wee k 5 2. If a p plica ble, i n vesti gat ors will e nc o ura ge 
s u bjects t o kee p t heir i ns uli n d oses sta ble. D ow n-titrati o n of i ns uli n will be all o we d o nl y as 
necessar y t o pre ve nt h y p o gl yce mia a n d will be at t he discreti o n of t he I n vesti gat or. I ns uli n ma y 
be u p-titrate d or a d de d as resc ue as warra nte d b y a h y per gl yce mic state. H o me gl uc ose meters t o 
m o nit or  gl uc ose  c o ntr ol  will  be  dis pe nse d  t o  s u bjects  a n d  self- bl o o d  gl uc ose  m o nit ori n g  
re q uire me nts a n d pr oce d ures will be e x plai ne d. S u bjects will als o be i nstr ucte d o n t he use of t he 
s u bject diar y t o rec or d self- m o nit ori n g gl uc ose le vels a n d dail y i ns uli n d ose, if a p plica ble. S u bjects 
will als o recei ve a bl o o d ket o ne mete r f or testi n g w he n D K A is s us pecte d. 
After t he lea d-i n peri o d, eli gi ble s u bjects wit h  H b A 1c of 6. 5 % t o 1 0. 5 % at scree ni n g will be 
ra n d o mize d 1: 1: 1 t o recei ve oral, d o u ble- bli n d, da pa glifl ozi n 5 m g (a p pr o xi matel y 8 1 s u bjects), 
sa xa gli pti n 2. 5 m g (a p pr o xi matel y 8 1 s u bjects), or place b o (ap pr o xi matel y 8 1 s u bjects). Da y 1 
Ra n d o mizati o n will be stratifie d base d o n baseli ne a nti- dia betes treat me nt re gi me n (sta ble baseli ne 
d ose of metf or mi n (I R or X R), a st a ble baseli ne d ose of i ns uli n, or a sta ble baseli ne c o m bi nati o n 
of metf or mi n (I R or X R) a n d i ns uli n), ge n der, a n d a ge ( 1 0 t o bel o w 1 5 years of a ge, 1 5 t o 
bel o w 1 8 years of a ge).  
S u bjects will be i nstr ucte d t o i n ge st t w o bli n de d ta blets dail y, as per Ta ble 3. 1- 1.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 6 
T a ble 3. 1- 1:  
Tre at me nt Peri o d t o Wee k 1 4 
T a blet c o m p o ne nts b ase d o n tre at me nt ar m assi g n me nt 
S u bjects ra n d o mize d t o 
Da pa glifl ozi n 5 m g ar m recei ve: 
Acti ve Da pa glifl ozi n 5 m g ta blet  
Sa xa gli pti n Place b o ta blet 
S u bjects ra n d o mize d t o 
Sa xa gli pti n 2. 5 m g ar m recei ve: 
Da pa glifl ozi n 5 m g Place b o ta blet 
Acti ve Sa xa gli pti n 2. 5 m g ta blet 
S u bjects ra n d o mize d t o 
Place b o ar m recei ve: 
Da pa glifl ozi n 5 m g Place b o ta blet   
Sa xa gli pti n Place b o ta blet 
 
T a ble 3. 1- 2:   
Tre at me nt Peri o d Wee k 1 4 t o Wee k 5 2 
T a blet c o m p o ne nts b ase d o n tre at me nt ar m assi g n me nt 
S u bjects desi g nate d t o 
Da pa glifl ozi n 1 0 m g ar m recei ve: 
Acti ve Da pa glifl ozi n 1 0 m g ta blet 
a n d Da pa glifl ozi n 5 m g Place b o 
ta blet 
Sa xa gli pti n Place b o ta blet 
S u bjects desi g nate d t o 
Da pa glifl ozi n 5 m g ar m recei ve: 
Acti ve Da pa glifl ozi n 5 m g ta blet 
a n d Da pa glifl ozi n 1 0 m g Place b o 
ta blet 
Sa xa gli pti n Place b o ta blet 
S u bjects desi g nate d t o 
Sa xa gli pti n 5 m g ar m recei ve: 
Da pa glifl ozi n 5 m g Place b o ta blet 
a n d Da pa glifl ozi n 1 0 m g Place b o 
ta blet 
Acti ve Sa xa gli pti n 5 m g ta blet 
S u bjects desi g nate d t o 
Sa xa gli pti n 2. 5 m g ar m recei ve: 
Da pa glifl ozi n 5 m g Place b o ta blet 
a n d Da pa glifl ozi n 1 0 m g Place b o 
ta blet 
Acti ve Sa xa gli pti n 2. 5 m g ta blet 
S u bjects desi g nate d t o Place b o ar m 
recei ve: 
Da pa glifl ozi n 5 m g Place b o ta blet 
a n d Da pa glifl ozi n 1 0 m g Place b o 
ta blet 
Sa xa gli pti n Place b o ta blet 
 
H b A 1c res ults will be bli n de d f oll o wi n g I P a d mi nistrati o n o n Da y 1 u ntil after st u d y c o m pleti o n 
( Secti o n 5. 9 ). A bli n de d H b A 1c assess me nt will be perf or me d at Wee k 1 2 f or all s u bjects. A 
sec o n d ra n d o mizati o n will be perf or me d at t he Wee k 1 4 visit, base d o n t he Wee k 1 2 H b A 1c 
assess me nt. All s u bjects wit h Wee k 1 2 H b A 1c va l ues < 7 % will re mai n o n pre vi o usl y assi g ne d 
l o w- d ose ra n d o mize d treat me nt ( da pa glifl ozi n 5 m g, or sa xa gli pti n 2. 5 m g, or place b o) after t he 
Wee k 1 2 assess me nt. S u bjects assi g ne d t o t he da pa glifl ozi n treat me nt ar m at Da y 1 Ra n d o mizati o n 
wit h Wee k 1 2 H b A 1c val ues ≥ 7 % will be re-ra n d o mize d i n a 1: 1 rati o t o co nti n ue o n t he l o w- d ose 
treat me nt ( da pa glifl ozi n 5 m g) or u p-titrate t o t he hi g h- d ose treat me nt ( da pa glifl ozi n 1 0 m g) after 
t he Wee k 1 2 assess me nt. Si milarl y, s u bjects assi g ne d t o t he sa xa gli pti n treat me nt ar m at Da y 1 
Ra n d o mizati o n wit h Wee k 1 2 H b A 1c val ues ≥ 7 % will be re-ra n d o mize d i n a 1: 1 rati o t o c o nti n ue 
o n t he l o w- d ose treat me nt (sa xa gli p ti n 2. 5 m g) or u p-titrate t o t he hi g h- d ose treat me nt (sa xa gli pti n 
5 m g) after t he Wee k 1 2 assess me nt. S u bjects assi g ne d t o t he place b o treat me nt ar m at Da y 1 
Ra n d o mizati o n wit h Wee k 1 2 H b A 1c val ues ≥ 7 % will c o nti n ue o n place b o treat me nt after t he 
Wee k 1 2 assess me nt. T o mai ntai n t he bli n di n g of treat me nts as well as H b A 1c res ults, all place b o 
s u bjects a n d all s u bjects ta ki n g sa xa gli pti n or da pa glifl ozi n wit h a n H b A 1c < 7 % at Wee k 1 2 will 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 7 
g o t hr o u g h a d u m m y sec o n d ra n d o mizati o n pr ocess t hat will be i n disti n g uis ha ble (f or t he s u bjects 
a n d site pers o n nel) fr o m t he act ual sec o n d ra n d o mizati o n. D uri n g t he Wee k 1 4 visit, bli n de d st u d y 
dr u g will be dis pe nse d t o all s u bjects i n acc or da nce wit h t he treat me nt assi g n me nts base d o n 
Wee k 1 2 H b A 1c assess me nts. S u bjects will be i nstr u cte d t o i n gest t hree ( 3) ta blets dail y as per 
Ta ble 3. 1- 2 . 
After c o m pleti o n of t he S T treat me nt peri o d, a ll s u bjects will e nter t he L T treat me nt peri o d 
S u bjects w h o are recei vi n g bac k gr o u n d me dicati o n wit h i ns uli n o nl y, or i ns uli n + metf or mi n (a n d 
w h o are t heref ore n ot eli gi ble f o r t he t hir d ra n d o mizati o n) will c o nti n ue wit h t heir ra n d o mize d 
st u d y me dicati o n assi g ne d after t he Wee k 1 2 assess me nt i n t he d o u ble- bli n d L T treat me nt peri o d 
(Fi g ure 3. 1- 1 ).  
After c o m pleti o n of assess me nts at Wee k 2 6, a s u bset of eli gi ble s u bjects w h o are recei vi n g 
bac k gr o u n d me dicati o n wit h metf or mi n o nl y will u n der g o a t hir d ra n d o mizati o n (ra n d o mize d 
wit h dra wal of bac k gr o u n d me dica ti o n) at eit her Wee k 3 2 or Wee k 4 0. Eli gi bilit y f or ra n d o mize d 
wit h dra wal  fr o m  bac k gr o u n d  me dicati o n  will  be  re stricte d  t o  s u bjects  w h o  are  recei vi n g  
bac k gr o u n d treat me nt wit h metf or mi n  o nl y, a n d w h o ha ve H b A 1c < 7. 5 % at Wee k 2 6 or Wee k 3 2, 
pr o vi de d t he y ha ve n ot i nitiate d resc ue gl yce mic  c o ntr ol t hera p y or bee n wit h dra w n fr o m st u d y 
dr u g. S u bjects w h o are recei vi n g  bac k gr o u n d me dicati o n wit h metfor mi n o nl y, w h o d o n ot q ualif y 
f or t he t hir d ra n d o mizati o n at Wee k 3 2 d ue t o a n H b A 1c ≥ 7. 5 % at Wee k 2 6, ma y q ualif y f or t he 
t hir d ra n d o mizati o n at Wee k 4 0 if H b A 1c < 7. 5 % at Wee k 3 2. S u bjects w h o ha ve passe d Wee k 4 0 
will n ot be i ncl u de d i n t he ra n d o mize d wit h dra wal of bac k gr o u n d me dicati o n. D uri n g t he t hir d 
ra n d o mizati o n: 
 Eli gi ble s u bjects w h o are recei v i n g acti ve treat me nt will be gr o u pe d i nt o t wo se parate strata 
f or  sa xa gli pti n  a n d  da pa glifl ozi n,  a n d  t he n  ran d o mize d  1: 1  wit hi n  eac h  strata  t o  eit her  
disc o nti n ue bac k gr o u n d me dicati o n wit h metf or mi n or t o c o nti n ue bac k gr o u n d me dicati o n 
wit h metf or mi n. F or s u bjects o n acti ve treat me nt  w h o are ra n d o mize d t o wit h dra w bac k gr o u n d 
treat me nt wit h metf or mi n, t h ose w h o are c urre ntl y recei vi n g hi g h d oses of sa xa gli pti n ( 5 m g) 
or da pa glifl ozi n ( 1 0 m g) will c o nti n ue t o recei ve t he hi g h d oses, w hereas s u bjects w h o are 
c urre ntl y recei vi n g l o w d os es of sa xa gli pti n ( 2. 5 m g) or da pa glifl ozi n ( 5 m g) will ha ve t heir 
d oses u p-titrate d t o t he hi g h d oses (sa xa gli pti n 5 m g or da pa glifl ozi n 1 0 m g). S u bjects i n t he 
acti ve treat me nt ar ms w h o are ra n d o mize d t o c o ntin ue bac k gr o u n d me dicati o n wit h metf or mi n 
will c o nti n ue wit h t heir c urre nt d ose of eit her sa xa gli pti n or da pa glifl ozi n (Fi g ure 3. 1- 2 ). 
 Eli gi ble s u bjects w h o are recei vi n g place b o wi ll be ra n d o mize d 1: 1: 1 t o eit her wit h dra w 
bac k gr o u n d me dicati o n wit h metf or mi n a n d s witc h t o acti ve treat me nt wit h eit her sa xa gli pti n 
5 m g or da pa glifl ozi n 1 0 m g or t o re ma i n o n bac k gr o u n d me dicati o n wit h metf or mi n a n d 
c o nti n ue wit h place b o ( Fi g ure 3. 1- 2 ).  
Disc o nti n uati o n  of  bac k gr o u n d  metf or mi n  will  o cc ur  i n  a n  u n bli n de d  ma n ner.  E x p os ure  t o  
m o n ot hera p y i n s u bjects u n der g oi n g ra n d o mize d wit h dra wal of metf or mi n will last fr o m t he start 
of metf or mi n wit h dra wal  f or t hat s u bject (f oll owi n g ra n d o mizati o n at Wee k 3 2 or Wee k 4 0) u ntil 
t he e n d of Wee k 5 2, w he n all s u bjects will disco nti n ue st u d y me dicati o ns. After Wee k 5 2, all 
s u bjects will ta ke t he m ost a p pro priate me dicati o n at t he discre ti o n of t he treati n g p h ysicia n.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 8 
Resc ue d s u bjects a n d s u bjects w h o disc o nti n ue I P will n ot be eli gi ble f o r ra n d o mize d wit h dra wal 
of bac k gr o u n d me dicati o n at Wee k 3 2 or Wee k 4 0.  
S u bjects wit h H b A 1c ≥ 7. 5 % at Wee k 2 6 a n d Wee k 3 2 a n d s u bjects w h o are recei vi n g bac k gr o u n d 
treat me nt wit h eit her i ns uli n o nl y, or i ns ulin + metf or mi n, i ncl u di n g t h os e ra n d o mize d t o recei ve 
place b o, will c o nti n ue t heir ra n d o mize d st u d y me dicati o n assi g ne d after t he Wee k- 1 2 assess me nt 
i n t he d o u ble- bli n d L T treat me nt peri o d. 
E x pl orat or y a nal yses f or t he m o n ot hera p y peri o d will i ncl u de o nl y s u bject s w h o are o n bac k gr o u n d 
me dicati o n wit h metf or mi n a n d ha ve H b A 1c meas ure me nt < 7. 5 % at Wee k 2 6 or Wee k 3 2. 
A nal yses will be perf or me d usi n g t he H b A 1c val ue at t he wit h dra wal base li ne. T he refere nce ti me 
p oi nt t o be use d as ‘ w it h dra wal baseli ne’ will be t he cl osest ti me p oi nt o n or bef ore t he t hir d 
ra n d o mizati o n. T he peri o d starti n g fr o m t his baseli ne t o Wee k 5 2 will be referre d t o as t he 
‘ra n d o mize d wit h dra wal peri o d’. 
F or s u bjects recr uite d i nt o t he st u d y pri or t o t h e st u d y site i m ple me ntati o n of t he t hir d pr ot oc ol 
a me n d me nt, partici pati o n i n t he t hir d ra n d o miza ti o n ( wit h p ossi ble wit hdra wal of bac k gr o u n d 
me dicati o n wit h metf or mi n) will be  at t he s u bject’s discreti o n.  
A d verse e ve nts a n d seri o us a d verse e ve nts ( S A Es)  will be assesse d d uri n g a Wee k 5 6 p h o ne visit. 
I n case a visit is dela ye d f or a n y reas o n, s u bse q ue nt visits s h o ul d be sc he d ule d s uc h t hat a n i nter val 
of at least 1 2 wee ks is mai ntai ne d bet wee n t he: 
 Wee k 1 4 visit a n d t he Wee k 2 6 visit. 
 T hir d ra n d o mizati o n (f or s u bjects u n der g oi n g t h ir d ra n d o mizati o n; occ urri n g at t he Wee k 3 2 
or t he Wee k 4 0 visit) a n d t he Wee k 5 2 visit. 
If  m ore  t ha n  1 2  wee ks  ela pse  bet wee n  t he  H b A 1c  c ollecti o n  at  Wee k  2 6  a n d  t he  t hir d  
ra n d o mizati o n at Wee k 3 2, or t he H b A 1c c ollecti o n at Wee k 3 2 a n d t he t hir d ra n d o mizati o n at 
Wee k 4 0, t he s u bject s h o ul d n ot g o t hr o u g h t his ra n d o mizati o n, as t he H b A 1c val ue w o ul d n o 
l o n ger be relia ble t o ascertai n eli gi bilit y f or t he t hir d ra n d o mizati o n. S h ort- a n d l o n g-ter m peri o d 
st u d y visits ca n be dela ye d b y a ma xim u m of 1 1 m o nt hs i n t otal. If t he d urati o n of I P a d mi nistrati o n 
is l o n ger t ha n 5 2 ( + 1) wee ks, t he safet y f oll o w- u p peri o d s h o ul d be s h orte ne d s uc h t hat t he 
c o m plete st u d y d urati o n d oes n ot e xcee d 1 0 4 wee ks ( + 7 da ys). A wi n d o w peri o d of - 2 8 da ys t o 
+ 7 da ys fr o m t he ori gi nal sc he d ule d date will be all o we d f or t he Wee k- 1 0 4 visit. 
S u bjects w h o disc o nti n ue st u d y dr u g bef ore t he e n d of t he st u d y treat m e nt peri o d will e nter a 
n o n-treat me nt, f oll o w- u p p hase, i n w hic h s u bjects will f oll o w t heir visit sc he d ules wit h m o difie d 
assess me nts u ntil  st u d y c o m pleti o n.  S u bjects  w ill  atte n d  a  p ost-st u d y visit  at  Wee k  1 0 4,  f or  
assess me nt of meas ures of gr o w t h a n d mat urit y. T his visit s h o uld be c o m plete d wit h o ut dela y (at 
1 0 4 wee ks ( + 7 da ys) fr o m Da y 1, re gar dless of w het her a n y ot her st u d y vi sits were dela ye d. 
All s u bjects wit h H b A 1c > 8. 0 % at a n d after Wee k 2 6 will be resc ue d.  
Disc o nti n ue d s u bjects will still be e val uate d f or resc ue a n d will n ot be re place d. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
3 9 
Gl yce mic resc ue para meters are i ncl u de d f or s u bject s w h o meet t he criteria f or lac k of gl yce mic 
c o ntr ol  i n  b ot h  t he  2 6- wee k  S T  treat me nt  pe ri o d  a n d  t he  2 6- wee k  safet y  e xte nsi o n  peri o d.  
I n vesti gat ors ma y use i ns uli n as resc ue at t heir discreti o n.  
T he I n vesti gat or, S p o ns or, site a n d s u bject will be bli n ded t o t he s u bjects’ H b A 1c res ults f oll o wi n g 
a d mi nistrati o n of I P o n Da y 1 u nt il after st u d y c o m pleti o n. I n t he e ve nt of a n H bA 1c res ult > 8. 0 % 
d uri n g t he L T peri o d ( w he n t hese val ues re q uire s u bj ect resc ue), t he i n vesti gat or will be i nf or me d 
via a n H b A 1c alert fr o m t he ce ntral la b orat or y b ut will re mai n bli n de d t o t he H b A 1c res ult. 
Resc ue d s u bjects will c o nti n ue treat me nt o n st u d y dr u g u ntil Wee k 5 2. 
Sa m ples  f or  a nal ysis  of  plas ma  le vels  of  da pa glifl ozi n,  sa xa gli pti n,  a n d  its  meta b olite  
5- O H-sa xa gli pti n will be c ollecte d u p t o 1 h o u r pre- d ose a n d a p pr o xi matel y 2 h o urs p ost- d ose 
( 1 h o ur) d uri n g t he Wee k 6, 1 2, 2 0, a n d 2 6 visits.  
Sa m ples f or a nal ysis of F P G will be c ollecte d u p t o 1 h o ur pre- d ose d uri n g t he Da y 1 visit, a n d u p 
t o 1 h o ur pre- d ose a n d a p pro xi matel y 2 h o urs p ost- d ose (  1 h o ur) d uri n g t he Wee k 6, 1 2, 2 0, a n d 
2 6 visits ( Secti o n 5. 5 ). 
Plas ma sa m ples f or a nal ysis of D P P- 4 acti vit y will be c ollecte d u p t o 1 h o ur pre- d ose d uri n g t he 
Da y 1 visit, a n d at 2 (  1) h o urs p ost- d ose d uri n g t he Wee k 6, 1 2, 2 0, a n d 2 6 visits.  
All plas ma sa m ples will be dra w n i n t he fasti n g c o n diti o n. S u bjects s h o ul d fast f or at least 8 h o urs 
pri or t o sa m pli n g.  
All st u d y s u bjects will f oll o w t he sc he d ules of assess me nts prese nte d i n Secti o n 5. 1 . 
T he st u d y desi g n sc he matic f or all s u bjects n ot u n der g oin g ra n d o mize d wit h dr a wal of bac k gr o u n d 
me dicati o n at Wee k 3 2 or Wee k 4 0 is prese nte d i n Fi g ure 3. 1- 1 . 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 2 
writte n c o nse nt. Asse nt s h o ul d be o btai ne d acc or di n g t o l ocal re g ulati o ns  a n d if c hil d is 
ca pa ble. 
2.  T ar get P o p ul ati o n 
a) Pre vi o usl y dia g n ose d wit h T 2 D M b y W o rl d Healt h Or ga nizati o n/ A D A criteria 
b)  H b A 1c  6. 5 % a n d  1 0. 5 % o btai ne d d uri n g t he 6- m o nt h scree ni n g peri o d 
c) C urre ntl y o n diet a n d e xercise a n d sta ble d os e of at least 1 0 0 0 m g metf or mi n (I R or X R) 
f or a mi ni m u m of 8 wee ks, or sta ble d ose of i ns uli n f or a mi ni m u m of 8 wee ks, or a sta ble 
c o m bi nati o n of at least 1 0 0 0 m g  metf or mi n (I R or X R) a n d i ns uli n f or a mi ni m u m of 
8 wee ks pri or t o Da y 1 Ra n d o mizati o n. F or t h ose c hil dre n o n i ns uli n, i n vesti gat ors will 
c o nfir m t hat atte m pts at re m o vi n g i ns uli n fr o m  t he s u bject’s t hera pe utic re gi me n ha d bee n 
pre vi o usl y ma de b ut ha d n ot bee n s uccessf ul. 
d)  S u bject  re-e nr oll me nt:  T his  st u d y  per mits  t h e  re-e nr oll me nt  of  a  s u bject  t hat  has  
disc o nti n ue d t he st u d y as a pre-tr eat me nt fail ure (i.e., s u bject has n ot bee n ra n d o mize d / has 
n ot bee n treate d).  
i) If re-e nr olle d, t he s u bject m ust be re-c o nse nte d. All scre e ni n g pr oce d ures will be 
re peate d. S u bjects ma y o nl y be re-scree ne d t wice. 
3.  A ge a n d Re pr o d ucti ve St at us 
a) Male a n d fe male s u bjects eli gi ble if reac he d 1 0 years of a ge at scree ni n g, a n d u p t o b ut n ot 
i ncl u di n g 1 8 years of a ge at ra n d o mizati o n. At least 3 0 % of t otal s u bjects will be bet wee n 
t he a ges of 1 0 a n d 1 4 years a n d at least o ne t hir d, b ut n o m ore t ha n t w o t hir ds, fe male 
s u bjects. 
b)  W o me n  of  c hil d beari n g  p ote ntial  ( W O C B P)  m ust  ha ve  a  ne gati ve  pre g na nc y  test  
( mi ni m u m se nsiti vit y 2 5 I U/ L or e q ui vale nt u nits of beta- h u ma n c h ori o nic g o na d otr o pi n) 
wit hi n 2 4 h o urs pri or t o  t he start of st u d y dr u g. 
c) W o me n m ust n ot be breastfee di n g. 
d)  W o me n  of  c hil d beari n g  p ote ntial  m ust  a gree  t o  f oll o w  i nst r ucti o ns  f or  met h o d(s)  of  
c o ntrace pti o n f or t he d urati o n of treat me nt wit h st u d y dr u gs: sa xa gli pti n, a n d da pa glifl ozi n, 
pl us 5 half-li ves of st u d y dr u gs or 3 0 da ys ( w hi c he ver is l o n ger), pl us  3 0 da ys ( d urati o n of 
o v ulat or y c ycle) f or a t otal of 6 0 da ys p ost-treat me nt c o m pleti o n. 
W o me n of c hil d beari n g p ote ntial w h o are c o nti n u o usl y n ot heter ose x uall y acti ve are e xe m pt fr o m 
c o ntrace pti ve re q uire me nts. H o we ve r, t he y m ust still u n der g o pre g na nc y testi n g as descri be d i n 
Ta ble 5. 1- 1 . 
I n vesti gat ors  s hall  c o u nsel  W O C B P  o n  t he  i mp orta nce  of  pre g na nc y  pre ve nti o n  a n d  t he  
i m plicati o ns of a n u ne x pecte d pre g na nc y. I n vesti gat ors s hall a d vi se W O C B P o n t he use of hi g hl y 
effecti ve met h o ds of c o ntrace pti o n. Hi g hl y effecti ve met h o ds of c o ntrace pti o n ha ve a fail ure rate 
of < 1 % w he n use d c o ns iste ntl y a n d c orrectl y. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 3 
At a mi ni m u m, s u bjects m ust a gree t o use o ne hi g hl y effecti ve met h o d of c o ntrace pti o n as liste d 
bel o w: 
A.  HI G H L Y E F F E C TI V E M E T H O D S O F C O N T R A C E P TI O N 
Hi g hl y effecti ve met h o ds of c o ntrace pti o n ha ve a fail ure ra te of < 1 % w he n use d c o nsiste ntl y a n d 
c orrectl y. W o me n of c hil d beari n g p o te ntial are e x pecte d t o use o ne of t he hi g hl y effecti ve met h o ds 
of c o ntrace pti o n liste d bel o w. C o ntrace pti o n met h o ds are as f oll o ws: 
1.  Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass o ciate d wit h i n hi biti o n of o v ulati o n 
2.  H or m o nal  met h o ds  of  c o ntrace pti o n  i ncl u di n g  oral  c o ntrace pti ve  pills  c o ntai ni n g  
c o m bi ne d estr o ge n + pr o gester o ne , va gi nal ri n g, i njecta bles, i m pla nts a n d i ntra uteri ne 
de vices (I U Ds) 
3.  N o n h or m o nal I U Ds 
4.  Bilateral t u bal occl usi o n 
5.  Vasect o mise d part ner wit h d oc u me nte d az o os per mia 9 0 da ys  after pr oce d ure 
a. Vasect o mise d  part ner  is  a  hi g hl y  effecti ve  birt h  c o ntr ol  met h o d  pr o vi de d  t hat  
part ner is t he s ole se x ual part ner of t he W O C B P trial partici pa nt a n d t hat t he 
vasect o mise d part ner has r ecei ve d me dical assess me nt of t he s ur gical s uccess. 
6.  I ntra uteri ne h or m o ne-releasi n g s yste m  
7.  C o m plete a bsti ne nce 
a. C o m plete  a bsti ne nce  is  defi ne d  as  t he  c o m plete  a v oi da nce  of  heter ose x ual  
i nterc o urse (refer t o Gl ossar y of Ter ms). 
b.  C o m plete a bsti ne nce is a n acce pta ble f or m of c o ntrace pti o n f or all st u d y dr u gs a n d 
m ust be use d t hr o u g h o ut t he d urati o n of t he st u d y treat me nt ( pl us 5 half-li ves of t he 
i n vesti gati o nal dr u g pl us 3 0 da ys). 
c. It  is  n ot  necessar y  t o  use  a n y  ot her  met h o d  of  c o ntrace pti o n  w he n  c o m plete  
a bsti ne nce is electe d. 
d.  S u bjects w h o c h o ose c o m plete a bsti ne nce m ust  c o nti n ue t o ha ve pre g na nc y tests.  
e. Acce pta ble alter nate met h o ds of hi g hl y e ffecti ve c o ntrace pti o n m ust be disc usse d 
i n t he e ve nt t hat t he s u bject c h o oses t o f ore g o c o m plete a bsti ne nce. 
f. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n 
of t he cli nical trial a n d t he preferre d a n d us ual lifest yle  of t he s u bject. 
B.  L E S S E F F E C TI V E M E T H O D S O F C O N T R A C E P TI O N 
1.  Dia p hra g m wit h s per mici de 
2.  Cer vical ca p wit h s per mici de 
3.  Va gi nal s p o n ge wit h s per mici de 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 4 
4.  Male or fe male c o n d o m w it h or wit h o ut s per mici de *1 2, 1 3 
5.  Pr o gest o ge n- o nl y oral h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he 
pri mar y m o de of acti o n. 
*  A male a n d a fe male c o n d o m m ust n ot be use d t o get her. 
C.  U N A C C E P T A B L E M E T H O D S O F C O N T R A C E P TI O N 
1.  Peri o dic a bsti ne nce (cale n dar, s y m p t ot her mal, p ost- o v ulati o n met h o ds) 
2.  Wit h dra wal (c oit us i nterr u pt us) 
3.  S per mici de o nl y 
4.  Lactati o n a me n orr hea met h o d 
3. 3. 2  E x cl u si o n  Crit eri a  
1.  T ar get Dise ase E xce pti o ns 
a) Prese nce of T y pe 1 dia betes, as de m o nstrate d b y: 
 Pree xisti n g dia g n osis of  T y pe 1 dia betes,  
O R 
 P ositi vit y at scree ni n g of ei t her a nti b o dies t o gl uta mic aci d decar b o x ylase ( G A D) or 
pr otei n  t yr osi ne  p h os p hatase-li ke  pr ot ei n  a nti b o dies  (I A- 2)  A N D  a b n or mall y  l o w  
le vels of C- pe pti de. G A D a n d I A- 2 a nti b o d y testi n g will be perf or me d i n all scree ne d 
s u bjects, C- pe pti de o nl y i n ot her wise eli gi ble, a nti b o d y- p osit i ve s u bjects. All i nsta nces 
of  a nti b o d y- p ositi ve  s u bjects  wit h  n or mal  or  ele vate d  C- pe pti de  val ues  will  be  
disc usse d b y t he I n vesti gat or wit h t he st u d y me dical m o nit ors a n d S p o ns or’s st u d y 
direct or t o c o nfir m st u d y eli gi bilit y .1 4, 1 5, 1 6 
b)  Pre vi o us dia g n osis of m o n o ge nic eti ol o g y of T y pe 2 dia betes s uc h  as mat urit y o nset 
dia betes of t he y o u n g ( M O D Y), ge netic dis or der s wit h str o n g ass ociati o ns wit h i ns uli n 
resista nce/ dia betes  a n d/ or  o besit y  s uc h  as T ur ner’s  S y n dr o me  a n d  Pra der- Willi,  or  
sec o n dar y  dia betes  (ster oi d  use,  C us hi n g’s  disease,  acr o me gal y),  sec o n dar y  dia betes  
mellit us, or dia betes i nsi pi d us 
c) Dia betes ket oaci d osis wit hi n 6 m o nt hs of scree ni n g 
d)  C urre nt use of t he f oll o wi n g me dicati o ns f or t h e treat me nt of dia betes, or use wit hi n t he 
s pecifie d ti mefra me pri or t o scree ni n g f or t he mai n st u d y: 
i) Ei g ht wee ks: s ulf o n yl ureas, al p h a gl uc osi dase i n hi bit ors, meti g li ni de, oral or i njecta ble 
i ncreti ns or i ncreti n mi metics, ot her a nti- dia betes me dicati o ns n ot ot her wise s pecifie d. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 5 
ii) Si xtee n  wee ks:  t hiaz oli di ne di o nes,  D P P- 4  i n hi bit ors  ( w it h  n o  re p orte d  me dicati o n  
relate d  A Es  relate d  t o  D P P- 4  i n hi bit ors),  S G L T- 2  i n hi bit ors  ( wit h  n o  re p orte d  
me dicati o n relate d A Es rela te d t o S G L T- 2 i n hi bit ors) 
e) I nitiati o n or disc o nti n uati o n of prescri pti o n or n o n- prescri pti o n wei g ht l oss dr u gs wit hi n 
8 wee ks of scree ni n g. Use of prescri pti o n or n o n- prescri pti o n wei g ht l oss dr u gs m ust be 
sta ble d uri n g t he st u d y. 
2.  Me dic al Hist or y a n d C o nc urre nt Dise ases 
a) Pre g na nt, p ositi ve ser u m pre g na nc y test, pla n ni n g t o bec o me pre g na nt d uri n g t he cli nical 
trials, or breastfee di n g 
b)  Hist or y of u nsta ble or ra pi dl y pr o gressi ve re nal disease 
c) Hist or y of u nres ol ve d vesic o- ureteral refl u x 
d)  Hist or y of or c urre nt, ac ute  or c hr o nic pa ncreatitis 
e) Hist or y of he m o gl o bi n o pat h y, wit h t he e xce pti o n of sic kle cell trait or t halasse mia mi n or; 
or c hr o nic or rec urre nt he m ol ysis 
f) Mali g na nc y wit hi n 5 years of t he scree ni n g vi sit ( wit h t he e xce pti o n of treate d basal cell 
or treate d s q ua m o us cell carci n o ma) 
g)  Si g nifica nt c o- m or bi dit y t hat, i n t he o pi ni o n of t he I n vesti gat ors, will i ncrease t he ris k t o 
t he s u bject s uc h as i m m u n os u p pressio n, or c urre nt treat me nt f or ca ncer 
h)  Re place me nt or c hr o nic s yste mic  c ortic oster oi d t hera p y, define d as a n y d ose of s yste mic 
c ortic oster oi d ta ke n f or > 4 wee ks wit h i n 3 m o nt hs pri or t o t he Da y 1 visit 
N O T E: i n hale d, nasal s pra y, or t o pical ster oi ds  if li mite d t o mi n or s urface area are all o we d. 
3.  P h ysic al a n d L a b or at or y Test Fi n di n gs 
a) A b n or mal  re nal  f u ncti o n,  w hic h  is  defi ne d  as  a n  esti mate d  gl o mer ular  filtrati o n  rate  
(e G F R) calc ulate d b y t he Sc h wartz F or m ula < 8 0 m L/ mi n/ 1. 7 3 m2 ( 1. 3 3 m L/s)1 7  
b)  A n  a b n or mal  t h yr oi d-sti m ulati n g  h or m o ne  ( T S H)  val ue  at  e n r oll me nt  will  be  f urt her  
e val uate d f or free T 4. S u bjects wit h a b n or mal free T 4 val ues will be e xcl u de d.  
( N ote: I n s u bjects w h o ha ve ha d a pri or dia g n osis of a t h yr oi d dis or der a n d w h o are c urre ntl y 
recei vi n g t h yr oi d re place me nt t hera p y, retest of T S H ma y be all o we d, as deter mi ne d b y t he 
I n vesti gat or,  after  a  mi ni m u m  of  6  wee ks  f oll o wi n g  t he  a dj ust me nt  of  t h yr oi d  h or m o ne  
re place me nt t hera p y. S uc h cases s h o ul d be disc usse d wit h t he Sp o ns or pri or t o retesti n g. T he 
s u bject m ust ha ve all e nr oll me nt pr oce d ures a n d lab orat or y assess me nts perf or me d as part of t his 
retest, a n d all of t hese m ust meet e nr oll me nt eli gi bilit y criteria. T he s u bject’s n u m ber will h o we ver 
re mai n t he sa me as i nitiall y assi g ne d.) 
c) He mat uria (c o nfir me d b y micr osc o p y at scree n i n g) wit h n o e x pla nati o n as j u d ge d b y t he 
I n vesti gat or u p t o ra n d o mizati o n.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 6 
d)  As partate a mi n otra nsferase ( A S T) or ala ni n e a mi n otra nsferase ( A L T) > 2 × u p per li mit of 
n or mal ( U L N), or cli nicall y si g nifica nt he patic disease. 
e) Ser u m t otal bilir u bi n ( T B)  2 x U L N u nless e xcl usi vel y ca use d b y Gil bert’s s y n dr o me 
f) P ositi ve
 ser ol o gic
 e vi de nce
 of
 c urre nt  i nfecti o us
 li ver
 disease
 i ncl u di n g
 
