Conditions: Diabetes Mellitus, Type 2
Keywords: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 256
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine if there will be a greater mean reduction from baseline in glycated hemoglobin (HbA1c) achieved after 26 weeks of oral double-blind add-on therapy of dapagliflozin or saxagliptin compared to placebo in paediatric T2DM patients with HbA1c levels of 6.5 to 10.5% on diet and exercise and metformin, insulin, or metformin plus insulin.

Detailed description:

Arms:
arm 1: Oral route. Start with a low dose of dapagliflozin administered once daily and remain on the low dose regardless of your HbA1c at week 12. arm 2: Oral route. Start with a low dose of Dapagliflozin administered once daily and up titrate to the high dose Dapagliflozin administered once daily if HbA1c \>= 7% at week 12 arm 3: Oral route. Start with a low dose of saxagliptin administered once daily and remain on the low dose regardless of your HbA1c at week 12 arm 4: Oral route. Start with a low dose of saxagliptin administered once daily and up titrate to the high dose if HbA1c \>= 7% at week 12 arm 5: Oral route. Placebo tablets administered for 52 weeks

Interventions: intervention 1: Dapagliflozin intervention 2: Saxagliptin intervention 3: Placebo
Intervention descriptions: intervention 1: Tablets, Oral, 5mg , Once daily Tablets, Oral, 10mg, Once daily intervention 2: Tablets, Oral, 2.5mg Once daily Tablets, Oral, 5mg, Once daily intervention 3: Matching placebo to dapagliflozin 5mg and 10 mg/saxagliptin 2.5 mg and 5 mg, Tablets, oral, Once daily

Protocol document:
SAP_003.pdf: 
Pr ot oc ol N u m b er: D 1 6 8 0 C 0 0 0 1 9  
 
Offici al Titl 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  D ec e m b er  2 0 2 2  


St atistic al A n al ysis Pl a n
St u d y C o de
C V 1 8 1 3 7 5 / D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber
5. 0
Date
0 7 D E C 2 0 2 2
A 2 6 Wee k, M ultice nter, R a n d o mize d, Pl ace b o -C o ntr olle d, D o u ble -Bli n d, 
P ar allel Gr o u p, P h ase 3 Tri al wit h a 2 6 Wee k S afet y E xte nsi o n Peri o d 
E v al u ati n g t he S afet 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 Pe di atric P atie nts wit h T y pe 2 Di a betes 
Mellit us w h o are bet wee n 1 0 a n d bel o w 1 8 ye ars of a ge 






Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4
T A B L E O F C O N T E N T S
P A G E
TI T L E P A G E .......................................................................................................1
SI G N A T U R E O F S T U D Y S T A TI S TI CI A N ........................................................2
SI G N A T U R E O F G L O B A L P R O D U C T S T A TI S TI CI A N ..................................3
T A B L E O F C O N T E N T S .....................................................................................4
LI S T O F A B B R E VI A TI O N S ............................................................................1 3
A M E N D M E N T HI S T O R Y ................................................................................1 7
1.
S T U D Y D E T AI L S .............................................................................................2 0
1. 1
St u d y  o bject i ves................................................................................................. 2 0
1. 1. 1
Pri mar y o bject i ve...............................................................................................2 0
1. 1. 2
Sec o n dar y  o bjecti ves..........................................................................................2 0
1. 1. 3
S af et y o bj ect i ves................................................................................................2 2
1. 1. 4
E x pl or at or y  o bjecti ves .......................................................................................2 2
1. 1. 5
P har mac o ki net ic / P har mac o d y na mic o bjecti ve..................................................2 3
1. 2
St u d y  desi g n ......................................................................................................2 3
1. 3
N u m ber of s u bjects ............................................................................................3 0
1. 4
Bli n di n g a n d u n bli n di n g .....................................................................................3 1
1. 5
Pr ot oc ol  a me n d me nts .........................................................................................3 2
1. 6
Ti mi n g of a nal yses a n d re p orti n g .......................................................................3 6
1. 7
Data m o ni t ori n g c o m mittees ..............................................................................3 6
1. 8
A d j u dicati on c o m mit tees....................................................................................3 6
1. 8. 1
Car di o vasc ular a dj u dicat i on c o m mittee ..............................................................3 6
1. 8. 2
He pati c a dj u dicat i on c o m mit t e e .........................................................................3 6
1. 8. 3
Di a bet ic Ket oaci d osis ( D K A) a dj u dicat i on c o m mit t e e........................................3 7
2.
A N A L Y SI S S E T S .............................................................................................3 7
2. 1
Treat me nt gr o u ps ...............................................................................................3 7
2. 2
Defi nit i on o f a nal ysis sets ..................................................................................3 7
2. 2. 1
E nr olle d S u bjects Data Set .................................................................................3 7
2. 2. 2
Ra n d o mise d S u bjects Data Set ...........................................................................3 7
2. 2. 3
U p -titr atio n Ra n d o mise d S u bjects Data Set ........................................................3 7
2. 2. 4
E val ua ble S u bjects Data Set ...............................................................................3 8
2. 2. 5
Treate d S u bjects Data Set ...................................................................................3 8
2. 2. 6
Ra n d o mise d Wit h dra wal S u bjects Data Set ........................................................3 8
2. 2. 7
P har mac o ki net ic ( P K) A nal ysis Data Set............................................................3 8


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5
2. 3
Vi ol at i ons a n d de viat i ons ...................................................................................3 8
3.
E N D P OI N T S .....................................................................................................4 2
3. 1
Pri mar y efficac y e n d p o i nts.................................................................................4 2
3. 2
Sec o n dar y  efficac y e n d p oi nts .............................................................................4 2
3. 3
E x pl or at or y  efficac y e n d p oi nts...........................................................................4 2
3. 3. 1
E x pl or at or y  efficac y e n d p oi nts f or s h ort ter m assess me nt of da pa glifl ozi n 
a n d sa xa gli pti n...................................................................................................4 3
3. 3. 2
E x pl or at or y  efficac y e n d p oi nts f or s h ort ter m pl us l on g -t er m assess me nt of 
da pa glifl ozi n a n d sa xa gli pti n ..............................................................................4 3
3. 3. 3
E x pl or at or y  efficac y e n d p oi nts f or m o n ot hera p y assess me nt of 
da pa glifl ozi n a n d sa xa gli pti n ..............................................................................4 3
3. 4
S af et y e n d p o i nts................................................................................................. 4 3
3. 4. 1
A d verse e ve nts ...................................................................................................4 3
3. 4. 2
Deat hs ................................................................................................................4 6
3. 4. 3
Ot her safet y e ve nts .............................................................................................4 6
3. 4. 3. 1
Di a bet ic ket oaci d osis .........................................................................................4 6
3. 4. 3. 2
H y p o gl ycae mia ..................................................................................................4 6
3. 4. 4
S af et y La b orat or y  t ests.......................................................................................4 6
3. 4. 4. 1
Pre g na nc y testi n g ...............................................................................................4 7
3. 4. 5
Vi t al si g ns..........................................................................................................4 8
3. 4. 6
Electr ocar di o gra ms ............................................................................................4 8
3. 4. 7
P h ysical e xa mi nat i ons ........................................................................................4 8
3. 4. 8
B o d y  wei g ht, heig ht a n d b o d y  mass i n de x ..........................................................4 8
3. 4. 9
Meas ures of gr o wt h a n d mat urit y .......................................................................4 9
3. 5
Ot her varia bles ...................................................................................................5 0
3. 5. 1
D e m o gra p hic a n d baseli ne c haracterist ic varia bles.............................................5 0
3. 5. 2
Me dical hist or y ..................................................................................................5 3
3. 5. 3
Pri or a n d c o nc o mita nt m e dicat i ons .....................................................................5 3
3. 5. 4
E x p os ure t o st u d y  treat me nt ...............................................................................5 4
3. 5. 5
E x p os ure t o resc ue me dicat i on ...........................................................................5 5
3. 5. 6
Treat me nt c o m plia nce ........................................................................................5 5
3. 6
P har mac o ki net ic/ p har mac o d y na mic assess me nts...............................................5 6
4.
A N A L Y SI S M E T H O D S ....................................................................................5 7
4. 1
Ge neral pri nci ples ..............................................................................................5 7
4. 1. 1
Defi nit i ons .........................................................................................................5 8
4. 1. 2
Desc ript i ve s u m maries of c o nti n u o us varia bles ..................................................5 9
4. 1. 3
Descri pt i ve s u m maries of cate g orical varia bles ..................................................5 9
4. 1. 4
S u m maries of s hift i n cate g orical varia bles ........................................................6 0
4. 1. 5
Treat me nt re gi me ns ............................................................................................6 0
4. 1. 6
Treat me nt a n d d ose assi g n me nts ........................................................................6 1
4. 1. 7
Data s u m maries a n d list i n gs...............................................................................6 1
4. 1. 7. 1
Vi sit wi n d o ws....................................................................................................6 5


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6
4. 1. 7. 2
Ha n dli n g of rescree ne d s u bjects .........................................................................6 8
4. 1. 7. 3
Ha n dli n g of i m pla usi ble gl uc ose res ults .............................................................6 8
4. 1. 8
Missi n g data .......................................................................................................6 8
4. 1. 9
Wei g hte d a nal ysis o f c o varia nce ( A N C O V A) ....................................................6 8
4. 1. 1 0
Pr o p orti o n of  s u bjects wit h a pre-defi ne d c haracterist ic (res p o n ders) at 
Wee k t
...............................................................................................................7 0
4. 1. 1 1
E sti mates f or ti me-t o-e ve nt a nal yses ..................................................................7 1
4. 1. 1 2
M ul tiple i m p utati o n ............................................................................................7 1
4. 1. 1 2. 1
M o n ot o ne Data Patter n .......................................................................................7 2
4. 1. 1 2. 2
Retri e ve d Dr o p -O uts M ult i ple I mp ut ati o n Met h o d .............................................7 3
4. 1. 1 2. 3
Was h -o ut m ul tiple i m p utati o n m et ho d ................................................................7 4
4. 1. 1 2. 4
C o m bi ni n g m ult i ple i m p utati o n res ults...............................................................7 5
4. 1. 1 2. 5
M ul tiple i m p utati o n u n der M A R h y p ot hesis .......................................................7 6
4. 1. 1 2. 6
Ti p pi n g p oi nt a nal ysis ........................................................................................7 6
4. 2
St u d y  p o p ulat i on ................................................................................................7 7
4. 2. 1
S u bject dis p osit i on .............................................................................................7 7
4. 2. 2
Gl o bal/c o u ntr y  sit u atio n i m pact .........................................................................7 8
4. 2. 3
D e m o gra p hic a n d ot her baseli ne c haracterist ics..................................................7 9
4. 2. 4
S pecific a n d ge neral me dical hist or y ..................................................................7 9
4. 2. 5
Pri or a n d c o nc o mita nt m e dicat i ons .....................................................................7 9
4. 3
E xte nt of e x p os ure t o st u d y  treat me nt ................................................................. 8 0
4. 3. 1
E xte nt of e x p os ure t o I P treat me nt ......................................................................8 0
4. 3. 2
E x p os ure t o resc ue me dicat i on ...........................................................................8 0
4. 3. 3
C o m plia nce t o I P treat me nt ................................................................................8 1
4. 4
Pri mar y efficac y e n d p o i nt a nal ysis.....................................................................8 1
4. 4. 1
Pri mar y a nal ysis o f t he pri mar y e n d p o i nt ...........................................................8 1
4. 4. 2
Se nsit i vity a nal ysis f or pri mar y e nd p oi nt ............................................................8 2
4. 4. 2. 1
A nal ysis e xcl u di n g data f oll o wi n g resc ue me dicat i o n i nitiati on/earl y  
treat me nt disc o nt i n uati on ...................................................................................8 2
4. 4. 2. 2
A nal ysis base d o n E val ua ble S u bjects Data Set ..................................................8 3
4. 4. 2. 3
Missi n g data patter ns
.........................................................................................8 3
4. 4. 2. 4
Ti p pi n g p oi nt a nal ysis ........................................................................................8 4
4. 4. 3
S u b gr o u p a nal yses f or pri mar y e n d p oi nt ............................................................8 4
4. 4. 3. 1
A nal ysis of c ha n ge fr o m baseli ne i n H b A 1c at Wee k 2 6 wit hi n s u b gr o u ps.........8 4
4. 4. 3. 2
Metf or mi n s u b gr o u p a nal ysis f or pri mar y a nal ysis of c ha n ge fr o m baseli ne 
i n H b A 1c at Wee k 2 6 .........................................................................................8 5
4. 4. 4
Ot her a nal yses f or pri mar y  e n d p oi nt...................................................................8 5
4. 4. 4. 1
A nal ysis of c ha n ge fr o m baseli ne i n H b A 1c at Wee k 6, Wee k 1 2, a n d 
Wee k 2 0 .............................................................................................................8 5
4. 5
Sec o n dar y  efficac y e n d p oi nt a nal ysis................................................................. 8 5
4. 5. 1
Hi erarc hical Testi n g ...........................................................................................8 5
4. 5. 2
C o m paris o n of m ea n re d uct i on i n H b A 1c fr om 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 ........................8 7


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7
4. 5. 2. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of c ha n ge fr om baseli ne i n 
H b A 1c 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 
pl ace b o e xcl u di n g data f o ll owi n g resc ue me dicat i on i nitiati on/earl y  
treat me nt disc o nt i n uati on ...................................................................................8 7
4. 5. 2. 2
S u b gr o u p a nal ysis f or sec o n dar y  e n d p oi nt of c ha n ge fr om baseli ne i n 
H b A 1c 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 
pl ace b o ..............................................................................................................8 7
4. 5. 2. 3
Metf or mi n s u b gr o u p a nal ysis f or pri mar y a nal ysis of sec o n dar y e n d p oi nt 
of  c ha n ge fr o m baseli ne i n H b A 1c 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 7
4. 5. 3
C o m paris o n of m ea n re d uct i on i n H b A 1c fr om 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 pl ace b o ........................................8 8
4. 5. 3. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of mea n re d ucti o n i n H b A 1c 
fr om baseli ne at Wee k 2 6 bet wee n t he l ow- d ose treat me nt re gi me n a n d 
pl ace b o e xcl u di n g data f o ll owi n g resc ue me dicat i on i nitiati on/earl y  
treat me nt disc o nt i n uati on ...................................................................................8 8
4. 5. 3. 2
Metf or mi n s u b gr o u p a nal ysis f or sec o n dar y e n d p oi nt of c ha n ge fr o m 
baseli ne i n H b A 1c 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 ........................................................................................................8 8
4. 5. 4
C o m paris o n of m ea n re d uct i on i n F P G fr om baseli ne at Wee k 2 6 bet wee n 
o verall dr u g treat me nt a n d place b o .....................................................................8 8
4. 5. 4. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt 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 a n d place b o e xcl u di n g 
data f oll o wi n g resc ue me dicat i on i nitiati on/earl y  tr e at me nt disc o nti n uati on .......8 9
4. 5. 4. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of mea n re d uct i on i n F P G 
fr om baseli ne at Wee k 2 6 bet wee n o verall dr u g treat me nt a n d place b o ...............8 9
4. 5. 4. 3
Missi n g data patter ns
.........................................................................................8 9
4. 5. 5
C o m paris o n of m ea n re d uct i on i n F P G fr om baseli ne at Wee k 2 6 bet wee n 
t he lo w -d ose/ hi g h -d ose treat me nt re gi me n a n d place b o ......................................8 9
4. 5. 5. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt 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 m e nt re gi me n 
a n d place b o e xcl u di n g data f o ll owi n g resc ue me dicati o n i nit iati on/earl y  
treat me nt disc o nt i n uati on ...................................................................................8 9
4. 5. 6
C o m paris o n of m ea n re d uct i on i n F P G fr om baseli ne at Wee k 2 6 bet wee n 
t he lo w -d ose treat me nt re gi me n a n d place b o ......................................................9 0
4. 5. 6. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt 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 
e xcl u di n g data f o ll owi n g resc ue me dicat i on i nitiati o n/earl y treat me nt 
di sc o nti n uati on ...................................................................................................9 0
4. 5. 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 % at Wee k 2 6 bet wee n o verall dr u g treat me nt 
a n d place b o ........................................................................................................9 0
4. 5. 7. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of perce nta ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n o verall dr u g treat me nt 
a n d place b o ........................................................................................................9 1


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8
4. 5. 7. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of perce nta ge of s u bjects 
wi t 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 2 6 
bet wee n o verall dr u g treat me nt a n d place b o .......................................................9 1
4. 5. 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 % 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 ...........................................................................9 1
4. 5. 8. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of perce nta ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % 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 ...........................................................................9 1
4. 5. 8. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of perce nta ge of s u bjects 
wi t 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 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 ........................9 2
4. 5. 9
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 % 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 ..........................................................................................9 2
4. 5. 9. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of perce nta ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % 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 ..........................................................................................9 2
4. 5. 9. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of perce nta ge of s u bjects 
wi t 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 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 ........................................9 2
4. 5. 1 0
C o m paris o n of m ea n re d uct i on i n H b A 1c fr om 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 ....................................................................................9 3
4. 5. 1 0. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt of mea n re d ucti o n i n H b A 1c 
fr om 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 e xcl u di n g data 
f oll owi n g resc ue me dicat i on i nitiati on/earl y  treat me nt disc o nti n uati on ...............9 3
4. 5. 1 0. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of m ea n re d uct i on i n H b A 1c 
fr om 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 ...................................9 3
4. 5. 1 1
C o m paris o n of m ea n re d uct i on i n F P G fr om 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 ................................................................................................9 4
4. 5. 1 1. 1
Se nsit i vity a nal ysis f or sec o n dar y e n d p oi nt 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 o se 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 e xcl u di n g data f o ll owi n g 
resc ue me dicatio n i ni tiatio n/earl y treat m e nt disc o nti n uati on ...............................9 4
4. 5. 1 1. 2
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of mea n re d uct i on i n F P G 
fr om 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 ...................................9 4
4. 5. 1 2
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 % at Wee k 2 6 bet wee n t h e hi g h-d ose a n d t he 
l ow- 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 ................9 5
4. 5. 1 2. 1
Metf or mi n s u b gr o u p a nal ysis f or c o mparis o n of t he perce nta ge of s u bjects 
wi t 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 2 6 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9
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 ....................................................................................9 5
4. 6
E x pl or at or y  efficac y a nal yses.............................................................................9 5
4. 6. 1
E x pl or at or y  efficac y e n d p oi nts f or s h ort-t er m peri o d..........................................9 5
4. 6. 1. 1
A nal ysis of s u bjects re q uiri n g gl ycae mic resc ue me dicat i on or 
di sc o nti n ui n g st u d y me dicat i on d ue t o lac k o f effic ac y .......................................9 6
4. 6. 1. 2
Ti me t o gl ycae mic resc ue me dicat i on or disc o nt i n uati o n of st u d y 
me dicat i on d ue t o l ac k of efficac y ......................................................................9 6
4. 6. 1. 3
Perce nta ge of s u bjects w h o i nit iate gl ycae mic resc ue me dicati on .......................9 6
4. 6. 2
E x pl or at or y  efficac y e n d p oi nts f or s h ort-t er m a n d l o n g-t er m p erio d ...................9 6
4. 6. 2. 1
A nal ysis of c ha n ge fr o m baseli ne at Wee k 5 2 i n H b A 1c a n d F P G ......................9 7
4. 6. 2. 2
A nal ysis 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 H b A 1c le vel < 7 % at Wee k 5 2 ............................................................9 7
4. 6. 2. 3
A nal ysis of s u bjects re q uiri n g gl ycae mic resc ue me dicat i on or 
di sc o nti n ui n g st u d y me dicat i on d ue t o lac k o f effic ac y .......................................9 8
4. 6. 2. 4
Ti me t o gl ycae mic resc ue me dicat i on or disc o nt i n uati o n of st u d y 
me dicat i on d ue t o l ac k of efficac y ......................................................................9 8
4. 6. 2. 5
Perce nta ge of s u bjects w h o i nit iate gl ycae mic resc ue me dicati on .......................9 8
4. 6. 3
E x pl or at or y  efficac y a nal yses f or m o n ot hera p y assess me nt d uri n g t he 
ra n d omise d wit h dra wal peri o d ...........................................................................9 8
4. 6. 3. 1
O bser ve d a n d c ha n ge fr o m wi t hdra wal baseli ne i n H b A 1c a n d F P G ..................9 9
4. 6. 3. 2
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 % at t he 
e n d of t he wit h dra wal peri o d ..............................................................................9 9
4. 6. 3. 3
Ti me t o gl ycae mic resc ue me dicat i on or disc o nt i n uati o n of st u d y 
me dicat i on d ue t o l ac k of efficac y ......................................................................9 9
4. 6. 3. 4
Perce nta ge of s u bjects w h o i nit iate gl ycae mic resc ue me dicati on .......................9 9
4. 7
S af et y .................................................................................................................9 9
4. 7. 1
A d verse e ve nts ................................................................................................. 1 0 1
4. 7. 1. 1
All a d verse e ve nts ............................................................................................1 0 1
4. 7. 1. 2
Deat hs ..............................................................................................................1 0 4
4. 7. 1. 3
S eri o us a d verse e ve nts .....................................................................................1 0 4
4. 7. 1. 4
A d verse e ve nts lea di n g t o disc o nt i n uati on of st u d y me dicat i on ........................1 0 5
4. 7. 2
Ot her safet y a nal ys es .......................................................................................1 0 6
4. 7. 2. 1
A m p utati o n ......................................................................................................1 0 6
4. 7. 2. 2
A d j u dicate d Dia betic ket oaci d osis ( D K A)........................................................1 0 6
4. 7. 2. 3
Car di o vasc ular a n d he pat ic a dj u dicate d e ve nts.................................................1 0 6
4. 7. 2. 4
H y p o gl ycae mia ................................................................................................1 0 6
4. 7. 3
La b orat or y  e val uati ons .....................................................................................1 0 7
4. 7. 3. 1
S af et y lab orat or y  para meters o ver ti me ............................................................1 0 8
4. 7. 3. 2
Ele vate d li ver f u nct i on tests .............................................................................1 0 9
4. 7. 3. 3
Ele vate d li ver tests a n d/ or re p orte d he patic a d v erse e ve nts ...............................1 1 0
4. 7. 3. 4
Mar ke d l a b orat or y a b n or malities ......................................................................1 1 0
4. 7. 3. 5
Fast i n g li pi d pa nel............................................................................................1 1 1
4. 7. 3. 6
Pre g na nc y test res ults .......................................................................................1 1 1
4. 7. 4
Vi t al si g ns........................................................................................................1 1 1


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0
4. 7. 5
Electr ocar di o gra ms ..........................................................................................1 1 1
4. 7. 6
B o d y  wei g ht, heig ht a n d B MI ..........................................................................1 1 2
4. 7. 7
Meas ures of gr o wt h a n d mat urit y .....................................................................1 1 2
4. 7. 7. 1
Ta n ner sta ges ...................................................................................................1 1 2
4. 7. 7. 2
P u bert y stat us...................................................................................................1 1 3
4. 7. 7. 3
Gr o wt h a n d mat urit y mar kers ...........................................................................1 1 3
4. 7. 7. 4
B o ne bi o mar kers ..............................................................................................1 1 3
4. 8
P har mac o ki net ic a nal yses.................................................................................1 1 4
4. 9
P har mac o d y na mic a nal yses ..............................................................................1 1 4
4. 1 0
Si te 4 9 1 0..........................................................................................................1 1 4
5.
I N T E RI M A N A L Y S E S ( N O T A P P LI C A B L E) ................................................1 1 5
6.
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L ...........................................1 1 5
7.
R E F E R E N C E S ................................................................................................1 1 6
8.
A P P E N DI X .....................................................................................................1 1 8
8. 1
Fl o w c hart/ti me a n d e ve nts sc he d ule ................................................................1 1 8
8. 2
Ha n dli n g missi n g or partial e ve nt dates ............................................................1 3 1
8. 3
Ha n dli n g missi n g or partial me dicat i on dates (e xcl u di n g resc ue i ns uli n) ..........1 3 2
8. 4
Ha n dli n g missi n g or partial me dicat i on dates (resc ue i ns uli n o nl y) ...................1 3 3
8. 5
Ha n dli n g missi n g or partial T 2 D M dia g n osis dates ..........................................1 3 3
8. 6
Deri vi n g a ge at eac h visit .................................................................................1 3 4
8. 6. 1
A ge use d t o deri ve n or malise d hei g ht, b o d y  wei g ht a n d B MI e x presse d as 
z- sc ore .............................................................................................................1 3 4
8. 7
Cli nic al la b orat or y varia bles .............................................................................1 3 5
8. 7. 1
Mar ke d a b n or malit y crit eri a for safet y la b orat or y v aria bles ..............................1 3 5
8. 8
S u b gr o u ps ........................................................................................................1 3 7
8. 9
Cl assificat i on of h y p o gl ycae mia e pis o des ........................................................1 3 7
8. 1 0
P u bert y stat us a n d hei g ht vel ocity use d t o cate g orise gr o wt h a n d 
mat urati o n m ar kers as well as b o ne bi o mar kers ................................................1 3 9
8. 1 0. 1
Ta n ner sta gi n g ................................................................................................. 1 3 9
8. 1 0. 2
H ei g ht vel o ci t y................................................................................................. 1 4 0
8. 1 0. 3
P u bert y stat us...................................................................................................1 4 0
8. 1 1
Ge o gra p hical re gi o ns .......................................................................................1 4 1
8. 1 2
Re p orti n g c o n ve nt i ons .....................................................................................1 4 1
8. 1 3
Treat me nt prese ntati o n f or ta bles a n d fi g ures ...................................................1 4 2
8. 1 4
O ver vie w of pri mar y a n d se nsit i vity efficac y a nal yses .....................................1 4 5
8. 1 5
O ver vie w of pri mar y a n d se nsit ivi t y s af et y a nal yses.........................................1 6 0


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1
LI S T O F T A B L E S
Ta ble 1 Pr ot oc ol Hist or y ....................................................................................................3 2
Ta ble 2 List of rele va nt pr ot oc ol de viat i ons d uri n g t he S T peri o d .......................................3 9
Ta ble 3 List of rele va nt pr ot oc ol de viat i ons d uri n g t he S T + L T peri o d ................................4 1
Ta ble 4 List of I m p orta nt Pr ot oc ol De viat i ons ....................................................................4 1
Ta ble 5 De m o gra p hic a n d Baseli ne C haracterist ics ............................................................5 1
Ta ble 6 Di a betes-Relate d Baseli ne C haracterist ics .............................................................5 2
Ta ble 7 Baseli ne Re nal F u ncti o n C haracterist ics ................................................................5 2
Ta ble 8 C ut -off dates f or a nal yses b y a nal ysis t y pe a n d st u d y  p eri o d ..................................6 3
Ta ble 9 Vi sit wi n d o ws f or S T perio d assess me nts ..............................................................6 6
Ta ble 1 0 Visit wi n d o ws f or L T peri o d a n d p ost -stu d y ( Wee k 1 0 4) assess me nts .................6 6
Ta ble 1 1 Visit wi n d o ws f or ra n d o mise d wit h dra wal peri o d assess me nts .............................6 7
Ta ble 1 2 C ha n ges of a nal ysis fr o m pr ot oc ol .....................................................................1 1 5
Ta ble 1 3 Scree ni n g pr oce d ural o utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) ...............................1 1 8
Ta ble 1 4 S h ort -t er m pr oce d ural o utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9]) .............................1 2 0
Ta ble 1 5 L o n g -t er m pr oce d ural o utli ne ( C V 1 8 1 3 7 5 [ D 1 6 8 0 C 0 0 0 1 9])..............................1 2 4
Ta ble 1 6 Earl y treat me nt disc o nt i n uati on ( E T D) f oll o w -u p n o n -treat me nt p hase..............1 2 8
Ta ble 1 7 P har mac o ki net ic/ P har mac o d y na mic sa m pli n g sc he d ule.....................................1 3 0
Ta ble 1 8 Mar ke d la b orat or y  a b n or malities .......................................................................1 3 5
Ta ble 1 9 S u b gr o u ps a nal yses ...........................................................................................1 3 7
Ta ble 2 0 Cl assificat i on of h y p o gl ycae mia e pis o des ..........................................................1 3 7
Ta ble 2 1 Ta n ner sta gi n g criteria .......................................................................................1 3 9
Ta ble 2 2 Ge o gra p hic Re gi o ns ..........................................................................................1 4 1
Ta ble 2 3 O ver vie w of pri mar y a n d se nsitivi t y efficac y a nal yses.......................................1 4 5
Ta ble 2 4 O ver vie w of pri mar y  a n d se nsitivi t y s afet y a nal yses ..........................................1 6 0
LI S T O F FI G U R E S
Fi g ure 1 Sc he mat ic of gr o u p c o m paris o ns i n st u d y pri mar y a n d sec o n dar y o bjecti ves........2 2


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2
Fi g ure 2 St u d y  desi g n sc he matic f or s u bjects n ot u n der g oi n g ra n d o mise d with dra wal 
of  bac k gr o u n d me dicat i on at Wee k 3 2 or Wee k 4 0 .............................................2 7
Fi g ure 3 St u d y  desi g n sc he matic f or s u bjects u n der g oi n g ra n d omise d wit h dra wal o f 
bac k gr o u n d me dicat i on at Wee k 3 2 or Wee k 4 0 .................................................2 8
Fi g ure 4 S u b gr o u ps f oll o wi n g t he t hir d ra n d o misati o n at Wee k 3 2 or Wee k 4 0 ..................2 9


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3
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 D ia betes A ss ociat i on
A E
A d verse e ve nt
A E O SI
A d verse e ve nt of s pecial i nterest
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A N A
A nt i n uclear A nti b o d y
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 nsfer ases
C
A nat o mical t hera pe ut ic c he mical (classificati on)

Astra Z e neca
B MI
B o d y  mass i n de x
B P
Bl o o d press ure
B U N
Bl o o d Urea Ni tr o g e n
C D C
Ce nters f or Disease C o ntr ol a n d Pre ve nt i on
C D T
Car b o h y drate deficie nt tra nsferri n
CI
C o nfi de nce i nter val
C M V
C y t o me galo vir us
C K
Creati ne Ki nase
C R F
Case re p ort f or m
C S R
Cli nical st u d y  re p ort 
C T X - 1
Car b o x yter mi nal cr oss -li n ke d tel o pe pti de of T ype 1 c olla ge n
C V
C oefficie nt of Variati o n
DI LI
Dr u g -i n d uce d li ver i nj ur y
D K A
Di a bet ic ket oaci d osis
D M C
Data m o ni t ori n g c o m mittee
D P P - 4
Di pe pt i dyl- p e pti dase - 4
E B V
E pstei n -Barr vir us


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4
Ter m
Defi niti o n
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
e G F R
Esti mate d gl o mer ular filtrati o n rate
E M A
E ur o pea n Me dici nes A ge nc y
E T D
Earl y treat m e nt disc o nti n uatio n
F S H
F o llicle sti m ulati n g h or m o ne
F P G
Fast i n g plas ma gl uc ose
G A D
Gl uta mic aci d decar b o x ylase
G G T
Ga m ma -gl uta m yl -tra ns pe ptidase
H A V
He pati tis A vir us
H b A 1c
Gl yc os ylate d h ae mo gl o bi n
H Bs A g
He pati tis B s urface a nti ge n
H C G
Beta -h u ma n c h ori o nic g o na d otr o pi n
H C O 3
Bi car b o nate
H C V
He pati tis C vir us
H D L
Hi g h de nsi t y li p o pr otei n
H S V
Her pes Si m ple x Vir us
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 di n g pr otei n- 3
I P
I n vesti gati onal pr o d uct
I R
I mme diate release
I S P A D
I nter nati o nal S ociety of  Pae diatri c a n d A d olesce nt Dia betes
I T T
I nte nt-t o-treat
I U
I nter nati o nal u nit
I WR S
I nteracti ve we b/ v oice rec o g nitio n s yste m
K
P otassi u m
L D H
Lactate de h y dr o ge nase
L D L
L o w de nsit y li p o pr otei n
L H
L ut ei nizi n g h or m o ne
L K M
Li ver/ Ki d ne y Micr os o mal A nt i b o d y
L L N
L o wer li mit of n or mal


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5
Ter m
Defi niti o n
L L O Q
L o wer Li mit of q ua nt ificati o n
L S Mea ns
Least s q uares mea ns
L T
L o n g -t er m
M A
Mar ke d a b n or malit y 
M A R
Missi n g at ra n d o m
M C M C
Mar k o v C hai n M o nte Carl o
Me d D R A
Me dical dict i onar y  for r e g ul at or y affairs
MI
M ul tiple i m p utati o n
MI -R D
M ul tiple i m p utati o n retri e ve d dr o p-o uts
MI -W O
M ul tiple i m p utati o n w as h - o ut
M N A R
Missi n g n ot at ra n d o m
Na
S o di u m
O R
O d ds rati o
P K
P har mac o ki net ic
P O 4
P h os p hate
Pre T x
Pre -treat me nt
P T
Preferre d ter m
P T H
Parat h y r oid h or m o ne
P T/I N R
Pr ot hr o m bi n t i me
R B C
Re d bl o o d cell
R P D
Rele va nt pr ot oc ol de viat i on
S A E
S eri o us a d verse e ve nt
S A P
Stati stical a nal ysis pla n
S C S M
S u p pl y  C hai n St u d y Ma na ge me nt
S D
Sta n dar d de viat i on
S E
Sta n dar d err or
SI
Sta n dar d I nter nati o nal ( u nit)
S M A
A nt i-S m o ot h M uscle A nt i b o d y
S M B G
Self -m o nit ori n g bl o o d gl uc ose
S O C
S y st e m or ga n class
S T
S h ort -t er m


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6
Ter m
Defi niti o n
S T + L T
S h ort -t er m + lo n g -t er m
T B
T ot al  bilir u bi n
T 2 D M
T y pe 2 di a betes mellit us
TI B C
T ot al  iro n  bi n di n g ca pacit y
T S H
T h y r oid st i m ulati n g h or m o ne
U A C R
Uri nar y  al b u mi n t o creati ni ne rati o
U L N
U p per li mit of n or mal
U S/ U S A
U nite d States of A merica
W B C
W hite bl o o d cell
W O C B P
W o me n of c hil d beari n g p ote ntial
W H O D D
W o rld heal t h or ga nisat i on dr u g di ctio n ar y
X R
E xte n de d release


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7
A M E N D M E N T H I S T O R Y
Versi o n/ D ate
Brief descri pti o n of c h a n ge
V 1. 0 2 6 J u ne 2 0 1 8
I nitial S A P a p pr o ve d
V 2. 0 0 1 N o ve m ber
2 0 1 9
A d diti o n 
of ra n d o mise d wit h dra wal 
peri o d a n d e x pl orat or y a nal yses f or 
s u bjects w h o are ra n d o mise d t o wit h dra w bac k gr o u n d metf or mi n
A d diti o n of wei g hte d a nal yses d uri n g t he c o mbi ne d s h ort-term a n d l o n g-t er m 
peri o d t o acc o u nt f or s u bjects w h o u n d er g o t he t hir d ra n d o misati o n
A d diti o n of e x pl orat or y ti me t o eve nt e n d p oi nts d uri n g t he s h ort-t er m a n d the 
c o m bi ne d s h ort ter m a n d l o n g-t er m peri o d relati ve t o ti me t o r esc ue me dicati o n 
i nitiati o n or disc o nti n uati o n fr o m stu d y me dicati o n d ue t o lac k of efficac y 
Re m o v al of a nal yses base d o n mi xe d m o del f or re peate d meas ures
A d diti o n of a m p utati o n a nal ysis
V 2. 1 1 2 Fe br uar y 
2 0 2 1
U p dates t o i nc or p orate pr ot oc ol a me n d me nt # 5
A d diti o n of Wee k 1 0 4 a nal yses prese nte d b y ori gi nal treat me nt
A d diti o n of XI G D U O ™ ( da pa glifl ozi n/ metf or mi n) s u b gr o u p a nal yses
A d diti o n of gl o bal/c o u ntr y sit uati o n a nal yses
U p date t o c o m plia nce deri vati o n t o ha n dle kits n ot ret ur ne d
A d diti o n of e x p os ure a n d c o m plia nce se nsiti vit y a nal yses acc o u nti n g f or 
i nterr u pti o ns
U p date t o se nsiti vit y a nal yses usi n g t he E val ua ble S u bjects Data Set t o e xcl u de 
r ec or ds c ollecte d after r esc ue me dicati o n 
i nitiati o n or earl y treat me nt 
disc o nti n uati o n
A d diti o n of ti p pi n g p oi nt a nal ysis f or t he pri mar y efficac y e n d p oi nt H b A 1c
A d diti o n of deri vati o n f or selectin g t he F P G r ec or d at eac h visit f or use i n t he 
sec o n dar y efficac y a nal ysis
A d diti o nal a nal yses a d de d f or i nci de nce rate of ma r ke dl y a b n or ma l la b orat or y 
r es ults
A d diti o nal a nal yses a d de d f or gr o wt h a n d ma t urati o n ma r kers a n d b o ne 
bi o mar kers i n SI u nits
A d di ti o n of deri vati o n f or hei g ht vel ocit y i m p utati o n
A d diti o n of treat me nt prese ntati o n f or ta bles a n d fi g ures a p pe n di x
F or mat u p dates t o ali g n wit h Da pa glifl ozi n c o n ve nti o ns g ui de


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 8
Versi o n/ D ate
Brief descri pti o n of c h a n ge
V 2. 2 2 9 Marc h 
2 0 2 1
Re m o val of acc o u nti n g f or i nterr u pti o n c o m plia nce a n d e x p os ure a nal yses
A d diti o nal i nf or mati o n o n h o w t o c h o ose b e t wee n t h e MI -R D or MI -W O 
met h o ds a n d s pecifie d t hat t he met h o d will be c o nsiste nt f or eac h e n d p oi nt b ut 
ca n differ bet wee n treat me nts
C ha n ge of see d us e d f or m u lti ple i m p utati o n a n d n u m ber of i m p utati o ns 
re d uce d fr o m 1, 0 0 0 t o 2 0 0
A d diti o n of deri vati o n t o c ut off t he L T peri o d a n d P ost ter m f oll o w -u p p e ri o d 
w he n t he Wee k 5 6 visit was misse d
C ha n ge of s plit of A E s u m maries a n d listi n gs f or t he S T + L T a n d Wee k 1 0 4 
f oll o w-u p peri o ds
A d diti o n of Resc ue I ns uli n partial start a n d e n d date i m p utati o n
V 3. 0 2 5 J u ne 2 0 2 1
A d diti o n of deri vati o n t o c ut off t he assess me nts a n d e ve nts t hat occ urre d o n or 
bef or e t he Wee k 3 2 visit w he n t he Wee k 3 2 visit was misse d f or t he se nsiti vit y 
a nal yses t hat use data u p t o We e k 3 2 t o e x cl u de data fr o m t he ra n d o mise d 
wit h dra wal a nal yses
C ha n ge t o Wee k 3 2 a n d Wee k 4 0 visit wi n d o w f or t he L T peri o d t o use t he t hir d 
ra n d o misati o n treat me nt start date as t he c ut off (if a p plica ble)
V 3. 1 2 7 Ja n uar y
2 0 2 2
U p dates t o i nc or p orate pr ot oc ol a me n d me nt # 6
Pri mar y efficac y e n d p oi nt u p date d t o use o verall treat me nt a n d t he s ec o n dar y 
efficac y e n d p oi nts wer e 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
S a m p le size s ecti o n was u p date d
Al p ha was u p date d t o be 0. 0 5 a n d 9 7. 5 % c o nfi de nce i nter vals re m o ve d fr o m 
efficac y a nal yses
E x p os ure b y act ual d ose a n d treat me nt ta ke n s u m maries a d de d
A d diti o n of der i vati o n of s u b gro u p b y treat me nt i nteracti o n p -val ue f or i m p ute d 
data
U p date t o or der of se nsiti vit y a nal yses f or pri mar y e n d p oi nt
U p date t o metf or mi n s u b gr o u p a nal yses
Ali g n me nt bet wee n m o del use d f or c o x pr o p orti o nal -hazar ds a n d Ka pla n -M e i er 
l o g ra n k t o i ncl u de stratificati o n fact ors
V 4. 0 0 9 Fe br uar y 
2 0 2 2
Pr ot oc ol a me n d me nt # 6 date i ncl u de d
U p versi o ne d f or si g nat ures


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 9
Versi o n/ D ate
Brief descri pti o n of c h a n ge
V 4. 1 2 1 N o ve m ber 
2 0 2 2
C ha n ge of treat me nt prese ntati o n f or P K a nal ysis t o use t he hi g hest d os e 
r ecei ve d i n t he S T peri o d 
A d diti o n 
of S T peri o d a nal yses f or s u bject dis p ositi o n r elate d t o t he
gl o bal/c o u ntr y sit uati o n a nal ysis a n d I P Ds
U p date t o r eas o ns f or e x cl usi o ns f or t he ra n d o mise d wit h dra wal s u bjects data 
set t o acc o u nt f or s u bjects w h o were u na ble t o g o t hr o u g h t he 3 r d ra n d o misati o n 
d ue t o t he pr ot oc ol a me n d me nt n ot bei n g a p pr o ve d
A d diti o nal c o nc o mita nt me dicati o n a nal ysis bet wee n Wee k 5 6 a n d Wee k 1 0 4
U p date t o c o m plia nce w or di n g w here c o m plia nce ca n n ot be calc ulate d
A d diti o n al r etrie ve d dr o p-o ut a nal ysis f or H b A 1c a n d F P G f or t he S T peri o d
A d diti o nal F P G missi n g data s u m mar y
U p date t o c o m m o n P T A E
S T + L T peri o d ta ble prese ntati o n t o i ncl u de 
i nci de nce rate a n d a d diti o n of metf or mi n s u b gr o u p a nal ysis
A d diti o n of listi n gs of preferre d t er ms use d i n t h e selecti o n of A E O SIs a n d 
C O VI D -1 9 relate d A Es
U p date t o D K A e ve nts secti o n t o clarif y t hat t hese are s us pecte d D K A e ve nts
A d diti o n of listi n gs f or a d diti o nal data c ollecte d d uri n g t he Wee k 1 0 4 f oll o w-
u p peri o d
V 5. 0 0 7 Dece m ber 
2 0 2 2
C ha n ges of a nal ysis fr o m pr ot oc ol secti o n c o m plete d
U p versi o ne d f or si g nat ures


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 0
1.
S T U D Y D E T AI L S
T his st atistical anal ysis pla n ( S A P) descri bes t he statistical met h o ds t o be use d d uri n g t h e 
re p orti n g a n d a nal yses of  data c o llecte d u n der Astra Ze neca
( A Z) Pr ot oc ol C V 1 8 1 3 7 5
( D 1 6 8 0 C 0 0 0 1 9). T hi s S A P s h o uld be rea d i n c o nj u nct i on wi t h the st u d y pr ot oc ol an d case
re p ort f or m (C R F). T he versi o n of  this S A P has bee n de vel o pe d usi n g Re vise d Pr ot oc ol  Nu m ber 
0 6 date d 0 7 Fe br uar y 2 0 2 2 , a n d versi o n 4 . 0 of  the C R F date d 2 4 Fe br uar y 2 0 2 1 . A n y f urt her 
c ha n ges t o t he pr ot oc ol or C R F ma y necessitate u p dates t o t he S A P.
1. 1
St u d y o bjecti ves
1. 1. 1
Pri m ar y o bjecti ve
T o deter mi ne if t here will  be a greater mea n 
re d uctio n fr om 
baseli ne i n gl yc os ylate d 
ha e mo gl o bi n (H b A 1c ) ac hie ve d aft er 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 mpare d t o place b o i n pae diatric T y p e 2 dia betes 
mellit us (T 2 D M ) s u bjects wi t h Hb A 1c le vels of 6. 5 t o 1 0. 5 % o n di et a n d e xercise a n d 
met f 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.
1. 1. 2
Sec o n d ar y o bjecti ves
(a)
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 H b A 1c ac hie ve d 
aft er 2 6 wee ks of  oral d o u bl e- bli n d a d d- o n t hera p y of da pa glifl o zi n 5 m g 
or 
sa xa gli pti n 2. 5 m g ( wit h titr atio n t o t h e hi g h -d ose f or t hose w h o d o n ot ac hie ve t h e 
gl ycae mic t ar g et of  Hb A 1c < 7 % at 1 2 wee ks) c o mpare d t o place b o i n pae diatric
T 2 D M s u bjects wi t h Hb A 1c le vels of  6. 5 t o 1 0. 5 % o n di et a n d e xercise a n d 
met f 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 ba seli ne H b A 1c ac hie ve d 
aft er 2 6 wee ks of  or al do u bl e- 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 pla c e b o i n pae di atric 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 met f or mi n (I R or X R), i ns uli n, or 
met f or mi n (I R or X R) pl us i ns uli n.
(c)
T o c o m p are mea n re d ucti on fr om baseli ne of  Hb A 1c at Wee k 2 6 ac hie ve d w hile 
r e mai ni n g o n t he l ow- d ose dr u g ( da pa glifl ozi n 5 m g or sa xa gli pti n 2. 5 m g) vers u s 
u p- titr atio 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 mo n gst 
pae di atric T 2 D M s u bjects o n diet a n d e xercise a n d met f or mi n (I R or X R), i ns uli n, or 
met f 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 me a n re d uctio n fr om baseli ne i n Fast i n g 
Pl as 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 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 mpare d t o place b o i n 
pae di atric T 2 D M s u bjects wi t h Hb A 1c of  6. 5 t o 1 0. 5 % o n di et a n d e xercise a n d 
met f 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. 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 1
(e)
T o deter mi ne if t here will be a greater mea n re d uctio n fr o m baseli ne F P G ac hie ve d 
aft er 2 6 wee ks of  oral d o u bl e- bli n d a d d- o n t hera p y of da pa glifl o zi n 5 m g 
or 
sa xa gli pti n 2. 5 m g ( wit h titr atio n t o t h e hi g h -d ose f or t hose w h o d o n ot ac hie ve t h e 
gl ycae mic t arget of  Hb A 1c < 7 % at 1 2 wee ks) c o mpare d t o place b o i n pae diatric
T 2 D M s u bjects wi t h Hb A 1c le vels of  6. 5 t o 1 0. 5 % o n di et a n d e xercise a n d 
met f 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 uctio n fr o m baseli ne F P G ac hie ve d 
aft er 2 6 wee ks of  or al do u bl e- 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 pae di atric 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 met f or mi n (I R or X R), i ns uli n, or 
met f 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 uctio n fr o m baseli ne of  FP G at Wee k
2 6 ac hie ve d w hile 
r e mai ni n g o n t he l ow- 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- titr atio 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 mo n gst  
pae di atric T 2 D M s u bjects o n diet a n d e xercise a n d met f or mi n (I R or X R), i ns uli n, or 
met f 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 per ce nta ge of  su bjects wi t h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n 
H b A 1c 
le vel < 7 % aft er 2 6 wee ks 
of  oral d o u bl e-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 doses a n d re gi me ns c o m bi n e d]) vers us place b o i n pae 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 met f 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  su bjects wi t h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n 
H b A 1c 
le vel < 7 % aft er 2 6 wee ks 
of  oral d o u bl e- 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 hose 
w h o d o n ot ac hie ve t he gl ycae mic tar get of  Hb A 1c < 7 % at 1 2 wee ks) vers us place b o  
i n pae diatri c T 2 D M s u bjects wit h H b A 1c le vels o f 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  su bjects wi t h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a n 
H b A 1c 
le vel < 7 % aft er 2 6 wee ks 
of  oral d o u bl e- 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 pae diatri c 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 di et 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 mpare t he per ce nta ge of  pae diatri c T 2 D M s u bjects o n di et a n d e xercise a n d 
met f or mi n (I R or X R), i ns uli n, or met f or mi n (I R or X R) pl us i ns uli n wi t 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 2 6 w hile re mai ni n g o n t he
l ow- 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- titr atio 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 mo 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.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 2
Of  not e  sec o n dar y object i ves will be prese nte d i n hierarc hical testi n g or der a n d labelle d 
n u me ricall y in Sect i on  4. 5. 1 . 
At  the e n d of  26 wee ks of  in vest i gati onal pr o d uct (I P) a d mi nistrati o n, stu d y  partici pa nts will 
bel o n g t o o n e of  fo ur s u b gr o u ps (I-I V); t he pri mar y o bject i ve a n d sec o n dar y o bjecti ves a t o k 
will e n c o mpass c o mparis o ns of  res ults fro m  mul tiple c o m bi nat i ons of t hese s u b gr o u ps, as 
sc he matise d bel o w .
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 a n d sec o n d ar y o bjecti ves
1. 1. 3
S afet y o bjecti ves

T o assess t he safety a n d t olera bilit y, i ncl u di n g t he i nci de nce of  ad v erse e ve nts ( A Es) a n d 
e ve nts of h y p o gl ycae mia , of  da pa glifl ozi n a n d sa xa gli pti n as a d d-o n  to diet a n d e xercise a n d 
met f 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 pae 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  sh o rt-t er 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) wi t h da pa glifl ozi n a n d sa xa gli pti n 
as a d d-o n  to diet a n d e xercise a n d met f or mi n (I R or X R), or i ns uli n, or met f or mi n (I R or 
X R) pl us i ns uli n i n pae diatri c T 2 D M s u bjects w he n a d mi nistere d f or u p t o 2 6 w ee ks of S T 
d o u bl e- bli n d tr e at 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 o f gr o wt h a n d mat uri t y a n d Ta n ner sta gi n g a n d mar kers of b o ne healt h 
i n pae diatri c 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  to 
di et a n d e xercise a n d metf or mi n (I R or X R), or i ns uli n, or met f 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 ditio n al 5 2 wee ks aft er t he st u d y has bee n c o m p lete d a n d st u d y-
r elate d treat me nt has bee n disc o nt i n ue d.