a nti- he patitis  A  vir us  ( H A V)  (I g M),  he patitis  B  s urface  a nti ge n  ( H Bs A g),  or  
a nti- he patitis C vir us ( H C V). S u bjects w h o ha ve is olate d p os iti ve a nti- he patitis B s urface 
a nti b o dies ma y be i ncl u de d. 
g)  A ne mia of a n y eti ol o g y defi ne d as he m o gl o bi n  1 0. 7 g/ d L ( 1 0 7 g/ L) f or fe males a n d 
 1 1. 3 g/ d L ( 1 1 3 g/ L) f or males. S u bjects w h o are c o nsi dere d t o ha ve a ne mia acc or di n g t o 
l ocal g ui deli nes s h o ul d be e xcl u de d. 
h)  V ol u me- de plete d  s u bjects.  S u bjects  at  ris k  f or  v ol u me  de pleti o n  d ue  t o  c o-e xisti n g  
c o n diti o ns or c o nc o mita nt me dicati o ns, s uc h as l o o p di uretics, s h o ul d caref ull y m o nit or 
t heir v ol u me stat us. 
i) Cli nicall y si g nifica nt a b n or malities i n a n y pr e- Da y 1 Ra n d o mizati o n la b orat or y a nal yses 
or  electr ocar di o gra m  ( E C G)  t hat,  i n  t he  I n vesti gat or’s  o pi ni o n,  w o ul d  precl u de  
ra n d o mizati o n. 
4.  Aller gies a n d A d verse Dr u g Re acti o n 
a) K n o w n aller g y, se nsiti vit y or c o ntrai n dicati o n t o a n y st u d y dr u g or its e xci pie nt/ ve hicle 
5.  Ot her E xcl usi o n Criteri a 
a) S u bject is c urre ntl y a b usi n g alc o h ol or ot her dr u gs or has d o ne s o wit hi n t he last 6 m o nt hs 
pri or t o t he scree ni n g visit. 
b)  Pris o ners or s u bjects w h o are i n v ol u ntaril y i ncarcerate d. ( N ote: u n der certai n s pecific 
circ u msta nces a pers o n w h o has bee n i m pris o ne d ma y be i ncl u de d or per mitte d t o c o nti n ue 
as a s u bject. Strict c o n d iti o ns a p pl y a n d S p o ns or/ desig nee a p pr o val is re q uire d.) 
c) S u bjects w h o are c o m p uls oril y de tai ne d f or treat me nt of eit her a ps yc hiatric or p h ysical 
(e. g., i nfecti o us disease) ill ness. 
d)  Ps yc hiatric or c o g niti ve dis or der t hat will, i n t he o pi ni o n of i nvesti gat ors, li mit t he s u bject’s 
a bilit y t o c o m pl y w it h t he st u d y me dicati ons a n d m o nit ori n g. 
e) S u bjects  w h o  ha ve  c o ntrai n dicati o ns  t o  t h era p y  as  o utli ne d  i n  t he  sa xa gli pti n  a n d  
da pa glifl ozi n I n vesti gat or Br oc h ure or l ocal pac ka ge i nserts. 
f) Partici pati o n a n d recei vi n g I P i n a n ot he r cli nical st u d y d uri n g t he pri or 3 m o nt hs. 
Eli gi bilit y criteria f or t his st u d y ha ve bee n caref ull y c o nsi dere d t o e ns ure t he safet y of t he st u d y 
s u bjects a n d t hat t he res ults of t he st u d y ca n be use d. It is i m perati ve t hat s u bjects f ull y meet all 
eli gi bilit y criteria. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 7 
3. 3. 3  W o m e n of C hil d b e ari n g P ot e nti al 
A W O C B P is defi ne d as a n y fe male w h o has e x perie nce d me narc he a n d w h o has n ot u n der g o ne 
s ur gical sterilizati o n ( h ysterect o m y or bilateral o o p h orect o m y)  a n d is n ot p ost me n o pa usal. 
3. 4  S cr e e n  F ail ur e s  
Scree n fail ures are defi ne d as s u bjects w h o si g ne d t he i nf or me d c o nse nt f or m t o partici pate i n t he 
cli nical st u d y b ut are n ot s u bse q ue ntl y ra n d o ml y assi g ne d t o st u d y treat me nt. A mi ni mal set of 
scree n fail ure i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure s u bjects t o 
meet t he C o ns oli date d Sta n dar ds of Re p orti n g Tr ials p u blis hi n g re q uire me nts a n d t o res p o n d t o 
q ueries fr o m Re g ulat or y A ut h orit ies. Mi ni mal i nf or mati o n i nclu des de m o gra p h y, scree n fail ure 
details, eli gi bilit y criteria, a n d a n y S A E. 
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y be 
re-scree ne d t wice. A re-scree ne d s u bject will be assi g ne d a ne w s u bject n u m ber t hat is differe nt 
fr o m t hat assi g ne d d uri n g t he i nitial scree ni n g. Re-scree ni n g s h o uld be d oc u me nte d s o t hat its 
effect o n st u d y res ults, if a n y, ca n be assesse d. 
T hese s u bjects s h o ul d ha ve t he reas o n f or st u d y wit h dra wal rec or de d i n t he electr o nic case re p ort 
f or m (e C R F). 
3. 5  C o n c o mit a nt  Tr e at m e nt s  
3. 5. 1  Pr o hi bit e d  a n d/ or  R e stri ct e d Tr e at m e nt s 
 O nce c o nse nte d s u bjects ma y n o t recei ve a n y prescri pti o n a nti h y per gl yce mic me dicati o n ot her 
t ha n st u d y dr u g, metf or mi n a n d/ or i ns uli n.  
 O nce c o nse nte d, s u bjects s h o ul d n ot  be gi n treat me nt wit h a n y s yste mic c ortic oster oi d t hera p y 
lasti n g  5 da ys of t hera p y (i n hale d, nasal, a n d t o pical are all o we d). S u bjects w h o re q uire 
s yste mic c ortic oster oi d t hera p y s h o ul d be disc usse d wit h t he Me dical M o nit or pri or t o starti n g 
t hera p y w he ne ver p ossi ble. 
 O nce c o nse nte d, s u bjects s h o ul d n ot c o m me nce or m o dif y t hera p y wit h a n y prescri pti o n or 
o ver-t he-c o u nter wei g ht l oss me dicati o ns. 
 O nce c o nse nte d, s u bjects s h o ul d n ot u n der g o a n y bariatric s ur ger y. 
 O nce  c o nse nte d,  s u bjects  s h o ul d  n ot  c o m m e nce  t hera p y  wit h  p ote nt  c yt oc hr o me  
P 4 5 0  3 A 4/ 3 A 5  ( C Y P 3 A 4/ 5)  i n hi bit ors  i n  c o u n tries  w here  d ose  a dj ust me nt  d ue  t o  p ote nt  
s yste mic C Y P 3 A 4/ 5 i n hi bit or use w o ul d be re q uire d b y t he saxa gli pti n la bel. 
3. 5. 2  Ot h er  R e stri ct i o n s a n d Pr e c a uti o n s 
 S u bjects m ust c o m pl y wit h t heir prescri be d d osi n g re gi me n t o preser ve st u d y i nte grit y a n d 
e ns ure s u bject safet y. 
 S u bjects s h o ul d be ca uti o ne d t hat a n y ne w pres cri pti o n, o ver-t he-c o u nter or her bal/ n utriti o nal 
t hera pies s h o ul d be disc usse d t h or o u g hl y wit h t he I n vesti gat or as c o nc o mita nt use c o ul d res ult 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 8 
i n alterati o ns t o t heir gl yce mic c o ntr ol a n d ma y place t he m at ris k f or si g nifica nt h y p o gl yce mic 
e pis o des. 
 Me dicati o n ot her t ha n t h ose w hic h are pr ot oc ol pr o hi bite d as descri be d a b o ve, c o nsi dere d 
necessar y  f or  t he  s u bject’s  sa fet y  a n d  well bei n g,  ma y  be  gi ve n  at  t he  discreti o n  of  t he  
I n vesti gat or a n d m ust be rec or de d i n t he a p pr o priate secti o ns of t he case re p ort f or m ( C R F). 
 S u bjects m ust ma ke e ver y atte m pt t o a d here t o t he diet a n d e xercise c o u nseli n g a n d t o t he st u d y 
fl o w c hart/ti me a n d e ve nts sc he d ule (see Secti o n 5. 1 ). 
 W o me n of c hil d beari n g p ote ntial m ust i m me diatel y c o ntact t he I n vesti gat or if t he y s us pect 
t he y mi g ht be pre g na nt a n d if t he y ha ve c ha n ged or pla n t o c ha n ge t h eir birt h c o ntr ol met h o d. 
3. 6  Di s c o nti n u ati o n of t h e St u d y 
T he S p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y ti me 
f or  a n y  reas o n  at  t he  s ole  discreti o n  of  t he  S p o ns or.  St u d y  sites  will  be  cl ose d  u p o n  st u d y  
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w h e n all re q uire d d oc u me nts a n d st u d y s u p plies ha ve 
bee n c ollecte d a n d a st u d y-site cl os ure visit has bee n perf or me d. 
T he i n vesti gat or ma y i nitiate st u d y- site cl os ure at a n y ti me, pr o vi ded t here is reas o na ble ca use a n d 
s ufficie nt n otice is give n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n vesti gat or ma y i ncl u de b ut are n ot 
li mite d t o: 
 Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C or 
l ocal Healt h A ut h orities, t he S p o nsor's pr oce d ures, or G C P g ui deli nes 
 I na de q uate recr uit me nt of partici pa nts b y t he i n vesti gat or 
 Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt 
If  t he  st u d y  is  pre mat urel y  ter mi nate d  or  s us pe n de d,  t he  S p o ns or  s hall  pr o m ptl y  i nf or m  t he  
i n vesti gat ors, t he I E Cs/I R Bs, t he Re g ulat or y A ut h orities, a n d a n y c o ntract researc h or ga nizati o n(s) 
use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifi e d b y t he a p plica ble 
re g ulat or y re q uire me nts. T he I n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure 
a p pr o priate partici pa nt t h era p y a n d/ or f oll o w- u p. 
3. 7  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 F oll o wi n g A n y Tr e at m e nt wit h 
St u d y Dr u g  
S u bjects M U S T disc o nti n ue I P (a n d n o n-I P at t he discreti o n of t he I n vesti gat or) f or a n y of t he 
f oll o wi n g reas o ns: 
 S u bject’s re q uest t o st o p st u d y treat me nt 
 A n y cli nical A E, la b orat or y a b n or malit y or i nterc urre nt ill ness w hic h, i n t he o pi ni o n of t he 
I n vesti gat or, i n dicates t hat c o nti n ue d partici pati o n i n t he st u d y is n ot i n t he best i nterest of t he 
s u bject 
 Ter mi nati o n of t he st u d y b y t he S p o ns or/ desi g nee  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
4 9 
 L oss of a bilit y t o freel y pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y i ncarcerati o n f or 
treat me nt of eit her a ps yc hiatric or p hysical (e. g., i nfecti o us disease) ill ness 
 U n bli n di n g a s u bject f or a n y reas o n (e mer ge nc y or n o n-e mer ge nc y) 
 Se vere n o n-c o m plia nce t o pr ot oc ol, as j u d ge d b y  t he I n vesti gat or a nd/ or S p o ns or/ desi g nee 
 Safet y reas o ns as j u d ge d b y t he I n ve sti gat or a n d/ or S p o ns or/ desi g nee 
 Pre g na nc y 
 F or s u bjects o n metf or mi n, de vel o p me nt of c o ntrai n dicati o ns t o metf or mi n t hera p y as per l ocal 
la bel 
 S u bjects  e x perie nci n g  decrease d  re nal  f u ncti o n  m ust  be  e val uate d  as  per  I n vesti gat or’s  
discreti o n  
 S u bjects wit h e G F R < 5 0 m L/ mi n f or s ustai ne d peri o d of ti me ( 1 2 t o 1 6 wee ks) m ust 
be disc o nti n ue d 
 S u bjects wit h a ce ntral la b orat or y A L T a n d/ or A S T > 3 x U L N will be sc he d ule d f or a f oll o w- u p 
visit wit hi n 3 da ys f oll o wi n g t he recei pt of t he res ult (see A p pe n di x 1 a n d A p pe n di x 2 f or 
f urt her g ui da nce). S u bjects s h o ul d be disc o nti nue d fr o m st u d y dr u g if t h e i nitial a n d re peat 
la b orat or y tests meet a n y of t he f oll o wi n g criteria: 
 A L T a n d/ or A S T are > 3 x U L N a n d T B > 2 x U L N 
 A L T a n d/ or A S T are > 5 x U L N f or  1 4 c o nsec uti ve da ys, at a n y ti me after i nitial 
c o nfir mat or y res ults 
 A L T a n d/ or A S T are  1 0 x U L N 
I n  t he  case  of  pre g na nc y,  t he  I n vesti gat or  m ust  i m me diatel y  n otif y  t he  S p o ns or  Me dical  
M o nit or/ desi g nee of t his e ve nt. T he st u d y dr u g will be per ma ne ntl y disc o nti n ue d i n a n a p pr o priate 
ma n ner.  
All s u bjects w h o disc o nti n ue I P ea rl y ( pri or t o t he Wee k 5 2 visit) will re mai n i n t he st u d y a n d 
s h o ul d  c o m pl y  wit h  pr ot oc ol-s pecifie d  f oll o w- u p  pr oce d ures  i n cl u di n g  site  visits  a n d  p h o ne  
c o ntacts as o utli ne d i n Secti o n  5 . T he o nl y e xce pti o n t o t his re q uire me nt is w he n a s u bject 
wit h dra ws c o nse nt f or all st u d y pr oce d ures i ncl u di n g p ost-treat me nt st u d y f oll o w- u p or l oses t he 
a bilit y t o c o nse nt freel y (i.e., is i m pris o ne d or i n v ol u ntaril y i ncarcerate d f or t he treat me nt of eit her 
a ps yc hiatric or p h ysical ill ness). 
If a s u bject disc o nti n ues I P earl y ( pri or t o t he Wee k 5 2 visit), at t he ne xt visit t he s u bject s h o ul d 
be assesse d acc or di n g t o t he f oll o w- u p sc he d u le f or Earl y Treat me nt Disc o nti n uati o n ( E T D) 
(Ta ble 5. 1- 4 ). T he reas o n f or earl y disc o nti n uati o n m ust be d oc u me nte d i n t he s u bject’s me dical 
rec or ds a n d e ntere d o n t he a p pr o priate C R F pa ge. 
S u bjects w h o disc o nti n ue I P earl y wi ll still be e val uate d f or resc ue. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 0 
After disc o nti n u ati o n of I P t he m a n a ge me nt of  t he s u bject’s di a betes will be u n der t he c are 
a n d directi o n of t he I n vesti g at or.  
3. 7. 1  Pr o c e d ur e s f or H a n dli n g P ati e nt s  I n c orr e ctl y E nr oll e d or R a n d o mi z e d  
S u bjects w h o fail t o meet t he i n cl usi o n/e xcl usi o n criteria m ust n ot, u n der a n y circ u msta nces, be 
e nr olle d or ra n d o mize d. T here ca n be n o e xce pti o ns t o t his r ule. 
S u bjects w h o are i nc orrec tl y e nr olle d, b ut are n ot yet ra n d omize d, s h o ul d be wit h dra w n fr o m t he 
st u d y. T he pr oce d ures i ncl u de d i n t he pr ot oc ol f or t he disc o nti n uati o n of s uc h s u bjects m ust be 
f oll o we d. S u bjects s h o ul d be f urt her treate d acc or di n g t o t he I n vesti gat or’s j u d g me nt a n d l ocal 
t hera p y tra diti o n. 
If a s u bject n ot meeti n g t he st u d y criteria is ra n d o mize d i n err or, a n d if t he err or is  i de ntifie d after 
Da y 1 Ra n d o mizati o n, a disc ussi o n m ust occ ur bet wee n t he S p o ns or Me dical M o nit or/ desi g nee 
a n d t he I n vesti gat or re gar di n g w het her t o c o nti n ue  or disc o nti n ue t he s u bject fr o m t he st u d y dr u g. 
If a gree me nt t o c o nti n ue i n t he st u d y is reac he d, t he s u bject s h o ul d c o m plete t he st u d y u nless t here 
are safet y c o ncer ns or if t he s u bject wit h dra ws t he c o nse nt. I n s it uati o ns i n w hic h a n a gree me nt 
ca n n ot be reac he d, t he s u bject s h o ul d ha ve t he ra n d o mize d t hera p y st o p pe d a n d be  disc o nti n ue d 
fr o m t he st u d y. T he pr oce d ures i nclu de d i n t he pr ot oc ol f or t he di sc o nti n uati o n of s uc h s u bjects 
m ust be f oll o we d. T he S p o ns or Me dical M o nit or/ desi g nee is t o e ns ure all s uc h c o ntacts wit h t he 
I n vesti gat or a n d s uc h decisi o ns are a p pr o priatel y d oc u me nte d. 
Wit h dra w n s u bjects will n ot be re place d. 
3. 7. 2  R e s c u e G ui d eli n e s f or S u bj e ct s wit h Pr ot o c ol- D efi n e d L a c k of Gl y c e mi c 
C o ntr ol 
D uri n g t he c o urse of t he trial, s u bjects ma y be eli gi ble f or t he a d diti o n of o pe n-la bel resc ue 
me dicati o n t o t heir bli n de d treat me nt re gi me n i n  or der t o treat o n g oi n g h y per gl yce mia. I ns uli n 
ma y be use d as resc ue, at t he I n vesti gat or’s di screti o n. S u bjects w h o were alrea d y ta ki n g i ns uli n 
at t he start of t he st u d y ma y be s witc he d t o a fl e xi ble i ns uli n d ose f oll o wi n g a Resc ue Visit. F or 
s u bjects o n baseli ne i ns uli n, persiste ntl y i ncreased d oses of i ns uli n 2 0 % or m ore a b o ve baseli ne 
d ose, des pite a d vice a n d c o u nsel t o kee p t he i n s uli n d ose sta ble, ma y be c o nsi dere d a n ot her 
p ote ntial ma nifestati o n of p o or gl yce mic c o ntr ol, a n d s h o ul d be e v al uate d f or resc ue. O nl y i ns uli n 
ma y be use d as resc ue me dicati o n, b ut s u bjects ca n be resc ue d wit h o ut t he use of me dicati o n. 
Pre-s pecifie d gl yce m ic criteria (see Ta ble 3. 5. 2- 1 ), base d u p o n self- m o nit ori n g bl o o d gl uc ose 
( S M B G)  F P G,  or  si n gle  ce ntral  la b orat or y  F P G  a n d  re peat  co nfir mat or y  F P G  ha ve  bee n  
esta blis he d d uri n g t he treat me nt  peri o d, starti n g at Wee k 6, an d u p t o, b ut n ot i ncl u di n g, t he 
Wee k 5 2 visit, t o deter mi ne eli gi bilit y f or o pe n- la bel resc ue me dicati o n. A n y per ma ne nt c ha n ges 
i n d ose of basal i ns uli n s h o ul d be d o ne after e val uati o n of resc ue criteria, i ncl u di n g b ot h S M B G 
a n d ce ntral la b orat or y F P G val ues. T o mai ntai n st u d y i nte grit y, plas ma gluc ose sa m ples use d t o 
deter mi ne eli gi bilit y f or resc ue m ust reflect fasti n g val ues. S u bjects w h o are n ot fasti n g at t he ti me 
of sa m ple c ollecti o n will be as ke d t o ret ur n w he n i n a fasti n g state. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 1 
T a ble 3. 5. 2- 1:  
L ac k of Gl yce mic C o ntr ol Criteri a f or I niti ati o n of Resc ue 
Me dic ati o n 
St u d y wee k 
Resc ue criteri o n 
Wee k 6 visit u p t o a n d n ot 
i ncl u di n g Wee k 2 6 visit 
F P G > 1 3. 3 m m ol/ L ( 2 4 0 m g/ d L) base d o n 3 c o nsec uti ve fasti n g S M B G 
val ues f oll o we d b y a c o nfir mat or y ce ntral la b orat or y F P G 
or 
Si n gle ce ntral la b orat or y F P G f oll o we d b y a c o nfir mat or y ce ntral 
la b orat or y F P G 
Wee k 2 6 visit u p t o a n d n ot 
i ncl u di n g Wee k 5 2 visit 
F P G > 1 0 m m ol/ L ( 1 8 0 m g/ d L) base d  o n S M B G f or 3 c o nsec uti ve da ys 
f oll o we d b y a c o nfir mat or y ce ntral la b orat or y F P G 
or 
Si n gle ce ntral la b orat or y F P G f oll o we d b y a c o nfir mat or y ce ntral 
la b orat or y F P G 
or 
H b A 1c > 8. 0 % ( w hile H b A 1c val ues w ill re mai n bli n de d t hr o u g h o ut t he 
st u d y, sites will be n otifie d t o all o w resc ue if val ues e xcee d t his 
t hres h ol d) 
 
S u bjects m ust be re sc ue d f oll o wi n g o ne of t hese sce nari os: 
 S u bjects wit h a S M B G F P G val ue meeti n g t he lac k  of gl yce mic c o ntr ol criteri o n at a n y ti me 
d uri n g t he pre-s pecifie d st u d y peri o d will be i n str ucte d t o re peat F P G meas ure me nts o n 2 
f urt her c o nsec uti ve da ys. If all 3 dail y val ues meet t he rele va nt  lac k of gl yce mic c o ntr ol 
criteri o n s u bjects s h o ul d be sc he d ule d f or a f oll o w- u p visit ( w it hi n 1 - 5 da ys) t o o btai n a 
ce ntral la b orat or y F P G val ue a n d re vie w of t he s u bject’s gl uc ose meter rea di n gs. If t he ce ntral 
la b orat or y F P G val ue meets t he criterio n, t he s u bject m ust be resc ue d. 
 S u bjects wit h a ce ntral la b orat or y F P G val ue meeti n g t he lac k of gl yce mic  c o ntr ol criteri o n at 
a pre-s pecifie d visit will be sc he d ule d f or a f oll o w- u p visit ( wit hi n 3 - 5 da ys) t o o btai n a 
sec o n d ce ntral la b orat or y F P G val ue a n d re vie w t he s u bject’s gl uc ose meter rea di n gs. If t he 
sec o n d ce ntral la b orat or y F P G val ue als o meets t he criteri o n, t he s u bject m ust be resc ue d. 
 S u bjects wit h a ce ntral la b orat or y H b A 1c val ue m eeti n g t he lac k of gl yce mic c o ntr ol criteri o n 
at or f oll o wi n g t he pre-s pecifie d Wee k 2 6 visit m ust be resc ue d. 
S u bjects w h o meet resc ue criteria m ust first c o m plete t he Resc ue Visit pr oce d ures bef ore recei vi n g 
o pe n-la bel resc ue me dicati o n t o e n s ure t hat i m p orta nt trial e n d p oi nt meas ure me nts are c ollecte d. 
F oll o wi n g c o m pleti o n of t he Resc ue Visit, resc ue d s u bjects ma y i nitiate or u p-titrate o pe n-la bel 
i ns uli n as resc ue me dicati o n, at t he discreti o n of t he I n vesti gat ors. I ns uli n s h o ul d be i nitiate d at 
t he l o west starti n g d ose a n d titrate d i n acc or da nce wit h t he a p pr o ve d pr o d uct la bel i n t he a p plica ble 
c o u ntr y  at  t he  discreti o n  of  t he  I n vesti gat or,  i n  a d diti o n  t o  t heir  bli n de d  st u d y  me dicati o n.  
A d diti o nal visits f or titra ti o n of resc ue me dicati o n s h o ul d be sche d ule d as per t h e I n vesti gat or’s 
j u d g me nt i n acc or da nce wit h t he a p pr o ve d pr o d uct la bel f or t hat c o u ntr y a n d b y t he s u bject’s 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 2 
gl yce mic res p o nse. Resc ue d s u bjects will t he n c o nti n ue i n t he st u d y acc or di n g t o t heir ori gi nal 
visit sc he d ule. 
N ote:  Resc ue  me dic ati o n  will  N O T  be  pr o vi de d  b y  t he  S p o ns or  u nless  t his  is  a  l oc al  
re q uire me nt. 
3. 7. 3  Di s c o nti n u ati o n G ui d eli n e s D u e t o Pr ot o c ol- D efi n e d H y p o gl y c e mi a 
E pi s o d e s  
S u bjects  s h o ul d  n ot  be  disc o nt i n ue d  fr o m  a n y  treat me nt  p hase base d  o n  si n gle  e pis o des  of  
h y p o gl yce mia or s y m pt o ms of h y p o gl yce mia u nless cli nicall y i n dicate d. T he assess me nt of a 
si n gle fi n ger-stic k or ce ntral la b orat or y gl uc ose val ue s h o ul d n ot be t he s ole assess me nt use d t o 
deter mi ne s u bject disc o n ti n uati o n f or h y p o gl yce mia. 
Cli nical i n dicati o ns f or disc o nti n uati o n of bli n de d st u d y dr u g beca use of h y p o gl yce mia ma y 
i ncl u de t he f oll o wi n g: 
 M ulti ple occasi o ns of e pis o des o utli ne d bel o w t hat , i n t he o pi ni o n of t he I n vesti gat or, i n dicate 
t hat c o nti n ue d treat me nt wit h st u d y t hera p y is n ot i n t he best i nterest of t he s u bject. T his 
i ncl u des, b ut is n ot li mite d t o: 
 Se vere h y p o gl yce mia as defi ne d b y A D A criteria .1 8 
 Rec urre nt s y m pt o ms s u g gesti v e of h y p o gl yce mia (e. g., s wea ti n g, s ha ki ness, i ncrease d 
heart rate ( H R), c o nf usi o n, dizzi ness, li g ht- hea de d ness, or h u n ger) i n t he a bse nce of 
e n vir o n me ntal  fact ors  k n o w n  t o  c o ntri b u te  t o  h y p o gl yce mia  (i.e.,  e xcess  p h ysical  
acti vit y, c o nc urre nt ill ness, or misse d or dela ye d meal). 
 Rec urre nt  d oc u me nte d  ca pillar y  or  pl as ma  bl o o d  gl uc ose  val ues  <  5 4  m g/ d L  
( < 3. 0 m m ol/ L). 
 A  s u bject  ma y  als o  be  disc o nti n ue d  fr o m  t h e  st u d y  beca use  of  se vere  h y p o gl yce mia  as  
deter mi ne d b y t he I n vesti gat or. 
S u bjects w h o disc o nti n ue bli n de d st u d y dr u g d ue t o h y p o gl yce mia will c o nti n ue t o be f oll o we d i n 
li ne wit h Secti o n 5  u ntil deat h or t he c o ncl usi o n of t he st u d y. 
D o w n-titr ati o n of bli n de d st u d y dr u g a n d/ or  b ac k gr o u n d a nti h y per gl yce mic a ge nt d uri n g 
t he st u d y 
D o w n-titrati o n of bli n de d st u d y dr u g a n d/ or bac k gr o u n d metf or mi n will n ot be  all o we d at a n y ti me 
d uri n g t he st u d y. S u bjects o n bac k gr o u n d i ns uli n tr eat me nt w h o e x perie nce m ulti ple or se vere 
e pis o des of h y p o gl yce mia ma y d o w n-titrate i ns uli n treat me nt d uri n g t he st u d y. T he d o w n-titrati o n 
s h o ul d be mi ni mize d, b ut is at t he I n vesti gat or’s discreti o n. 
3. 7. 4  Di s c o nti n u ati o n G ui d eli n e s D u e t o Di a b eti c K et o a ci d o si s 
T here ha ve bee n p ost- mar keti n g re p orts of ket o aci d osis, i ncl u di n g D K A, i n  patie nts wit h T y pe 1 
a n d T y pe 2 dia betes mellit us ta ki n g da pa glifl ozi n a n d ot her S G L T- 2 i n hi bit ors, alt h o u g h a ca usal 
relati o ns hi p has n ot bee n esta blis he d. Da pa glifl ozi n is n ot a n a p pr o ve d treat me nt f or T y pe 1 
dia betes. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 3 
S u bjects w h o prese nt wit h si g ns a n d s y m pt o ms c o nsiste nt wit h ket oaci d osis, i n cl u di n g na usea, 
v o miti n g, a b d o mi nal pai n, malaise,  a n d s h ort ness of breat h, s h o uld be assesse d f or ket oaci d osis, 
e ve n if bl o o d gl uc ose le vels are bel o w 1 4 m m ol/ L ( 2 5 0 m g/ d L). If ket oaci d osis is s us pecte d, 
disc o nti n uati o n or te m p orar y i nte rr u pti o n of bli n de d st u d y dr u g sh o ul d be c o nsi dere d, a n d t he 
s u bject s h o ul d be pr o m ptl y e val uate d. 
A s u bject wit h a n y s y m pt o ms t hat ma y be c o ns iste nt wit h a n e ve nt of D K A s h o ul d c o ntact t he 
I n vesti gat or, ha ve bl o o d ket o ne le vels meas ure d a n d st u d y dr u g i nterr u pte d. S u bjects s h o ul d 
c o nti n ue i n t he st u d y d uri n g t h e st u d y dr u g i nterr u pti o n a n d u n de r g o all sc he d ule d assess me nts. 
Treat me nt wit h t he st u d y dr u g ma y res u me w he n t h e s y m pt o ms res ol ve or at t he I n vesti gat or’s 
discreti o n. I n t he case of a n esta blis he d D K A, st u d y dr u g s h o ul d be i nterr u pte d u ntil t he e ve nt has 
res ol ve d. 
Pre dis p osi n g  fact ors  t o  ket oaci d osis  i ncl u de  a  l o w  beta-cell  f u ncti o n  reser ve  res ulti n g  fr o m  
pa ncreatic dis or ders (e. g., T y pe 1 dia betes, hist or y of pa ncreatitis, or pa ncreatic s ur ger y), i ns uli n 
d ose re d ucti o n, re d uce d cal or ic i nta ke, or i ncrease d i ns uli n re q uire me nts d ue t o i nfecti o ns, ill ness 
or s ur ger y a n d alc o h ol a b use. 
3. 8  P o st- St u d y Dr u g F oll o w- u p 
P ost-st u d y dr u g f oll o w- u p is of cri tical i m p orta nce a n d is esse ntial t o preser vi n g s u bject safet y a n d 
t he i nte grit y of t he st u d y. S u bjects w h o disc o nti n ue st u d y dr u g m ust c o nti n ue t o be f oll o we d f or 
c ollecti o n of o utc o me a n d/ or s u r vi val f oll o w- u p data as re q uire d a n d i n li ne wit h Secti o n 5  u ntil 
deat h or t he c o ncl usi o n of t he st u d y. 
Please n ote t hat after t he disc o nt i n uati o n of st u d y dr u g, t he ma na ge ment of t he s u bject’s dia betes 
will be u n der t he care a n d directi o n of t he I n vesti gat or. 
T he o nl y e xce pti o n t o a n y of t hese f oll o w- u p met h o ds are w he n a s u bject wit h dra ws c o nse nt f or 
all st u d y pr oce d ures, i ncl u di n g p ost- treat me nt st u d y f oll o w- u p or l oses t he a bilit y t o c o nse nt freel y 
(i.e., is i m pris o ne d or i n v ol u ntaril y i ncarcerate d f or t he treat me nt of eit her a ps yc hiatric or p h ysical 
ill ness). 
3. 8. 1  Wit h dr a w al of C o n s e nt 
S u bjects w h o re q uest t o disc o nti n ue st u d y dr u g will re mai n i n t he st u d y a n d m ust c o nti n ue t o be 
f oll o we d f or pr ot oc ol-s pecifie d f oll o w- u p pr oce d ures. T he o nl y e xce pti o n t o t his is w he n a s u bject 
s pecificall y  wit h dra ws  c o nse nt  f or  a n y  f urt her  c o ntact  wit h  hi m/ her  or  pers o ns  pre vi o usl y  
a ut h orize d b y s u bject t o pr o vi de  t his i nf or mati o n. A s u bject wh o c o nsi ders wit h dra wi n g fr o m t he 
st u d y m ust be i nf or me d b y t he i n vesti gat or a b o ut m o difie d f oll o w- u p o pti o ns  (e. g., site visits wit h 
li mite d pr oce d ures, h o me n ursi n g, p h o ne calls, less fre q ue nt visits , or c o nti n uati o n i n t he st u d y 
wit h o ut f urt her treat me nt). 
S u bjects s h o ul d n otif y t he I n vesti gat or of t he decisi o n t o wit h dra w  c o nse nt fr o m f ut ure f oll o w- u p 
i n writi n g, w he ne ver p ossi ble. A s u bject w h o wit h dra ws c o nse nt will al wa ys be as ke d a b o ut t he 
reas o n(s) a n d t he prese nce of a n y A E. T he wit h dra wal of c o nse nt s h o ul d be e x plai ne d i n detail i n 
t he me dical rec or ds b y t he I n vesti gat or, as t o w het her t he wit h dra wal is fr o m f urt her treat me nt 
wit h st u d y dr u g o nl y or als o fr o m st u d y pr oce d ur es a n d/ or p ost-treat me nt st u d y f oll o w- u p, a n d 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 4 
e ntere d o n t he a p pr o priate C R F pa ge. If dee me d nece ssar y, t he I n vesti gat or will f oll o w- u p s u bjects 
as me dicall y i n dicate d. 
If a s u bject wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he S p o ns or ma y retai n a n d 
c o nti n ue t o use a n y data c ollec te d bef ore s uc h a wit h dra wal of c o nse nt. If a s u bject wit h dra ws 
fr o m t he st u d y, it s h o ul d be c o nfir me d if he/s he still a grees f or e xisti n g sa m ples t o be use d i n li ne 
wit h t he ori gi nal c o nse nt. If he/s he re q uests wit h dr a wal of c o nse nt f or use of sa m ples, destr ucti o n 
of a n y sa m ples ta ke n a n d n ot teste d s h o ul d be carri e d o ut i n li ne wit h w hat was state d i n t he 
i nf or me d c o nse nt a n d l ocal re g ulati o n T he i n vesti gat or m ust d oc u me nt t he decisi o n o n use of 
e xisti n g sa m ples i n t he site st u d y rec o r ds a n d i nf or m t he Gl o bal St u d y Tea m. 
Wit h dr a w al of I nf or me d C o nse nt f or d o n ate d bi ol o gic al s a m ples  
If a s u bject wit h dra ws c o nse nt t o t he use of d o nate d bi ol o gical sa m ples, t he sa m ples will be 
destr o ye d, a n d t he acti o n d oc u me nte d. If sa m ples are alrea d y a nal yze d , t he S p o ns or is n ot o bli ge d 
t o destr o y t he res ults of t his researc h. 
T he i n vesti gat or m ust e ns ure: 
 S u bject’s  wit h dra wal  of  i nf or me d  c o nse nt  t o  t he  use  of  d o nate d  sa m ples  is  n otifie d  
i m me diatel y t o t he S p o ns or/ desi g nee. 
 Bi ol o gical sa m ples fr o m t hat s u bject, if st ore d at t he st u d y site, are i m me diatel y i de ntifie d, 
destr o ye d, a n d t he acti o n d oc u me nte d. 
 T he la b orat or y h ol di n g t he sa m ples is i nf or me d a b o ut t he wit h dra w n c o nse nt i m me diatel y a n d 
t hat sa m ples are destr o ye d, a n d t he acti o n d oc u me nte d. 
 T he s u bject a n d S p o ns or/ des i g nee are i nf or me d a b o ut t he sa m ple dis p osal. 
3. 8. 2  L o st t o F oll o w- u p 
All reas o na ble eff orts m ust be ma de t o l ocate s u bjects t o deter mi ne a n d re p ort t heir o n g oi n g stat us. 
T his i ncl u des f oll o w- u p wit h pers o ns a ut h orize d b y t he s u bject as n ote d a b o ve. L ost t o f oll o w- u p 
is defi ne d b y t he i na bilit y t o reac h t he s u bject after a mi ni m u m of t hree d oc u me nte d p h o ne calls, 
fa xes, or e mails as well as lac k of res p o nse b y su bject t o o ne re gi stere d mail letter. All atte m pts 
s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds. If it is deter mi ne d t hat t he s u bject has die d, 
t he site will use per missi ble l ocal met h o ds t o o btai n t he date a n d ca use of deat h. 
If t he I n vesti gat or’s use of a t hir d- part y re prese ntati ve t o assist i n t he f oll o w- u p p orti o n of t he 
st u d y  has  bee n  i ncl u de d  i n  t he  s ubject’s  i nf or me d  c o nse nt,  t he n  t he  I n vesti gat or  ma y  use  a  
S p o ns or-retai ne d t hir d- part y re prese n tati ve t o assist site staff wit h o btai ni n g t he s u bject’s c o ntact 
i nf or mati o n or ot her data necessar y t o c o m plete t he f oll o w- u p p orti o n of t he st u d y. T he site staff 
a n d re prese ntati ve will c o n d uct searc hes i n a le gall y per missi ble ma n ner t hat ma y i ncl u de p u blic 
rec or ds a n d data base researc h, s ocial me dia researc h, a n d ge neal o gical resear c h. P h ysical researc h 
of l ocal m u nici pal res o urces, as all o we d b y l ocal  la ws a n d re g ulati o ns, ma y be c o n d ucte d. If after 
all atte m pts, t he s u bject re mai ns l ost t o f oll o w- u p, t he n t he last k n o w n ali ve date as deter mi ne d b y 
t he I n vesti gat or s h o ul d be re p orte d a n d d oc u me nte d i n t he s u bject’s me dical rec or ds. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: - 0 7- Fe b- 2 0 2 2 
5 5 
4
 S T U D Y
 D R U G
 
St u d y dr u g i ncl u des b ot h I n vesti gat i o nal [ Me dici nal] Pr o d uct (I P/I MP) a n d N o n-i n vesti gati o nal 
[ Me dici nal] Pr o d uct ( N o n-I P/ N o n-I M P) an d ca n c o nsist of t he f oll o wi n g: 
 All pr o d ucts, acti ve or place b o, bei n g teste d or us e d as a c o m parat or i n a cli nical trial  
 Ot her  dr u gs  a d mi nistere d  as  part  of  t he  st u d y  t hat  are  critical  t o  clai ms  of  efficac y  
(e. g., bac k gr o u n d t hera p y, resc ue me dicati o ns). 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n  
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
5 6 
T a ble 4- 1:  
St u d y Dr u gs f or C V 1 8 1 3 7 5: Pr o d uct Descri pti o n: S h ort-ter m D o u ble- Bli n de d Tre at me nt Peri o d a n d 
L o n g-ter m S u bject- a n d Site- B li n de d Tre at me nt Peri o d 
Pr o d uct Descri pti o n / 
Cl ass a n d D os a ge F or m 
P ote nc y 
I P / 
N o n-I M P 
Bli n de d or O pe n 
L a bel 
M a n uf act urer
 P ac k a gi n g/
 
A p pe ar a nce
 
St or a ge C o n diti o ns 
( per l a bel) 
Sa xa gli pti n Fil m C oate d 
Ta blet  
(as t he free base) 
5 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Plai n, yell o w, bic o n ve x, 
r o u n d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Sa xa gli pti n Fil m C oate d 
Ta blet (as t he free base) 
2. 5 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Plai n, yell o w, bic o n ve x, 
r o u n d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Place b o f or Sa xa gli pti n 
Fil m C oate d Ta blets  
2. 5/ 5 m g 
0 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Plai n, yell o w, bic o n ve x, 
r o u n d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Da pa glifl ozi n Fil m C oate d 
Ta blet  
5 m g 
5 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Gree n, plai n, dia m o n d 
s ha pe d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Place b o f or Da pa glifl ozi n 
Fil m C oate d Ta blets  
5 m g 
0 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Gree n, plai n, dia m o n d 
s ha pe d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Da pa glifl ozi n Fil m C oate d 
Ta blet 
1 0 m g 
1 0 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Gree n, plai n, dia m o n d 
s ha pe d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
Place b o f or Da pa glifl ozi n 
Fil m C oate d Ta blets 
1 0 m g 
0 m g  
I P  
Bli n de d La bel  
Astra Ze neca 
Gree n, plai n, dia m o n d 
s ha pe d, fil m c oate d ta blet, 
H D P E b ottle 
St ora ge c o n diti o ns  
( per la bel),  
pri nte d o n I P b ottles 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
5 7 
4. 1  I n v e sti g ati o n al  Pr o d u ct  
A n I P, als o k n o w n as a n I M P i n  s o me re gi o ns, is defi ne d a p har mace utical f or m of a n acti ve 
s u bsta nce or place b o bei n g teste d or use d as a refere nce i n a cli nical st u d y, i ncl u di n g pr o d ucts 
alrea d y wit h a mar keti n g a ut h orizati o n b ut use d or  asse m ble d (f or m ulate d or pac ka ge d) differe ntl y 
t ha n t he a ut h orize d f or m, or use d f or a n u na ut h orize d i n dicati o n, or w he n use d t o gai n f urt her 
i nf or mati o n a b o ut t he a ut h orize d f or m. 
T he I P s h o ul d be st ore d i n a sec u re area acc or di n g t o l ocal re g ulati o ns. It is t he res p o nsi bilit y of 
t he I n vesti gat or t o e ns ure t hat I P is o nl y dis pe nse d t o st u d y s u bjects. T he I P m ust be dis pe nse d 
o nl y fr o m official st u d y sites b y a ut h orize d pers o n nel acc or di n g t o l ocal re g ulati o ns, e xce pt w here 
t he  I P  has  t o  be  se nt  directl y  t o  t he  s u bjects’  h o mes  d ue  t o  t he  c or o na vir us  disease  2 0 1 9  
( C O VI D- 1 9)  pa n de mic.  O nl y  s u bjects  ra n d o mize d i n  t he  st u d y  ma y  r ecei ve  I Ps,  a n d  o nl y  
a ut h orize d site staff ma y s u p pl y or a d mi nister I Ps. U ntil dis pe nsati o n t o st u d y partici pa nts, all I Ps 
m ust be st ore d i n a sec ure, e n vi r o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area 
i n acc or da nce wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he I n vesti gat or a n d 
a ut h orize d site staff. 
T he I Ps are descri be d i n  Ta ble 4- 1 . T he ta blets ma y c o ntai n lact ose, w hic h ma y ca use disc o mf ort 
i n lact ose i nt olera nt i n di vi d uals. Pri mar y pac ka gi n g of t he I P will be carrie d o ut b y Astra Ze neca 
or t heir desi g nee i n acc or da nce wit h G o o d Ma n ufact uri n g Practice ( G M P). Bac k gr o u n d t hera p y 
metf or mi n (I R or X R) a n d i ns uli n (as a p pr o priate) will n ot be pr o vi de d b y t he S p o ns or u nless t his 
is a l ocal re q uire me nt.  
La beli n g: La bels will be pre pare d i n acc or da n ce wit h G M P a n d l ocal re g ulat or y g ui deli nes. T he 
la bels will f ulfill G M P A n ne x 1 3 re q uire me nts f or labeli n g. La bel te xt will be tra nslate d i nt o l ocal 
la n g ua ge acc or di n g t o t he re gi o nal re g ulat or y re q uire me nts. 
4. 2  N o n-I n v e sti g ati o n al  Pr o d u ct  
Ot her me dicati o ns use d as s u p p ort or resc ue me dica ti o n f or pre ve ntati ve, diag n ostic, or t hera pe utic 
reas o ns, as c o m p o ne nts of t he sta n dar d of care f or a gi ve n dia g n osis, ma y be c o nsi dere d as n o n-I Ps.  
S u bjects are e x pecte d t o be o n bac k gr o u n d me dicati o n of metf or mi n  (I R or X R) a n d/ or i ns uli n. 
I ns uli n,  as  per  l ocal  la beli n g  a n d  sta n dar d  of  care,  will  be  use d  f or  resc ue  as  descri be d  i n  
Secti o n  3. 6 . 
4. 3  St or a g e a n d Di s p e n si n g 
T he pr o d uct st ora ge ma na ger s h o ul d e ns ure t hat t he st u d y dr u g is st ore d i n acc or da nce wit h t he 
e n vir o n me ntal  c o n diti o ns  (te m perat ure,  li g ht,  a n d  h u mi dit y)  as  deter mi ne d  b y  t he  
S p o ns or/ desi g nee. If c o ncer ns re gar di n g t he q ualit y or a p peara nce of t he st u d y dr u g arise, t he st u d y 
dr u g s h o ul d n ot be dis pe nse d a n d t he S p o ns or/ des i g nee s h o ul d be c o ntacte d i m me diatel y. All st u d y 
dr u gs s h o ul d be ke pt i n a sec ure place u n der a p pr o priate st ora ge c o n diti o ns. T he I P la bel o n t he 
b ottle  s pecifies  t he  a p pr o priate  st ora ge.  T he  I n vesti gat or  a n d/ or  desi g nee  m ust  c o nfir m  t hat  
a p pr o priate  te m perat ure  c o n diti o ns  ha ve  bee n  mai ntai ne d  d uri n g  tra nsit  f or  all  st u d y  dr u gs  
recei ve d a n d a n y discre pa ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y dr u gs. 
St u d y dr u g n ot s u p plie d b y t he S p o ns or will be st or e d i n acc or da nce wit h t he pac ka ge i nsert. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
5 8 
I n vesti gati o nal  pr o d uct  d oc u me ntati o n  ( w het her  s u p plie d  b y  t he  S p o ns or  or  n ot)  m ust  be  
mai ntai ne d t hat i ncl u des all pr ocesses re q uire d t o e ns ure dr u g is acc uratel y a d mi nistere d. T his 
i ncl u des d oc u me ntati o n of dr u g st ora ge, a d mi nistrati o n a n d, as a p pl ica ble, st ora ge te m perat ures, 
rec o nstit uti o n, a n d use of re q uire d pr ocesses (e. g., re q uire d dil ue nts, a d mi nistrati o n sets). T he 
I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble f or 
st u d y dr u g acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., recei pt, rec o nciliati o n, a n d 
fi nal dis p ositi o n rec or ds). 
F urt her g ui da nce a n d i nf o r mati o n f or t he fi nal dis p ositi o n of u n use d st u d y dr u gs are pr o vi de d i n 
Secti o n  4. 8 . 
4. 4  M et h o d  of  A s si g ni n g  S u bj e ct I d e ntifi c ati o n 
At t he scree ni n g visit eac h s u bject will be a ssi g ne d a u ni q ue se q ue ntial s u bject n u m ber b y t he 
I nteracti ve We b/ V oice Res p o nse S yste m (I X R S). T his n u m ber will be use d f or i de ntificati o n 
t hr o u g h o ut t he st u d y a n d will n ot be use d f or a n y ot her partici pa nt. 
Ra n d o mize d sc he d ules will be ge nerate d a n d ke pt b y t he S p o ns or/ desi g nee. S u bjects will be 
ra n d o ml y assi g ne d t o 1 of 3 bli n de d treat me nt gr o u ps b y t he I X R S i n a 1: 1: 1 rati o. Da y 1 
Ra n d o mizati o n will be stratifie d b y ge n der, a ge at ra n d o mizati o n ( 1 0 t o bel o w 1 5 years of a ge, 1 5 
t o bel o w 1 8 years of a ge) a n d baseli ne me dicati o n ( metf or mi n al o ne, i ns uli nmetf or mi n).  
S u bjects e nteri n g t he 2- wee k le a d-i n peri o d 
F oll o wi n g c o m pleti o n of t he Scree ni n g acti vities, s u bjects w h o meet  all t he i ncl usi o n a n d n o ne of 
t he e xcl usi o n criteria will be re gistere d b y t he I X R S i nt o t he lea d-i n peri o d. 
S u bjects e nteri n g t he 2 6- wee k d o u ble- b li n de d s h ort-ter m tre at me nt peri o d 
F oll o wi n g c o m pleti o n of t he lea d-i n peri o d, s u bj ects w h o meet t he criteria will be ra n d o ml y 
assi g ne d  b y  t he  I X R S  at  t he  Da y  1  Ra n d o mizati o n  visit,  t o  o ne  of  t he  f oll o wi n g  t hree  ( 3)  
d o u ble- bli n d treat me nt ar ms i n a 1: 1: 1 rati o: 
 Bli n de d da pa glifl ozi n 5 m g 
 Bli n de d sa xa gli pti n 2. 5 m g 
 Bli n de d place b o 
S u bjects at Wee k 1 2 Bli n de d H b A 1c Assess me nt 
 A bli n de d H b A 1c assess me nt will be perf or me d  at Wee k 1 2 f or all s u bjects o n treat me nt. 
H b A 1c res ults will be bli n de d t hr o u g h o ut t he st u d y u ntil after st u d y c o m pleti o n. A sec o n d 
ra n d o mizati o n  will  be  perf or me d  at  Wee k 1 4,  base d  o n  t he  Wee k  1 2  bli n de d  H b A 1c  
assess me nt. All s u bjects wit h Wee k 1 2 H b A 1c va l ues < 7 % will re mai n o n pre vi o usl y assi g ne d 
ra n d o mize d treat me nt ( bli n de d dapa glifl ozi n 5 m g, or bli n de d sa xa gli pti n 2. 5 m g, or bli n de d 
place b o) after t he Wee k 1 2 assess me nt.     
 S u bjects assi g ne d t o t he bli n de d da pa glifl ozi n treat me nt ar m at Da y 1 Ra n d o mizati o n wit h 
Wee k 1 2 H b A 1c val ues ≥ 7 % will be re-ra n d o mize d i n a 1:1 rati o t o c o nti n ue o n t he l o w- d ose 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
5 9 
treat me nt  ( bli n de d  da pa glifl ozi n  5  m g)  or  u p-titrate  t o  t he hi g h- d ose  treat me nt  ( bli n de d  
da pa glifl ozi n 1 0 m g) after t he Wee k 1 2 assess me nt.   
 S u bjects assi g ne d t o t he bli n de d sa xa gli pti n treat me nt ar m at Da y 1 Ra n d o mizati o n wit h 
Wee k 1 2 H b A 1c val ues ≥ 7 % will be re-ra n d o mize d i n a 1:1 rati o t o c o nti n ue o n t he l o w- d ose 
treat me nt  ( bli n de d  sa xa gli pti n  2. 5  m g)  or  u p-titrate  t o  t he hi g h- d ose  treat me nt  ( bli n de d  
sa xa gli pti n 5 m g) after t he Wee k 1 2 assess me nt. 
 S u bjects assi g ne d t o t he bli n de d place b o treat me nt ar m at Da y 1 Ra n d o mizati o n wit h Wee k 1 2 
H b A 1c val ues ≥ 7 % will c o nti n ue o n place b o after t he Wee k 1 2 assess me nt. 
 T o mai ntai n t he bli n di n g of treat me nts as well as H b A 1c res ults, all place b o s u bjects a n d all 
s u bjects ta ki n g sa xa gli pti n or da pa glifl ozi n wit h a n H b A 1c < 7 % at Wee k 1 2 will g o t hr o u g h 
a d u m m y sec o n d ra n d o mizati o n pr ocess t hat will be  i n disti n g uis ha ble (f or t he s u bjects a n d site 
pers o n nel) fr o m t he act ual sec o n d ra n d o mizati o n. 
 D uri n g t he Wee k 1 4 visit, bli n de d st u d y dr u g will be  dis pe nse d t o all s u bjects i n acc or da nce 
wit h t he treat me nt assi g n me nts base d o n Wee k 1 2 H b A 1c assess me nts. 
S u bjects e nteri n g t he 2 6- wee k d o u ble- bli n d l o n g-ter m e xte nsi o n peri o d 
F oll o wi n g c o m pleti o n of t he 2 6- wee k d o u ble- bli n de d tr eat me nt peri o d, s u bjects  will e nter t he L T 
d o u ble- bli n d treat me nt peri o d. All s u bjects will re ma i n i n t heir sa me ra n d o mizati o n assi g n me nt 
base d o n t heir Wee k 1 2 ra n d o mizati o n gr o u pi n g.  
S u bjects  eli gi ble  f or  r a n d o mize d  wit h dr a w al  of  b ac k gr o u n d  me dic ati o n  ( metf or mi n)  at  
Wee k 3 2 or Wee k 4 0 
After c o m pleti o n of Wee k 2 6 assess me nts, a s u bs et of eli gi ble s u bjects will u n der g o ra n d o mize d 
wit h dra wal of bac k gr o u n d me dicati o n at Wee k 3 2 (if H b A 1c < 7. 5 % at Wee k 2 6) or Wee k 4 0 (if 
s u bject di d n ot q ualif y at Wee k 2 6 a n d H b A 1c ≥ 7. 5 % at Wee k 2 6 a n d < 7. 5 % at Wee k 3 2). 
Eli gi bilit y f or ra n d o mize d wit h dra wal of bac k gr o u n d me di cati o n is descri be d i n Secti o n 3. 1.  
Eli gi ble s u bjects w h o are rece i vi n g acti ve treat me nt will be ra n d o mize d 1: 1 t o eit her: 
 Disc o nti n ue bac k gr o u n d treat me nt wit h metf or mi n ; s u bjects w h o are c urre ntl y recei vi n g hi g h 
d oses of sa xa gli pti n ( 5 m g) or da pa glifl ozi n ( 1 0 m g) will c o nti n ue t o recei ve t he hi g h d oses. 
S u bjects w h o are c urre ntl y recei vi n g l o w d oses of  sa xa gli pti n ( 2. 5 m g) or da pa glifl ozi n ( 5 m g) 
will ha ve t heir d oses u p-titrate d t o t he hi g h d oses (sa xa gli pti n 5 m g or da pa glifl ozi n 1 0 m g).  
 C o nti n ue bac k gr o u n d me dicati o n wit h metf or mi n;  t hese s u bjects will c o nti n ue wit h t heir 
c urre nt d ose of eit her sa xa gli pti n or da pa glifl ozi n. 
A s u bset of s u bjects fr o m t he place b o ar m will be ra n d o mize d 1: 1: 1 t o eit her: 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 0 
 Wit h dra w bac k gr o u n d me dicati o n a n d s witc h t o acti ve treat me nt wit h sa xa gli pti n 5 m g  
 Wit h dra w bac k gr o u n d me dicati o n a n d s witc h t o acti ve treat me nt wit h da pa glifl ozi n 1 0 m g 
 Re mai n o n bac k gr o u n d me dicati o n wit h me tf or mi n a n d c o nti n ue wit h place b o  
D uri n g t he t hir d ra n d o mizati o n visit, s u bjects will e it her be i nf or me d t hat t he y will re mai n o n t heir 
c urre nt  bac k gr o u n d  me dicati o n  or  will  be  as ke d  t o  disc o nti n ue  bac k gr o u n d  treat me nt  wit h  
metf or mi n  a n d  will  be  dis pe nse d  a  ne w  set  of  st u d y  dr u gs.  Disc o nti n uati o n  of  bac k gr o u n d  
metf or mi n will occ ur i n a n u n bli n de d ma n ner. 
If  m ore  t ha n  1 2  wee ks  ela pse  bet wee n  t he  H b A 1c  c ollecti o n  at  Wee k  2 6  a n d  t he  t hir d  
ra n d o mizati o n at Wee k 3 2, or t he H b A 1c c ollecti o n at Wee k 3 2 a n d t he t hir d ra n d o mizati o n at 
Wee k 4 0, t he s u bject s h o ul d n ot g o t hr o u g h t his  ra n d o mizati o n as t he H b A 1c val ue w o ul d n o 
l o n ger  be  relia ble  t o  ascertai n  eli gi bilit y  f or  t he  t hir d  ra n d o mizati o n.  H o we ver,  s u bjects  n ot  
q ualif yi n g base d o n t heir H b A 1c val ue at t he Wee k  2 6 visit beca use m ore t ha n 1 2 wee ks ela pse d 
bet wee n t he Wee k 2 6 a n d Wee k 3 2 visits, ma y still be a ble t o q ualif y base d o n t he H b A 1c val ue 
at t he Wee k 3 2 visit, if n o m ore t ha n 1 2 wee ks ela pses bet wee n t he Wee k 3 2 visit a n d t he Wee k 4 0 
visit a n d t he s u bject ot he r wise meets criteria.  
At all st u d y visits w he n st u d y dr u g is dis pe n se d, eac h s u bject will be assi g ne d u ni q ue Kit I D 
n u m bers b y t he I X R S. Kit I D n u m bers will be assi g ne d n o n-se q ue ntiall y a n d will c orres p o n d t o 
t he n u m bers pri nte d o n t he b ottles c o ntai ni n g st u d y dr u g, a n d will be rec or de d o n t he a p pr o priate 
e C R F. T he I X R S will be a vaila ble 2 4 h o urs per da y, 7 da ys a wee k. 
4. 5  S el e cti o n a n d Ti mi n g of D o s e f or E a c h S u bj e ct 
S u bjects s uccessf ull y c o m pleti n g t he lea d-i n peri o d a n d meeti n g all eli gi bilit y criteria will be 
ra n d o mize d ( 1: 1: 1) t o receive eit her da pa glifl ozi n 5 m g, or sa xa gli pti n 2. 5 m g or place b o ( o n t o p 
of bac k gr o u n d t hera p y). 
Da pa glifl ozi n 5 m g or 1 0 m g ta bl ets or matc hi n g place b o ta blets wi ll be a d mi nistere d orall y o nce 
dail y d uri n g t he bli n de d treat me nt peri o ds. S u bjects will be i nstr ucte d t o ta ke o ne ta blet fr o m eac h 
b ottle pr o vi de d ( 2 b ottles u p t o Wee k 1 4 [ Ta ble 3. 1- 1 ] a n d 3 b ottles fr o m Wee k 1 4 t o Wee k 5 2 
[Ta ble 3. 1- 2 ]. 
S u bjects  i nitiall y  ra n d o mize d  ( Da y  1  t o  Wee k  1 4)  t o  t he  da pa glifl ozi n  5  m g  gr o u p  will  be  
a d mi nistere d o ne acti ve da pa glifl o zi n 5 m g ta blet, a n d o ne sa xa gl i pti n place b o ta blet. S u bjects 
re-ra n d o mize d ( Wee k 1 4 t o Wee k 5 2) t o t he da pa glifl ozi n 5 m g gr o u p a n d s u bjects i nitiall y 
ra n d o mize d t o t he da pa glifl ozi n 5 m g gr o u p w h o di d n ot q ualif y f o r t he sec o n d ra n d o mizati o n will 
be a d mi nistere d o ne acti ve da pa gl ifl ozi n 5 m g ta blet, o ne da pa glifl ozi n 1 0 m g place b o ta blet a n d 
o ne sa xa gli pti n place b o ta blet. S u bjects re-ra n d o mize d ( Wee k 1 4 t o Wee k 5 2) t o t he da pa glifl ozi n 
1 0 m g gr o u p will be a d mi nistere d o ne acti ve da pa glifl ozi n 1 0 m g ta blet, o ne da pa glifl ozi n 5 m g 
place b o ta blet a n d o ne sa xa gli pti n place b o ta blet. 
Sa xa gli pti n 2. 5 m g or 5 m g ta blets or matc hi n g place b o ta blets will be a d mi nistere d orall y o nce 
dail y d uri n g t he bli n de d treat me n t peri o ds. S u bjects i nitiall y ra n d o mize d ( Da y 1 t o Wee k 1 4) t o 
t he sa xa gli pti n 2. 5 m g gr o u p will be a d mi nistere d o ne acti ve sa xa gli pti n 2. 5 m g ta blet a n d o ne 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 1 
da pa glifl ozi n 5 m g place b o ta blet . S u bjects re-ra n d o mize d ( Wee k 1 4 t o Wee k 5 2) t o t he sa xa gli pti n 
2. 5 m g gr o u p a n d s u bjects i nitiall y ra n d o mize d t o t he sa xa gli pti n 2. 5 m g gro u p w h o di d n ot q ualif y 
f or t he sec o n d ra n d o mizati o n will be a d mi nistere d o ne acti ve sa xa gli pti n 2. 5 m g ta blet, o ne 
da pa glifl ozi n  5  m g  place b o  ta blet,  a n d  o ne  da pa glifl ozi n  1 0  m g  place b o  ta blet.  S u bjects  
re-ra n d o mize d ( Wee k 1 4 t o Wee k 5 2) t o t he sa xa gli pti n 5 m g gr o u p will be a d mi nistere d o ne 
acti ve sa xa gli pti n 5 m g ta blet, o ne  da pa glifl ozi n 5 m g place b o ta blet, a n d o ne da pa glifl ozi n 1 0 m g 
place b o ta blet.  
Sa xa gli pti n a n d da pa glifl ozi n ma tc hi n g place b o ta blets will be a d mi nistere d orall y o nce dail y 
d uri n g t he bli n de d treat me n t peri o ds. S u bjects i nitiall y ra n d o mize d ( Da y 1 t o Wee k 1 4) t o t he 
Place b o gr o u p will be a d mi nistere d o ne sa xa gli pti n  place b o ta blet a n d o ne da pa glifl ozi n 5 m g 
place b o ta blet. After t he sec o n d ra n d o mizati o n ( Wee k 1 4 t o Wee k 5 2), place b o s u bjects will be 
a d mi nistere d  o ne  sa xa gli pti n  pl ace b o  ta blet,  o ne  da pa glifl ozi n  5  m g  place b o  ta blet,  a n d  o ne  
da pa glifl ozi n 1 0 m g place b o ta blet (see  Ta ble 3. 1- 1 a n d Ta ble 3. 1- 2). 
T he ta blet c o m p o ne nts f or eac h st u d y treat me nt descri be d i n Ta ble 3. 1- 2  will als o a p pl y f or t h ose 
s u bjects u n der g oi n g ra n d o mize d wit h dra wal of bac k gr o u n d me dicati o n at Wee k 3 2 or Wee k 4 0. 
4. 6  Bli n di n g/ U n bli n di n g  
Bli n di n g of treat me nt assi g n me n t is critical t o t he i nte grit y of t his cli nical st u d y.  
Met h o ds use d t o e ns ure bli n di n g i ncl u de:  
 I n vesti gati o nal pr o d uct will be la bele d usi n g a u niq ue material kit I D, w hic h is li n ke d t o t he 
Da y 1 ra n d o mizati o n c o de, t he Wee k 1 4 ra n d o mizati o n c o de, a n d t he Wee k 3 2/ Wee k 4 0 
ra n d o mizati o n c o de.  
 T he I X R S will assi g n t he b ottle of st u d y mate rial t o be dis pe nse d t o eac h s u bject.  
 T his  is  a  d o u ble- bli n d  st u d y  w herei n  eac h  s u bj ect  will  recei ve  eit her  t he  acti ve  dr u g  or  
matc hi n g place b o. T he acti ve dr u g a n d place b o ta blets will be i de ntical a n d prese nte d i n 
i de ntical pac ka gi n g t o e ns ure bli n di n g of t he me dicati o n. 
H o we ver, i n t he e ve nt of a me dical e mer ge nc y or  pre g na nc y i n a n i n di vi d ual s u bject i n w hic h 
k n o wle d ge of t he I P is critical t o t he s u bject's ma na ge me nt, t he bli n d f or t h at s u bject ma y be br o ke n 
b y t he I n vesti gat or. T he s u bject’s safet y ta kes pri o rit y o ver a n y ot her c o nsi derati o ns i n deter mi ni n g 
if a treat me nt assi g n me nt s h o ul d be u n bli n de d. 
Bef ore brea ki n g t he bli n d of a n i n di vi d ual s u bject's  treat me nt, t he I n vesti gat or s h o ul d deter mi ne 
t hat  t he  u n bli n de d  i nf or mati o n  is  necessar y,  i.e.,  t hat  it  will  alter  t he  s u bject's  i m me diate  
ma na ge me nt. I n ma n y cases, partic ul arl y w he n t he e mer ge nc y is clea rl y n ot relate d t o t he I P, t he 
pr o ble m ma y be pr o perl y ma na ge d b y ass u mi n g t hat t he s u bject is  recei vi n g acti ve pr o d uct. It is 
hi g hl y desira ble t hat t he decisi o n t o u n bli n d treat me nt assi g n me nt be disc usse d wit h t he Me dical 
M o nit or, b ut t he I n vesti gat or al wa ys has ulti mate a ut h orit y f or t he decisi o n t o u n bli n d. T he  
Pri nci pal  I n vesti gat or  s h o ul d  o nl y  call  i n  f or  e mer ge nc y  u n bli n di n g  A F T E R  t he  decisi o n  t o  
disc o nti n ue t he s u bject has bee n ma de. 
F or t his st u d y, t he met h o d of u n bli n di n g f o r e mer ge nc y p ur p oses is via t he I X R S.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 2 
A n y  re q uest  t o  u n bli n d  a  s u bject  f or  n o n-e mer ge nc y  p ur p oses  s h o ul d  be  disc usse d  wit h  t he  
Me dical M o nit or. 
T he e xce pti o n is f or t h ose pers o n nel a nal yzi n g t he P K data, t he Astra Ze neca S u p pl y C hai n St u d y 
Ma na ge me nt ( S C S M) tea m a n d t he res p o nsi ble pers o n nel carr yi n g o ut t he pac ka gi n g a n d la beli n g 
of I Ps. T he Da y 1 Ra n d o mizati o n c o de will be pr o vi de d t o e ns ure a p pr o priate treat me nt all ocati o n 
a n d t hat o nl y P K sa m ples fr o m s u bjects w h o were o n t he rele va nt acti ve st u d y treat me nt are 
a nal yze d. 
F or s u bjects w h o are ra n d o mize d  t o wit h dra w bac k gr o u n d metf ormi n, t he i n vesti gat or ma y be 
partiall y u n bli n de d t o t he s u bj ect’s treat me nt assi g n me nt. 
If a s u bject wit h dra ws fr o m t he st u d y, t he n his/ he r e nr oll me nt/ra n d o mizati o n c o des ca n n ot be 
re use d. Wit h dra w n s u bjects will n ot be re place d. 
4. 7  Tr e at m e nt  C o m pli a n c e  
Eac h ti me st u d y me dicati o n is di s pe nse d, c o m plia nce will be rei nf orce d. W he n st u d y me dicati o n 
is ret ur ne d, c o m plia nce will be assesse d base d u p o n s u bject’s i nter vie w a n d a c o u nt of t he ta blets 
ret ur ne d. C o m plia nce s h o ul d be bet wee n  8 0 % a n d  1 2 0 % of t hat prescri be d. T he i n vesti gat or 
( or desi g nee) will rec or d t he a m o u nts of st u d y me dicati o n dis pe nse d a n d ret ur ne d at eac h visit, as 
well as d oc u me nt reas o ns f or n o n-c o m plia nce i n t h e s o urce d oc u me nt. T he dates of all st u d y 
me dicati o n d osi n g, i ncl u di n g i nterr u pti o ns, misse d  d oses, me dicati o n err ors, or o ver d ose (see 
Secti o n  6. 5 ), m ust be rec or de d o n t he e C R F. 
If t he s u bject is n ot  8 0 % c o m plia nt wit h stu d y dr u g d oses d uri n g t he st u d y, t he n t he peri o d of 
n o n-c o m plia nce s h o ul d be n ote d as  a si g nifica nt pr ot oc ol de viati o n a n d t he S p o ns or/ desi g nee 
s h o ul d be n otifie d. T he s u bject s h o ul d be re-ed ucate d re gar di n g t he i m p orta nce of st u d y dr u g 
c o m plia nce. 
4. 8  D e str u cti o n of St u d y Dr u g 
F or t his st u d y, st u d y dr u gs (t h ose s u p plie d b y t he S p o ns or or s o urce d b y t he I n vesti gat or) s uc h as 
partiall y use d st u d y dr u g b ottles, vials a n d s yri n ges are t o be destr o ye d l ocall y at a site a p pr o ve d 
b y t he l ocal Re g ulat or y A ut h orit y i n  acc or da nce wit h l ocal re g ulati o ns. 
A n y  u n use d  st u d y  dr u gs  ca n  o nl y  be  destr o ye d  after  bei n g  i ns pecte d  a n d  rec o ncile d  b y  t he  
res p o nsi ble St u d y M o nit or u nless st u d y dr u g b ottles m ust be i m me diatel y destr o ye d as re q uire d 
f or safet y, or t o meet l ocal re g ulati o ns (e. g., c yt ot o xics or bi ol o gics). 
O n-site destr ucti o n is all o we d pr o vi de d t he f oll o wi n g mi ni mal sta n dar ds are met: 
 O n-site dis p osal practices m ust n ot e x p ose h u ma ns t o ris ks fr o m t he dr u g. 
 O n-site  dis p osal  practices  a n d  pr oce d ures  ar e  i n  a gree me nt  wit h  a p plica ble  la ws  a n d  
re g ulati o ns, i ncl u di n g a n y s pecial re q uire me nts f or c o ntr oll e d or hazar d o us s u bsta nces. 
 Writte n pr oce d ures f or o n-site dis p osal are a vaila ble a n d f oll o we d. T he pr oce d ures m ust be 
file d  wit h  t he  site’s  sta n dar d  o perati n g  proce d ures  ( S O Ps)  a n d  a  c o p y  pr o vi de d  t o  t he  
S p o ns or/ desi g nee u p o n re q uest. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 3 
 Rec or ds  are  mai ntai ne d  t hat  all o w  f or  tracea b ilit y  of  eac h  c o ntai ner, i ncl u di n g  t he  date  
dis p ose d of, q ua ntit y dis p ose d, a n d i de ntificati o n of t he pers o n dis p osi n g t he c o ntai ners. T he 
met h o d of dis p osal, i.e., i nci nera t or, lice nse d sa nitar y la n dfill, or lice nse d waste dis p osal 
ve n d or m ust be d oc u me nte d. 
 Acc o u nta bilit y a n d dis p osal rec o r ds are c o m plete, u p-t o- date, an d a vaila ble f or t he M o nit or t o 
re vie w t hr o u g h o ut t he cli nical trial peri o d. 
If c o n diti o ns f or destr ucti o n ca n n ot be met, t he res p o nsi ble St u d y M o nit or will ma ke arra n ge me nts 
f or ret ur n of st u d y dr u g t o t he C R O St u d y M o nit or. 
4. 9  R et ur n of I n v e sti g ati o n al Pr o d u ct 
It is t he I n vesti gat or’s res p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y c o ntai ners, pr o vi de d t hat 
pr oce d ures f or pr o per dis p osal ha ve  bee n esta blis he d acc or di n g t o ap plica ble fe deral, state, l ocal, 
a n d i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d pr o vi de d t hat a p pr o pr iate rec or ds of dis p osal are 
ke pt. 
4. 1 0  R et ai n e d S a m pl e s f or Bi o a v ail a bilit y/ Bi o e q ui v al e n c e 
N ot a p plica ble. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 4 
5
 S T U D Y
 A S S E S S M E N T S  A N D P R O C E D U R E S 
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n Secti o n  5. 1. 
T he I n vesti gat or will e ns ure t hat data are rec or de d o n t he e C R Fs. T he electr o nic data ca pt ure 
( E D C) s yste m will be use d f or data c ollecti o n a n d q uer y ha n dli n g. 
T he I n vesti gat or e ns ures t he acc ura c y, c o m plete ness, le gi bilit y, a n d ti meli ness of t he data rec or de d 
a n d of t he pr o visi o n of a ns wers t o data q ueries  acc or di n g t o t he Cli nical St u d y A gree me nt. T he 
I n vesti gat or will si g n t he c o m plete d e C R Fs. A c o p y of t he c o m plete d e C R Fs will be arc hi ve d at 
t he st u d y site. 
I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he S p o ns or i m me dia tel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he s u bject s h o ul d c o nti n ue or disc o nti n ue st u d y dr u g. 
A d here nce t o t he st u d y desi g n re q uire me nts,  i ncl u di n g t h ose s pecifie d i n Secti o n 5. 1 , is esse ntial 
a n d re q uire d f or st u d y c o n d uct. 
If sc he d ule d visits at cli nical sites will be si g nifica ntl y i m pacte d b y t he C O VI D- 1 9 pa n de mic (e. g., 
t here is a ris k t hat t he s u bject ma y be e x p ose d t o C O VI D- 1 9 w he n vi siti n g t he site), h o me visits 
b y st u d y site pers o n nel/ ve n d or are a ll o we d i n c o u ntries w here t his is l o gisticall y feasi ble a n d 
c o nsi dere d acce pta ble. Bef ore s uc h a visit, a ris k  assess me nt t hat c o nsi ders t he p ote ntial ris ks t o 
b ot h t he s u bject a n d t he st u d y pe rs o n nel has t o be perf or me d. 
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial s u bjects meet 
all eli gi bilit y criteria. T he I n vesti gat or will mai ntai n  a scree ni n g l o g t o rec or d details of all s u bjects 
scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as a p plica ble. 
Pr oce d ures c o n d ucte d as part of t he s u bject’s r o uti ne cli nical ma na ge me nt (e. g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he i nf o r me d c o nse nt f or m ma y be utilize d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ures me t t he pr ot oc ol-s pecifie d criteria a n d were perf or me d wit hi n 
t he ti me fra me defi ne d i n Secti o n 5. 1. 
A p pr o xi matel y 2 3 0 m L of bl o o d will be c ollecte d fr o m eac h s u bject. Re peat or u nsc he d ule d bl o o d 
sa m ples ma y be ta ke n f or safet y reas o ns or d ue t o tec h nical iss ues wit h t he sa m ples.

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 5 
5. 1  Fl o w C h art/ Ti m e a n d E v e nt s S c h e d ul e  
T a ble 5. 1- 1:  
Scree ni n g Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
Scree ni n g 
M a xi m u m 
6 m o nt hs a  
Le a d-i n 
W k – 2 b  
N otes 
 
Eli gi bilit y Assess me nts 
 
 
 
I nf or me d C o nse nt 
X 
  
 
O btai n writte n Asse nt (If a p plica ble) 
X 
  
 
I ncl usi o n/ E xcl usi o n Criteria 
X 
  
 
Me dical Hist or y 
X 
  
 
Re vie w C o nc o mita nt Me dicati o n 
X 
X  
 
E C G
 
 
X
 
 
S afet y Assess me nts 
 
 
 
P h ysical E xa mi nati o n 
 
X  
 
Tar gete d P h ysical E xa mi nati o n 
X 
  
 
Ta n ner Sta gi n g (I n vesti gat or 
deter mi ne d/ Self-re p orte d) 
 X
 
See
 
A p pe n di x
 
3
 
Vital Si g ns 
X 
X  
 
Hei g ht
 X
 
 
 
B o d y Wei g ht 
X 
  
 
B MI
 X
 
 
 
Seri o us A d verse E ve nts Assess me nt 
X 
X  
 
A d verse E ve nts Assess me nt 
 
X  
 
L a b or at or y Tests 
 
 
 
Sta n dar d Safet y La b orat or y Pa nel ( Bl o o d/ Uri ne)  
X 
  
See A p pe n di x 1 
G A D/I A 2 A ut oa nti b o dies 
X 
  
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 6 
T a ble 5. 1- 1:  
Scree ni n g Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
Scree ni n g 
M a xi m u m 
6 m o nt hs a  
Le a d-i n 
W k – 2 b  
N otes 
 
C- pe pti de
 X
 
 
C- pe pti de will o nl y be perf or me d i n  ot her wise eli gi ble G A D a n d I A 2 
a nti b o d y- p ositi ve s u bjects 
H b A 1c
 X
 
 
 
Pre g na nc y Test ( W O C B P o nl y) 
X 
 
F or W O C B P o nl y uri ne test wit h refle x ser u m test, if p ositi ve  
T S H
 X
 
 
A n a b n or mal T S H val ue at e nr oll me nt will be f urt her e val uate d b y 
free T 4 
He patitis Scree ni n g Pa nel 
X 
 
I ncl u des He patitis Scree n Pa nel (a nti- H A V [I g M], H Bs A g, a n d 
a nti- H C V) 
St u d y Dr u g / I X R S 
 
 
 
C o ntact I X R S 
X 
X  
 
Ge ner al 
 
 
 
Pr o vi de Dietar y a n d E xercise C o u nseli n g 
 X
 
 
Pr o vi de gl uc ose meter a n d s u p plies / i nstr ucti o ns 
 X
 
 
Pr o vi de l o gs / i nstr ucti o ns  
 X
 
 
Assess me nt of si g ns a n d s y m pt o ms of 
h y p o gl yce mia e pis o des 
 X
 
 
a T he scree ni n g peri o d lasts a ma xi m u m of 6 m o nt hs. A n y scree ni n g pr oce d ures a n d assess me nts ca n be reteste d as deter mi ne d b y t he  I n vesti gat ors d uri n g t he 
6- m o nt h scree ni n g peri o d if s u bjects fail t o meet t he eli gi bilit y  criteria at t he first atte m pt a n d t he I n vesti gat ors belie ve that s u bjects ma y meet t he eli gi bilit y 
criteria wit hi n 6 m o nt hs. A n y a d diti o nal tests s h o ul d be rec or de d as u nsc he d ule d assess me nts i n t he E D C s yste m. 
b T he lea d-i n peri o d s h o ul d start wit hi n 6 wee ks after c o m pleti o n of  t he scree ni n g visit, a n d ma y start as earl y as 2 wee ks after c o m pleti o n of t he scree ni n g visit if 
all la b orat or y res ults ha ve bee n recei ve d. 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 7 
T a ble 5. 1- 2:  
S h ort-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
D a y 
1 a  
W k 
2 a, b  
W k 
6 a  
W k 
1 2 a   
W k 
1 4 a,c  
W k 
2 0 a   
W k 2 6/ E T D 
(e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a,c  
N otes 
Eli gi bilit y Assess me nts 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
  
  
  
  
 
  
 
Re vie w c o nc o mita nt me dicati o ns / 
pr oce d ures 
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y p h o ne 
S afet y Assess me nts 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n 
  
  
  
  
  
 
X  
 
Tar gete d P h ysical E xa mi nati o n  
X  
  
X  
X  
  
X  
 
 
Ta n ner Sta gi n g (I n vesti gat or 
deter mi ne d/ Self-re p orte d) 
 
 
 
 
 
 
 
 
  
X
  
See
 
A p pe n di x
 
3
 
Vital Si g ns 
X  
  
X  
X  
X  
X 
X  
 
Hei g ht
 X
 
 
X
 
X
 
 
X
 
X
 
 
B o d y Wei g ht 
X  
  
X  
X  
  
X 
X  
 
E C G
 
 
 
 
 
 
 
X
 
 
Assess me nt of si g ns a n d s y m pt o ms of 
h y p o gl yce mia e pis o des 
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y P h o ne 
Seri o us A d verse E ve nt Assess me nt  
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y P h o ne  
A d verse E ve nts Assess me nt 
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y P h o ne 
L a b or at or y Tests  
 
 
 
 
 
 
 
 
 
 
 
 
 
Sta n dar d Safet y La b orat or y Pa nel 
( Bl o o d/ Uri ne) 
X
 
 X
 X
 
 
  X
  
X
  
See
 
A p pe n di x
 
1
 
Fasti n g Li pi d pa nel 
X  
  
  
  
  
 
X  
T otal c h olester ol, tri gl yceri des, H D L, a n d L D L 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 8 
T a ble 5. 1- 2:  
S h ort-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
D a y 
1 a  
W k 
2 a, b  
W k 
6 a  
W k 
1 2 a   
W k 
1 4 a,c  
W k 
2 0 a   
W k 2 6/ E T D 
(e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a,c  
N otes 
Fasti n g Plas ma Gl uc ose ( F P G) d  
X
 
 X
 X
 
 
  X
  
X
 
O n Da y 1, t he F P G sa m ple will be c ollecte d 
pre- d ose o nl y.  
At t he W k 6, 1 2, 2 0 a n d 2 6 visits F P G sa m ples 
will be c ollecte d pre- d ose a n d a p pr o xi matel y 
2 h o urs p ost- d ose (  1 h o ur) 
All sa m ples will be dra w n i n t he fasti n g 
c o n diti o n. 
H b A 1c
 X
 
 
X
 
X
 
 
X
 
X
 
Res ults mas ke d f oll o wi n g I P a d mi nistrati o n o n 
Da y 1 u ntil after st u d y c o m pleti o n  
Pre g na nc y Test ( W O C B P o nl y)  
X  
  
X  
X  
X  
X 
X 
W O C B P m ust ha ve a ne gati ve ser u m or uri ne 
pre g na nc y test wit hi n 2 4 h o urs pri or t o t he start 
of st u d y dr u g. 
H o me pre g na nc y kits will be pr o vi de d. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
6 9 
T a ble 5. 1- 2:  
S h ort-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
D a y 
1 a  
W k 
2 a, b  
W k 
6 a  
W k 
1 2 a   
W k 
1 4 a,c  
W k 
2 0 a   
W k 2 6/ E T D 
(e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a,c  
N otes 
S p ot Uri ne Gl uc ose 
X  
  
X  
X  
  
X 
X 
Res ults bli n de d t o t he S p o ns or, I n vesti gat or, 
site, a n d s u bject f or t he d urati o n of t he st u d y 
f oll o wi n g I P a d mi nistrati o n o n Da y 1 u ntil after 
st u d y c o m pleti o n  
Gr o wt h, b o ne a n d mat urati o n mar kers   
X  
  
  
  
  
 
X 
T h yr oi d-sti m ulati n g h or m o ne ( T S H), free 
t h yr o xi ne, l utei nizi n g h or m o ne ( L H), 
f ollicle-sti m ulati n g h or m o ne ( F S H), estra di ol, 
t otal test oster o ne, i ns uli n-li ke gr o wt h fact or- 1 
(I G F- 1), i ns uli n-li ke gr o wt h fact or bi n di n g 
pr otei n- 3 (I G F B P- 3), calcit o ni n, 2 5- h y dr o x y 
vita mi n D, b o ne al kali ne p h os p hatase, 
oste ocalci n, parat h yr oi d h or m o ne ( P T H) a n d 
car b o x yter mi nal cr oss-li n ke d tel o pe pti de of 
T y pe 1 c olla ge n ( C T X- 1) 
Plas ma sa m ples f or a nal ysis of 
da pa glifl ozi n, sa xa gli pti n a n d 
5- O H-sa xa gli pti n d  
 