T o assess t he safety a n d t olera bilit y of da pa glifl ozi n ( or sa xa gli pti n) m o n o t hera p y in 
pae di atric s u bjects w h o are ra n d o mise d t o wit hdra w bac k gr o u n d met f or mi n.
1. 1. 4
E x pl or at or y o bjecti ves

T o c o m p are t he perce nta ge of  su bjects re q uiri n g gl ycae mic
resc ue me d icatio n  or 
di sc o nti n ui n g st u d y me dicatio n  due t o lac k of  efficac y wi t h da pa glifl o zi n or sa xa gli pti n 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 3
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 pa e di atric T 2 D M s u bjects wi t h Hb A 1c of  6. 5 t o 1 0. 5 % o n di et a n d e xercise a n d 
met f 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 on of  gl ycae mic resc ue me dicat i on or disc o nt i n uati on of  st u d y 
me dicat i on d ue t o lac k o f efficac y wit h da pa glifl ozi n, sa xa gli pt i 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 pae di atric
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 1c ac hie ve d wi t h da pa glifl ozi n t hera p y 
vers us pl ace b o, a n d se paratel y, ac hie ve d wi t h sa xa gli pt i n t hera p y vers us place b o aft er 
5 2- wee ks of oral bli n de d a d d -o n treat m e nt i n pae diatri c 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 F P G ac hie ve d wit h da pa glifl ozi n t hera p y vers us 
pl ace 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 o f 
or al  bli n de d a d d-o n treat m e nt i n pae diatri c T 2 D M s u bjects wi t h H b A 1c of 6. 5 t o 1 0. 5 % o n 
di et a n d e xercise a n d met f 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  su 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 % after 5 2 wee ks of oral bli n de d a d d -o n t hera p y  with da pa glifl o zi n vers us place b o, 
or sa xa gli pti n vers us pl ace b o i n pae diatri c T 2 D M s u bjects wi t h H b A 1 c of 6. 5 t o 1 0. 5 % o n 
di et a n d e xercise a n d met f 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  mo 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 mise d
t o wit h dra w bac k gr o u n d met f or mi n relati ve t o 
da pa glifl ozi n + met f or mi n (a n d se paratel y sa xa gli pti n + met f or mi n) a n d relati ve t o place b o
+ met f or mi n d uri n g t he ra n d o mise d wi t hdra wal p eri 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 ycae mic res p o nse ( H b A 1c < 7 %) a n d ti me t o resc ue or 
di sc o nti n uati on d ue t o l ac k of gl ycae mic c o ntr ol.
1. 1. 5
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 r elat i ons hi p of  da pa glifl ozi n 
a n d, se paratel y, sa xa gli pti n a n d its met a b o lite 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 ye ars wi t h T2 D M base d o n t he c o llecti o n of  po p ul at i on P K 
sa m ples.
1. 2
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 ult ice ntre, ra n d o mise d, pl ace b o -c o nt r olle d, 
d o u bl e-bli n d, paralle l-gr o u p st u d y with a 2 6 -wee k safet y e xt e nsio 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 pt i n ( 2. 5 m g a n d 5 m g) 
i n pae diatri c s u bjects wi t h T2 D M, a n d a n a d dit i onal p ost -stu 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 st u d y  will c o nsist of 4 st u d y p erio ds:


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 4
(i)
Scree ni n g peri o d. T his peri o d starts wit h e nr o l me nt a n d e n ds at t he start of t he lea d-
i n p eri o d.
(ii)
Le a d -i n peri o d . D uri n g t his 2- wee k p eri o d, s u bjects will be i nstr ucte d o n a di et 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 oci at i on [A D A ] or 
si milar l ocal g ui deli nes) t o be f oll owe d f or t he st u d y d urat i on. S u bjects will mai ntai n 
t heir baseli ne t ypes a n d/ or d oses of  ant i dia betic t hera p y thr o u g h o ut t he st u d y. N o 
pl ace b o or st u d y me dicat i on will be pr o vi de d d uri n g t he lea d-i n p eri o d.
(iii)
2 6 -wee k d o u ble -bli n d s h ort-ter m ( S T) tre at me nt peri o d . O n t he Da y  1 visit, 
s u bjects w h o meet all pr ot oc ol-s pecific e nr ol me nt a n d ra n d o misati on crit eria will be 
ra n d omise d .
(iv)
2 6- wee k d o u ble -bli n d l o n g-ter m ( L T) tre at me nt peri o d. After c o mplet i n g t he S T 
treat me nt perio d, all s u bjects will e nter t he 2 6-wee k L T treat me nt peri o d .
T he 5 2 -wee k treat m e nt perio d will be refere nce d as t he S T + L T treat me nt peri o d. 
T he R a n d o mise d
wit h dr a w al peri o d is defi ne d, f or t hose s u bjects eli gi ble f or t he 3 r d
ra n d omisat i on , as t he ti me fr om 3
r dra n d o misati on ( Wee k 3 2 or Wee k 4 0) u ntil e n d of L T peri o d 
( Wee k 5 2).
S u b jects w h o disc o nti n ue I P treat me nt bef ore t he e n d of t he st u d y  treat me nt perio d will e nter a 
n o n- treat me nt, f oll ow- u p p hase i n w hic h s u bjects will f o ll ow t heir visit sc he d ules wi t h m odifie d 
assess me nts u nt il st u d y c o mplet i on.
I n a d diti on, t here will be 2 p ost -stu d y visits:
(i)
Wee k 5 6
( p h o ne visit), t o assess A Es a n d seri o us a d verse e ve nts ( S A Es). 
(ii)
Wee k 1 0 4 ( office visi t), t o assess meas ures of  gr o wt h a n d mat uri t y, hei g ht, wei g ht , 
A Es a n d S A Es.
A p pr o xi matel y  2 4 3 pae diatri c s u bjects a ge d 1 0 t o bel o w 1 8 years of a ge will be ra n d omise 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 omise d t o eac h treat me nt ar m.
Ra n d o mise d sc he d ules will be ge nerate d a n d ke pt b y t he S p o ns or or desi g nee. Ra n d o misat i on
will be stratifie d base d o n baseli ne a nt i-di a betes treat me nt re gi me n (sta ble baseli ne d ose of  
met f or mi n [IR or X R ], a sta ble baseli ne d ose of i ns uli n, or a sta ble c o m bi natio n of  metfor m i n 
[I R or X R] a n d i ns uli n), se x, a n d a ge (≥1 0 t o < 1 5 years, ≥1 5 t o < 1 8 ye ars). Eac h s u bject will be 
assi g ne d a u niq ue se q ue nti al su bject n u m ber b y t he I nteracti ve W e b / V oi ce Res p o nse S yste m 
(I W R S). T his s u bject i de ntifier 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.
Af t er ra n d omisati o n, it is e x pecte d t hat at least 5 0 % of s u bjects will be o n a sta ble baseli ne d ose 
of  met f or mi n, wi t h or wit h o ut c o nc urre nt i ns uli n t hera p y. At  least 3 0 % of  total  ra n d omise d


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 5
s u bjects will be bet wee n t he a ges of  10 a n d 1 4 ye ars a n d at least o ne t hir d, b ut n o m o re t ha n 
t wo t hi r ds, fe male s u bjects.
After t he lea d-i n p eri o d, eli gi ble s u bjects wi t h Hb A 1c of  6. 5 % t o 1 0. 5 % at  scree ni n g will b e 
ra n d omise d ( Da y 1). A bli n de d H b A 1c assess me nt will be perf or me d at Wee k 1 2. At  Wee k 1 4, 
s u bjects will be u p -titr atio n ra n d o mise d t o ne w treat me nt assi g n me nts, based o n t he Wee k
1 2
H b A 1c assess me nt .
T he ne w treat me nt assi g n me nts fr o m Wee k 1 4 will be deter mi ne d as f o ll ows. 

All s u bjects wi t 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 ow- d ose ra n d omise d
treat me nt (bli n de d da pa 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 gl ifl ozi n treat me nt ar m at Da y 1 ra n d omisat i on
wi t h Wee k 1 2 H b A 1c val ues ≥ 7 % (irres pective of w het her t he y were resc ue d or n ot 
pri or t o W ee k 1 2) will be U p -titratio n Ra n d o mise d
i n a 1: 1 rati o t o c o nt i n ue o n t he 
l ow- d ose 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 xagli pt i n treat me nt ar m at Da y 1 ra n d omisat i on
wi t h Wee k 1 2 H b A 1c val ues ≥ 7 % (irres pecti ve of w het her t he y were resc ue d or n ot
pri or t o W ee k 1 2) will be U p -titratio n Ra n d o mise d
i n a 1: 1 rati o t o c o nt i n ue o n t he 
l ow -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 pt i n 5 m g) after t he Wee k 1 2 assess me nt. 

T o m ai ntai n t he bli n di n g of treat me nts as well as H b A 1c res ults, a ll place b o s u bjects 
a n d all s u bjects ta ki n g sa xa gli pt i 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 2 n d ra n d o misati on pr ocess t hat will be i n dist i n g uis ha ble (for 
t he s u bjects a n d site pers o n nel) fr o m t he act ual 2 n d ra n d omisat i on.
After a 2 6- wee k, d o u ble -bli n d, S T treat me nt peri o d, t he pri mar y efficac y en d p o i nt will b e 
assesse d. Da pa glifl ozi n a n d, se paratel y, sa xa gli pt i n, will be c o m pare d a gai nst t he si n gle s hare d 
pl ace b o c o mparat or.
After c o mplet i on of  the S T treat me nt p eri 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 dicat i on wi t h ins 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 or t he t hir d ra n d o misati on ) will c o nt i n ue wi t h their 
ra n d omise d
st u d y me dicatio n assi g ne d aft er 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 perio d u ntil Wee k 5 2 or earl y d isc o nti n uati o n of  I P. 
S u bjects w h o are recei vi n g bac k gr o u n d me dicat i on wi t h met f or mi n o nl y  will u n der g o a t hir d 
ra n d omisat i on (ra n d o mise d wi t hdra wal  of bac k gr o u n d me d icati on) at ei t her Wee k 3 2 or Wee k 
4 0. Eli gi bilit y f or ra n d omise d
wi t hdra wal  fr o m bac k gr o u n d me d icati on will be r estricte d t o 
s u bjects w h o are recei vi n g bac k gr o u n d me dicat i on wit h met f 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 ycae mic c o ntr ol 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 6
t hera p y or bee n wit h dra w n fr om 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 m e dicat i on 
wi t h met f 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 omisat i on 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 omisati 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 omise d
wi t hdra wal  of bac k gr o u n d me d icati on. Resc ue d s u bjects a n d s u bjects w h o disc o nt i n ue I P will 
n ot be eli gi ble f or ra n d o mise d wi t hdra wal  of bac k gr o u n d me dicat i on at Wee k 3 2 or Wee k 4 0.
D uri n g t he t hir d ra n d omisat i on:

Eli gi ble s u bjects w h o are recei vi n g act i ve treat me nt will be gr o u pe d i nt o t wo se parate 
strata f or da pa glifl ozi n a n d sa xa gli pti n, a n d t he n ra n d omise d 1: 1 wit hi n eac h strata t o 
eit her disc o nt i n ue bac k gr o u n d me dicati on w ith met f or mi n or t o c o nt i n ue bac k gr o u n d 
me dicat i on wi t h metfor m i n. F or s u bjects o n acti ve treat me nt w h o are ra n d o mise d t o 
wi t hdra w bac k gr o u n d me dicati o n wi t h metfor m i 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 pt i 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 ow d oses of  sa xa gli pt i n 
( 2. 5 m g) or da pa glifl ozi n ( 5 m g) will ha ve their 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 mise d t o c o nt i n ue bac k gr o u n d me dicat i o n wit h metf or mi n will  co nti n ue 
wi t h t h eir 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 d omise d
1: 1: 1 t o eit h er 
wi t hdra w bac k gr o u n d me dicat i on w ith met f or mi n a n d s witc h t o acti ve treat me nt with 
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 dicat i on wi t h met f or mi n a n d c o nti n ue with pl ace b o. 
T he st u d y  desi g n sc he matic f or s u bjects n ot u n der g oi n g ra n d omise d wi t hdra wal  of bac k gr o u n d 
me dicat i on at Wee k 3 2 or Wee k 4 0 is prese nte d i n  Fi g ure 2.






Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
2 9
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 mis 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 misati o n d ue t o H b A 1c ≥ 7. 5 % at Wee k 2 6 ma y  q u alif 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 misati 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 misati 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 misati o n.
S u bjects w h o disc o nt i n ue I P pri or t o t he Wee k 
5 2 visit s h o uld ha ve all earl y tr e at me nt 
di sc o nti n uati on ( E T D) p r oce d ures perf or me d ( E T D v isit). S u bjects will t he n c o nt i n ue i n t he 
st u d y acc or di n g t o t he Earl y Disc o nt i n ue d f oll ow - u p visit sc he d ule, u ntil st u d y co m plet i on.
Di sc o nti n ue d s u bjects will n ot be re place d.
S u bjects w h o are resc ue d pri or t o t he Wee k 5 2 visit s h o ul d ha ve all resc ue pr oce d ures perf or me d 
pri or t o t h eir first i nta ke of  resc ue ( Resc ue v isit). S u bjects w h o are resc ue d pri or t o Wee k 1 2 
a n d ha ve n ot disc o nt i n ue d I P will g o t hr o u g h t he sec o n d ra n d omisati o n , as descri be d a b o ve. 
Resc ue d s u bjects will c o nt i 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.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 0
S c he d ules of  st u d y assess me nts a n d pr oce d ures b y st u d y perio d ar e pr o vi de d i n t he A p pe n d i x
(Secti o n 8. 1 ).
1. 3
N u m ber of s u bjects
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 pt i 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 ult i plicity a dj ust me nt  with res pect t o t he c o mparis o ns will be ma de usi n g a 
hierarc hical a p pr oac h.
N o 
c o m par is o ns bet wee n da pa glifl o zi n a n d sa xa gli pti n will  be 
perf or m e 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 o zi 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) 
wi t h a p pr o xi matel y 8 0 % p o w er f or e a c h c o m paris o n at a t w o -side d al p ha le vel of 0. 0 5. If 2 4 3 
p ae diatric s u bjects are ra n d o mise d a n d a n al yse d, a n d eac h treat me nt c o mp ar e d t o pl a c e b o at a 
2 side d al p ha = 0. 0 5 level, t his will  pr o vid e a p pr o xi matel y 80 % p o wer f or eac h c o mparis 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 om baseli ne vers us pl ace b o ass u mi n g a sta n dar d 
de viat i on of 1. 7 %.
D a y  1 Ra n d o misati on will be stratifie d base d o n t he baseli ne a nt i-di a betic treat me nt re gi me n 
(sta ble baseli ne d ose of  metfor m i n [I R or X R ], a sta ble baseli ne d ose of  ins uli n, or a sta ble 
c o m bi nat i on of met f or mi n [I R or X R] a n d i ns uli n), se x, a n d a ge (≥1 0 t o < 1 5 y ears, ≥1 5 t o < 1 8
years ).
T he sta n dar d de viat i on est i mate of 1. 7 % is base d o n a bli n de d re vie w of t he o n g o i n g st u d y data.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 1
1. 4
Bli n di n g a n d u n bli n di n g
T he i n vesti gat or, A Z pers o n nel, C R O pers o n nel, a n d s u bjects will re mai n bli n de d t o treat m e nt 
all ocat i on t hr o u g h o ut t he S T + L T treat me nt peri o d. T he data base use d f or t he a nal ysis of  the 
S T + L T data will be l oc ke d after all s u bjects ha ve c o m plete d t he S T + L T treat me nt peri o d of  t he 
st u d y. T he l oc ke d data base will be u n bli n de d t o t he S p o ns or a n d t he C R O stu d y t e a m f or 
re p orti n g p ur p oses.
After D a y  1, a n d for t he d urati o n of  the st u d y, t he H b A 1c a n d t he uri nar y gl uc ose val ues, 
i ncl u di n g t he uri nar y gl uc ose: creati ni ne r atio, will be mas ke d t o t he S p o ns or a n d will n ot be 
a vaila ble t o t he i n vesti gat or. I n t he e ve nt of  an H b A 1c res ult > 8 . 0 % d uri n g t he L T treat me nt  
p eri o d ( w he n t hese val ue s 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  but will re mai n bli n de d t o t he H b A 1c res ult.
F or s u bjects w h o are ra n d omise d t o wit hdra w bac k gr o u n d metf or mi n, t he i n vesti gat or a n d t he 
s p o ns or ma y be part iall y u n bli n de d
t o t he s u bject’s tr e at me nt assi g n me nt . Gi ve n
t hat  
d isc o nti n uat i on of  bac k gr o u n d met f or mi n will occ ur i n a n u n bli n de d ma n ner, all s u bjects w h o 
are ra n d o mise d t o wit h dra w bac k gr o u n d met f or mi n will  either ma i ntai n or start hi g h -d ose 
da p a glifl ozi n or sa xa gli pt i n as m o n ot hera p y.
Bli n di n g is critic al to t he i nte grit y of t his cli nical trial. 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, d uri n g w hic h k n o wle d ge of t he i de ntit y o f the i n vesti gati o nal pr o d uct 
is critical t o t he s u bject's ma na ge me nt, pr oce d ures are i n place t o ha ve t he bli n d br o ke n f or a n 
i n di vi d ual s u bject. A listi n g of  all s u bjects w h ose treat m e nt is u n bli n de d d uri n g t he stu d y will 
be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). 
T he e xce pti o n is f or t hose pers o n nel a nal ysi n g t he P K data , t hose a nal ysi n g di pe pt i dyl -
pe pti dase - 4 ( D P P- 4) data, t he A Z S u p pl y C hai n St u d y  Ma na ge me nt ( S C S M) tea m an d t h e 
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 labelli n g of  IPs. T he Da y  1 Ra n d o misat i on
c o de will be pr o vi de d t o e ns ure a p pr o priate treat me nt all ocat i on 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 ysed. Si milarl y , t he Da y  1 
Ra n d o misat i on c o de will be pr o vi de d t o e ns ure a p pr o priate treat me nt all ocat i on a n d t hat o nl y 
D P P- 4 sa m ples fr o m s u bjects w h o were o n acti ve st u d y treat me nt are a nal ysed.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 2
1. 5
Pr ot oc ol a me n d me nts
T his a me n de d S A P is base d o n (Re vise d Pr ot oc ol N u m ber 0 6 date d 0 7 Fe br uar y 2 0 2 2).
T a ble 1 Pr ot oc ol Hist or y
D oc u me nt
D ate of 
iss ue
S u m m ar y of c h a n ge
Ori gi nal Pr ot oc ol
0 2- Mar - 2 0 1 6
N ot a p plica ble
Re vise d Pr ot oc ol 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 
U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) s pecifie d 
preferre d st u d y o bjecti ves a n d desi g n.
Re vise d Pr ot oc ol 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 he 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 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 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 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 mise 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 mise 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 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 di ficati 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 scree 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 maturit y 
ma r 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 ni sati o n acr oss all 
A Z cli nical st u d y pr ot oc ols.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 3
D oc u me nt
D ate of 
iss ue
S u m m ar y of c h a n ge
Re vis e d Pr ot oc ol 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 misati o n visit (f or s u bjects u n der g oi n g t hir d 
ra n d o misati o n) a n d t he Wee k 5 2 visit i n case t he Wee k 1 4 or 
t hird ra n d o misati 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-t er m p eri 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 saf et 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 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 misati 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 misati 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 misati o n as t he H b A 1c val ue w o ul d n o l o n ger be 
r elia ble t o ascertai n eli gi bilit y f or t he t hir d ra n d o misati o n.
Ot her u p dates i ncl u de g ui d a 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.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 4
Re vise d Pr ot oc ol 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 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 mpare 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 mar y o bjecti ve, t he 
pri m ar 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 u s 
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 ass 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 mple 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: 
T e 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 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 5
D oc u me nt
D ate of 
iss ue
S u m m ar y of c h a n ge
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 Wee k 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, 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 ( 7 9 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 diat ric 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 ass u mi n g a sta n dar d de viati o n of 1. 7 %.”
T e 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 btai 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 bli s 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.
N o pr ot oc ol a me n d me nts or a d mi nistrati ve letters t hat ma y affect t he S A P ha ve bee n pr ocesse d 
be y o n d Pr ot oc ol  versi o n 0 6 o n w hic h t his S A P is base d o n.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 6
1. 6
Ti mi n g of a n al yses a n d re p orti n g
T here will be 2 data base l oc k p oi nts. 
1.
A nal ysis of  data fr o m t he S T treat me nt p eri o d , t he c o m bi ne d S T + L T treat me nt p eri o d 
(a t otal of 5 2 wee ks) a n d i ncl u di n g t he n o n- treat me nt f oll ow- u p visit at Wee k 5 6 will be 
perf or m e d aft er all s u bjects ha ve c o m p lete d or h a ve bee n disc o nt i n ue d fr om t he st u d y
(incl u di n g c o m p leti on of n o n -treat me nt f o ll ow- u p after t he last d ose, w here a p plica ble) . 
2.
A nal ysis of  data fr o m t he a d ditio n al 4 8- wee k f oll o w-u p peri o d t o assess meas ures of  
gr o wt h o ver ti me will be p erf or m e d aft er all su bjects ha ve c o m p lete d or ha ve bee n 
di sc o nti n ue d fr om t his perio d (a t otal  of 1 0 4 wee ks).
1. 7
D at a m o nit ori n g c o m mittees
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 mprise d of  Pae di atric 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 an d efficac y of t he i nter ve nt i ons 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  the cli nical trial. T he D M C will pr o vi de rec o m me n dati ons 
a b o ut st o p pi n g or c o nti n ui n g t he trial a nd will  be g o ver ne d b y a se parate D M C C harter.
1. 8
A dj u dic ati o n c o m mittees
1. 8. 1
C ar di o v asc ul ar a dj u dic ati o n co m mittee
A n i n de pe n de nt Car di o vasc ular A d j u dicati on C o m mittee, bli n de d t o t he treat me nt of  the 
s u bjects, will a dj u dicate all p ote ntial e ve nts of c o n gesti ve heart fail ure re q uiri n g h os pi talisatio n
(see st u d y pr ot o c ol for m ore details).
A se parate A d j u dicati on C harter will defi ne a n d descri be t he pr oce d ure f or t he ha n dli n g, 
re p orti n g a n d classificat i on of t hese e ve nts.
1. 8. 2
He p atic a dj u dic ati o n co m mittee
A n i n de pe n de nt He patic A dj u dicati o n C om mittee, bli 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 
ab n or m alities, 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 ab n or malit ies s uc h as ele vate d As partate a mi n otra nsferase (A S T ) a n d/ or Ala ni ne 
a mi n otra nsferase ( A L T ) wi t h or wit ho ut t otal  bilir u bi n ( T B) ele vat i ons (see st u d y pr ot oc ol for 
m o re details).
A se parate A d j u dicati on C harter will defi ne a n d descri 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 on of t hese e ve nts.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 7
1. 8. 3
Di a betic Ket o aci d osis ( D K A) a dj u dic ati o n co m mittee
A n i n de pe n de nt D K A A d j u dicati on C o m m ittee, bli n de d t o t he treat me nt of  the s u bjects, will 
a dju dicate all p ote ntial e ve nts of D K A.
A se parate A d j u dicati on C harter will defi ne a n d descri 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 on of t hese e ve nts.
2.
A N A L Y SI S S E T S
2. 1
Tre at me nt gr o u ps
T he “as ra n d omise d ” tr e at me nt gr o u p is defi ne d as t he treat me nt gr o u p t o w hic h a s u bject was 
ra n d omise d at t he start of t he d o u ble-bli n d treat me nt peri o d (e ve n if t he treat me nt t he y recei ve d 
was differe nt).
T he “as treate d” treat me nt gr o u p is t he sa me as t he “as ra n d omise d ” treat me nt gr o u p, e xce pt i n 
cases w here i nf or mati on was a vaila ble w hic h i n dicate d t hat a s u bject recei ve d a differe nt 
treat me nt f or t he e nt ire c o urse of t heir partici pat i on i n t he st u d y ( or peri o d). I n t his case, t he “as 
treate d” treat me nt gr o u p is set t o t he treat me nt t h e s u bject act uall y recei ve d. I n case a s u bject 
ne ver recei ve d t he tr e at me nt as assi g ne d b y ra n d o misatio n , t he n t he “as t reate d” treat me nt gr o u p 
is t he first treat me nt recei ve d.
2. 2
Defi niti o n of a n al ysis sets
2. 2. 1
E nr olle d S u bjects D at a Set
T he E nr olle d S u bjects D ata S et will c o nsist of all s u bjects w h o si g n i nf or me d c o nse nt.
2. 2. 2
R a n d o mise d S u bjects D at a Set
T he Ra n d o mise d
S u bjects D ata S et  is t he pri m ar y  efficac y dataset a n d will c o nsist of all
ra n d omise d
s u bjects w h o recei ve at least o ne d ose of  st u d y me dicat i on d uri n g t he treat me nt  
p eri o d. T hi s is als o k n o w n as t he I nte nt-t o-Treat
(I T T) p o p ulat i on. I n a nal yses of  the 
Ra n d o mise d S u bjects Data S et , s u bjects will ge nerall y  be prese 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 omise d at t he start of t he S T treat me nt perio d (e ve n if t he treat me nt t h e y 
recei ve d is differe nt).
2. 2. 3
U p -titr ati o n R a n d o mise d S u bjects D at a Set
T he U p -titr atio n Ra n d o mise d S u bjects D at a S et will c o nsist of t he s u bse t of  ra n d omise d s u bjects 
w h o are U p -titr atio n Ra n d o mise 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 (re gar dless of  resc ue me d icati on i nitiati on) . T his data set will be use d f or efficac y a nal ysis 
c o mpari n g l ow -d ose a n d hi g h -d ose treat me nt re gi me ns i n s u bjects w h o d o n ot ac hie ve 
gl ycae mic c o ntr ol (H b A 1c
< 7 %) at Wee k 
1 2. I n a nal yses of  the U p -titr atio n Ra n d o mise d
S u bjects Data Set, s u bjects will be prese 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 omise d at t he sec o n d ra n d omisat i on.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 8
2. 2. 4
E v al u a ble S u bjects D at a Set
T he E val ua ble S u bject s Data S et will be a s u bset of t he Ra n d o mise d S u bjects D ata S et . All data 
p oi nts after a rel e va nt pr ot oc ol de viati on will be e xcl u de d fr om t his dataset. Rele va nt pr ot oc ol 
de viat i ons ( R P Ds) are defi ne d as de v iati ons t hat c o ul d p ote nti all y affect t he i nter preta bilit y of  
t he stu d y res ults (as descri be d i n Ta ble 2 a n d Ta ble 3) . All decisi o ns t o e x cl u de s u bjects fr om 
t he Ra n d o mise d S u bjects D ata S et t o for m  t he E val ua ble S u bject s D ata S et will be ma d e prior 
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  po p ulati o n. T his dataset will be use d f or se nsiti vity a nal ysis of  the pri mar y efficac y 
e n dp oi nt if greater t ha n 1 0 % of s u bjects i n a n y treat me nt gr o u p i ncl u de d i n t he pri mar y a nal ysis 
(o verall da pa glifl ozi n or o verall sa xa gli pti n, a n d all place b o s u bjects) ha ve R P Ds. I n a nal yses 
of  t he E val ua ble S u bjects Data Set, s u bjects will be prese nte d i n t he tr e at me nt gr o u p t o w hic h 
t he y were ra n d omise d at t he start of t he S T treat me nt peri o d.
2. 2. 5
Tre ate d S u bjects D at a Set
T he Treate d S u bject s Data S et (als o k n o w n as Safet y  Anal ysis Data Set) is t he pri mar y s afet 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  st u d y me dicat i on. I n 
a nal yses of  t he Treate d S u bjects D at a S et , s u bjects will ge nerall y be prese nte d b y ra n d o mise d
treat me nt gr o u p, e xce pt if i nf or mat i on i n dic ates t hat a s u bject recei ve d a differe nt treat me nt f or 
t he e nt ire c o urs e of t heir parti ci pat i on i n t he st u d y ( or peri o d) . I n t his case, t he safety 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 pt i ons t o t hi s will 
b e ma de f or s ome a nal yses of  the effects of  mo n ot h era p y or ra n d o mise d wi t hdra wal of  
met f or mi n.
2. 2. 6
R a n d o mise d Wit h dr a w al S u bjects
D at a Set
T he Ra n d o mise d
Wit h dra wal S u bjects Data Set will be a s u bset of  the Ra n d o mise 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 met f or mi n ra n d o misati on strata of 
bac k gr o u n d me dicat i on w h o will be re-ra n d omise d
at Wee k 3 2 or Wee k 4 0 (as descri be d i n 
Secti o n 1. 2 ). T his data set will be use d t o a nal yse efficac y a n d safety d uri n g t he ra n d o mise d
wi t hdra wal  p erio d usi n g t he treat m e nt assig n me nt fr o m  t he t hir d ra n d omisat i on.
2. 2. 7
P h ar m ac o ki netic ( P K) A n al ysis D at a Set
T he P K A nal ysis Data Set will be use d f or all P K a nal yses a n d will c o nsist of all s u bjects w h o 
recei ve at least o ne d ose of st u d y me dicat i on ( da pa glifl ozi n or sa xa gli pti n) a n d ha ve at least 1 
P K sa m ple c o llecte d. T he P K data will be prese nte d usi n g t he hi g hest treat me nt act uall y 
recei ve d d uri n g t he S T peri o d (as descri be d i n Secti on  2. 1 ).
2. 3
Vi ol ati o ns a n d de vi ati o ns
S u bjects w h o de viate fr o m pr ot oc ol c o n dit i ons ( e. g. , i m p orta nt i ncl usi on/e xcl usi o n cr iteria) will 
be re p orte d as ha vi n g i m p orta nt pr ot oc ol de viat i ons . A list of  Im p orta nt pr ot oc ol de viat i ons is 
pr o vi de d i n  Ta ble 4.
I mp orta nt pr ot oc ol  de viati ons are i de nt ifie d i n t he site de viati on l ogs a n d are cate g orise d usi n g 
t he Pr ot oc ol de viat i on g ui da nce d oc u m e nt.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
3 9
I mp orta nt pr ot oc ol de viat i ons t hat are deter mi ne d t o affect t he pri mar y efficac y res ults are 
dee m e d R P Ds . T he R P Ds f or t his st u d y are liste d i n Ta ble 2 a n d Ta ble 3.
A se nsit i vity a nal ysis o f the pri mar y efficac y e n d p oi nt will be c o n d ucte d if greater t ha n 1 0 % of 
s u bjects i ncl u de d i n t he pri mar y  anal ysis (o verall  da pa glifl ozi n or o v erall sa xa gli pti n, a n d all 
pl ace b o s u bjects) ha ve R P Ds d uri n g t he S T peri o d. T hi s a p plies f or da pa glifl ozi n or sa xa gli pt i n 
se paratel y. T his se nsitivi t y anal ysis wil l e x clu d e d at a fr o m s u bjects wi t h RP Ds d uri n g t he S T 
p eri o d . T here will be n o data e xcl usi o ns f or i m p orta nt pr ot oc ol de viati ons n ot dee me d R P Ds.
S u bjects ha vi n g R P Ds will be s u m marise d b y t reat me nt gr o u p a n d o verall f or t he S T a n d S T + L T 
p eri o d , a n d a listi n g b y s u bject will be pr o vi de d f or t he S T + L T peri o d . S u bjects wi t h ot her 
i m p orta nt (e xcl u di n g r ele va nt) pr ot oc ol de viat i ons will be s u m marise d f or t he S T a n d S T + L T 
p eri o d a n d liste d f or t he S T + L T peri o d se paratel y. A n y s u bject wi t h bot h  rele va nt a n d o t her 
i m p orta nt (e xcl u di n g r ele va nt) pr ot oc ol de viat i ons will a p pear i n b ot h listi n gs. A n y pr ot oc ol 
de viat i ons wit h a start date pri or t o Da y  1 will be prese nte d f or t he S T peri o d.
Di sallo w e d c o nc o mita nt me dicat i ons are s pecifie d i n t he pr ot oc ol a n d will be c o nfir me d b y t he 
st u d y p h ysicia n. T he c urre nt A T C c o des c orres p o n di n g t o t hese me dicat i ons will be pr o vi de d 
b y a me dicall y q ualifie d e x pert pri or t o u n bli n di n g a n d data base l oc k/freeze. 
T a ble 2 List of rele v a nt pr ot oc ol de vi ati o n s d uri n g t he S T peri o d
N u m ber
R P D criteri a
E xcl usi o n Le vel
1
Ra n d o mise d S u bjects wit h o ut T 2 D M or wit h ce ntral 
la b orat or y H b A 1c o btai ne d at e nr ol me nt n ot wit hi n ± 
0. 2 % of t he pr ot oc ol -s pecific H b A 1c ra n ge
C o m plete e xcl usi o n
2
Ra n d o mise d S u bjects n ot satisf yi n g t he tar get p o p ulati o n 
baseli ne a nti h y per gl yce mic t hera p y re q uire me nt
(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 )
C o m plete e xcl usi o n
3
Ra n d o mise d S u bjects wit h ra n d o misati o n strata err or –
a ge, se x, bac k gr o u n d me dicati o n
C o m plete e xcl usi o n
4
Ra n d o mise d S u bjects w h o use d a nti h y per gl yce mic 
me dicati o n ( ot her t ha n pr ot oc ol all o we d me dicati o n) f or 7 
or m ore c o nsec uti ve da ys d uri n g t he S T peri o d
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t h e 7t h da y of 
a d mi nistrati o n 
n o n- pr ot oc ol re q uire d 
a nti h y per gl yce mic 
me dicati o n will be 
e x cl u de d)


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 0
N u m ber
R P D criteri a
E xcl usi o n Le vel
5
Ra n d o mise d S u bjects w h o were treate d wit h a n y s yste mic 
c ortic oster oi d t hera p y f or ≥ 5 c o nsec uti ve da ys i nitiate d or 
c ha n ge d d uri n g S T peri o d, or wit hi n 5 da ys pri or t o 
ra n d o misati o n
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t h e 5t h da y of 
s yste mic c ortic oster oi d 
t hera p y will be e xcl u de d)
6
Ra n d o mise d s u bjects w h ose bac k gr o u n d Metf or mi n d ose 
was n ot sta ble a n d/ or bac k gr o u n d I ns uli n d ose i ncreases 
or decreases 2 0 % or m ore a b o ve baseli ne d ose a n d/ or 
t here is a ga p of greater t ha n 1 4 da ys of bac k gr o u n d 
Metf or mi n or I ns uli n d uri n g t he S T treat me nt peri o d
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t he date bac k gr o u n d 
Metf or mi n d ose c ha n ge d 
or bac k gr o u n d I ns uli n d ose 
i ncrease d/ d ecr ease d ≥2 0 %
or 1 5 t h da y of ga p i n 
bac k gr o u n d me dicati o n )
7
Ra n d o mise d s u bjects wit h treat me nt c o m plia nce < 8 0 % or 
> 1 2 0 % d uri n g t he S T treat me nt p e ri o d
C o m plete e xcl usi o n
8
Ra n d o mise d S u bjects w h o recei ve n o d o u ble -bli n d 
me dicati o n f or 1 4 or m ore c o nsec uti ve da ys d uri n g t he S T
treat me nt p e ri o d
Partial e xcl usi o n 
( All efficac y data starti n g 
wit h t h e 1 4t h da y of 
i nterr u pti o n will be 
e x cl u de d)
9
Ra n d o mise d s u bjects w h o recei ve d i nc orrect st u d y 
me dicati o n f or 1 4 or m ore c o nsec uti ve da ys d uri n g t he S T
treat me nt p e ri o d
Partial e xcl usi o n 
( All efficac y data starti n g 
wit h t h e 1 4t h da y of 
i nc orrect st u d y me dicati o n 
will be e xcl u de d)
1 0
A b n or ma l free t hyr o xi ne val ues at e nr ol me nt
C o m plete e xcl usi o n
1 1
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 
ha e mol ysis
C o m plete e xcl usi o n


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 1
T a ble 3 List of rele v a nt pr ot oc ol de vi ati o ns d uri n g t he S T + L T peri o d
N u m ber
R P D criteri a
E xcl usi o n Le vel
1 2
Ra n d o mise d S u bjects w h o use d a nti h y per gl yce mic 
me dicati o n ( ot her t ha n pr ot oc ol all o we d me dicati o n) f or 7 
or m ore c o nsec uti ve da ys d uri n g t he S T + L T treat me nt 
peri o d
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t he 7t h da y of 
a d mi nistrati o n 
n o n- pr ot oc ol re q uire d
a nti h y per gl yce mic 
me dicati o n will be 
e x cl u de d)
1 3
Ra n d o mise d S u bjects w h o were treate d wit h a n y s yste mic 
c ortic oster oi d t hera p y f or ≥ 5 c o nsec uti ve da ys i nitiate d or 
c ha n ge d d uri n g S T + L T treat me nt peri o d, or wit hi n 5 da ys 
pri or t o ra n d o misati o n
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t he 5t h da y of 
s yste mic c ortic oster oi d 
t hera p y will be e xcl u de d)
1 4
Ra n d o mise d s u bjects w h ose bac k gr o u n d Metf or mi n d ose 
was n ot sta ble a n d/ or bac k gr o u n d I ns uli n d ose i ncreases
or decreases 2 0 % or m ore a b o ve baseli ne d ose a n d/ or 
t here is a ga p of greater t ha n 1 4 da ys of bac k gr o u n d 
Metf or mi n or I ns uli n d uri n g t he S T + L T treat me nt peri o d
Partial e xcl usi o n
( All efficac y data starti n g 
wit h t he date bac k gr o u n d 
Metf or mi n d ose c ha n ge d 
or bac k gr o u n d I ns uli n d ose 
i ncrease d/ d ecr ease d ≥2 0 %
or 1 5 t h da y of ga p i n 
bac k gr o u n d me dicati o n )
1 5
Ra n d o mise d s u bjects wit h treat me nt c o m plia nce < 8 0 % or 
> 1 2 0 % d uri n g t he S T + L T treat me nt p e ri o d
C o m plete e xcl usi o n
1 6
Ra n d o mise d S u bjects w h o recei ve n o d o u ble -bli n d 
me dicati o n f or 1 4 or m ore c o nsec uti ve da ys d uri n g t he 
S T + L T treat me nt peri o d
Partial e xcl usi o n 
( All efficac y data starti n g 
wit h t h e 1 4t h da y of 
i nterr u pti o n will be 
e x cl u de d)
1 7
Ra n d o mise d s u bjects w h o recei ve d i nc orr ect st u d y 
me dicati o n f or 1 4 or m ore c o nsec uti ve da ys d uri n g t he 
S T + L T treat me nt peri o d
Partial e xcl usi o n 
( All efficac y data starti n g 
wit h t h e 1 4t h da y of 
i nc orrect st u d y me dicati o n 
will be e xcl u de d)
T a ble 4 List of I m p ort a nt Pr ot oc ol De vi ati o ns
N u m ber
I m p ort a nt pr ot oc ol de vi ati o n criteri a
0 1
I ncl usi o n Criteria
0 2
E xcl usi o n Criteria


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 2
N u m ber
I m p ort a nt pr ot oc ol de vi ati o n criteri a
0 3
St u d y Dr u g
0 4
Assess me nt Safet y
0 5
La b/ E n d p oi nt Data 
0 6
Visit Wi n d o w
0 7
I nf or me d C o nse nt
0 8
Pr o hi bite d C o -Me dicati o n
0 9
O ver d ose/ Mis use
1 0
Ot her ( diar y c o m pleti o n, site staff q ualificati o ns, safet y re p orts etc. )
3. 
E N D P OI N T S
3. 1
Pri m ar y effic ac y e n d p oi nts
T he pri mar y  efficac y e n d p o i nt f or a nal ysis is t he c ha n ge fro m  baseli ne i n H b A 1c at Wee k 2 6 
of  t he S T peri o d. A nal ysis of H b A 1c will be perf or me d o nl y i n co n ve nti o n al  ( U S) u nits ( %).
H b A 1c will  be assesse d at t he ti me p oi nts s h o w n i n t he A p pe n di x ( Sectio n 8. 1 ), a n d at  n o n-
treat me nt / u nsc he d ule d visits (if a p plica ble), base d o n a si n gle ce ntral la b orat or y test at eac h 
ti me p oi nt. F o r t he pri mar y a nal ysis, missi n g H b A 1c
at Wee k 2 6 will be i m p ute d base d o n 
m ult iple i m p utati o n (as descri be d i n Secti o n 4. 1. 1 2 ).
3. 2
Sec o n d ar y effic ac y e n d p oi nts
T he sec o n dar y  efficac y e n d p o i nts are:

C ha n ge fr o m base li ne i n F P G at Wee k 2 6.
C e ntral la b orat or y meas ure me nts of FP G will be use d f or t he a nal ysis a n d will be restricte d 
t o meas ure me nts o btai ne d i n t he fast i n g state. Fasti n g plas ma gl uc ose will be assesse d at t he 
ti me p oi nts s h o w n i n A p pe n di x ( Secti on 8. 1 ) a n d at n o n- treat me nt / u nsc he d ule d visit s (if 
a p plica ble), base d o n a si n gle ce ntral la b orat or y test at  eac h ti me p oi nt . F or sec o n dar y
a nal yses, m ult i ple i m p utati o n will be use d t o im p ute mi ssi n g F P G val ues f or Wee k 2 6 (as 
descri be d i n Secti o n  4. 1. 1 2 ).

Perce nta ge of  s u bjects wi t h baseli ne H b A 1c ≥ 7 % w h o ac hie ve a H b A 1c le vel < 7 % at Wee k
2 6.
3. 3
E x pl or at or y effic ac y e n d p oi nts
T he f o ll owi n g e x pl orat or y  efficac y e nd p oi nts are defi ne d f or t he st u d y:


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 3
3. 3. 1
E x pl or at or y effic ac y e n d p oi nts f or s h ort ter m assess me nt of d a p a glifl ozi n a n d 
s a x a gli pti n

Perce nta ge of  su bjects w h o re q uire gl ycae mic resc ue me d icatio n or disc o nt i n ue t he st u d y 
me dicat i on d ue t o l ac 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 on of  gl ycae mic resc ue me d icati on or disc o nt i n uati on of  st u d y me dicat i on 
d ue t o l ac k of efficac y d uri n g t he 2 6-wee k treat me n t perio d .
3. 3. 2
E x pl or at or y effic ac y e n d p oi nts f or s h ort ter m pl us l o n g-ter m assess me nt of 
d a p a glifl ozi n a n d s a x a gli pti 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  su bjects wi t h baseli ne H b A 1c ≥7 % w h o ac hie ve a H b A 1c level < 7 % at  
Wee k
5 2.

Ti me t o i nitiati on of  gl ycae mic resc ue me d icati on or disc o nt i n uati on of  st u d y me dicat i on 
d ue t o l ac k of efficac y d uri n g t he 5 2-wee k treat me nt peri o d .
3. 3. 3
E x pl or at or y effic ac y e n d p oi nts f or m o n ot her a p y assess me nt of d a p a glifl ozi n
a n d s a x a gli pti n

C ha n ge fr o m with dra wal baseli ne i n H b A 1c d uri n g t he ra n d omise d wi t hdra wal  p erio d .

C ha n ge fr o m with dra wal baseli ne i n F P G d uri n g t he ra n d o mise d wi t hdra wal peri o d .

Perce nta ge of  su bjects w h o ac hie ve or ma i ntai n a n H b A 1c le vel < 7 % at t he e n d of  th e 
ra n d omise d wi t hdra wal  p erio d .

Ti me t o i nitiati on of  gl ycae mic resc ue me d icati on or disc o nt i n uati on of  st u d y me dicat i on 
d ue t o lac k o f efficac y usi n g t he start ti me of ra n d o mise d wi t hdra wal peri o d as t he refere nce 
p oi nt .
3. 4
S afet y en d p oi nt s
T he assess me nt of safet y will be base d o n t he a nal yses of t he i nci de nce of A Es, S A Es, a d verse 
e ve nts of s pecial i nterest ( A E O SI), h y p o gl ycae mic e ve nts, disc o nt i n uati ons d ue t o A Es, mar ke d 
a b n or malities i n cli nical la b orat or y tests, vit al 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. 
3. 4. 1
A d verse e ve nts
A Es (serio us a n d n o n -serio us, e xcl u di n g h y p o gl ycae mic or D K A e ve nts t hat are n ot re p orte d as 
S A Es) will be c ollecte d t hr o u g h o ut t he st u d y u p t o Wee k 5 6 , a n d wi ll als o be c ollecte d q uarterl y 
bet wee n Wee k 5 6 a n d Wee k 1 0 4 via p h o ne assess me nt . A d verse e ve nts will be classifie d b y 
s yste m or ga n class ( S O C) a n d preferre d ter m ( P T) acc or di n g t o t he Me dical Dict i onar y  for 
Re g ulat or y  Acti vities ( Me d D R A), base d o n t he Me d D R A versi o n c urre nt at  the t i me of data base 
l oc k. Eac h s u bject will be c o u nte d o nce wit hi n a S O C or P T i n A E fre q ue nc y ta bles, u n der t he 
ma xi m u m i nte nsit y wi t hi n eac h cate g or y. F or s u m maries of A Es b y relati ons hi p t o st u d y  dr u g, 
as assesse d b y t he i n vestigat or (relate d, n ot relate d), s u bjects will be c o u nte d u n der t he m o st 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 4
r elate d i nsta nce wit hi n eac h S O C or P T. F or t he s u m mar y of A Es t hat occ urre d i n ≥5 % of t he 
s u bjects wit hi n a treat me nt gr o u p ( base d o n P Ts) t he n u m ber of A Es will als o be prese nte d . 
E ve nts will be c o nsi dere d treat me nt -e mer ge nt if:

T he e ve nt starte d o n or after t he first d ose of I P ( Da y 1) a n d u p t o a n d i ncl u di n g 4 da ys f or 
A Es a n d 3 0 da y s for S A Es after t he l ast d ose date.

T he e ve nt starte d bef ore Da y 1 b ut i ncrease d i n i nte nsit y or rel ate d ness t o st u d y me dicat i on 
o n or after Da y  1.

T he e ve nt o nset date is missi n g or partial ( u nless t he st o p date of t he e ve nt i n dicates t hat t he 
e ve nt ca n n ot be treat me nt e mer ge nt ). 

E ve nts will be c o nsi dere d treat me nt e mer ge nt u nless t he y ca n be pr o ve n n ot t o be s o fr om 
t he data.
Details f or ha n dli n g of missi n g a n d partial e ve nt dates f or deter mi ni n g treat me nt e mer ge nce are 
pr o vi de d i n t he A p pe n di x ( Sectio n 8. 2 ).
List i n gs will i ncl u de t he A E d urati o n, calc ulate d as A E st o p date - A E start date + 1. A E d urati o n 
will be calc ulate d o nl y whe n c o mplete dates (at least d a y , m o nt h, year) f or t he start a n d st o p 
date are pr o vi de d. Eac h A E will be gra de d f or i nte nsit y ( mil d, m o derate, se vere). If i nte nsit y is 
mi ssi n g, t he e ve nt will be re gar de d as se vere. Eac h A E will als o be assesse d f or relat i ons hi p t o 
t he st u d y d r u g (relate d, n ot relate d). A d verse e ve nts wi t h missi n g relati o ns hi p t o st u d y dr u g will 
be c o nsi dere d treat me nt -r elate d f or t he p ur p ose of  s u m marisi n g A Es relate d t o stu d y dr u g. 
A d verse e ve nts wi t h 
missi n g fla g i n dicati n g s erio us will be c o nsi dere d serio us f or A E 
s u m maries. 
A n y treat me nt f or A Es will be re p orte d u n der pri or a n d c o nc o mita nt me d icati ons (e xcl u di n g 
resc ue me d icatio n w hic h will be re p orte d se paratel y). T he A E n u m ber will be rec or de d t o t he 
c orres p o n di n g me dicat i on f or cr oss-li n ki n g p ur p oses. 
A d verse e ve nts of s peci al i nterest
A d verse e ve nts of  special i nterest will be selecte d b y Me d D R A P T a n d i ncl u de, b ut are n ot 
li mite d t o: a m p utati o ns/ peri p heral re vasc ularisat i 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 lab orat or y  ab n or malit ies (i ncl u di n g li ver f uncti o n test a b n or malit ies 
acc o m pa nie d b y ja u n dice or h y per bilir u bi ne mia); h y perse nsit i vity reacti ons (incl u di n g 
a na p h yla xis, a n gioe de ma, e xf o liati ve s ki n c o n ditio ns); se vere c uta ne o us a d verse reactio ns 
(incl u di n g b ull o us pe m p hi g oi d); ge ni tal m yc otic i nfecti o ns; necr otisi n g fasciitis of the per i ne um 
( F o ur nier’s 
ga n gre ne); 
uri nar y  tract 
i nfecti o ns (incl u di n g 
ur ose p sis/ p yel one p hri tis); 
o p p ort u nist ic i nfecti o ns; decrease d l y m p h oc yt e a n d/ or t hr o m b oc yt e c o u nts; or al  sof t tiss u e 
c o n ditio ns (e. g., st o matitis); pa ncreat itis; car diac fail ure (in cl u di n g h os pi talisati on 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 o l ume de plet i on; b o ne 
fract ures; h y perli pi dae mia ; h y p o gl ycae mic
e ve nts; h y per gl ycae mic
e ve nts; ket oaci d osis; 
mali g na ncies (i ncl u di n g bla d der ca ncer); a n d art hral gia.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 5
A d verse e ve nts of s pecial i nterest will be pr o gra m mat icall y i de ntifie d base d o n a pre defi ne d list 
of  P Ts . 
A m p utati o ns a n d u n derl yi n g c o n ditio n s rele va nt t o a m p utati o n will be rec or de d o n a s pecific 
C R F pa ge. T he A E lea di n g t o a m p utati o n s h o uld be rec or de d i n the e C R F as a n A E/ S A E. E ve nts 
p ote nti all y placi n g t he s u bject at  ris k f or a lo 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 n A E/ S A E w het her or n ot a n a m p utati o n has ta ke n place.
A fi nal re vie w will ta ke place pri or t o data base l oc k t o e ns ure ne w t er ms n ot alrea d y i ncl u de d 
i n t he o l der Me d D R A versi o n are ca pt ure d wit hi n t he cate g ories f or t he ne w hi g her Me d D R A 
versi o n. T he list will be pr o vi de d b y A Z pri or t o Wee k 5 6 data base l oc k.
He p atic a d verse e ve nts
A list of  PTs will be selecte d b ef or e Wee k 
5 6 data base l oc k of  the st u d y to facilitate 
i de ntificati on of e ve nts of he pat ic dis or ders. 
I nci de nce r ate (e x p os ure-a dj uste d)
W here 
s pecifie d, e ve nt s u m maries ma y i ncl u de the e x p os ure a dj uste d i nci de nce rate. T he 
i nci de nce rate will be e x presse d per 1 0 0 patie nt-years . T his is calc ulate d as: 
           = 1 0 0 ∗
        ℎ
≥1            s u m[mi n (          ,         )]
T he s u m  of mi n( e x p os ure ti me , ti me t o e ve nt) will be c o m p ute d b y  s u m mi n g u p t he mi ni m u m 
of  e x p os ure ti me or ti me t o e ve nt per s u bj ect acr oss all s u bjects f or eac h treat me nt a n d d ose as 
treate d ( defi ne d i n Secti on  2. 1 ). 
F or a nal yses usi n g first treat me nt as treate d (t otal da pa glifl ozi n, t otal sa xa gli pt i n, pl ace b o), 
e x p os ure ti me a n d t i me t o e ve nt are defi ne d as:
E x p os ure ti me ( years) per s u bject i s co m p ute d as (last date of e x p os ure f or t hat s u bject 
- date of  first d ose i n t he st u d y + 1)/ 3 6 5. 2 5. Ti me t o e ve nt ( years) f or s u bjects ha vi n g 
t he e ve nt is c o mp ute d as (date of  onset of  eve nt – date of  first d ose i n t he stu d y 
+ 1 )/ 3 6 5. 2 5.
F or a nal yses usi n g d ose at o ns et of AE t o a c c o u nt f or t he c ha n ge i n tr e at me nt a n d d ose at  t he 
2 n d a n d 3 r d ra n d o misati ons, e x p os ure ti me a n d ti me t o e ve nt are defi ne d as:
E x p os ure ti me ( y ears) per s u bject f or eac h treat me nt a n d d ose as treate d is c o m p ute d as 
(last date of  ex p os ure t o treat me nt a n d d ose f or t hat s u bject - date of  first e x p os ure t o 
treat me nt a n d d ose + 1)/ 3 6 5. 2 5. Ti me t o e ve nt ( years) f or s u bjects ha vi n g t he e ve nt  
w hilst o n t he c urre nt treat me nt a n d d ose is c o m p ute d as ( date of o nset of e ve nt – date o f 
first e x p os ure t o treat me nt a n d d ose + 1)/ 3 6 5. 2 5. 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 6
F or i nci de nce rate a nal yses f or e ve nts pri or t o resc ue, if n o e ve nt occ urre d pri or t o resc ue 
me dicat i on i nitiati on t he n t he date of resc ue me dicati o n i nit iati on is use d i nstea d of last date of 
e x p os ure.
3. 4. 2
De at hs
Deat hs i n t he st u d y  incl u de all  deat hs rec or de d o n t he dis p ositio n pa ge of  t he C R F (i.e. , reas o n 
f or disc o nti n uati on is deat h), t he A E pa ge (e ve nts wit h fatal o utc o me), or t he S A E pa ge ( S A Es 
t hat res ult i n deat h). 
3. 4. 3
Ot her s afet y e ve nts
3. 4. 3. 1
Di a betic ket o aci d osis
A D K A e ve nt will n ot be re p orte d o n a n A E C R F pa ge u nless t he e ve nt f ulfille d S A E cri t eria, 
i n w hic h case it sh o ul d als o be re p orte d i n t he S A E f or m. Se parate pa ges t o ca pt ure details of  
D K A e ve nts are c o nt ai ne d wi t hi n t he C R F. Details i ncl u de sig ns a n d s y m pt o ms, c o ntri b ut i n g 
fact ors, w het her l ocal la bs were perf or m e d, a n d w het her t he e ve nt is classifie d as a n S A E. 
A d j u dicati on fi n di n gs ( defi nite D K A , pr o ba ble D K A, p ossi ble D K A , n ot D K A ) will als o be 
pr o vi de d f or D K A e ve nts se nt t o t he A dj u dicat i on c o m mittee.
3. 4. 3. 2
H y p o gl yc ae mi a
H y p o gl ycae mia e ve nt will n ot be re p orte d o n a n A E C R F pa ge u nless t he e ve nt f ulfille d S A E 
criteria, i n w hic h case it sh o ul d als o be re p orte d i n t he S A E f or m. H y p o gl ycae mic e ve nt s t hat 
meet S A E criteria will be rec or de d as S A Es b y t he I n vest i gat or i n t he A E C R F pa ges. Se parate 
pa ges t o ca pt ure details of h y p o gl ycae m ia e ve nts are c o ntai ne d wit hi n t he C R F. Details i ncl u de 
s y m pt o ms, c o ntri b uti n g fact ors, bl o o d gl uc ose meas ure me nts d uri n g t he e pis o de, date a n d ti me
of  last meal, t hir d part y  int er ve nt i on, a n y treat me nt(s) recei ve d, a n d w het her t he e pis o de is 
classifie d as a n S A E. A n y self-m o nit ore d bl o o d gl uc ose (S M B G) me as ure me nts ta ke n b y t h e 
s u bjects o n t he da ys t hat t he y ex peri e nce h y p o gl ycae mia s y m pt o ms will be rec or de d i n the C R F.  
H y p o gl ycae mia e pis o des will be classifie d usi n g A D A 1 a n d I nter nat i onal S oci et y of  Pae diatric
a n d A d o lesce nt Di a betes (I S P A D)2 cate g ories. Deri vat i on d etails base d o n t he i nf or mati on 
c ollecte d i n t he se parate C R F pa ges f or h y p o gl ycae mia are pr o vide d i n t he A p pe n di x ( Sectio n
8. 9 ).
3. 4. 4
S afet y L a b or at or y tests
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 lab orat or y  eval uat i ons 
(see A p pe n di x S e cti o n 8. 1 ) a n d will be perf or me d b y ce ntral a n d l ocal la b orat ories. T he ce ntral 
la b orat or y for t his st u d y will p erf or m  the 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 f oll owi n g selecte d lab orat or y  para meters will b e 
s u m marise d:
H a e m at ol o gy:

H ae mat ocrit ,


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 7

H ae mo gl o bi n ,

P latelet c o u nt,

W hit e blo o d cell ( W B C) c o u nt,
Bl o o d c he mistry:

B ilir u bi n, t otal,

A la ni ne a mi n otra nsferase ( A L T),

A l kali ne p h os p hatase ( A L P),

A s partate a mi n otra nsferase ( A S T),

Ur at e,

Esti mate d G F R (e G F R) usi n g Sc h wartz e q uatio n ( deri ve d b y t he ce ntral la b orat or y):
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 0. 4 1 3 x ( hei g ht [c m])/ser u m creati ni ne [ m g/ dl],

C reati ni ne, ser u m,

E lectr ol ytes - s o diu m , p otassiu m, p h os p hate, c hl ori de, ma g nesi u m a n d calci u m,

P r otei n, t otal,
Uri ne A n alysis:

Al b u mi n,

A l b u mi n t o creati ni ne rati o,

G l uc ose: creati ni ne rati o,

S p ot uri ne f or gl uc ose .
A d dit i onall y , e G F R will als o be descri be d b y a ge gr o u p usi n g t he ra n d omisat i on str at a: ≥ 1 0 
a n d < 1 5 years; ≥ 1 5 a n d < 1 8 y ears.
F asti n g ser u m li pi d p a nel:

C h o lest er ol, t otal,

T rigl yceri des, 

H i gh de nsit y li p o pr otei ns ( H D L) c h o lester ol,

C alc ulate d l o w de nsit y li p o pr otei ns ( L D L) c h o lester ol.
3. 4. 4. 1
Pre g n a nc y t esti n g
Pre g na nc y will  be re p orte d as a n S A E. F or w o me n of  chil d -beari n g p ote nti al (W O C B P ),
pre g na nc y will be rec or de d i n t he s u bject's dail y e -di ar y base d o n uri ne H C G pre g na nc y testi n g 
perf or m e d at sit e or a t ho m e. If a urine H C G t est is p osi tive, ser u m pre g na nc y testi n g will b e 
perf or m e d b y t he ce ntral la b orat or y for c o nfir mati o n. T he st u d y dr u g will be disc o nt i n ue d i n 
s u bjects disc o vere d t o be pre g na nt at a n y ti me d uri n g t he st u d y.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 8
3. 4. 5
Vit al si g ns
Vi t al si g ns i ncl u de b l oo d press ure (B P) ( m m H g) a n d heart rate ( beats per mi n ute). T hese 
meas ure me nts will be o btai ne d at t he ti me p oi nts i n dicate d i n t he A p pe n di x ( Secti on 8. 1 ). 
3. 4. 6
Electr oc ar di o gr a ms
E lectr ocar di o gra ms (E C Gs) will be assesse d d uri n g t he lea d-i n visit , Wee k 2 6 , Wee k 5 2, a n d, 
if a p plica ble, d uri n g t he E T D a n d Resc ue visit s. O verall  e val uati on of E C G is c o llecte d b y visit 
as n or mal or a b n or mal, a n d t he rele va nce of t he a b n or malit y is ter me d as “cli nicall y si g nifica nt” 
or “ n o t clinicall y  si gnifica nt ". A n y E C G fi n di n g t hat is j u d ge d b y t he i n vesti gat or as a 
p ote nti all y clinicall y  si g nifica nt c ha n ge ( w orse ni n g) c o m pare d wi t h t he baseli ne val ue will be
rec or de d as a n A E.
3. 4. 7
P h ysic al ex a mi n ati o ns
C o m plete a n d t ar gete d p h ysical e xa mi nat i ons will be perf or me d at t he ti me p oi nts i n dicate d 
i n t he A p pe n d i x ( Sectio n 8. 1 ).
A b n or m al fi n di n gs pri or t o sig ni n g t he i nf or me d c o nse nt will be rec or de d i n t he C R F i n t h e
me dical hist or y  or A E pa ges de pe n di n g o n t hei r o ns et d at e. An y p h ysical e xa mi nat i on fi n di n g 
t hat is j u d ge d b y t he i n vesti gat or as a p ote ntiall y cli nicall y si g nifica nt c ha n ge ( w orse ni n g) 
c o mpare d wit h a baseli ne val ue s h o uld be re p orte d as A Es. N o p h ysical e xa mi nat i on s u m maries 
will be prese nte d.
3. 4. 8
B o d y w ei g ht, h eig ht a n d b o d y m ass in de x
B o d y  wei g ht a n d hei g ht will be meas ure d at t he ti me p oi nts i n dicate d i n t he A p pe n di x ( Secti on
8. 1 ). Bo d y  mass i n de x ( B MI ) at eac h t i me p oi nt is deri ve d fr o m t he act ual w eig ht ( k g) di vi de d 
b y t he act ual hei g ht ( m) s q uare d meas ure d at t hat ti me p oi nt. If either wei g ht or hei g ht is missi n g 
at a gi ve n visit, n o i m p utati o n of  B MI will be perf or m e d.
I n a d ditio n, t he z- sc ore a dj ust e d f or a ge a n d se x usi n g Ce ntres
f or Disease C o ntr ol  an d 
Pre ve nt i on (C D C ) f or n or m alise d b o d y  wei g ht, hei g ht a n d B MI will be deri ve d at eac h ti me 
p oi nt.
Met h o d of B MI calc ulati o n:

C o n vert p o u n ds ( l b.) t o kil o gra ms ( k g = l b. / 2. 2),

C o n vert i nc hes (i n) t o ce nti metres (c m = i n X 2. 5 4),

B MI = ( wei g ht i n k g) / ( hei g ht i n c m/ 1 0 0) 2,
R o u n d t o o ne deci mal place (if 0. 0 5 or greater, r o u n d u p) .
N or m alise d hei g ht, wei g ht a n d B MI will als o be s u m marise d a dj uste d f or a ge a n d se x a n d will 
be deri ve d as z -sc ore usi n g C D C gr o wt h c harts. Z -sc ores are calc ulate d as:
 =
      ∗∗  −1  ∗

Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
4 9
w here:

val ue = t he c hil d’s hei g ht, wei g ht or B MI;

M, L a n d S c orres p o n d t o val ues i n t he gr o wt h c har t3 a n d var y acc or di n g t o t he c hil d’s se x 
a n d a ge ( m o nt hs) or se x a n d hei g ht.
Details re gar di n g a ge deri vati o n are gi ve n i n t he A p pe n di x ( Sectio n 8. 6. 1 ). F or s u bjects ≥2 0 
years o l d t he n or malise d val ue will be base d o n t he a ge of 2 3 9. 5 m o nt hs.
I n a d ditio n, n or m alise d B MI will als o be prese nte d usi n g t he f o ll owi n g cate g or ies of  perce nt iles:
≥9 5 t h (r efers t o O bese), ≥8 5 t h a n d < 9 5 t h (r efers t o O ver wei g ht), ≥5 t h a n d < 8 5 t h (r efers t o 
Heal t h y Wei g ht), a n d < 5 t h (refers t o U n der wei g ht).
3. 4. 9
Me as ures of gr o wt h a n d m at urit y
Meas ures of gr o wt h a n d mat uri t y i ncl u de Ta n ner sta gi n g a n d ce ntral la b orat or y e val uat i ons of
gr o wt h a n d mat urati o n mar kers a n d b o ne bi o mar kers . T hese will be assesse d d uri n g t he lea d-i n
visit ( Ta n ner sta gi n g o nl y ) or Da y 1 pri or t o first d ose ( gr o wt h, b o ne a n d mat urati o n mar kers
o nl y ), a n d at Wee k 2 6, Wee k
5 2, Wee k 1 0 4, a n d (if a p plica ble) at t he E T D , Resc ue a n d n o n-
treat me nt fol l ow- u p visits.
Ta n ner sta gi n g is a meas ure of p u bertal de vel o p me nt rate d o n a scale of sta ge 1 t o st a ge 5 (f or 
details see A p pe n di x Secti o n 8. 1 0. 1 ). Ta n ner sta gi n g will be deter mi ne d base d o n i n vesti gat or 
assess me nt a n d t he s u bjects’ self-re p orts.
Gr o wt h a n d m at ur ati o n m ar kers

T h y r oid- sti m ulati n g h or m o ne ( T S H),

Free t h y r o xi ne (assesse d at Scree ni n g if T S H i s a b n or mal),

L ut ei nis i n g h or mo ne ( L H) (fe males o nl y) ,

F o llicle-sti m ulati n g h or m o ne ( F S H) (fe males o nl y) ,

Oe stra diol  (fe males o nl y) ,

T ot al  test oster o ne ( males o nl y),

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 bi o m ar kers

B o ne al kali ne p h os p hatase ,

Oste ocal ci n,

Parat h y r oid h or m o ne ( P T H) ,


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 0

Car b o x yter mi nal cr oss -li n ke d tel o pe pti de of T ype 1 c olla ge n ( C T X - 1).
3. 5
Ot her v ari a bles
Ot her varia bles i ncl u de d e m o gra p hics, di a betes-r elate d a n d ot h er baseli ne c haracterist ics, 
ra n d omisat i on stratificati on fact ors, e x p os ure t o resc ue me d icati on (ins uli n), a n d e x p os ure a n d
c o mplia nce t o st u d y  me dicat i on.
3. 5. 1
De m o gr a p hic a n d b aseli ne c h ar acteristic v ari a bles
D e m o gra p hics data are c ollecte d o n or pri or t o first ra n d o misati o n. F or s u bjects t hat are 
rescree ne d, d e m o gra p hics data c ollecte d at re-scree ni n g will be use d i n t he a nal ysis .
D e m o gra p hic a n d baseli ne c haracteristics are liste d i n Ta ble 5 . Di a betes-r elate d baseli ne 
c haracterist ics are liste d i n Ta ble 6 . Re nal f u ncti on baseli ne c haracterist ics are liste d i n Ta ble 
7.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 1
T a ble 5 De m o gr a p hic a n d B aseli ne C h ar acteristics
C h ar acteristic
S u m m ari se d as
C ate g ories
Se x
Cate g orical
Male
Fe male
A ge
Cate g orical a n d 
C o nti n u o us
≥1 0 a n d < 15 y ea rs
≥ 1 5 a n d < 1 8 y ea rs
Race
Cate g orical
W hite
Blac k or Africa n A merica n
Asia n
Nati ve Ha waiia n or Ot her Pacific Isla n der
A merica n I n dia n or Alas ka Nati ve
Ot her
Et h nicit y
Cate g orica l
His pa nic/ Lati n o
N o n -His pa nic / Lati n o
Baseli ne Hei g ht (c m) a n d 
N or malise d Hei g ht
C o nti n u o us
-
Baseli ne B o d y W ei g ht ( k g) a n d 
N or malise d Wei g ht
C o nti n u o us
-
N or malise d B MI
Cate g orical a n d 
C o nti n u o us
Perce ntiles as defi ne d b y C D C *
≥ 9 5t h
≥8 5t h a n d < 9 5t h
≥5t h a n d < 8 5t h
< 5t h
Ge o gra p hic re gi o n
Cate g orical
Re gi o ns as defi ne d i n A p pe n di x Ta ble 2 2
Asia/ Pacific 
E ur o pe
Lati n A merica
N ort h A merica
* ≥9 5 t h refers t o O bese; ≥8 5 t h a n d < 9 5 t h refers t o Over wei g ht; ≥5 t h a n d < 8 5 t h refers t o He alt hy Wei g ht; < 5 t h
refers t o U n der wei g ht.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 2
T a ble 6 Di a betes - Rel ate d B aseli ne C h ar acteristics
C h ar acteristic
S u m m ari se d as
C ate g ories
D urati o n of T y pe 2 Dia betes 
Mellit us (see bel o w f or calc ulati o n)
Cate g orical a n d 
C o nti n u o us
< 2 y ea rs
2 a n d 5 y ea rs
> 5 y ea rs
H b A 1c
Cate g orical a n d 
C o nti n u o us
< 6. 5 %
≥ 6. 5 a n d < 8 %
8 a n d ≤1 0. 5 %
> 1 0. 5 %
F P G
C o nti n u o us
Bac k gr o u n d a nti -dia betic me dicati o n
Cate g orical
Metf or mi n o nl y
I ns uli n o nl y
Metf or mi n + I ns uli n
Bac k gr o u n d a nti -dia betic me dicati o n 
t otal dail y  d ose
C o nti n u o us
Metf or mi n d ose 
I ns uli n d ose
C o m bi nati o ns of ra n d o misati o n
stratificati o n fact ors
Cate g orical
Male - ≥ 1 0 a n d < 1 5 years - Metf or mi n o nl y
Male - ≥ 1 0 a n d < 1 5 years - I ns uli n o nl y
Male - ≥ 1 0 a n d < 1 5 years - Metf or mi n + 
I ns uli n
Male - ≥ 1 5 a n d < 1 8 year s - Metf or mi n o nl y
Male - ≥ 1 5 a n d < 1 8 years - I ns uli n o nl y
Male - ≥ 1 5 a n d < 1 8 years - Metf or mi n + 
I ns uli n
Fe male - ≥ 1 0 a n d < 1 5 years - Metf or mi n o nl y
Fe male - ≥ 1 0 a n d < 1 5 years - I ns uli n o nl y
Fe male - ≥ 1 0 a n d < 1 5 years - Metf or mi n + 
I ns uli n
Fe m ale - ≥ 1 5 a n d < 1 8 years - Metf or mi n o nl y
Fe male - ≥ 1 5 a n d < 1 8 years - I ns uli n o nl y
Fe male - ≥ 1 5 a n d < 1 8 years - Metf or mi n + 
I ns uli n
T a ble 7 B aseli ne Re n al F u ncti o n C h ar acteristics
C h ar acteristic
S u m m ari se d as
C ate g ories
e G F R
Cate g orical a n d 
C o nti n u o us
< 6 0 m L/ mi n/ 1. 7 3 m 2
6 0 a n d < 9 0 m L/ mi n/ 1. 7 3 m 2
9 0 a n d < 1 2 0 m L/ mi n/ 1. 7 3 m 2
1 2 0 m L/ mi n/ 1. 7 3 m 2
T ot al D ail y D ose of Metf or mi n or I ns uli n


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 3
If se veral me dicati ons are o n g oi n g o n Da y  1, t he d oses will be s u m me d.
D ur ati o n of di a betes
D urati o n of  dia betes will be calc ulate d as t he n u m ber of  years fr om T 2 D M di a g n osis date t o 
i nf or me d c o nse nt date:
(D ate of i nf or me d c o nse nt - date of T 2 D M dia g n osis + 1 ) / 3 6 5. 2 5. 
R ul es f or ha n dli n g missi n g or partial T 2 D M dia g n osis dates are pr o vi de d i n t he A p pe n di x
( Sectio n 8. 4 ). D urati o n of  diabetes , e ve n if parti all y im p ute d, will be i ncl u de d i n t he r ele va nt  
listi n g. O nl y o bser ve d da tes will be prese nte d i n t he listi n gs.
3. 5. 2
Me dic al h ist or y
Me dical hist or y i ncl u des me dical c o n dit i ons wi t h o nset pri or t o t he i nf or me d c o nse nt si g nat ure, 
t hat st o p pe d prior t o scree ni n g or were o n g oi n g at scree ni n g. Me dical c o n dit i ons wi ll be c o de d 
usi n g t he c urre nt versi o n of  Me d D R A
at t he ti me of  data base l oc k t o ma p eac h ver bat i m ter m 
t o a S O C a n d P T .
3. 5. 3
Pri or a n d co nc o mit a nt m e dic ati o ns
I nf or mat i on o n a ll pri or a n d c o nc o mit a nt me d icati ons a n d t hera pies will be re vie we d t hr o u g h o ut 
t he st u d y a n d at Wee k 5 6 . Treat me nt details f or s u bjects recei vi n g bac k gr o u n d i ns uli n a n d/ or 
met f or mi n will be rec or de d se paratel y t o ot her n o n-st u d y me dicat i ons. All me dicat i ons will be 
c o de d usi n g t he c urre nt versi o n ( at t he ti me of  data base l oc k) of  W o rld Heal t h Or ga nisatio n 
D r u g Dicti o nar y  (W H O D D) , a nd t he A nat o mical T hera pe utic C he mical ( A T C) classificati o n 
s yste m.
Me dicat i ons will be classifie d as pri or or c o nc o mit a nt. A pri or me dicat i on is defi ne d as a n y 
me dicat i on t hat starte d a n d st o p pe d pri or t o t he first ra n d o mise d d ose. C o nc o mita nt me dicat i ons
are t h ose wi t h eit her

A rec or de d me dicat i on start date falli n g wi t hi n t he a nal ysis p eri o d ( S T or S T + L T 
treat me nt perio d) , or

A
rec or de d me d icati on start date pri or to t he first da y of  do u ble -bli n d st u d y 
me dicat i on wi t ho ut a n y rec or de d me d icatio n st o p date pri or t o t he start of  the S T 
treat me nt perio d , or

A rec or de d me dicat i on star t date prior t o t he first d a y of S T st u d y me dicatio n wi t h a 
rec or de d me d icatio n st o p date after t he start of t he S T treat me nt peri o d .
R ul es f or class if yi n g me dicat i ons as prior or c o nc o mi t a nt i n c as e of p artial, missi n g or i n vali d 
start a n d st o p dates are descri be d i n t he A p pe n di x ( Secti o n 8. 3 ). O nl y o bser ve d dates will b e 
prese nte d i n t he list i n gs.
A nt i dia betic c o nc o mit a nt me dicatio ns will be selecte d usi n g W H O -D D A T C c o di n g :


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 4

All i ns uli n a nti dia betic me dicat i on ( A 1 0 A)

All n o n- i ns uli n a nti dia betic me dicatio n ( A 1 0 b ut n ot A 1 0 A)
3. 5. 4
E x p os ure t o s t u d y tre at me nt 
St u d y  me dicati on is dis pe nse d at ra n d o misati on a n d at  the t i me p oi nts i n dicate d i n t he A p pe n di x 
( Sectio n 8. 1 ). Fr o m  Da y 1 to Wee k
1 4 s u bjects are i nstr ucte d t o ta ke t wo t a bl ets dail y . Fr o m 
Wee k 1 4 t o Wee k 5 2
s u bjects are i nstr ucte d t o ta ke t hree ta blets dail y.
F or t he S T a n d S T + L T peri o d, s u bjects’ e x p os ure will be prese nte d u n der t he first treat me nt 
recei ve d (i. e. t ot al da pa gliflo zi n, t ot al  sa xa gli pti n, a n d place b o). A d dit i onal s u m maries will  be 
prese nte d b y act ual dose a n d tr e at me nt t o acc o u nt f or s u bjects o n acti ve st u d y me dicat i on 
s witc hi n g t o hi g h -d ose at Wee k 1 4 a n d s u bjects c ha n gi n g treat me nt or u p -titrati n g after t he t hir d 
ra n d omisat i on.
F or t he ra n d omise d wi t hdra wal  perio d, s u bjects’ e x p os ure will be prese nte d u n der t he treat me nt 
recei ve d aft er t he t hir d ra n d o misati on (i.e. acc o u nti n g f or su bjects s witc hi n g fr om place b o t o 
da pa glifl ozi n or sa xa gli pt i n).
E x p os ure pri or t o resc ue me dicat i on i nit iati on i ncl u des e x p os ure u p t o a n d o n t he da y o f resc ue 
me dicat i on i nitiati on.
Treat me nt d urati o n ( da y s) will be calc ulate d as:

S T peri o d: date of last d ose d uri n g t he S T peri o d - date of first d ose + 1 ,

S T + L T peri o d: date of last d ose - date of first d ose + 1 ,

Ra n d o mise d
Wit h dra wal p eri o d: date of  last d ose - date of  first d ose i n t he 
Ra n d o mise d Wit h dra wal  p erio d + 1.
Treat me nt d urati o n ( da ys) b y d ose (l ow, hi g h) f or da pa glifl o zi n a n d sa xa gli pti n will be 
calc ulate d as:
F or s u bjects w h o were ra n d o mise d t o u p- titr ate at Wee k 1 4:

L o w -d ose: date of last d ose u p t o Wee k 1 4 visit – date of first d ose + 1 ,

Hi g h -d ose: 
o
F or t he S T peri o d: date of last d ose d uri n g t he S T perio d – date of first d ose 
after t he Wee k 1 4 visit + 1,
o
F or t he S T + L T peri o d: date of last d ose – date of first d ose after t he Wee k 1 4 
visit + 1 ,


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 5
F or s u bjects w h o were ra n d o mise d t o n ot u p- titrate or were res p o n ders at  Wee k 1 4 (l o w-d ose 
o nl y):

S T peri o d: date of last d ose d uri n g t he S T peri o d - date of first d ose + 1 ,

S T + L T peri o d: date of l ast d ose - date of first d ose + 1 .
3. 5. 5
E x p os ure t o resc ue me dic ati o n
If a s u bject has resc ue i ns uli n rec or ds wit h o verla p pi n g start a n d e n d dates, t he n ma xi m u m t otal 
dail y  d ose of resc ue i ns uli n will be calc ulate d as:

If t he resc ue i ns uli n rec or ds ha ve differe nt preferre d na mes t he n t he t otal dail y d ose 
f or eac h rec or d will be s u m me d,

If t he resc ue i ns uli n rec or ds ha ve t he sa me pr ef erre d na me t he n fr om t he start of  
o verla p t he ma xi m u m t otal dail y dose will be t he t otal dail y d ose fr om t he resc ue 
i ns uli n rec or d wit h t he lar ger d ose.
P arti al resc ue i ns uli n start a n d e n d dates are i m p ute d as defi ne d i n A p pe n di x 8. 4 .
3. 5. 6
Tre at me nt c o m pli a nce
Treat me nt c o m p lia nce ( %) f or t h e st u d y me dicat i on d uri n g t he treat me nt peri o d is defi ne d f or 
eac h s u bject as 1 0 0 X t he n u m ber of  ta blets ta ke n o ver t he peri o d di vi de d b y t he n u m ber of 
ta blets t hat s h o ul d ha ve bee n ta ke n i n that treat me nt peri o d (t he s u m of the n u m ber of t he ta blets 
t hat s h o ul d ha ve bee n ta ke n i n eac h e x p os ure rec or d wit hi n t hat peri o d) . C o m p lia nce will b e 
deri ve d base d o nl y o n c o m plete dis pe nse d a n d ret ur ne d i nf or mat i on (i.e. n o i m p utatio n will be 
d o ne o n f ull y missi n g ret ur ne d ki ts, missi n g ret ur ne d date , or u n k n o w n n u m ber of  ret ur ne d 
ta blets) a n d c orres p o n di n g e x p os ure rec or ds. If o ne or m o re kit s (incl u di n g u nsc he d ule d ki ts) 
f or a visit were n ot ret ur ne d, t he n t he kits a n d e x p os ure rec or d f or t hat visit are n ot use d i n t he 
c o mplia nce calc ulat i on.
C o m plia nce f or t he S T peri o d will s u m visit s fro m  Da y 0 u p t o a n d i ncl u di n g Wee k 
2 6, 
c o mplia nce f or t he S T + L T p eri o d will s u m all visit s, a n d c o m p lia nce f or t he ra n d omise d 
wi th dra wal p eri o d will s u m visits aft er t he t hir d ra n d o misati on ( Wee k 3 2 or Wee k 
4 0 as 
a p plica ble) .

T he n u m ber of  t a bl ets ta ke n i n a peri o d is: n di s pe nse d ( 7 0 ta blets x t he n u m ber of  
ki ts dis pe nse d) - n ret ur ne d d uri n g t hat peri o d. 

T he n u m ber of  ta blets t hat s h o ul d ha ve bee n ta ke n f or eac h e x p os ure rec or d is 
calc ulate d as f oll o ws:
F or e x p os ure rec or ds u p t o a n d i ncl u di n g Wee k 
1 4 visit ( or earl y tr e at me nt 
di sc o nti n uati on f or s u bjects w h o disc o nti n ue treat me nt pri or t o Wee k 1 4):


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 6
o
( Date of  last d ose i n t he visit – date of first d ose i n t he visit + 1) X 2 ta blets/ da y
F or e x p os ure rec or ds aft er Wee k 1 4 visit:
o
( Date of last d ose i n t he visit – date of first d ose i n t he visit + 1) X 3 ta blets/ da y
If t he s u bject u n der we nt t he t hir d ra n d om isatio n t o wit hdra wal  fr o m metfor m i n, 
t he n t he n u m ber of ta blets t hat s h o ul d ha ve bee n ta ke n i n t he ra n d omise d
wi t hdra wal  p erio d is :
o
(Date of  last d ose - date of first d ose + 1) X 3 ta blets/ da y , for visi ts after t he 
t hir d ra n d o misati on ( Wee k 3 2 or Wee k 4 0 as a p pl ica ble)
A s u bject is c o nsi dere d c o mplia nt if o verall tr e at me nt c o mplia nce is bet wee n 8 0 % a n d 1 2 0 % 
of  t hat prescri be d. If c o m p lia nce ca n n ot be calc ul at e d for a  s u bject, t he n t heir c o mplia nce will 
be prese nte d as U n k n o w n i n t he s u m mar y ta bles.
3. 6
P h ar m ac o ki netic / p h ar m ac o d y n a mic assess me nts
Bl o o d sa mples f or deter mi nati o n of  plas ma levels of  da pa glifl ozi n, sa xa gli pti n a n d its 
meta b o lite 5- O H -sa xa gli pti n will be ta ke n at t he ti mes prese nte d i n t he A p pe n di x Sect i on 8. 1
(Ta ble 1 7) . I n a d dit i on, F P G will be c o llecte d at  pre-d ose a n d 2 h o urs p ost d 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 t he A p pe n di x Secti o n 8. 1 (Ta ble 1 7 ) f or t he 
p har mac o d y na mic assess me nts. Plas ma c o nce ntrati o n data will be s u m marise d as part of  this 
S A P a n d i ncl u de d i n t he C S R. 
P har mac o ki net ics a n d e xp os ure -res p o nse relati o ns hi p a nal ysis will be s u m marise d a n d re p orte d 
i n a se parate re p ort as nee de d. If s uc h a re p ort is pr o d uce d, full  details of t he a nal ytical met h o ds 
use d will be descri be d .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 7
4.
A N A L Y SI S M E T H O D S
4. 1
Ge ner al pri nci ples
S A S versi o n  9. 4, or hi g her, will be use d t o pr o d uce all ta bles, listi n gs, a n d fi g ures. All t a bl e, 
listi n g, a n d fi g ure s pecificati ons are pr o vi de d as se parate d oc u m e nts; t hese m u st be rea d i n 
c o nju nct i on wi t h t he c orres p o n di n g S A P versi on. 
T he c o nfir mat or y a nal yses of  the pri mar y  an d sec o n dar y en d p o i nts wit hi n eac h dr u g 
( da pa glifl ozi n vs. pl ace b o a n d sa xa gli pti n vs. place b o) will be p erf or me d usi n g a hierarc hical 
testi n g a p pr oac h wi t hi n eac h dr u g at t he t wo- si de d 0. 0 5 lev el  (wi t h corres p o n di n g 9 5 % CIs). 
N o c o m par is o ns will be perf or me d bet wee n da pa glifl ozi n a n d sa xa gli pt i n.
W he n fittin g m o d el s w hic h i n v ol ve t he stratificat i o n varia bles, i n case of n o n-c o n ver ge nce t he 
stratificati on level ma y be c o m bi ne d wi t h ot her le vels or o ne or m o re stratificati on varia bles 
ma y be re m o ve d fr o m t he mo d el .
F or eac h i m p utatio n a n d statistic al mo d el  descri be d belo w a dj uste d o n ra n d o misati on strata, i n 
case of  no n -c o n ver ge nce (i.e.: beca use of  sparse data), t he f oll owi n g bac k - u p m o dels will b e 
use d i n t he prese nte d or der :
1)
Re m o ve ra n d omisat i on strata of se x,
2)
Re m o ve ra n d omisat i on strata of se x a n d a ge,
3)
Re m o ve ra n d omisat i on strata of  se x a n d a ge a n d c o lla pse ra n d omisat i on strata of 
bac k gr o u n d me d icatio n i n t w o m o dalit ies t o prese nt ( metfor m i n o nl y  an d i ns uli n o nl y 
gr o u pe d wi t h metf or mi n + i ns uli n),
4)
Re m o ve ra n d omisat i on strata of se x, a ge a n d bac k gr o u n d me d icati on.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 8
4. 1. 1
Defi niti o ns
B aseli ne 
U nless state d ot her wise, f or eac h s u bject, baseli ne val ue of  a para meter (e. g., efficac y la b orat or y 
para m eter, safet y la b orat or y test, E C G or p h y sical meas ure me nt e n d p oi nt) is defi ne d as t he last 
assess me nt o n or prior t o t h e d at e of  t he first d ose of t he d o u ble-bli n d st u d y me dicat i on i n t h e 
S T treat m e nt perio d ( Da y  1).
If t here are m ulti ple assess me nts wit h t he sa me date a n d time, t he a vera ge val ue will be use d as 
baseli ne.
F or s u bjects b el o n gi n g t o t he Ra n d o mise d
Wit h dra wal  Su bjects Data Set, t he wi t hdra wal 
baseli ne val ue f or a gi ve n para m eter is defi ne d as t he cl o sest a vaila ble val ue o n or bef ore t he 
d a y  of first d ose i n t he Ra n d omise d Wit h dra wal peri o d .
C h a n ge fr o m b aseli ne
C ha n ge fr o m baseli ne t o a n y Wee k t i n the a nal ysis peri o d (i.e., S T treat me nt peri o d a n d S T + L T 
treat me nt perio d) i s defi ne d as f oll ows: 
C Week t = M Week t - Mb aseli ne ,
w here:

C Wee k t is t he c ha n ge fr o m baseli ne at Wee k t,

M Wee k t is t he meas ure me nt at Wee k t,

M baseli ne is t he meas ure me nt at baseli ne.
T he “ Wee k t” t o w hic h a me as ure me nt belo n gs is deter mi ne d usi n g t he c o n ve nt i ons descri be d 
i n Ta ble 8 ( Sectio n  4. 1. 6 ).
L ast o bser v ati o n c arrie d f or w ar d ( L O C F)
A p ost -baseli ne missi n g val ue will be i m p ute d b y t he last a vaila ble n o n- missi n g p ost -baseli ne 
or p ost -wit h dra wal baseli ne (as a p plica ble) val ue. If t he first sc he d ule d p ost -baseli ne or p ost -
wi t hdra wal  baseli ne val ue is missi n g , n o i m p utati o n will be d o ne.
D a y 1 is t he date of first d ose of st u d y dr u g i n t he S T peri o d. 
St u d y d a y is defi ne d rel at i ve t o t he date of first d ose ( Da y 1) recei ve d i n S T tr e at me nt  p erio d, 
a n d is calc ulate d as: 

If assess me nt date is bef ore t he date of first d ose: assess me nt date - date of first d ose 
i n t he S T p eri o d ( Da y  1).

If assess me nt date is o n or after t he date of first d ose: assess me nt date - date of first  
d ose i n t he S T peri o d ( Da y 1) + 1.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
5 9
Tre at me nt res p o nse t o H b A 1c
A treat me nt res p o n der at Wee k t is a s u bject wit h H b A 1c < 7 % at Wee k t (irres pecti ve of 
baseli ne val ue). H b A 1c res p o nse at Wee k t will be deri ve d b y dic h ot o misi n g H b A 1c val ues at 
Wee k t ( bi nar y varia ble, set t o 1 if H b A 1c < 7 % at Wee k t a n d 0 if H b A 1c ≥ 7 % at Wee k t). 
W here s pecifie d, missi n g H b A 1c res p o nses at Wee k t will be deri ve d fr o m i m p ute d c o nti n u o us 
val ues of H b A 1c f or Wee k t. 
Resc ue me dic ati o n i niti ati o n
Resc ue me dicat i on i nitiati on is defi ne d as t he first date/ti me of  resc ue i ns uli n rec or de d o n t h e 
Resc ue I ns uli n e C R F. Partial resc ue i ns uli n start dates are i m p ute d as defi ne d i n A p pe n di x  8. 4 .
Pri or t o resc ue me dic ati o n i niti ati o n
A n assess me nt or e ve nt is defi ne d as prior t o resc ue if t he date/ti me of t he assess me nt or e ve nt 
occ urre d pri or t o t h e date/ti me of  first resc ue me d icati on. If t he assess me nt or e ve nt o nl y has 
date c o llecte d, t he n pri or t o r es c u e i ncl u des assess me nts or e ve nts t hat occ urre d o n t he d a y  of 
first resc ue me dicatio n.
S u bjects ma y ha ve bee n resc ue d (i.e. ha d a resc ue visit per t he pr ot oc ol g ui da nce), b ut ha ve n ot 
ha d t heir i ns uli n d ose i ncrease d if t h e y were o n bac k gr o u n d i ns uli n or starte d i ns uli n if t he y 
were o n bac k gr o u n d metf or mi n o nl y , if t heir hi g h H b A 1c or F P G res ults meet i n g t he resc ue 
crit erio n were ma na ge d b y  diet a n d e xercise. T hese s u bjects w h o did n ot start or i ncrease t otal 
dail y i ns uli n d ose after t he resc ue vi sit a n d is t h us n ot rec or de d o n t he Resc ue I ns uli n e C R F will 
be i ncl u de d i n t he se nsiti vity a nal yses.
4. 1. 2
Descri pti ve su m m aries of co nti n u o us v ari a bles
Descri pt i ve s u m mar y st atistics f or c o nti n u o us varia bles will i ncl u de: n u m ber of  no n -missi n g 
rec or ds n, mea n, sta n dar d de viati on ( S D), me dia n, mi ni m u m a n d ma xi m u m. If a p pr o pri at e, 1 st
a n d 3 r d q uartiles will als o be prese nte d. F or P K pl as ma c o nce ntratio ns, s u m mar y stati stics will 
a d ditio nall y i ncl u de ge o met ric mea n, ge o metri c S D (f oll owi n g bac k tra nsf or mati on of  a l og 
tra nsf or me d ge o metric mea n) a n d t he c oefficie nt of variat i on ( C V %).
Data re p orti n g details (s uc h as n u m ber of  deci mals) are pr o vi de d i n t he A p pe n di x
( Sectio n
8. 1 2 ).
4. 1. 3
Descri pti ve su m m aries of c ate g oric al v a r i a bles
Cate g orical data will be s u m marise d f or eac h treat me nt gr o u p or re gi me n as t he n u m ber a n d 
perce nta ge of s u bjects i n eac h cate g or y. Perce nta ges will be calc ulate d o ut of t he t otal nu m b er 
of  s u bjects i n t he a nal ysis set (a n d treat me nt gr o u p as a p pr o priate) f or t he varia ble s u m marise d.
Wei g hte d pr o p orti o ns will be calc ulate d as t he wei g hte d c o u nt of s u bjects wit h t he e ve nt o ut of 
t he t otal n u m ber o f w ei g hte d s u bjects i n t he a nal ysis set (a n d treat me nt gr o u p as a p pr o priate).