 X
 X
 
 X
  
X #
 
Sa m ples will be c ollecte d pre- d ose a n d 
a p pr o xi matel y 2 h o urs p ost- d ose (  1 h o ur) 
Sa m ples will be dra w n i n t he fasti n g c o n diti o n.  
# N o sa m ples will be dra w n at t he Resc ue Visit 
or t he Wee k 2 6 Visit f oll o wi n g Earl y 
Treat me nt Disc o nti n uati o n Visit 
Plas ma sa m ples f or D P P- 4 acti vit y d  
X
 
 X
 X
 
 
  X
  
X
 
O n Da y 1 plas ma sa m ples f or D P P- 4 acti vit y 
will be dra w n pre- d ose o nl y. 
At t he Wee ks 6, 1 2, 2 0 a n d 2 6 visits, plas ma 
sa m ples f or D P P- 4 acti vit y will be dra w n at 
2 h o urs (  1 h o ur) p ost- d ose o nl y. 
Sa m ples will be dra w n i n t he fasti n g c o n diti o n. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 0 
T a ble 5. 1- 2:  
S h ort-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
D a y 
1 a  
W k 
2 a, b  
W k 
6 a  
W k 
1 2 a   
W k 
1 4 a,c  
W k 
2 0 a   
W k 2 6/ E T D 
(e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a,c  
N otes 
St u d y Dr u g / I X R S 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o ntact I X R S 
X  
  
X  
  
X  
X 
X  
 
First ra n d o mizati o n 
X  
  
  
  
  
 
  
 
Sec o n d ra n d o mizati o n 
  
  
  
  
X  
 
  
 
Dis pe nse St u d y Dr u g 
X  
  
X  
  
X  
X  
X * 
* N o st u d y dr u g dis pe nse d d uri n g E T D or 
Resc ue Visit. 
Resc ue d s u bjects will c o nti n ue wit h t heir 
c urre nt assi g ne d I P re gi me n. 
St u d y Dr u g C o m plia nce Re vie w  
  
  
X  
  
X  
X 
X  
 
Ge ner al  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o vi de diet a n d e xercise c o u nseli n g 
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y P h o ne 
Dis pe nse meter s u p plies 
X
 
 X
 X
 
 
  X
  
X
 
 
 
Re vie w dail y diar y of fi n ger-stic k 
gl uc ose val ues 
X  
X *  
X  
X  
X  
X 
X  
* Assesse d b y P h o ne 
Pr o vi de l o gs / i nstr ucti o ns  
X
 
 X
 X
 
 
  X
  
X
 
 
 
Assess Resc ue 
  
  
X  
X  
X  
X 
X  
 
a  Visits ma y be sc he d ule d  7 da ys ( of ori gi nal sc he d ule) t o all o w fle xi bilit y of sc he d uli n g. Wee k 1 2 a n d Wee k 1 4 visits s h o ul d be sc he d ule d at least 7 days a part. 
T he visit wi n d o w f or t he Resc ue Visit asse ss me nts starts at t he site’s recei pt of t he H b A 1c alert or F P G c o nfir mati o n.  
b  P h o ne  assess me nts   
c I n case t he Wee k 1 4 visit is dela ye d, s u bse q ue nt visits s h o ul d be dela ye d t o mai ntai n a n i nter val of at least 1 2 wee ks bet wee n t he Wee k- 1 4 a n d Wee k- 2 6 visits. 
S h ort- a n d l o n g-ter m peri o d st u d y visits ca n be dela ye d b y a ma xi m u m of 1 1 m o nt hs i n t otal.. If t he d urati o n of I P a d mi nistrati o n is l o n ger t ha n 5 2 ( + 1) wee ks, 
t he safet y f oll o w- u p peri o d s h o ul d be s h orte ne d s uc h t hat t he c o m plete st u d y d urati o n d oes n ot e xcee d 1 0 4 wee ks ( + 7 da ys). 
d  Sa m ples  will be dra w n at t he ti mes s h o w n i n Ta ble 5. 5- 1  Sa m pli n g Sc he d ule 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 1 
 
T a ble 5. 1- 3:  
L o n g-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
W k 
3 2 a,c  
W k 
3 6 
a, b  
W k 
4 0 a,c  
W k 
4 6 a, b  
W k 5 2 / 
e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a  
W k 5 6 a,c  
Q u arterl y 
bet wee n 
W k 5 6 
a n d W k 
1 0 4 
W k 1 0 4 
P ost-st u d y 
Visit d  
N otes 
Eli gi bilit y Assess me nts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w c o nc o mita nt 
me dicati o ns/ pr oce d ures 
X  
X *  
X  
X *  
X  
  
  
  
* Assesse d b y P h o ne 
S afet y Assess me nts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n 
  
  
  
 
X 
 
 
  
 
Tar gete d P h ysical 
E xa mi nati o n 
X
 
 X
 
 
 
 
 
 
 
 
 
 
 
 
 
Ta n ner Sta gi n g (I n vesti gat or 
deter mi ne d/ Self-re p orte d) 
 
 
 
 
  
X
 
 
 
 
  
X
 A p pe n di x
 
3
 
Vital Si g ns 
X  
  
X  
 
X 
 
 
  
 
Hei g ht
 X
 
 
X
 
 
X
 
 
 
X
 
 
B o d y Wei g ht 
X  
  
X  
 
X 
 
 
X  
 
E C G
 
 
 
 
 
X
 
 
 
 
 
Assess me nt of si g ns a n d 
s y m pt o ms of h y p o gl yce mia 
e pis o des 
X  
X *  
X  
X *  
X  
  
  
  
* Assesse d b y P h o ne 
Seri o us A d verse E ve nt 
Assess me nt 
X  
X *  
X  
X *  
X  
X *  
X *  
X  
* Assesse d b y P h o ne 
A d verse E ve nts Assess me nt  
X  
X *  
X  
X *  
X 
X *  
X *  
X  
* Assesse d b y P h o ne 
L a b or at or y Tests  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sta n dar d Safet y La b orat or y 
Pa nel ( Bl o o d/ Uri ne) 
X
 
 X
 
 
  
X
 
 
 
 
 
 
  A p pe n di x
 
1
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 2 
T a ble 5. 1- 3:  
L o n g-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
W k 
3 2 a,c  
W k 
3 6 
a, b  
W k 
4 0 a,c  
W k 
4 6 a, b  
W k 5 2 / 
e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a  
W k 5 6 a,c  
Q u arterl y 
bet wee n 
W k 5 6 
a n d W k 
1 0 4 
W k 1 0 4 
P ost-st u d y 
Visit d  
N otes 
Fasti n g Li pi d pa nel 
  
  
  
 
X 
 
 
 
T otal c h olester ol, tri gl yceri des, 
H D L, a n d L D L 
Fasti n g Plas ma Gl uc ose ( F P G)  
X  
  
X  
 
X 
 
 
  
 
H b A 1c
 X
 
 
X
 
 
X
 
 
 
 
Res ults mas ke d f oll o wi n g I P 
a d mi nistrati o n o n Da y 1 u ntil 
after st u d y c o m pleti o n  
Pre g na nc y Test ( W O C B P 
o nl y) 
X
 X *
 X
  X *
  
X
 
 
 
 
 
 
 
* Pare nt will pr o vi de res ult 
o ver t he p h o ne. 
H o me pre g na nc y kits will be 
pr o vi de d.  
Gr o wt h, b o ne a n d mat urati o n 
mar kers  
 
 
 
 
  
X
 
 
 
 
  
X
 
T h yr oi d-sti m ulati n g h or m o ne 
( T S H), free t h yr o xi ne, 
l utei nizi n g h or m o ne ( L H), 
f ollicle-sti m ulati n g h or m o ne 
( F S H), estra di ol, t otal 
test oster o ne, i ns uli n-li ke 
gr o wt h fact or- 1 (I G F- 1), 
i ns uli n-li ke gr o wt h fact or 
bi n di n g pr otei n- 3 (I G F B P- 3), 
calcit o ni n, 2 5- h y dr o x y 
vita mi n D, b o ne al kali ne 
p h os p hatase, oste ocalci n, 
parat h yr oi d h or m o ne ( P T H) 
a n d car b o x yter mi nal cr oss-
li n ke d tel o pe pti de of T y pe 1 
c olla ge n ( C T X- 1) 
St u d y Dr u g/I X R S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o ntact I X R S 
X  
  
X  
 
X 
 
 
  
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 3 
T a ble 5. 1- 3:  
L o n g-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
W k 
3 2 a,c  
W k 
3 6 
a, b  
W k 
4 0 a,c  
W k 
4 6 a, b  
W k 5 2 / 
e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a  
W k 5 6 a,c  
Q u arterl y 
bet wee n 
W k 5 6 
a n d W k 
1 0 4 
W k 1 0 4 
P ost-st u d y 
Visit d  
N otes 
T hir d ra n d o mizati o n  
X  
  
X *  
 
 
 
 
 
T he t hir d ra n d o mizati o n will 
a p pl y o nl y t o s u bjects w h o are 
eli gi ble f or ra n d o mize d 
wit h dra wal of bac k gr o u n d 
me dicati o n (i.e., s u bjects w h o 
ha ve bac k gr o u n d me dicati o n 
wit h metf or mi n o nl y a n d 
H b A 1c < 7. 5 % at Wee k 2 6 or 
Wee k 3 2 
* R a n d o miz ati o n at Wee k 4 0 
o nl y f or eli gi ble s u bjects n ot 
r a n d o mize d at Wee k 3 2  
I nstr ucti o n re gar di n g 
metf or mi n wit h dra wal 
X
 
 X *
 
 
 
 
 
 
 
 
 
 
S u bjects wit h dra w n fr o m 
bac k gr o u n d me dicati o n wit h 
metf or mi n f oll o wi n g t he t hir d 
ra n d o mizati o n will be 
re mi n de d t o st o p ta ki n g 
metf or mi n. 
* O nl y s u bjects r a n d o mize d 
at Wee k 4 0  
Dis pe nse St u d y Dr u g 
X  
  
X  
 
 
 
 
 
N o dr u g dis pe nse d d uri n g E T D 
or Resc ue Visit. 
Resc ue d s u bjects will c o nti n ue 
wit h t heir c urre nt assi g ne d I P 
re gi me n. 
St u d y Dr u g C o m plia nce 
Re vie w  
X
 
 X
 
 
  
X
 
 
 
 
 
 
 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 4 
T a ble 5. 1- 3:  
L o n g-ter m Pr oce d ur al O utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) 
Pr oce d ure 
W k 
3 2 a,c  
W k 
3 6 
a, b  
W k 
4 0 a,c  
W k 
4 6 a, b  
W k 5 2 / 
e arl y 
disc o nti n u ati o n 
of I P)/ Resc ue a  
W k 5 6 a,c  
Q u arterl y 
bet wee n 
W k 5 6 
a n d W k 
1 0 4 
W k 1 0 4 
P ost-st u d y 
Visit d  
N otes 
Ge ner al  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o vi de diet a n d e xercise 
c o u nseli n g 
X  
X *  
X  
X *  
  
  
  
  
* Assesse d b y P h o ne 
Dis pe nse Meter S u p plies 
X
 
 X
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w dail y diar y of fi n ger-
stic k gl uc ose val ues 
X  
X *  
X  
X *  
X  
  
  
  
* Assesse d b y P h o ne 
Pr o vi de l o gs / i nstr ucti o ns  
X
 
 X
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess Resc ue 
X  
X *  
X  
X *  
 
 
 
  
* Assesse d b y P h o ne 
Tele p h o ne c o ntact wit h 
s u bject/ pare nt (re mi n der calls) 
 
 
 
 
 
 
 
 
  
X
 
 
 
 
 
a  Visits ma y be sc he d ule d  7 da ys ( of ori gi nal sc he d ule) t o all o w fle xi bilit y of sc he d uli n g. T he visit wi n d o w f or t he Resc ue Visit assess me nts starts at t he site’s 
recei pt of t he H b A 1c alert or F P G c o nfir mati o n. 
b  P h o ne  assess me nts.  
c I n case t he t hir d ra n d o mizati o n visit (at Wee k 3 2 or Wee k 4 0) is dela ye d, s u bse q ue nt visits s h o ul d be dela ye d t o mai ntai n a n i n ter val of at least 1 2 wee ks bet wee n 
t his visit a n d t he Wee k 5 2 visit. S h ort- a n d l o n g-ter m st u d y peri o d visits ca n be dela ye d b y a ma xi m u m of 1 1 m o nt hs i n t otal. If t he d urati o n of I P a d mi nistrati o n 
is l o n ger t ha n 5 2 ( + 1) wee ks, t he safet y f oll o w- u p peri o d s h o ul d be s h orte ne d s uc h t hat t he c o m plete st u d y d urati o n d oes n ot e xcee d 1 0 4 wee ks ( + 7 da ys). 
d Visit ma y be sc he d ule d at a n y ti me bet wee n Da y - 2 8 t o + 7 da ys of  t he ori gi nal sc he d ule d date t o all o w fle xi bilit y of sc he d uli n g. 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 5 
T a ble 5. 1- 4:  
E arl y Tre at me nt Disc o nti n u ati o n ( E T D) F oll o w- u p N o n- Tre at me nt P h ase 
Pr oce d ure 
N o n-
tre at me nt 
F oll o w- u p, 
u p t o a n d 
i ncl u di n g 
W k 2 6 
Office 
Visit a, b  
N o n-
tre at me nt 
F oll o w- u p, 
p ast W k 2 6 
a n d 
i ncl u di n g 
W k 5 2 
Office 
Visit a, b  
N o n-
tre at me nt 
F oll o w- u p 
P h o ne 
Assess me nt 
( D a y 1 u p 
t o a n d 
i ncl u di n g 
W k 5 6) b,c  
Q u arterl y 
bet wee n  
W k 5 6 a n d  
W k 1 0 4 
W k 1 0 4  
P ost-
st u d y 
Visit c 
N otes 
S afet y Assess me nts  
Tar gete d p h ysical 
e xa mi nati o n 
X
 X
 
 
 
 
 
 
 
 
Vital si g ns 
X  
X 
 
 
  
 
B o d y wei g ht & hei g ht 
X  
X 
 
  
X  
 
Re vie w c o nc o mita nt 
me dicati o ns 
X
 X
  X
 
 
 
 
 
 
Seri o us A d verse E ve nts 
Assess me n t 
X  
X  
X  
X *  
X  
* Assesse d b y P h o ne 
A d verse E ve nts Assess me nt  
X   
X   
X   
X *  
X  
* Assesse d b y P h o ne 
Sta n dar d safet y la b orat or y 
p a nel ( Bl o o d) 
X
 X
 
 
 
 
 
 
 
A p pe n di x
 
1
 
Fasti n g Plas ma Gl uc ose 
( F P G) 
X
 X
 
 
 
 
 
 
 
 
H b A 1c
 X
 
X
 
 
 
 
 
Tele p h o ne re mi n der calls 
 
 
 
X 
 
 
Ta n ner Sta gi n g  
X *  
X * 
 
 
X 
A p pe n di x 3; * o nl y at ti me p oi nts c orres p o n di n g t o 
ori g i nally  sc he d ule d Wee k 2 6 a n d Wee k 5 2 visits 
Gr o wt h, b o ne a n d mat urati o n 
mar kers 
X
 X
 
 
 
X 
T h yr oi d-sti m ulati n g h or m o ne ( T S H), free t h yr o xi ne, 
l utei nizi n g h or m o ne ( L H), f ollicle-sti m ulati n g h or m o ne 
( F S H), estra di ol, t otal testoster o ne, i ns uli n-li ke gr o wt h 
fact or- 1 (I G F- 1), i ns uli n-li ke gr o wt h fact or bi n di n g 
pr otei n- 3 (I G F B P- 3), calcit o ni n, 2 5- h y dr o x y vita mi n D, 
b o ne al kali ne p h os p hatase, oste ocalci n, p arat h y r oi d 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 6 
T a ble 5. 1- 4:  
E arl y Tre at me nt Disc o nti n u ati o n ( E T D) F oll o w- u p N o n- Tre at me nt P h ase 
Pr oce d ure 
N o n-
tre at me nt 
F oll o w- u p, 
u p t o a n d 
i ncl u di n g 
W k 2 6 
Office 
Visit a, b  
N o n-
tre at me nt 
F oll o w- u p, 
p ast W k 2 6 
a n d 
i ncl u di n g 
W k 5 2 
Office 
Visit a, b  
N o n-
tre at me nt 
F oll o w- u p 
P h o ne 
Assess me nt 
( D a y 1 u p 
t o a n d 
i ncl u di n g 
W k 5 6) b,c  
Q u arterl y 
bet wee n  
W k 5 6 a n d  
W k 1 0 4 
W k 1 0 4  
P ost-
st u d y 
Visit c 
N otes 
S afet y Assess me nts  
h or m o ne ( P T H) a n d car b o x yter mi nal cr oss-li n ke d 
tel o pe pti de of T y pe 1 c olla ge n ( C T X- 1) 
a I n- office assess me nts t o occ ur at ti me p oi nts c orres p o n di n g t o ori gi nall y sc he d ule d Da y 1 t o Wee k 2 6 ( S h ort-ter m) a n d past Week 2 6 t o Wee k 5 2 ( L o n g-ter m) 
visits. 
b  P h o ne assess me nts o nl y t o occ ur at ti me p oi nts c orres p o n di n g t o ori gi nall y sc he d ule d t hat is n ot i de ntifie d a b o ve as a n i n- off ice visit. 
c Visit ma y be sc he d ule d  at a n y ti me bet wee n Da y - 2 8 t o + 7 da ys of t he ori gi n al sc he d ule d date t o all o w fle xi bilit y of sc he d uli n g. S h ort- a n d l o n g-ter m peri o d 
st u d y visits ca n be dela ye d b y a ma xi m u m of 1 1 m o nt hs i n t otal. If t he d urati o n of I P a d mi nistrati o n is l o n ger t ha n 5 2 ( + 1) weeks, t he safet y f oll o w- u p peri o d 
s h o ul d be s h orte ne d s uc h t hat t he c o m plete st u d y d urati o n d oes n ot e xcee d 1 0 4 wee ks ( + 7 da ys).  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 7 
5. 1. 1  R et e sti n g/ R e a s s e s s m e nt D uri n g S cr e e ni n g or L e a d-I n P eri o d 
T he la b orat or y para meters liste d bel o w ma y be re peate d o nce i n a n eff ort t o fi n d all p ossi ble 
well- q ualifie d s u bjects. C o ns ultati o n wit h t he Me di cal M o nit or ma y be nee de d t o i de ntif y w het her 
re peat testi n g of a n y partic ular para meter is cli nicall y rele va nt. 
Retesti n g/reassess me nt of  scree ni n g criteria are all o we d if an y of t he m d oes n ot meet eli gi bilit y 
criteria at i nitial scree ni n g, a n d t he I n vesti gat ors belie ve t he y may ret ur n wit hi n t he eli gi bilit y 
ra n ge wit hi n 6 m o nt hs. Retesti n g/reassess me nt fre q ue ncies of t hese varia bles are at t he discreti o n 
of t he I n vesti gat ors, b ut s h o ul d occ ur at least o nce e ver y 3 m o nt hs. T he I n vesti gat ors will e ns ure 
t hat all ot her eli gi bilit y criteria are still bei n g met if a s u bject q ualifies after retesti n g/reassess me nt. 
If a s u bject t ur ns 1 8 years of a ge d uri n g t he scree ni n g peri o d, he/s he will be c o nsi d ere d as scree n 
fail ure a n d t h us n ot eli gi ble f or t he st u d y. 
A n y  ne w  res ult  will  o verri de  t h e  pre vi o us  res ult  (i.e.,  t he  m ost  c urre nt  res ult  pri or  t o  
Ra n d o mizati o n) a n d is t he val ue b y w hic h st u d y i ncl usi o n will be assesse d, as it re prese nts t he 
s u bject’s m ost c urre nt, cli nical state. 
5. 2  St u d y  M at eri al s  
St u d y tea m will s u p pl y t he sites w it h t he f oll o wi n g materials: 
 Bl o o d gl uc ose meters. O ne ( 1) meter will be pr o v i de d t o eac h st u d y s u bject at e nr oll me nt a n d 
o ne ( 1) meter will be pr o vi de d t o eac h i n vesti gati ve site.  
 Gl uc ose test stri ps 
 La ncets 
 Gl uc ose c o ntr ol s ol uti o ns 
 Ket o ne meters a n d test stri ps 
 Electr o nic e C R Fs [ S A E F or ms, Pr e g na nc y S ur veilla nce F or ms]  
 S u bject e d ucati o n a n d si te s u p p ort materials  
 S u bject alert car ds 
 St u d y dr u g i n ve nt or y c o ntr ol f or ms 
 S u bject diar y: 
 Use of t he s u bject diar y is ma n dat or y f o r t he st u d y a n d will be mai ntai ne d b y eac h 
st u d y s u bject f or re p orti n g of S M B G res ults, st u d y me dicati o n d osin g, ket o ne res ults, 
h y p o gl yce mia  e pis o des,  if  a p plica ble,  a n d  W O C B P  uri ne  pre g na nc y  res ults,  if  
a p plica ble.  
o  S u bjects  are  t o  rec or d  a n y  h y p o gl yce mic  s y m pt o ms  t he y  ma y  e x perie nce  a n d  
S M B G val ues if t he y c o n d ucte d t he test w he n  t he y ha ve s y m pt o ms i n t heir diaries. 
All e ve nts rec or de d i n t he s u bject diar y are t o be re vie we d b y site staff acc or di n g 
t o Secti o n 5. 3. 1 . 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 8 
 A n y ot her materials as l o call y re q uire d or a gree d. 
 T he ce ntral la b orat or y will pr o vi de all la b orat or y-relate d materials i ncl u di n g h o me pre g na nc y 
testi n g kits f or W O C B P t o t he st u d y sites.  
5. 3  S af et y  A s s e s s m e nt s  
Safet y  assess me nts  will  i ncl u de  A E  re p orti n g,  as  well  as  mar ke d  a b n or malities  i n  cli nical  
la b orat or y tests. Please refer t o A p pe n di x 1 f or details o n ce ntral la b orat or y assess me nts.  
T he pr oce d ures descri be d i n t he secti o ns t hat f o ll o w will als o be c o m plete d t o e ns ure s u bjects’ 
safet y.  
It is t he I n vesti gat or's res p o nsi bilit y t o re p ort, as a p plica ble base d o n t he I n vesti gat or's j u d g me nt 
a n d t he s u bject's me dical hist or y, re late d A Es as defi ne d i n Secti o n 6 . A d diti o nal i nf or mati o n, 
i ncl u di n g  b ut  n ot  li mite d  t o,  c o m pleti o n  of  s u p ple me ntal  e C R Fs  or  q uesti o n naires  ma y  be  
re q ueste d f or certai n A Es a n d/ or la b orat or y a b n or malities w hic h are re p orte d/i de ntifie d d uri n g t he 
c o urse of t he st u d y. 
5. 3. 1  S elf- M o nit ori n g Bl o o d Gl u c o s e a n d G ui d a n c e o n M a n a g e m e nt a n d 
R e p orti n g of H y p o gl y c e mi a E pi s o d e s 
5. 3. 1. 1  S elf- M o nit ori n g of Bl o o d Gl u c o s e 
Gl uc ose meters will be s u p plie d t o  eac h st u d y site. At e ntr y t o t he lea d-i n peri o d ( Wee k - 2 visit), 
s u bjects will recei ve a gl uc ose meter, s u p plies, a n d i nstr ucti o n o n t heir use. S u p plies will be 
pr o vi de d t o all o w f or a p pr o xi matel y 6 0 bl o o d gl uc ose assess me nts per m o nt h f or t he d urati o n of 
t he st u d y. S u bjects s h o ul d be e nc oura ge d t o meas ure a n d rec or d fasti n g bl o o d gl uc ose le vels at 
least o nce per da y. T he i n vesti gator ma y re q uire m ore fre q ue nt rea di n gs base d o n l ocal cli nical 
practice. S u bjects s h o ul d bri n g t hei r gl uc ose meter wit h t he m t o eac h st u d y visit t o e ns ure t hat it 
is f u ncti o ni n g pr o perl y. S u bjects ma y kee p t he gluc ose meter at t he e n d of t he st u d y, b ut t he 
S p o ns or will n ot c o nti n ue t o pr o vi de gl uc os e meter s u p plies o nce t he st u d y is c o m plete. 
I n t he occ urre nce of h y p o gl yce mic s y m pt o ms or i n t he e ve nt of a n u n us uall y hi g h or l o w bl o o d 
gl uc ose val ue, s u bjects s h o ul d c o ntact t he I n vesti g at or. I n a d diti o n, st u d y s u bjects s h o ul d c o m pl y 
wit h site’s i nstr ucti o ns wit h re gar d t o S M B G a n d s h o ul d re p ort t o t he site bl o o d gl uc ose val ues 
a n d/ or si g ns a n d s y m pt o ms s u g ge sti ve of a h y p o gl yce mia e pis o de. 
T he me m or y of t he gl uc ose mete r s h o ul d be re vie we d t o c o m pare rea di n gs wit h t he s u bject’s 
h y p o gl yce mia e pis o de l o g, as a p plica ble. T he gl uc os e val ues s h o ul d be re vi e we d b y t h e site t o 
i de ntif y a n y u n us ual hi g h or l o w val ues, a n d t o c o nfir m t hat t he val ues (fr o m t he gl uc ose meter’s 
me m or y a n d/ or fr o m t he s u bject’s h y p o gl yce mia l o g) were o btai ne d f or t he s u bject. If fi n ger-stic k 
gl uc ose val ues are disc or da nt fr o m gl yce mic c o nt r ol assesse d b y t he ce ntral la b orat or y or wit h 
cli nical s y m pt o ms, t he s u bject’s gl uc ose meter s h o ul d be teste d a n d t he pr oce d ure f or usi n g it 
re vie we d wit h t he s u bject.  
5. 3. 1. 2  G ui d a n c e o n M a n a g e m e nt a n d R e p orti n g of H y p o gl y c e mi a E pi s o d e s 
H y p o gl yce mia ma y be a n e x pecte d  e ve nt i n s u bjects w h o are treate d f or dia betes. S u bjects a n d 
t heir fa mil y me m bers m ust be a ware of t he p ossi bilit y t hat  h y p o gl yce mia ma y occ ur a n d t he 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
7 9 
da n gers ass ociate d wit h l o w bl o o d s u gar. St u d y s u bjects m ust be pr o perl y i nstr ucte d o n t he 
rec o g niti o n  a n d  ma na ge me nt  of  h y p o gl yce mia.  S u bjects  s h o ul d  re c or d  i n  t heir  diaries  a n y  
h y p o gl yce mic s y m pt o ms. T he y s h o ul d be e nc o ura ge d  t o meas ure, w he n p ossi ble, t heir bl o o d 
gl uc ose val ues w he n t he y ha ve s y m pt o ms of h y p o gl yce mia. S u bjects s h o ul d carr y wit h t he m easil y 
i n gesti ble f or ms of car b o h y drate at all ti mes i n or der t o treat a n e ve nt of h y p o gl yce mia s h o ul d it 
occ ur. 
D uri n g cli nical trials, s u bjects fre q ue ntl y re p ort s y m pt o ms of h y p o gl yce mia w he n as ke d, e ve n 
w he n  treate d  wit h  place b o  or  me dicati o ns  n ot  ot her wise  a ss ociate d  wit h  h y p o gl yce mia.  As  
h y p o gl yce mia is a n i m p orta nt e ve nt ass ociate d wit h  dia betes t hera p y, all e pis o des w hic h c o ul d be 
c o nsiste nt wit h t he cli nical defi niti o n of h y p o gl y ce mia as assesse d b y t he I n vesti gat or s h o ul d be 
d oc u me nte d a n d re p orte d o n t he a p pr o priate e C R F pa ge. 
T he I n vesti gat or is res p o nsi ble f or q uesti o ni n g t he s u bject a b o ut all s ym pt o ms re p orte d o n t he 
h y p o gl yce mia p orti o n of t he diar y a n d f or deter mi ni n g if t he y meet t he cli nical defi niti o n of 
h y p o gl yce mia. O nl y s y m pt o ms a n d/ or bl o o d gl uc ose va l ues dee me d b y t he In vesti gat or t o meet 
t he defi niti o n of h y p o gl yce mia s h o ul d be re p orte d o n t he h y p o gl yce mia e C R F pa ges. Si g ns a n d 
s y m pt o ms  of  h y p o gl yce mia,  h y p o gl yce mia  e pis o de or  disc o nti n uati o n  d ue  t o  h y p o gl yce mia  
s h o ul d n ot be re p orte d o n t he A E e C R F pa ge, u nless t he e ve nt f ulfills pr ot ocol criteria f or a n S A E 
(see Secti o n 6. 2 ), i n w hic h case a n S A E f or m m ust be c o m plete d i n a d diti o n t o t he h y p o gl yce mia 
e C R F pa ges f or h y p o gl yce mia. 
H y p o gl yce mia e pis o des will be cla ssifie d i n t he Cli nical St u d y Re p ort ( C S R) acc or di n g t o t he 
A D A criteria 1 8 a n d t he I nter nati o nal S ociet y f or Pe diatric a n d A d ol esce nt Dia betes (I S P A D) 
criteria .1 9 
5. 3. 2  S elf- M o nit ori n g Bl o o d K et o n e T e st i n g a n d G ui d a n c e o n M a n a g e m e nt a n d 
R e p orti n g of Di a b eti c K et o a ci d o si s E pi s o d e s 
Dia betic ket oaci d osis has bee n i de ntifie d as a p ot e ntial ris k i n s u bjects wit h dia betes recei vi n g 
S G L T- 2 i n hi bit ors. S u bjects a n d t h eir fa mil y me m bers m ust be a ware of t he p ossi bilit y t hat D K A 
ma y occ ur, a n d of t he si g ns a n d s y m pt o ms a n d t h e da n gers ass ociate d wit h D K A. S u bjects will 
recei ve a se parate bl o o d ket o ne meter, a de vice si milar t o t he bl o o d gl uc ose meter, a n d s ufficie nt 
s u p plies f or testi n g w he n D K A is s us pecte d. S u bjects will be trai ned i n t he pr oce d ure of c o n d ucti n g 
bl o o d ket o ne testi n g acc or di n g t o  t he ma n ufact urer’s s pecificatio ns, a n d will be i nstr ucte d t o 
meas ure t heir bl o o d ket o ne s usi n g t he ket o ne meter pr o vi de d b y t he S p o ns or: 
 W he n e x perie nci n g p ote ntial s y m pt o ms/si g ns of D K A, i ncl u di n g b ut n ot li mite d t o e xcessi ve 
t hirst, na usea a n d v o miti n g, fre q ue nt uri nati o n, wea k ness or fati g ue, fe ver, fr uit y-sce nte d 
breat h, c o nf usi o n, a n d/ or c o ns iste ntl y ele vate d bl o o d gl uc ose: at least o nce a da y 
Bl o o d ket o ne test res ults, s y m pt o ms p ote ntiall y ass ociate d wit h D K A a n d rele va nt ris k fact ors 
(e. g., misse d i ns uli n i njecti o n, i nfecti o n, etc.) s h o ul d be rec or de d i n t he s u bject diar y. As D K A 
ma y prese nt differe ntl y a n d occ ur at l o wer gl uc ose val ues t ha n e x pecte d, partic ular atte nti o n 
s h o ul d be pai d t o e pis o des of na usea a n d v o mitin g as i n dicati ve of D K A s y m pt o ms, partic ularl y 
i n s u bjects re q uiri n g i ns uli n t hera p y. S u bjects s h o uld c o ntact t he site f or assista nce wit h dia betes 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 0 
ma na ge me nt i n t he e ve nt t hat t he y de vel o p s uc h  s y m pt o ms or w he n t he bl o o d ket o ne rea di n g is 
0. 6 m m ol/ L or a b o ve, e ve n if t heir bl o o d gl uc ose le vels are n ot ele vate d at t hat ti me.  
T he acti o n, f oll o w- u p a n d m o nit ori n g pla n will be at t he discreti o n of t he I n vesti gat ors a n d will 
de pe n d o n t heir j u d g me nt of se verit y base d o n si g ns /s y m pt o ms of D K A, ris k fact ors, rele va nt 
c o ntri b uti n g fact ors, a n d bl o o d gl uc ose le vel ( wit h t he ca veat t hat t he bl o o d gl uc ose le vel ma y be 
l o wer t ha n w o ul d be ot her wise e x pecte d gi ve n ele vate d ket o ne le vels):  
 A n y ele vate d bl o o d ket o ne val ue ( ≥ 0. 6 m m ol/ L) s h o ul d be t h oro u g hl y re vie we d b y t he site, 
i n t he c o nte xt of c o nc o mita nt cli nical s y m pt o ms of D K A, a n d of p ossi ble disc or da nce bet wee n 
fi n ger-stic k bl o o d val ues a n d gl yce mic c o ntr ol assesse d b y t he ce ntral la b orat or y or wit h 
cli nical s y m pt o ms.  
I n t he prese nce of s uc h disc or da nce, t he s u bject’s gl uc ose a n d ket o ne  meters s h o ul d be teste d a n d 
t he pr oce d ure f or usi n g it re vie we d wit h t he s u bject. I n vesti gat ors will de ter mi ne if a n y of t he 
re p orte d ele vate d ket o ne val ues are act uall y i n dicati ve of a D K A e ve nt. If yes, i n vesti gat ors will 
d oc u me nt all D K A relate d s y m pt o ms, rele va nt ris k fact ors, a n d a vaila ble la b orat or y test res ults 
(i ncl u di n g bl o o d ket o ne val ues an d bl o o d gl uc ose val ues meas ure d b y t he gl uc ose/ ket o ne meter) 
o n t he D K A e C R F pa ges a n d re p ort t his e ve nt t o t he S p o ns or. Si g ns a n d s y m p t o ms ass ociate d wit h 
D K A e ve nts s h o ul d n ot be re p orte d o n t he A E e C R F pa ge, u nless t he e ve nt f ulfills pr ot oc ol criteria 
f or a n S A E (see Secti o n 6. 1 ), i n w hic h case a n S A E f or m m ust be c o m plete d i n a d diti o n t o t he 
D K A e C R F pa ges. 
A n i n de pe n de nt D K A A dj u dicati o n C o m mittee, bli n de d t o t he treat me nt of  t he s u bjects, will 
a dj u dicate all p ote ntial e ve nts of D K A.  
A se parate A dj u dicati o n C harter will defi ne a n d de scri be t he pr oce d ure f or t he ha n dli n g, re p orti n g 
a n d classificati o n of t hese e ve nts. 
5. 3. 3  G ui d a n c e o n A s s e s s m e nt of Ur i n ar y I nf e cti o n s a n d H e m at uri a 
5. 3. 3. 1  G ui d a n c e o n A s s e s s m e nt of  Uri n ar y Tr a ct I nf e cti o n s 
T he f oll o wi n g is prese nte d t o assi st i n t he classificati o n a n d ma na ge me nt of uri nar y tract i nfecti o ns 
( U TI). It is n ot i nte n de d t o s u p pla nt i n vesti gat ors’ cli nical j u d g me nt. 
St u d y  dr u g  s h o ul d  be  wit h hel d  i n  s u bjects  wit h  cli nical  e vi de nce  of  u p per  tract  U TI  
(e. g., p yel o ne p hritis) or pres u me d urose psis u ntil t he c o urse of treat me nt of t he i nfecti o n has bee n 
c o m plete d a n d cli nical rec o ver y has occ urre d. 
It is rec o m me n de d t hat a f oll o w- u p uri ne c ult ure be o btai ne d wit hi n 7 da ys  of cli nical rec o ver y 
fr o m all U TIs. W het her or n ot a d diti o nal t hera p y is prescri be d beca use of c ult ure res ults s h o ul d be 
deter mi ne d b y I n vesti gat or j u d g me nt, afte r c o ns ultati o n wit h t he Me dical M o nit or. 
It is t he I n vesti gat or's res p o nsi bilit y t o re p ort, as a p plica ble base d o n I n vesti gat or's j u d g me nt a n d 
s u bject's me dical hist or y, relate d A Es as defi ne d i n Secti o n 6 . 
A d diti o nal  i nf or mati o n,  i ncl u di n g  b ut  n ot  li mite d  t o  c o m pleti o n  of  s u p ple me ntal  e C R Fs  or  
q uesti o n naires  ma y  be  re q ueste d  f or  certai n  A Es  a n d/ or  la b orat or y  a b n or malities  w hic h  are  
re p orte d/i de ntifie d d uri n g t he c o urse of t he st u d y. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 1 
As y m pt o m atic b acteri uri a  
D uri n g e nr oll me nt, treat me nt, a n d f o ll o w- u p of s u bjects i n t his trial, t he I n vesti gat or ma y disc o ver 
a s u bject wit h as y m pt o matic bact eri uria. As y m pt o matic bacteri uria is defi ne d as t he prese nce 
of  1 05  c ol o n y f or mi n g u nits/ m L of bacteria, i n a pr o perl y c olle cte d v oi de d uri ne s peci me n, 
wit h o ut si g ns or s y m pt o ms t y picall y attri b ute d t o  U TI. I n t his st u d y, t he ce ntral la b orat or y will 
re p ort uri nar y di pstic k test res ults f or he m o gl o bi n b ut will n ot r o uti nel y re p ort t he res ults of uri nar y 
di pstic k  tests  f or  le u k oc yte  esterase  as  a  sc ree ni n g  test  f or  p y uria  i n  s ur veilla nce  uri ne  
e xa mi nati o ns. 
5. 3. 3. 2  G ui d a n c e o n A s s e s s m e nt of H e m at uri a 
All e ve nts of he mat uria ( micr osc o pic a n d/ or ma cr osc o pic) d uri n g t he st u d y s h o ul d be w or ke d u p 
f or a p ossi ble ca use as per l ocal g ui deli nes. 
5. 3. 4  G ui d a n c e o n A s s e s s m e nt of C ar di o v a s c ul ar E v e nt s 
A n i n de pe n de nt Car di o vasc ular A dj u dicati o n C o m mi ttee t hat is bli n de d t o t he treat me nt of t he 
s u bjects will i n de pe n de ntl y a dju dicate all e ve nts of  heart fail ure re q uirin g h os pitalizati o n. A n 
a dj u dicati o n ma n ual/c harter of o pe rati o ns f urt her defi nes a n d descri bes t he pr oce d ure f or t he 
ha n dli n g, re p orti n g a n d classi ficati o n of t hese e ve nts. 
5. 3. 5  G ui d a n c e o n A s s e s s m e nt of H e p ati c L a b or at or y A b n or m aliti e s 
A n i n de pe n de nt He patic A dj u dicati o n C o m mittee, bl i n de d t o t he treat me nt of t he s u bjects, will 
deter mi ne  t he  pr o ba bilit y  t hat  dr u g-i n d uce d  li ver  i nj ur y  ( DI LI)  is  t he  ca use  of  li ver-relate d  
a b n or malities, i ncl u di n g,  b ut n ot li mite d t o: 
 He patic e ve nts relate d or lea di n g t o deat h ( occ urri n g wit hi n 3 0 days bef ore deat h)  
 Li ver la b orat or y a b n or malities s uc h as  
o  A S T a n d/ or A L T  3 x U L N a n d T B  2 x U L N ( wit hi n 1 4 da ys of t he A S T a n d/ or A L T 
ele vati o n)  
o  A S T a n d/ or A L T  1 0 x U L N 
A se parate A dj u dicati o n C harter will defi ne a n d de scri be t he pr oce d ure f or t he ha n dli n g, re p orti n g 
a n d classificati o n of t hese cases. 
T he f oll o wi n g is prese nte d t o assist i n t he e val ua ti o n a n d ma na ge me nt of hepatic la b orat or y val ues. 
It  is  n ot  i nte n de d  t o  s u p pla nt  t he  I n vesti gat or’s  cli nical  j u d g me nt.  S u bjects  w h o  e x perie nce  
A L T  a n d/ or  A S T  val ues  >  3 x  U L N  c o nfir me d  wit h  a  re peate d  test  will  ha ve  t he  f oll o wi n g  
perf or me d wit hi n 3 da ys of t he c o nfir me d la b orat or y res ults: 
 A d verse e ve nt assess me nt 
 P h ysical e xa mi nati o n f or ja u n dice a n d ot her si g ns of li ver diseases 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 2 
 Re vie w of rele va nt ris k fact or s a n d c urre nt hist or y f oc usi n g o n p ossi ble ca uses of t he i ncrease d 
A L T a n d/ or A S T a n d/ or T B, i ncl u di n g: 
o  Use
 of
 s us pect
 c o nc o mita nt
 me di cati o n
 (i ncl u di n g
 o ver-t he-c o u nter
 
[i.e., aceta mi n o p he n/ paraceta m ol], her bal a n d vita mi n pre parati o ns) 
o  Rece nt alc o h ol c o ns u m pti o n or recreati o nal dr u g/ narc otic use 
o  Rece nt u nacc ust o me d p h ysical e xerti o n  
o  Occ u pati o nal or e n vir o n me ntal e x p os ure t o he pat ot o xi ns 
o  Ot her c o n diti o ns w hic h ma y ca use li ver diseases or w h ic h ma y ca use a b n or mal test 
res ults 
o  S pecialize d li ver la b orat o r y pa nel (see A p pe n di x 1 ) 
A d diti o nal  i nf or mati o n,  i ncl u di n g  b ut  n ot  li mite d  t o  c o m pleti o n  of  s u p ple me ntal  e C R Fs  or  
q uesti o n naires,  ma y  be  re q uest e d  f or  certai n  A Es  a n d/ or  la b orat or y  a b n or malities  w hic h  are  
re p orte d /i de ntifie d as part of t he he patic safet y s ur veilla nce. 
F or s u bjects w h o are disc o nti n ue d fr o m st u d y me dicati o n as a res ult of s ustai ne d ele vate d li ver 
safet y a b n or malities, as descri be d i n Secti o n 3. 6 , a d diti o nal bl o o d sa m pli n g m ust be d o ne wit hi n 
3 da ys of t he c o nfir me d la b orat or y res ults (see A p pe n di x 1  a n d A p pe n di x 2 ), i n c o nj u ncti o n wit h 
a n E T D visit, i n a d diti o n t o t he pr oce d ures n ote d a b o ve. A refe rral c o ns ultati o n t o a he pat ol o gist 
or gastr oe nter ol o gist (s p ecializi n g i n li ver a b n or mal ities) s h o ul d be o btai ne d.  
A n y a d diti o n al tests a n d/ or e x a mi n ati o ns s h o u l d be c arrie d o ut at t he discreti o n of t he 
I n vesti g at or. A n y f urt her i n vesti g ati o ns a n d l ab or at or y res ults f or s u bjects wit h a b n or m al 
l a b or at or y v al ues at t he f oll o w- u p visit s h o ul d be m a de a v ail a ble t o t he S p o ns or/ desi g nee 
u p o n re q uest. 
5. 3. 6  P h y si c al  E x a mi n ati o n  
 A  tar gete d  p h ysical  e xa mi nati o n  s h o ul d  i n cl u de  car di o vasc ular,  l u n gs,  a b d o me n,  a n d  
e xtre mities, a n d a n y or ga n s yste ms perti ne nt t o t he s u bject’s si g ns, s y m pt o ms, or A Es. 
 A c o m plete p h ysical e xa mi nati o n s h o ul d i ncl u de ge neral a p pear a nce, hea d, e yes, ears, n ose, 
t hr oat, nec k, car di o vasc ular, l u n gs, a b d o me n, l ym p h n o des, e xtre mities, ne ur ol o gical, s ki n, a n d 
m usc ul os keletal. 
T he i n di vi d ual perf or mi n g t he p h ysi cal e xa mi nati o ns m ust be lice n se d b y state la w ( or a p plica ble 
l ocal la w) t o perf or m t his pr oce d ure. 
5. 3. 7  M e a s ur e s of Gr o wt h a n d M at urit y 
Meas ures  of  gr o wt h  a n d  mat urit y  will  i ncl u de  Ta n ner  sta gi n g  a n d  la b orat or y  e val uati o ns  of  
gr o wt h, b o ne a n d mat urati o n mar kers. 
Ta n ner  sta gi n g  ( A p pe n di x  3 )  will  be  deter mi ne d  b y  I n vesti gat or  as sess me nt  a n d  s u bjects’  
self-re p orts.   

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 3 
Gr o wt h, b o ne a n d mat urati o n mar kers will i ncl u de: 
 T h yr oi d-sti m ulati n g h or m o ne ( T S H) a n d free t h yr o xi ne 
 L utei nizi n g  h or m o ne  ( L H),  f ollicle-sti m ula ti n g  h or m o ne  ( F S H),  estra di ol,  a n d  t otal  
test oster o ne 
 I ns uli n-li ke  gr o wt h  fact or- 1  (I G F- 1)  a n d  i ns uli n-li ke  gr o wt h  fact or  bi n di n g  pr otei n- 3  
(I G F B P- 3) 
 Calcit o ni n, 2 5- h y dr o x y vita mi n D, b o ne al ka li ne p h os p hatase, oste ocalci n, a n d P T H 
 Car b o x yter mi nal cr oss-li n ke d tel o pe p ti de of T y pe 1 c olla ge n ( C T X- 1) 
5. 3. 8  Bl o o d Pr e s s ur e, Ort h o st ati c Bl o o d Pr e s s ur e a n d H e art R at e 
Bl o o d press ure, ort h ostatic B P a n d H R meas ure me nts m ust be ta ke n c o nsiste ntl y  t hr o u g h o ut t he 
st u d y. O nl y t he ri g ht or t he left ar m s h o ul d be use d c o nsiste ntl y w he n meas uri n g t hese para meters. 
D oc u me nt w hic h ar m was use d al o n g wit h t he o bser ver’s i nitials; t he sa me ar m s h o ul d be use d f or 
eac h p ositi o n a n d at eac h visit. T he s u bject s h o ul d be all o we d at least 5 mi n utes of rest bef ore 
meas ure me nt. Bl o o d press ure s h o ul d be meas ure d wit h t he s u bject’s ar m resti n g o n a ta ble, a n d 
wit h s u bject’s bac k s u p p ort a n d feet flat o n t he fl o or. 
Bl o o d press ure a n d H R will be deter mi ne d fr o m t h ree re plicate meas ure me nts o btai ne d at least 
1 mi n ute a part; t he ti me  bet wee n t hese meas ure me nts s h o uld n ot e xcee d 1 5 mi n utes. T he a vera ge 
B P a n d H R will be deter mi ne d fr o m t hese t hree re plicate meas ure me nts a n d re p orte d i n t he e C R F.  
Ort h ostatic B P a n d H R meas ure m e nts s h o ul d be o btai ne d f oll o wi n g c o m pleti o n of seate d B P a n d 
H R meas ure me nt. 
T he s u pi ne B P a n d H R m ust be m eas ure d pri or t o t he sta n di n g B P. T he s u bject s h o ul d rest i n t he 
s u pi ne p ositi o n f or at least 5 mi n utes pri or t o meas ure me n t of B P a n d H R.  
T he s u bject will t he n sta n d f or 2 t o 3 mi n utes. After t his ti me, meas ure t he B P wit h t he ar m 
s u p p orte d at t he a ntec u bital f ossa at heart le vel. Sta n di n g B P a n d H R will be deter mi ne d fr o m 
t hree re plicate meas ure me nts o btai ne d at least 1 mi n ute a part. T he a vera ge B P a n d H R will be 
deter mi ne d fr o m t hese t hree re plicate m eas ure me nts a n d re p orte d i n t he e C R F. 
All meas ure me nts s h o ul d occ ur at least 8 h o urs af ter t he last i n gesti o n of caffei ne, alc o h ol, or 
nic oti ne.  
It is critic al t h at t he B P a n d H R me as ure me nts be o bt ai ne d pri or t o t he a d mi nistr ati o n of 
bli n de d st u d y me dic ati o n. 
5. 3. 9  G ui d a n c e o n V ol u m e D e pl eti o n 
Da pa glifl ozi n has a m o dest di ure tic effect. T he ris k of v ol u me de pleti o n is e n ha nce d w he n t w o 
di uretics are use d i n c o m bi nati o n a n d i n s u bjects t hat ot her wise are at ris k f or v ol u me de pleti o n. 
T heref ore, ca uti o n s h o ul d be e xercise d w he n a d mi n isteri n g da pa glifl ozi n t o s u bjects at ris k f or 
v ol u me de pleti o n d ue t o c o-e xisti n g c o n diti o ns or c o nc o mit a nt me dicati o ns, s uc h as l o o p di uretics. 
T hese s u bjects s h o ul d be caref ull y m o nit ore d f or v ol u me stat us, electr ol ytes, a n d re nal f u ncti o n. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 4 
5. 3. 1 0 S u p pl e m e nt al Vi sit s 
5. 3. 1 0. 1
 R e s c u e
 Vi sit
 
A n y  s u bject  w h o  q ualifies  f or  resc ue  d uri n g  t h e  st u d y  peri o ds  m ust  ha ve  all  Resc ue  visit  
pr oce d ures perf or me d bef ore resc ue t hera p y is i n itiate d. T he I X R S m ust be calle d t o rec or d t he 
s u bject stat us (i.e., resc ue status). All s u bjects w h o are resc ue d b ut ha ve n ot u n der g o ne E T D s h o ul d 
re mai n i n t he st u d y, f ollo w t he visit sc he d ule, a n d c o nti n ue treat me nt wit h st u d y dr u gs. 
S u bjects w h o disc o nti n ue I P earl y will still be e val uate d f or resc ue a n d f oll o w t he visit sc he d ule, 
b ut will c o nti n ue t he st u d y wit h o ut I P a d mi nistrati o n after t he Resc ue Visit. 
After Resc ue Visit, t he s u bject will c o nti n ue i n  t he treat me nt peri o d acc or di n g t o t he re g ular visit 
sc he d ule. 
T he Resc ue s u p ple me ntal e C R F will be c o m plete d t o c ollect resc ue-relate d e n d p oi nt data.  
All prescri be d resc ue me dicati o n a n d d osa ge(s) al o n g wit h a n y c h a n ges s h o ul d als o be rec or de d 
i n t he e C R F. 
5. 3. 1 0. 2
 E arl y
 Tr e at m e nt
 Di s c o nti n u ati o n Vi sit 
A n y  s u bject  w h o  disc o nti n ues  d uri n g  t he  st u d y  pe ri o ds  m ust  ha ve  all  E T D  visit  pr oce d ures  
perf or me d bef ore st u d y disc o nti n uati o n. T he I X R S m u st be calle d t o rec or d t he s u bject stat us 
(i.e., E T D stat us). All s u bjects w h o disc o nti n ue st u d y dr u g s ho ul d re mai n i n t he st u d y.  
After E T D visit pr oce d ures  are perf or me d, t he s u bject will c o nti n ue i n  t he treat me nt peri o d 
acc or di n g t o t he Earl y Disc o nti n ue d f oll o w- u p visit sc he d ule ( Ta ble 5. 1- 4 ). 
T he E T D s u p ple me ntal e C R F will nee d t o be c o m plete d.  
5. 3. 1 0. 3
 Ot h er
 S u p pl e m e nt a l ( U n s c h e d ul e d) Vi sit s 
At a n y ti me d uri n g t he trial, t he I n vesti gat or ma y at  his/ her discreti o n arra n ge f or a s u bject t o ha ve 
a n u nsc he d ule d (s u p ple me ntal) assess me nt(s), es peci all y i n t he case of A Es t hat re q uire f oll o w- u p. 
If a s u bject is see n f or a n u nsc he d ule d assess me nt, t he a p pr o pr iate s u p ple me ntal pages of t he e C R F 
m ust be c o m plete d. 
5. 3. 1 1 I m a gi n g A s s e s s m e nt f or t h e St u d y 
N ot a p plica ble. 
5. 4  Effi c a c y  A s s e s s m e nt s  
Assess me nts c o nsist of t he ce ntral la b orat or y me as ure me nt of H b A 1c a n d ot her rele va nt la b orat or y 
tests, c ollecte d d uri n g t he st u d y. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 5 
5. 5  P h ar m a c o ki n eti c/ P h a r m a c o d y n a mi c A s s e s s m e nt s 
T a ble 5. 5- 1:  
S a m pli n g Sc he d ule 
St u d y D a y 
Ti me  
( Rel ati ve t o 
D osi n g)  
H o ur a  
P K  
Bl o o d S a m ple b  
Pl as m a Gl uc ose b  Pl as m a
 
D P P- 4
b  
Da y 1 
Pre- d ose 
 
X 
X 
Wee k 6 
0 ( Pre- d ose) 
X 
X 
 
Wee k 6 
2 (  1 hr) 
X 
X
 X
 
Wee k 1 2  
0 ( Pre- d ose) 
X 
X
 
 
Wee k 1 2 
2 (  1 hr) 
X 
X
 X
 
Wee k 2 0  
0 ( Pre- d ose) 
X 
X
 
 
Wee k 2 0 
2 (  1 hr) 
X 
X
 X
 
Wee k 2 6  
0 ( Pre- d ose) 
X 
X 
 
Wee k 2 6 
2 (  1 hr) 
X c 
X
 X
 
a Pre- d ose sa m ples ma y be c ollecte d u p t o 1 h o ur pre- d ose 
b All sa m ples will be c ollecte d i n a fasti n g c o n diti o n 
c P har mac o ki netic sa m ples will n ot be c ollecte d at a n y visi t f oll o wi n g a n Earl y Treat me nt Disc o nti n uati o n Visit.  
 
Bl o o d sa m ples f or deter mi nati o n of plas ma le vels of da pa glifl ozi n, sa xa gli pti n a n d its meta b olite 
5- O H-sa xa gli pti n, gl uc ose a n d D P P- 4 acti vit y will be ta ke n at t he ti mes prese nte d i n  Ta ble 5. 5- 1 . 
Sa m ples ma y be c ollecte d at a d diti o nal ti me p oi nts d uri n g t he st u d y if warra nte d a n d a gree d u p o n 
bet wee n t he i n vesti gat or a n d t he S p o ns or, e. g., f or safet y reas o ns. T he ti mi n g of sa m pli n g ma y be 
altere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a vaila ble data  (e. g., t o o btai n data cl oser t o 
t he ti me of pea k or tr o u g h matri x c o nce ntrati o ns) t o e ns ure a p pr o priate m o nit ori n g. Sa m ples will 
be c ollecte d, la bele d, st ore d a n d s hi p pe d as deta ile d i n t he La b orat or y Ma n ual. Sa m ples s h o ul d be 
st ore d i n a sec ure st ora ge s pace wit h a deq uate meas ures t o pr otect c o nfi de ntialit y. 
All P K a n d p har mac o d y na mic ( P D) sa m ples wi ll be c ollecte d i n a fasti n g c o n diti o n. 
Sa m ples f or deter mi nati o n of dr u g c o nce ntrati o n i n plas ma will be a nal yze d b y a n a p p oi nte d 
la b orat or y o n be half of t he S p o ns or/ desi g nee usi n g a p pr o priate bi oa nal ytical met h o ds. T he P K 
la b orat or y will be u n bli n de d t o treat me nt, a n d P K data will n ot be tra nsferre d u ntil after data base 
l oc k. F ull details of t he a nal ytical met h o ds use d will be descri be d i n a se parate bi oa nal ytical re p ort. 
O nl y P K sa m ples fr o m s u bjects o n rele va nt acti ve st u d y dr u g will be a nal yze d; t hese sa m ples will 
n ot be c ollecte d after treat me nt disc o nti n uati o n. Sa m ples fr o m s u bjec ts n ot d ose d wit h t he rele va nt 
acti ve st u d y treat me nt will o nl y be a nal yze d o n a ‘f or ca use’ basis, f or e xa m ple, if t here is a 
s us pici o n t hat a s u bject has bee n d ose d i nc orrectl y.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 6 
P har mac o ki netic  sa m ples  will  be  dis p ose d  of  after  t he  Bi oa nal ytical  Re p ort  fi nalizati o n  or  
6 m o nt hs after iss ua nce of t he draft Bi oa nal ytical Re p ort ( w hic he v er is earlier), u nless re q ueste d 
f or  f ut ure  a nal yses.  P har mac o ki netics  a n d  ex p os ure-res p o nse  relati o ns hi p  a nal ysis  ma y  be  
s u m marize d a n d re p orte d se paratel y fr o m t he C S R as nee de d.  
All P K sa m ples still wit hi n t he k n o w n  sta bilit y of t he a nal yses of i nterest at t he ti me of recei pt b y 
t he bi oa nal ytical la b orat or y will be a nal yze d. 
P har mac o ki netic sa m ples ma y be dis p ose d of or a n o n y mize d b y p o oli n g. A d diti o nal a nal yses ma y 
be c o n d ucte d o n t he a n o n y mize d, p o ole d P K sa m ples t o  f urt her e val uate a n d vali date t he a nal ytical 
met h o d. A n y res ults fr o m s uc h a nal yses ma y be re p orte d se paratel y fr o m t he C S R. 
I nc urre d sa m ple re pr o d uci bilit y a nal ysis, if a n y, will be perf or me d  al o n gsi de t he bi oa nal ysis of t he 
test sa m ples. T he res ults fr o m t he e val uati o n ma y be re p orte d se para tel y fr o m t he C S R. 
I n a d diti o n, P K sa m ples will be arc hi ve d f or p ote ntial meta b olite a nal ysis, if t he nee d arises a n d 
t o t he e xte nt p ossi ble. 
P har mac o d y na mic sa m ples will be  st ore d a n d pr ocesse d as detaile d i n t he La b orat or y Ma n ual. 
O nl y D P P- 4 sa m ples fr o m s u bjects  o n rele va nt acti ve st u d y dr u g will be a nal yze d. All sa m ples 
will be dis p ose d of after testi n g has b ee n c o m plete d b y t he a nal ytical la b.  
5. 6  Bi o m ar k er  A s s e s s m e nt s  
N ot a p plica ble 
5. 7  O ut c o m e s  R e s e ar c h  A s s e s s m e nt s  
N ot a p plica ble 
5. 8  Ot h er  A s s e s s m e nt s   
5. 8. 1  Di et a n d E x er ci s e C o u n s eli n g 
Starti n g at e ntr y i nt o t he lea d-i n peri o d, s u bjects will be i nstr ucte d o n a diet a n d a n e xercise 
pr o gra m i n acc or da nce wit h t he A D A or si milar l ocal g ui deli n es t o be f oll o we d f or t he st u d y 
d urati o n. 
A re gistere d dietitia n, re gistere d  n urse, p h ysicia n, Certifie d Dia betes E d ucat or ( C D E), n utriti o nist, 
or ot her q ualifie d me m ber of t he st u d y tea m w h o has a p pr o priate d oc u me nte d trai ni n g, will pr o vi de 
t his c o u nseli n g. 
5. 8. 2  W ei g ht, H ei g ht, a n d B MI 
B o d y wei g ht a n d hei g ht will be meas ure d acc or d i n g t o t he sc he d ule prese nte d i n t he st u d y fl o w 
c hart/ti me a n d e ve nt sc he d ule (see Secti o n 5. 1 ) a n d will be rec or de d i n t he e C R F.  
T he st u d y-site staff s h o ul d use a di gi tal precisi o n scale if p ossi ble a n d rec or d t he wei g ht t o t he first 
deci mal p oi nt (e. g., 6 9. 3 k g). T he s u bject s h o ul d wear a sta n dar d h os pital-t y pe g o w n or e q ui vale nt 
li g ht i n d o or cl ot hi n g, s h oes re m o ve d, a n d bla d der e m pt y f or t he b o d y wei g ht meas ure me nt at eac h 
visit. S u bjects s h o ul d be wei g he d o n t he sa me scale at all visits. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 7 
Meas ure me nt of hei g ht s h o ul d be perf or me d wit h t he s u bject’s s h oes re m o ve d. T he s u bject’s k nees 
s h o ul d be strai g hte ne d, hea d hel d erect a n d e yes f or war d. 
B o d y mass i n de x is deter mi ne d b y wei g ht ( k g) di vi de d b y hei g ht ( m) s q uare d. 
Met h o d of B MI Calc ulati o n: 
 Use act ual hei g ht a n d wei g ht 
 T o calc ulate B MI: 
o  C o n vert p o u n ds (l bs) t o k il o gra ms ( k g = l b / 2. 2) 
o  C o n vert i nc hes (i n) t o ce nti meters (c m = i n X 2. 5 4) 
o  B MI = ( wei g ht i n k g) / ( hei g ht i n c m/ 1 0 0) 2 
o  R o u n d t o o ne deci mal place (i f 0. 0 5 or greater, r o u n d u p) 
5. 9  R e s ult s of C e ntr al A s s e s s m e nt s 
Bl o o d a n d uri ne sa m ples will be o btai ne d at s pecifie d ti me p oi nts f or la b orat or y e val uati o ns 
(see A p pe n di x 1). T he ce ntral la b orat or y f or t his st u d y will perf or m t he a nal ysis of all sc he d ule d 
la b orat or y tests a n d will pr o vi de refere nce ra n ges f or t hese tests. T he ce ntral la b orat or y will 
pr o vi de s pecific i nstr ucti o ns f or c ollecti o n, pr o cessi n g, pac ka gi n g, a n d s hi p pi n g of all sa m ples.  
T he H b A 1c val ues a n d uri nar y gl uc ose val ues, i n cl u di n g t he uri nar y gl uc ose:creati ni ne rati o will 
be bli n de d t o t he S p o ns or, I n vesti gat or, site, a n d s u bject f or t he d urati o n of t he st u d y f oll o wi n g I P 
a d mi nistrati o n o n Da y 1 u ntil after st u d y c o m pleti o n. I n t he e ve nt of a n H b A 1c res ult > 8. 0 % 
d uri n g t he L T peri o d ( w he n t hese val ues re q uire s u bj ect resc ue), t he i n vesti gat or will be i nf or me d 
via a n H b A 1c alert fr o m t he ce ntral la b orat or y, b u t will re mai n bli n de d t o t he H b A 1c res ult. After 
st u d y c o m pleti o n at Wee k 5 6 (a n d data l oc ke d a n d a nal ysis c o m plete d), t he a b o ve meas ure me nts 
will be u n bli n de d a n d a vaila ble t o  t he S p o ns or a n d I n vesti gat or. 
6
 A D V E R S E
 E V E N T S
 
A n A dverse Eve nt  ( A E) is defi ne d as a n y ne w u nt o war d me dical occ urre nce or w orse ni n g of a 
pree xisti n g me dical c o n diti o n i n a cli nical i n vest i gati o n s u bject a d mi nistere d st u d y dr u g a n d t hat 
d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his trea t me nt. A n A E ca n t heref ore be a n y 
u nfa v ora ble a n d u ni nte n de d si g n (s uc h as a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of st u d y dr u g, w het her or n ot c o nsi dere d  relate d t o t he st u d y 
dr u g. 
T he ca usal relati o ns hi p t o st u d y dr u g  is deter mi ne d b y a p h ysicia n a n d s h o ul d be use d t o assess all 
A Es. T he ca usal relati o ns hi p ca n  be o ne of t he f oll o wi n g: 
 Relate d: T here is a reas o na bl e ca usal relati o ns hi p bet wee n st u d y dr u g a d mi nistrati o n a n d t he 
A E. 
 N ot relate d: T here is n ot a reas o na ble ca usa l relati o ns hi p bet wee n st u d y dr u g a d mi nistrati o n 
a n d t he A E.  
T he ter m "reas o na ble ca usal relati o ns hi p" mea ns t here is e vi de nce t o  s u g gest a ca usal relati o ns hi p.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 8 
A d verse  e ve nts  ca n  be  s p o nta n e o usl y  re p orte d  or  elicite d  d uri n g  o pe n-e n de d  q uesti o ni n g,  
e xa mi nati o n, or e val uati o n of a s u bject. (I n or der t o pre ve nt re p orti n g bias, s u bjects s h o ul d n ot be 
q uesti o ne d re gar di n g t he s pecific o cc urre nce of o ne or m ore A Es.) 
T he S p o ns or/ desi g nee will be re p orti n g A Es t o Re g ulat or y A ut h orities a n d Et hics C o m mittees 
acc or di n g t o l ocal a p plica ble la ws i ncl u di n g E u r o pea n Directi ve 2 0 0 1/ 2 0/ E C a n d F o o d a n d Dr u g 
A d mi nistrati o n C o de of Fe deral Re g ulati o ns 2 1 C F R Parts 3 1 2 a n d 3 2 0. 
A n y A Es t hat are u nres ol ve d at t he s u bject’s last  A E assess me nt or ot her assess me nt/ visit as 
a p pr o priate i n t he st u d y are f oll o we d u p b y t he I n ve sti gat or f or as l o n g as me dicall y i n dicate d, b ut 
wit h o ut  f urt her  rec or di n g  i n  t he  C R F.  Astra Ze neca  retai ns  t he  ri g ht  t o  re q uest  a d diti o nal  
i nf or mati o n f or a n y s u bject wit h o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if j u d ge d necessar y. 
6. 1  S eri o u s A d v er s e E v e nt s 
A Seri o us A dverse Eve nt ( S A E)  is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:  
 Res ults i n deat h 
 Is life-t hreate ni n g ( defi ne d as 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 me of 
t he e ve 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 ha ve ca use d deat h if it were 
m ore se vere) 
 Re q uires  i n patie nt  h os pitaliz ati o n  or  ca uses  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n  
(see N O T E bel o w) 
 Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 Is a c o n ge nital a n o mal y/ birt h defect 
 Is a n i m p orta nt me dical e ve nt ( defi ne d as a me dical e ve nt(s) t h at ma y 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, base d u p o n a ppr o priate me dical a n d 
scie ntific j u d g me nt, ma y je o par dize t he s u bject or ma y re q uire i nter ve nti o n [e. g., me dical, 
s ur gical] t o pre ve nt o ne of t he ot her seri o us o utc o mes liste d i n t he defi niti o n a b o ve.) E xa m ples 
of s uc h e ve nts i ncl u de, b ut are n ot li mite d t o, i n te nsi ve treat me nt i n a n e mer ge nc y r o o m or at 
h o me  f or  aller gic  br o nc h os pa s m;  bl o o d  d yscrasias  or  c o n v ulsio ns  t hat  d o  n ot  res ult  i n  
h os pitalizati o n. P ote ntial DI LI is als o c o nsi der e d a n i m p orta nt me dical e ve nt. ( See Secti o n  6. 6 
f or t he defi niti o n of p ote ntial DI LI.) 
S us pecte d tra ns missi o n of a n i nfecti o us a ge n t (e. g., pat h o ge nic or n o n pat h o ge nic) via t he st u d y 
dr u g is a n S A E.  
Alt h o u g h pre g na nc y, o ver d ose, ca ncer, a n d DI LI ar e n ot al wa ys seri o us b y re g ulat or y defi niti o n, 
t hese e ve nts m ust be ha n dle d as S A Es. ( See Secti o n 6. 1. 1  f or re p orti n g pre g na ncies). 
A n y c o m p o ne nt of a st u d y e n d p oi nt t hat is c o nsi dere d relate d t o st u d y t hera p y (e. g., deat h is a n 
e n d p oi nt, if deat h occ urre d d ue t o a na p h yla xis, a n a p h yla xis m ust be re p orte d) s h o ul d be re p orte d 
as a n S A E (see Secti o n  6. 1. 1 f or re p orti n g details). 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
8 9 
N O T E :  
T he f oll o wi n g h os pitalizati o ns are n ot c o ns i dere d S A Es i n t his cli nical st u d y: 
 A visit t o t he e mer ge nc y r o o m or ot her h os pita l de part me nt < 2 4 h o urs, t hat d oes n ot res ult i n 
a d missi o n ( u nless c o nsi dere d a n i m p orta nt me dical or life-t hreate ni n g e ve nt) 
 Electi ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt 
 A d missi o ns as per pr ot oc ol f or a pla n ne d me dical/s ur gical pr oce d ure 
 R o uti ne  healt h  assess me nt  re q uiri n g  a d missi o n  f or  baseli ne/tr e n di n g  of  healt h  stat us  
(e. g., r o uti ne c ol o n osc o p y) 
 Me dical/s ur gical a d missi o n ot her t ha n t o re me d y ill healt h a n d pla n ne d pri or t o e ntr y i nt o t he 
st u d y. A p pr o priate d oc u me ntati o n is re q uire d i n t hese cases 
 A d missi o n e nc o u ntere d f or a n ot her life circ u msta n ce t hat carries n o beari n g o n healt h stat us 
a n d re q uires n o me dical/s ur gical i nter ve nti o n (e. g., lac k of h o usi n g, ec o n o mic i na de q uac y, 
care gi ver res pite, fa mil y circ u m sta nces, a d mi nistrati ve reas o n) 
 A d missi o n f or a d mi nistrati o n of a ntica ncer t hera p y i n t he a bse nce of a n y ot her S A Es (a p plies 
t o o nc ol o g y pr ot oc ols) 
6. 1. 1  S eri o u s A d v er s e E v e nt C oll e cti o n a n d R e p orti n g 
F oll o wi n g t he s u bject’s writte n c o ns e nt t o partici pate i n t he st u d y, a ll S A Es, w het her relate d or n ot 
relate d  t o  st u d y  dr u g,  m ust  be  c ollecte d,  i ncl u di n g  t h ose  t h o u g ht  t o  be  ass ociate d  wit h  
pr ot oc ol-s pecifie d pr oce d ures. Al l S A Es m ust be c ollecte d t hat occ ur d uri n g t he sc ree ni n g peri o d 
a n d wit hi n 2 8 da ys of disc o nti n uati o n of d osi n g.  
T he i n vesti gat or m ust re p ort a n y S A E t hat occ urs after t hese ti me peri o ds a n d t hat is belie ve d t o 
be relate d t o st u d y dr u g or pr ot oc ol-s pecifie d pr oce d ure.  
Seri o us a d verse e ve nts will als o be c ollecte d q uarterl y fr o m t he Wee k 5 6  visit t o t he Wee k 1 0 4 
p ost-st u d y visit.  
A n S A E re p ort m ust be c o m plete d f or a n y e ve n t w here d o u bt e xists re gar di n g its seri o us ness.  
If t he I n vesti gat or belie ves t hat a n S A E is n ot relate d t o st u d y dr u g, b ut is p ote ntiall y relate d t o t he 
c o n diti o ns of t he st u d y (s uc h as wit h dra wal of pre vi o us t hera p y or a c o m plicati o n of a st u d y 
pr oce d ure), t he relati o ns hi p m ust be s pecifie d i n t he narrati ve se cti o n of t he S A E Re p ort F or m. 
Seri o us a d verse e ve nts, w het her relate d or n ot relate d t o st u d y dr u g, a n d pre g na ncies m ust be 
re p orte d t o S p o ns or ( or desi g nee) wit hi n 2 4 h o urs of a ware ness of t he e ve nt.  
All S A Es will be rec or de d i n t he C R F. If a n y S A E occ urs i n t he c o urse of t he st u d y, t he n 
I n vesti gat ors or ot her site perso n nel m ust i nf or m t he a p pr o pri ate Astra Ze neca re prese ntati ves 
wit hi n o ne da y i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he bec o mes a ware of 
it. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 0 
T he desi g nate d Astra Ze neca re prese nta ti ve will w or k wit h t he I n vesti gat or t o e ns ure t hat all t he 
necessar y  i nf or mati o n  is  pr o vi de d  t o  t he  Astra Ze neca  Patie nt  Safet y  data  e ntr y  site  
wit hi n 1  c ale n d ar d a y of i nitial recei pt f or fatal a n d life-t hreate ni n g e ve nts a n d wit hi n 5 c ale n d ar  
d a ys of i nitial recei pt f or all ot her S A Es. 
F or  fatal  or  life-t hreate ni n g  A Es  w here  i m p orta nt  or  rele va nt  i nf or ma ti o n  is  missi n g,  acti ve  
f oll o w- u p m ust be u n derta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel m ust i nf or m 
Astra Ze neca re prese ntati ves of a n y f oll o w- u p i nf o r mati o n o n a pre vi o usl y re p orte d S A E wit hi n 
o ne cale n dar da y i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he bec o mes a ware 
of it. 
Seri o us a d verse e ve nts m ust be rec or de d o n t he S A E Re p ort F or m; pre g na ncies o n a Pre g na nc y 
S ur veilla nce F or m (electr o nic or pa per f or m s). T he preferre d met h o d f or S A E data re p orti n g 
c ollecti o n is t hr o u g h t he e C R F. T h e pa per S A E/ pre g na nc y s ur veilla n ce f or ms are o nl y i nte n de d as 
a bac k- u p o pti o n w he n t he e C R F s yste m is n ot f u ncti o ni n g. I n t his case, t he pa per f or ms are t o be 
tra ns mitte d via e mail or c o nfir med facsi mile (fa x) tra ns missi o n t o:  
S A E  E m ail A d dress:  
 
U S A 
S A E Tele p h o ne N u m ber: 
 
S A E F acsi mile N u m ber: 
 
Ot her  
S A E F acsi mile N u m ber: 
 
S A E Tele p h o ne N u m ber: 
 