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 0
4. 1. 4
S u m m aries of shift i n cate g oric al v ari a bles
Descri pt i ve s u m maries of  cha n ge fr om baseli ne i n selecte d cate g orical varia bles will b e 
pr o vi de d usi n g s hift ta bles. O nl y s u bjects wi t h baseli ne a n d p ost -treat me nt or p ost -stu d y /foll o w -
u p (as a p plica ble) assess me nts will be i ncl u de d i n t he s hift ta ble s u m maries. Fre q ue ncies a n d 
perce nta ges of s u bjects wi t hi n eac h treat me nt gr o u p or re gi me n will be ge nerate d f or l e v els of 
cr oss-classif icati ons of  baseli ne, t he o n-treat me nt val ue a n d t he p ost -stu d y /foll o w -u p val ue (if 
a p plica ble) of  the para meter. T he o n -treat me nt val ue ca n eit her be t he val ue at a certai n ti me 
p oi nt, or (f or e xa m ple, lab orat or y  tests) t he mi ni m u m/ ma xi m u m val ue i n t he di r e ctio n of 
t o xicit y whic h has bee n o bser ve d d uri n g t he a nal ysis p eri o d. S u m maries of  shifts will o nl y 
i ncl u de t he fre q ue nc y a n d perce nta ge of  su bjects b y s hift cate g or y an d tr e at me nt gr o u p . N o
differe nces i n t hese perce nta ges bet wee n treat me nt gr o u ps or re gi me ns will  be assesse d .
4. 1. 5
Tre at me nt re gi me ns
T he f o ll owi n g treat m e 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 ni tial tr e at me nt of t he l ow- d ose ( 5 mg of  da pa glifl ozi n or 2. 5 mg of 
sa xa gli pti n) f oll owe d b y u p- titrati n g t o t he hi g h -d ose ( 1 0 m g of  d a pa glifl ozi n or 5 m g of  
sa xa gli pti n) f or t h ose w h o d o n ot ac hie ve t he gl yc ae mic tar get of H b A 1c < 7 % at Wee k 1 2
( n ot res p o n di n g a n d r e-ra n d o mise d t o hi g h -d ose) a n d c o nti n ui n g treat me nt wit h t he l ow-
d os e f or t h ose ac hi e vi n g t he gl ycae mic tar get of H b A 1c < 7 % at Wee k 1 2 (res p o n di n g a n d 
n ot re -ra n d o mise d; Gr o u ps I & III i n Fi g ure 1 ).

L o w -d ose: I nit ial treat me nt of t he l o w-d ose ( 5 m g of d a pa glifl o zi n or 2. 5 m g of sa xa gli pt i n) 
f oll owe d b y c o nt i n ui n g treat me nt o n t he l ow- d ose dr u g f or t hose w h o d o n ot ac hie ve t he 
gl ycae mic tar get of  Hb A 1c < 7 % at Wee k 1 2 ( n ot res p o n di n g a n d re-ra n d omise d
t o l ow-
d ose) a n d t hose ac hie vi n g gl ycae mic tar get of  H b A 1c
< 7 % at Wee k 1 2 (res p o n di n g a n d 
n ot re -ra n d o mise d; Gr o u ps I & II i n Fi g ure 1) .

Pl ace b o, all s u bjects ra n d omise d t o place b o . 
S u bjects w h o are recei vi n g bac k gr o u n d me d icatio n wi t h ins uli n o nl y , or met f or mi n + i ns uli 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 misati on ) will c o nt i n ue wi t h their 
ra n d omise d
st u d y me dicatio n assi g ne d aft er 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 plet i on o f 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 d icati on wi t h metfor mi n o nl y  will u nder g o a t hir d ra n d o misati on
(ra n d o mise d wi t hdra wal  of bac k gr o u n d me d icati o n) at eit her Wee k 
3 2 or Wee k 
4 0. T he 
f oll owi n g treat m e nt c o mparis o ns are c o nsi dere d f or t his a nal ysis:

F or s u bjects i nitiall y ra n d o mise d t o d a pa glifl o zi n ( or sa xa gli pt i n): I nitial treat me nt of  the 
o verall (c o m bi ne d l ow -d ose a n d hi g h -d ose) d a pa glifl o zi n ( or sa xa gli pti n) wi t h m et f or mi n 
c o mpare d t o hi g h -d ose d a pa glifl ozi n ( or sa xa gli pt i n) wit h o ut m et f or mi n.

F or s u bjects i nit iall y ra n d o mise d t o place b o: I nit ial treat me nt of  the p lace b o wit h m etfor m i n 
c o mpare d t o hi g h -d ose d a pa glifl ozi n ( or sa xa gli pt i n) wit h o ut m et f or mi n.

F or all s u bjects, re gar dless of  init ial ra n d o misati on, base d o n t hir d ra n d o misati o n (for A E
a n d mar ke d a b n or malit y [M A ] la b orat or y a nal ysis o nl y) .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 1
F or Wee k 1 0 4 a nal yses, s u bjects will be s u m marise d base d o n b ot h t he first a n d last treat me nt 
recei ve d a n d als o re peate d f or t he s u bset of Wee k 1 0 4 c o m pleters (s u bjects w h o ha d t he Wee k 
1 0 4 visit) .
Refer t o A p pe n di x 8. 1 3 f or f ull details o n t he prese ntati o n of  the treat me nt labels f or t he 
a nal ysis.
4. 1. 6
Tre at me nt a n d d ose assi g n me nts
F or d ose at o nset a nal yses, s u bjects will be prese nte d u n der t he treat me nt a n d d ose recei ve d. 
F or assess me nts ta ke n o n t he da y  of t he pla n ne d d o se c ha n ge ( Wee k 1 4, Wee k 3 2/ 4 0 [if 
s u bject u n der we nt t he t hir d ra n d omisat i on ]), s u bjects will be assi g ne d t o t he pre vi o us d ose. 
F or e ve nts (a d verse e ve nts) t hat occ urre d o n t he da y o f t he pla n ne d d ose c ha n ge, s u bjects will 
be assi g ne d t o t he ne w d ose.
F or P K a nal yses, s u bjects will be prese nte d u n der t he treat me nt a n d d ose recei ve d o n t he da y 
of  t he assess me nt.
4. 1. 7
D at a s u m m aries a n d listi n gs
Da pa glifl ozi n a n d sa xa gli pti n will be s u m marise d se paratel y. F or de m o gra p hics a n d efficac y 
a nal yses, a nal yses will be prese nte d b y tr e at me nt re gi me n (lo w -d ose, l ow- d ose/ hi g h -d ose). I n 
a d ditio n, f or de m o gra p hics, a n d ( w here s pecifie d) efficac y a nal yses, a nal yses will als o be 
pr o vi de d f or o verall dr u g (c o m bi ni n g all d oses of eac h dr u g) . F or safet y a nal yses, a nal yses will 
be prese nte d b y  o verall dr u g. T he 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.
D e m o gra p hics a n d efficac y anal yses will be base d o n t he Ra n d o mise d
S u bjects Data Set a n d 
t he ra n d o mise d treat me nt assi g n me nt. Selecte d d e m o gra p hics a n d efficac y su m maries a n d 
a nal yses will als o be pr o vi de d f or t he U p -titratio n Ra n d o mise d
a n d Ra n d o mise d Wit h dra wal 
S u bjects D ata S et s. I n ad di tio n t o t h e a nal yses base d o n t he Ra n d o mise d S u bjects Data Set , a 
se nsiti vity a na l ysis of t he pri mar y efficac y e n d p oi nt will be p erf or m e d usi n g t he E val ua ble 
S u bjects Data Set if greater t ha n 1 0 % of  s u bjects of a n y treat me nt or place b o ha ve R P Ds. Safet y 
a nal yses will be base d o n t he Treate d S u bjects Data Set a n d t he act ual treat me nt assi g n me nt. 
I n a d ditio n, wi t hi n t he a nal yses of  da pa glifl ozi n a n d sa xa gli pti n se paratel y, t he o verall 
(c o m bi ne d l ow- 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 gr 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 or sa xa gli pti n treat me nt gr o u ps will be c o m bi ne d a n d 
c o mpare d t o t he (c o m m o n) pl ace b o gr o u p.
Data su m maries a n d s pecific a nal yses b y st u d y p eri o d wi ll be restricte d t o t he c ut -off d at es 
defi ne d i n Ta ble 8 . C o m par is o ns are base d o n o nset dates f or e ve nts a n d t he date of asse ss me nt 
f or ot her para meters (la b orat or y tests, vit al si g ns etc.). T he S T a n d S T + L T peri o ds start fr om 
Baseli ne ( d a y of first d ose i n t he S T peri o d) a n d t he Ra n d o mise d Wit h dra wal peri o d starts fr o m
Ra n d o mise d Wit h dra wal Baseli ne ( d a y of first d ose i n t he Ra n d o mise d
Wit h dra wal p eri o d) . 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 2
T he ti me is i ncl u de d i n t he c o m par is o ns o nl y  if b ot h dates be i n g c o m pare d ha ve t he ti me 
pr o vi de d. 
F or t hose data w hic h will be liste d, eac h s u bject will a p pear i n t he listi n gs wi t h their s u bject 
i de ntifier, a ge, se x, race a n d bac k gr o u n d me dicat i o n. O nl y su bjects wi t h data a vaila ble will be 
prese nte d i n t he listi n gs. If a visit t o o k place b ut n o d a t a is e ntere d f or t he t ype of  assess me nt 
bei n g liste d ( ot her t ha n ' N ot D o ne'), t he e ntr y will n ot be liste d. S u bject data listi n gs will  be 
s orte d b y s u bject i de ntifier, treat me nt gr o u p, d ose (lo w, l ow/ hi g h) as per first ra nd o misat i on,
u p- titr atio n , a n d t hir d ra n d omisat i on , a n d if a p plica ble, para m eter gr o u p, para meter na me,  
n o mi nal visi t na me, a nal ysis visit n a me ( Baseli ne, Wee k 2, et c.), visit date a n d date/ti me of  
assess me nt ( wit h corres p o n di n g d a y  relat i ve t o first d ose), u nless s pecifie d ot h er wise. E ve nts 
t hat occ urre d after first resc ue me dicat i on use will be fla g ge d i n t he efficac y listi n gs.






Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 5
F or a nal yses usi n g data u p t o Wee k 3 2, i n cases w here Wee k 3 2 visit date is missi n g a n i m p ute d 
Wee k 3 2 date will be deri ve d usi n g t he earliest p ossi ble date of  t he f oll owi n g:

Wee k 2 6 date (tar get d a y  18 3) e xtra p olate d t o esti mate t he Wee k 3 2 date (tar get da y 
2 2 5)

T hi r d ra n d o misati on date

Ne xt visit date after Wee k 3 2
F or a nal yses prese nt i n g t he p ost -st u d y visit, n o n-treat me nt f oll ow- u p visit s or Wee k 1 0 4, n o  
c ut -off dates a p pl y. U nsc he d ule d Wee k 1 0 4 visits will be s u m marise d as Wee k 1 0 4.
4. 1. 7. 1  
Visit w i n d o ws
As s u bjects d o n ot al wa ys a d here t o t he ter ms a n d c o n diti ons defi ne d i n t he st u d y pr ot oc ol, visit  
wi n d o ws will be use d t o assi g n eac h cli nical  assess me nt t o a sc he d ule d visit (for data t hat will 
be s u m marise d b y visit, as s h o w n i n  Ta ble 9, Ta ble 1 0, a n d Ta ble 1 1) .
T o a p pl y t he visit wi n d o ws, n ote t he f oll o wi n g r ules f or defi ni n g t he start a n d e n d of eac h st u d y 
p eri o d:

T he S T peri o d starts fr o m Da y 1 (start date of I P) a n d e n ds o n t he start date of t he Wee k 
2 6 visit or earl y disc o nt i n uati on fr o m t he st u d y, whic he ver is earlier . F or s u bjects w h o 
di d n ot e nter t he L T peri o d, t here is n o c ut -off date.

F or s u bjects e nteri n g t he L T p eri o d, t he L T p eri o d st arts fr o m t he da y aft er t he e n d of  
t he S T peri o d a n d e n ds o n t he date of  Week 5 6 visi t or e arl y disc o nti n uati on fr om t he 
st u d y, w hic he ver is earlier. 

T he Ra n d o mise d
Wit h dra wal p eri o d starts fr o m t he date of  first i nta ke of  t hird 
ra n d omisat i on tr e at me nt (i. e., I P iss ue d o n t he Wee k 3 2 or Wee k 4 0 visi t) a n d e n ds o n 
t he date of Wee k 5 6 visit or earl y  disc o nti n uatio n fr o m  t he st u d y, w hic he ver is earlier.

T he p ost -stu d y peri o d starts fr o m t he d a y  after t he e n d of t he L T peri o d a n d e n ds o n t he 
date of Wee k 1 0 4 visit or date of l ost t o f o ll ow- u p, w hic he ver is earlier. 
F or s u bjects w h o e nt ere d t he L T peri o d b ut s ki p pe d t he Wee k 2 6 visit, t he n t he e ve nt date fr o m 
t he C o nti n uati o n L o n g T er m  Fol l ow u p C R F will be use d (if a vaila ble). F or s u bjects w h o 
e ntere d t he p ost -stu d y peri o d b ut s ki p pe d t he Wee k 5 6 visit, t he n t he latest visit date d uri n g t he 
S T + L T peri o d will be use d t o e xtra p olate t he esti mate d Wee k 5 6 date (tar get da y  3 9 5).
Pri or t o sl otti n g t h e d at a m ust be restri cte d t o t he c ut -offs defi ne d f or eac h varia ble a n d perio d 
as per Ta ble 8. Sl otti n g m ust be re peate d f or eac h t ype of  anal ysis a p plica ble t o a varia ble 
( pri mar y a nd eac h se nsit i vity a nal ysis).
Vi sit wi n d o ws f or p ost-baseli ne (after Da y 1) assess me nts t hat will be sl ott e d f or t he S T peri o d 
are s h o w n i n Ta ble 9 . Visi t wi n d o ws f or assess me nts t hat will be slott e d f or t he L T a n d 
ra n d omise d wi t hdra wal p eri o d a n d t he p ost -stu d y ( Wee k 1 0 4) visit are s h o w n i n Ta ble 1 0 a n d 
Ta ble 1 1 . 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 6
T a ble 9 V isit w i n d o ws f or S T peri o d assess me nts
Visit
T ar get 
D a y
D a y R a n ge b y T y pe of Assess me nt
Vit al Si g ns
S afet y l a b or at or y p a nel, 
F P G, H b A 1c, P K / P Da, 
U ri nar y gl uc ose, Hei g ht, 
Wei g ht
Gr o wt h a n d m at ur ati o n 
m ar kers, T a n ner st a gi n g, 
E C G, F asti n g l i pi d p a nel
Wee k 6
4 3 
2 t o 6 4
2 t o 6 4
Wee k 1 2
8 5 
6 5 t o 9 2
6 5 t o 1 1 3
Wee k 1 4
9 9 
9 3 t o 1 2 0
Wee k 2 0
1 4 1 
1 2 1 t o 1 6 2
1 1 4 t o 1 6 2
Wee k 2 6
1 8 3 
1 6 3 t o Wee k 2 6 / E D
( w hic he ver is earlier)
1 6 3 t o Wee k 2 6 /E D 
( w hic he ver is earlier)
2 t o Wee k 2 6 /E D ( w hic he ver 
is earlier)
E D = Earl y disc o nti n uati o n fr o m t he st u d y.
a P K / P D assess me nts i ncl u de plas ma sa m ples f or a nal ysis of da pa glifl ozi n, sa xa gli pti n, 5 -O H -sa xa gli pti n, F P G 
a n d D P P-4 acti vit y.
T a ble 1 0 Visit wi n d o ws f or L T peri o d a n d p ost -st u d y ( Wee k 1 0 4) assess me nts
Visit
T ar get 
D a y
( L T 
D a y a)
D a y R a n ge b y T y pe of Assess me nt
Vit al si g ns, S afet y l a b or at or y p a nel, 
F P G, H b A 1c, Hei g ht, Wei g ht
Gr o wt h a n d m at ur ati o n m ar kers, 
T a n ner st a gi n g, E C G, F asti n g li pi d 
p a nel
Wee k 3 2
2 2 5 
( 4 3)
L T S T D T t o 2 5 2 / R W S T D T [ o nl y 
a p plica ble f or s u bjects g oi n g t hr o u g h t he 
t hir d ra n d o misati o n] ( w hic he ver is 
earlier)
Wee k 4 0
2 8 1
( 9 9)
2 5 3 / R W S T D T + 1 [ o nl y a p plica ble f or 
s u bjects g oi n g t hr o u g h t he t hir d 
ra n d o misati o n] ( whi c he ver is earlier) t o
3 2 2
Wee k 5 2
3 6 5
( 1 8 3)
3 2 3 t o Wee k 5 6/ E D ( w hic he ver is earlier)
L T S T D T t o Wee k 5 6 / E D ( w hic he ver is 
earlier)
Gr o wt h a n d m at ur ati o n m ar kers, T a n ner st a gi n g, Hei g ht, Wei g ht, B MI
Wee k 1 0 4
7 2 8
W eek 5 6 + 1 da y t o Week 1 0 4 / date of last c o ntact (if earlier t ha n Wee k 1 0 4)
E D = Earl y disc o nti n uati o n fr o m t he st u d y. L T S T D T = L T start date ( i.e., da y f oll o wi n g t he last da y of t he S T
peri o d ). R W S T D T = ra n d o mise d wit h dra wal peri o d start date (i.e., date of first I P d ose recei ve d i n ra n d o mise d 
wit h dra wal peri o d). 
a L T da y is t he tar get da y c o u nti n g fr o m t he start of t he L T peri o d (L T S T D T ). Tar get da y is base d o n c o u nti n g 
fr o m Da y 1 ( date of first I P d ose i n t he st u d y).


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 7
T a ble 1 1 Visit wi n d o ws f or r a n d o mise d wit h dr a w al peri o d assess me nts
Visit
T ar get 
D a y
D ate R a n ge b y T y pe of Assess me nt
Vit al si g ns, S afet y l a b or at or y p a nel, 
F P G, H b A 1c, Hei g ht, Wei g ht
Gr o wt h a n d m at ur ati o n m ar kers, 
T a n ner st a gi n g, E C G, F asti n g li pi d 
p a nel
Wit h dra wal 
Baseli ne
T he cl osest a vaila ble val ue o n or bef ore R W S T D T
Wee k 4 0
2 8 1
R W S T D T + 1 da y t o 3 2 2 (f or s u bjects 
w h o were t hir d ra n d o mise d at Wee k 3 2 
o nl y )
Wee k 5 2
3 6 5
R W S T D T + 1 da y (f or s u bjects w h o 
were t hir d ra n d o mise d at Wee k 4 0) or 
3 2 3 (f or s u bjects w h o were t hir d 
ra n d o mise d at Wee k 3 2) 
t o Wee k 5 6 visit/ E D ( w hic he ver is 
earlier)
R W S T D T t o Wee k 5 6 visit/ E D 
( w hic he ver is earlier)
E D = Earl y st u d y disc o nti n uati o n. R W S T D T = ra n d o mise d wit h dra wal peri o d start date (i.e., date of first I P d ose 
recei ve d i n ra n d o mise d wit h dra wal peri o d). 
F or lab orat or y  an d n o n- la b orat or y para meters, if a s u bject has m o re t ha n o ne meas ure me nt 
i ncl ud e d wi t hi n a wi n d o w, t he assess me nt closest t o t he tar get da y  will be use d. I n case of ti es 
bet wee n o bser vat i ons l ocate d o n differe nt si des of t he tar get da y, t he earlier assess me nt will be 
use d. I n case of t ies locate d o n t he sa me si de of t he tar get da y  (i. e. more t ha n o ne val ue f or t he 
sa me d a y  but differe nt ti me), t he val ue wi t h the earlier e ntr y date/ti me will be use d. F or 
o bser vat i ons wi t h the sa me date a n d time , i ncl u di n g missi n g ti mes a n d i ncl u di n g p ote nti al 
baseli ne val ues , a n a vera ge will be ta ke n if t he t w o or m ore val ues wit h t he sa me date a n d ti me.
I n a d ditio n, f or t he efficac y F P G a nal yses as t here are m ult i ple ti me p oi nts c ollecte d at  eac h 
visit, t he n t he rec or d wit h t he earliest ti me o n t he d a y  selecte d usi n g t he a b o ve defi ni tio n will 
be use d f or eac h visit in t he a nal ysis. If t here are m ult i ple val ues c ollecte d wit h t he sa me ti m e, 
t he n a n a vera ge will be ta ke n. If t here are m ulti ple val ues c ollecte d o n t he sa me da y w here o ne 
of  the rec or ds o nl y has t he date a vaila ble, t he n t he rec or ds wit h t he date/ti me prese nt are selecte d
o ver t he rec or ds wit h o nl y date prese nt. O nl y F P G assess me nts d oc u me nte d wit h t he s u bject i n 
a fast i n g state will be s u m marise d a nd liste d .
F or t he s hift ta bles f or n o mi nal E C G para meter of nor m al/a b n or mal t he f oll owi n g r ul es a p pl y. 
If m ore t ha n o ne E C G meas ure me nt is perf or me d wit hi n a s pecifie d ti me wi n d o w, a n a b n or mal 
E C G val ue will  be c h os e n o v er a n or mal E C G val ue. If t w o or m or e a b n or mal or t w o or m or e 
n or m al E C G val ues are wit hi n t he sa me t i me wi n d o w, t he o ne cl osest t o t he tar get date will be 
use d.
Data c ollecte d d uri n g u nsc he d ule d visit s will als o be sl otte d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 8
4. 1. 7. 2
H a n dli n g of rescree ne d s u bjects
A rescree ne d s u bject is d efi ne d as a s u bject w h o fails t he i nitial scree ni n g att e mpt a n d is t he n 
scree ne d faile d a n d rescree ne d u n der a ne w s u bject i de ntifier. S uccessf ul rescree n s u bjects will 
n ot be c o u nte d as a scree n fail ure. I n case of  rescree ni n g, all t he data (i ncl u di n g t hat fr o m t he 
i nitial scree ni n g a n d rescree ni n g) will be prese nte d u n der t he latest rescree ne d s u bject I D a n d 
will be use d i n s u m mar y ta bles, fi g ures a n d listi n gs. T he e xce pt i on is for d e m o gra p hi c a n d 
baseli ne c haracterist ics a nal yses, w here t he data c ollecte d un der t he latest rescree ne d s u bject I D 
will be use d (e. g. a ge, date of dia betes me llit us dia g n osis) . F or rescree ne d s u bjects , t he origi n al 
s u bject i de ntifier(s) will als o be prese nte d i n t he de m o gra p h y list i n g f or cr oss-li n ki n g p ur p oses. 
Rec or ds fr o m t he i nitial scree ni n g att e mpt (s) will be fla g ge d i n A E , pri or a n d c o nc o mita nt 
me dicat i on , me dical hist or y, lab orat or y , a n d vital si g n listi n gs.
4. 1. 7. 3
H a n dli n g of i m pl a usi b le gl uc ose res ults
It was i de ntifie d pri or t o Wee k 5 6 data base l oc k d uri n g o n g oi n g data re vie w t hat t here was a n 
i m pla usi ble F P G val ue rec or de d f or o ne s u bject at t heir Da y 1 visit. T his was i n vesti gate d a n d 
c o nfir me d b y t he ce ntral la b orat or y  a n d it was deci de d t hat t he res ults will be use d i n t he 
pri mar y  a nal ysis. 
A se nsit i vity a nal ysis o f t he sec o n dar y efficac y e n d p oi nts f or F P G e xcl u di n g t his res ult a n d 
a n y ot her o utliers ma y be c o n d ucte d p ost- Wee k 5 6 data base l oc k, if dee me d necessar y.
4. 1. 8
Missi n g d at a
If n ot state d ot her wise , n o i m p utati o n of  missi n g data will be d o ne. Eff orts will be ma de t o 
f oll ow t he s u bjects a n d c o llect t he data e ve n after t he s u bjects disc o nt i n ue t he treat me nt. 
F or t he pri mar y a n d sec o n dar y efficac y anal ysis base d o n lab orat or y  data (i.e. H b A 1c, F P G)
missi n g data will be ha n dle d usi n g m ult i ple i m p utatio n, as descri be d i n Secti o n 4. 1. 1 2 . 
A p pr oac hes t hat will be use d t o ha n dle missi n g data f or ot her efficac y a nal yses will be descri be d 
i n t he res pecti ve a nal ysis secti ons. 
I nf or mat i on re gar di n g ha n dli n g of  missi n g or partial e ve nt or me d icati on dates is pr o vi de d i n 
t he A p pe n di x ( Sect i ons  8. 2 a n d 8. 3 ). 
4. 1. 9
Wei g hte d a n al ysis of co v ari a nce ( A N C O V A)
I n s u m maries of pri mar y  a n d sec o n dar y efficac y e n d p oi nts e xa mi ni n g t he c ha n ge fr o m baseli ne 
at Wee k t, a n A N C O V A m o d el  of t he differe nces bet wee n Wee k t a n d baseli ne meas ure me nts 
will be use d, c o nt r olli n g f or baseli ne val ue as a c o variate, a n d treat me nt gr o u p (re gi me n) a n d 
ra n d omisat i on strata as fi xe d effects. O nl y mai n effects of  the ra n d omisat i on strata will b e 
i ncl u de d i n t he m o del. T he m o d el  will ha ve t he f ollo wi n g f or m :
D t,ij m = i nterce pt + ß [Y 0,ij m] + τ j + ω m + err or ij m
w here:


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
6 9

D t,ij m = Y t,ij m - Y0,i j m = t he Wee k t c ha n ge fr om baseli ne of s u bject i i n treat me nt gr o u p j
a n d strat u m m .

Y 0,ij m is t he baseli ne meas ure me nt of s u bject i i n treat me nt gr o u p j a n d i n strata m , 

Y t,ij m is t he Wee k t meas ure me nt of s u bject i i n treat me nt gr o u p j a n d i n strata m ,

ß is t he sl o pe of D t,ij m re gressi n g o n t he baseli ne meas ure me nt, 

τj is t he mea n effect of treat me nt gr o u p j,

ω m is t he mea n effect of ra n d omisat i on strat u m m ,

I nterce pt, a n d τ jare u n k n o w n para meters t o be esti mate d fr o m t he data.
Wei g hts 
will be use d i n t he A N C O V A m o d el  to test t he treat me nt re gi me ns c o mpare d t o 
pl ace b o,    : τ   −τ   = 0 a n d    : τ   −τ   = 0 .
T he wei g ht mat rices t o t est h yp ot heses    a n d    are de n ote d b y  a n d  res pecti vel y, 
defi ne d as f o ll ows :
 =   ⎣
⎢
⎢
⎢
⎡
  ×   ×    × (   ) /   × (   )⎦
⎥
⎥
⎥
⎤
 =   ⎣
⎢
⎢
⎢
⎡
  ×   ×    × (   )  × (   ) /  ⎦
⎥
⎥
⎥
⎤
w here r is t he pr o p orti o n of res p o nse ( H b A 1c < 7 %) , n is t he n u m ber of s u bjects wit hi n a n ar m , 
a n d base d o n a 1: 1: 1 ra n d o misati o n .
 : F or t he c o m paris o n of t he l o w -d ose/ hi g h -d ose treat me nt re gi me n vers us place b o ( use d f or 
sec o n dar y e n d p oi nts), 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 ow- d ose will be assi g ne d a wei g ht of  1. T he da pa gl iflozi 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 ow- d ose will b e 
assi g ne d a w ei 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 be assi g ne d 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 omisat i on a n d all place b o s u bjects will be assi g ne d a wei g ht of 1.
 : F or t he c o m paris o n of t he l o w -d ose treat me nt re gi me n vers us place b o ( use d f or sec o n dar y 
e n d p o i nts), all da pa glifl ozi n a n d sa xa gli pti n su bjects w h o ha d H b A 1c < 7 % at Wee k 1 2 a n d 
r e mai ne d o n t he l ow- d ose will be assi g ne d a wei g ht of  1. 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 ow- d ose will be assi g ne d a 
w ei g ht of  2. T he da pa gliflozi 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 be assi g ne d 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 omisati o n a n d all place b o s u bjects will be assi g ne d a wei g ht of 1.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 0
F or t he c o mparis o n of  overall dr u g treat me nt vers us pl ace b o ( use d f or t he pri mar y e n d p o i nt 
a nal ysis a n d s o me sec o n dar y e n d p o i nts) n o wei g ht i n g will be use d (i.e. all treat me nt gr o u ps will 
be assi g ne d a wei g ht of 1).
It f oll ows t hat para m eters ca n be est i mate d wit h a p pr o priate desi g n a n d wei g ht m atri x b y 
 = (   )      ~  (,  )
s uc h t hat  =            a n d t he desi g n matri x f or i-t h s u bject   = [ 1
       ɣ     ].
T he m o d el  will pr o vi de least s q uares me a n ( L S mea n)
est i mates a n d 2- si de d 9 5 % c o nfi de nce 
i nter vals f or mea n c ha n ges fr o m baseli ne wi t hi n eac h tr e at me nt gr o u p (re gi me n) a n d differe nces 
i n mea n c ha n ge fr o m baseli ne bet wee n a treat me nt gr o u p ( re gi me n) a n d place b o. N ote t hat CIs 
will n ot be o btai ne d di rectl y fr o m the m o d el , b ut will be deri ve d b y c o m bi ni n g t he res ults 
o btai ne d fr om r u n ni n g t he A N C O V A m o d el  in eac h i m p ute d data set, as descri be d i n Sect i on 
4. 1. 1 2. 4 . If t here is n o missi n g data f or all tr e at me nt gr o u ps i n t he a nal ysis at a visit, t he n t he 
A N C O V A m o d el  will be r u n o n t he n o n -i m p ute d data a n d n o c o m bi ni n g of  res ults fr om eac h 
i m p ute d data set is necessar y.
Sta n dar di se d mo d el  resi d uals will be used t o e xa mi ne m o del ass u m pt i ons a n d t o detect o utliers 
a n d p ote ntiall y i nfl ue nt ial obser vat i ons. T he "I nfl ue nce Dia g n ostics" o ut p ut pr o d uce d b y P R O C 
MI X E D a n d b o x pl ots of  sta n dar dise d resi d uals will be use d t o facilitate t his dia g n ostic a nal ysis. 
If i nfl uent ial o utliers are prese nt a d ditio n al  se nsiti vit y anal yses will be perf or m e d wi t h the 
o utliers e xcl u de d, i n or der t o assess t heir i m pact o n treat me nt (re gi me n) c o mparis o ns.
4. 1. 1 0
Pr o p orti o n of s u bjects wit h a pre -defi ne d c h ar acteristic (res p o n ders) at Wee k t
T he pr o p orti o n of  su bjects wi t h a pre -defi ne d c h ar acteristic (res p o n ders) at Wee k t will b e 
a nal ysed usi n g a w ei g hte d or u n wei g hte d l ogi stic re gressi on w he n t here are at least 5 res p o n ders 
b y tr e at me nt gr o u p. F or pr o p orti o n of  res p o n ders (e. g., meet i n g H b A 1c criteria), esti mates, 
c o nfi de nce i nter vals, a n d tests will be o btai ne d usi n g a wei g hte d or u n wei g hte d l ogistic 
re gressi o n. O d ds r atios (a n d c orres p o n di n g sta n dar d err ors [S E ]) re prese nti n g t he res p o n der 
o d ds i n t he da pa glifl ozi n /sa xa gli pti n treat me nt gr o u p ( or re gi me n) vers us place b o gr o u p will be 
ge nerate d a djust e d f or baseli ne varia ble (e. g., a d j ustme nt  for baseli ne H b A 1c) a n d eac h 
ra n d omisat i on stratificati on fact or usi n g t he S A S L O GI S TI C pr oce d ure.
T he fre q ue ncies of  res p o nse/ n o n-res p o nse a n d t he ass ociate d cr u de res p o nse rates (as 
perce nta ges) will be prese nte d b y treat me nt gr o u p ( or re gi me n). I n ad di tio n, wei g hte d or n o n-
w ei g hte d a djuste d perce nta ges, sta n dar d err ors, a n d 9 5 % CIs f or eac h tr e at me nt gr o u p ( or 
re gi me n) will als o be dis pla ye d. A d j uste d o d d r atio a n d c orres p o n di n g 9 5 % L o g li keli h o o d
c o nfi de nce i nter val, a n d p -val ues ( u nc orrecte d) will als o be prese nte d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 1
F or t he H b A 1c res p o n der e n d p o i nts, if t here is n o missi n g data f or all tr e at me nt gr o u ps i n t h e 
a nal ysis at Wee k t, t he n t he l ogist ic re gressio n  mo d el  or Fis her’s e xact test will be r u n o n t he 
n o n- i m p ute d data a n d n o c o m bi ni n g of res ults fr o m eac h i m p ute d data set is necessar y.
I n case of  no n -c o n ver ge nce beca use of  sparse data s u bse q ue nt bac k u p m o dels will be use d i n 
r e mo vi n g ra n d o misati on strata i n se q ue ntial or der a n d/ or c olla psi n g t he ra n d o misati o n strata of 
bac k gr o u n d me dicat i on as defi ne d i n Sect i on 4. 1 . A s u bse q ue nt bac k - u p m o del i n t he or der 
prese nte d Secti o n 4. 1 will o nl y be pr o vi de d if t he prece di n g bac k-u p m o d el  d oes n ot c o n ver ge.
W he n t here are less t ha n 5 res p o n ders i n a n y treat me nt gr o u p, t he u na dj uste d (a n d differe nce) 
pr o p orti o ns, w ei g hte d or n o n- wei g hte d e xact 9 5 % c o nfi de nce i nter val, a n d p- val ues fr om t he 
w ei g hte d or u n wei g hte d F is her’s e xact test ( w he n a p plica ble) will be pr o vi de d.
4. 1. 1 1 Esti m ates f or ti me -t o-e ve nt a n al yses
C o x pr o p orti o nal hazar ds m o dels wit h stratificat i on fact ors (i ncl u di n g s e x, a ge gr o u p [ ≥1 0 a n d 
< 1 5 years , ≥1 5 a n d < 1 8 years ] a n d bac k gr o u n d a nti dia betic me d icati on [ met f or mi n o nl y , 
i ns uli n o nl y , m etfor m i n + i ns uli n]) as c o variates will be dis pla ye d b y treat me nt gr o u p. Ti me t o 
e ve nt (i n d a y s) will be calc ulate d as: date of  eve nt - date of  first d ose + 1. S u bject s t hat 
p er m a ne nt l y disc o nt i n ue tr e at me nt b ut re mai n i n t he st u d y will be i ncl u de d i n t he a nal ysis.
S u bjects w h o d o n ot ha ve t he e ve nt will be ce ns ore d at t he Wee k t visit date or t he last visit date 
f or t h ose wit hdra wi n g fr o m t he st u d y before Wee k t vi sit. S u bjects l ost t o f oll o w -u p d uri n g t he 
a p plica ble p eri o d will be ce ns ore d at  their latest assess me nt date w hereas s u bjects ha vi n g 
s kip pe d Wee k t visit will be ce ns ore d at t he ir next  visit date or t he latest Wee k t assess me nt date
a mo n gst all  s u bjects ( w hic he ver is earlier).
Ka pla n -Meier pl ots  of ti me t o e ve nt varia bles will be dis pla ye d b y tr e at me nt gr o u p. U nles s 
ot her wi se s pecifie d, t he pl ot wi ll be prese nte d o nl y w he n t here are at least 5 “e ve nts” i n eac h 
treat me nt gr o u p. A d diti o nall y, a ta ble will  acc o m pa n y t he pl ot a n d wi ll dis pla y t he Ka pla n -
Meier 
esti mates of  the c u mulat i ve e ve nt pr o ba bilit ies ( wit h 95 % CI calc ulate d base d o n 
Gree n w o o d’s met h o d w he n a p plica ble) of  su bjects wit h e ve nt at  specific ti me p oi nts b y 
treat me nt gr o u p. If t he esti mate d l ower b o u n d of 9 5 % CI is be l ow 0 or t he esti mate d u p per 
b o u n d of 9 5 % CI is o ver 1, t he n it will be r estricte d t o 0 or 1 res pecti vel y. T h e p -val ue fr om a 
p air wise L o g -Ra n k t est (stratifie d b y se x, a ge, a n d bac k gr o u n d me dicat i on) of  the n u ll 
h y p ot hesis of  no differe nce bet wee n tr e at me nt  ar ms i n t he pr o ba bilit y of  an e ve nt will b e 
prese nte d.
4. 1. 1 2
M ulti ple im p ut ati o n
Missi n g q ua nt itati ve W e e k t d at a at st u d y  e nd p oi nt will be i m p ute d fr o m o ne o f t he 2 missi n g 
n ot at ra n d o m ( M N A R) i m p utati o n m o dels f or missi n g Wee k t data. 
T he preferre d m o d el  will be t o use a “retrie ve d dr o p -o ut” m ul tiple i m p utati o n ( MI-R D) m o d el 
t o re prese nt t he M N A R pr ocess. T his 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 nt i 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 t 
H b A 1c val ue. If a n y of  the re q uire d i m p utati o n m o dels nee de d f or a n y of  the re gi me ns (lo w, 
l ow/ hi g h, o verall) wi t hi n da pa glifl ozi n or sa xa gli pti n ha ve less t ha n 5 retrie ve d dr o p -o ut 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 2
o bser vat i ons a vaila ble t o fit the m o d el , t he n MI -W O 
“ was h-o ut ” me t ho d will be use d f or
a nal yses of all re gi me ns f or t hat e n d p oi nt . T hi s is a “c o p y to refere nce met h o d”. B ot h MI -R D 
or MI -W O will be i m ple me nte d usi n g a baseli ne t o pre dict Wee k t val ues i n t he M N A R
m o del. 
T he ra n d omisat i on strata will be c o de d usi n g i n dicat or varia bles as f oll ow s a n d use d i n t he 
m ult i ple i m p utati o n ste ps:

ra n d omisat i on strata of bac k gr o u n d me dicat i on will be c o de d as
o
met ( 1) a n d i ns ( 0) if metf or mi n o nl y,
o
met ( 0) a n d i ns ( 1) if i ns uli n o nl y, 
o
met ( 0) a n d i ns ( 0) if metf or mi n + i ns uli n;

ra n d omisat i on strata of  bac k gr o u n d me dicat i on if ra n d omisat i on strata of  ins uli n o nl y  
a n d i ns uli n wit h metf or mi n are gr o u pe d will be c o de d as
o
met i ns ( 1) if metf or mi n o nl y,
o
met i ns ( 0) if i ns uli n o nl y or i ns uli n with metf or mi n ;

ra n d omisat i on strata of a ge gr o u p will be c o de d as 
o
a ge ( 1) if a ge ≥1 0 a n d < 1 5 y ears, 
o
a ge ( 0) if a ge ≥1 5 a n d < 1 8 y ears;

ra n d omisat i on strata of  se x will be c o de d as 
o
se x ( 1) if male,
o
se x ( 0) if fe male.
Eac h i m p utati o n m o del will use a c o m m o n see d val ue of 2 7 1 7.
I n case of n o n-c o n ver ge nce beca use of s parse data , s u bse q ue nt bac k u p i m p utatio n m o dels will 
be use d i n r e mo vi n g ra n d omisati o n
strata i n se q ue ntial or der a n d/ or c o lla psi n g t h e 
ra n d omisat i on str at a of bac k gr o u n d me dicat i on as defi ne d i n Sect i on 4. 1 . A s u bse q ue nt bac k -
u p m o d el  in t he or der prese nte d Secti o n 4. 1 will o nl y be pr o vi de d if t he prece di n g bac k -u p 
m o d el  d oes n ot c o n ver ge.
4. 1. 1 2. 1
M o n ot o ne
D at a P atter n
Pri or t o i m p utati o n, i nter mitte nt missi n g H b A 1c/ F P G val ues (i.e., missi n g val ues b ot h prece de d 
a n d f oll o we d b y at least o ne n o n-missi n g val ue) will be i m p ute d u n der a “ missi n g at ra n d o m”
( M A R) m o d el  for missi n g data usi n g a Mar k o v 
c hai n M o nte 
Carl o ( M C M C) met h o d of  
i m p utatio n.
Si nce i n ge neral t he missi n g patter n will n ot be m o n ot o ne, t he first ste p f or a n y  of t he met h o ds 
prese nte d bel o w will be t o use t he Mar k o v C hai n M o nte Carl o ( M C M C) met h o d i n c o nj u ncti o n 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 3
wi t h the M O N O T O N E stat e me nt of  the S A S MI pr oce d ure t o partiall y i m p ute q ua nt itati ve 
para m eters, se paratel y f or eac h treat me nt re gi me n (i.e. l ow- d ose, l ow- d ose / hi g h-d ose a n d 
pl ace b o ) a n d b y wei g ht , t o create i m p ute d datasets wit h j ust e n o u g h missi n g q ua ntitati ve val ues 
t o ge nerate t wo h u n dre d ( 2 0 0) i m p ute d data sets wit h a m o n ot o ne missi n g data patter n (f or eac h 
treat me nt re gi me n), ass u mi n g a M A R 
missi n g data patter n. S u bjects wi t hdra wi n g fr o m I P 
b efor e t he u p- titr atio n will be assi g ne d a wei g ht of 1 a n d will be i ncl u de d i n eac h i m p utati o n 
m o d el  (l ow -d ose a n d l ow- d ose / hi g h-d ose re gi me n). I n dicat ors of  ra n d omisat i on strata (as 
descri be d i n Secti o n 4. 1. 1 2 ) an d visit (i.e., baseli ne H b A 1c / F P G alo n g wi t h all visits p er 
pr ot oc ol u p t o Wee k t ) will be t he para meters i ncl u de d i n M C M C m o dels.
T he ra n d o m see d n u m ber f or t he M C M C sta ge will be 2 7 1 7.
4. 1. 1 2. 2
Retrie ve d Dr o p -O uts M ulti ple I m p ut ati o n Met h o d
Missi n g
H b A 1c/ F P G data will be i m p ute d se paratel y b y treat me nt re gi me n of  eac h dr u g (i. e., 
l ow- d ose, l ow- d ose / hi g h-d ose, a n d place b o) a n d wei g ht (as a p plica ble) . S u bject s n ot g oi n g 
t hr o u g h u p-titr atio n ra n d o misati on d ue t o disc o nt i n uati on of st u d y  me dicatio n will be assi g ne d 
a weig ht of 1 a n d i m p ute d i n t he b ot h t he l ow- d ose a n d l o w-d ose / hi g h-d ose re gi me ns.
Usi n g m o n ot o ne datasets ge nerate d as descri b e d i n Sect i on 4. 1. 1 2. 1 , the r e mai ni n g missi n g 
H b A 1c/ F P G data will be i m p ute d se paratel y f or eac h tr e at me nt gr o u p a n d wei g ht (as a p plica ble)
usi n g a R E G R E S SI O N met h o d i n c o nj u nct i on w ith t he M O N O T O N E state me nt a n d t he M N A R 
state me nt of t he S A S MI pr oce d ure.

Ste p 1: T he i m p utati o n m o d el  use d t o create m o n ot o ne data patter n (see Secti o n
4. 1. 1 2. 1 ) will 
i ncl u de fact ors a n d c o variates i n t he f oll owi n g 
or der: i n dicat ors 
re prese nti n g ra n d omisati o n
strata of  se x, a ge gr o u p a n d bac k gr o u n d me d icati on , 
baseli ne H b A 1 c/ F P G as well as H b A 1c/ F P G fr o m all visits per pr ot oc ol  u p t o Wee k t.

Ste p 2: Usi n g a n i m p utati o n m o del wit h t er ms f or i n dicat ors re prese nti n g ra n d o misatio n
strata of se x, a ge gr o u p a n d bac k gr o u n d me d icati on , baseli ne H b A 1c / F P G f oll owe d b y 
Wee k t H b A 1c / F P G, f or eac h tr e at me nt re gi me n a n d wei g ht , su bjects t hat disc o nt i n ue 
treat me nt pri or t o Wee k 
t wit h baseli ne a n d a n ( off-tr e at me nt) Wee k 
t assess me nt  
a vaila ble will be use d t o i m p ute wit hi n e a c h m issi n g Wee k t val ues (f or t hat treat me nt  
re gi me n) aft er baseli ne. Se parate m o dels will be perf or m e d f or eac h treat me nt re gi men
a n d wei g ht
(as a p plica ble) t o i m p ute Wee k 
t missi n g data i n t he m ult i pl y im p ute d 
m o n ot o ne datasets ge nerate d b y S te p 1. F o r t his ste p, o ne i m p utati o n will be perf or me d 
f or eac h of t he 20 0 i m p ute d datasets fr o m Ste p 1 t o f or m “c o m plete datasets”.

Ste p 3 : I mp ute d v al ues fr om eac h of  t he 2 0 0 i m p utatio n datasets selecte d fr o m Ste p 2 
a n d t he n o n- missi n g 
data will be use d t o calc ulate c ha n ge fr o m baseli ne. T he 
H b A 1c/ F P G c ha n ge fr om baseli ne va l ues at Wee k t will be a nal ysed b y a n A N C O V A 
wi t h ter ms f or baseli ne H b A 1c / F P G, ra n d omisati o n
strata, a n d treat me nt gr o u p as 
descri be d i n Sect i on 4. 1. 9 . In case of  no n -c o n ver ge nce, t he i m p utati o n a n d A N C O V A 
m o d el  will be si m plifie d b y r e mo vi n g/c olla psi n g t he ra n d o misati on strata i n dicat or 
varia bles i n a ste p wise ma n ner as descri be d i n Secti o n 4. 1 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 4

Ste p 4 : Res ults fr om eac h A N C O V A m o d el  will be c o m bi ne d as descri be d i n Sect i on
4. 1. 1 2. 4 .
If c o n ver ge nce i n all treat me nt re gi me ns (incl u di n g place b o) is st ill n ot ac hie ve d t he alter nati ve 
i m p utatio n m et h o d ( MI -was h o ut) will be use d.
4. 1. 1 2. 3
W as h -o ut m ulti ple i m p ut ati o n met h o d
Usi n g t he m o n ot o ne datasets ge nerate d as descri be d i n Secti o n 4. 1. 1 2. 1 , t he re mai ni n g missi n g 
data will be i m p ute d se paratel y f or eac h treat me nt gr o u p usi n g a R E G R E S SI O N met h o d i n 
c o nju nct i on 
wi t h the 
M O N O T O N E 
state me nt 
a n d 
eit her M N A R 
state me nt 
(f or 
da pa glifl ozi n /sa xa gli pti n treat me nt gr o u p s) or M A R (f or place b o treat m e nt gr o u p) of t he S A S 
MI pr oce d ure. Wei g ht will n ot be i ncl u de d i n t he i m p utati o n m o del.