F or  st u dies  ca pt uri n g  S A Es  t hr o u g h  E D C,  elect r o nic  s u b missi o n  is  t he  re q uire d  met h o d  f or  
re p orti n g. I n t he e ve nt t he electr o nic s yste m is u na vaila ble f or tra n s missi o n, pa per f or ms m ust be 
use d a n d s u b mitte d i m me diatel y. W he n pa per f or m s are use d, t he ori gi nal pa per f or ms are t o 
re mai n o n-site. 
If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w- u p re p orts are re q uire d. ( N ote: F oll o w- u p 
S A E re p orts m ust i ncl u de t he sa me i n vesti gat or ter m(s) i nitiall y re p orte d.)  
If a n o n g oi n g S A E c ha n ges i n its i nte nsit y or relati o ns hi p t o stu d y dr u g or if ne w i nf or mati o n 
bec o mes a vaila ble, t he S A E re p or t m ust be u p date d a n d s u b mitted wit hi n 2 4 h o urs t o t he S p o ns or 
( or desi g nee) usi n g t he sa me pr oce d ure use d f or tra ns mitti n g t he i nitial S A E re p ort. 
After t he i nitial S A E re p ort, t he I n vesti gat or is  re q uire d t o pr oacti vel y f oll o w eac h s u bject at 
s u bse q ue nt visits/c o ntacts. All S A Es will be f oll o we d u ntil res o l uti o n, sta bilizati o n, t he e ve nt is 
ot her wise e x plai ne d, or t he s u bject is l ost t o f oll o w- u p. 
6. 2  N o n s eri o u s A d v er s e E v e nt s 
A  n o nseri o us a dverse eve nt  is a n A E n ot classifie d as seri o us. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 1 
I nte nsit y will be gra de d acc or di n g t o t he f oll o wi n g defi niti o ns: 
 Mil d (a ware ness of si g n or s y m pt o m, b ut easil y t olerate d) 
 M o derate ( disc o mf ort s ufficie nt t o ca use i nterfere nce wit h n or mal acti vities) 
 Se vere (i nca pacitati n g, wit h i na bil it y t o perf or m n or mal acti vities) 
It is i m p orta nt t o disti n g uis h bet wee n seri o us a n d se vere A Es. Se verit y is a meas ure of i nte nsit y 
w hereas seri o us ness is defi ne d b y t he criteria i n Secti o n  6. 1 . A n A E of se vere i nte nsit y nee d n ot 
necessaril y be c o nsi dere d seri o us. F or e xa m ple, na usea t hat persists f or se veral h o urs ma y be 
c o nsi dere d se vere na usea, b ut n ot a n S A E u nl ess it meets t he criteria s h o w n i n Secti o n  6. 1 . O n t he 
ot her ha n d, a str o ke t hat res ults i n o nl y a li mite d de gree of disa bilit y ma y be c o nsi dere d a mil d 
str o ke b ut w o ul d be a n S A E w he n it satisfies t he criteria s h o w n i n Secti o n 6. 1 . 
6. 2. 1  N o n s eri o u s  A d v er s e  E v e nt C oll e cti o n a n d R e p orti n g 
T he c ollecti o n of n o nseri o us A E i n f or mati o n s h o ul d be gi n at i nitiati o n of st u d y dr u g. N o nseri o us 
A E i nf or mati o n s h o ul d als o be c ollecte d fr o m t he start of a place b o lea d-i n peri o d or ot her 
o bser vati o nal  peri o d  i nte n de d  t o  es ta blis h  a  baseli ne  stat us  f or  t he  s u bjects.  N o nseri o us  A E  
i nf or mati o n will als o be c ollecte d q uarterl y fr o m t he Wee k 5 6 visit t o t he Wee k 1 0 4 p ost-st u d y 
visit. 
After t he i nitial n o nseri o us  A E re p ort, t he I n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
s u bject  at  s u bse q ue nt  visits/c o ntacts.  All  n o nseri o us  A Es  will  be  f oll o we d  u ntil  res ol uti o n,  
sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, t he s u bject is l ost t o f oll o w- u p, or re p orte d as S A Es 
if t he y bec o me seri o us (see Secti o n 6. 1. 1 ). F oll o w- u p is als o re q uire d f or n o nseri o us A Es t hat 
ca use i nterr u pti o n or disc o nti n uati o n of st u d y dr u g a n d f or t h os e prese nt at t he e n d of st u d y 
treat me nt as a p pr o priate. All i de ntifie d n o nseri o us A Es m ust be  rec or de d a n d descri be d o n t he 
n o nseri o us A E pa ge of t he C R F  ( pa per or electr o nic).  
C o m pleti o n of s u p ple me ntal C R Fs ma y be re q ueste d f or A Es a n d/ or la b orat or y a b n or malities t hat 
are re p orte d/i de ntifie d d uri n g t he c o urse of t he st u d y. 
6. 3  L a b or at or y  T e st  R e s ult A b n or m aliti e s 
T he f oll o wi n g la b orat or y test re s ult a b n or malities s h o ul d be ca pt ure d o n t he n o nseri o us A E C R F 
pa ge or S A E Re p ort F or m ( pa per or electr o nic) as a p pr o priate: 
 A n y la b orat or y test res ult t hat is cli nicall y si g nifica nt or meets t he defi niti o n of a n S A E  
 A n y la b orat or y test res ult a b n or malit y t hat re q ui re d t he s u bject t o ha ve st u d y dr u g disc o nti n ue d 
or i nterr u pte d 
 A n y la b orat or y test res ult a b n or ma lit y t hat re q uire d t he s u bject t o recei ve s pecific c orrecti ve 
t hera p y. 
It is e x pecte d t hat, w here ver p ossi ble, t he cli nical rat her t ha n la b orat or y ter m w o ul d be use d b y t he 
re p orti n g i n vesti gat or (e. g., a ne mia vers us l o w he m o gl o bi n val ue). 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 2 
6. 4  Pr e g n a n c y  
If, f oll o wi n g i nitiati o n of t he st u d y dr u g, it is s u bse q ue ntl y disc o vere d t hat a st u d y s u bject is 
pre g na nt or ma y ha ve bee n pre g na nt at t he ti me of st u d y e x p os ure, i ncl u di n g d uri n g at least 
5  half-li ves  after  pr o d uct  a d mi nistrati o n,  t he  I n ve sti gat or  m ust  i m mediatel y  n otif y  t he  
Me dical  M o nit or  or  a p pr o priate  Astra Ze neca  re pr ese ntati ve  of  t his  e v e nt  a n d  c o m plete  a n d  
f or war d a Pre g na nc y S ur veilla nce F or m t o Astra Ze neca or desi g nee wit hi n 2 4 h o urs of a ware ness 
of t he e ve nt a n d i n acc or da nce wit h S A E re p orti n g pr oce d ures descri be d i n Secti o n  6. 1. 1 .  
If pre g na nt, t he st u d y dr u g s hall be i m me diatel y disc o nti n ue d. 
F oll o w- u p i nf or mati o n re gar di n g t h e c o urse of t he pre g na nc y, i n cl u di n g peri natal a n d ne o natal 
o utc o me  a n d,  w here  a p plica ble,  offs pri n g  i nf o r mati o n  m ust  be  re p orte d  o n  t he  Pre g na nc y  
S ur veilla nce F or m. 
6. 5  O v er d o s e  
A n o ver d ose is defi ne d as t he acc i de ntal or i nte nti o nal a d mi nistrati o n of  a n y d ose of a pr o d uct t hat 
is c o nsi dere d b ot h e xcessi ve (a b o ve t hera pe utic ran ge) a n d me dicall y i m p orta nt  (i.e., wit h cli nical 
se q uel). All occ urre nces of o ver d ose m ust be re p orte d as S A Es (see Secti o n 6. 1. 1  f or re p orti n g 
details). 
6. 6  P ot e nti al Dr u g-I n d u c e d Li v er I nj ur y 
W here ver p ossi ble, ti mel y c o nfir mati o n of i nitial li ver-relate d la b orat or y a b n or malities s h o ul d 
occ ur pri or t o t he re p orti n g of a p o te ntial DI LI e ve nt. All occ urre nces of p ote ntial DI LIs, meeti n g 
t he defi ne d criteria, m ust be rep orte d as S A Es (see Secti o n  6. 1. 1  f or re p orti n g details). 
P ote ntial DI LI is defi ne d as:  
1.  
A mi n otra nsferase ( A T) ( A L T or A S T) ele vati o n > 3 ti mes U L N 
A N D 
2.  
T otal bilir u bi n > 2 ti m es U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os p hatase), 
A N D 
3.  
N o ot her i m me diatel y a p pare nt  p ossi ble ca uses of A T ele vati o n a n d h y per bilir u bi ne mia, 
i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre-e xisti n g c hr o nic or ac ute li ver disease, or 
t he a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he pat ot o xic. 
6. 7  M e di c ati o n  Err or  
Me dicati o n err ors wit h Astra Ze n eca I P are c ollecte d i n all st u dies w here me dicati o n err or is 
p ossi ble. 
If a me dicati o n err or occ urs i n t he c o urse of t he st u d y, t he I n ves ti gat or or ot her site pers o n nel 
i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves i m me diatel y, a n d n o  later t ha n 2 4 h o urs of 
w he n he or s he bec o mes a ware of it. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 3 
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all rele va nt 
i nf or mati o n
 is
 c o m plete d
 wit hi n
 1
 (i nitiall y
 fatal/life-t hreate ni n g
 or
 f oll o w- u p
 
fatal/life-t hreate ni n g) or 5 ( ot her seri o us i nitial a n d f oll o w- u p) cale n dar da ys if t here is a n S A E 
ass ociate d wit h t he me dicati o n e rr or (see Secti o n 6. 1. 1) a n d wit hi n 3 0 da ys f or all ot her me dicati o n 
err ors. 
T he defi niti o n of a Me dicati o n E rr or ca n be f o u n d i n A p pe n di x 4 . 
6. 8  Ot h er S af et y C o n si d er ati o n s 
A n y  si g nifica nt  w orse ni n g  n ote d  d uri n g  i nteri m  or  fi nal  p h ysical  e xa mi nati o ns,  E C G,  x-ra y  
fil mi n g, a n y ot her p ote ntial safet y assess me nt re q uire d or n ot re q uire d b y pr ot oc ol s h o ul d als o be 
rec or de d as a n o n-seri o us or seri o us A E, as a p pr o priate, a n d re p orte d acc or di n gl y.  
F or t he p ur p oses of re g ulat or y re p orti n g, t he f oll o wi n g e ve nts  m ust be re p orte d i n 2 4 h o urs 
re gar dless of w het her t he e ve nts are classifie d as seri o us  or n o n-seri o us: 
Li ver f u ncti o n test ( L F T) a b n or m alities acc o m p a nie d b y j a u n dice or h y per bilir u bi ne mi a 
T his cate g or y of e ve nts i ncl u des all A Es w here he pat ocell ular da ma ge ( wit h ele vati o n of A L T or 
A S T > 3 x U L N)  is  c o m bi ne d  w it h  he patic  d ysf u nctio n  ( wit h  ele vati o n  of  T B  >  2 x  U L N)  or  
ja u n dice. Wit h res pect t o L F T a b n or malities, b ot h ce ntral la b res ults a n d A Es will be m o nit ore d. 
O p p ort u nistic i nfecti o ns 
T his cate g or y of e ve nts i ncl u des i nfecti o ns of i nterest t hat are c o nsiste nt wit h AI D S defi ni n g 
dia g n oses  a n d  are  s pecific  f or  i m m u n os u p pressi o n,  i ncl u di n g  u n us ual  i nfecti o ns  ca use d  b y  
bacteria, m yc o bacteria, f u n gi , vir uses a n d pr ot oz oa.  
Se vere H y perse nsiti vit y 
T his  cate g or y  of  e ve nts  i ncl u des  all  cases  of  se vere  h y perse n siti vit y  i ncl u din g:  a n gi oe de ma,  
a na p h yla xis, a n d Ste ve ns-J o h ns o n S y n dr o me. 
W he n o ne of t hese e ve nts meets t he criteria f or a S A E, re p ort t he e ve nt usi n g S A E re p orti n g 
pr oce d ures ( Secti o n  6. 1. 1 ). W he n o ne of t hese e ve nts d oes n ot meet t he criteria f or a S A E, re p ort 
t he e ve nt wit hi n 2 4 h o urs as a n o n-seri o us e ve nt. 
F or eac h n o n-seri o us e ve nt i n t hese t hree cate g o ries, n otif y t he Me dical M o nit or wit hi n 2 4 h o urs 
t o disc uss t he ne xt ste ps i n re p orti n g. 
6. 8. 1  A d v er s e E v e nt s of I nt er e st  
T he f oll o wi n g are p ossi ble safet y c o ncer ns ass o ciate d wit h D P P- 4 i n hi bit ors a n d/ or S G L T- 2 
i n hi bit ors, w hic h s h o ul d be c o nsi dere d a d verse e ve nts of i nterest a n d m ust be ca pt ure d w he n 
s p o nta ne o usl y  re p orte d:  a m p utati o ns/ peri p heral  re vasc ularizati o ns,  c ha n ges  i n  gr o wt h;  
dr u g-i n d uce d li ver i nj ur y/ mar ke d he patic la b orat or y a b n or malities (i ncl u di n g li ver f u ncti o n test 
a b n or malities  acc o m pa nie d  b y  ja u n di ce  or  h y per bilir u bi ne mia);  h y perse nsiti vit y  reacti o ns  
(i ncl u di n g  a na p h yla xis,  a n gi oe de ma,  e xf oliati ve  s ki n  c o n diti o ns);  se vere  c uta ne o us  a d verse  
reacti o ns (i ncl u di n g b ull o us pe m p hig oi d); ge nital m yc otic i nfecti o ns; necr otizi n g fasciitis of t he 
peri ne u m  ( F o ur nier’s  ga n gre ne);  uri nar y  tract  i nfecti o ns  (i ncl u di n g  ur ose psis/ p yel o ne p hritis);  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 4 
o p p ort u nistic  i nfecti o ns;  decrease d  l y m p h oc yte  a n d/ or  t hr o m b oc yte  c o u nts;  oral  s oft  tiss ue  
c o n diti o ns  (e. g.,  st o matitis);  pa nc reatitis;  car diac  fail ure  (i ncl u di n g  h os pitalizati o n  f or  heart  
fail ure);  ac ute  ki d ne y  i nj ur y,  re nal  i m pair me nt  a n d/ or  re nal  fail ure;  v ol u me  de pleti o n;  b o ne  
fract ures;  h y perli pi de mia;  h y p o glyce mic  e ve nts;  h y per gl yce mi c  e ve nts;  ket oaci d osis;  
mali g na ncies (i ncl u di n g bla d de r ca ncer); a n d art hral gia. 
F or t he p ur p oses of re g ulat or y re p orti n g, base d o n w het her A Es i n t he a b o ve cate g ories meet t he 
criteria  f or  seri o us  or  n o nseri o us  A Es,  t he y  will  be  c ollecte d  a n d  re p orte d  acc or di n g  t o  t he  
a p pr o priate g ui deli nes, as de scri be d a b o ve i n Secti o ns 6. 1. 1  a n d 6. 2. 1 , res pecti vel y.  
T o e ns ure t hat data o n a m p u tati o ns are s yste maticall y c ollecte d, a m p utati o ns  a n d u n derl yi n g 
c o n diti o ns rele va nt t o a m p utati o n will be rec or d e d o n a s pecific e C R F pa ge. T he A E lea di n g t o 
a m p utati o n s h o ul d be rec or de d i n t he e C R F as A E/ S A E. E ve nts p otentiall y placi n g t he s u bject at 
ris k f or a l o wer li m b a m p utati o n (“ prece di n g e ve nts”) s h o ul d als o be rec or de d i n t he e C R F as 
A E/ S A E w het her or n ot a n a m p utati o n has ta ke n place. T hese will be c ollecte d o n a de dicate d 
e C R F pa ge. 
After t he i nitial A E re p ort, t he I n vesti gat or is  re q uire d t o pr oacti vel y f oll o w eac h s u bject at 
s u bse q ue nt visits/c o ntacts. All A Es of i nterest will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he 
e ve nt is ot her wise e x plai ne d, or t h e s u bject is l ost  t o f oll o w- u p. 
7  
D A T A M O NI T O RI N G C O M MI T T E E A N D O T H E R E X T E R N A L C O M MI T T E E S 
7. 1  D at a M o nit ori n g C o m mitt e e 
A n  i n de pe n de nt  Data  M o nit ori n g  C o m mittee  ( D M C)  c o m prise d  of  Pe diatric  a n d  E n d ocri ne  
t hera pe utic area s pecialists a n d statisticia ns will be f or me d a n d will c o n ve ne o n a re g ular basis t o 
re vie w trial data. T he D M C will be res p o nsi ble f or safe g uar di n g t he i nterests of t he s u bjects i n t he 
trial b y assessi n g t he safet y a n d efficac y of t he i nter ve nti o ns d uri n g t he trial a n d f or re vie wi n g t he 
o verall c o n d uct of t he cli nical trial. T he D M C will pr o vi de rec o m me n dati o ns a b o ut st o p pi n g or 
c o nti n ui n g t he trial a n d will be g o ver ne d b y a se parate D M C C harter. 
7. 2  C ar di o v a s c ul ar A dj u di c ati o n C o m mitt e e 
A n i n de pe n de nt Car di o vasc ular A d j u dicati o n C o m mittee, bli n de d t o t he treat me nt of t he s u bjects, 
will  a dj u dicate  all  p ote ntial  e ve nts  of  c o n gest i ve  heart  fail ure  re q uirin g  h os pitalizati o n  (see  
Secti o n  5. 3. 4  f or m ore details). 
A se parate A dj u dicati o n C harter will defi ne a n d de scri be t he pr oce d ure f or t he ha n dli n g, re p orti n g 
a n d classificati o n of t hese e ve nts. 
7. 3  H e p ati c A dj u di c ati o n C o m mitt e e 
A n i n de pe n de nt He patic A dj u dicati o n C o m mittee, bl i n de d t o t he treat me nt of t he s u bjects, will 
deter mi ne t he pr o ba bilit y t hat DI LI  is t he ca use of li ver-relate d a b n or malities, i ncl u di n g b ut n ot 
li mite d t o, he patic dis or ders lea di n g t o deat h, a n d li ver la b orat or y a b n or malities s uc h as ele vate d 
A S T a n d/ or A L T wit h or wit h o ut  T B ele vati o ns (see Secti o n 5. 3. 5  f or m ore details).  
A se parate A dj u dicati o n C harter will defi ne a n d de scri be t he pr oce d ure f or t he ha n dli n g, re p orti n g 
a n d classificati o n of t hese e ve nts. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 5 
7. 4  Di a b eti c  K et o a ci d o si s  A dj u di c ati o n C o m mitt e e 
A n i n de pe n de nt D K A A dj u dicati o n C o m mittee, bli n de d t o t he treat me nt of  t he s u bjects, will 
a dj u dicate all p ote ntial e ve nts of D K A.  
A se parate A dj u dicati o n C harter will defi ne a n d de scri be t he pr oce d ure f or t he ha n dli n g, re p orti n g 
a n d classificati o n of t hese e ve nts. 
8
 S T A TI S TI C A L
 C O N SI D E R A TI O N S
 
8. 1  S a m pl e Si z e D et er mi n ati o n 
T he sa m ple size f or t his st u d y wa s selecte d t o be c o nsiste nt wit h t he researc h h y p ot heses. 
Da pa glifl ozi n a n d sa xa gli pti n will be c o m pare d  wit h place b o se paratel y. Wit hi n eac h gr o u p of 
h y p ot heses,  m ulti plicit y  a dj ust me nt  wit h  res p ect  t o  t he  c o m paris o ns  will  be  ma de  usi n g  a  
hierarc hical a p pr oac h. N o c o m paris o ns bet wee n da pa glifl ozi n a n d sa xa gli pti n will be perf or me d. 
T he sa m ple size f or t his st u d y is base d o n t he a bilit y t o detect a 0. 7 5 % i m pr o ve me nt  o ver place b o 
f or  da pa glifl ozi n  or  sa xa gli pti n i n  c ha n ge  fr o m  baseli ne  i n  H b A 1c  at  Wee k  2 6  ( S T)  wit h  
a p pr o xi matel y 8 0 % p o wer f or eac h  c o m paris o n at a 2-si de d al p ha le vel of 0. 0 5. If 2 4 3 pe diatric 
s u bjects are ra n d o mize d a n d a nal yze d, a n d eac h treat me nt c o m pare d t o place b o at a 2-si de d 
al p ha = 0. 0 5 le vel, t his will pr o vi de a p pr o xi matel y  8 0 % p o wer f or eac h c o m paris o n t o detect a 
0. 7 5 % re d ucti o n i n H b A 1c c ha n ge fr o m baseli ne vers us place b o ass umi n g a sta n dar d de viati o n of 
1. 7 %. 
Da y 1 Ra n d o mizati o n will be stratifie d base d o n t h e baseli ne a nti dia betic treat me nt re gi me n (sta ble 
baseli ne d ose of metf or mi n I R or X R, a sta ble baseli ne d ose of i ns u li n, or a sta ble c o m bi nati o n of 
metf or mi n a n d i ns uli n), ge n der, a n d a ge ( 1 0 t o bel o w 1 5 years of a ge, 1 5 t o bel o w 1 8 years of 
a ge).  
T he sta n dar d de viati o n esti mate  of 1. 7 % is base d o n a bli n de d re vie w of t he o n g oi n g st u d y data. 
8. 2  P o p ul ati o n s f or A n al y s e s 
 T he E nr olle d S u bjects Data Set will c o nsist of  all s u bjects w h o si g n i nf or me d c o nse nt. 
 T he Ra n d o mize d S u bjects Data Set is t he pri mar y efficac y dataset a n d will c o nsist of all 
ra n d o mize d s u bjects w h o recei ve at least o ne d ose of st u d y me dicati o n d uri n g t he treat me nt 
peri o d.  T his  is  als o  k n o w n  as  t he  I nte nt-t o- Treat  (I T T)  p o p ulati o n.  I n  a nal yses  of  t he  
Ra n d o mize d S u bjects Data Set, s u bjects will ge nerall y be pres e nte d i n t he treat me nt gr o u p t o 
w hic h t he y were ra n d o mize d at t he start of t he S T treat me nt peri o d (e ve n if t he treat me nt t he y 
recei ve d is differe nt).  
 T he U p-titrati o n Ra n d o mize d S u bjects Data Set will c o nsist of t he s u bset of ra n d o mize d 
s u bjects w h o are re-ra n d o mize d beca use t heir H b A 1c is greater t ha n or e q ual t o 7 at Wee k 1 2.   
 T he E val ua ble S u bjects Data Set will be a s u bset of t he Ra n d o mize d S u bjects Data Set. All 
data p oi nts after a rele va nt pr ot oc ol de viati o n will be e xcl u de d fr o m t his dataset. Rele va nt 
pr ot oc ol de viati o ns are defi ne d as de viati o ns w hic h c o ul d p ote ntiall y affect t he i nter preta bilit y 
of t he st u d y res ults. All decisi o ns t o e xcl u de data fr o m t he Ra n d o mize d S u bjects Data Set t o 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 6 
f or m t he E val ua ble S u bjects Data Set will be ma de pri or t o t he u n bli n di n g of t he st u d y. T he 
set of s u bjects wit hi n t his dataset is als o k n o w n as t he Per- Pr ot oc ol p o p ulati o n. T his dataset 
will be use d f or se nsiti vit y a nal ysis of t he pri m ar y efficac y e n d p oi nt if > 1 0 % of s u bjects i n 
a n y treat me nt gr o u p ha ve rele va nt pr ot oc ol de via ti o ns. All rele va nt pr ot ocol de viati o ns will be 
fi nalize d pri or t o t he data base l oc k. 
 T he Treate d S u bjects Data Set is t he pri mar y safet y dataset a n d will c o nsist of all s u bjects w h o 
recei ve at least o ne d ose of stu d y me dicati o n. I n a nal yses of t he Treate d S u bjects Data Set, 
s u bjects will ge nerall y be prese nte d b y ra n d omize d treat me nt gr o u p, e xce pt if i nf or mati o n 
i n dicates t hat a s u bject recei ve d a differe nt treat me nt f or t he e ntire c o urse of t heir partici pati o n 
i n t he st u d y ( or peri o d). I n t his case, t he safet y data f or s uc h a s u bject will be prese nte d b y t he 
first treat me nt act uall y recei ve d. E xce pti o ns t o t his will be ma de f or s o me a nal yses of t he 
effects of m o n ot hera p y or ra n d o mize d  wit h dra wal of metf or mi n.   
 T he Ra n d o mize d Wit h dra wal S u bjects Data Set wi ll be a s u bset of t he Ra n d o mize d S u bject 
Data Set a n d will c o nsist of all s u bjects bel o n gi n g t o t he metf or mi n ra n d o mizati o n strata of 
bac k gr o u n d t hera p y w h o will be re-ra n d o mize d at Wee k 3 2 or Wee k 4 0 (as descri be d i n 
Secti o n 3. 1 ). T his data set will be use d t o a nal yze efficac y a n d safet y d uri n g t he ra n d o mize d 
wit h dra wal peri o d usi n g t he treat me nt a ssi g n me nt fr o m t he t hir d ra n d o mizati o n.  
8. 3  E n d p oi nt s  
8. 3. 1  Pri m ar y  E n d p oi nt  
C ha n ge fr o m baseli ne i n H b A 1c at Wee k 2 6 
8. 3. 2  S e c o n d ar y  E n d p oi nt s  
 C ha n ge fr o m baseli ne i n F P G at Wee k 2 6 
 Perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 %, w h o ac hie ve a n H b A 1c le vel < 7. 0 % at 
Wee k 2 6 
8. 3. 3  E x pl or at or y  E n d p oi nt s  
8. 3. 3. 1  E x pl or at or y  Effi c a c y E n d p oi nt s f or S h ort-t er m A s s e s s m e nt of S a x a gli pti n 
a n d D a p a glifl o zi n 
 Perce nta ge  of  s u bjects  w h o  re q uire  gl yce mic  resc ue  me dicati o n  or  disc o nti n ue  t he  st u d y  
me dicati o n d ue t o lac k of efficac y d uri n g t he 2 6- wee k treat me nt peri o d 
 Ti me t o i nitiati o n of gl yce mic resc ue me di cati o n or disc o nti n uati o n of st u d y me dicati o n d ue 
t o lac k of efficac y d uri n g t he 2 6- wee k treat me nt peri o d 
8. 3. 3. 2  E x pl or at or y  Effi c a c y  E n d p oi nt s f or S h ort-t er m pl u s L o n g-t er m 
A s s e s s m e nt of S a x a gli pti n a n d D a p a glifl o zi n 
 C ha n ge fr o m baseli ne i n H b A 1c at Wee k 5 2 
 C ha n ge fr o m baseli ne i n F P G at Wee k 5 2 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 7 
 Perce nta ge  of  s u bjects  wit h  baseli ne  H b A 1c  ≥ 7 %  w h o  ac hie ve  a n  H b A 1c  le vel  <  7 %  at  
Wee k 5 2 
 Ti me t o i nitiati o n of gl yce mic resc ue me di cati o n or disc o nti n uati o n of st u d y me dicati o n d ue 
t o lac k of efficac y d uri n g t he 5 2- wee k treat me nt peri o d 
8. 3. 3. 3  E x pl or at or y  Effi c a c y  E n d p oi nt s f or M o n ot h er a p y A s s e s s m e nt of 
S a x a gli pti n a n d D a p a glifl o zi n 
 C ha n ge i n H b A 1c d uri n g t he ra n d o mize d wit h dra wal peri o d 
 C ha n ge i n F P G d uri n g t he ra n d o mize d wit h dra wal peri o d 
 Perce nta ge  of  s u bjects  w h o  ac hie ve  or mai ntai n  a n H b A 1c  le vel  <  7 %  at  t he  e n d  of  t he 
ra n d o mize d wit h dra wal peri o d 
 Ti me t o i nitiati o n of gl yce mic resc ue me di cati o n or disc o nti n uati o n of st u d y me dicati o n d ue 
t o lac k of efficac y usi n g t he start ti me of ra n d o mize d wit h dra wal peri o d as t he refere nce p oi nt 
8. 3. 3. 4  S af et y E n d p oi nt s  
Safet y e n d p oi nts c o nsist of t he i nci de nce of A Es, S A Es, h y p o gl yce mic e ve nts, disc o nti n uati o ns 
d ue t o A Es, mar ke d a b n or malities i n cli nical la b o rat or y tests, vital si g ns, Ta n ner sta gi n g, meas ures 
of gr o wt h a n d mat urati o n, D K A e ve n ts, a n d safet y la b orat or y tests. 
8. 4  A n al y s e s  
A nal yses will be perf or me d b y Astra Ze neca or its re prese ntati ves. A c o m pre he nsi ve statistical 
a nal ysis pla n will be de vel o pe d a n d fi nalize d bef ore data base l oc k a n d will descri be t he s u bject 
p o p ulati o ns t o be i ncl u de d i n t he a nal yses, a n d pr oce d ures f or acc o u nti n g f or missi n g, u n use d, a n d 
s p uri o us data. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal ys es of t he pri mar y a n d 
sec o n dar y e n d p oi nts. A n y de viati o ns fr o m t his pla n will be rep orte d i n t he C S R. 
A nal ysis of data will be perf or me d after all s u bjects ha ve c o m plete d or ha ve bee n disc o nti n ue d 
fr o m t he st u d y. I n a d diti o n, all rele vant q ueries m ust be res ol ve d, a n d t he data base m ust be l oc ke d 
pri or t o t he fi nal a nal ysis. 
Da pa glifl ozi n a n d sa xa gli pti n will be s u m mariz e d se paratel y. A c o m m o n place b o gr o u p will be 
i ncl u de d i n eac h s u m mar y. 
I n a d diti o n, wit hi n t he a nal yses of da pa glifl ozi n a n d sa xa gli pti n, t he o verall (c o m bi ne d l o w- d ose 
a n d hi g h- d ose) efficac y a n d safet y a nal yses wi ll be re peate d f or t he s u b gr o u p of s u bjects o n a 
sta ble baseli ne d ose of metf or min I R or X R ( wit h or wit h o ut i n s uli n). F or t hese a nal yses, t he 
da pa glifl ozi n a n d sa xa gli pti n  re gi me ns wit hi n eac h treat me nt will be c o m bi ne d i nt o o ne s u b gr o u p 
a n d  c o m pare d  t o  t he  c orres p o n di n g  (c o m m o n)  place b o  s u b gr o u p.  P- val ues  c orres p o n di n g  t o  
s u b gr o u p c o m paris o ns will be re p orte d f or t he pri mar y a n d sec o n dar y efficac y e n d p oi nts, a n d will 
be re p orte d at t he n o mi n al si g nifica nce le vel. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 8 
8. 4. 1  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 
Fre q ue nc y distri b uti o ns a n d s u m m ar y statistics f or de m o gra p hic a n d ot her baseli ne c haracteristics 
(a ge,  ge n der,  race,  et h nicit y,  b o d y  wei g ht,  B MI,  a n d  re gi o n) ,  i ncl u di n g  dia betes-relate d  
c haracteristics  ( d urati o n  of  T 2 D M,  H b A 1c,  F P G,  a n d  Da y  1  Ra n d o mizati o n  strata)  will  be  
s u m marize d b y treat me nt gr o u p base d o n first ran d o mizati o n a n d o verall usi n g t he Ra n d o mize d 
S u bjects Data Set. T he a nal yses will be re peate d  usi n g t he Ra n d o mize d With dra wal S u bjects Data 
Set. N o statistical test will be carrie d o ut f or c o m paris o n of a n y baseli ne meas ure me nt a m o n g t he 
treat me nt gr o u ps. 
8. 4. 2  Effi c a c y  A n al y s e s  
All efficac y a nal yses will be perf or me d usi n g t he Ra n d o mize d S u bjects Data Set u nless ot her wise 
s pecifie d. I n a d diti o n, t he pri mar y efficac y a nal ysis will be perf or me d usi n g t he E val ua ble S u bjects 
Data Set if > 1 0 % of t he s u bjects i n a n y treat me nt gr o u p ha ve rele va nt  pr ot oc ol de viati o ns. 
F urt her m ore,  t o  acc o u nt  f or  ra n d o mizati o n  wit h dra wal,  a nal yses  de dicate d  t o  m o n ot hera p y  
assess me nt will be perf or me d o n t he Ra n d o mize d Wit h dra wal S u bjects Data Set. 
T he I T T esti ma n d ( w hic h will be  esti mate d b y usi n g data re gar dless of pre mat ure treat me nt 
disc o nti n uati o n a n d re gar dless of  resc ue t hera p y i nitiati o n, wit h missi n g val ues ass u me d n ot 
missi n g at ra n d o m, i m p ute d base d o n all a vaila ble data) will be e val uate d as t he pr i mar y esti ma n d.  
All s u bjects ta ki n g da pa glifl ozi n or sa xa gli pti n i ncl u di n g t h os e w h o are resc ue d will g o t hr o u g h 
t he  sec o n d  ra n d o mizati o n  if  t heir  H b A 1c  val ues  are  ≥ 7 %  at  Wee k  1 2.  After  t he  sec o n d  
ra n d o mizati o n, s u bjects will bel o n g t o o ne of t he f oll o wi n g treat me nt gr o u ps: 
1.  S u bjects res p o n di n g at Wee k 1 2 a n d re mai ni n g o n t he l o w- d ose 
2.  S u bjects n ot res p o n di n g at Wee k 1 2 a n d re-ra n d o mize d t o t he l o w- d ose 
3.  S u bjects n ot res p o n di n g at Wee k 1 2 a n d re-ra n d o mize d t o t he hi g h- d ose 
F or t he place b o ar m, t hese t hree gr o u ps  will be c o m bi ne d i nt o o ne place b o gr o u p. 
T he f oll o wi n g treat me nt re gi me ns are c o nsi dere d f or a nal ysis: 
 L o w- d ose/ hi g h- d ose: I nitial treat me nt of t he l o w- d ose f oll o we d b y u p-titrati n g t o t he hi g h- d ose 
f or t h ose w h o d o n ot ac hie ve t he gl yce mic tar get of H b A 1c < 7 %  at Wee k 1 2 a n d c o nti n ui n g 
treat me nt  wit h  t he  l o w- d ose  f or  t h ose  ac hie vi n g  t he  gl yce mic  tar get  of  H b A 1c  <  7 %  at  
Wee k 1 2 ( Gr o u ps 1 & 3) 
 L o w- d ose: I nitial treat me nt of t he l o w- d ose f oll o we d b y c o nti n ui n g treat me nt o n t he l o w- d ose 
dr u g f or t h ose w h o d o n ot ac hie ve t he gl yce mic tar get of H b A 1c < 7 % at Wee k 1 2 a n d 
c o nti n ui n g treat me nt wit h t he l o w- d ose f or t h os e ac hie vi n g t he gl yce mic tar get of H b A 1c < 7 % 
at Wee k 1 2 ( Gr o u ps 1 & 2)  
F oll o wi n g t he t hir d ra n d o mizati o n: 
 S u bjects i nitiall y ra n d o mize d t o da pa glifl ozi n ( or sa xa gli pti n) wit h metf or mi n as bac k gr o u n d 
t hera p y will be re-ra n d o mize d i n a 1: 1 rati o t o eit her da pa glifl ozi n ( or sa xa gli pti n) al o ne or t o 
da pa glifl ozi n ( or sa xa gli pti n) wit h  metf or mi n as bac k gr o u n d t hera p y  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
9 9 
 S u bjects  i nitiall y  ra n d o mize d  t o  place b o  wit h  metf or mi n  as bac k gr o u n d  t hera p y  will  be  
re-ra n d o mize d i n a 1: 1:1 rati o t o da pa glifl ozi n al o ne or sa xa gli pti n al o ne or place b o wit h 
metf or mi n as bac k gr o u n d t hera p y 
W he n fitti n g m o dels t hat i n v ol ve t he stratificati o n varia bles, if t he data are t o o s parse wit hi n o ne 
or m ore stratificati o n cells, le vels of stratifica ti o n varia bles ma y be c o m bi ne d, a n d/ or o ne or m ore 
stratificati o n varia bles ma y be re m o ve d fr o m t he m o del. Details will be pr o vi de d i n t he statistical 
a nal ysis pla n. 
8. 4. 2. 1  Pri m ar y Effi c a c y A n al y si s 
T he pri mar y e n d p oi nt is t he c ha n ge fr o m baseli ne t o Wee k 2 6 of t he S T treat me nt peri o d i n H b A 1c. 
T he pri mar y efficac y a nal ysis w ill be perf or me d usi n g a n a nal ysis of c o varia nce ( A N C O V A). F or 
t his a nal ysis, all d ose le vels f or a treat me nt will be c o m bi ne d i nt o o ne treat me nt gr o u p f or eac h 
dr u g. Se parate m o dels will be use d f or da pa glifl o zi n a n d sa xa gli pti n a nal yses, a n d eac h a nal ysis 
will  i ncl u de t he  (c o m m o n)  place b o c o ntr ol.  Eac h  m o del  will  ha ve  ter ms  f or  baseli ne  val ue, 
treat me nt gr o u p, a n d ra n d o mizati o n strata. F or eac h dr u g, t he c o m paris o n vs place b o will be teste d 
at a 2-si de d al p ha le vel of 0. 0 5. P oi nt esti mates a n d 9 5 % c o nfi de nce i nter vals will be calc ulate d 
base d o n ma xi m u m li keli h o o d f or t he a dj uste d mea n  c ha n ges wit hi n eac h treat me nt gr o u p as well 
as f or t he differe nces i n a dj uste d me a n c ha n ges bet wee n treat me nt gr o u ps.  
 
T he I T T esti ma n d ( w hic h will be esti mate d usi n g all a vaila ble data re gar dless of pre mat ure 
treat me nt disc o nti n uati o n a n d re gar dless of resc ue t hera p y i nitiati o n) will be e val uate d as t he 
pri mar y esti ma n d. Missi n g val ues f or Wee k 2 6 will be i m p ute d usi n g a m ulti ple i m p utati o n met h o d 
ass u mi n g t he data are n ot missi n g  at ra n d o m. M ulti ple i m p utatio n usi n g retrie ve d dr o p- o uts will 
be use d if t here is s ufficie nt data fr o m ‘retrie ve d dr o p- o uts’, defi ne d as s u bjects w h o disc o nti n ue d 
t he treat me nt ( b ut n ot t he st u d y) a n d ha d a Wee k 2 6 H b A 1c val ue. T he details of t he i m p utati o n 
met h o ds will be prese nte d i n t he statistical a nal ysis pla n. T o assess t he r o b ust ness  of t he pri mar y 
efficac y a nal ysis f or t he c ha n ge i n H b A 1c fr o m ba seli ne t o Wee k 2 6, a d diti o nal se nsiti vit y a nal ysis 
ma y be perf or me d usi n g t he E val ua ble S u bjects Data Set if > 1 0 % of t he s u bjects i n a n y treat me nt 
gr o u p i n t he Ra n d o mize d S u bj ects Data Set ha ve rele va nt pr ot oc ol de viati o ns. 
T he pri mar y e n d p oi nt will als o be c o m pare d bet wee n t he  l o w- d ose/ hi g h- d ose treat me nt re gi me n 
a n d place b o, se paratel y f or b ot h da pa glifl ozi n a n d sa xa gli pti n. I n a d diti o n, u p-titrati n g t o hi g h-
d ose a n d c o nti n ui n g o n l o w- d ose wi ll be c o m pare d i n t he s u bset of s u bjects w h o ha d H b A 1c ≥ 7 % 
at Wee k 1 2. T hese a nal yses are descri be d u n der sec o n dar y efficac y a nal yses.  
8. 4. 2. 2  S e c o n d ar y Effi c a c y A n al y s e s 
Sec o n dar y efficac y a nal yses w ill als o be perf or me d se paratel y f or eac h dr u g ( da pa glifl ozi n a n d 
sa xa gli pti n). F or eac h dr u g, t he f oll o wi n g se q ue ntial testi n g or der will be e m pl o ye d t o c o ntr ol 
m ulti plicit y of testi n g f or t he sec o n dar y o bjecti ves.  
1.  C o m paris o n  of  mea n  re d ucti o n  i n  H b A 1c  fr o m  baseli ne  at  Wee k  2 6  bet wee n  
l o w- d ose/ hi g h- d ose treat me nt re gi me n a n d place b o 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 0 
2.  C o m paris o n of mea n re d ucti o n i n H b A 1c fr o m baseli ne at Wee k 2 6 bet wee n t he l o w- d ose 
treat me nt re gi me n a n d place b o 
3.  C o m paris o n  of  mea n  re d ucti o n  i n  F P G  fr o m  baseli ne  at  Wee k  2 6  bet wee n  o verall  dr u g  
treat me nt (all d oses a n d re gi me ns c o m bi ne d) a n d place b o 
4.  C o m paris o n  of  mea n  re d ucti o n  i n  F P G  fr o m  baseli ne  at  Wee k  2 6  bet wee n  t he  
l o w- d ose/ hi g h- d ose treat me nt re gi me n a n d place b o  
5.  C o m paris o n of mea n re d ucti o n i n F P G fr o m baseli ne at Wee k 2 6 bet wee n t he l o w- d ose 
treat me nt re gi me n a n d place b o 
6.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % at Wee k 2 6 bet wee n o verall dr u g treat me nt (all d oses a n d re gi me ns c o m bi ne d) 
a n d place b o 
7.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % at Wee k 2 6 bet wee n t he l o w- d ose/ hi g h- d ose treat me nt re gi me n a n d place b o 
8.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % at Wee k 2 6 bet wee n t he l ow- d ose treat me nt re gi me n a n d place b o 
9.  C o m paris o n of mea n re d ucti o n i n H b A 1c fr o m baseli ne at Wee k 2 6 bet wee n t he hi g h- d ose a n d 
t he l o w- d ose i n s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2 
1 0.  C o m paris o n of mea n re d ucti o n i n F P G fr o m ba seli ne at Wee k 2 6 bet wee n t he hi g h- d ose a n d 
t he l o w- d ose i n s u bjects w h o d o n ot ac hie ve a n H b A 1c < 7 % at Wee k 1 2 
1 1.  C o m paris o n of t he perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c 
le vel < 7. 0 % at Wee k 2 6 bet wee n t he hi g h- d ose a n d t he l o w- d ose i n s u bjects w h o d o n ot 
ac hie ve a n H b A 1c < 7 % at Wee k 1 2 
 
F or eac h dr u g, a wei g hte d A N C O V A will be perf or me d f or t he c ha n ge fr o m baseli ne i n H b A 1c at 
Wee k 2 6 t o c o m pare t he place b o a n d t he l o w- d ose/ hi g h- d ose treat me nt re gi me n. F or t his a nal ysis, 
all da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d H b A 1c < 7 % at Wee k 1 2 a n d re mai ne d o n t he 
l o w- d ose will get a wei g ht of o ne. T he da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d H b A 1c 
≥ 7 % at Wee k 1 2 a n d c o nti n ue d o n t he l o w- d ose will get a wei g ht of 0. T he da pa glifl ozi n a n d 
sa xa gli pti n s u bjects w h o ha d H b A 1c ≥ 7 % at Wee k 1 2 a n d recei ve d t he hi g h- d ose will get a wei g ht 
of 2. All s u bjects w h o d o n ot u n der g o t he sec o n d ra n d o mizati o n a n d all place b o s u bjects will get 
a wei g ht of o ne. 
F or eac h dr u g, a wei g hte d A N C O V A will be perf or me d f or t he c ha n ge fr o m baseli ne i n H b A 1c at 
Wee k 2 6 t o c o m pare t he place b o a n d t he l o w- d ose treat me nt re gi me n. F or t his a nal ysis, all 
da pa glifl ozi n a n d sa xa gli pti n s u bjects w h o ha d H b A 1c < 7 % at Wee k 1 2 a n d re mai ne d o n t he 
l o w- d ose  will  get  a  wei g ht  of  o ne.  T he  da pa glifl ozi n  a n d  sa xa gli pti n  s u bjects  w h o  ha d  
H b A 1c ≥ 7 % at Wee k 1 2 a n d c o nti n ued o n t he l o w- d ose will get a wei g ht of 2. T he da pa glifl ozi n 
a n d sa xa gli pti n s u bj ects w h o ha d H b A 1c ≥ 7 % at Wee k 1 2 a n d recei ve d t he hi g h- d ose will get a 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 1 
wei g ht of 0. All s u bjects w h o d o n ot u n der g o t h e sec o n d ra n d o mizati o n a n d all place b o s u bjects 
will get a wei g ht of o ne. 
F or s u bjects o n da pa glifl ozi n a n d sa xa gli pti n w h o ha d H b A 1c ≥ 7 % at Wee k 1 2, t he c ha n ge fr o m 
baseli ne H b A 1c at Wee k 2 6 ( S T) will be c o m pare d bet wee n t he s u bjects w h o are re-ra n d o mize d 
t o re mai n o n t he l o w- d ose a n d t he s u bjects wh o are re-ra n d o mize d t o t he hi g h- d ose usi n g a n 
A N C O V A. T his a nal ysis will be base d o n t he U p-titrati o n Ra n d o mize d S u bjects Data Set. 
 