Ste p 1 : T he i m p utati o n m o d el  use d t o create m o n ot o ne data patter n (see Secti o n 
4. 1. 1 2. 1 ) will 
i ncl u de fact ors a n d c o variate i n t he f oll owi n g 
or der: i n dicat ors 
re prese nti n g ra n d omisati o n
strata of  se x, a ge gr o u p a n d bac k gr o u n d me d icati on , 
baseli ne H b A 1c /F P G as well as H b A 1c / F P G fr o m all visits per pr ot oc ol  u p t o Wee k t.

Ste p 2: F o r s u bjects fr o m da pa glifl ozi n /sa xa gli pti n tr e at me nt gr o u p, Wee k t data fr om 
t he place b o gr o u p s u bjects wi t h no n -missi n g baseli ne will be use d i n m o delli n g t he 
M N A R pr ocess. T he i m p utati o n m o d el  will i ncl u de, i n t he f oll owi n g or der, i n dicat ors 
re prese nti n g ra n d o misati on strata of se x, a ge gr o u p a n d bac k gr o u n d me d icati on as well 
as, baseli ne H b A 1c/ F P G a n d Wee k t H b A 1c /F P G .
W hile 
f or s u bjects fr o m place b o treat me nt gr o u p, missi n g da t a will be i m p ute d 
se q ue ntiall y at eac h assess me nt usi n g a M A R i m p utati o n base d o n all n o n-missi n g data 
fr om 
t hat visit a n d data fr o m all pri or visits (after i m p utati o n). T he i n dicat ors 
re prese nti n g ra n d omisat i on strata will be i ncl u de d i n m o delli n g t he M A R pr ocesses i n 
t he sa me or der as descri be d i n Ste p 1. T heref ore, t he m o d el  will i ncl u de, i n t he f o ll owi n g 
or der, i n dicat ors re prese nti n g ra n d omisati o n
strata of  se x, a ge gr o u p a n d bac k gr o u n d 
me dicat i on as well as, baseli ne H b A 1c / F P G, a n d H b A 1c/ F P G fr o m all visits p er 
pr ot oc ol  prior t o a n d i ncl u di n g Wee k t .

Ste p 3 : I mp ute d v al ues fr om eac h of  t he 2 0 0 i m p utatio n datasets selecte d fr o m Ste p 2 
a n d t he n o n- missi n g data will be a nal ysed b y A N C O V A a p plie d at Wee k t, wit h t er ms 
f or baseli ne H b A 1c / F P G, ra n d o misati on strata a n d treat me nt gr o u p as descri be d i n 
Secti o n  4. 1. 9 . I n case of n o n-c o n ver ge nce, t he i m p utati o n a n d A N C O V A m o del will be 
si m plifie d b y r e mo vi n g/c olla psi n g t he ra n d omisati o n
strata i n dicat or varia bles i n a 
ste p wise ma n ner as descri be d in Sect i on 4. 1 .

Ste p 4 : Res ults fr om eac h A N C O V A m o d el  will be c o m bi ne d as descri be d i n Sect i on
4. 1. 1 2. 4 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 5
4. 1. 1 2. 4
C o m bi ni n g m ulti ple i m p ut ati o n res ults
C o nti n u o us e n d p oi nts
T he anal ysis m o d el  will be e val uate d i n eac h of  the i m p ute d datasets, a n d t he p oi nt esti mates 
a n d S Es will be c o m bi ne d usi n g R u bi n's r ules t o pr o d uce vali d gl o bal est i mates wi t h 
c orres p o n di n g CIs a n d p -val ues. S A S MI A N A L Y Z E pr oce d ure will be use d f or t his p ur p o se.
C ate g oric al e n d p oi nts
H b A 1c will  be cate g orise d as < 7 % (res p o n ders) or ≥7 % ( n o n -res p o n ders) a n d will be deri ve d 
fr om dic h ot o misi n g t he i m p ute d c o nti n u o us val ues of H b A 1c. 
A l ogist ic re gressio n  (t he S A S L O GI S TI C pr oce d ure) will be use d w he n t here are at least 5 
res p o n ders b y treat me nt re gi me n. If t here are less t ha n 5 s u bjects i n a n y tr e at me nt re gi me n, t h e 
Fis her’s e xact test will be use d.

If t he l ogi stic m o d el  is use d, pri or t o a p pl yi n g R u bi n's r ules (as descri be d i n Secti o n 
4. 1. 1 2. 4 ) t he o d ds rati o a n d its S E will be l o g -tra nsf or me d (as detaile d b el o w ).
If Fis her's e xact test is use d, t he fi nal est i mates f or t he pr o p orti o n of  res p o n ders, differe nce i n 
pr o p orti o n of  res p o n ders a n d p- val ue will  corres p o n d t o t he me dia n of  these est i mates acr oss 
all i m p ute d data sets.
L o g -tr a nsf or m ati o n of o d ds r ati o esti m ates
R u bi n's c o m bi nat i on r ules ass u me t hat t he m u lti ple i m p utatio n est i mates are as y m pt oticall y 
n or m all y distri b ute d. H o we ver, t he esti mates of o d ds rati os f o ll ow a l o g -n or mal distri b ut i on. A 
l og tra nsf or mat i on ca n be use d t o n or mali se t hese esti mates i n or d er t o be a ble t o a p pl y R u bi n’s 
c o m bi nat i on r ul es, as f o ll ows:

O btai n l o g -tra nsf or me d o d ds rati o ( O R) a n d S E fr o m eac h i m p ute d dataset
l og _ O R =l o g( O R)
l og _ O R _ S E =l o g( u p per _ CI) - l og(l o wer _ CI)/( 2 * 1. 9 6)

C o m bi ne tra nsf or me d est i mates usi n g MI A N A L Y Z E

Bac k -tra nsf or m c o m bi ne d esti mates ( E S TI M A T E a n d S T D E R R are t he res ults fr o m P R O C 
MI A N A L Y Z E):
P o ol e d _ O R = E X P( E S TI M A T E) 
P o ol e d _lo wer _ CI = p o ol e d _ O R * E X P( -1. 9 6 * S T D E R R)
P o ol e d _ u p per _ CI = p o ole d _ O R * E X P( + 1. 9 6 * S T D E R R)
T he a b o ve c o de ass u mes t hat 9 5 % CIs are use d. If d iffere nt wi dt h is re q uire d, t he 1. 9 6 m ulti pl e 
will nee d t o be a dj uste d acc or di n gl y.
F urt her i nf or mat i on a n d t he S A S c o de ca n be f o u n d i n Refere nce 4 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 6
4. 1. 1 2. 5
M ulti ple i m p ut ati o n u n der M A R h y p ot hesis
Usi n g t he m o n ot o ne datasets ge nerate d as descri be d i n Secti o n 4. 1. 1 2. 1 , t he re mai ni n g missi n g 
H b A 1c or F P G data will be i m p ute d se paratel y f or eac h tr e at me nt re gi me n a n d wei g ht
(as 
a p plica ble) usi n g a R E G R E S SI O N m et ho d i n c o nj u nct i on wi t h t he M O N O T O N E state me nt of  
t he S A S MI pr oce d ure a n d M A R ass u m pt i on.

Ste p 1: Pri or t o i m p utati o n, t he M C M C met h o d will be use d i n t he MI pr oce d ure t o i m p ute 
j ust e n o u g h missi n g val ues u n der a “ missi n g at ra n d o m” ( M A R) m o del t o ge nerat e 2 0 0
i m p ute d data sets wit h a m o n ot o ne missi n g data patter n. T he i m p utati o n m o del wit h 
i ncl u de fact ors a n d c o variates i n t he f oll o wi n g or der: i n dicat ors of ra n d omisat i on strata 
a n d baseli ne H b A 1c/ F P G as well as H b A 1c/ F P G at all visits per pr ot oc ol pri or t o Wee k t.

Ste p 2: Missi n g 
data will be i m p ute d se q ue ntiall y at eac h assess me nt usi n g a M A R 
i m p utatio n base d o n all n o n -missi n g data fr o m t hat visit a n d data fr o m all prior visi ts ( aft er 
i m p utatio n). T he i n dicat ors re prese nti n g ra n d omisati o n strata will be i ncl u de d i n t he sa me 
or der as descri be d i n Ste p 1. T heref ore, t he m o d el  will i ncl u de, i n t he f oll owi n g or der, 
i n dicat ors re prese nti n g ra n d o misati on strata of se x, a ge gr o u p, a n d bac k gr o u n d me dicati o n 
as well as, baseli ne H b A 1c / F P G, tr e at me nt re gi me n, a n d all pre vi o us H b A 1c / F P G val ues 
(all visit s per pr ot oc ol pri or t o Wee k t).

Ste p 3 : I mp ute d val ues fr om eac h of  t he 2 0 0 i m p utati o n datasets selecte d fr om Ste p 2 a n d 
t he n o n- missi n g data will be a nal ysed b y A N C O V A a p plie d at Wee k t, wit h ter ms f or 
baseli ne H b A 1c, ra n d omisat i on strata, a n d treat me nt re gi me n as descri be d i n Secti o n 4. 1. 9 .
I n case of  no n -c o n ver ge nce, t he i m p utati o n m o del will be si m plifie d r e mo vi n g/c olla psi n g 
t he ra n d omisat i on strata i n dicat or varia bles i n a ste p wise ma n ner as descri be d i n Sect i on
4. 1 .

Ste p 4 : Res ults fr o m eac h A N C O V A m o d el  will be c o m bi ne d as descri be d i n Secti o n
4. 1. 1 2. 4 .
4. 1. 1 2. 6
Ti p pi n g p oi nt a n al ysis
A series o f a nal yses will be perf or me d wit h i ncreasi n g val ues of δ ( w here δ re prese nts H b A 1c 
[ %]) u ntil t he a nal ysis c o ncl usi on of a statist icall y sig nifica nt treat m e nt effe ct n o lo n ger h o l ds. 
T he val ue o f δ t hat o vert ur ns t he pri mar y  r es ults will re prese nt a tip pi n g p oi nt. A n 
i nter pretatio n of  cli nical pla usi bility of  t he ass u m ptio n u n derl yi n g t he ti p pi n g p oi nt will be 
pr o vi de d. V alu es of  δ will be e xa mi ne d u ntil a p- value > 0. 0 5 0 0 0 i s o btai ne d f or t he differe nce 
bet wee n gr o u ps i n L S Mea ns . 
Usi n g t he m o n ot o ne datasets ge nerate d as descri be d i n Sect i on  4. 1. 1 2. 1 a n d Ste p 1 of eit her 
MI -R D (as descri be d i n Sect i on 4. 1. 1 2. 2 ) or MI-W O (as descri be d i n Sect i on 4. 1. 1 2. 3 ) 
de pe n de nt o n if t here is s ufficie nt data t o perf or m t he MI -R D m o d el  (as s pecifie d i n Secti on 
4. 1. 1 2 ) t he re mai ni n g ste ps will be perf or me d:


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 7

Ste p 2: T he MI pr oce d ure will be use d wi t h a MO N O T O N E state me nt t o i m p ute t he 
r e mai ni n g m o n ot o ne missi n g data i n t he m ult i ple i m p ute d data sets ge nerate d i n t he first 
ste p. T he i m p ute d data f or Wee k 2 6 will first be esti mate d u n der t he M A R ass u m ptio n
( δ = 0). I n s u bse q ue nt m o dels, a c o m m o n set of δ val ues will t he n be a d de d t o t he M N A R
i m p ute d val ues f or Wee k 2 6 f or t he acti ve tr eat me nt re gi me ns ( o nl y), w hile i m p ute d 
val ues f or t he place b o treat me nt gr o u p re mai n wit h n o δ a d dit i on.
F or t he first i m p utati o n m o d el  (δ = 0), 2 0 0 i m p utati on datasets will be ge nerate d usi n g 
t he 2 0 0 m o n ot o ne datasets ge nerate d i n Ste p 1. F or t he s u bse q ue nt i m p utati o n m o dels 
( δ > 0), t he sa me m o n ot o ne datasets as t h ose use d f or t he first i m p utati o n m o del will be 
use d.

Ste p 3: F o r eac h val ue of d el t a, im p ute d val ues fr o m eac h o f the 2 0 0 i m p utatio n datasets 
selecte d fr om Ste p 2 a n d t he n o n -missi n g data will be a nal ysed b y A N C O V A a p plie d at 
Wee k t, wit h t er ms f or baseli ne H b A 1c, ra n d omisati o n
strata a n d treat me nt gr o u p as 
descri be d i n Sect i on 4. 1. 9 . In case of  no n -c o n ver ge nce, t he i m p utati o n a n d A N C O V A 
m o d el  will be si m plifie d b y r e mo vi n g/c olla psi n g t he ra n d o misati on strata i n dicat or 
varia bles i n a ste p wise ma n ner as descri be d i n Secti o n 4. 1 .

Ste p 4: F or eac h val ue of delta, r es ults fr o m eac h A N C O V A m o del will be c o m bi ne d as 
descri be d i n Secti o n 4. 1. 1 2. 4 .
4. 2
St u d y p o p ul ati o n
St u d y  p o p ulati on data f or t he treat me nt peri o d will be prese nte d. A ta ble prese nt i n g t he n u m ber 
a n d perce nta ge of  su bjects i n t he Ra n d o mise d
S u bjects Data Set , U p -titr atio n Ra n d o mise d
S u bjects Data Set, E val ua ble
S u bjects Data Set , T reate d S u bjects Data Set , Ra n d o mise d
Wit h dra wal S u bjects Data Set a n d P har mac o ki net ic A nal ysis D ata S et will be pr o vi de d.
S u bjects e xcl u de d fr o m eac h a nal ysis set a n d reas o n(s) f or e xcl usi o n will be liste d.
F or t he Ra n d o mise d Wit h dra wa l S u bjects Data Set, s u bjects w h o passe d Wee k 3 2/ Wee k 4 0 
pri or t o pr ot oc ol  a me n d me nt 4 bei n g a p pr o ve d i n t heir c o u ntr y were n ot eli gi ble t o q ualif y for 
t his p ote ntial ra n d omisat i on a n d will be prese nte d u n der t he reas o n f or e xcl usi o n “ Ot her” i n t he 
s u m mar y ta ble.
4. 2. 1
S u bject dis p ositi o n
T he su bject dis p osi tio n f or t he scree ni n g peri o d, S T + L T p eri o d, ra n d o mise d wi t hdra wal peri o d
a n d p ost -stu d y visit Wee k 1 0 4 will be s u m marise d:

Di s p ositio n  for t h e scree ni n g peri o d will be base d o n t he E nr olle d S u bjects Data Set
( w h o si gne d i nf or me d c o nse nt) , a n d will i ncl u de t he n u m ber of  su bjects e nr olle d, 
passe d t he scree ni n g perio d, disc o nti n ue d fr o m t he scree ni n g perio d a n d a s u m mar y 
of  t he c orres p o n di n g reas o ns f or disc o nti n uati on. T he n u m ber of rescree ns a n d t otal 
n u m ber o f ti mes rescree ne d will als o be prese nte d f or s u bjects w h o were rescree ne d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 8

Di s p ositio n  for t he c o m bi ne d S T + L T
treat me nt peri o d will be base d o n t h e
Ra n d o mise d S u bjects Data Set a n d will be prese nte d b y ra n d omise d treat me nt gr o u p 
a n d o verall usi n g o verall treat me nt re gi me n a n d place b o . T his s u m mar y will i ncl u de 
s u bjects t hat e ntere d t he S T treat me nt peri o d, c o m plet e d t he S T treat me nt peri o d, 
di sc o nti n ue d fr om t he st u d y duri n g t he S T treat me nt peri o d a n d reas o ns f or stu d y 
di sc o nti n uati on, disc o nt i n ue d tr e at me nt d uri n g t he S T treat me nt p eri o d a n d reas o ns 
f or treat me nt di sc o nti n uati on , s u bjects u p- titrati on stat us, s u bjects t hat e ntere d t he L T 
treat me nt peri o d, c o mplete d t he L T treat me nt peri o d, disc o nti n ue d fr om t he st u d y 
d uri n g t he L T treat me nt peri o d a n d reas o ns f or st u d y disc o nt i n uati on, disc o nt i n ue d 
treat me nt d uri n g t he L T treat m e nt peri o d a n d reas o ns f or tr e at me nt disc o nt i n uati on,  
a n d s u bjects w h o c o m plete d t he 5 6 -wee k visit .
I n a d diti on, f or W ee k 1 0 4 f o ll ow -u p C S R t he s u m mar y  will als o i nclu de t he n u m ber 
of  su bjects w h o c o ntin ue d i nto t he p ost -t er m ext e nsio n , c o mplete d t he Wee k 1 0 4 
visit, disc o nti n ue d d uri n g t he p ost -t er m e xte nsi on.

Di s p ositio n  for t h e ra n d o mise d wi t hdra wal  p erio d will be base d o n t he Ra n d o mise d
Wit h dra wal S u bjects Data Set . T hi s will be prese nte d b y ra n d omise d treat me nt gr o u p 
f or t he 1st a n d 3 r d ra n d o misati on s a n d o verall. T his s u m mar y will i ncl u de t he n u m ber 
of  s u bjects w h o we nt t hr o u g h t he 3 r d ra n d omisat i on , were ra n d omise d t o wit h dra wal
fr om M etf or m i n, c o m p lete d t he ra n d o mise d wi t h dra wal p eri o d, di sc o nti n ue d fr om 
t he ra n d omise d wi t hdra wal p eri o d a n d a s u m mar y of  t he c orres p o n di n g reas o ns f or 
di sc o nti n uati on , c o mplete d 
I P d uri n g 
t he 
ra n d omise d
wi t hdra wal  
perio d, 
di sc o nti n ue d I P d uri n g t he ra n d omise d
wi t hdra wal  perio d an d a s u m mar y of  th e 
c orres p o n di n g reas o ns f or I P disc o nti n uati o n, a n d s u bjects w h o c o m p lete d t he 5 6-
wee k visit .

T he n u m ber of s u bjects c o mplet i n g t he st u d y a n d w h o disc o nt i n ue d t he st u d y relate d 
t o t he gl o bal/c o u ntr y  sit u atio n will be ta b ulate d b y di sc o nti n uati on reas o n se paratel y
f or t he S T peri o d, S T + L T peri o d , a n d Wee k 1 0 4 f oll o w -u p peri o d .
I n a d diti on, s u bjects fr om Ra n d o mise d S u bjects D ata S et will be s u m marise d b y c o u ntr y  a n d 
st u d y sit e.
S u bject dis p osit i on will als o be liste d b y s u bject.
4. 2. 2
Gl o b al/c o u ntr y sit u ati o n i m p act
A n o verall s u m mar y o f t he n u m ber a n d perce nta ge of s u bjects i n t he st u d y  d uri n g t he 
gl o bal/c o u ntr y  sit u atio n will  be pr o vide d usi n g t he Ra n d o mise d S u bjects Data Set, i ncl u di n g:

S u bjects ra n d o mise d pri or t o t he start of t he g l obal/c o u ntr y  sit u atio n ( pri or t o 1 1 
Marc h 2 0 2 0),

S u bjects w h o are n o l o n ger i n t he st u d y  at t he start of t he gl o bal/c o u ntr y sit u atio n 
( disc o nti n ue d st u d y or c o mplete d Wee k 1 0 4 visit),

S u bjects o n g oi n g i n t he st u d y  at t he start of t he gl o bal/c o u ntr y sit uati on,
o
S u bjects i n t he S T + L T peri o d ( u p t o Wee k 5 6),
o
S u bjects i n t he Wee k 1 0 4 f o ll ow -u p peri o d,


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
7 9

S u bjects ra n d o mise d after t he start of t he gl o bal/c o u ntr y  sit u atio n.
F urt her m ore, t he n u m ber a n d perce nta ge of s u bjects i m pacte d b y t he glo b al/c o u ntr y sit u atio n
will be prese nte d o verall a n d b y i m pact cate g or y  (visit i m pacte d, st u d y  dr u g i m pacte d, dr u g 
acc o u nta bilit y i m pacte d, c o nc o mita nt me dicati on n ot starte d , wit hdra wal  fr o m st u d y d ue t o 
gl o bal/c o u ntr y  sit u atio n ).
I mp orta nt pr ot oc ol de viat i ons t hat are relate d t o t he glo bal/c o u ntr y  sit u atio n will be 
s u m marise d wit hi n t he i m p orta nt pr ot oc ol de viat i on ta ble b y de viat i on cate g or y . T hese will be 
i de ntifie d usi n g pr ot oc ol de viati ons starti n g wit h t he w or d “ C O VI D”.
I n a d diti on, t o ca pt ure s u p ple me ntar y inf or mat i on o n t he gl o bal/c o u ntr y  sit u atio n i m pact,
details o n visits i m pacte d, c o nc o mita nt me dicati o ns n ot starte d, dis pe nsat i on or ret ur ni n g o f 
st u d y me dicat i on ki ts, a n d e x p os ure start dates t hat were i m pacte d will be c ollecte d. Details 
o n t he gl o bal/c o u ntr y  sit u atio n data will be liste d b y- s u bject usi n g t he E nr olle d S u bjects Data 
Set . T his will be prese nte d f or t he Wee k 5 6 C S R usi n g all data u p t o Wee k 5 6 data base l oc k 
a n d als o f or t he Wee k 1 0 4 C S R a d de n d u m usi n g all data u p t o Wee k 1 0 4 data base l oc k. 
4. 2. 3
De m o gr a p hic a n d ot her b aseli ne c h ar acteristics
Fre q ue nc y distri b uti o ns a n d s u m mar y statistics f or d e m o gra p hic s a n d b aseli ne c haracteristics
(a ge, se x, race, et h nicit y,  baseli ne b o d y  wei g ht, n or m alise d baseli ne b o d y  wei g ht, baseli ne 
hei g ht, n or malise d basel i ne hei g ht, baseli ne B MI,
n or m alise d baseli ne B MI , a n d r e gio n) , 
i ncl u di n g dia betes -r elate d c haracterist ics ( d uratio n of t y pe 2 dia betes, baseli ne H b A 1c, baseli ne 
F P G , bac k gr o u n d a nt i dia betic me dicat i on , t otal dail y d ose of  metfor m i n a n d ins uli n, a n d
baseli ne re nal f unct i on [e G F R]) will b e s u m marise d b y tr e at me nt gr o u p base d o n first 
ra n d omisat i on
a n d o verall usi n g t he
Ra n d o mise d
S u bjects Data 
Set, t he U p -titr atio n
Ra n d o mise d S u bjects Data Set , t he Ra n d o mise d Wit h dra wal S u bjects Data Set a n d, if dee me d 
necessar y , t he E val ua ble S u bjects Data Set . N o statist ical test will be carrie d o ut f or c o mparis o n 
of  d e mo gra p hics or baseli ne c haracterist ics a mo n g t he treat m e nt gr o u ps.
Ra n d o misat i on stratificati o n fact ors (i ncl u di n g a ge gr o u p, se x, a n d bac k gr o u n d a ntidia betic 
me dicat i on) will be s u m marise d b y tr e at me nt gr o u p base d o n first ra n d o misati on a n d o verall 
usi n g t he Ra n d o mise d
S u bjects Data Set. A listi n g of  differe nces bet wee n t he stratificat i on 
fact ors rec or de d o n t he I W R S a n d c ollecte d o n t he C R F will be prese nte d. F or a ge, o nl y  s u bjects 
wi t h a c o mplete date of birt h c ollecte d will be c o m pare d.
4. 2. 4
S pecific a n d ge ner al m e dic al hist or y
T he n u m ber a n d perce nta ge of  su bjects wi t h ge neral me dical hist or y  fi n di n gs a n d c urre nt  
me di cal c o n ditio n s will be s u m marise d b y S O C a n d P T (s orte d b y decreasi n g fre q ue nc y b y 
S O C a n d P T base d o n t he t otal gr o u p) b y treat me nt gr o u p a n d o verall usi n g the Ra n d o mise d
S u bjects Data Set . All me dical hist or y details will be liste d. 
4. 2. 5
Pri or a n d c o nc o mit a nt me dic ati o ns
T he n u m ber a n d perce n ta ge of s u bjects ta ki n g c o nc o mita nt me dicat i ons will be s u m marise d f or 
t he S T a n d S T + L T peri o ds b y W H O D D A T C classificat i on , ge neric ter m a n d treat me nt gr o u p


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 0
base d o n t he Treate d S u bjects Data Set. C o nc o mita nt me d icati ons will be liste d f or t he 
c o m bi ne d S T + L T peri o d a n d i n a d dit i on d ur i n g the st u d y . Pri or me d icati ons w ill n ot be i ncl u de d 
i n t he s u m maries b ut will be i ncl u de d a n d i de nt ifie d i n t he me dicati ons listi n g.
C o nc o mita nt a nt i-di a betes me d icatio ns will be rec or de d o ver t he c o urse of  the st u d y an d will 
be i ncl u de d i n c o nc o mit a nt me d icati on s u m maries. T hese will als o be s u m marise d se paratel y 
b y i ns uli n a nt i-di a betes c o nc o mita nt me d icati ons a n d n o n- i ns uli n a nt i-dia betes c o nc o mita nt 
me dicat i ons (as descri be d i n Sect i on  3. 5. 3 ). A se parate ta ble will be prese nte d f or i ns uli n a nti-
di a betes c o nc o mita nt me dicat i ons use d as resc ue me dicat i on.
I n a d ditio n, a s u m mar y of  disallo we d me dicat i ons (as defi ne d i n t he pr ot oc ol) will be pr o vid e d 
f or eac h peri o d. Disall o we d me dicati o ns use d c o nc o mita nt l y d uri n g t he st u d y will be fla g ge d i n 
t he list i n gs.
A s u m mar y o f all c o nc omit a nt me dicat i ons starte d bet wee n Wee k 5 6 a n d Wee k 1 0 4 (re gar dless 
of  pr ot oc ol defi ne d disall owe d me dicat i ons) will be pr o vi de d.
Se parate listi n gs f or t he S T + L T peri o d will be pr o vi de d f or ba c k gr o u n d met f or mi n a n d
bac k gr o u n d i ns uli n a n d a furt her listin g will be pr o vi de d f or i ns uli n as resc ue me dic atio n.
4. 3
E xte nt of e x p os ure t o st u d y tre at me nt
4. 3. 1
E xte nt of e x p os ure t o I P tre at me nt
E xte nt of  ex p os ure t o I P w ill be s u m marise d (re gar dless of  resc ue me dicat i on i nitiati on ) usi n g 
t he Treate d S u bjects Data Set f or t he S T a n d S T + L T treat me nt peri o ds , a n d t he Ra n d o mise d
Wit h dra wal S u bjects Data Set f or t he ra n d o mise d wi t hdra wal peri o d . T hese s u m maries will be 
re peate d f or e x p os ure pri or t o resc ue me dicat i on i nitiati on.
E xte n t of  e x p os ure is defi ne d as last d ose date - first d ose date + 1, wit h t he last d ose date bei n g 
t he last d ose of  the c o ncer ne d p eri o d . E xt e nt of  ex p os ure ( d a ys) will be s u m marise d b y t reat me nt 
gr o u p as a c o nti n u o us varia ble as well as f or pre -s pecifie d da y ra n ges ( S T peri o d: 1-7, 8 - 1 4, 1 5-
2 8, 2 9 -4 2, 4 3 -5 6 , 5 7-7 0, 7 1 -8 4, 8 5 -9 8, 9 9 -1 4 0, 1 4 1 - 1 8 2, > 1 8 2 da ys; S T + L T perio d: 1 -9 0, 9 1 -
1 8 0, 1 8 1- 2 7 0, 2 7 1 -3 6 5, a n d > 3 6 5 da ys ; ra n d o mise d wi t hdra wal  perio d: 1 -7, 8- 1 4, 1 5 -2 8, 2 9-
4 2, 4 3- 5 6 , 5 7- 7 0, 7 1- 1 1 2, 1 1 3 -1 5 4, > 1 5 4 ). I n a d dit i on, t he e x p os ure i n t er ms of  t ot al patie nt -
years will be s u m marise d b y treat me nt gr o u p usi n g t he s u m o f the e x p os ure t o I P of  all s u bjects 
(in year s) i n a treat me nt gr o u p.
I n di vi d ual s u bject d osi n g a n d e x p os ure t o I P b y st u d y p erio d will be liste d.
A listi n g of s u bjects b y batc h n u m ber of st u d y me dicat i on will als o be ge nerate d .
4. 3. 2
E x p os ure t o r esc ue me dic ati o n
T he ma xi mal t ot al dail y d ose (i ns uli n u nits) will be s u m marise d usi n g t he Treate d S u bjects Data 
S et f or t he f or t he S T , S T + L T peri o ds, a n d t he Ra n d o mise d Wit h dra wal S u bjects Data Set f or 
t he ra n d omise d
wi t hdra wal p eri o d. F or t he S T peri o d, t he s u m mar y will i ncl u de all resc ue 
me dicat i on use d u p t o t he start of  the L T peri o d. F or t he S T + L T peri o d t he s u m mar y will i ncl u de 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 1
all resc ue me dicat i on us e d u p t o t h e last d a y  in t h e S T + L T peri o d (irres pecti ve of  w het her t he 
s u bject ha d earl y disc o nt i n ue d I P treat me nt) . F or t he ra n d o mise d wi t hdra wal  perio d t he 
s u m mar y will i ncl u de all resc ue me dicat i on use d fr o m t he ra n d o mise d wi t hdra wal  baseli ne u p 
t o t he last da y i n t he ra n d o mise d wi t hdra wal  peri o d (irres pecti ve of  whet her t he s u bject ha d 
earl y disc o nti n ue d I P treat me nt). Resc u e treat me nt  details will  be liste d as descri be d i n Secti o n 
4. 2. 5 .
I n a d ditio n, t he n u m ber a n d perce nta ge of  su bjects i nitiati n g resc ue me d icatio n pri or t o Wee k 
1 2 b y cate g orical H b A 1c ( < 7 %, ≥ 7 %) res ult at Wee k 1 2 will be s u m marise d.
4. 3. 3
C o m pli a nce t o I P tre at me nt
C o m plia nce t o I P treat me nt will be s u m marise d f or t he S T a n d S T + L T peri o d s base d o n t he 
Treate d S u bjects Data Set a n d f or t he ra n d o mise d wi t hdra wal  p erio d base d o n t he Ra n d o mise d
Wit h dra wal S u bjects Data Set , as t he n u m ber a n d perce nta ge of  su bjects wi t h < 8 0 %, ≥8 0 % 
a n d ≤1 2 0 %, a n d > 1 2 0 % c o m plia nce. St u d y treat me nt c o m plia nce b y s u bject a n d st u d y peri o d 
will be i ncl u de d i n t he c orres p o n d i n g listi n gs f or e x p os ure t o I P treat me nt. 
4. 4
Pri m ar y effic ac y e n d p oi nt a n a l ysis
4. 4. 1
Pri m ar y a n al ysis of t he pri m ar y e n d p oi nt
T he pri mar y  efficac y anal ysis will  co m pare t he mea n re d ucti o n i n H b A 1c fr om baseli ne at Wee k 
2 6 bet wee n o verall dr u g treat me nt (lo w -d ose a n d hi g h -d ose) a n d pl ace b o . T he I T T esti ma n d 
( w hic h will be est i mate d usi n g data re gar dless of  pre mat ure treat me nt disc o nt i n uati on , 
re gar dless of resc ue me dicati on i nit iati on a n d wi t h m ulti ple i m p utati o n) will be e val uate d as t he 
pri mar y  esti ma n d.
List i n gs of  H b A1c a n d F P G res ults use d f or t he efficac y a nal ysis will be prese nte d wit h fla gs 
t o ide nt if y data c ollecte d pri or t o resc ue me dicati o n i nitiati on or treat me nt disc o nt i n uati on.
T he pri mar y  efficac y anal ysis w ill be perf or m e d usi n g a n A N C O V A m o d el , as descri be d i n 
Secti o n 4. 1. 9 . Se parate m o dels will be use d f or da pa glifl ozi n a n d sa xa gli pt i 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) pl ace b o c o nt r ol. Eac h m o d el  will ha ve ter ms f or baseli ne 
H b A 1c val ue, treat me nt gr o u p, a n d ra n d o misati on strata varia bles (a ge gr o u p, se x a n d 
bac k gr o u n d me dicat i on) . Mi ssi n g val ues f or Wee k 2 6 will be i m p ute d usi n g m ult i ple i m p utati on
met h o d ass u mi n g t he data are n ot missi n g at ra n d o m. N o wei g hts will be use d i n t he m ulti p l e 
i m p utatio n or A N C O V A f or t his a nal ysis.
A n o ver vie w of t he a nal ysis ste ps are as f o ll ows:
i)
I mp ute missi n g Wee k 2 6 H b A 1c data usi n g m ult i ple i m p utati o n (as descri be d i n Sect i on 
4. 1. 1 2 ).
ii) A nal yse data b y a p pl yi n g t he A N C O V A m o d el  ( descri be d i n Secti o n 4. 1. 9 ) i n eac h of  t he 
i m p ute d data sets t o calc ulate t he L S mea ns a n d c orres p o n di n g S Es 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 mea n c ha n ges 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 2
bet wee n treat me nt gr o u ps. If a n y stratificati on varia bles i n t he i m p utati o n m o d el  are
c olla pse d, t he n t he A N C O V A m o del will be c o lla pse d c orres p o n di n gl y.
iii) C o m bi ne p oi nt esti mates a n d S Es usi n g R u bi n's r ules (as per Secti o n 4. 1. 1 2 . 4) t o pr o d uce 
vali d gl o bal esti mates wit h c orres p o n di n g p- val ues a n d CIs.
C o m bi ne d L S me a ns a n d 9 5 % c o nfi de nce i nter vals f or t he mea n c ha n ge i n H b A 1c f or eac h 
treat me nt gr o u p
as well as t he diffe re nce i n t he esti mate d me a n c ha n ge bet wee n t h e 
da pa glifl ozi n/sa xa gli pt i n tr e at me nt gr o u p a n d place b o will be calc ulate d. T he p- val ue of  the 
differe nce i n Wee k 
2 6 esti mates bet wee n da pa glifl ozi n/sa xa gli pt i n a n d pl ace b o will b e 
prese nte d.
B ot h t he MI -R D a n d w as h -o ut i m p utati o n met h o ds will be prese nte d f or t he pri mar y  e nd p oi nt.
If all of  t he i m p utati o n m o dels ha ve at least 5 o bser vat i ons, t he n MI -R D will be t he pri mar y 
a nal ysis a n d was h -o ut will be t he se nsiti vity a nal ysis. C o n verse l y, if a n y of  t he i m p utati o n 
m o dels ha ve less t ha n 5 o bser vat i ons, t he n was h -o ut will be t he pri mar y a nal ysis a n d MI -R D 
will be t he se nsit i vity a nal ysis. A s u m mar y o f the n u m ber a n d perce nta ge of s u bjects w h o were 
retrie ve d dr o p-o uts will be prese nte d b y  visit for t he S T pe rio d f or b ot h H b A 1c a n d F P G.
4. 4. 2
Se nsiti vit y a n al ysis f or pri m ar y e n d p oi nt
4. 4. 2. 1
A n al ysis e xcl u di n g d at a f oll o wi n g resc ue me dic ati o n i niti ati o n/e arl y t re at me nt 
disc o nti n u ati o 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 pri mar y e n d p o i nt of t he c ha n ge 
i n H b A 1c fr o m baseli ne t o Wee k 
2 6, a n a d diti o nal se nsiti vity a nal ysis will  be perf or m e d 
e xcl u di n g data f ollo wi n g resc ue me dicati on i nit iati o n or earl y disc o nt i n uati o n of treat me nt ( i.e. , 
t hose data will be c o nsi dere d missi n g a n d will be i m p ute d t o get her wit h ot her missi n g Wee k 2 6 
data ). T his a nal ysis will be p erf or m e d as f or t he pr i mary a nal ysis of  t he pri mar y e n d p o i nt but
c ha n gi n g t he met h o d of i m p utati o n as descri be d bel o w.
M ul tiple i m p utatio n f or t his se nsitivit y a nal ysis will ass u me M A R 
wi t hi n eac h tr e at me nt  
re gi me n. T his mea ns t hat t he di stri b uti on o f missi n g data i n s u bjects w h o disc o nt i n ue d treat me nt  
earl y or w h o use d resc ue me dicati o n pri or t o Wee k 2 6 will be i m p ute d base d o n data fr o m ot her 
s u bjects i n t he sa me treat me nt re gi me n w h o c o m plete d t he S T treat me nt a n d di d n ot use resc ue
d uri n g t he S T peri o d .
T he f o ll owi n g t w o ste ps will be use d:

Ste p 1: Pri or t o i m p utati o n, t he M C M C met h o d will be use d as descri be d i n 
Secti o n 4. 1. 1 2. 1 . T he i m p utati o n m o d el  with i ncl u de fact ors a n d c o variates i n 
t he f oll owi n g or der: i n dicat ors of  ra n d omisati o n strata a n d baseli ne H b A 1c as 
well as Wee k 6, Wee k 1 2, Wee k 2 0 a n d Wee k 2 6 H b A 1c.

St e p 2: Usi n g t he m o n ot o ne datasets ge nerate d as descri be d a b o ve, im p ute 
missi n g Wee k 2 6 H b A 1c data usi n g m ult i ple i m p utati o n u n der M A R h y p ot hesis 
(as descri be d i n Secti on 4. 1. 1 2. 5 ).


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 3
D u m m y  co di n g of  cate g orical varia bles will be i m ple me nte d pri or t o i m p utati o n as descri be d
i n Secti o n 4. 1. 1 2 .
D o w nstrea m ste ps (a nal ysis of  eac h i m p ute d data set usi n g t he A N C O V A m o d el  descri be d i n 
Secti o n 4. 1. 9 , a n d c o m bi ni n g res ults as descri be d i n Secti o n 4. 1. 1 2. 4 ) will be p erf or m e d as f or 
t he primar y  a nal ysis. 
4. 4. 2. 2
A n al ysis b ase d o n E v al u a ble S u bjects D at a Set
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 pri mar y e n d p o i nt of the c ha n ge 
i n H b A 1c fr om baseli ne t o Wee k 2 6, a n a d dit i onal se nsit i vity a nal ysis usi n g t he sa me a p pr oac h 
as t he se nsiti vity efficac y anal ysis i n S e cti o n 4. 4. 2. 1 ma y be p erf or me d usi n g t he E val ua ble 
S u bjects Data Set if greater t ha n 1 0 % of t he s u bj e cts for a n y treat me nt gr o u p or place b o i n t he 
Ra n d o mise d S u bjects Data Set ha ve r ele va nt pr ot oc ol de viat i ons. F or t his a nal ysis all H b A 1c 
c ollecte d aft er rele va nt pr ot oc ol de viat i ons o nset or aft er resc ue me d icati on i nitiati on/earl y 
di sc o nti n uati on of  treat me nt wil l be set t o missi n g pri or t o m ult i ple i m p utati o n pr ocess. A n
A N C O V A m o del will be use d f or t his a nal ysis.
4. 4. 2. 3
Missi n g d at a p atter ns
T he patter n of  missi n g data f or t h e pri mar y  e nd p oi nt will be pr o vi de d (as pr o d uce d b y P R O C 
MI i n S A S). T his s u m mar y arra n ges t he
res p o nse data (i n t his case H b A 1c) i nt o " patter ns" (f or 
e xa m ple, t he n u m ber a n d perce nta ge of  su bjects wi t h no missi n g data at a n y visit, or wit h 
missi n g data o nl y  for t he last visit, or wit h missi n g data f or t he last t wo visits, a n d s o o n) 
re gar dless of /e xcl u di n g val ues aft er resc ue me d icatio n i nitiati on or pre mat ure e n d of  st u d y 
me dicat i on, b y treat me nt gr o u p. T hi s als o pr o vid e s mea n H b A 1c b y missi n g data patter n.
I n a d ditio n, descri pt i ons of  missi n g H b A 1c as well as H b A 1c data c ollecte d f oll owi n g resc ue
me dicat i on i nit iati on or disc o nti n uati o n st u d y me dicati o n will i ncl u de a descri pt i on per visit b y 
treat me nt gr o u p d uri n g t he s h ort -t er m p erio d of :

t he c u mulati ve n u m ber of s u bjects w h o disc o nt i n ue d st u d y me dicat i on,

t he c u mulat i ve n u m ber of  su bjects w h o d isc o nti n ue d st u d y me dicat i on b ut still o n 
st u d y,

t he c u mulati ve n u m ber of s u bjects resc ue d,

t he c u mulati ve n u m ber of s u bjects resc ue d b ut still o n st u d y ,

t he c u mulati ve n u m ber of s u bjects resc ue d or w h o disc o nti n ue d st u d y  me dicat i on,

t he c u mulat i ve n u m ber of  su bjects resc ue d or w h o disc o nt i n ue d st u d y me dicat i on 
b ut s till o n st u d y,
o
t he n u m ber of  su bjects resc ue d or w h o disc o nt i n ue d st u d y me dicatio n b ut 
still ha vi n g a Wee k t H b A 1c val ue,
o
t he n u m ber of  su bjects resc ue d or w h o disc o nt i n ue d st u d y me dicat i on a n d 
missi n g Wee k t H b A 1c val ue,


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 4

t he c u mulati ve n u m ber of s u bjects wit h dra w n fr o m st u d y ,

t he n u m ber of s u bjects still o n treat me nt, still o n st u d y , n ot resc ue d b ut w h o misse d 
a gi ve n visit ,

t he n u m ber of s u bjects missi n g Wee k t H b A 1c val ue,

a gra p hical s u m mar y prese nt i n g t he m o n ot o ne missi n g data patter n fr om baseli ne t o 
Wee k 2 6 prese nt i n g H b A 1c val ues re gar dless of resc ue me dicat i on i nit iati o n as well 
as prese nt i n g H b A 1c val ues c o llecte d pri or t o resc ue me dicat i on i nitiati o n or 
di sc o nti n uati on of  st u d y me dicati on b y treat me nt gr o u p, al o n g wit h a c orres p o n di n g 
s u m mar y ta ble.
4. 4. 2. 4
Ti p pi n g p oi nt a n al ysis
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 pri mar y e n d p o i nt of the c ha n ge 
i n H b A 1c fr om baseli ne t o Wee k 2 6, a n a d dit i onal se n sitivi t y a nal ysis usi n g a ti p pi n g p oi nt will 
be p erf or m e d at Wee k 2 6 as descri be d i n Sect i on  4. 1. 1 2. 6 f or t he sa me A N C O V A m o d el  us e d 
f or t he pri mar y anal ysis ( Secti o n  4. 4. 1 ).
4. 4. 3
S u b gr o u p a n al yses f or pri m ar y e n d p oi nt
4. 4. 3. 1
A n al ysis of c h a n ge fr o m b aseli ne i n H b A 1c at Wee k 2 6 wit hi n s u b gr o u ps
T he s u b gr o u p- b y-tr e at me nt i nteracti o n will be assesse d f or t he pri mar y efficac y e n d p o i nt usi n g 
the MI -W O i m p utati o n met h o d a n d t he A N C O V A m o d el  use d f or t he pri mar y a nal ysis of  t he 
c ha n ge fr om baseli ne i n H b A 1c at Wee k 
2 6 wi t h su b gr o u p, a n d s u b gr o u p- b y-tr e at me nt  
i nteract i on as a d ditio nal  effects. Se parate i m p utati o n m o dels f or eac h s u b gr o u p will be use d. 
T his will 
be re peate d f or s u b gr o u ps base d o n race, et h nicit y,  se x, a ge gr o u p
( usi n g 
ra n d omisat i on str at a), re gi o n, baseli ne a nt i dia betic treat me nt , baseli ne H b A 1 c, a n d baseli ne 
B MI , usi n g t he cate g ories defi ne d i n t he A p pe n di x (Ta ble 1 9) . T he a dj uste d mea n c ha n ges fr o m 
baseli ne, S Es, 9 5 % CIs , a n d p- val ue f or eac h s u b gr o u p a n d t he n o mi nal p -val ue f or s u b gr o u p 
b y treat me nt i nteracti o n will be calc ulate d.
T he s u b gr o u p b y tr e at me nt i nteractio n p- val ue will be calc ulate d as t he me d ia n p- val ue fr om 
t he set of all i m p utatio ns.
M o d el s f or s u b gr o u p a nal yses w hic h e val uate baseli ne H b A 1c le vel will  in cl u de t er ms f or t h e 
cate g orise d baseli ne H b A 1c le vel a n d n ot (c o nti n u o us) baseli ne val ues. 
Stati stical si g nifica nce of  a Wee k 2 6 treat m e nt re gi me n *s u b gr o u p i nteractio n will be assesse d 
at a n u na dj uste d 0. 1 0 le vel.
I n a d ditio n, a f orest pl ot of adj uste d me a n differe nce fr om pl ace b o ± 9 5 % c o nfi de nce i nter va l 
( CI), p-val ues f or eac h s u b gr o u p cate g or y a n d p- val ue f or i nteractio n b y s u b gr o u p will b e 
di s pla ye d.
S u bjects wi t h missi n g data f or t h e gr o u pi n g varia ble will be e xcl u de d fr o m t he c orres p o n di n g 
s u b gr o u p a nal ysis. F or eac h s u b gr o u p, if, i n a n y treat me nt gr o u p, t he n u m ber of s u bjects is less 
t ha n 1 0 f or a s u b gr o u p cate g or y, a djuste d est i mates a n d t heir differe nces a n d c orres p o n di n g 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 5
statistics will n ot be dis pla ye d f or t hat s u b gr o u p, a n d o nl y  descri pt i ve statistics will be prese nte d 
f or that cate g or y a n d i ncl u de d i n t he a nal ysis res ults. I nteractio n p- val ue will n ot be pr o vi d e d 
eit her.
F or baseli ne a nt i dia betic treat me nt s u b gr o u p, if t he n u m ber of s u bjects wit hi n ‘i ns uli n o nl y’ or 
‘ metf or mi n + i ns uli n’ cate g or y is less t ha n 1 0, t he n t hese t w o c ate g ories will be gr o u pe d i nto 
‘i ns uli n +/- met f or mi n’. I n case of n o n- c o n ver ge nce beca use o f s parse data, s u bse q ue nt bac k u p 
i m p utatio n m o d el s will be use d c olla psi n g t he ra n d o misati on str at a of bac k gr o u n d me d icatio n 
as defi ne d i n Secti o n  4. 1 a n d c olla psi n g t he re gi o n i nt o ‘N ort h A merica + E ur o pe ’ a n d ‘Rest of 
t he W orl d ’.
4. 4. 3. 2
Metf or mi n s u b gr o u p a n al ysis f or pri m ar y a n al ysis of c h a n ge fr o m b aseli ne i n 
H b A 1c at Wee k 2 6
T he A N C O V A m o del use d f or t he pri mar y a nal ysis ( Sectio n  4. 4. 1 ) of  t he c ha n ge fr om 
baseli ne i n H b A 1c at Wee k 2 6 will als o be re peate d f or t he s u b gr o u p of s u bjects o n a sta bl e 
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). T he sa me m ult i ple i m p utati o n 
met h o d use d f or t he pri mar y a nal ysis of  t he e n d p oi nt wi ll be use d f or t h is s u b gr o u p a nal ysis.
T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utatio n ste p f or i ns uli n o nl y 
a n d i ns uli n wit h metf or mi n will  be gr o u pe d as defi ne d i n Sect i on  4. 1. 1 2 .
4. 4. 4
Ot her a n al yses f or pri m ar y e n d p oi nt
4. 4. 4. 1
A n al ysis of c h a n ge fr o m b aseli ne i n H b A 1c at Wee k 6, Wee k 1 2, a n d Wee k 2 0
A d dit i onal a nal yses f or c ha n ge fr o m baseli ne i n H b A 1c will be perf or me d at Wee k 6, Wee k 1 2 
a n d Wee k 2 0. Data will be m ult i pl y im p ute d base d o n t he sa me a p pr oac h as descri be d f or t he 
pri mar y  anal ysis i n Sect i on 4. 4. 1 , a n d will i ncl u de all data re gar dless of  resc ue me d icati on 
i nitiati on or a d here nce. A nal ysis will be base d o n t he sa me m ult i pl y i m p ute d data sets pr o d uce d 
f or t he pri mar y a nal ysis of  the pri mar y e n d p o i nt. A nal ysis will be p erf or m e d b y fittin g t he 
A N C O V A m o d el  descri be d f or t he pri mar y e n d p oi nt i n Sectio n 4. 1. 9 . T he a nal ysis m o d el  will 
be e v alu ate d i n eac h i m p ute d data set a n d t he res ults will be c o m bi ne d usi n g R u bi n's r ules as 
descri be d i n Secti o n 4. 1. 1 2. 4 f or eac h visit.
I n a d diti on, a li ne pl ot of  L S me a n ± 9 5 % c o nfi de nce i nter val ( CI) b y visit u p t o Wee k 2 6 will 
be dis pla ye d.
4. 5
Sec o n d ar y effic ac y e n d p oi nt a n al ysis
4. 5. 1
Hier arc hic al Testi n g
Sec o n dar y  efficac y e n d p oi nt a nal yses will als o  be perf or m e d se paratel y for eac h dr u g 
(da pa glifl o zi n a n d sa xa gli pti n). F or eac h dr u g, t he f oll owi n g se q ue ntial testi n g or der will b e 
e mpl o y e d t o c o ntr ol m ult i plicity of  testi n g f or t he sec o n dar y object i ves at a famil y -wise T y pe I 
err or rate of  0. 0 5 ( 2-side d). F or eac h gr o u pi n g of e n d p o i nts, f or e xa m ple f or all re d uct i on i n 
H b A 1c/ F P G fr o m baseli ne e n d p oi nts f or t he Ra n d o mise d S u bjects Data Set, f or eac h treat me nt  
( da pa glifl ozi n a n d sa xa gli pt i n) t he sa me m ulti ple i m p utatio n m et h o d will be use d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 6
1.
C o m paris o n of  mea n re d uctio n i n H b A 1c fr o m baseli ne at Wee k 2 6 bet wee n t he l ow-
d ose / hi g h-d ose treat me nt re gi me n a n d pl ace b o
2.
C o m paris o n of  mea n re d uctio n i n H b A 1c fr o m baseli ne 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
3.
C o m paris o n of me a n re d uctio 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  a n d place b o 
4.
C o m paris o n of  mea n re d uctio n i n F P G fr om baseli ne at Wee k 2 6 bet wee n t he l ow-
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 lo w -d ose 
treat me nt re gi me n a n d place b o
6.
C o m par is o n of  the perce nta ge of  su bjects wi t 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 2 6 bet wee n o verall dr u g treat me nt a n d place b o
7.
C o m paris o n of  the perce nta ge of  su bjects wi t 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 2 6 bet wee n t he lo w -d ose / hi g h-d ose treat me nt re gi me n a n d 
pl ace b o
8.
C o m paris o n of  the perce nta ge of  su bjects wi t 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 2 6 bet wee n t he lo w -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 on i n H b A 1 c fr o m baseli ne at Wee k 
2 6 bet wee n t h e 
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 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  su bjects wi t 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 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 ( da pa glifl ozi n o r sa xa gli pti n) if t he pri mar y e n d p oi nt is si g nifica nt, t he statistical 
tests will be f or mall y e val uate d, startin g fr om t he first sec o n dar y efficac y en d p o i nt a n d 
c o nti n ui n g i n t he or der a b o ve. Eac h sec o n dar y en d p oi nt f or a gi ve n dr u g will be teste d if t he 
pre vi o us sec o n dar y en d p o i nt is si g nifica nt at  the t w o-si de d 0. 0 5 level. T he testi n g pr oce d ure 
will st o p at  t he first sec o n dar y e nd p oi nt t hat d oes n ot reac h st atistical si g nifica nce. Fr o m  t he n 
o n war ds, p- val ues a n d CIs will c o nt i n ue t o be re p orte d, b ut n o c lai m will  be base d t hese p-
val ues. A clear di sti ncti on will be ma de bet wee n p- val ues w here b y  clai ms ca n a n d ca n n ot be 
ma de.
Hi erarc hical test i n g of t he pri mar y a n d sec o n dar y efficac y e n d p oi nts will be prese nte d f or eit her
t he Ra n d o mise d S u bjects Data Set or U p -titratio n Ra n d o mise d S u bjects Data Set (as a p plica ble 
per e n d p oi nt) . P oi nt esti mates, 9 5 % CIs a n d p-val ues will be s u m marise d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 7
4. 5. 2
C o m p aris o n of me a n re d ucti o n i n H b A 1c fr o m b aseli ne at Wee k 2 6 bet wee n t he 
l o w-d ose / hi g h-d ose tre at me nt re gi me n a n d pl ace b o
Data will be m ult i pl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis
of  t he pri mar y e n d p oi nt i n Secti o n 4. 4. 1 at all sc he d ule d t i me p oi nts u p t o a n d i ncl u di n g Wee k 
2 6 , a n d will i ncl u de all data re gar dless of  resc ue me dicat i on i nitiati on or a d here nce. A nal ysis 
will be p erf or me d b y fittin g t he w ei g hte d A N C O V A m o d el  descri be d i n Secti o n 4. 1. 9 . T he 
a nal ysis m o del will be e val uate d i n eac h i m p ute d data set a n d t he res ults will be c o m bi ne d usi n g 
R u bi n's r ul es as descri be d i n Secti o n 4. 1. 1 2. 4 .
T he wei g ht mat ri x W 1
descri be d i n Sect i on 4. 1. 9 f or t he c o m paris o n of t he l o w-d ose / hi g h-
d ose treat me nt re gi me n vers us place b o will be use d f or t his a nal ysis. 
I n a d diti on, a li ne pl ot of L S mea n ± 9 5 % c o nfi de nce i nter val ( CI) b y visit u p t o Wee k 2 6 will 
be dis pla ye d.
4. 5. 2. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of c h a n ge fr o m b aseli ne i n H b A 1 c at 
Wee k 
2 6 bet wee n t he l o w-d ose / hi g h-d ose
tre at me nt re gi me n a n d pl ace b o
e xcl u di n g 
d at a 
f oll o wi n g resc ue 
me dic ati o n 
i niti ati o n/e arl y t re at me nt 
disc o nti n u ati o n
T he a b o ve pri mar y  a nal ysis ( Sectio n 4. 5. 2 ) f or t he c o m par is o n of  mea n re d uctio n i n H b A 1c 
fr om 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 will 
be re peate d e xcl u d i n g data f oll owi n g 
resc ue me d icatio n i nitiati o n or earl y tr e at me nt 
di sc o nti n uati on b ut missi n g data will be i m p ute d ass u mi n g M A R 
as descri be d i n Sect i on 
4. 1. 1 2. 5 . A wei g hte d A N C O V A m o del will be use d f or t his a nal ysis.
4. 5. 2. 2
S u b gr o u p a n al ysis f or sec o n d ar y e n d p oi nt of c h a n ge fr o m b aseli ne i n H b A 1c at 
Wee k 2 6 bet wee n t he l o w-d ose / hi g h-d ose tre at me nt re gi me n a n d pl ace b o
T he a b o ve pri mar y  anal ysis ( Sectio n 4. 5. 2 ) f or t he c o m par is o n of  mea n re d uctio n i n H b A 1c 
fr om baseli ne at Wee k 2 6 bet wee n t he l ow- d ose/ hi g h -d ose treat m e nt re gi me n a n d place b o will 
be re peate d f or s u b gr o u ps base d o n race, et h n icity,  se x, a ge gr o u p ( usi n g ra n d o misati on strata), 
r e gio n, baseli ne a nti dia betic treat me nt, baseli ne H b A 1c a n d baseli ne B MI, usi n g t he cate g ories 
defi ne d i n t he A p pe n di x (Ta ble 1 9 ) a n d will foll o w  t he s a me a p pr oac h as t he o ne descri be d i n 
Secti o n  4. 4. 3. 1 usi n g a wei g hte d A N C O V A m o del .
4. 5. 2. 3
Metf or mi n 
s u b gr o u p a n al ysis f or p r i m ar y a n al ysis of sec o n d ar y e n d p oi nt of 
c h a n ge fr o m b aseli ne i n H b A 1c at Wee k 
2 6 bet wee n t he l o w-d ose / hi g h-d ose
tre at me nt re gi me n a n d pl ace b o
T he wei g hte d A N C O V A m o del use d f or t he pri mar y  a nal ysis ( Sectio n  4. 5. 2 ) of  t he c ha n ge 
fr om baseli ne i n H b A 1c at Wee k 2 6 will als o 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 mi n I R or X R ( wi t h or wit ho ut i ns uli n). T he sa me m ult i ple 
i m p utatio n m et h o d use d f or t he pri mar y a nal ysis of t he e n d p oi nt will be use d f or t his s u b gr o u p 
a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utati o n ste p f or 
i ns uli n o nl y a n d ins uli n wit h metf or mi n will  be gr o u pe d as defi ne d i n Secti on  4. 1. 1 2 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 8
4. 5. 3
C o m p aris o n of me a n re d ucti o n i n H b A 1c fr o m b aseli ne at Wee k 2 6 bet wee n t he 
l o w-d ose tre at me nt re gi me n a n d pl ace b o
Data will be m ult i pl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis 
of  t he pri mar y e n d p oi nt i n Secti o n 4. 4. 1 at all sc he d ule d t i me p oi nts u p t o a n d i ncl u di n g Wee k 
2 6 , a n d will i ncl u de all data re gar dless of  resc ue me dicat i on i nitiati on or a d here nce. A nal ysis 
will be perf or m e d b y fitti n g t he w ei g hte d A N C O V A m o d el descri be d i n Secti o n 4. 1. 9 i n eac h 
o f t he i m p ute d data sets a n d c o m bi ni n g t he res ults usi n g R u bi n's r ul es, as descri be d i n Sect i on
4. 1. 1 2. 4 . T he wei g ht matri x W 2 descri be d i n Secti o n 4. 1. 9 f or t he c o mparis o n of t he l ow -d ose 
treat me nt re gi me n vers us place b o will be use d f or t his a nal ysis. 
4. 5. 3. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n H b A 1c fr o m 
b aseli ne at Wee k
2 6 bet wee n t he l o w-d ose tre at me nt re gi me n a n d pl ace b o
e xcl u di n g 
d at a 
f oll o wi n g resc ue 
me dic ati o n 
i niti ati o n/e arl y t re at me nt 
disc o nti n u ati o n
T he a b o ve pri mar y  a nal ysis ( Sectio n 4. 5. 3 ) f or t he c o m par is o n of  mea n re d uctio n i n H b A 1c 
fr om baseli ne 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 will be re peate d 
e xcl u di n g data f oll owi n g resc ue me dicat i on i nitiatio n or earl y treat me nt disc o nt i n uati o n b ut  
missi n g data will be i m p ute d ass u mi n g M A R as descri be d i n Sect i on 4. 1. 1 2. 5 .
4. 5. 3. 2
Metf or mi n s u b gr o u p a n al ysis f or sec on d ar y e n d p oi nt of c h a n ge fr o m b aseli ne 
i n H b A 1c at Wee k 2 6 bet wee n t he l o w-d ose tre at me nt re gi me n a n d pl ace b o
T he w ei g hte d A N C O V A m o del use d f or t he pri mar y  a nal ysis ( Secti o n 4. 5. 3 ) f or t he c ha n ge 
fr om baseli ne i n H b A 1c at Wee k 2 6 will als o 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 mi n I R or X R ( wit h or wit h o ut i ns uli n). T he sa me m ult i ple 
i m p utatio n m et h o d use d f or t he pri mar y a nal ysis of t he e n d p oi nt will be use d f or t his s u b gr o u p 
a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utati o n ste p f or 
i ns uli n o nl y a n d i ns uli n with metf or mi n will  b e gr o upe d as defi ne d i n Sect i on  4. 1. 1 2 .
4. 5. 4
C o m p aris o n of me a n re d ucti o n i n F P G fr o m b aseli ne at Wee k 
2 6 bet wee n 
o ver all dr u g tre at me nt a n d pl ace b o 
Data will be m ult ipl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y  
a nal ysis of  t he pri mar y e n d p oi nt i n Secti on 4. 4. 1 at all sc he d ule d ti me p o i nts u p t o a n d 
i ncl u di n g Wee k 2 6, re placi n g H b A 1c wit h F P G , a n d will i ncl u de all data re gar dless of resc ue 
me dicat i on i nitiati on or a d here nce . O nl y F P G assess me nts d oc u m e nte d wit h t he s u bject i n a 
fasti n g state will be s u m marise d a n d liste d. A nal ysis will be perf or me d b y fitti n g t he 
A N C O V A m o del descri be d f or t he pri mar y  a nal ysis of t he pri mar y e n d p o i nt in Secti o n 4. 4. 1
(re placi n g H b A 1c wit h F P G). T he a nal ysis m o del will be e val uate d i n eac h i m p ute d data set 
a n d t he res ults will be c o m bi ne d usi n g R u bi n's r ules as descri be d i n Secti o n 4. 1. 1 2. 4 . N o 
w ei g hts will  be use d i n t he mul tiple i m p utati o n or A N C O V A f or t his a nal ysis.
I n a d diti on, a li ne pl ot of L S mea n ± 9 5 % c o nfi de nce i nter val ( CI) b y visit u p t o W ee k 2 6 will 
be dis pla ye d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
8 9
4. 5. 4. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n F P G fr o m 
b aseli ne at Wee k 2 6 bet wee n o ver all dr u g tre at me nt a n d pl ace b o e xcl u di n g d at a 
f oll o wi n g resc ue me dic ati o n i niti ati o n /e arl y tre at me nt disc o nti n u ati o n
T he a b o ve pri mar y  a nal ysis ( Sectio n  4. 5. 4 ) f or t he c o mparis o n of mea n re d uct i on 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 (l o w -d os e a n d hi g h-d ose) a n d place b o will 
be re peate d e xcl u di n g data f oll owi n g 
resc ue me d icatio n i nitiati o n or earl y tr e at me nt 
di sc o nti n uati on b ut missi n g data will be i m p ute d ass u mi n g M A R 
as descri be d i n Sect i on
4. 1. 1 2. 5 .
4. 5. 4. 2
Metf or mi n s u b gr o u p a n al ysis f or c o m p aris o n of me a n re d ucti o n i n F P G fr o m 
b aseli ne at Wee k 2 6 bet wee n o ver all dr u g tre at me nt a n d pl ace b o
T he A N C O V A m o del use d f or t he pri mar y F P G a nal ysis ( Sect i on  4. 5. 4 ) of t he c ha n ge fr om 
baseli ne i n F P G at Wee k 2 6 bet wee n o verall dr u g treat me nt a n d pla ce b o will als o 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 mi n I R or X R ( wit h or wit h o ut 
i ns uli n). T he sa me m ulti ple i m p utati o n met h o d use d f or t he pri mar y a nal ysis of t he e n d p o i nt 
will be use d f or t his s u b gr o u p a nal ysis. T h e i n dicat or f or bac k gr o u n d me dicat i on use d i n t he 
m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d i ns uli n wit h metf or mi n will be gr o u pe d as 
defi ne d i n Sect i on  4. 1. 1 2 . N o wei g hts will be use d i n t he m ulti ple i m p utati o n or A N C O V A f or 
t his a nal ysis. 
4. 5. 4. 3
Missi n g d at a p atter ns
A s u m mar y  of missi n g F P G as well as F P G data c ollecte d f oll owi n g resc ue me dicat i on 
i nitiati on or disc o nti n uati o n st u d y  me dicat i on will be p rese nte d f or t he s h ort-t er m p erio d, as 
descri be d i n Secti o n  4. 4. 2. 3 .
4. 5. 5
C o m p aris o n of me a n re d ucti o n i n F P G fr o m b aseli ne at Wee k 2 6 bet wee n t he 
l o w- dose / hi g h-d ose tre at me nt re gi me n a n d pl ace b o
Data will be m ult ipl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y  
a nal ysis i n Sect i on 4. 4. 1 at all sc he d ule d ti me p o i nts u p t o a n d i ncl u di n g Wee k 2 6, re placi n g 
H b A 1c wit h F P G , a n d will i ncl u de all data re gar dless of resc ue me dicat i on i nitiati on or 
a d here nce. A nal ysis will be perfor m e d b y fitti n g t he weig hte d A N C O V A m o del descri be d i n 
Secti o n 4. 1 . 9(re placi n g H b A 1c wit h F P G) . T he a nal ysis m o del will be e val uate d i n eac h 
i m p ute d data set a n d t he res ults will be c o m bi ne d usi n g R u bi n's r ules as descri be d i n Sect i on
4. 1. 1 2. 4 . T he wei g ht mat rix W 1
descri be d i n Secti o n 4. 1. 9 f or t he c o mparis o n of t he l o w -
d ose / hi g h-d ose treat me nt re gi me n vers us place b o will be use d f or t his a nal ysis. 
I n a d diti on, a li ne pl ot of L S mea n ± 9 5 % c o nfi de nce i nter val ( CI) b y visit u p t o Wee k 2 6 will 
be dis pla ye d.
4. 5. 5. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n F P G fr o m 
b aseli ne at Wee k 
2 6 bet wee n t he l o w-d ose / hi g h-d ose tre at me nt re gi me n a n d 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 0
pl ace b o e xcl u di n g d at a f oll o wi n g resc ue me dic ati o n i niti ati o n/e arl y tre at me nt 
disc o nti n u ati o n
T he a b o ve pri mar y  a nal ysis ( Sectio n  4. 5. 5 ) f or t he c o mparis o n of mea n re d uct i on i n F P G fr o m 
baseli ne at Wee k 2 6 bet wee n t he l ow- d ose / hi g h-d os e treat me nt re gi me n a n d place b o will b e 
re peate d e xcl u di n g data 
f oll owi n g 
resc ue me dicat i on 
i nitiati on
or 
earl y tr e at me nt 
di sc o nti n uati on b ut missi n g data will be i m p ute d ass u mi n g M A R 
as descri be d i n Sect i on 
4. 1. 1 2. 5 . A wei g hte d A N C O V A m o del will be use d f or t his a nal ysis.
4. 5. 6
C o m p aris o n of me a n re d ucti o n i n F P G fr o m b aseli ne at Wee k 2 6 bet wee n t he 
l o w-d ose tre at me nt re gi me n a n d pl ace b o
Data will be m ult ipl y  i mp ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis 
of  t he pri mar y e n d p oi nt i n Secti o n 4. 4. 1 at all sc he d ule d t i me p oi nts u p t o a n d i ncl u di n g 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 , re placi n g H b A 1c with F P G , a n d will 
i ncl u de all data re gar dless of  resc ue me d icatio n i nitiati on or a d here nce . A nal ysis will b e 
perf or m e d b y fittin g t he w ei g hte d A N C O V A m o del
descri be d in S e cti o n 4. 1. 9 (re placi n g 
H b A 1c wit h F P G). T he wei g ht matri x W 2 descri be d i n Secti o n 4. 1. 9 f or t he c o mparis o n of t he 
l ow- d ose treat me nt re gi me n vers us place b o will be use d f or t his a nal ysis. T he a nal ysis m o d el  
will be e val uate d i n eac h i m p ute d data set a n d t he res ults will be c o m bi ne d usi n g R u bi n's r ules
as descri be d i n Sect i on 4. 1. 1 2. 4 .
4. 5. 6. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n F P G fr o m 
b aseli ne at Wee k 
2 6 be t wee n t he l o w-d ose tre at me nt re gi me n a n d pl ace b o
e xcl u di n g 
d at a 
f oll o wi n g resc ue 
me dic ati o n 
i niti ati o n/e arl y t re at me nt 
disc o nti n u ati o n
T he a b o ve pri mar y  F P G a nal ysis ( Sectio n  4. 5. 6 ) f or t he c o mparis o n of mea n re d uctio n i n F P G 
fr om 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 will be re peate d 
e xcl u di n g data f oll owi n g resc ue me dicat i on i nitiatio n or earl y tr e at me nt disc o nt i n uati o n, b ut  
missi n g data will be i m p ute d ass u mi n g M A R as descri be d i n Sect i on  4. 1. 1 2. 5 .
4. 5. 7
C o m p aris o n of t he perce nt a ge of s u bjects wit h b aseli ne H b A 1c ≥ 7 % w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n o ver all d r u g tre at me nt a n d 
pl ace b o
Data will be m ult i pl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis
of  the pri mar y e n d p o i nt i n Sect i on 4. 4. 1 , a n d will i ncl u de all data re gar dless of  resc ue 
me dicat i on i nit iati on or a d here nce. H b A 1c res p o nse ( < 7 %) will be deri ve d fr o m dic h ot o misi n g
t he i m p ute d c o nti n u o us val ues of H b A 1c. 
T he pr o p orti o n of res p o n ders (s u bjects ac h ie vi n g a n H b A 1c < 7 % at Wee k 2 6) will be a nal ysed 
usi n g l ogist ic re gressio n a n d s u m marise d as descri be d i n Sect i on 4. 1. 1 0 . N o  wei g ht s will b e 
use d i n t he m ult i ple i m p utati o n or l o gistic re gressi o n f or t his a nal ysis.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 1
4. 5. 7. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of perce nt a ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n o ver all d r u g tre at me nt a n d 
pl ace b o
T he a b o ve pri mar y  a nal ysis ( Sectio n  4. 5. 7 ) of  t he perce nta ge of s u bjects wi t 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 2 6 bet wee n o verall dr u g treat me nt (l o w -d ose 
a n d hi g h-d ose) a n d place b o will be re peate d wit h t he differe nce t hat s u bjects wit h a n y baseli ne 
H b A 1c val ue will be use d . A l ogist ic re gressi on m o d el will be use d f or t his a nal ysis.
4. 5. 7. 2
Metf or mi n 
s u b gr o u p a n al ysis f or c o m p aris o n of perce nt a ge of s u bjects wit h 
b aseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n 
o ver all dr u g tre at me nt a n d pl ace b o
T he l o gi stic re gressi on m o d el  us e d for t h e pri mar y a nal ysis ( Secti on  4. 5. 7 ) 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 % at Wee k 2 6 
bet wee n o veral l dr u g treat m e nt (lo w -d ose a n d hi g h -d ose) a n d place b o will als o 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 met f or mi n I R or X R ( wit h or wit h o ut 
i ns uli n). T he sa me m ult i ple i m p utati o n met h o d use d f or t he pri mar y a nal ysis of t he e n d p o i nt 
will be use d f or t his s u b gr o u p a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he 
m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d i ns uli n wit h metf or mi n will be gr o u pe d as 
defi ne d i n Sect i on  4. 1. 1 2 .
4. 5. 8
C o m p aris o n of t he perce nt a ge of s u bjects wit h b aseli ne H b A 1c ≥ 7 % w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 
2 6 bet wee n t he l o w-d ose / hi g h-d ose
tre at me nt re gi me n a n d pl ace b o
Data will be m ult i ply i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis
of  the pri mar y e n d p o i nt i n Sect i on 4. 4. 1 , a n d will i ncl u de all data re gar dless of  resc ue 
me dicat i on i nit iati on or a d here nce. H b A 1c res p o nse ( < 7 %) will be deri ve d fr o m dic h ot o misi n g
t he i m p ute d c o nt i n u o us val ues of  Hb A 1c a n d R u bi n’s r ules will be use d t o c o m bi ne a nal yses 
acr oss t he m u lti ple i m p utati o ns. Esti mates will be deri ve d fr o m a wei g hte d l ogi stic re gressi on 
or Fis her's e xact test (as a p pr o priate) a n d c o m bi ne d as descri be d i n Sect i on 4. 1. 1 2. 4 . T he wei g ht  
m atri x W 1
( descri bed i n Secti on 4. 1. 9 ) f or t he c o m paris o n of the l o w -d ose / hi g h-d ose treat me nt  
re gi me n vers us place b o will be use d f or t his a n al ysis. 
4. 5. 8. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of perce nt a ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 
2 6 bet wee n t he l o w-d ose / hi g h-d ose
tre at me nt re gi me n a n d pl ace b o
T he a b o ve pri mar y  a nal ysis ( Secti on  4. 5. 8 ) of  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 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 will be re peate d wit h n o restrict i on o n baseli ne H b A 1c val ues . A 
w ei g ht e d l o gi stic m o d el  will be use d f or t his a nal ysis.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 2
4. 5. 8. 2
Metf or mi n 
s u b gr o u p a n al ysis f or c o m p aris o n of perce nt a ge of s u bjects wit h 
b aseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n 
t he l o w-d ose / hi g h-d ose tre at me nt re gi me n a n d pl ace b o
T he wei g hte d l o gist ic re gressi on m o d el  us e d for t he pri mar y a nal ysis ( Secti on  4. 5. 8 ) 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 % 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 will als o be re peate d f or 
t he s ub gr o u p of s u bjects o n a sta ble baseli ne d ose of met f or mi n I R or X R ( wit h or wit h o ut 
i ns uli n). T he sa me m ult i ple i m p utati o n met h o d use d f or t he pri mar y a nal ysis of t he e n d p o i nt 
will be use d f or t his s u b gr o u p a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he 
m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d i ns uli n wit h metf or mi n will be gr o u pe d as 
defi ne d i n Sect i on  4. 1. 1 2 .
4. 5. 9
C o m p aris o n of t he perce n t a ge of s u bjects wit h b aseli ne H b A 1c ≥ 7 % w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 
2 6 bet wee n t he l o w-d ose tre at me nt 
re gi me n a n d pl ace b o
Data will be m ult i pl y i m p ute d base d o n t he sa me a p pr oac h as descri be d f or t he pri mar y a nal ysis
of  t he pri mar y e n d p oi nt i n Secti on 4. 4. 1 , bet wee n t he l o w -d ose treat me nt re gi me n a n d place b o , 
a n d will i ncl u de all d at a re gar dless of  resc ue me dicat i on i nitiati on or a d here nce. H b A 1c 
res p o nse ( < 7 %) will be deri ve d fr o m dic h ot o misi n g t he i m p ute d c o nti n u o us val ues of H b A 1c
a n d R u bi n’s r ules will be use d t o c o m bi ne a nal yses acr oss t he m u lti ple i m p utatio ns . Esti mates 
will be deri ve d fr o m l ogist ic re gressi on or Fi s her's e xact test (as a p pr o priate) a n d c o m bi ne d as 
descri be d i n Sect i on 4. 1. 1 2. 4 . T he wei g ht matri x W 2 
descri be d i n Sect i on 4. 1. 9 f or t he 
c o mparis o n of t he l o w -d ose trea t me nt re gi me n vers us place b o will be use d f or t his a nal ysis.
4. 5. 9. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of perce nt a ge of s u bjects w h o 
ac hie ve a n H b A 1c le vel < 7 % at Wee k 
2 6 bet wee n t he l o w-d ose tre at me nt 
re gi me n a n d pl ace b o
T he a b o ve a nal ysis ( Sectio n 4. 5. 9 ) of  perce nta ge of  su bjects wi t 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 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 
will be re peate d wit h n o restricti o n o n baseli ne H b A 1c val ues .
4. 5. 9. 2
Metf or mi n 
s u b gr o u p a n al ysis f or c o m p aris o n of perce nt a ge of s u bjects wit h 
b aseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7 % at Wee k 2 6 bet wee n 
t he l o w-d ose tre at me nt re gi me n a n d pl ace b o
T he w ei g hte d l ogi stic re gressi on m o d el  us e d for t he pri mar y a nal ysis ( Secti on  4. 5. 9 ) 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 % at Wee k 
2 6 bet wee n t he lo w -d ose treat me nt re gi me n a n d place b o will als o be re peate d f or t he 
s u b gr o u p of s u bjects o n a sta bl e baseli ne d ose of met f or mi n I R or X R ( wit h or wit h o ut 
i ns uli n). T he sa me m ult i ple i m p utati o n met h o d use d f or t he pri mar y a nal ysis of t he e n d p o i nt 
will be use d f or t his s u b gr o u p a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he 
m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d i ns uli n wit h metf or mi n will be gr o u pe d as 
defi ne d i n Sect i on  4. 1. 1 2 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 3
4. 5. 1 0
C o m p aris o n of me a n re d ucti o n i n H b A 1c fr o m b aseli 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
A nal ysis will be base d o n t he U p -titratio n Ra n d o mise d S u bjects Data Set a n d f urt her restricte d 
t o s u bjects o n da pa glifl o zi n (or sa xa gli pti n) w h o ha d H b A 1c ≥ 7 % at Wee k 1 2 a n d will i ncl u de 
all data re gar dless of  resc ue me dicat i on i nit iati on or a d here nce . Missi n g data i n val ues of  Hb A 1c 
at Wee k 2 6 will be i m p ute d usi n g t he m ult i ple i m p utati o n a p pr oac h descri be d i n Secti o n 4. 1. 1 2 .
If t he MI -W O met h o d i s us e d, Place b o s u bjects fr o m t he Ra n d o mise d s u bjects data set will b e 
use d i n t he i m p utati o n m o dels t o i m p ute missi n g val ues f or acti ve treat me nt s u bjects i n t he U p -
titr atio n ra n d o mise d s u bjects data set.
C ha n ge fr o m baseli ne H b A 1c at all sc he d ule d ti me p oi nts u p t o a n d i ncl u di n g Wee k 2 6will b e 
c o mpare d bet wee n t he s u bjects w h o are U p -titrati o n Ra n d o mise d t o re mai n o n t he l ow- d ose 
a n d t he s u bjects w h o are u p- titr atio n ra n d omise d t o t he hi g h -d ose usi n g t he A N C O V A m o del 
descri be d i n Sect i on 4. 1. 9 , with o ut wei g hts. T he a nal ysis will be e val uate d i n eac h i m p ute d data 
set a n d t he res ults will be c o m bi ne d usi n g R u bi n’s r ules as descri be d i n Se ct i on 4. 1. 1 2. 4 . T he 
i n dicat or f or bac k gr o u n d me d icati on use d i n t he m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d 
i ns uli n wi t h met f or mi n will  be gr o u pe d as defi ne d i n Secti o n 4. 1. 1 2 . N o  wei g ht s will be use d 
i n t he m ulti ple i m p utati o n or A N C O V A f or t his a nal ysis.
4. 5. 1 0. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n H b A 1c fr o m 
b aseli 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 e xcl u di n g d at a f oll o wi n g resc ue 
me dic ati o n i niti ati o n/e arl y tre at me nt disc o nti n u ati o n
T he a b o ve a nal ysis ( Secti o n  4. 5. 1 0 ) for t he c o m paris o n of mea n re d uct i on 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 bj ects w h o d o n ot ac hie ve 
a n H b A 1c < 7 % at Wee k 1 2 will be re peate d e xcl u di n g data f o ll owi n g resc ue me dicati o n 
i nitiati on or earl y treat me nt disc o nt i n uati on b ut missi n g data will be i m p ute d ass u mi n g M A R 
as descri be d i n Sect i on  4. 1. 1 2. 5 . N o wei g hts will be use d i n t he m ult i ple i m p utatio n or 
A N C O V A f or t his a nal ysis.
4. 5. 1 0. 2
Metf or mi n s u b gr o u p a n al ysis
f or c o m p aris o n of me a n re d ucti o n i n H b A 1c 
fr o m b aseli 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
T he A N C O V A m o del use d f or t he pri mar y a nal ysis ( Secti o n  4. 5. 1 0 ) of t he 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 will als o 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 met f or mi n I R or X R ( wi t h or wit ho ut i ns uli n). T he sa me m ult i ple 
i m p utatio n m et h o d use d f or t he pri mar y a nal ysis of t he e n d p oi nt will be use d f or t his s u b gr o u p 
a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utati o n ste p f or 
i ns uli n o nl y a n d ins uli n wit h metf or mi n will  be gr o u pe d as defi ne d i n Secti on  4. 1. 1 2 . N o 
w ei g hts will  be use d i n t he mul tiple i m p utati o n or A N C O V A f or t his a nal ysis.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 4
4. 5. 1 1
C o m p aris o n of me a n re d ucti o n i n F P G fr o m b aseli 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
A nal ysis will be base d o n t he U p -titratio n Ra n d o mise d S u bjects Data Set a n d f urt her restricte d 
t o s ubjects o n da pa glifl o zi n (or sa xa gli pti n) w h o ha d H b A 1c ≥ 7 % at Wee k 1 2 a n d will i ncl u de 
all data re gar dless of resc ue me d icati on i nitiati on or a d here nce . Mi ssi n g data i n val ues of F P G 
at Wee k 2 6 will be i m p ute d usi n g t he m ult i ple i m p utati o n a p pr oac h describe d i n Secti o n 4. 1. 1 2 .
If t he MI -W O met h o d i s us e d, Place b o s u bjects fr o m t he Ra n d o mise d s u bjects data set will b e 
use d i n t he i m p utati o n m o dels t o i m p ute missi n g val ues f or acti ve treat me nt s u bjects i n t he U p -
titr atio n ra n d o mise d s u bjects data set.
C ha n ge fr om baseli ne F P G at all sc he d ule d ti me p oi nts u p t o a n d i ncl u di n g Wee k 2 6 will b e 
c o mpare d bet wee n t he s u bjects w h o are U p -titrati o n Ra n d o mise d t o re mai n o n t he l ow -d ose 
a n d t he s u bjects w h o are U p -titr atio n Ra n d o mise d t o t he hi g h-d ose usi n g t he A N C O V A m o del 
descri be d i n Sect io n 4. 1. 9 , with o ut wei g hts. T he a nal ysis will be e val uate d i n eac h i m p ute d data 
set a n d t he res ults will be c o m bi ne d usi n g R u bi n’s r ules as descri be d i n Sect i on 4. 1. 1 2. 4 . N o  
w ei g hts will  be use d i n t he mul tiple i m p utati o n or A N C O V A f or t his a nal ysis.
4. 5. 1 1. 1
Se nsiti vit y a n al ysis f or sec o n d ar y e n d p oi nt of me a n re d ucti o n i n F P G fr o m 
b aseli 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 e xcl u di n g d at a f oll o wi n g resc ue 
me dic ati o n i niti ati o n /e arl y tre at me nt disc o nti n u ati o n
T he a b o ve pri mar y a nal ysis ( Sectio n  4. 5. 1 1 ) f or t he c o m paris o n of me a 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 will be re peate d e xcl u di n g data f o ll owi n g resc ue me dicati o n i nitiati on
or earl y t reat me nt di sc o nti n uatio n b ut missi n g data will be i m p ute d ass u mi n g M A R as descri be d 
i n Sect i on 4. 1. 1 2. 5 . T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utati on 
ste p f or i ns uli n o nl y a n d i ns uli n wi t h met f or mi n will be gr o u pe d as defi ne d i n Sect i on  4. 1. 1 2 . 
N o wei g hts will be use d i n t he m ult i ple i m p utatio n or A N C O V A f or t his a nal ysis.
4. 5. 1 1. 2
Metf or mi n s u b gr o u p a n al ysis
f or c o m p aris o n of me a n re d ucti o n i n F P G fr o m 
b aseli 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
T he A N C O V A m o del use d f or t he pri mar y a nal ysis ( Sectio n  4. 5. 1 1 ) of  t he 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 will als o 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 met f or mi n I R or X R ( wit h or wit h o ut i ns uli n). T he sa me m ult i ple 
i m p utatio n m et h o d use d f or t he pri mar y a nal ysis of t he e n d p oi nt will be use d f or t his s u b gr o u p 
a nal ysis. T he i n dicat or f or bac k gr o u n d me dicat i on use d i n t he m ult iple i m p utati o n ste p f or 
i ns uli n o nl y a n d i ns uli n with metf or mi n will  be gr o u pe d as defi ne d i n Secti on  4 . 1. 1 2. N o  
w ei g hts will  be use d i n t he mul tiple i m p ut ati o n or A N C O V A f or t his a nal ysis.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 5
4. 5. 1 2
C o m p aris o n of t he perce nt a ge of s u bjects wit h b aseli ne H b A 1c ≥ 7 % w h o 
ac hie ve a n H b A 1c le vel < 7 % 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
A nal ysis will be base d o n t he U p -titr atio n Ra n d o mise d S u bjects Data Set , f urt her restricte d t o 
s u bjects o n da pa glifl ozi n (or sa xa gli pti n) w h o ha d H b A 1c ≥ 7 % at Wee k 1 2 a n d will i ncl u de all 
data re gar dless of  resc ue me d icati on i nitiati on or a d here nce . Missi n g data i n val ues of  Hb A 1c 
at Wee k 2 6 will be i m p ute d usi n g t he m ult i ple i m p utati o n a p pr oac h descri be d i n Secti o n 4. 1. 1 2 .
If t he MI -W O met h o d i s us e d, Place b o s u bjects fr o m t he Ra n d o mise d s u bjects data set will b e 
use d i n t he i m p utati o n m o dels t o i m p ute missi n g val ues f or acti ve treat me nt s u bjects i n t he U p -
titr atio n ra n d o mise d s u bjects data set.
H b A 1c res p o nse ( < 7 %) will be deri ve d fr o m dic h ot o mis i n g t he i m p ute d c o nti n u o us val ues of 
H b A 1c. Esti mates will be deri ve d fr o m l o gi stic re gressi on or Fis her's e xact test (as a p pr o priate) 
a n d c o m bi ne d as descri be d i n Sect i on 4. 1. 1 2. 4 . N o wei g hts will be use d i n t he m u lti ple 
i m p utatio n or l ogi stic re gressi o n f or t his a nal ysis.
4. 5. 1 2. 1
Metf or mi n s u b gr o u p a n al ysis
f or c o m p aris o n of t he perce nt a ge of s u bjects 
wit h b aseli ne H b A 1c ≥ 7 % w h o ac hie ve a n H b A 1c le vel < 7 % 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
T he l o gi stic re gressi on m o d el  us e d for t he pri mar y a nal ysis ( Secti on  4. 5. 1 2 ) 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 % 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 will als o be re peate d f or t he s ub gr o u p of s u bjects o n a sta ble baseli ne d ose of 
met f or mi n I R or X R ( wit h or wit h o ut i ns uli n). T he sa m e m ultiple i m p utati o n m et h o d use d f or 
t he pri mar y a nal ysis o f t he e n d p o i nt will be use d f or t his s u b gr o u p a nal ysis. T he i n dicat or f or 
bac k gr o u n d me dicat i on use d i n t he m ult i ple i m p utati o n ste p f or i ns uli n o nl y a n d i ns uli n wit h 
met f or mi n will be gr o u pe d as defi ne d i n Sect i on  4. 1. 1 2 . N o wei g hts will be use d i n t he 
m ult i ple i m p utati o n or l ogistic re gressi o n f or t his a nal ysis.
4. 6
E x pl or at or y effic ac y a n al yses
E x pl or at or y  en d p o i nts will n ot be statisticall y teste d. As wi t h the p ri mar y a n d sec o n dary 
efficac y a nal yses, se parate mo d el s will be use d f or da pa glifl ozi 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 gr o u p. E x pl orat or y  anal yses will be perf or me d 
f or o verall da pa glifl ozi n a n d o verall sa xa glipt i n se paratel y, b y c o m bi ni n g all treat m e nt gr o u ps
(lo w -d ose a n d hi g h -d ose) .
Details are pr o vi de d bel o w.
4. 6. 1
E x pl or at or y effic ac y e n d p oi nts f or s h ort -ter m peri o d
T hese a nal yses will  be co n d ucte d o n t he Ra n d o mise d
S u bjects Data Set a n d t he c o mparis o ns 
will be bet wee n o verall da pa glifl ozi n ( or sa xa gli pt i n) a n d place b o.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 6
4. 6. 1. 1
A n al ysis of s u bjects re q uiri n g gl yc ae mic resc ue me dic ati o n or disc o nti n ui n g 
st u d y me dic ati o n d ue t o l ac k of effic ac y
T he pr o p orti o n of  su bjects re q uirin g gl ycae mic resc ue me d icatio n or disc o nt i n ui n g st u d y 
me dicat i on d ue t o lac k of efficac y at or pri or t o Wee k 2 6 will be a nal ysed bet wee n o verall dr u g 
treat me nt (lo w -d ose a n d hi g h -d ose) a n d pl ace b o usi n g a l ogi stic re gressi on . 
T his will be a nal ysed usi n g a l o gist ic re gressi o n a n d s u m marise d as descri be d i n Sect i on  4. 1. 1 0 . 
N o wei g hts will be use d i n t he l o gist ic re gressi on f or t his a nal ysis.
I n a d diti on, t his a nal ysis will be re peate d f or t he s u b gr o u p of s u bjects o n a sta bl e baseli ne d ose 
of  met f or mi n I R or X R ( wit h or wit h o ut i ns uli n).
4. 6. 1. 2
Ti me t o gl yc ae mic resc ue me dic ati o n or disc o nti n u ati o n of st u d y me dic ati o n d ue 
t o l ac k of effic ac y
A time -t o-e ve nt a nal ysis ( w here e ve nt is first use of  resc ue me dicat i on or disc o nti n uati o n of  
st u d y me dicat i on d ue t o lac k of  efficac y, w hic he ver is earlier) d uri n g t he 2 6- wee k treat me nt  
p eri o d will be a nal ysed usi n g a C o x pr o p orti o nal hazar ds m o del as descri be d i n Secti o n  4. 1. 1 1 . 
Esti mates of t he hazar d rati o a n d 9 5 % CI will be pr o vi de d.
I n a d ditio n, a n a nal ysis base d o n Ka pla n -Meier esti mates will be calc ulate d a n d 9 5 % CIs a n d 
n o m i nal p- val ue fr om a pair wise lo g ra n k test will be prese nte d.
R ul es for ce ns ori n g are descri be d i n Sect i on  4. 1. 1 1 .
I n a d diti on, b ot h a nal yses will 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  metfor m i n I R or X R ( wi t h or wit ho ut i ns uli n). N o Ka pla n -Meier pl ot wi ll be prese nte d f or 
t he s u b gr o u p a nal ysis.
4. 6. 1. 3
P erce nt a ge of s u bjects w h o i niti ate gl yc ae mic resc ue me dic ati o n
T he n u m ber a n d perce nta ge of  su bjects w h o re q uire gl ycae mic resc ue me dicat i on d uri n g t he 
2 6- wee k treat me nt peri o d will be pr o vi de d.
I n a d diti on, t his a nal ysis will be re peate d f or t he s u b gr o u p of s u bjects o n a sta bl e baseli ne d ose 
of  met f or mi n I R or X R ( wit h or wit h o ut i ns uli n).
4. 6. 2
E x pl or at or y effic ac y e n d p oi nts f or s h ort -ter m a n d l o n g-ter m peri o d
T hese a nal yses will  be c o n d ucte d o n t he Ra n d o mise d
S u bjects Data Set a n d t he c o mparis o ns 
will be bet wee n o verall da pa glifl ozi n ( or sa xa gli pt i n) a nd place b o.
T hese a nal yses will first be prese nte d wi t ho ut c o nsi deri n g t he t hir d ra n d o misati on , i.e. i ncl u di n g 
all s u bject’s data u p t o Wee k 5 2 or last visit (if earlier t ha n Wee k 5 2). T he n, t o acc o u nt f or t he 
ra n d omise d wi t hdra wal of bac k gr o u n d metf or mi n a t Wee k 3 2 or Wee k 4 0, a d ditio nal a nal yses 
will be perf or me d :