C ha n ge fr o m baseli ne at Wee k 2 6 ( S T) i n F P G will be  a nal yze d si milarl y as t he a nal yses of c ha n ge 
fr o m baseli ne i n H b A 1c at Wee k 2 6. 
T he pr o p orti o n of s u bjects ac hie vi n g H b A 1c < 7. 0 % at Wee k 2 6 ( S T) will be a nal yze d usi n g a 
wei g hte d  l o gistic  re gressi o n  wit h  a dj ust me nt  f or  t he  baseli ne  H b A 1c  meas ure me nt  a n d  t he  
ra n d o mizati o n strata. Wei g hti n g f or t he s u bjects will be a p plie d si milarl y t o t he wei g hti n g i n t he 
a nal ysis of c ha n ge fr o m baseli ne i n H b A 1c. S u bjects wit h missi n g res p o nse at Wee k 2 6 will be 
i m p ute d b y dic h ot o mizi n g t he i m p ute d val ues of H b A 1c at Wee k 2 6.  
8. 4. 2. 3  E x pl or at or y Effi c a c y A n al y s e s 
E x pl orat or y  a nal yses  will  be  perf or me d  f or  o ve rall  sa xa gli pti n  a n d  o verall  da pa glifl ozi n  
se paratel y, b y c o m bi ni n g all l o w- d ose a n d hig h- d ose treat me nt gr o u ps  as a p pr o priate.  
As wit h t he pri mar y a n d sec o n dar y efficac y a nal yses, se parate m o dels will be use d f or sa xa gli pti n 
a n d da pa glifl ozi n a nal yses, a n d eac h a nal ysis  will i ncl u de t he (c o m m o n) place b o gr o u p.  
A d diti o nall y, s u bjects bel o n gi n g t o  t he ra n d o mizati o n strata of bac k gr o u n d t hera p y metf or mi n 
al o ne wit h H b A 1c < 7. 5 % at Wee k 2 6 or Wee k 3 2 will be eli gi ble f or a t hir d ra n d o mizati o n: 
 S u bjects i nitiall y ra n d o mize d t o t he acti ve ar m wi ll be ra n d o mize d 1: 1 t o eit her disc o nti n ui n g 
bac k gr o u n d  t hera p y  wit h  metf or mi n  or  t o  c o nti n ui n g  c urre nt  trea t me nt.  F or  s u bjects  
ra n d o mize d t o wit h dra w metf or mi n, t h ose recei vi n g t he l o w- d ose will be u p-titrate d t o t he 
hi g h- d ose w hereas t h ose recei vi n g t he hi g h- d ose will c o nti n ue o n t he hi g h- d ose. 
 T hese s u bjects will be use d t o assess t he effe ct of da pa glifl ozi n ( or sa xa gli pti n) m o n ot hera p y 
vers us  da pa glifl ozi n  ( or  sa xa gli pti n)  wit h  metf or mi n  a d d- o n  t hera p y.  T his  a nal ysis  will  
esti mate t he effect of metf or mi n o n efficac y i n t he prese nce of da pa glifl ozi n ( or sa xa gli pti n) 
a n d i n dicate t he effects t hat w o ul d be l ost/ g ai ne d if wit h dra wi n g me tf or mi n (a n d usi n g o nl y 
m o n ot hera p y). 
 S u bjects i nitiall y ra n d o mize d t o t he place b o ar m will be ra n d o mize d 1: 1: 1 t o eit her disc o nti n ue 
metf or mi n a n d s witc h t o t he da pa glifl ozi n hi g h- d ose, or t o di sc o nti n ue metf or mi n a n d s witc h 
t o t he sa xa gli pti n hi g h- d ose, or t o c o nti n ue wit h t heir c urre nt treat me nt ( place b o + metf or mi n).  
 T hese s u bjects will be use d t o assess t he effe ct of da pa glifl ozi n ( or sa xa gli pti n) m o n ot hera p y 
vers us metf or mi n al o ne  at stea d y state.  
E x pl or at ory effic acy e n d p oi nts f or s h ort-ter m  assess me nt of s a x a gli pti n a n d d a p a glifl ozi n  
T hese a nal yses will be c o n d ucte d o n t he Ra n d o mize d S u bjects Data Set. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 2 
C o m paris o n of t he perce nta ge of s u bjects w h o re q uire gl yce mic resc ue me dicati o n or disc o nti n ue 
t he st u d y me dicati o n d ue t o lac k of efficac y at or pri or t o Wee k 2 6 w ill be perf or me d bet wee n 
o verall da pa glifl ozi n ( or sa xa gli pti n) a n d place b o. 
T he pr o p orti o n of s u bjects w h o re q uire gl yce mic  resc ue me dicati o n or disc o nti n ue t he st u d y 
me dicati o n d ue t o lac k of efficac y at Wee k 2 6 will be a nal yze d usi n g a l o gistic re gressi o n wit h 
a dj ust me nt  f or  t he  baseli ne  H b A 1c  meas ure me nt,  treat me nt,  a n d  t he  ra n d o mizati o n  strata.  
Ni net y fi ve perce nt c o nfi de nce i n ter vals f or t he a dj uste d perce nta ges/res p o ns e rate wit hi n eac h 
treat me nt gr o u p as well as f or t he a dj uste d o d ds rati os f or eac h treat me nt gr o u p a n d place b o, 9 5 % 
c o nfi de nce  i nter vals,  a n d  p- val ue  will  be  calc ulate d  wit h  a dj ust me nt  f or  baseli ne  H b A 1c  
meas ure me nt a n d ra n d o mizati o n strata. 
T he a nal ysis will use s u bjects i n t he pri mar y ef ficac y data set (i.e., Ra n d o mize d S u bjects Data 
Set). 
Ti me t o gl yce mic resc ue me dicati o n or disc o nti n ua ti o n of st u d y me dicati o n d ue t o lac k of efficac y 
d uri n g t he 2 6- wee k treat me nt peri o d will be a n al yze d usi n g a C o x pr o p orti o nal hazar ds m o del 
wit h stratificati o n fact or as c o va riate. Esti mates of t he hazar d rati o a n d 9 5 % c o nfi de nce i nter val 
will be pr o vi de d. Ka pla n- Meier esti mates will be calc ulate d a n d pl otte d b y treat me nt gr o u p. F or 
t he a nal ysis d uri n g t he 2 6- wee k treat me nt, all s u bjects will be ce ns ore d at t he Wee k 2 6 visit date 
or last st u d y date (f or t h ose wit h dra wi n g fr o m t he st u d y pri or t o Wee k 2 6 visit), if resc ue or 
treat me nt disc o nti n uati o n d ue t o lac k of efficac y has n ot occ urre d b y t he n.  
T hese a nal yses will use s u bjects fr o m t he Ra n d o mize d S u bjects Data Set . 
E x pl or at ory effic acy e n d p oi nts f or s h ort-ter m a n d l o n g-ter m assess me nt of s a x a gli pti n a n d 
d a p a glifl ozi n  
C ha n ge fr o m baseli ne at Wee k 5 2 ( L T) i n H b A 1c a n d, se paratel y, F P G will be a nal yze d usi n g a n 
A N C O V A m o del. 
Perce nta ge of s u bjects wit h baseli ne H b A 1c ≥ 7 % ac hie vi n g a n H b A 1c < 7 % at Wee k 5 2 ( L T), 
will be a nal yze d usi n g a l o gistic re gressi o n wit h  a dj ust me nt f or t he baseli ne H b A 1c meas ure me nt 
a n d t he ra n d o mizati o n strata.  
Ti me t o i nitiati o n of gl yce mic  resc ue me dicati o n or disc o ntin uati o n of st u d y me dicati o n d ue t o 
lac k of efficac y d uri n g t he 5 2-wee k treat me nt peri o d will be a nal yze d usi n g a C o x pr o p orti o nal 
hazar ds m o del wit h stratificati o n fact ors as c o va riates. Esti mates of t he hazar d rati o a n d 9 5 % 
c o nfi de nce i nter vals will be pr o v i de d. Ka pla n- Meier esti mates will be calc ulate d a n d pl otte d b y 
treat me nt gr o u p. F or t he a nal ysis d uri n g t he 5 2- wee k treat me nt peri o d, all s ubjects will be ce ns ore d 
at t he Wee k 5 2 visit date or last st u d y date (f o r t h ose wit h dra wi n g fr o m t he st u d y pri or t o Wee k 5 2 
visit), if resc ue or treat me nt disc o nti n uati o n d ue t o  lac k of efficac y has n ot occ urre d b y t he n. T hese 
a nal yses will use s u bjects fr o m t h e Ra n d o mize d S u bjects Data Set. 
T o acc o u nt f or t he ra n d o mize d wit h dra wal of  bac k gr o u n d metf or mi n at Wee k 3 2 or Wee k 4 0, 
a d diti o nal wei g hte d a nal yses of c ha n ge i n H b A 1c, F P G, a n d t he perce nta ge of s u bjects wit h 
H b A 1c < 7 % will be perf or me d e xcl u di n g s u bjects  ra n d o mize d t o wit h dra w fr o m metf or mi n. F or 
t he  wei g hte d  a nal yses,  da pa glifl ozi n  ( or  sa xagli pti n)  s u bjects  w h o  we nt  t hr o u g h  t he  t hir d  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 3 
ra n d o mizati o n a n d wit h dre w metf or mi n will get a wei g ht of zer o, a n d t h ose ra n d o mize d t o sta y o n 
metf or mi n will get a wei g ht of 2. All ot her da pa g lifl ozi n ( or sa xa gli pti n) su bjects will get a wei g ht 
of 1. Place b o s u bjects ra n d o mize d t o wit h dra w metf or mi n a n d s witc h t o acti ve treat me nt will get 
a wei g ht of zer o. Place b o s u bjects ra n d o mize d t o sta y o n metf or mi n will get a wei g ht of 3. All 
ot her place b o s u bjects will get a wei g ht of 1. A N C O V A m o dels will be utilize d f or t he wei g hte d 
a nal yses of c ha n ge i n H b A 1c a n d F P G, a n d a l o gistic re gressi o n m o del will be use d f or t he 
wei g hte d a nal ysis of t he perce nta ge  of s u bjects wit h H b A 1c < 7 %.  
E x pl or at ory effic acy a n alysis f or m o n ot her a py assess me nt  
T hese a nal yses will be c o n d ucte d d uri n g t he ra n d o mize d  wit h dra wal peri o d usi n g t he Ra n d o mize d 
Wit h dra wal S u bjects Data Set. 
T he refere nce ti me p oi nt t o be use d as ‘ wit h dra wal baseli ne’ will be t he cl osest ti me p oi nt o n or 
bef ore t he t hir d ra n d o mizati o n visit. T h e f oll o wi n g e n d p oi nts will be assesse d:  
 C ha n ge fr o m wit h dra wal  baseli ne i n H b A 1c 
 C ha n ge fr o m wit h dra w al baseli ne i n F P G 
 Perce nta ge of s u bjects w h o ac hie ve or mai nta i n a H b A 1c le vel < 7. 0 % at t he e n d of t he 
wit h dra wal peri o d 
 Ti me  t o  resc ue  t hera p y  i nitiati o n  or  disc o n ti n uati o n  of  st u d y  me dicati o n  d ue  t o  lac k  of  
gl yce mic c o ntr ol d uri n g t he wit h dra wal peri o d usi n g wit h dra wal baseli ne as t he refere nce ti me 
p oi nt 
T he  a b o ve  e n d p oi nts  will  be  s u m marize d  wit hi n  eac h  treat me nt  gr o u p  fr o m  t he  ori gi nal  
ra n d o mizati o n as f oll o ws: 
 F or s u bjects i nitiall y ra n d o mize d  t o t he da pa glifl ozi n ( or sa xa gli pti n) gr o u p, t he s u bjects 
re-ra n d o mize d t o wit h dra w metfor mi n will be c o m pare d t o t he s u bjects re-ra n d o mize d t o sta y 
o n metf or mi n. Se parate a nal yses will be perf or m e d f or s u bjects res pecti vel y ra n d o mize d t o 
eit her t he da pa glifl ozi n or sa xa gli pti n gr o u p.  
 F or s u bjects i nitiall y ra n d o mize d t o t he place b o gr o u p, t he s u bjects w h o were re-ra n d o mize d 
t o s witc h t o da pa glifl ozi n ( or sa xa gli pti n) m o n othera p y will be c o m pare d t o t he s u bjects w h o 
were re-ra n d o mize d t o sta y o n place b o wit h bac k gr o u n d metf or mi n. Se parate a nal yses will be 
perf or me d  res pecti vel y  f or  s u bjects  re-ra n d o mize d  t o  t he  da pa glif l ozi n  a n d  f or  t h ose  
re-ra n d o mize d t o t he sa xa gli pti n gr o u p, usi n g t h ose re-ra n d o mize d t o re mai n o n place b o as 
c o m parat or.  
T he o bser ve d a n d c ha n ge fr o m wit h dra wal baseli ne i n H b A 1c a n d i n F P G will be s u m marize d. 
Perce nta ge  of  s u bjects  w h o  ac h ie ve  or  mai ntai n  a n  H b A 1c  level  <  7. 0 %  at  t he  e n d  of  t he  
wit h dra wal peri o d will als o be s u m marize d. 
Ti me  fr o m  baseli ne  wit h dra wal  ( da ys)  t o  i n itiati o n  of  gl yce mic  resc ue  me dicati o n  or  
disc o nti n uati o n of st u d y me dicati o n d ue t o lac k of efficac y d uri n g t he ra n d o mize d wit h dra wal 
peri o d will be s u m marize d usi n g Ka pla n- Meier esti mates. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 4 
8. 4. 3  S af et y  A n al y s e s  
T he assess me nt of safet y will be base d o n t he a nal yses of A Es, vital si g ns, p h ysical e xa mi nati o ns, 
E C Gs, h y p o gl yce mia e ve nts, D K A e ve n ts, safet y la b orat or y e val uatio ns, a n d meas ures of gr o wt h 
a n d mat urit y.  
Da pa glifl ozi n  a n d  sa xa gli pti n  will  be  s u m marize d  se paratel y.  B ot h  l o w- d ose  a n d  hi g h- d ose  
sa xa gli pti n  a n d  da pa glifl ozi n  gr o u ps,  res pectivel y,  will  be  c o m bi ne d  f or  sa xa gli pti n  a n d  
da pa glifl ozi n t o pr o vi de t he safet y s u m mar y f o r o verall sa xa gli pti n a n d o verall da pa glifl ozi n 
c o m pare d t o place b o. A c o m m o n place b o gr o u p will be i ncl u de d i n eac h s u m mar y. 
8. 4. 3. 1  S h ort-t er m a n d L o n g-t er m A s s e s s m e nt 
T he n u m ber a n d perce nt of s u bjects  wit h at least o ne A E will be s u m marize d f or eac h treat me nt 
gr o u p, i ncl u di n g s u m maries of A Es, S A Es, a n d A E s lea di n g t o disc o nti n uati o n. S u m maries will 
i ncl u de t he n u m ber of s u bjects wit h e ve nts b y s yste m or ga n class a n d preferre d ter m. I n a d diti o n, 
t he pr o p orti o n of s u bjects e x perie nci n g at least o ne e pis o de of h y p o gl yce mia d uri n g t he 2 6 wee ks 
of S T treat me nt a n d 5 2 wee ks of treat me nt ( S T + L T) will be s u m marize d b y treat me nt gr o u p. 
T he i nci de nce of mar ke d la b orat or y a b n or malities t hr o u g h  2 6 wee ks ( S T), a n d se paratel y, t hr o u g h 
5 2 wee ks ( S T + L T) will be s u m mar ize d f or eac h treat me nt gr o u p. 
Val ues a n d c ha n ges fr o m baseli ne at eac h sc he d ule d ti me p oi nt f or cli nical la b orat or y para meters, 
b o d y wei g ht a n d vital si g ns, i ncl u di n g seate d B P  a n d H R, will be s u m marize d b y treat me nt gr o u p 
usi n g descri pti ve statistics. T he n or malit y/a b n or malit y of E C G traci n gs, as deter mi ne d b y t he 
I n vesti gat or, will be s u m marize d b y s hift ta bles o verall a n d b y E C G traci n g at baseli ne. Ta n ner 
sta gi n g a n d meas ures of gr o wt h will als o be s u m marize d b y treat me nt gr o u p usi n g descri pti ve 
statistics. 
T he Treate d S u bjects Data Set will be use d f or a ll safet y a nal yses, i ncl u di n g data after resc ue 
( pri mar y safet y a nal ysis). A d diti o nal se nsiti vit y a nal yses o n data c ollecte d pri or t o resc ue will be 
perf or me d f or A Es, h y p o gl yce mia e ve nts, a n d c li nical la b orat or y mar ke d a b n or malities. T he  
pri mar y a nal yses of e ve n ts of h y p o gl yce mia will be perf or me d e xcl u di n g data after resc ue. Safet y 
a nal yses will be perf or me d usi n g data fr o m t he S T treat me nt peri o d (at t he ti me of t he pri mar y 
e n d p oi nt a nal ysis) a n d t he n a gai n at t he fi nal data base l oc k ( 5 2 wee ks) o n t he c o m bi ne d S T + L T 
treat me nt peri o d.  
Meas ures of gr o wt h, b o ne, a n d mat urati o n mar ker s will be s u m marize d f or S T a n d t he c o m bi ne d 
S T + L T treat me nt peri o ds.  
F or t hese a nal yses, safet y data will be s u m m arize d b y treat me nt gr o u p base d o n t he treat me nt 
recei ve d ( da pa glifl ozi n/sa xa gli pti n/ place b o) usi n g t he Treate d S u bjects Data Set. 
8. 4. 3. 2  A d diti o n al L o n g-t er m S af et y A s s e s s m e nt 
D ue t o t he ra n d o mize d wit h dra wal  desi g n, a d diti o nal safet y a nal yses will be perf or me d u p t o 
Wee k 3 2 al o n g wit h m o difie d a nal yses perf or me d at Wee k 5 2 t o acc o u nt f or t he ra n d o mize d 
wit h dra wal. T hese assess me nts of safet y will be base d o n t he safet y para meters alrea d y descri be d 
( Secti o n 8. 4. 3 ).  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 5 
Selecte d safet y a nal yses perf or me d d uri n g t he S T a n d L T peri o ds ( Secti o n  8. 4. 3. 1 ) will als o be 
c o n d ucte d d uri n g t he treat me nt peri o d u p t o Wee k 3 2 t o acc o u nt f or ra n d o mize d wit h dra wal. T his 
will i ncl u de a nal yses of A Es, h y p o gl yce mia e ve n ts, D K A e ve nts, a n d cli nical la b orat or y mar ke d 
a b n or malities. All safet y  data will be s u m marize d b y treat me nt gr o u p base d o n t he treat me nt 
recei ve d ( da pa glifl ozi n/sa xa gli pti n/ place b o) usi n g t he Treate d S u bjects Data Set. 
T o assess t he effects of da pa gl ifl ozi n ( or sa xa gli ptin) vers us place b o o n safet y e n d p oi nts f or 
s u bjects o n bac k gr o u n d me dicati o n (i.e., e xcl u din g s u bjects re-ra n d o mize d t o wit h dra w fr o m 
metf or mi n) a wei g hte d a nal ysis will be c o n d ucte d f or select safe t y para meters usi n g t he Treate d 
S u bjects Data Set usi n g t he ori gi nal ra n d o mize d gr o u ps.  
Da pa glifl ozi n ( or sa xa gli pti n) s u bjects w h o we nt t hr o u g h t he la st ra n d o mizati o n a n d wit h dre w 
metf or mi n will get a wei g ht of zer o a n d t h ose ra n d o mize d t o sta y o n metf or mi n will get a wei g ht 
of 2.   
Place b o s u bjects ra n d o mize d t o wit h dra w metf or mi n a n d s witc he d t o acti ve treat me nt will get a 
wei g ht of zer o. Place b o s u bjects ra n d o mize d t o sta y  o n metf or mi n will get a wei g ht of 3. All ot her 
s u bjects will get a wei g ht of 1.  
A d diti o nal safet y a nal yses will be perf or me d o n  t he Treate d S u bjects Data Set o n A Es, D K A 
e ve nts, h y p o gl yce mia e ve nts, a n d cli nical la b orat or y mar ke d a b n or malities d uri n g t h e S T a n d L T 
treat me nt peri o ds t o c o m pare safet y e n d p oi nts per treat me nt recei ve d at t he ti me of t he e ve nt.  
F or place b o s u bjects re-ra n d o mize d t o s witc h t o da pa glifl ozi n ( or saxa gli pti n), e ve nts a n d cli nical 
la b orat or y mar ke d a b n or malities will be classifie d i n t he placeb o gr o u p u p t o t he be gi n ni n g of t he 
ra n d o mize d  wit h dra wal  peri o d  a n d  i n  t he  da pa glifl ozi n  ( or  sa xa gli pti n)  gr o u p  d uri n g  t he  
ra n d o mize d wit h dra wal peri o d. 
F urt her m ore, as t he le n gt h of e x p os ure i n t h e treat me nt recei ve d f oll o wi n g t he re-ra n d o mizati o n 
wit h dra wal pr ocess ma y be s h orte r f or t he s u bjects w h o s witc h fr o m place b o t o da pa glifl ozi n ( or 
sa xa gli pti n); t hese e ve nts a n d mar ke d a b n or malities a nal yses will re p ort i nci de nce rates a dj uste d 
f or e x p os ure ti me. 
8. 4. 3. 3  M o n ot h er a p y S af et y A s s e s s m e nt 
T he  m o n ot hera p y  safet y  assess me nt  will  i ncl u de  sta n dar d  safet y  assess me nts  ( Secti o n  8. 4. 3 ) 
occ urri n g d uri n g t he ra n d o mize d wit h dra wal peri o d. T hese a nal yses will be c o n d ucte d d uri n g t he 
ra n d o mize d wit h dra wal peri o d usi n g t he Ra n d o mize d Wit h dra w al S u bjects Data Set. 
T he refere nce ti me p oi nt t o be use d as ‘ wit h dra wal baseli ne’ will be t he cl osest ti me p oi nt o n or 
bef ore t he t hir d ra n d o mizati o n visit. 
T he  safet y  assess me nts  will  be  c o m pare d  wi t hi n  eac h  treat me nt  gr o u p  fr o m  t he  ori gi nal  
ra n d o mizati o n as f oll o ws: 
 F or s u bjects i nitiall y ra n d o mize d  t o t he da pa glifl ozi n ( or sa xa gli pti n) gr o u p, t he s u bjects 
re-ra n d o mize d t o wit h dra w metfor mi n will be c o m pare d t o t he s u bjects re-ra n d o mize d t o sta y 
o n metf or mi n. Se parate a nal yses will be perf or m e d f or s u bjects res pecti vel y ra n d o mize d t o 
eit her t he da pa glifl ozi n or sa xa gli pti n gr o u p.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 6 
 F or s u bjects i nitiall y ra n d o mi ze d t o t he place b o gr o u p, t he s u bject s re-ra n d o mize d t o s witc h t o 
da pa glifl ozi n ( or sa xa gli pti n) m o n ot hera p y will be  c o m pare d t o t he s u bjects re-ra n d o mize d t o 
sta y o n place b o wit h a d d- o n metf or mi n. Se parate a nal yses will be perf or me d res pecti vel y f or 
s u bjects  re-ra n d o mize d  t o  t he  da pa glifl ozi n  gr o u p  a n d  f or  t h ose  re-ra n d o mize d  t o  t he  
sa xa gli pti n gr o u p, usi n g t h ose re-ra nd o mize d t o place b o as c o m parat or. 
 A d diti o nal a nal ysis will als o be  perf or me d t o c o m pare all s u bjects ta ki n g da pa glifl ozi n ( or 
sa xa gli pti n) m o n ot hera p y vs t h ose ta ki n g place b o wit h bac k gr o u n d metf or mi n d uri n g t he 
ra n d o mize d wit h dra wal peri o d (ad di n g place b o s u bjects ra n d o mize d t o wit h dra w metf or mi n 
a n d s witc he d t o da pa glifl ozi n [ or sa xa gli pti n]) m o n ot hera p y t o da pa glifl ozi n ( or sa xa gli pti n) 
s u bjects ra n d o mize d t o wit h dra w metf or mi n). 
F or assess me nt of e ve nts, o nl y t h ose wit h a n o nset date occ urri n g o n or  after t he ra n d o mize d 
wit h dra wal will be i ncl u d e d i n t hese a nal yses. 
8. 4. 3. 4  W e e k 1 0 4 A s s e s s m e nt 
Selecte d safet y a nal yses desc ri be d a b o ve at Wee k 5 2 ( Secti o ns 8. 3. 3. 1, 8. 3. 3. 2 , a n d 8. 3. 3. 3 ) ca n 
be re peate d at Wee k 1 0 4 ( usi n g t he sa me treat m e nt gr o u pi n gs). A nal yses will be perf or me d o n t he 
Treate d S u bjects Data Set. A d diti o nall y, select e d a nal yses will be perf or me d o n t he Ra n d o mize d 
Wit h dra wal S u bjects Data Set t o assess t he effects of m o n ot hera p y. 
T he f oll o wi n g para meters will be s u m marize d: 
 Meas ures of gr o wt h, b o ne, a n d mat urati o n mar k ers as well as Ta n ner sta ge assess me nt  
 Hei g ht, b o d y wei g ht a n d B MI  
8. 4. 4  P h ar m a c o ki n eti c  A n al y s e s  
Plas ma sa m ples will be a nal yze d f or da pa glifl o zi n, sa xa gli pti n a n d its me ta b olite 5- O H-sa xa gli pti n 
b y vali date d assa ys. 
Plas ma  c o nce ntrati o n  val ues  f or  da pa glifl o zi n,  sa xa gli pti n  a n d  5- O H-sa xa gli pti n  will  be  
s u m marize d usi n g descri pti ve statistics b y visit a n d ti me p oi nt. T he plas ma c o nce ntrati o n val ues 
ma y be use d i n p o p ulati o n P K a n d/ or p o p ulati o n P K/ P D a nal yses t hat  will be re p orte d se paratel y 
fr o m t he C S R. 
8. 4. 5  P h ar m a c o d y n a mi c  A n al y s e s  
P har mac o d y na mic a nal yses will i n cl u de b ut will n ot be li mite d t o  a nal ysis of D P P- 4 acti vit y a n d 
F P G. 
T he a nal yses will be re p orte d  se paratel y fr o m t he C S R. 
8. 4. 6  Bi o m ar k er  A n al y s e s  
N ot a p plica ble. 
8. 4. 7  O ut c o m e s  R e s e ar c h  A n al y s e s  
N ot a p plica ble. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 7 
8. 4. 8  Ot h er A n al y s e s  
N ot a p plica ble. 
8. 5  I nt eri m  A n al y s e s  
N ot a p plica ble.   
9
 S T U D Y
 M A N A G E M E N T
 
9. 1  C o m pli a n c e  
9. 1. 1  C o m pli a n c e wit h t h e Pr ot o c ol a n d Pr ot o c ol R e vi si o n s 
T he st u d y s hall be c o n d ucte d as descri be d i n t his a p pr o ve d pr ot oc ol. All re visi o ns t o t he pr ot oc ol 
m ust be disc usse d wit h, a n d be pre pare d b y, t he S p o ns or/ desi g nee. T he i n vesti gat or s h o ul d n ot 
i m ple me nt  a n y  de viati o n  or  c ha n ge  t o  t he  pr ot oc ol  wit h o ut  pri or  re vie w  a n d  d oc u me nte d  
a p pr o val/fa v ora ble  o pi ni o n  fr o m  t h e  I R B/I E C  of  a n  a me n d me nt,  e xce pt  w here  necessar y  t o  
eli mi nate a n i m me diate hazard(s) t o st u d y s u bjects.  
If a de viati o n or c ha n ge t o a pr ot oc ol is i m ple me nte d t o eli mi nate a n i m me diate hazar d(s) pri or t o 
o btai ni n g I R B/I E C a p pr o val/fa v ora ble o pi ni o n, as s o o n as p ossi ble t he de viati o n or c ha n ge will be 
s u b mitte d t o: 
 I R B/I E C f or re vie w a n d ap pr o val/fa v ora ble o pi ni o n 
 T he S p o ns or/ desi g nee 
 Re g ulat or y A ut h orit y(ies), if re q uire d b y l ocal re g ulati o ns 
D oc u me ntati o n of a p pr o val si g ne d b y t he c hair pers o n or desi g nee of t he I R B(s)/I E C(s) m ust be 
se nt t o t he S p o ns or/ desi g nee. 
T o pre ve nt i nterr u pti o n of st u d y dr u g a d mi nis trati o n, s o me c ha n ges fr o m A me n d me nt 0 5 were 
i m ple me nte d bef ore a p pr o val fr o m t he I R B/I EC d ue t o t he o n g oi n g C O VI D- 1 9 pa n de mic a n d o nl y 
f or s u bjects affecte d b y t he pa n demic/l ocal restricti o ns relate d t o t he pa n de mic, i n acc or da nce wit h 
t he a d vice fr o m Re g ulat or y A ut h orities. 
If a n a me n d me nt s u bsta ntiall y alters t he st u d y desi g n or i ncreases t he p ote ntial ris k t o t he s u bject: 
( 1)  t he  c o nse nt  f or m  m ust  be  re vise d  a n d  s u b mitte d  t o  t he  I R B(s)/I E C(s)  f or  re vie w  a n d  
a p pr o val/fa v ora ble o pi ni o n; ( 2) t he re vise d f or m m ust be use d t o o btai n c o nse nt fr o m s u bjects 
c urre ntl y e nr olle d i n  t he st u d y if t he y are affecte d b y t he a me n d me nt; a n d ( 3) t he ne w f or m m ust 
be use d t o o btai n c o nse nt fr o m ne w s u bjects pri or t o e nr oll me nt.  
If t he re visi o n is d o ne via a n a d mi nistrati ve letter, i n vesti gat ors m ust i nf or m t heir I R B(s)/I E C(s). 
T o pre ve nt i nterr u pti o n of st u d y dr u g a d mi nis trati o n, s o me c ha n ges fr o m A me n d me nt 0 5 were 
i m ple me nte d  after  ver bal  i nf or me d  c o nse nt  was  o btai ne d  fr o m  s u bjects  affecte d  b y  t he  
pa n de mic/l ocal  restricti o ns  relate d  t o  t he  pa n d e mic.  Writte n  c o nse nt  will  be  o btai ne d  after  
a p pr o val of t he i nf or me d c o nse nt f or m b y a p pl ica ble Re g ulat or y A uth orities/I R B(s)/I E C(s). 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 8 
9. 1. 2  M o nit ori n g  
T he S p o ns or/ desi g nee re prese ntati ves will re vie w da ta ce ntrall y t o i de ntif y p ote ntial iss ues t o 
deter mi ne a sc he d ule of o n-site visits f or tar gete d re vie w of st u d y rec or ds. 
Re prese ntati ves of t he S p o ns or ( or desi g nee) m ust  be all o we d t o visit all st u d y site l ocati o ns 
peri o dicall y t o assess t he data q ualit y a n d st u d y i nte grit y. O n site  t he y will re vie w st u d y rec or ds 
a n d directl y c o m pare t h e m wit h s o urce d oc u me nts , disc uss t he c o n d uct of t he st u d y wit h t he 
I n vesti gat or, a n d verif y t hat t he facilities re mai n acce pta ble. Off-site m o nit ori n g visits a n d re m ote 
s o urce data verificati o n are all o we d w he n restricti o ns d ue t o t he C O VI D- 1 9 pa n de mic pre ve nt 
o n-site visits (e. g., m o nit ors ma y n ot be a ble t o access t he sites i n a ti me l y ma n ner). S h o ul d t his 
occ ur, it s h o ul d be d oc u me nte d a n d t he reas o ns be  a vaila ble f or re vie w b y t he S p o ns or a n d d uri n g 
i ns pecti o ns b y a n y Re g ulat or y A ut h orities. Re m ote m o nit ori n g s h o ul d be f oc use d o n re vie w of 
critical st u d y site d oc u me ntati o n a n d s o urce data  a n d t he m o nit ori n g acti vities, i ncl u di n g re m ote 
re vie w  of  s o urce  d oc u me nts,  s h o ul d  be  d oc u me nted  i n  t he  sa me  le vel  of  detail  as  o n-site  
m o nit ori n g acti vities. A n y res ulti n g acti o ns t o a d dress iss ues i de ntifie d fr o m t he re m ote s o urce 
d oc u me nt re vie w s h o ul d be c o nsiste nt wit h pr o ce d ures a n d pr ocesses descri be d i n t he st u d y 
m o nit ori n g pla n. 
I n  a d diti o n,  t he  st u d y  ma y  be  e val uate d  b y  t he  S p o ns or  ( or  desi g nee)  i nter nal  a u dit ors  a n d  
g o ver n me nt i ns pect ors w h o m ust be all o we d acce ss t o C R Fs, s o urce d oc u me nts, ot her st u d y files, 
a n d st u d y facilities. T he S p o ns or ( or desi g nee)  a u dit re p orts will be ke pt c o nfi de ntial. 
T he i n vesti gat or m ust n otif y t he S p o ns or ( or desi g nee) pr o m ptl y of  a n y i ns pecti o ns sc he d ule d b y 
Re g ulat or y  A ut h orities,  a n d  pr o m ptl y  f or w ar d  c o pies  of  i ns pecti o n  re p orts  t o  t he  
S p o ns or/ desi g nee.  
9. 1. 2. 1  S o ur c e  D o c u m e nt ati o n  
T he  I n vesti gat or  is  res p o nsi ble  f or  e ns uri n g  t hat  t he  s o urce  data  are  acc urate,  le gi ble,  
c o nte m p ora ne o us, ori gi nal a n d attr i b uta ble, w het her t he data are ha n d- writte n o n pa per or e ntere d 
electr o nicall y. If s o urce data are cr eate d (first e ntere d), m o difie d, mai ntai ne d, arc hi ve d, retrie ve d, 
or  tra ns mitte d  electr o nicall y  via  c o m p uterize d  s yste ms  (a n d/ or  a n y  ot her  ki n d  of  electr o nic  
de vices) as part of re g ulate d cli nical trial acti v ities, s uc h s yste ms m ust be c o m plia nt wit h all 
a p plica ble la ws a n d re g ulati o ns g o ver ni n g use of electr o nic rec or ds a n d/ or  electr o nic si g nat ures. 
S uc h s yste ms ma y i ncl u de, b ut ar e n ot li mite d t o, electr o nic me di cal/ healt h rec or ds ( E M Rs/ E H Rs), 
A E trac ki n g/re p orti n g, pr ot oc ol re q uire d asse ss me nts, a n d/ or dr u g acc o u nta bilit y rec or ds). 
W he n pa per rec or ds fr o m s uc h s yste ms are use d i n  place of electr o nic f or mat t o perf or m re g ulate d 
acti vities, s uc h pa per rec or ds s h o ul d be certifie d  c o pies. A certifie d c o p y c o nsists of a c o p y of 
ori gi nal i nf or mati o n t hat has bee n  verifie d, as i n dicate d b y a dated si g nat ure, as a n e xact c o p y 
ha vi n g all of t he sa me attri b utes a n d i nf or mati o n as t he ori gi nal. Da ta e ntere d i n t he e C R F t hat are 
tra nscri be d  fr o m  s o urce  d oc u me nts  m ust  be  c o nsiste nt  wit h  t he  s o urce  d oc u me nts  or  t he  
discre pa ncies m ust be e x plai ne d. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 0 9 
9. 1. 3  I n v e sti g ati o n al Sit e Tr ai ni n g 
T he S p o ns or/ desi g nee will pr o vi de q ualit y i n vesti ga ti o nal staff trai ni n g pri or t o st u d y i nitiati o n. 
Trai ni n g t o pics will i ncl u de b ut are n ot li mite d t o : G C P, A E re p orti n g, st u d y details a n d pr oce d ure, 
electr o nic C R Fs, st u d y d oc u me ntati o n, i nf or me d  c o nse nt, a n d e nr oll me nt of W O C B P. 
9. 2  R e c or d s  
9. 2. 1  R e c or d s  R et e nti o n  
T he i n vesti gat or m ust retai n all st u d y rec o r ds a n d s o urce d oc u me nts f or t he ma xi m u m peri o d 
re q uire d b y a p plica ble reg ulati o ns a n d g ui deli nes, or i nstit uti o n pr oce d ur es, or f or t he peri o d 
s pecifie d  b y  t he  S p o ns or/ desi g nee,  w hic he ver  is l o n ger.  T he  i n vesti gat or  m ust  c o ntact  t he  
S p o ns or/ desi g nee pri or t o destr o yi n g a n y rec or ds ass ociate d wit h t he st u d y. 
T he S p o ns or/ desi g nee will n otif y t h e I n vesti gat or w he n t he st u d y rec or ds are n o l o n ger nee de d. 
If t he I n vesti gat or wit h dra ws fr om t he st u d y (e. g., rel ocati o n, retire me nt), t he rec or ds s hall be 
tra nsferre d t o a m ut uall y a gree d u p o n desi g nee (e. g., a n ot her i n vesti gat or, I R B). N otice of s uc h 
tra nsfer will be gi ve n i n writin g t o t he S p o ns or/ desi g nee.  
9. 2. 2  St u d y Dr u g R e c or d s  
It is t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat a c urre nt dis p ositi o n rec or d of st u d y dr u g 
(i n ve nt orie d a n d dis pe nse d) is mai ntai ne d at t he st u d y site t o i ncl u de I Ps. A n y u n use d I P se nt 
directl y t o s u bjects’ h o me s s h o ul d be ret ur ne d t o t he site at t he ne xt o n-site visit. Rec or ds or l o gs 
m ust c o m pl y wit h a p plica ble re g ulati o ns a n d g ui deli nes a n d s h o ul d i ncl u de: 
 A m o u nt recei ve d a n d place d i n st ora ge area 
 A m o u nt c urre ntl y i n st ora ge area 
 La bel i de ntificati o n n u m ber or batc h n u m ber 
 A m o u nt dis pe nse d t o a n d ret ur ne d b y eac h s u bject, i ncl u di n g u ni q ue s u bject i de ntifiers 
 A m o u nt tra nsferre d t o a n ot her area/site f or dis pe nsi n g or st ora ge 
 N o nst u d y dis p ositi o n (e. g., l ost, waste d) 
 A m o u nt destr o ye d at st u d y site, if a p plica ble 
 A m o u nt ret ur ne d t o t he S p o ns or/ desi g nee 
 Retai n sa m ples f or bi oa vaila bilit y/ bi oe q ui vale nce, if a p plica ble 
 Dates a n d i nitials of pers o n res p o nsi ble f or I P  dis pe nsi n g/acc o u nta bilit y, as per t he Dele gati o n 
of A ut h orit y F or m 
T he S p o ns or/ desi g nee will pr o vi de f o r ms t o facilitate i n ve nt or y c o ntr ol if t he i n vesti gati o nal site 
d oes n ot ha ve a n esta blis he d s yste m  t hat meets t hese re q uire me nts.  