A d di tio n al wei g hte d a nal yses o f 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 
wi t h H b A 1 c < 7 % will be p erf or m e d e x clu di n g s u bjects ra n d omise d t o wit hdra w fr om 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 7
met f or mi n ( Secti ons 4. 6. 2. 1 a n d 4. 6. 2. 2 ). F o r t he wei g hte d a nal yses, 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 t hir d ra n d o misati on a n d wi t hdre w met f or mi n 
will be assi g ne d a wei g ht of  0, a n d t hose ra n d o mise d t o sta y o n met f or mi n will  b e 
assi g ne d a wei g ht of 2. All ot her da pa glifl ozi n ( or sa xa gli pti n) s u b jects will be assi g ne d
a wei g ht of 1. Place b o s u bjects ra n d omise d t o wit h dra w met f or mi n a n d s witc h t o acti ve 
treat me nt will be assi g ne d a wei g ht of  0 . Pl ace b o s u bjects ra n d o mise d t o sta y o n 
met f or mi n will  be assig ne d a weig ht of  3. All ot her place b o s u bjects will be assi g ne d a 
w ei g ht of  1. F or t his a nal ysis, s u bjects wit h a wei g ht of  0 will be e xcl u de d fr om t he 
s u m mar y statistics, m ulti ple i m p utati o n ste ps, a n d A N C O V A/l o gistic re gressi on m o d el .
4. 6. 2. 1
A n al ysis of c h a n ge fr o m b aseli ne at Wee k 5 2 i n H b A 1c a n d F P G
C ha n ge fr om baseli ne at Wee k 5 2 i n H b A 1c a n d, se paratel y, F P G will  be a nal ysed usi n g t he 
A N C O V A m o del descri be d i n Sect i on 4. 1. 9 . T hi s a nal ysis i ncl u des all data re gar dless o f resc ue
me dicat i on i nitiati on or a d here nce. T he a nal ysis will be e val uate d i n eac h i m p ute d data set a n d 
t he res ults will be c o m bi ne d usi n g R u bi n’s r ules as descri be d i n Sect i on 4. 1. 1 2. 4 . Mi ssi n g data 
i n v al ues of  Hb A 1c at Wee k 
5 2 will be i m p ute d usi n g t he m ult i ple i m p utati o n a p pr oac h 
descri be d i n Sect i on 4. 1. 1 2 . P oi nt esti mates a n d 2- side d 9 5 % CIs f or t he mea n c ha n ge wi t hi n 
eac h treat me nt gr o u p, as well as t he differe nce i n mea n c ha n ge bet wee n eac h dr u g a n d place b o  
will be calc ulate d. N o mi nal p- val ues will be prese nte d. N o wei g hts will be use d i n t he m ult i pl e 
i m p utatio n or A N C O V A f or t his a nal ysis.
A d dit i onal a nal yses f or c ha n ge fr o m baseli ne i n H b A 1c a n d F P G will be perf or me d at Wee k 6, 
Wee k 1 2, Wee k 2 0, Wee k 2 6, Wee k 3 2 a n d Wee k 4 0. Data will  be m u lti pl y im p ute d base d o n 
t he sa me a p pr oac h as descri be d f or t he i n Secti o n  4. 5. 4 , a n d will i ncl u de all d at a r e g ar dless of 
resc ue me dicati o n i nitiati on or a d here nce. A nal ys e s will be base d o n t he sa me m ulti pl y i m p ute d 
data sets pr o d uce d f or Wee k 5 2 assess me nts. A nal ysis will  be p erf or m e d b y fitti n g t he sa me
A N C O V A m o del as t he o ne descri be d a b o ve a n d i n Secti on 4. 1. 9 . T he a nal ysis m o del will b e 
e val uate d i n eac h i m p ute d data set a n d t he res ults will be c o m bi ne d usi n g R u bi n's r ules as 
descri be d i n Secti o n 4. 1. 1 2. 4 f or eac h visit.
I n a d diti on, a li ne pl ot of L S me a ns ± 9 5 % c o nfi de nce i nter val ( CI) b y  visit u p t o Wee k 5 2 
will be dis pla ye d f or b ot h H b A 1c a n d F P G.
4. 6. 2. 2
A n al ysis of t he perce nt a ge of s u bjects wit h b a seli ne H b A 1c ≥ 7 % w h o ac hie ve a 
H b A 1c le vel < 7 % at Wee k 5 2
Data will be m ult i pl y i m p ute d base d usi n g t he s a me a p pr oac h as descri be d f or t he pri mar y 
a nal ysis i n Sect i on 4. 4. 1 , a n d will incl u de all  d at a r e g ar dless of resc ue me d icati on i nitiati on or 
a d here nce. H b A 1c res p o nse ( < 7 %) will be deri ve d fr o m dic h ot o misi n g t he i m p ute d c o nti n u o us 
val ues of  Hb A 1c a n d R u bi n’s rules will  be use d t o c o mbi ne a nal yses acr oss t he m ulti p l e 
i m p utatio ns. T he pr o p orti o n of res p o n ders (s u bjects ac hie vi n g a n H b A 1c < 7 % at Wee k 5 2 ) will 
be a nal ysed usi n g l o gist ic re gressi on a n d s u m marise d as descri be d i n Sect i on  4. 1. 1 0 .N o  wei g ht s 
will be use d i n t he m ult i ple i m p utati o n or l o gistic re gressi on f or t his a nal ysis.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 8
4. 6. 2. 3
A n al ysis of s u bjects re q uiri n g gl yc ae mic resc ue me dic ati o n or disc o nti n ui n g 
st ud y me dic ati o n d ue t o l ac k of effic ac y
T he pr o p orti o n of  su bjects re q uirin g gl ycae mic resc ue me d icatio n or disc o nt i n ui n g st u d y 
me dicat i on d ue t o lac k of efficac y at or pri or t o Wee k 5 2 will be a nal ysed bet wee n o verall dr u g 
treat me nt (lo w -d ose a n d hi g h -d ose) a n d place b o usi n g a l o gist ic re gressi on. 
T his will be a nal ysed usi n g a l o gist ic re gressi on a n d s u m marise d as descri be d i n Sect i on  4. 1. 1 0 . 
N o wei g hts will be use d i n t he l o gist ic re gressi on f or t his a nal ysis.
4. 6. 2. 4
Ti me t o gl yc ae mic resc ue me dic ati o n or disc o nti n u ati o n of st u d y me dic ati o n d ue 
t o l ac k of effic ac y
A time -t o-e ve nt a nal ysis ( w here e ve nt is first use of  resc ue me dicat i on or disc o nti n uati o n of  
st u d y me dicat i on d ue t o lac k of  efficac y, w hic he ver is earlier) d uri n g t he 5 2- wee k treat me nt  
p eri o d will be a nal ysed usi n g a C o x pr o p orti o nal hazar ds m o del as descri be d i n Secti o n  4. 1. 1 1 . 
Esti mates of t he hazar d rati o a n d 9 5 % CI will be pr o vi de d.
I n a d ditio n, a n a nal ysis base d o n Ka pla n -Meier esti mates will be calc ulate d a n d 9 5 % CIs an d 
n o mi nal p -val ue fr om a pair wise lo g ra n k test will be prese nte d.
R ul es for ce ns ori n g are descri be d i n Sect i on  4. 1. 1 1 .
4. 6. 2. 5
Perce nt a ge of s u bjects w h o i niti ate gl yc ae mic resc ue me dic ati o n
T he n u m ber a n d perce nta ge of  su bjects w h o re q uire gl ycae mic resc ue me dicat i on d uri n g t he 
5 2- wee k treat me nt peri o d will be pr o vi d e d.
I n a d diti on, t his a nal ysis will be re peate d f or t he s u b gr o u p of s u bjects o n a sta bl e baseli ne d ose 
of  met f or mi n I R or X R ( wit h or wit h o ut i ns uli n).
4. 6. 3
E x pl or at or y 
e ffic ac y a n al yses 
f or m o n ot her a p y 
a ssess me nt d uri n g 
t he 
r a n d o mise d wit h dr a w al 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 omise d
wi t hdra wal p eri o d usi n g t h e 
Ra n d o mise d Wit h dra wal  S u bjects Data Set.
T he e n d p o i nts will be s u m marise d wi t hi n eac h treat me nt gr o u p (as defi ne d i n Secti o n 2. 1 ) fr om 
t he origi nal ra n d omisat i on as f o ll ows:
•
F or s u bjects i nitiall y ra n d o mise d t he da pa glifl ozi n ( or sa xa gli pti n) gr o u p, t he s u bjects 
r e-ra n d o mise d t o wit hdra w met f or mi n will  be c o m pare d t o the s u bjects re-ra n d o mise d
t o sta y o n met f 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 omise d t o eit her da pa glifl ozi n or sa xa gli pt i n gr o u p. 
•
F or s u bjects i nitiall y ra n d o mise d t o t he pl ace b o gr o u p, t he s u bjects w h o were re-
ra n d omise 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 w h o were r e-ra n d o mise d t o sta y on place b o wi t h bac k gr o u n d metf or mi n. 
Se parate a nal yses will 
be p erf or m e d res pecti vel y f or s u bjects re-ra n d o mise d t o 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
9 9
da pa glifl ozi n a n d f or t h ose re -ra n d o mise d t o sa xa gli pti n, usi n g t he t h ose re-ra n d o mise d
t o place b o as c o mparat or.
4. 6. 3. 1
O bser ve d a n d c h a n ge fr o m wit h dr a w al b aseli ne i n H b A 1c a n d F P G
Descri pt i ve s u m maries of  obser ve d a n d c ha n ge fr om wi t hdra wal baseli ne i n H b A 1c a n d, 
se paratel y, FP G f or wi t hdra wal  baseli ne a n d p ost -wi t hdra wal  baseli ne visits will  be pr o vi d e d . 
T his a nal ysis will i ncl u de all data re gar dless of  resc ue me dicat i on i nitiati o n or a d here nce. N o 
i m p utatio n will be pe rfor m e d.
4. 6. 3. 2
P erce nt a ge of s u bjects w h o ac hie ve or m ai nt ai n a H b A 1c le vel < 7 % at t he e n d 
of t he wit h dr a w al peri o d
T he n u m ber a n 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 % at t he e n d 
of  the w ith dra wal p eri o d will be pr o vi de d. T his a nal ysis will i ncl u de all data re gar dless of  resc ue 
me dicat i on i nitiati on or a d here nce. N o i m p utati o n will be perf or me d.
4. 6. 3. 3
Ti me t o gl yc ae mic resc ue me dic ati o n or disc o nti n u ati o n of st u d y me dic ati o n d ue 
t o l ac k of effic ac y
A time -t o-e ve nt a nal ysis ( w here e ve nt is first use of  resc ue me dicat i on or disc o nti n uati o n of  
st u d y me dicat i on d ue t o lac k of  efficac y, w hic he ver is earlier) d uri n g t he 5 2- wee k treat me nt  
p eri o d will be a nal ysed. Date of  first d ose will be d at e of  first d os e i n the ra n d o mise d wi t hdra wal 
p eri o d. Ka pl a n-Meier esti mates will be calc ulate d, a n d 9 5 % CIs will be prese nte d. N o  Ka pla n -
Meier pl ot will be prese nte d f or t his a nal ysis.
R ul es for ce ns ori n g are descri be d i n Sect i on  4. 1. 1 1 .
4. 6. 3. 4
Perce nt a ge of s u bjects w h o i niti ate gl yc ae mic resc ue me dic ati o n
T he n u m ber a n d perce nta ge of  su bjects w h o re q uire gl ycae mic resc ue me dicat i on d uri n g t he 
ra n d omise d wi t hdra wal  treat me nt peri o d will be pr o vi de d. Date of first d ose will be date of first  
d ose i n t he ra n d omise d wi t hdra wal  p erio d.
4. 7
S afet y
S af et y a nal yses will  be c o n d ucte d f or t he S T , S T + L T , a n d ra n d o mise d wi t hdra wal  (as 
a p plica ble) p eri o ds. A n a d ditio n al  safet y a nal ysis will be pr o vi de d f or t he p ost -st u d y visit at 
Wee k 1 0 4, t o s u m marise assess me nts of meas ures of gr o wt h a n d mat urit y b y treat me nt gr o u p . 
S u m maries will be base d o n t he Treate d S u bjects Data Set u nless ot her wise state d.
T he pri mar y  anal yses of  safet y will
i ncl ude data re gar dless of  resc ue me dicat i on i nitiati on , 
u nless ot her wise s pecifie d . A d diti onal se nsit i vity a nal yses o n data c ollecte d pri or t o resc ue will 
be p erf or m e d for A Es a n d la b orat or y  mar ke d a b n or malities. 
Da p a glifl ozi n a n d sa xa gli pti n will be s u m marise d se paratel y. B ot h l ow- d ose a n d hi g h -d ose 
da pa glifl ozi n/ sa xa gli pti n gr o u ps will be c o m bi ne d f or da pa glifl o zi n/sa xa gli pt i n t o pr o vid e t he 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 0
safety s u m mar y for o verall da pa glifl o zi n/sa xa gli pti n c o mpare d t o place b o. A c o m m o n pl ace b o 
gr o u p will be i ncl u de d i n eac h s u m mar y.
A d dit i onal a nal yses will be perf or me d d uri n g t he S T + L T peri o d t o acc o u nt f or t he ra n d omise d
wi t hdra wal  desi g n:

S af et y a nal yses c o n d ucte d d uri n g t he S T + L T peri o d will als o be c o n d ucte d d uri n g t he 
treat me nt perio d u p t o Wee k 3 2.

S af et y a nal yses c o n d ucte d d uri n g t he S T + L T peri o d will als o be c o n d ucte d base d o n t he 
treat me nt recei ve d at t he ti me of  the assess me nt t o acc o u nt f or c ha n ges i n treat me nt 
d uri n g t he ra n d o mise d wi t hdra wal peri o d (da pa glifl ozi n/sa xa gli pt i n/ place b o).

Wei g hte d 
a nal ysis will  be c o n d ucte d f or select safety para meters i ncl u di n g a d verse 
e ve nts, mar ke d a b n or mal la bs a n d E C Gs usi n g t he ori gi nal ra n d o mise d gr o u ps t o assess 
t he effects of  da pa glifl ozi n ( or sa xa gli pti n) vers us pl ace b o o n safety e n d p o i nts f or 
s u bjects o n bac k gr o u n d me dicati o n (i.e. , e xcl u di n g s u bjects re-ra n d o mise d t o wit hdr a w 
fr om metf or mi n).
T he wei g ht mat ri x de n ote d b y   is defi ne d as f oll ows:
 =   ⎣
⎢
⎢
⎢
⎢
⎢
⎢
⎡
  ×    ×    × (   )  ×     ×    × (   ) ⎦
⎥
⎥
⎥
⎥
⎥
⎥
⎤
w here r is t he pr o p orti o n of  su bjects eli gi ble f or t he t hir d ra n d omisat i on a n d n is t he 
n u m ber of s u bjects wit hi n a n ar m.
 : F or t he w ei g hte d a nal yses, da pa glifl o zi n ( or sa xa gli pti n) s u bjects w h o we nt t hr o u g h 
t he t hir d ra n d o misati on a n d wit hdre w metf or mi n will be assi g ne d a wei g ht of zer o, a n d 
t hose ra n d o mise d t o sta y on met f or mi n will b e assi g ne d a wei g ht of  2. All ot h er 
da pa glifl ozi n ( or sa xa gli pti n) s u bjects will be assi g ne d a wei g ht of  1. Pl ace b o s u bjects 
ra n d omise d
t o wit h dra w m et f or mi n a n d s witc h t o acti ve treat me nt will be assi g ne d a 
w ei g ht of  0. Pl ace b o s u bjects ra n d o mise d t o sta y o n met f or mi n will be assi g ne d a wei g ht 
of  3. All ot her place b o s u bjects will be assi g ne d a wei g ht of 1.

S af et y a nal yses will be c o n d ucte d d uri n g t he ra n d o mise d wi t hdra wal  perio d usi n g t he 
Ra n d o mise d Wit h dra wal  S u bjects Data Set. 
F or s u bjects i nit iall y ra n d o mise d t o t he da pa glifl ozi n ( or sa xa gli pt i n) gr o u p, t he s u bjects 
r e-ra n d o mise d t o wit hdra w met f or mi n wi ll be c o m pare d t o t h e s u bjects re-ra n d omise 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 omise d t o eit her da pa glifl ozi n or sa xa gli pt i n gr o u p.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 1
F or s u bjects i nitiall y ra n d o mise 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 omise 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 w h o were r e-ra n d o mise d t o sta y on place b o wi t h bac k gr o u n d met f or mi n. 
Se parate a nal yses will 
be p erf or m e d res pecti vel y f or s u bjects re-ra n d o mise d t o 
da pa glifl ozi n a n d f or t h ose re -ra n d o mise d t o sa xa gli pti n, usi n g t he t h ose re-ra n d o mise d
t o place b o as c o mparat or.
A d dit i onal a nal yses (for A Es , h y p o gl ycae mic e ve nts, a n d M A labs o nl y) will als o b e 
perf or m e d t o c o mpare 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 
vers us t hose ta ki n g place b o wit h bac k gr o u n d met f or mi n d uri n g t he ra n d o mise d
wi t hdra wal p eri o d (a d di n g place b o s u bjects ra n d o mise d t o wit h dra w met f 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 pt i n) 
s u bjects ra n d o mise d t o wit hdra w m et f or mi n).
4. 7. 1
A d verse e ve nts
4. 7. 1. 1
All a d verse e ve nts
A d verse e ve nts will be s u m marise d as n u m ber a n d perce nta ge of  su bjects b y treat me nt gr o u p
e x perie nci n g at least o ne A E wi t hi n a cate g or y. W here s pecifie d, t he n u m ber of  eve nts a n d 
i nci de nce rate will als o be pr o vid e d. N o st ati stical t est will be p erf or m e d t o co m pare A E rates 
bet wee n treat me nt gr o u ps. 
O nl y treat me nt e mer ge nt A Es wi t h onset u p t o t he c ut -off dates defi ne d i n Ta ble 8 will b e 
i ncl ude d i n A E s u m maries.
All A Es
(incl u di n g pre -treat me nt e ve nts) will be liste d. W here 
r ele va nt, A E listi n gs will als o i ncl u de t he m o st rece nt treat me nt d ose recei ve d o n or pri or t o A E
o nset .
T he pri mar y  anal yses of  AEs will i ncl u de data re gar dless of resc ue me d icati on i nitiati on . 
A d dit i onal se nsitivit y a nal yses f or A Es will be restricte d t o data c o llecte d pri or resc ue 
me dicat i on i nitiati on.
A n o verall A E s u m mar y will be pr o vi de d f or t he S T , S T + L T a n d ra n d omise d
wi t hdra wal
p eri o d s, prese nt i n g the n u m ber a n d perce nta ge of  s u bjects b y treat me nt gr o u p re p ortin g at least  
1 A E
(e xcl u di n g h y p o gl ycae mic a n d D K A e ve nts t hat are n ot re p orte d as S A Es) f or t he 
cate g ories prese nte d bel o w. I ncide nce rates (as descri be d i n Sect i on  3. 4. 1 ) a dj uste d f or e x p os ure 
ti me f or S T + L T peri o d mi g ht als o be re p orte d (as a p pr o priate). T he s u m mar y will be pr ovi de d 
f or b ot h pri mar y a n d se nsitivit y a nal yses f or all treate d s u bjects:

At  least o ne A E,

At  least o ne h y p o gl ycae mia e ve nt ,

At  least o ne A E or h y p o gl ycae mia e ve nt ,

At  least o ne S A E,

At  least o ne h y p o gl ycae mia S A E, 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 2

At  least o ne a dj u dicate d D K A S A E,

At  least o ne A E lea di n g t o disc o nti n uati on of st u d y me dicat i on,

At  least o ne S A E lea di n g t o disc o nti n uati on of st u d y me dicat i on,

At  least o ne h yp o gl ycae mia S A E l ea di n g t o disc o nti n uati on of st u d y  me dicatio n,

At  least o ne a dj u dicate d D K A S A E lea di n g t o disc o nti n uat i on of st u d y  me dicatio n,

Deat hs ,

At  least o ne related A E ,

At  least o ne relate d S A E,

At  least o ne A E O SI.
T his a nal ysis will be re peate d f or t he c o m bi ne d S T + L T peri o d u p t o Wee k 3 2 a n d als o b y 
treat me nt gr o u p recei ve d at t he ti me of A E o nset.
A wei g hte d a nal ysis f or t he o verall A E s u m mar y will als o be pr o vi de d base d o n t he S T + L T 
p eri o d , t o a c c o u nt for t he ra n d o mise d wi t hdra wal desi g n (see Sectio n 4. 7 f or details), a n d will 
i ncl u de all data re gar dless of resc ue me dicatio n i niti at i on.
I n a d ditio n, t he o verall A E s u m mar y will  be re peate d f or s u b gr o u ps base d o n race, et h nicit y,  
se x, a ge gr o u p ( usi n g ra n d o misati on str at a), re gi o n, baseli ne a nt i dia betic tr e at me nt, baseli ne 
H b A 1c a n d baseli ne B MI, usi n g t he cate g ories defi ne d i n t he A p pe n di x (Ta ble 1 9 ). T hi s will 
be pr o vi de d base d o n t he S T + L T peri o d a n d will i ncl u de all data re gar dless of  resc ue me dicati on 
i nitiati on a n d pri or t o resc ue me dicat i on i nitiati o n. T he o verall A E s u m mar y will  als o b e 
prese nte d f or t h e s u b gr o u p of s u bjects o n a sta ble baseli ne d os e of  metfor m i n I R or X R ( wi t h 
or wi t ho ut i ns uli n).
T he n u m ber a n d perce nta ge of s u bjects wi t h at least o ne A E will be s u m marise d b y S O C, P T 
a n d tr e at me nt gr o u p . A Es will be s orte d b y decreasi n g fre q ue nc y wi t hi n eac h S O C a n d P T 
acc o r di n g t o t he o verall act i ve treat me nt gr o u p , a n d, w here a p plica ble, b y hi g h d ose acti ve 
treat me nt or active treat me nt wit h bac k gr o u n d me dicat i on . As a p pr o priate t he n u m ber o f eve nts 
will als o be dis pla ye d.
All a d verse e ve nts will be s u m marise d b y S O C a n d P T (i ncl u di n g i nci de nce r at e prese nte d f or 
P Ts f or t he S T + L T peri o d ), re gar dless of  resc ue me dicat i on i nitiati o n u nless ot her wi s e 
s pecifie d, f or:

T he S T peri o d a n d t he c o m bi ne d S T + L T peri o d (i ncl u di n g i nci de nce rate).

T he S T peri o d a n d t he c o m bi ne d S T + L T peri o d (i ncl u di n g i nci de nce rate), pri or t o resc ue 
me dicat i on i nitiati on.

T he c o m bi ne d S T + L T peri o d, u p t o Wee k 3 2.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 3

T he c o m bi ne d 
S T + L T p eri o d, e xcl u di n g s u bjects ra n d o mise d t o wit h dra wal fro m  
met f or mi n. A w ei g hte d a nal ysis will  be c o n d ucte d o n t he Treate d S u bject s Data Set usi n g 
t he origi nal ra n d omise d gr o u p a n d prese nti n g wei g hte d pr o p orti o ns.

T he c o m bi ne d S T + L T peri o d . A Es will be s u m marise d b y tr e at me nt gr o u p recei ve d at t h e 
ti me of  A E o nset. F or place b o s u bjects re-ra n d o mise d t o s witc h t o da pa glifl o zi n ( or 
sa xa gli pti n), A Es will be a nal ysed i n t he pl ace b o gr o u p t o t he be gi n ni n g of t he ra n d omise d
wi t hdra wal  perio d a n d i n t he da pa glifl ozi n ( or sa xa gli pti n) gr o u p if t he e ve nt o nset occ urs 
d uri n g t he ra n d omise d wi t hdra wal peri o d. A Es will be prese nte d as i nci de nce rate a djust e d 
f or e x p os ure, as descri be d i n Secti on  3. 4. 1 .

T he ra n d omise d wi t hdra wal  perio d. A Es wit h a date of o nset occ urri n g after t he wi t hdra wal 
baseli ne will be s u m marise d usi n g t he Ra n d o mise d Wit h dra wal S u bjects Data Set se paratel y 
f or t he t hree treat me nt c o mparis o ns descri be d i n Secti o n  4. 1. 5 .
T he f oll owi n g descri pt i ve s u m maries will als o be pr o vi de d f or t he S T, S T + L T a n d ra n d omise d
wi t hdra wal  p erio d , re gar dless of resc ue me dicati on i nit iati on , for :

A n y A E b y S O C, P T a n d ma xi m u m i nte nsit y ( mil d, m o derate, se vere).

A n y A E relate d t o st u d y dr u g (n ot relate d, relate d [i ncl u di n g A Es wit h missi n g relati ons hi p
t o st u d y dr u g]) b y S O C a n d P T .

A n y A E b y S O C a n d P T f or c o m m on P Ts (defi ne d as P Ts re p orte d b y ≥5 % of t he s u bjects
i n a n y tr e at me nt gr o u p wit hi n t he p eri o d). N u m ber of  eve nts (a n d i nci de nce rate f or t he 
S T + L T peri o d) will als o be prese nte d.

A n y n o n -serio us A E b y S O C a n d P T
S u m maries of A Es b y S O C a n d P T will be pr o vi de d b y treat me nt gr o u p f or t he S T, S T + L T a n d 
ra n d omise d
wi t hdra wal  perio d, re gar dless of  resc ue me d icati on i nitiati on , f or t he f oll owi n g 
s u b gr o u ps:

A ge gr o u p usi n g t he ra n d omisati o n strata (≥ 1 0 a n d < 1 5 y ears, ≥1 5 a n d < 1 8 y ears)

Se x ( male, fe male)

Race ( w hite, n o n -w hi t e)

Baseli ne a nt i dia betic treat me nt ( met f or mi n o nl y , i ns uli n o nl y , c o m bi nat i on of  metf or mi n 
a n d i ns uli n)
wi t h age, se x a n d baseli ne a nt i dia betic tr e at me nt cate g or y bei n g defi ne d base d o n ra n d omisati o n
strata.
T he S T + L T peri o d prese ntati o ns f or A n y A E b y S O C a n d P T a n d A n y A E b y S O C a n d P T f or 
c o m m o n P Ts will als o be prese nt e d f or t he s u b gr o u p of  su bjects o n a sta ble baseli ne d ose of  
met f or mi n I R or X R ( wit h or wit h o ut i ns uli n).


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 4
I n a d diti on, A Es n ot i ncl u de d i n t he S T + L T a nal ysis peri o d per  Ta ble 8 a n d t h ose A Es re p orte d 
q uarterl y  bet wee n Wee k 5 6 a n d Wee k 1 0 4 will als o be s u m marise d f or t he p ost -st u d y visit at 
Wee k 1 0 4.
N o f or mal c o m par is o ns are ma de bet wee n treat me nts. N o f or mal statistical testi n g will b e 
perf or m e d, o nl y s u m mar y st atistics are pr o vi de d.
A listi n g of all re p orte d A Es falli n g i nt o t he S T + L T peri o d will be pr o d uce d . A se parate list i n g 
will be pr o vi de d f or all A E s d uri n g t he st u d y .
A d verse e ve nts of s peci al i nterest
Me d D R A preferre d ter ms a n d t heir gr o u pi n gs will be use d t o i de ntif y  A E O SIs (as s pecifie d i n 
Secti o n 3. 4. 1 ) a n d will be liste d a n d d oc u m e nte d i n t he St u d y Master File. T he n u m ber a n d 
perce nta ge of s u bjects e x perie nci n g a n y of t he s pecifie d A E O SIs a n d t he i n di vi d ual ter ms t hat 
c o nstit ute eac h A E O SI gr o u pi n g will be prese nte d b y preferre d t er m f or t he S T , S T + L T a n d 
ra n d omise d wi t hdra wal  p eri o d s. I nci de nce rates of A E O SIs will als o be prese nte d f or P Ts f or 
t he S T + L T perio d. A gl ossar y  of t he preferre d ter ms use d t o i de ntif y A E O SIs will be pr o vi d e d
b y A E O SI cate g or y, alo n g wi t h a fla g i de ntif yi n g a n y preferre d t er m searc he d f or b ut n ot prese nt 
i n t he st u d y.
C O VI D -1 9 rel ate d a d verse e ve nts
A gl oss ar y  of pr ef erre d t er ms relate d t o C O VI D - 1 9 will be pr o vi de d , alo n g wi t h a fla g 
i de ntif yi n g a n y preferre d ter m searc he d f or b ut n ot prese nt i n t he st u d y.
4. 7. 1. 2
De at hs
Deat hs will be i de ntifie d fr om t he stat us pa ge, A E pa ge, or t h e S A E pa ge ( wit h a deat h date, 
ca use o f deat h, o utc o m e or S A E cate g orisat i on prese nt) of  t he C R F. A listi n g of all deat hs t hat 
occ ur will be pr o d uce d f or t h e S T + L T a n d Wee k 1 0 4 p eri o ds se paratel y, a n d w ill prese nt t he 
p eri o d of  occ urre nce. A n y deat hs t hat occ ur d uri n g t he st u d y will be descri be d i n de pt h as 
narrati ves i n t he C S R.
4. 7. 1. 3
Seri o us a d verse e ve nts
All S A Es (incl u di n g h y p o gl ycae mic a n d t ype 2 D K A
e ve nts classifie d as S A Es ) will b e 
descri be d i n narrati ves, re gar dl ess of in vest i gat or assess me nt of ca usality. S A Es wi t h a n o nset 
fr om D a y  1 of t he S T peri o d u p t o a n d i ncl u di n g 3 0 d a y s aft er t h e last d ose date i n p eri o d ( or 
u p t o a n d n ot i ncl u di n g t he start date of t he L T peri o d (if a p plica ble), w hic he ver c o mes first, f or 
t he S T peri o d) will be c o nsi dere d as occ urri n g d uri n g S T peri o d. F or s u bjects treate d d uri n g t he 
L T p eri o d, S A Es wi t h a n o ns et fr o m D a y 1 of t he S T p erio d u p t o a n d i ncl u di n g 3 0 da ys after 
t he last d ose date will be c o nsi dere d as occ urri n g d uri n g t he c o m bi ne d S T + L T peri o d. F or t he 
ra n d omise d
wi t hdra wal p eri o d, t his listi n g will i ncl u de all deat hs o n a n d aft er t he date of 
wi t hdra wal  baseli ne u ntil the date of  Wee k 5 2 or date of  last visit + 3 0 da ys (if earlier t han Wee k 
5 2). N u m ber of  eve nts a n d i nci de nce rates a djuste d f or e x p os ure ti me , as descri be d i n Secti o n 
3. 4. 1 , will be re p orte d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 5
T he f oll owi n g descri pti ve s u m maries will be pr o vi de d b y S O C, P T a n d treat me nt gr o u p
se paratel y for t he S T , S T + L T a n d ra n d o mise d wi t h dra wal p eri o d s:

A n y S A E

A n y S A E, u p t o Wee k 3 2 ( S T + L T peri o d o nl y)

A n y S A E e xcl u di n g A Es f o ll owi n g resc ue me dicati o n use (se nsit i vity a nal ysis)

A n y S A E relate d t o st u d y dr u g ( n ot relate d, relate d [i ncl u di n g S A Es wi t h missi n g 
r elat i ons hi p t o st u d y  dr u g])

A n y S A E lea di n g t o lea di n g t o disc o nt i n uati on of st u d y  me dicatio n
F or t he c o m bi ne d S T + L T peri o d, S A Es will als o be s u m marise d b y treat me nt gr o u p recei v e d at 
t he ti me of  SA E o nset. F or place b o s u bjects re-ra n d omise d
t o s witc h t o da pa glifl ozi n ( or 
sa xa gli pti n), S A Es will be a nal ysed i n t he place b o gr o u p t o t he be gi n ni n g of  the ra n d omise d
wi t hdra wal  perio d a n d i n t he da pa glifl o zi n ( or sa xa gli pti n) gr o u p if t he e ve nt o nset occ urs 
d uri n g t he ra n d o mise d wi t hdra wal  perio d. S A Es P Ts will be prese nte d as i nci de nce rate a dj uste d 
f or e x p os ure, as descri be d i n Secti on  3. 4. 1 . 
I n a d ditio n, all S A Es will als o be s u m marise d f or t he p ost -stu d y visi t at Wee k 1 0 4 f or t he 
Treate d S u bjects Data Set re gar dless of  resc ue me dicat i on i nitiati on. F or t he ra n d o mise d
wi t hdra wal  perio d , s u bjects g oi n g t hr o u g h t he t hir d ra n d o misati o n will  be prese nte d usi n g t he 
Ra n d o mise d Wit h dra wal S u bjects Data Set a n d will be s u m marise d se paratel y f or t he t hree 
treat me nt c o mparis o ns descri be d i n Sect i on  4. 1. 5 .
L isti n gs of  all S A Es (incl u di n g pre -treat me nt e ve nts or p ost -treat me nt e ve nts) b y s u bject will 
be pr o vi de d f or t he S T + L T peri o d. A se parate list i n g will be pr o vi de d f or S A Es re p orte d at t he 
p ost -stu d y visit at Wee k 1 0 4.
4. 7. 1. 4
A d verse e ve nt s le a di n g t o disc o nti n u ati o n of s t u d y m e dic ati o n
A d verse e ve nts wi t h an o nset d uri n g treat me nt f or w hic h t he acti o n ta ke n was
" dr u g 
p er m a ne nt l y dis c o nt i n ue d" will be s u m marise d b y S O C, P T, a n d treat me nt gr o u p f or b ot h t he 
pri mar y  (incl u di n g data re gardless of  resc ue me dicat i on i nitiati on ) a n d se nsiti vity safety 
a nal yses (e xcl u di n g data after resc ue). T his s u m mar y will i ncl u de all h y p o gl ycae mia e ve nts a n d 
all D K A e ve nts t hat are re p orte d as S A Es a n d will be prese nte d f or t he S T , S T + L T a n d 
ra n d omise d wi t hdr a w al  p eri o d s. N ote t hat, w he n s u m marisi n g A Es lea di n g t o disc o nti n uati on,  
n o u p per c ut -off da y wi n d o ws ( i.e. , 4 da ys a n d 3 0 da ys fr o m last d osi n g date f or A Es a n d S A Es 
res pecti vel y) will be a p plie d. F or S T peri o d a nal yses, t he o nl y u p per c ut -off dat e will be t h e 
start date of t he L T peri o d.
A s u bject listi n g of  disc o nti n uati on of  st u d y me dicatio n d ue t o A Es will be pr o vi d e d f or t he 
S T + L T peri o d .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 6
4. 7. 2
Ot her s afet y a n al yses
4. 7. 2. 1
A m p ut ati o n
All a m p utatio n e ve nts will be s u m marise d f or t he S T + L T peri o d. T he n u m ber a n d p r o p ortio n 
of
s u bjects wi t h am p utati o n, t ype of  eve nt (tra u ma b y acci de nt, s ur gical a m p utatio n, 
s p o nta ne o us/ n o n-s ur gical a m p utatio n), a mp utati o n lateral si de, l ocatio n of  am p utati o n, 
c o n ditio n a n d u n derl yi n g c o n ditio ns t hat trig gere d a mp ut ati o n , a n d s mo ker stat us will be 
prese nte d.
A listi n g of all a m p utati o n e ve nts will be pr o vi de d f or t he S T + L T peri o d.
4. 7. 2. 2
A dj u dic ate d Di a betic k et o aci d osis ( D K A)
All s us pecte d D K A e ve nts se nt f or a dj u dicat i on will be i ncl u de d i n s u m maries f or t he S T ,
S T + L T a n d ra n do mise d wi t hdra wal p eri o d s if t heir o nset falls bet wee n t he start of I P treat me nt 
a n d t he c ut -off dates defi ne d f or eac h peri o d i n Ta ble 8 . 
T he pr o p orti o n of  su bjects wit h s us pecte d D K A e ve nts se nt f or a dj u dicat i on , re gar dless of 
resc ue me d icati on i nitiati on, will be ta b ulate d b y treat me nt gr o u p per a dj u dicat i on cate g or y 
( defi nite D K A, pr o ba ble D K A, p ossi ble D K A, n ot D K A) f or t he S T, S T + L T a n d ra n d o mise d
wi t hdra wal  perio ds. T he pr o p orti o n of  su bjects wi t h s us pecte d D K A e ve nts se nt f or a dj u dicati o n 
lea di n g t o disc o nti n uati o n per a dj u dicat i on c at e g or y will als o be s u m marise d f or t he S T + L T 
p eri o d. W he n 
s u m marisi n g s us pecte d D K A e ve nts lea di n g t o d isc o nti n uati on
of  st u d y 
me dicat i on , n o u p per c ut -off d a y  wi n d o ws are a p plie d.
F urt her m or e, s us pecte d D K A e ve nts se nt f or a dj u dicat i on will be s u m marise d f or t he S T, 
S T + L T a n d ra n d omise d
wi t hdra wal p eri o ds b y treat me nt gr o u p per a dj u dicat i on cate g or y for
n u m ber of s u bjects wit h eac h si g n a n d s y m pt o m a n d se paratel y, ris k fact ors.
S us pecte d D K A e ve nts se nt f or a dj u dicati on will  als o be prese nte d S T, S T + L T a n d ra n d omise d
wi t hdra wal  perio ds b y treat me nt gr o u p per a dj u dicat i on cate g or y an d pr ef erre d t er m. T his
a nal ysis f or t he S T + L T peri o d will 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 met f or mi n I R or X R ( wit h or wit h o ut i ns uli n).
A listi n g of  s us pecte d D K A e ve nts se nt f or a dj u dicat i on will be ge nerate d f or a dj u dicati o n 
res ults, sig n s a n d s y m pt o ms, a n d ris k fact ors wit h a n o nset date/ti me fr om t he start date/ti me 
f or t he S T + L T peri o d . F o r t he S T + L T + Wee k 1 0 4 peri o d, t he listi n g will i ncl u de all d at a 
c ollecte d u p t o Wee k 1 0 4.
4. 7. 2. 3
C ar di o v asc ul ar a n d he p atic a dj u dic ate d e ve nts
Car di o vasc ula r a n d he patic e ve nts se nt f or a dj u dicati o n will be liste d o nl y.
4. 7. 2. 4
H y p o gl yc ae mi a
H y p o gl ycae mic e ve nts will be i ncl u de d i n s u m maries f or t he S T , S T + L T a n d ra n d omise d
wi t hdra wal  p er i ods if t heir o nset falls bet wee n t he start of  IP treat me nt a n d t he c ut-off d at es 
defi ne d f or eac h peri o d i n Ta ble 8 . T he pri mar y a nal ysis will be base d o n data i ncl u di n g 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 7
h y p o gl ycae mia e ve nts occ urri n g pri or t o resc ue me dicat i on i nitiati on ; se nsiti vity a nal yses will 
i ncl u de data after resc ue me d icati on i nitiati on.
T he n u m ber a n d pr o p orti o n of s u bjects wit h h y p o gl ycae mic e ve nts (incl u di n g t h ose re p orte d as 
S A Es) will be t ab ulate d i n eac h treat me nt gr o u p b y A D A a n d I S P A D cate g ories (see Sect i on 8. 9 )
f or:

T he S T peri o d a n d t he c o m bi ne d S T + L T peri o d, pri or t o resc ue me dicati on i nit iati on
(as pri mar y a nal yses).

T he S T peri o d a n d the c o m bi ne d S T + L T peri o d, re gar dless of  resc ue me d icati on 
i nitiati on (as se nsiti vity a nal yses).

T he c o m bi ne d S T + L T p eri o d, u p t o Wee k 3 2 , pri or t o resc ue me d icati on i nitiati on
(as pri mar y a nal yses).

T he c o m bi ne d S T + L T p eri o d, u p t o Wee k 
3 2, re gar dless of  resc ue me dicat i on 
i nitiati on (as se nsiti vity a nal yses).

T he ra n d omise d
wi t hdra wal p eri o d. T he e ve nts, wi t h a date o nset occ urri n g o n or
aft er t he ra n d o mise d wi t hdra wal pri or t o resc ue me dicat i on i nitiati on , will be 
s u m marise d se paratel y f or t he t hree treatme nt  c om paris o ns descri be d i n Sect i on  4. 1. 5
usi n g t he Ra n d o mise d Wit h dra wal S u bjects Data Set.
T he S T + L T peri o d pri or t o resc ue me dicat i on i nitiatio n a nal ysis will als o be re peate d f or t he 
s u b gr o u p of s u bjects o n a sta bl e baseli ne d ose of met f or mi n I R or X R ( wit h or wit h o ut 
i ns uli n).
H y p o gl ycae mic e ve nts t hat d o n ot f ulfil t he A D A or I S P A D cate g ories will be prese nte d as ‘ N ot 
classifie d’.
All i nf or mat i on (s y m pt o ms, ris k fact ors et c. ) c ollecte d i n t he se parate C R F pa ges f or 
h y p o gl ycae mic e ve nts ( w het her or n ot t he y fulfille d S A E crit eria) will be s u m marise d b y 
treat me nt gr o u p a n d liste d f or t he S T + L T peri o d . F or t he S T + L T + Wee k 1 0 4 peri o d, t he list i n g 
will i ncl u de all data c ollecte d u p t o Wee k 1 0 4.
H y p o gl ycae mic e ve nts meet i n g S A E criteria will als o be prese nte d i n t he listi n g.
4. 7. 3
L a b or at or y ev al u ati o n s
S afet y lab orat or y  eval uat i ons p erf or m e d b y ce ntral la b orat ories will be i ncl u de d i n s u m mary 
ta bles a n d b ot h ce ntral an d l ocal la b orat or y ev al u ati o ns will be i ncl u de d i n t he listi n gs. T h e 
la b orat or y dat a will be prese nte d i n C o n ve nti o nal ( U S) U nits a n d ad di tio nal  prese ntatio ns f or 
c ha n ges fr o m baseli ne will be re peate d usi n g SI u nits.
S u m maries of lab orat or y  data will incl u de assess me nts u p t o t he c ut - off dates defi ne d f or eac h 
p eri o d a n d para meter i n Ta ble 8 . Visit wi n d o ws are pr o vi de d i n Sect i on 4. 1. 7. 1 i n or der t o li n k 
eac h lab orat or y  test t o a sc he d ule d visi t. All c o nti n u o us lab orat or y  para meters s pecifie d i n 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 8
Secti o n 3. 4. 4 will be s u m marise d at eac h sc he d ule d time p oi nt b y tr e at me nt gr o u p usi n g 
descri pt i ve statistics (i ncl u di n g data re gar dless of resc ue me dicat i on init iati on ) d uri n g:
•
T he c o m bi ne d S T + L T peri o d. O bser ve d a n d c ha n ge fr om baseli ne val ues will be 
s u m marise d b y tr e at me nt gr o u p base d o n t he treat me nt recei ve d d uri n g t he S T p eri o d
( da pa glifl ozi n/sa xa gli pt i n/ place b o) usi n g t he Treate d S u bjects Data Set.
• 
The c o m bi ne d S T + L T p eri o d, u p t o Wee k 3 2. O bser ve d a n d c ha n ge fr o m baseli ne val ues 
will be s u m marise d b y tr e at me nt gr o u p base d o n t he tr e at me nt recei ve d d uri n g t he S T 
p eri o 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 he ra n do mise d wi t hdra wal  perio d. O bser ve d a n d c ha n ge fr om wi t hdra wal  baseli ne 
val ues will be s u m marise d f or t he first t w o treat me nt c o mparis o ns descri be d i n Secti o n 
4. 1. 5 usi n g t he Ra n d o mise d Wit h dra wal S u bject Data Set.
A d dit i onall y , e G F R will als o be descri be d b y a ge gr o u p (usi n g t he ra n d omisat i on strata) f or t he 
S T + L T a n d ra n d o mise d wi t hdr a w al  p erio ds usi n g SI u nits .
Mar ke d 
a b n or malit y la b orat or y assess me nt will be s u m marise d usi n g ce ntral la b orat ories 
assess me nts d uri n g t he S T , t he c o m bi ne d S T + L T a n d ra n d omise d wi t hdra wal p eri o ds f or b ot h 
c o n ve nt i onal a n d SI u nits.
Ha e mat olo g y , c he mistr y an d ur i nal ysis la b orat or y dat a f or t he S T + L T peri o d will be liste d usi n g 
b ot h c o n ve nti o nal a n d SI u nits w here a p plica ble . F or t he S T + L T + Wee k 1 0 4 peri o d, t he list i n g 
will i ncl u de all data c ollecte d u p t o Wee k
1 0 4. Fla gs will be a p plie d t o val ues falli n g o utsi d e 
refere nce ra n ges ( w hic h will be e x plicit l y note d o n t hese listi n gs w here a p plica ble). Treat me nt  
at t he ti me of a la b orat or y assess me nt will be i ncl u de d i n t he list i n gs a n d will c orres p o n d t o t he 
last d ose recei ve d b y a s u bject u p t o a n d i ncl u di n g t he date/ti me of t he la b orat or y assess me nt.
La b orat or y  d at a v al u es of t he f or m of “< x” (i.e. , b elo w t h e l ower li mit of q ua ntificati on) or > 
x (i.e. , a b o ve t he u p per li mit of  qua ntificat i on) will be i m p ute d as “ x” i n t he calc ulat i on of  
s u m mar y statistics b ut dis playe d as “ < x” or “ > x” i n t he list i n gs. F or deter mi ni n g if t he val ues 
are o ut of  ra n ge or falli n g wi t hi n t he M A la b crit eria, if a val ue is re p orte d as “ < x” or “ > x” 
w here x is t he l o wer or u p per criteria res pecti vel y, t he n t his will be re p orte d as “l o w” or “ hi g h” 
res pecti vel y for t he refere nce ra n ge i n dicat or a n d as meet i n g t he M A criteria.
N ote t hat pri or t o data base l oc k a n d u n bli n di n g, a nal ysis data f or uri nar y gl uc ose, a n d uri nar y 
gl uc ose: creati ni ne rati o will be base d o n d u m m y val ues (t o preser ve t he b li n d).
4. 7. 3. 1
S afet y l a b or at or y p ar a meters o ver t i me
F or all c o nt i n u o us la b orat or y para meters liste d i n Secti o n 3. 4. 4 , abs o l ute val ues a n d c ha n ges 
fr om baseli n e d uri n g t he S T + L T a n d ra n d o mise d wi t hdra wal p eri o ds will be s u m marise d b y 
treat me nt gr o u p usi n g descri pt i ve statistics (incl u di n g data re gar dless of  resc ue me dicat i on 
i nitiati on). Visit wi n d o ws are pr o vi de d i n Sect i on  4. 1. 7. 1 i n or der t o li n k eac h la b orat or y test t o 
a sc he d ule d visit.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 0 9
U nless ot her wi se s pecifie d, lab orat or y  data o btai ne d aft er t h e st art of st u d y me dicatio n d osi n g 
u p t o a n d i ncl u di n g 4 da ys ( 3 0 da ys f or li ver f u ncti o n la b orat or y tests) after t he last d osi n g date 
( or u p t o a n d n ot i ncl u di n g t he st art of t he L T treat me nt p erio d, w hi c he ver c o mes first, for S T 
p eri o d) will be c o nsi dere d as o btai ne d res pecti vel y d uri n g S T a n d t he L T peri o d. F o r t he 
ra n d omise d wi t hdra wal p eri o d, lab orat or y  data c ollecte d o n a n d aft er t he wi t hdra wal baseli ne 
u p t o a n d i ncl u di n g 4 da ys ( 3 0 da ys f or li ver f u nct i o n la b orat or y tests) after t he last d osi n g date 
i n t he ra n d o mise d wi t hdra wal  p erio d will be c o nsi dere d f or t he ra n d omise d wi t hdra wal  p erio d. 
La b orat or y  data o btai ne d fr o m t he d a y  after t he Wee k 5 6 visit u p t o t he last visit date of  the 
f oll ow- u p peri o d will be c o nsi dere d as o btai ne d d uri n g t he f o ll ow- u p peri o d.
S hift ta bles (in SI u nits) of  su bj ects wi t h val ues i n cate g ories of  lo w, n or m al, a n d hi g h ( base d 
o n n or m al ra n ges pr o vi de d b y t he ce ntral la b orat or y) will be s u m marise d b y tr e at me nt gr o u p 
usi n g t he l ow est val ues (for para meters wi t h a lo w er n or mal ra n ge defi ne d) a n d t he hi g hest 
val ues (f or para meters wit h a n u p per n or mal ra n ge defi ne d) o btai ne d d uri n g t he S T a n d S T + L T
p eri o ds. I n or der t o i de ntif y t he l owest or hi g hest p os t-baseli ne val ues i n a s u bject all 
assess me nts will be c o nsidere d, e ve n if t he y d o n ot c orres p o n d t o a visit -base d s u m mar y. F or 
t he s hift ta bles, t he last o bser vat i on, re gar dl ess of p ost -ra n d o misati on resc ue, prior t o Wee k 2 6
or Wee k 5 2 will be use d if n o Wee k 2 6 or Wee k 5 2 meas ure me nt is a vaila ble, res pecti vel y.
A d dit i onal s hift ta ble s u m maries f or eac h peri o d c o mpare d t o baseli ne will be pr o vi de d f or t he 
f oll owi n g:

S u bjects wi t h electr ol ytes (S o di u m , P otassi u m, Calci u m, P h os p hate, a n d Ma g nesi u m )
cate g or ies of  lo w, n or m al, a n d hi g h ( base d o n n or mal ra n ge of  ce ntr al la b orat or y) will b e 
s u m marise d b y tr e at me nt gr o u p usi n g t he hi g hest a n d l owest val ues o btai ne d d uri n g t h e 
p eri o d .