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 0 
9. 2. 3  C a s e R e p ort F or m s 
A n i n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vati o ns a n d other data perti ne nt t o t he i n vesti gati o n o n eac h i n di vi d ual treate d 
or e ntere d as a c o ntr ol i n t he i n vesti gati o n. Data t hat are deri ve d fr o m s o urce d oc u me nts a n d 
re p orte d o n t he C R F m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he disc re pa ncies m ust be 
e x plai ne d. A d diti o nal cli nical i nf o r mati o n ma y be c ollecte d a n d a nalyze d i n a n eff ort t o e n ha nce 
u n dersta n di n g of pr o d uct safet y. Case re p ort f or ms ma y be re q uest e d f or A Es a n d/ or la b orat or y 
a b n or malities t hat are re p or te d or i de ntifie d d uri n g t he c o urse of t he st u d y. 
F or sites usi n g t he S p o ns or/ desi g nee’s E D C t o ol, electr o nic C R Fs will be pre pare d f or all data 
c ollecti o n fiel ds e xce pt f or fiel ds s pecific t o S A Es a n d pre g na nc y, w hic h will be re p orte d o n t he 
electr o nic S A E f or m a n d Pre g na nc y S ur veilla nce  F or m, res pecti vel y. If electr o nic S A E f or m is 
n ot a vaila ble, a pa per S A E f or m ca n be use d. S pace s ma y be left bla n k o nl y i n t h ose circ u msta nces 
per mitte d b y st u d y-s pecific C R F c o m pleti o n g ui deli nes pr o vi de d b y t h e S p o ns or/ desi g nee. 
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y s u bjects m ust be pr otecte d, res pecti n g t he pri vac y 
a n d c o nfi de ntialit y r ules i n acc or da nce wit h t he a p plica ble re g ulat or y re q uire me nt(s). 
T he i n vesti gat or will mai ntai n a si g nat ure s heet t o d oc u me nt si g nat ures a n d i nitials of all pers o ns 
a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n C R Fs. 
T he c o m plete d C R F, i ncl u di n g a n y pa per or electr o nic S A E/ pre g na nc y C R Fs, m ust be pr o m ptl y 
re vie we d, si g ne d, a n d date d b y t he I nvesti gat or or q ualifie d p h ysicia n w h o is a s u bi n vesti gat or a n d 
w h o is dele gate d t his tas k o n t he Dele gati o n of A ut h orit y F or m. F or elec tr o nic C R Fs, re vie w a n d 
a p pr o val/si g nat ure is c o m plete d electr o nicall y t hr o u g h t he S p o ns or/ desi g nee’s E D C t o ol. T he 
i n vesti gat or m ust retai n a co p y of t he C R Fs i ncl u di n g rec or ds of  t he c ha n ges a n d c orrecti o ns. 
Eac h  i n di vi d ual  electr o nicall y  si g ni n g  electr o n ic  C R Fs  m ust  meet  S p o ns or/ desi g nee  trai ni n g  
re q uire me nts a n d m ust o nl y access t he S p o ns or/ desi g nee’s E D C t o ol usi n g t he u ni q ue user acc o u nt 
pr o vi de d b y t he S p o ns or/ desi g nee. User acc o u nts ar e n ot t o be s hare d or reassi g ne d t o ot her 
i n di vi d uals. 
9. 3  Cli ni c al St u d y R e p ort a n d P u bli c ati o n s 
T he C S R will be pre pare d after s u bjects ha ve c o m plete d 5 2 wee ks of ran d o mize d treat me nt a n d 
Wee k 5 6 f oll o w- u p data are a vaila ble.  
T he p ost-st u d y data ( Wee k 1 0 4 data) will be re p orte d se paratel y.  
A Si g nat or y I n vesti gat or m ust be selecte d t o si g n t he C S R. 
F or t he C S R t he Si g nat or y I n vesti gat or will be  selecte d as a p pr o priate base d o n t he f oll o wi n g 
criteria: 
 E xter nal Pri nci pal I n vesti gat or de si g nate d at pr ot oc ol de vel o p me nt 
 Nati o nal C o or di nati n g I n vesti gat or  
 St u d y Steeri n g C o m mittee c h air or t heir desi g nee 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 1 
 S u bject recr uit me nt (e. g., a m o n g t h e t o p q uartile of e nr ollers) 
 I n v ol ve me nt i n trial desi g n 
 Re gi o nal re prese ntati o n (e. g., a m o n g t o p q uartile of e nr ollers fr o m a s pecifie d re gi o n or 
c o u ntr y) 
 Ot her criteria (as deter m i ne d b y t he st u d y tea m) 
T he data c ollecte d d uri n g t his st u d y are c o nfi de ntial a n d pr o prietar y t o t he S p o ns or/ desi g nee. A n y 
p u blicati o ns or a bstracts arisi n g fr o m t his st u d y m ust a d here t o t he p u blicati o n re q uire me nts set 
f ort h i n t he cli nical trial a gree me nt ( C T A) g o ver ni n g [ St u d y site or  I n vesti gat or] partici pati o n i n 
t he st u d y. T hese re q uire me nts i ncl u de, b ut are n ot li mite d t o, s u b mitti n g pro p ose d p u blicati o ns t o 
t he S p o ns or/ desi g nee at t he earliest practica ble ti me pri or t o s u b missi o n or prese ntati o n a n d 
ot her wise wit hi n t he ti me pe ri o d set f ort h i n t he C T A. 
A descri pti o n of t his cli nical st u d y is a vaila ble o n htt p://astraze neca gr o u ptrials. p har mac m.c o m a n d 
htt p:// w w w.cli nicaltrials. g o v as will t he s u m mar y of t he st u d y res u lts w he n t he y are a vaila ble. T he 
cli nical  st u d y  a n d/ or  s u m mar y  of  t he  st u d y  re s ults  ma y  als o  be  a vaila ble  o n  ot her  we bsites  
acc or di n g t o t he re g ulati o ns of t he c o u nt ries i n w hic h t he st u d y is c o n d ucte d. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 2 
1 0  G L O S S A R Y  O F  T E R M S  
Ter m
 Defi niti o n
 
C o m plete A bsti ne nce 
C o m plete  a bsti ne nce  is  defi ne d  as  c o m plete  a v oi da nce  of  heter ose x ual  
i nterc o urse a n d is a n acce pta ble f or m of c o ntrace pti o n f or all st u d y dr u gs. T his 
als o mea ns t hat a bsti ne nce is t he preferre d a n d us ual lifest yle of t he s u bject. 
T his  d oes  n ot  mea n  peri o dic  a bst i ne nce  (e. g.,  cale n dar,  o v ulati o n,  
s y m pt ot her mal, pr ofessi o n of a bsti ne nce f or e ntr y i nt o a cli nical trial, p ost-
o v ulati o n  met h o ds)  a n d  wit h dra wal,  w hic h  are  n ot  acce pta ble  met h o ds  of  
c o ntrace pti o n.  W o me n  m ust  c o nti n ue  t o  ha ve  pre g na nc y  tests.  Acce pta ble  
alter nate met h o ds of hi g hl y effecti ve c o ntrace pti o n’s m ust be disc usse d i n t he 
e ve nt t hat t he s u bject c h o oses t o  f ore g o c o m plete a bsti ne nce. 
 
 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 3 
1 1  LI S T  O F  A B B R E VI A TI O N S  
Ter m
 Defi niti o n
 
5- O H-sa xa gli pti n
 5- h y dr o x y-sa xa gli pti n
 
A D A 
A merica n Dia betes Ass ociati o n 
A E
 a d verse
 
e ve nt
 
A L T
 ala ni ne
 
a mi n otra nsferase
 
A N C O V A
 a nal ysis
 
of c o varia nce 
A S T
 as partate
 
a mi n otra nsferase
 

a mi n otra nsferase 

Astra Ze neca 
B MI 
b o d y mass i n de x 
B M S
 Brist ol- M yers
 
S q ui b b
 
B P
 bl o o d
 
press ure
 
C F R 
C o de of Fe deral Re g ulati o ns  
C O VI D- 1 9
 c or o na vir us
 
disease
 
2 0 1 9
 
C R F
 case
 
re p ort
 
f or m
 
C S R 
Cli nical St u d y Re p ort  
C T A 
Cli nical Trial A gree me nt 
C T X- 1 
car b o x yter mi nal cr oss-li n ke d te l o pe pti de of T y pe 1 c olla ge n 
C Y P 3 A 4/ 5
 c yt oc hr o me
 
P 4 5 0
 
3 A 4/ 3 A 5
 
DI LI 
dr u g-i n d uce d li ver i nj ur y 
D K A
 dia betic
 
ket oaci d osis
 
D M C 
Data M o nit ori n g C o m mittee 
D P P- 4
 di pe pti d yl- pe pti dase- 4
 
E C G
 electr ocar di o gra m
 
e C R F 
electr o nic case re p ort f or m 
E D C 
electr o nic data ca pt ure 
e G F R 
esti mate d gl o mer ular filtrati o n rate 
E T D
 earl y
 
treat me nt
 
disc o nti n uati o n
 
F D A 
F o o d a n d Dr u g A d mi nistrati o n 
F P G 
fasti n g plas ma gl uc ose 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 4 
Ter m
 Defi niti o n
 
G A D 
gl uta mic aci d decar b o x ylase 
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  
G M P 
G o o d Ma n ufact uri n g Practice 
H A V 
he patitis A vir us 
H b A 1c
 gl yc os ylate d
 
he m o gl o bi n
 
H Bs A g 
he patitis B s urface a nti ge n 
H C G 
h u ma n c h ori o nic g o na d otr o pi n 
H C V 
he patitis C vir us 
H R
 heart
 
rate
 
I A- 2 
pr otei n t yr osi ne p h os p hatase-li ke pr otei n 
I C H
 I nter nati o nal
 
C o u nc il f or Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee 
I G F- 1
 i ns uli n-li ke
 
gr o wt h
 
fact or- 1
 
I G F B P- 3
 i ns uli n-li ke
 
gr o wt h fact or bi n din g pr otei n- 3 
I M P 
i n vesti gati o nal me dici nal pr o d uct/  
I N D 
I n vesti gati o nal Ne w Dr u g E xe m pti o n 
I P 
i n vesti gati o nal ( me dici nal) pr o d uct 
I R
 i m me diate
 
release
 
I R B
 I nstit uti o nal
 
Re vie w
 
B oar d
 
I T T
 i nte nt-t o-treat
 
L F T 
li ver f u ncti o n test 
L T
 l o n g-ter m
 
I U D
 i ntra uteri ne
 
de vice
 
I X R S
 I nteracti ve
 
We b/ V oice Res p o nse S yste m 
M O D Y
 mat urit y
 
o nset
 
dia betes of t he y o u n g 
n o n-I M P
 n o n-i n vesti gati o na l me dici nal pr o d uct  
n o n-I P
 n o n-i n vesti gati o na l ( me dici nal) pr o d uct 
P D
 P har mac o d y na mic(s)
 
P K
 P har mac o ki netic(s)
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 5 
Ter m
 Defi niti o n
 
P P G
 p ost pra n dial
 
gl uc ose
 
P T H
 parat h yr oi d
 
h or m o ne
 
S A E
 seri o us
 
a d verse
 
e ve nt
 
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 ori n g bl o o d gl uc ose 
S O P 
sta n dar d o perati n g pr oce d ures 
S T
 s h ort-ter m
 
S U
 S ulf o n yl urea
 
T B
 t otal
 
bilir u bi n
 
T 2 D M 
t y pe 2 dia betes mellit us 
T S H
 t h yr oi d-sti m ulati n g
 
h or m o ne
 
U K P D S 
U nite d Ki n g d o m Pr os pecti ve Dia betes St u d y 
U L N 
u p per li mit of n or mal 
U S/ U S A  
U nite d States of A merica 
U TI
 uri nar y
 
tract
 
i nfecti o n
 
W O C B P  
w o me n of c hil d beari n g p ote ntial 
X R
 e xte n de d
 
release
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 6 
1 2  R E F E R E N C E S  
1.  Al berti G, Zi m met P, S ha w J, Bl o o m gar de n Z, Ka uf ma n F, Sili n k M; C o nse ns us W or ks h o p 
Gr o u p. T y pe 2 dia betes i n t he y o u n g: t he e v ol vi n g e pi de mic: t he i nte r nati o nal dia betes 
fe derati o n c o nse ns us w or ks h o p. Dia betes Care 2 0 0 4; 2 7: 1 7 9 8- 8 1 1. 
2.  I nter nati o nal Dia betes Fe derati o n Cli nical G ui deli nes Tas k F orce. Gl o bal g ui deli ne f or 
t y pe  2  dia betes.  Br ussels:  I nter nati o nal  Dia betes  Fe derati o n;  2 0 0 5.  A vaila ble  fr o m:  
htt p:// w w w.i df. or g/ we b data/ d ocs/I D F % 2 0 G G T 2 D. p df. Accesse d o n 1 3 Fe br uar y 2 0 0 8. 
3.  A merica n Dia betes Ass ociati o n. T y pe 2 dia bet es i n c hil dre n a n d a d olesce nts. Dia betes 
Care 2 0 0 0; 2 3: 3 8 1- 9. 
4.  A merica n Dia betes Ass ociati o n. Sta n dar ds of  Me dical Care i n Dia betes 2 0 0 8. Dia betes 
Care 2 0 0 8; 3 1( S u p pl 1): S 1 2- 5 4. 
5.  G ora n MI, Ball G D C, Cr uz M L. O besit y a n d ris k  of t y pe 2 dia betes a n d car di o vasc ular 
disease i n c hil dre n a n d a d olesce nts. J Cli n E n d ocri n ol Meta b 2 0 0 3; 8 8: 1 4 1 7- 2 7. 
6.  Kra k off J, Ha ns o n R L, K o bes S, K n o wler W C. C o m paris o n of t he effect of plas ma gl uc ose 
c o nce ntrati o ns o n micr o vasc ular  disease bet wee n Pi ma I n dia n y o ut hs a n d a d ults. Dia betes 
Care 2 0 0 1; 2 4: 1 0 2 3- 8. 
7.  Dea n HJ, Sellers E A C. C o m or bi dities a n d micr o vasc ular c o m plicati o ns of t y pe 2 dia betes 
i n c hil dre n a n d a d olesce nts. Pe diatr Dia betes 2 0 0 7; 8( S u p pl 9): 3 5- 4 1. 
8.  E p pe ns M C, Crai g M E, C us u ma n o J, Hi n g S, C h a n g A K, H o war d NJ, et al. Pre vale nce of 
dia betes c o m plicati o ns i n a d olesce nts wit h t y pe  2 c o m pare d wit h t y pe 1 dia betes. Dia betes 
Care 2 0 0 6; 2 9: 1 3 0 0- 6. 
9.  Bl o o m gar de n, Z T. T y pe 2 dia betes i n t he y o u n g: t he e v ol vi n g e pi de mic. Dia betes Care 
2 0 0 4; 2 7: 9 9 8- 1 0 1 0. 
1 0.  Dia betes  C o ntr ol  a n d  C o m plic ati o ns  Trial  Researc h  Gr o u p.  T he  effect  of  i nte nsi ve  
treat me nt of dia betes o n t he de vel o p me nt an d pr o gressi o n of l o n g-te r m c o m plicati o ns i n 
i ns uli n- de pe n de nt dia betes mellit us. N E n gl J Me d 1 9 9 3; 3 2 9: 9 7 7- 8 6. 
1 1.  A merica n Dia betes Ass ociati o n – C hil dre n a n d A d olesce nts: Sta n dar ds of Me dical Care i n 
Dia betes 2 0 1 8. Dia betes Ca re 2 0 1 8; 4 1( S u p pl 1): S 1 2 6- 3 6. 
1 2.  Kestel ma n P, Tr ussell J. Efficac y of t he si m ulta ne o us use of c o n d o ms a n d s per mici des. 
Fa m Pla n n Pers pect 1 9 9 1: 2 3( 5): 2 2 6- 7. 
1 3.  Ga b ba y M B, T h o mas J, Gi b bs A, H ol d P. A ra n d o mize d cr oss o ver trial of t he i m pact of 
a d diti o nal s per mici de o n c o n d o m fail ure  rates. Se x Tra ns m Dis 2 0 0 8: 3 5: 8 6 2- 8. 
1 4.  Grass o  Y Z,  Re d d y  S K,  R ose nfel d  C R,  H usse i n  WI,  H o o g werf  BJ,  Fai ma n  C,  et  al.  
A ut oa nti b o dies t o I A- 2 a n d G A D 6 5 i n patie nts wit h t y pe 2 dia betes mellit us of varie d 
d urati o n: pre vale nce a n d c orrelati o n wit h cli n ical feat ures. E n d ocr Pract 2 0 0 1; 7( 5): 3 3 9- 4 5. 
1 5.  Kli n ge ns mit h GJ, P yle L, Arsla nia n S, C o pe la n d K C, C uttler L, Ka uf ma n F, Laffel L, et 
al. T he prese nce of G A D a n d I A- 2  a nti b o dies i n y o ut h wit h a t y pe 2 dia betes p he n ot y pe: 
res ults fr o m t he T O D A Y st u d y. Dia betes Care 2 0 1 0: 3 3: 1 9 7 0- 7 5. 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 7 
1 6.  v o n Oetti n ge n J E, W olfs d orf JI, Fel d ma n H A, R h o des E T. Utilit y of dia betes-ass ociate d 
a ut oa nti b o dies f or classificati o n of ne w o nset di a betes i n c hil dre n a n d a d olesce nts. Pe diatr 
Dia betes 2 0 1 6: 1 7: 4 1 7- 4 2 5. 
1 7.  Sc h wartz GJ, M u ñ oz A, Sc h nei der M F, Ma k R H, Kas kel F, Wara d y B A, et al. Ne w 
e q uati o ns t o esti mate G F R i n c hil dre n w it h C K D. J A m S oc Ne p hr ol 2 0 0 9; 2 0: 6 2 9- 6 3 7. 
1 8.  Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o g o-Jac k S, Fis h L, et al. H y p o gl yce mia 
a n d Dia betes: A Re p ort of a W or k gr o u p of t h e A merica n Dia betes Ass ociati o n a n d T he 
E n d ocri ne S ociet y. Dia betes Care. 2 0 1 3 Ma y; 3 6( 5): 1 3 8 4- 9 5. 
1 9.  Clar ke W, J o nes T, Re wers A, D u n ger D, Kli n ge ns mit h GJ. I S P A D Cli nical Practice 
C o nse ns us G ui deli nes 2 0 0 9 C o m pe n di u m. A ssess me nt a n d ma na ge ment of h y p o gl yce mia 
i n c hil dre n a n d a d olesce nts wit h dia betes. Pe diatr Dia betes 2 0 0 9; 1 0( S 1 2): 1 3 4- 1 4 4. 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 8 
A P P E N DI X 1  
C E N T R A L L A B O R A T O R Y A S S E S S M E N T S 
Bl o o d a n d uri ne sa m ples will be o btai ne d at s pecif ie d ti me p oi nts f or la b orat or y e val uati o ns. T he 
ce ntral la b orat or y f or t his st u d y wi ll perf or m t he a nal ysis of all sc he d ule d la b orat ory tests a n d will 
pr o vi de refere nce ra n ges f or t hese tests. T he de taile d met h o ds f or s peci me n c ollecti o n, ha n dli n g, 
pr ocessi n g,  s hi p pi n g,  a n d  st ora ge  will  be  s u p plie d  i n  t he  I n vesti gat or’s  La b orat or y  Ma n ual  
pr o vi de d b y t he Ce ntral La b orat or y. A ll cli nical la b orat or y tests will be perf or me d b y t he Ce ntral 
La b orat or y or desi g nate d refere nce la b orat or y. 
T he H b A 1c val ues a n d uri nar y gl uc ose val ues, i n cl u di n g t he uri nar y gl uc ose:creati ni ne rati o will 
be bli n de d t o t he S p o ns or, I n vesti gat or, site, a n d s u bject f or t he d urati o n of t he st u d y u ntil after 
st u d y c o m pleti o n. I n t he e ve nt of a n H b A 1c res ult > 8. 0 % d uri n g t h e L T peri o d ( w he n t hese val ues 
re q uire s u bject resc ue), t he i n vesti gat or will be i nf or me d via a n H b A 1c alert fr o m t he ce ntral 
la b orat or y, b ut will re mai n bli n de d t o t he H b A 1c res ult. 
T he f oll o wi n g secti o ns i n dicate t he la b orat or y tests re q uire d f or t his st u d y. F or c ou ntries usi n g 
c o n ve nti o nal u nits, t he res ults will be re p orte d usi n g c o n ve nti o nal u nits. F or c o u ntries usi n g 
SI u nits, t he res ults will be re p orte d usi n g SI u nits. I n cases of differe nces i n t he u nits as liste d i n 
t his pr ot oc ol c o m pare d t o t he u nits o n t he ce ntral la b orat or y re p orts, t he u nits fr o m t he ce ntral 
la b orat or y re p orts will be use d. 
P R O T O C O L- S P E CI FI C C E N T R A L L A B O R A T O R Y A S S E S S M E N T S:  
 H b A 1c ( %, m m ol/ m ol) 
 F P G ( m g/ d L, m m ol/ L) 
 Fasti n g ser u m li pi d pr ofile:  
 T otal- C ( m g/ d L, m m ol/ L) 
 Calc ulate d L D L- C ( m g/ d L, m m ol/ L) 
 Exce pt scree ni n g peri o d, reflex testi n g will occ ur f or Direct L D L- C if T G > 4 0 0 m g/ d L 
( 4. 5 2 m m ol/ L) 
 H D L- C ( m g/ d L, m m ol/ L) 
 T G ( m g/ d L, m m ol/ L) 
 A nti- Gl uta mic aci d decar b o x ylase ( G A D) a nti b o dies ( n m ol/ L or U/ m L) 
 N ote- t his test m ay als o be re p or te d as eit her p ositive or ne g ative 
 A nti- Pr otei n t yr osi ne p h os p hatase-li ke pr otei n (I A 2) a nti b o dies ( n m ol/ L or U/ m L) 
 N ote- t his test m ay als o be re p or te d as eit her p ositive or ne g ative 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 1 9 
E nr oll me nt- S pecific Refle x Testi n g   
Refle x testi n g refers t o s pecific tests w hic h are o nl y perf or me d w he n t he res ults of pri or tests are 
o utsi de a pre- deter mi ne d ra n ge. 
 T h yr oi d-sti m ulati n g h or m o ne ( T S H) 
 Reflex testi n g: a b n or m al T S H v al ue at e nr oll me nt will be f urt her ev al u ate d by free T 4 
 He patitis Scree n Pa nel:  
 A nti- he patitis C vir us a nti b o d y  
 He patitis B s urface a nti ge n  
 A nti- he patitis A vir us I g M 
 Reflex testi n g: L o w p ositi ve a n d p ositive res ults re q uire c o nfir m at ory testi n g.  
 C- pe pti de  
 Reflex  testi n g  will  o nly  be  perf or me d  i n  ot her wise  eli gi ble  G A D  a n d  
I A 2 a nti b o dy- p ositive s u bjects 
 
S peci alize d Li ver P a nel: 
F or  s u bjects  w h o  are  bei n g  m o nit ore d  fre q ue n tl y  as  a  res ult  of  c o nfir me d  A S T  a n d/ or  
A L T > 3 X U L N, a d diti o nal ce ntral la b orat or y tests will be perf or me d wit hi n 3 da ys of recei pt of 
c o nfir mat or y res ults. T hese la b orat or y tests will st u d y t he p ossi ble ca use s of t he i ncrease d A L T 
a n d/ or A S T a n d/ or T B, a n d ma y i ncl u de, b ut  are n ot li mite d t o, t he f oll o wi n g tests: 
 He patitis A I g M 
 He patitis Bs A g 
 He patitis B C ore A b I g M 
 He patitis C vir us R N A or RI B A 
 He patitis C A b 
 He patitis E I g M 
 E pstei n- Barr vir us ( E B V) I g M A b 
 Lactate de h y dr o ge nase ( L D H) 
 Ga m ma- gl uta m yl-tra ns pe pti dase ( G G T) 
 Car b o h y drate deficie nt tra nsferri n ( C D T) 
 Pr ot hr o m bi n ti me ( P T/I N R) 
 Ir o n Pa nel - ir o n, ferriti n, t otal ir o n bi n din g ca pacit y ( TI B C) 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 0 
 I m m u n ol o g y pa nel i ncl u di n g A nti n uclear A nti b o d y ( A N A), A nti- S m o ot h M uscle A nti b o d y 
( S M A) a n d A nti- Li ver/ Ki d ne y Micr os o mal A nti b o d y ( A nti- L K M) 
 A nti-tiss ue Tra ns gl uta mi nase A nti b o d y 
 
Li ver Disc o nti n u ati o n P a nel: 
F or s u bjects w h o are disc o nti n ue d fr o m t he st u d y as a res ult of s ustai ne d ele vate d li ver safet y 
a b n or malities,  a d diti o nal  ce ntral  la b orat or y  tests  will  be  perf or me d  at  t he  ti me  of  Earl y  
Ter mi nati o n ( E n d- of- Treat me nt) visit. Si milar t o t h e S pecialize d Li ver Pa nel, t hese la b orat or y tests 
will st u d y t he p ossi ble ca uses of t he i ncrease d A L T a n d/ or A S T a n d/ or T B, a n d ma y i ncl u de, b ut 
are n ot li mite d t o, t he f oll o wi n g tests: 
 C yt o me gal o vir us ( C M V) I g M A b 
 Her pes si m ple x vir us ( H S V) 1 a n d 2 
 Cer ul o plas mi n 
 T o x o plas m osis 
 Al p ha- 1 a ntitr y psi n 
F or s pecific details re gar di n g t he S pecialize d Li ver Pa nel a n d t he Li ver Disc o nti n uati o n Pa nel 
la b orat or y tests, refer t o t he Ce ntral La b orat or y Ma n ual f or t his st u d y. 
 
St a n d ar d S afet y L a b or at or y P a nels: 
T a ble A p pe n di x 1:  St a n d ar d S afet y L a b or at or y P a nels 
He m at ol o g y 
 
He m o gl o bi n ( g/ d L, g/ L) 
 
He mat ocrit ( %, V/ V) 
 
Re d bl o o d cell ( R B C) ( x 1 0 6/ U L, x 1 01 2/ L) 
 
R B C c o u nt i n dices:  
 
Mea n cell v ol u me ( M C V) (f L)  
 
Mea n cell he m o gl o bi n ( M C H) ( p g/cell) 
 
Mea n cell he m o gl o bi n c o nce ntrati o n ( M C H C) ( g H b/ d L, g H b/ L) 
 
W hite bl o o d cell c o u nt a n d differe ntial 
 
Platelet c o u nt ( x 1 0 9/ L) 
Ser u m C he mistr y 
 
A S T (I U/ L) 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 1 
T a ble A p pe n di x 1:  St a n d ar d S afet y L a b or at or y P a nels 
 
A L T (I U/ L) 
 
Al kali ne p h os p hatase ( A L K- P) (I U/ L)  
 
T otal bilir u bi n ( m g/ d L, µ m ol/ L) 
 
Ser u m creati ni ne ( Scr) use d t o calc ulate esti mate d gl o mer ular filtrati o n rate (e G F R)  acc or di n g t o t he Sc h warz 
f or m ula as f oll o ws: e G F R ( ml/ mi n/ 1. 7 3 m2) = 0. 4 1 3 *( hei g ht (c ms)/ser u m creati ni ne ( m g/ d L): 
 
*If ser u m creati ni ne c o nce ntrati o n is meas ure d i n SI u nits ( µ m oles/ L), di vi de t his n u m ber b y t he c o n versi o n fact or 
of 8 8. 4 t o get t he SI u nits ( m g/ dl) bef ore i nser ti n g i nt o t he Sc h wartz f or m ula t o calc ulate e G F R. 
Res ults will be re p orte d t o t he sites a n d t he S p o ns or. 
 
S o di u m ( m E q/ L, m m ol/ L) 
 
P otassi u m ( m E q/ L, m m ol/ L) 
 
C hl ori de ( m E q/ L, m m ol/ L) 
 
Calci u m ( m g/ d L, m m ol/ L) 
 
Ma g nesi u m ( m E q/ L, m m ol/ L) 
 
P h os p h or us ( m g/ d L, m m ol/ L) 
 
T otal pr otei n ( g/ d L, g/ L) 
 
Uric aci d ( m g/ d L, µ m ol/ L) 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 2 
T a ble A p pe n di x 1:  St a n d ar d S afet y L a b or at or y P a nels 
Uri ne A n al yses 
 
Creati ni ne 
 
Calc ulate d Uri nar y al b u mi n:creati ni ne rati o ( U A C R) 
 
Uri ne h u ma n c h ori o nic g o na d otr o p hi n ( H C G) pre g na nc y test f or w o me n of c hil d beari n g p ote ntial ( W O C B P) 
( H C G mi ni m u m se nsiti vit y of 2 5 I U/ L; perf or me d at site or at h o me). If a uri ne H C G test is p ositive, a bl o o d 
s peci me n  will  be  o bt ai ne d  a n d  a  ser u m  pre g n a ncy  test  will  be  perf or me d  by  t he  ce ntr al  l a b or at ory  f or  
c o nfir m ati o n. 
 
S p ot uri ne: 
 
Uri nar y gl uc ose:creati ni ne rati o 
 
Uri n al ysis wit h micr osc o p y : 
 
He mat uria 
 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 4 
A P P E N DI X 3  
T A N N E R A S S E S S M E N T S C A L E 
T he Ta n ner Scale (als o k n o w n as Ta n ner Sta gi n g) is a meas ure of  p u bertal de vel o p me nt (se x ual 
mat urati o n) i n c hil dre n a n d a d oles ce nts wit h c o m p o ne nts descri be d f o r eac h se x, rate d se paratel y 
o n a scale of sta ge o ne t o sta ge fi ve. T he sta ges defi ne p h ysical meas ure me nt of de vel o p me nt base d 
o n e xter nal pri mar y a n d sec o n dar y se x ual c haracteristics. Fe males are classifie d wit h re gar d t o 
breast a n d p u bic hair c haracteristic s. Males are classifie d wit h regar d t o ge nitalia  a n d p u bic hair 
c haracteristics. 
A q ualitati ve deter mi nati o n of t he s u bject’s se x ual mat urit y rati n g o n a scale of 1 t o 5 will be 
deter mi ne d  acc or di n g  t o  t h ose  criteria  esta blis he d  b y  Ta n ner  (s u m marize d  i n  Ta bles  1  a n d  
2 bel o w). Base d o n t he le vel of c o mf ort b y t he I n vesti gat or, care gi ver, or st u d y s u bject, t he 
meas ure of se x ual mat urit y ma y be o btai ne d b y 1) vis uall y o bser vi n g t he le vel of de vel o p me nt 
after t he s u bject disr o bes or 2) re q uesti n g t he care gi ver or s u bject p oi nt t o t he le vel of mat urit y 
fr o m a descri pti o n or selecti o n of pict ures t hat e x hi bit t he vari o us sta ges of mat urit y. 
T a ble 1: 
Cl assific ati o n of Se x M at urit y St a ges i n Girls 
St a ge
 P u bic
 
H air
 
Bre asts
 
1
 Prea d olesce nt
  
Prea d olesce nt
 
2 
S parse gr o wt h of l o n g, sli g htl y pi g me nte d d o w n y 
hair, strai g ht or o nl y sli g htl y c urle d; a p pears 
c hiefl y al o n g t he la bia 
Breast b u d sta ge; ele vati o n of breast a n d 
pa pilla as a s mall m o u n d; e nlar ge me nt of 
are ola dia meter 
3  
Dar ker, be gi n ni n g t o c url, i ncrease d a m o u nt 
F urt her e nlar ge me nt of breast a n d are ola wit h 
n o se parati o n of t heir c o nt o urs 
4 
Rese m bles a d ult t y pe b ut t he area c o vere d is still 
c o nsi dera bl y s maller t ha n i n m ost a d ults; n o 
s prea d t o t he me dial s urface of t he t hi g hs 
Pr ojecti o n of are ola a n d pa pilla f or m a 
sec o n dar y m o u n d a b o ve t he le vel of t he 
breast 
5 
A d ult i n q ua ntit y a n d t y pe, s prea d t o me dial 
s urface of t hi g hs 
Mat ure; pr ojecti o n of pa pilla o nl y d ue t o 
recessi o n of t he are ola t o t he ge neral c o nt o ur 
of t he breast 
 
T a ble 2: 
Cl assific ati o n of Se x M at urit y St a ges i n B o ys 
St a ge
 P u bic
 
H air
 
Ge nit ali a
 
1
 N o ne
  
Prea d olesce nt
 
2 
S parse gr o wt h of l o n g, sli g htl y pi g me nte d 
d o w n y hair, strai g ht or o nl y sli g htl y c urle d; 
a p pears c hiefl y at t he base of t he pe nis 
Scr ot u m a n d testes ha ve e nlar ge d; c ha n ge i n 
te xt ure of t he scr otal s ki n wit h s o me re d de ni n g 
3 
Dar ker, c oarser, a n d m ore c urle d; s prea ds 
s parsel y o ver t he j u ncti o n of t he p u bes 
Gr o wt h of t he pe nis, mai nl y i n le n gt h b ut wit h 
s o me i ncrease i n brea dt h; f urt her gr o wt h of 
testes a n d scr ot u m 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 5 
T a ble 2: 
Cl assific ati o n of Se x M at urit y St a ges i n B o ys 
St a ge
 P u bic
 
H air
 
Ge nit ali a
 
4 
Rese m bles a d ult t y pe b ut t he area c o vere d is 
still c o nsi dera bl y s maller t ha n i n m ost a d ults; 
n o s prea d t o t he me dial s urface of t he t hi g hs 
Pe nis f urt her e nlar ge d i n le n gt h a n d brea dt h 
wit h de vel o p me nt of gla ns. Testes a n d scr ot u m 
f urt her e nlar ge d wit h f urt her dar ke ni n g of t he 
scr otal s ki n 
5 
A d ult i n q ua ntit y a n d t y pe, s prea d t o me dial 
s urface of t hi g hs 
A d ult size a n d s ha pe. N o f urt her e nlar ge me nt 
of testes a n d scr ot u m 
 
A d diti o nal materials t o ai d i n  t he Ta n ner Sta ge assess me nt will be pr o vi de d u p o n re q uest. 
 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 6 
A P P E N DI X 4  
D E FI NI TI O N O F M E DI C A TI O N E R R O R 
F or t he p ur p oses of t his cli nical st u d y a me dicati o n err or is a n u ni nte n de d fail ure or mista ke i n t he 
treat me nt pr ocess f or a n Astra Ze neca i n vesti gati o nal pr o d uct t hat eit her ca uses har m t o t he s u bject 
or has t he p ote ntial t o ca use har m t o t he s u bject. 
A me dicati o n err or is n ot lac k of efficac y of t h e i n vesti gati o nal pr o d uct, b ut rat her a h u ma n or 
pr ocess-relate d fail ure w h ile t he i n vesti gati o nal pr o d uct is i n c o ntr ol b y t he st u d y  site staff or 
s u bject. 
Me dicati o n err or i ncl u des s it uati o ns w here a n err or: 
 occ urre d 
 was i de ntifie d a n d i nterce pte d bef ore t he pa rtici pa nt recei ve d t he in vesti gati o nal pr o d uct 
 di d n ot occ ur, b ut circ u msta nces were rec o g nize d t hat c o ul d ha ve le d t o a n err or 
 
E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors: 
 I n vesti gati o nal pr o d uct na me c o nf usi o n 
 Dis pe nsi n g err or, e. g., me dicati o n pre pare d i nc orre ctl y, e ve n if it was n o t act uall y gi ve n t o 
t he s u bject 
 I n vesti gati o nal pr o d uct n ot a d ministere d as i n dicate d, e. g., wr o n g r o ute or wr o n g site of 
a d mi nistrati o n 
 I n vesti gati o nal pr o d uct n ot ta ke n as i n dicate d, e. g., ta blet diss ol ve d i n water w he n it s h o ul d 
be ta ke n as a s oli d ta blet 
 I n vesti gati o nal pr o d uct n ot st ore d as i nstr ucte d, e. g., ke pt i n t he fri d ge w he n it s h o ul d be 
at r o o m te m perat ure 
 Wr o n g s u bject recei ve d t he me dicati o n (e xcl u di n g I V R S/I W R S err ors) 
 Wr o n g i n vesti gati o nal pr o d uct a d mi nistere d t o s u bject (e xcl u di n g I V R S/I W R S err ors) 
 
E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me dicati o n err ors i n cli nical st u dies: 
 Err ors relate d t o or res ulti n g fr o m I V R S/I W R S - i ncl u di n g t h os e t hat lea d t o o ne of t he 
a b o ve liste d e ve nts t hat w o ul d ot he r wise ha ve bee n a me dicati o n err or  
 S u bject acci de ntall y misse d i n ve sti gati o nal pr o d uct d ose(s), e. g., f or g ot t o ta ke me dicati o n 
 Acci de ntal o ver d ose ( will be ca pt ure d as a n o ver d ose) 
 S u bject faile d t o ret ur n u n use d  me dicati o n or e m pt y pac ka gi n g 

Cli nical Pr ot oc ol 
C V 1 8 1 3 7 5 ( D 1 6 8 0 C 0 0 0 1 9) 
B M S- 4 7 7 1 1 8 A N D B M S- 5 1 2 1 4 8 
sa xa gli pti n a n d da pa glifl ozi n 
Re vise d Pr ot oc ol N o: 0 6 
Date: 0 7- Fe b- 2 0 2 2 
1 2 7 
 Err ors relate d t o bac k gr o u n d a n d resc ue me dicati o n, or sta n da r d of care me dicati o n i n 
o pe n-la bel st u dies, e ve n if a n Astra Ze neca pr o d uct 
 Me dicati o n err ors are n ot re gar de d as A Es b ut A Es ma y occ ur as a c o nse q ue nce of t he 
me dicati o n err or 
 

SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 1 6 8 0c 0 0 0 1 9-cs p-a me n d me nt- 6
D oc u me nt Title:
D 1 6 8 0 C 0 0 0 1 9 Cli nical St u d y Pr ot oc ol A me n d me nt 6
D oc u me nt I D:
Versi o n L a bel:
3. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
1 4- Fe b- 2 0 2 2 0 8: 5 5 U T C
C o nte nt A p pr o val
1 4- Fe b- 2 0 2 2 1 5: 0 5 U T C
C o nte nt A p pr o val
1 5- Fe b- 2 0 2 2 0 9: 3 1 U T C
Q ualifie d Pers o n A p pr o val
1 4- Fe b- 2 0 2 2 1 2: 5 7 U T C
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n A N G E L, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.