S u bjects wit h Uri ne Al b u mi n E xcret i on Cate g ories ( U A C R ) assess me nts, will be prese n te d 
f or t he valu es at W e e k 2 6 (f or S T peri o d) or Wee k 5 2 (f or S T + L T peri o d) vers us baseli ne, 
base d o n t he f oll owi n g uri ne al b u mi n t o creati ni ne r atios : 0 - < 3 0 m g/ g
( 3. 4 g/ m o l) 
[ n or moal b u mi n uria] , ≥ 3 0 m g/ g ( 3. 4 g/ m o l) - < 3 0 0 m g/ g ( 3 3. 9 g/ m ol) [ micr oal b u mi n uria], 
≥3 0 0 m g/ g
( 3 3. 9 g/ m ol ) [ ma cr oalb u mi n uri a] . If the val ue at Wee k 2 6 or Wee k 5 2 is n ot 
a vaila ble, t he L O C F o bser vat i on will be use d i nstea d.
4. 7. 3. 2
Ele v ate d li ver f u ncti o n tests
T he f oll owi n g t hree crit eria will be s u m marise d b y tr e at me nt gr o u p f or t he S T, S T + L T a n d 
ra n d omise d
wi t hdra wal  perio ds i n e xa mi nat i on of  elevate d a mi n otra nsferases (A T ) ( A L T 
a n d/ or A S T) a n d T B:

( A S T or A L T > 3 X u p per li mit of n or mal [ U L N]) a n d ( bilir u bi n > 1. 5 X U L N wit hi n 1 4 da ys 
o n or after A T ele vat i on)

( A S T or A L T > 3 X U L N) a n d ( bilir u bi n > 2 X U L N wit hi n 1 4 da ys o n or after A T ele vat i on)

( A S T or A L T > 3 X U L N) a n d {( bilir u bi n > 2 X U L N a n d n o A L P ≥2 X U L N) wi t hi n 1 4 
da ys o n or after A T ele vat i on) } .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 0
T his a nal ysis will be c o n d ucte d re gar dless of resc ue me d icatio n i ni tiat i on. T he s u m maries will 
i ncl u de all data c ollecte d u p t o t he c ut-offs defi ne d i n Ta ble 8 . N o  c o m paris o n vs. baseli ne will 
be d o ne.
A listi n g of  all A S T, A L T a n d T B res ults will be pr o vi de d f or s u bjects wi t h AS T or A L T ≥
3 × U L N a n d T B ≥1. 5 × U L N at a n y p o i nt d uri n g t he st u d y. F or t hese s u m maries, li ver test data 
o btai ne d aft er t he start of  st u d y me dicatio n d osi n g u p t o a n d i ncl u di n g 3 0 da ys aft er t he last 
bli n d d osi n g date ( or u p t o a n d n ot i ncl u di n g t he start of t he L T peri o d, w hi c he ver c o mes first, 
f or S T perio d) will be c o nsi dere d as o btai ne d res pecti vel y d uri n g S T a n d t he L T t he peri o d.
4. 7. 3. 3
Ele v ate d li ver tests a n d/ or re p orte d he p atic a d verse e ve nts
A s u m mar y of s u bjects wit h ele vate d li ver tests (as defi ne d i n A p pe n di x Secti o n 8. 7. 1 ) a n d/ or 
he pat ic A Es will be pr o vi de d b y t reat me nt gr o u p f or t he S T, S T + L T a n d ra n d omise d wi t hdra wal 
p eri o ds. T he s u m mar y will  incl u de s u bjects wi t h AS T a n d/ or A L T ele vat i on, T B ele vati o n, 
c o m bi ne d A T a n d T B ele vat i on, a n d A L P ele vat i o n. He patic A Es ( defi ne d pri or t o data base 
l oc k) will be s u m marise d b y P T, i n decreasi n g fre q ue nc y of P T acc or di n g t o t he o verall act i ve 
ar m. A listi n g of all He patic A Es will be prese nte d f or t he S T + L T peri o d.
4. 7. 3. 4
M ar ke d l a b or at or y a b n or m alities
La b orat or y  ab n or m alities will be e val uate d base d o n M A val ues f or selecte d para m eters (see
pre -defi ne d crit eria detaile d i n A p pe n di x Secti o n 8. 7. 1 t o i de ntif y M As) . If b ot h t he baseli ne 
a n d o n -treat me nt val ues of  a para meter are be y o n d t he sa me M A li mit f or t he para meter, t he n 
t he o n -treat me nt val ue will be c o nsi dere d a M A o nl y  if it is m o re e xtre me (fart her fr o m t he 
li mit, e. g. w o rse ns) t ha n was t he baseli ne val ue. If t he baseli ne val ue is be y o n d t he l ow M A 
li mit, a n d t he p ost -baseli ne v al u e is be y o n d t he hi g h M A li mit ( or vice -versa), t he n t he p ost -
baseli ne val ue will be c o nsi dere d a M A. If baseli ne val ue is missi n g a n d t he p ost-baseli ne val ue 
is be y o n d t he M A li mit , t he n t he p ost -baseli ne val ue will be c o nsi dere d a M A.
La b orat or y  M As occ urri n g d uri n g t he S T , S T + L T , a n d S T + L T u p t o Wee k 3 2 peri o ds base d o n 
Treate d S u bjects Data Set will be s u m marise d b y treat me nt gr o u p. I n a d dit i on, la b orat or y  M As 
will be s u m marise d f or t he Ra n d o mise d
Wit h dra wal  p eri o d
base d o n t he Ra n d o mis e d
Wit h dra wal S u bjects Data Set, se paratel y f or t he t hree treat me nt c o m par is o ns descri be d i n 
Secti o n 4. 1. 5 . T he s u m maries will be prese nte d f or b ot h t he pri mar y a n d se nsiti vity safet y 
a nal yses. T he pri mar y a nal yses of  MAs will i ncl u de data re gar dless of  resc ue me d icati on 
i nitiati on . A d dit i onal se nsitivit y a nal yses will be pr o vi de d f or M As occ urri n g pri or t o resc ue 
me dicat i on i nitiati on.
F or t he S T + L T a nal ysis, i nci de nce rates of mar ke d a b n or malit ies will als o be prese nte d.
I n a d ditio n, la b orat or y MAs will be s u m marise d usi n g i nci de nce rates b y tr e at me nt gr o u p 
recei ve d at t he ti me of M A o nset f or t he S T + L T peri o d. F or place b o s u bjects re-ra n d o mise d t o 
s witc h t o da pa glifl ozi n ( or sa xa gli pti n), M As will be a nal ysed i n t he pl ace b o gr o u p t o t he 
be gi n ni n g of t he ra n d o mise d wi t hdra wal  p erio d a n d i n t he da pa glifl ozi n ( or sa xa gli pti n) gr o u p 
if t he e ve nt o nset occ urs d uri n g t he ra n d omise d wit h dra wal  p erio d.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 1
T he di recti on of c ha n ge ( hi g h or l o w) i n M A will be i n dicate d i n t he ta bles.
I n a d ditio n, a w ei g hte d a nal ysis f or t he la b orat or y M As will als o be pr o vi de d base d o n t he 
S T + L T peri o d, as descri be d i n Secti o n 4. 7 , t o acc o u nt f or t he ra n d o mise d wi t hdra wal desi g n .
A d dit i onall y , for eac h s u bject wit h a p ost -baseli ne M A f or a para meter, all t he s u bject’s val ues 
of  t hat para meter o ver t he treat me nt peri o d a n d t h e f o ll ow- u p peri o d, w here a p plica ble, will be 
liste d.
4. 7. 3. 5
F asti n g li pi d p a nel
S u m maries of  ch o lester ol, trigl yceri des, hi g h de nsit y li p o pr otei ns (H D L ) c h o lester ol, a n d 
calc ulate d l ow de nsit y li p o pr otei ns (L D L ) c h o lester ol will be pr o vi de d b y treat me nt gr o u p f or 
baseli ne, Wee k 2 6, a n d Wee k
5 2 ( S T + L T peri o d a nal ysis) wi t h corres p o n di n g c ha n ges fr om 
baseli ne, re gar dless of resc ue me dicat i on i nitiati on. L i pi d pa nel assess me nts will als o be liste d
f or t he S T + L T peri o d . F o r t he S T + L T + Wee k 1 0 4 peri o d, t he listi n g will i ncl u de all d at a 
c ollecte d u p t o Wee k 1 0 4.
4. 7. 3. 6
Pre g n a nc y test res ults
B y -s u bject listi n gs of pre g na nc y test res ults will be pr o vi de d f or t he S T + L T peri o d usi n g H C G 
a n d ser u m pre g na nc y test res ults fr o m t he ce ntral lab orat or y . F or t he S T + L T + Wee k 1 0 4 peri o d, 
t he list i n g will i ncl u de all data c ollecte d u p t o Wee k 1 0 4.
4. 7. 4
Vit al si g ns
Vi t al sig n me as ure me nts f or diast olic bl o o d press ure, s yst olic bl o o d press ure a n d heart rate at  
baseli ne, Wee k 6, Wee k 1 2, Wee k 1 4, Wee k 2 0, Wee k 2 6, Wee k 3 2, Wee k 4 0, Wee k 5 2 a n d 
c ha n ges fr o m baseli ne at eac h visit will be s u m marise d b y treat me nt gr o u p usi n g descri pt i ve 
statistics (incl u di n g data re gar dless of  resc ue me d icati on i nitiati on ) f or t he S T + L T peri o d . I n 
a d ditio n, t his a nal ysis will als o be p erf or m e d f or t he ra n d omise d wi t hdra wal  perio d usi n g t he 
Ra n d o mise d Wit h dra wal S u bjects Data Set f or the first t w o treat me nt c o m paris o ns descri be d i n 
Secti o n 4. 1. 5 . S u m maries of  vital si g ns data will i ncl u de assess me nts u p t o t he c ut -off dates 
defi ne d f or eac h p eri o d i n Ta ble 8 . Vi sit wi n d o ws are pr o vi de d i n Secti o n 4. 1. 7. 1 i n or der t o 
li n k eac h vital si g n measure me nt t o a sc he d ule d visit.
A listi n g of  vital si g ns will be pr o vi de d f or t he S T + L T peri o d . F o r t he S T + L T + Wee k 1 0 4 
p eri o d, t he list i n g will i ncl u de all data c ollecte d u p t o Wee k 1 0 4.
4. 7. 5
Electr oc ar di o gr a ms
T he n or m alit y/ a b n or malit y (f urt her classifie d b y c li nical si g nifica nce) of  the o verall E C G 
i nter pretatio n , as deter mi ne d b y t he i n vest i gat or, will be s u m marise d b y treat m e nt gr o u p base d 
o n o bser ve d d at a re gar dless of  resc ue me dicat i on i nitiati on usi n g fre q ue nc y ta bles o n n u m ber 
of  s u bjects w h o ha ve a n or mal/a b n or mal E C G traci n g at eac h sc he d ule d ti me of assess me nt f or 
t he a nal ysis p eri o d, o verall a n d b y t he E C G traci n g at baseli ne. T hese a nal yses will  be 
perf or m e d for S T + L T treat m e nt p erio d usi n g t he L O C F a p pr oac h.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 2
I n a d diti on, a wei g hte d a nal ysis f or t he n or malit y/ a b n or malit y o f the o verall E C G i nter pretati o n 
will als o be pr o vi de d base d o n t he S T + L T peri o d, as descri be d i n Secti o n 4. 7 , t o acc o u nt f or t he 
ra n d omise d wi t hdra wal  desi g n.
All E C G data will be liste d f or t he S T + L T peri o d.
4. 7. 6
B o d y wei g ht, hei g ht a n d B MI
B o d y  wei g ht ( k g), heig ht ( c m ) a n d B MI ( k g/ m2) meas ure me nts at baseli ne, Wee k 6, Wee k 1 2, 
Wee k 2 0, Wee k 2 6, Wee k 3 2, Wee k 4 0, Wee k 5 2, Wee k 1 0 4
a n d c ha n ges fr o m baseli ne at eac h 
visit will be s u m marise d usi n g descri pt i ve st atistics, re gar dless of resc ue me d icati on i nitiati on . 
S u m maries will  incl u de assess me nts perf or m e d u p t o t he c ut -off da tes defi ne d f or eac h perio d 
i n Ta ble 8 . Visi t wi n d o ws are pr o vide d i n Sect i on  4. 1. 7. 1 i n or der t o li n k eac h meas ure me nt t o 
a sc he d ule d visit. I n a d ditio n, n or m alise d hei g ht, b o d y wei g ht a n d B M I e x presse d as a z -sc ore 
a djuste d f or a ge at  t he assess me nt a n d se x usi n g C D C (see details i n Secti on 3. 4 . 8) will be als o  
be s u m marise d usi n g t he sa me a p pr oac h.
I n a d ditio n, b o d y  weig ht, hei g ht , a n d B MI will als o be s u m marise d d uri n g t he ra n d omise d
wi t hdra wal p eri o d usi n g t he Ra n d o mise d
Wit h dra wal  Su bjects Data Set f or t he first t wo 
treat me nt c o m par is o ns descri be d i n Secti o n 4. 1. 5 , a n d f or p ost -stu d y visi t at Wee k 1 0 4 usi n g 
t he Treate d S u bjects Data Set .
A listi n g of  bo d y  w eig ht, h ei g ht a n d B MI al o n g wit h z -sc ores b y s u bject will be pr o vid e d. F or 
t he S T + L T perio d t his list i n g will i ncl u de all data c ollecte d u p t o t he e n d of t he L T perio d. F or 
t he S T + L T + Wee k 1 0 4 peri o d, t he list i n g will i ncl u de all data c ollecte d u p t o Wee k 1 0 4.
4. 7. 7
Me as ures of gr o wt h a n d m at urit y
4. 7. 7. 1
T a n ner st a ges
Ta n ner sta ges will be s u m marise d base d o n o bser ve d data , re gar dless of  resc ue me d icati on 
i nitiati on. S u m maries of  descri pti ve statistics will be pr o vi de d f or baseli ne , Wee k 2 6 , Wee k 5 2,
a n d f or t he p ost-st u d y visit at Wee k 1 0 4 usi n g t he L O C F a p pr oac h i n t he peri o d. C ha n ges fr om 
baseli ne at t hese time p o i nts will be pr o vi de d usi n g s hift ta bles a n d b y visit acc or di n g t o baseli ne 
stat us. Als o, c ha n ge fr o m Wee k 2 6 stat us t o Wee k 5 2 a n d c ha n ge fr o m Wee k 5 2 stat us t o Wee k 
1 0 4 acc or di n g t o baseli ne stat us will be prese nte d. A wei g hte d a nal ysis, as descri be d i n Sect i on 
4. 7 , t o acc o u nt f or t he ra n d o mise d wi t hdra wal  desi g n ma y als o be prese nte d.
I n a d diti on, Ta n ner sta gi n g will als o be s u m marise d as a b o ve d uri n g t he ra n d omise d wi t hdra wal 
p eri o d , usi n g t he Ra n d o mise d Wit h dra wal S u bjects Data Set f or t he first t wo treat me nt 
c o mparis o ns descri be d i n Sect i on  4. 1. 5 . S u m maries of  descri pti ve statistics will be pr o vi de d f or 
wi t hdra wal  baseli ne, Wee k 
5 2 a n d Wee k 
1 0 4 usi n g t he L O C F a p pr oac h. C ha n ges fr om 
wi t hdra wal baseli ne at Wee k 5 2 a n d Wee k 1 0 4 will be pr o vi de d usi n g s hift ta bles, f or Wee k 5 2 
a n d Wee k 1 0 4 acc or di n g t o wit h dra wal baseli ne stat us a n d als o f or Wee k 1 0 4 acc or di n g t o 
Wee k 5 2 stat us.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 3
4. 7. 7. 2
P u bert y st at us
P u bert y st at us (as defi ne d i n A p pe n di x Sect i on  8. 1 0. 3 ) will be s u m marise d re gar dless of resc ue 
me dicat i on i nitiati on at Wee k 2 6 a n d Wee k 5 2 , w here t he hei g ht vel ocit y is base d o n c ha n ge 
fr om baseli ne , a n d Wee k 1 0 4, w here t he hei g ht vel ocity is base d o n c ha n ge fr o m Wee k 5 2 .
4. 7. 7. 3
Gr o wt h a n d m at urit y m ar kers
S u m maries of g r o wt h a n d mat urati o n mar kers (see Sectio n  3. 4. 9 ) i n SI a n d c o n ve nti o nal u ni ts
w ill be base d o n o bser ve d data , re gar dless of resc ue me dicat i on i nitiati on . Descri pt i ve 
s u m maries of  abs o l ute val ues a n d c ha n ges fr o m baseli ne ( w here a p plica ble) will be pr o vi d e d 
f or baseli ne, Wee k 2 6, Wee k 5 2 , a n d f or t he p ost -stu d y visit at Wee k 1 0 4 usi n g t he L O C F 
a p pr oac h. F or t he Wee k 1 0 4 a nal yses, c ha n ge fr o m Wee k 5 2 will als o be prese nte d.
I n a d ditio n, gr o wt h a n d mat urati o n mar kers will als o be s u m marise d d uri n g t he ra n d o mise d
wi t hdra wal p eri o d usi n g t he Ra n d o mise d
Wit h dra wal  Su bjects Data Set f or t he first t wo 
treat me nt c o mparis o ns descri be d i n Sect i on 4. 1. 5 . Descri pt i ve s u m maries of  abs ol ute val ues 
a n d c ha n ges fr om
wi t hdra wal baseli ne ( w here a p plica ble) will  be pr o vi de d f or wi t hdra wal 
baseli ne, Wee k 5 2 a n d Wee k 1 0 4 usi n g t he L O C F a p pr oac h .
A cate g oric al cha n ge fr o m baseli ne s u m mar y will als o be pr o d uce d b y treat me nt gr o u p, a ge
cate g or y (≥ 1 0 a n d < 1 5 years , ≥ 1 5 a n d < 1 8 years) usi n g t he ra n d omisat i on strata , a n d p u bert y 
stat us at Wee k 2 6, Wee k 5 2 a n d Wee k 1 0 4 (as defi ne d i n A p pe n di x S e cti o n 8. 1 0. 3 ) f or Wee k 
2 6, Wee k 5 2, a n d f or t h e p ost -stu d y visit at Wee k 1 0 4 usi n g t he L O C F a p pr oac h. Si milarl y, a 
cate g orical c ha n ge fr om 
wi t hdra wal baseli ne s u m mar y will 
als o be pr o d uce d
f or t he 
Ra n d o mise d
Wit h dra wal S u bjects Data Set f or Wee k 
5 2 a n d Wee k 
1 0 4 usi n g t he L O C F 
a p pr oac h.
A listi n g of t he gr o wt h a n d mat urati o n m ar kers alo n g wi t h t he Ta n ner sta ges b y s u bject will b e 
pr o vi de d . For t he S T + L T peri o d t hi s listi n g will i nclu de all data c ollecte d u p t o t he e n d of t he 
L T peri o d. F or t he S T + L T + Wee k 1 0 4 peri o d, t he listi n g will i ncl u de all d at a c o llecte d u p t o 
Wee k
1 0 4.
4. 7. 7. 4
B o ne bi o m ar kers
S u m maries of  b o ne bi o mar kers (see Sect i on 3. 4. 9 ) i n SI a n d c o n ve nt i onal u ni ts will be base d 
o n o bser ve d data, re g ar dless o f resc ue me d icatio n i ni tiat i on . Descri pti ve s u m maries of a bs ol ute 
val ues a n d c ha n ges fr o m baseli ne ( w here a p plica ble) will be pr o vi de d f or baseli ne, Wee k 2 6, 
Wee k 5 2, a n d f or t he p ost -stu d y visit at Wee k 1 0 4 usi n g t he L O C F a p pr oac h . F or t he Wee k 1 0 4 
a nal yses, c ha n ge fr o m Wee k 5 2 will als o be prese nte d.
I n a d ditio n, b o ne bi o mar kers will als o be s u m marise d as a b o ve f or s u bjects g oi n g t hr o u g h t he 
t hir d ra n d omisat i on usi n g t he Ra n d o mise d
Wit h dra wal  Su bjects Data Set f or t he first t wo 
tr eat me nt  c o m paris o ns descri be d i n Secti on  4. 1. 5 .
A cate g oric al cha n ge fr o m baseli ne s u m mar y will als o be pr o d uce d b y treat me nt gr o u p, a ge 
cate g or y (≥ 1 0 a n d < 1 5 years , ≥ 1 5 a n d < 1 8 years) usi n g t he ra n d omisat i on strata , a n d p u bert y 
stat us at  Wee k 2 6, Wee k 5 2 , a n d Wee k 1 0 4 (as defi ne d i n A p pe n di x Sect i on  8. 1 0. 3 ) f or Wee k 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 4
2 6, Wee k 5 2, a n d f or t h e p ost -stu d y visit at Wee k 1 0 4 usi n g t he L O C F a p pr oac h. Si milarl y, a 
cate g orical c ha n ge fr om 
wi t hdra wal baseli ne s u m mar y will 
als o be pr o d uce d
f or t he 
Ra n d o mise d Wit h dra wal S u bjects Data Set f or Wee k 
5 2 a n d Wee k 
1 0 4 usi n g t he L O C F 
a p pr oac h.
A listi n g of  t he b o ne bi o mar kers al o n g wit h t he Ta n ner sta ges b y  s u bject will be pr o vi de d. F or 
t he S T + L T perio d t his list i n g will i ncl u de all data c ollecte d u p t o t he e n d of the L T peri o d. F or 
t he S T + L T + Wee k 1 0 4 peri o d, t he list i n g will i ncl u de all data c ollecte d u p t o Wee k 1 0 4.
4. 8
P h ar m ac o ki netic a n al yses
P las ma sa m ples will 
be a nal ysed f or da pa glifl o zi n, sa xa gli pti n, a n d its
meta b olit e 
5- O H -sa xa gli pti n b y vali date d assa ys. Pl as ma c o nce ntrati o n v al 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 marise d f or t he S T peri o d usi n g descri pt i ve 
statistics b y visi t a nd time p oi nt f or t he P har mac o ki net ic A nal ysis Data Set . F or eac h a nal yte, 
descri pt i ve s u m maries will i ncl u de t he n, n u m ber of  su bjects ha vi n g a val ue bel o w t he L o wer 
Li mit of q ua nt ificati on ( L L O Q) [ n < L L O Q], arit h met ic mea n, S D, ge o metric mea n, ge o metric 
S D , C V % , me d ia n, mi ni m u m a n d ma xi m u m val ues will be prese nte d . A listi n g of  plas m a 
c o nce ntrati o n val ues will be prese nte d f or t he S T peri o d.
T he plas ma c o nce ntratio n val ues ma y 
be use d i n p o p ulati o n P K  an d/ or p o p ulat i on 
P K/ p har mac o d y na mic a nal yses t hat will be re p orte d se paratel y fr o m t he C S R.
4. 9
P h ar m ac o d y n a mic a n al yses
P h ar mac o d y na mic a nal yses will i ncl u de b ut will n ot be li mite d t o a nal ysis of  DP 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.
4. 1 0
Site 4 9 1 0
D ue t o c o ncer ns wi t h the data c ollecte d at sit e 4 9 1 0 a n d f oll o wi n g f urt her i n vesti gati on b y 
Astra Ze neca it was deci de d t hat all of  the ta bles, fi g ures, a n d listi n gs o utli ne d a b o ve will b e 
pr o d uce d e xcl u di n g t he data fr o m site 4 9 1 0. 
I n a d diti on, t he f o ll owi n g a nal ys es will be pr o d uce d i ncl u di n g s u bjects fr o m sit e 4 9 1 0:

S u bject dis p osit i on d uri n g t he S T + L T peri o d as o utli ne d i n S ect i on  4. 2. 1

D e m o gra p hics a n d baseli ne c haracteristics as o utli ne d i n S ect i on 4. 2. 3

All s u m maries a n d a nal yses ass ociate d wit h t he pri mar y a n d sec o n dar y efficac y 
e n d p o i nts as o utli ne d i n S ect i on s 4. 4. 1 , 4. 5. 2 , 4. 5. 3 , 4. 5. 4 , 4. 5. 5 , 4. 5. 6 , 4. 5. 7 , 4. 5. 8, 4. 5. 9 , 
4. 5. 1 0 , 4. 5. 1 1 , 4. 5. 1 2 ( n o se nsiti vity a nal yses will be perf or me d)

T he o verall s u m mar y of  TE A Es d uri n g t he S T + L T peri o d, re gar dless of  resc ue, as 
o utli ne d i n S ect i on 4. 7. 1. 1

T E A Es b y S O C a n d P T d uri n g t he S T + L T peri o d, re gar dless of  resc ue, as o utli ne d i n 
S ectio n 4. 7. 1. 1


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 5

Deat hs d uri n g t he S T + L T peri o d as o utli ne d i n S e ctio n  4. 7. 1. 2

S A Es d uri n g t he S T + L T peri o d, re gar dless o f resc ue, as o utli ne d i n S ect i on 4. 7. 1. 3

M A l a bs d uri n g t he S T + L T peri o d, re gar dless of resc ue, as o utli ne d i n S ect i on  4. 7. 3. 4

Pre g na nc y d uri n g t he S T + L T peri o d as o utli ne d i n S ectio n 4. 7. 3. 6

Vi t al si g ns d uri n g t he S T + L T peri o d, re gar dl ess of resc ue, as o utli ne d i n S ect i on s 4. 7. 4
a n d 4. 7. 6
5.
I N T E RI M A N A L Y S E S ( N OT A P P LI C A B L E)
6.
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L
T a ble 1 2 C h a n ges of a n al ysis fr o m pr ot oc ol
Secti o n of S A P Affecte d (If 
a p plic a ble)
C h a n ge
R ati o n ale
Secti o n 2. 2. 7
A P K a nal ysis data set was 
defi ne d i n t he S A P, b ut t his 
is n’t me nti o ne d i n t he st u d y 
pr ot oc ol.
It is necessar y t o ha ve a n 
a nal ysis set defi ne d f or t he P K 
data.
Secti o n 4. 1. 1
T he defi niti o n of t he 
wit h dra wal baseli ne differs 
bet wee n t he st u d y pr ot oc ol a n d 
t he S A P.
T his c ha n ge was ma de t o ali g n 
t he wit h dra wal baseli ne wit h 
h o w we defi ne d ose at o nset 
a n d h o w t o ha n dle sce nari os 
w her e t he ra n d o misati o n was 
d o ne o n a differe nt date t o t he 
ma i n visit.
Secti o n 4. 1. 1 0
Fis her’s e xact test is use d 
i nstea d of l o gistic re gressi o n 
w her e t her e are < 5 res p o n ders 
per treat me nt gr o u p.
T his a nal ysis was n ot 
me nti o ne d i n t he pr ot oc ol.
Secti o n 4. 1. 1 2
T he “ was h -o ut” i m p utati o n 
met h o d is use d w here t here is 
i ns ufficie nt data fr o m 
“r etrie ve d dr o p-o uts”.
T his a nal ysis was n ot 
me nti o ne d i n t he pr ot oc ol.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 6
Secti o n of S A P Affecte d (If 
a p plic a ble)
C h a n ge
R ati o n ale
Secti o ns 4. 4 a n d 4. 5
T he pri mar y efficac y e n d p oi nt 
was u p date d t o use o verall 
treat me nt a n d t he sec o n dar y 
efficac y e n d p oi nts 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.
T his was d ue t o pr ot oc ol 
a me n d me nt # 6.
Secti o n 4. 7. 1. 1
T he pr ot oc ol states t hat 
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 Sets o n all D K A 
e ve nts b ut i n t he S A P, we o nl y 
prese nt t he a nal ysis f or 
a dj u dicate d D K A S A Es.
A d diti o nal a nal yses were o nl y 
d o ne o n c o nfir me d D K As. 
Secti o n 4. 1 0
It was deci de d t hat all t he T F Ls 
will be pr o d uce d e xcl u di n g 
data c ollecte d fr o m Site 4 9 1 0. 
I n a d diti o n, a fe w a nal yses will 
be pr o d uce d i ncl u di n g s u bjects 
fr o m Site 4 9 1 0.
T his was d ue t o l oss of access 
t o t he s o urce data of s u bjects at 
Site 4 9 1 0. T his decisi o n was 
ma de f oll o wi n g i n vesti gati o n 
b y Astra Ze neca.
A p pe n di x 8. 1 3
T he pr ot oc ol states t hat 
“se parate a nal yses will be 
perf or me d f or s u bjects 
r es pecti vel 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” w hile i n t he S A P, we 
c o m bi ne t he ra n d o mise d 
wit h dra wal treat me nt i nt o o ne 
a nal ysis ta ble.
Prese nti n g t he data t his wa y 
was m ore i nf or mati ve. 
7.
R E F E R E N C E S
1.
Sea q uist E R, A n ders o n J, C hil ds B, Cr y er P, Da g o g o -Jac k S, Fis h L, Heller S R, 
R o dri g uez H, R ose nz wei g J, Vi gers k y R. H y p o gl ycae mia a n d dia betes: a re p ort of a 
w or k gr o u p of t he A merica n Dia betes Ass ociat i on a n d T he E n d ocri ne S ociet y.  
Di a betes Care. 2 0 1 3 Ma y; 3 6( 5): 1 3 8 4 - 9 5
2.
Cl ar ke W, J o nes T, Re wers A, D u n ger D, Kli n ge ns mit h G. I S P A D Cli nical Pract ice 
C o nse ns us G ui deli nes 2 0 0 9 C o m pe n di u m Assess me nt a n d ma na ge me nt of 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 7
h y p o gl ycae mia i n c hil dre n a n d a d olesce nts wit h dia betes. Pae di atric Di a betes 2 0 0 9; 
1 0: 1 3 4 - 1 4 5.
3.
A S A S Pr o gra m f or t he 2 0 0 0 C D C Gr o wt h C harts (a ges 0 t o < 2 0 y ears) , a vaila ble at:
htt ps:// w w w.c dc. g o v/ ncc d p h p/ d n p a o/ gr o wt hc h arts/r es o urc es/s as. ht m
4.
Rati tc h B, Li p k o vic h I, O' Kell y M. C o m bi ni n g A nal ysis Res ults fr o m M ultipl y  
I mp ute d Cate g orical Data. P har ma S U G 2 0 1 3 - Pa per S P 0 3, a vaila ble at: 
ht t ps:// p har mas u g. or g/ pr ocee di n gs/ 2 0 1 3/ S P/ P har ma S U G - 2 0 1 3-S P 0 3. p df
5.
Da n ne T, P hil ot he o u A, G ol d ma n D, et al. A ra n d o mise d trial c o mpari n g t he rate of
h y p o gl ycae mia – assesse d usi n g c o nti n u o us gl uc ose m o nit ori n g – i n 1 2 5 presc h o ol 
c hil dre n wit h t ype 1 di a betes treate d wit h ins uli n glar gi ne or N P H i ns uli n. Pae di atric
Di a betes 2 0 1 3: 1 4: 5 9 3 – 6 0 1.
6.
J o nes K L, Arsla nia n S, Peter o k o va V A, Par k J-S, T o mli ns o n MJ. Effect of Metf or mi n 
i n Pae diatri c Pat ient s wit h T yp e 2 Di a betes. Dia betes Care 2 5: 8 9 - 9 4, 2 0 0 2.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 8
8.
A P P E N DI X
8. 1
Fl o w c hart/ti me a n d e ve nts sc he d ule
T a ble 1 3 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
L e 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 y sical 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 Secti o n 8. 1 0. 1
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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 1 9
Pr oce d ure
Scree ni n g
M a xi m u m 6 
m o nt hs a
L e a d-i n
W k – 2 b
N otes
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 Secti o n  8. 7
G A D/I A 2 A ut oa nti b o dies
X
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 ol 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 nselli 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 ycae 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 t hat 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.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 0
T a ble 1 4 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 uea ,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 y sical 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 Secti o n 8. 1 0. 1
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 ycae 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 Secti o n  8. 7
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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 1
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 uea ,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 
pr e -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 on.
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.
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 u rati o n mar kers
X
X
T h y r oi d-sti m ulati n g h or m o ne ( T S H), free
t h yr oxi 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), o 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 n e  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 its 
meta b olite 5 -O H -sa xa gli pti nd
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. 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 2
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 uea ,c
N otes
# N o sa m ples will be dra w n at 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 pr e-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.
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 misati o n
X
Sec o n d ra n d o misati 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 nselli 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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 3
a
Visits ma y  be sc he d ule d 7 da y s ( 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 da ys 
a part. 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 Wee k
1 4 visit is dela ye d, s u bse q ue nt visits s ho ul d be dela y e 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 on 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 1 7 Sa m pli n g Sc he d ule .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 4
T a ble 1 5 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 y sical 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
See A p pe n di x Secti o n 8. 1 0. 1
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 ym pt o ms of h y p o gl ycae 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
See A p pe n di x Secti o n  8. 7
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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 5
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 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 y r oi d-sti m ulati n g 
h or m o ne ( T S H), free 
t h yr oxi 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), 
o 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 oni 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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 6
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 misati o n
X
X *
T he t hir d ra n d o misati 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 mise 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 mis 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 mise d at Wee k 3 2
I nstr ucti on 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 misati 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 mise 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
Ge ner al
Pr o vi de diet a n d e xercise 
c o u nselli n g
X
X *
X
X *
* Assesse d b y P h o ne
Dis pe nse Meter S u p plies
X
X


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 7
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
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 (f oll o w- u p 
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 on v isit (at Wee k 3 2 or Wee k 4 0) is dela ye d, s u bse q ue nt visits s ho ul d be dela y e d t o mai ntai n a n i nter 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 on o f 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 .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 8
T a ble 1 6 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 nt
X  
X 
X 
X  
X
A d verse E ve nts Assess me nt
X  
X 
X 
X  
X
Sta n dar d safet y la b orat or y 
pa nel ( Bl o o d)
X  
X
See A p pe n di x Secti o n  8. 7
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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 2 9
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 
Ta n ner Sta gi n g 
X *  
X *
X
See A p pe n di x Secti o n  8. 1 0. 1 ; * onl y  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 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 y r oi d-sti m ulati n g h or m o ne ( T S H), free 
t h yr oxi 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), o 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 y r 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)
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 Wee k 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 -office 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 nal sc he d ule d date t o all o w fle xi bilit y of sc he d uli n g . S h or t- 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). 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 2. 0
Date 0 7 D E C 2 0 2 2
T a ble 1 7 P h ar m ac o ki netic/ P h ar m ac o d y n a mic 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 - 4b
Da y 1
Pr e -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 Pr e-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 K sa m ples will n ot be c ollecte d at t he Wee k 2 6 Visit f oll o wi n g t he Earl y Treat me nt Disc o nti n uati o n Visit


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 1
8. 2
H a n dli n g missi n g or p arti al e ve nt d ates
F or data s u m maries, i n case of  missi n g or partial dates a n d/ or ti mes i m p utati o n r ules will b e 
a p plie d i n or der t o classif y A Es, h y p o gl ycae mic e ve nts, a n d D K A as o n treat me nt-e mer ge nt
a n d t o sl ot t he e ve nt t o a n a p pr o priate a nal ysis peri o d . 
P arti al d ates

F or parti al o nset dates: 
-
Calc ulate a s urr o gate date as t he first n o n -missi n g vali d date fr o m t he f o ll owi n g list  
(in or der of prece de nce):

Fi rst acti ve st u d y me dicat i on date

I nf or me d co nse nt date

If a vali d n o n- missi n g date is n ot a vaila ble f or a n y of  these dates, t he 
s urr o gate date will be set t o missi n g.
–
Base d o n t he i nf or mat i on pr o vi de d, set t he deri ve d date t o t he earliest p ossi ble 
date. If o nl y t he year is pr o vide d, i m p ute o nset date as 1 st Ja n uar y of t hat year. If 
t he year a n d m o nt h are pr o vi de d, i m p ute o nset date as 1 st d a y  of t hat mo nt h a n d 
year. 
–
If t he s urr o gate date is n o n-missi n g t he n:
i. If t he deri ve d date is o n or aft er t he s urr o gate date , use t he deri ve d date as 
calc ulate d
ii. If t he deri ve d date is pri or t o t he s urr o gate date a n d t he s urr o gate date is 
c o nsiste nt wit h t he partial data pr o vi de d f or t he o nset date, use t he s urr o gate 
date as t he deri ve d date
iii. If t he deri ve d date is prior t o t he s urr o gate date a n d t he s urr o gate date is n ot 
c o nsiste nt wit h t he parti al data pr o vi de d f or t he o nset date , t he n set t he 
deri ve d o nset date t o be t he latest p ossi ble date base d o n t he partial o nset  
date i nf or mat i on pr o vi de d. If o nl y a year is pr o vi de d, set t he deri ve d date t o 
Dece m ber 3 1st of t hat ye ar. If a year a n d m o nt h is pr o vide d, set t he deri ve d 
date t o t he last da y  of t hat mo nt h.
–
If all t hree dates use d t o deter mi ne t he s urr o gate date are missi n g, t he n base d o n t he 
i nf or mat i on pr o vi de d, set t he deri ve d date t o t he earliest p ossi ble date. If o nl y a year 
is pr o vi de d, set t he deri ve d date t o Ja n uar y  first of t h at ye ar. If a year a n d m o nt h is 
pr o vi de d, set t he deri ve d date t o t he first da y  of t hat mo nt h.

F or parti al st o p dates: 
–
If o nl y t he year is pr o vide d, i m p ute st o p date as 3 1 st Dece m ber of  t hat year, or e n d 
of  st u d y date f or t hat s u bject or deat h date, w hic he ver is earlier. 
–
If t he year a n d m o nt h are pr o vi de d, i m p ute st o p date as t he last da y of t hat mo nt h 
a n d year, or e n d of st u d y date f or t hat s u bject or deat h date, w hic he ver is earlie r. 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 2
If t he a b o ve r ules res ult i n ill o gical dates, t he i m p utati o n s h o ul d be u p date d acc or di n gl y, als o 
c o nsi deri n g w hic h of t he t w o dates ( o nset or st o p) is m ore c o m plete. F or e xa m ple, if t he 
i m p ute d start date is later t ha n t he i m p ute d st o p date, a n d t he sto p date is m ore c o m plete, t he n 
t he start date s h o ul d be i m p ute d t o be t he sa me as t he st o p date. T his deri ve d date will n ot be 
re p orte d i n s u m mar y ta bles or listi n gs.
Missi n g d ates

T he deri ve d o nset date will be calc ulate d as t he first n o n -missi n g vali d date fr o m  
t he f o ll owi n g list (i n or der of prece de nce):
o
Fi rst acti ve st u d y me dicat i on date
o
I nf or me d co nse nt date
o
If a vali d n o n- missi n g date is n ot a vaila ble f or a n y of  these dates, t he deri ve d 
o nset date will be set t o missi n g.

E ve nts wi t h missi n g o nset a nd st o p dates will be c o nsi dere d o n -treat me nt.

F or e ve nts wit h missi n g o nset a n d n o n -missi n g st o p dates (i m p ute d if partial as 
descri be d a b o ve), if t he st o p date is earlier t ha n t he treat me nt start date ( Da y  1) t he 
e ve nt will be c o nsi dere d as ha vi n g starte d pri or t o treat m e nt; ot her wise t he e ve nt 
will be c o nsi dere d o n -treat me nt.
8. 3
H a n dli n g missi n g or p arti al me dic ati o n d ates (e xcl u di n g resc ue 
i ns uli n)
I n or der t o classif y me dicat i ons as pri or or c o nc o mita nt a n d t o sl ot t he me d icati on t o a n 
a p pr o priate a nal ysis peri o d , partial missi n g or i n vali d start a n d st o p dates will be i m p ute d w here 
p ossi ble as f o ll ows:

If t he re p orte d start date is missi n g or i n vali d a n d t he i nf or me d c o nse nt date is n ot 
missi n g or i n vali d, t he n t he i m p ute d start date is set e q ual t o t he i nf or me d c o nse nt 
date. If t he i nf or me d c o nse nt date is missi n g or i n vali d a n d t he birt h date is n ot 
missi n g or i n vali d, t he n t he i m p ute d start date is set e q ual t o t he birt h date. If t he start 
date, t he inf or m e d c o nse nt date a n d t he birt h date are all i n vali d or missi n g, t he n t he 
i m p ute d start date is set e q ual t o missi n g.

If t he re p orte d start date is partiall y e ntere d, t he n t he i m p ute d start date is set e q ual t o 
t he earliest p ossi ble re p orte d start date base d o n t he partial e ntere d re p orte d start date.

If t he re p orte d e n d date is missi n g, c o nti n ui n g, u n k n o w n or i n vali d, t he n t he i m p ute d 
e n d date is set e q ual t o t h e last p ossi ble re p orte d e n d date base d o n t he re p orte d e n d 
dates .

If t he re p orte d e n d date o f t he me dicat i on is parti al, t he n t he i m p ute d e n d date is set 
e q ual t o t h e last p ossi ble re p orte d e n d date base d o n t he partial e ntere d re p orte d e n d 
date.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 3
I mp ute d dates will n ot a p pear o n t he list i n gs of n o n-st u d y me dicat i on.
8. 4
H a n dli n g missi n g or p arti al me dic ati o n d ates (resc ue i ns uli n o nl y)
I n or der t o select t he date of resc ue me dicati on i nitiati on a n d t o deri ve t he t otal dail y d ose of 
resc ue i ns uli n, partial start a n d st o p dates will be i m p ute d as f oll ows:

F or parti al start dates:
o
Calc ulate a s urr o gate date as t he first resc ue visi t start date. If t here is n o 
a vaila ble resc ue visit start date, t he s urr o gate date will be set t o missi n g.
o
Base d o n t he i nf or mat i on pr o vi de d, set t he deri ve d date t o t he earliest p ossi ble 
date. If o nl y t he y ear is pr o vide d, i m p ute o nset date as 1 st Ja n uar y of t hat year. 
If t he year a n d m o nt h are pr o vi de d, i m p ute o nset date as 1st d a y  of t hat mo nt h 
a n d year. 
o
If t he s urr o gate date is n o n-missi n g t he n:
i. If t he deri ve d date is o n or aft er t he s urr o gate date, use t he deri ve d date as 
calc ulate d
ii. If t he deri ve d date is pri or t o t h e s urr o gate date , t he n use t he s urr o gate date 
as t he deri ve d date.
o
If t he s urr o gate date is missi n g, t he n use t he deri ve d date.

F or parti al st o p dates:
o
If o nl y t he year is pr o vide d, i m p ute st o p date as 3 1 st Dece m ber of t hat y ear, or 
e n d of st u d y date f or t hat s u bject or deat h date, w hic he ver is earlier. 
o
If t he year a n d m o nt h are pr o vi de d, i m p ute st o p date as t he last da y of t hat 
m o nt h a n d year, or e n d of st u d y date f or t hat s u bject or deat h date, w hic he ver is 
earlier. 
I mp ute d dates will n ot a p pear o n t he list i n gs of n o n-st u d y me dicat i on.
8. 5
H a n dli n g missi n g or p arti al T 2 D M di a g n osis d ates
If t he T 2 D M dia g n osis date is partiall y missi n g, t he f o ll owi n g r ul es will t a ke effect:

Missi n g da y , b ut mo nt h a n d y ear are prese nt: t he da y will be i m p ute d as t he 1 5t h da y 
of  t h e mo nt h, or date of i nf or me d c o nse nt, w hic he ver is earlier .

Missi n g da y a n d m o nt h, b ut year is prese nt: t he da y a n d m o nt h will be i m p ute d as 3 0 
J u ne of t he year, or date of i nf or me d c o nse nt , w hic he ver is earlier.

Missi n g year, b ut da y a n d m o nt h are prese nt: N o i m p utati o ns will occ ur, a n d t he 
s u bject will be e xcl u de d fr om all s u m maries relate d t o d uratio n of  T 2 D M.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 4

Missi n g da y, m o nt h a n d year: N o i m p utati o ns will  occ ur, a n d t he s u bject will be 
e xcl u de d fr o m all s u m maries relate d t o d uratio n of T 2 D M.
If a n y s uc h i m p ute d date falls aft er t he i nf or me d c o nse nt date, t he n t he dia g n osi s date will b e 
ta ke n as e q ual t o t he i nf or me d c o nse nt date.
8. 6
Deri vi n g a ge at e ac h v isit
8. 6. 1
A ge use d t o deri ve n or m alise d hei g ht, b o d y wei g ht a n d B MI e x presse d as z -
sc ore
F or baseli ne assess me nt , a ge at t he ti me of  the assess me nt use d f or baseli ne will  be use d. At  
Wee k 6, Wee k 1 2, Wee k 2 0, Wee k 2 6, Wee k 3 2, Wee k 4 0, Wee k 5 2, pre mat ure e n d of  treat me nt 
visit, n o n -tr e at me nt fol l ow- u p visit , a n d Wee k 1 0 4 t he a ge ( mo nt hs) will be deri ve d as:
( Visit date – birt h date + 1) / 3 0. 5;
If o nl y year part of date of birt h is a vaila ble, t his will be i m p ute d t o 3 0 t h of  J u ne. If i m p ute d 
date of birt h res ults i n t he deri ve d a ge bei n g less t ha n t he I W R S a ge at scree ni n g, t he n use 
I W R S a ge.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 5
8. 7
C li nic al l a b or at or y v ari a bles
8. 7. 1
M ar ke d a b n or m alit y criteri a f or s afet y l a b or at or y v ari a bles
Cli nical la b orat or y varia bles will be s u m marise d a n d liste d usi n g t he u nits liste d here. T he 
criteria f or mar ke d a b n or malit y for eac h varia ble are liste d i n t he f oll owi n g ta ble. N ote t hat a 
p ost -baseli ne lab orat or y  val ue will be c o nsidere d a M A o nl y  if it satisfies t he s pecifie d criteria
as descri be d i n Sect i on 4. 7. 3. 4 .
T a ble 1 8 M ar ke d l a b or at or y a b n or m alities
C o n ve nti o n al ( U S) U nits:
M ar ke d A b n or m alit y Criteri a
Cli nic al L a b or at or y v ari a bles
U nits
L o w
Hi g h
He m at ol o g y
H ae mat ocrit
%
< 2 0. 0 %
> 5 5. 0 %
H ae mat ocrit
%
> 6 0. 0 %
Hae m o gl o bi n
g/ d L
< 6 g/ d L
> 1 8 g/ d L
Hae m o gl o bi n
g/ d L
> 2 0 g/ d L
Bl o o d C he mistr y
P r otei n, t otal
g/ d L
> 1 0 g/ d L
A L P
U/ L
> 3 X U L N
A L T
U/ L
> 3 X U L N
A S T
U/ L
> 3 X U L N
A L T
U/ L
> 5 X U L N
A S T
U/ L
> 5 X U L N
A L T
U/ L
> 1 0 X U L N
A S T
U/ L
> 1 0 X U L N
A L T
U/ L
> 2 0 X U L N
A S T
U/ L
> 2 0 X U L N
Bilir u bi n , t otal
m g/ d L
> 1. 5 X U L N if Pre T x 
U L N
Bilir u bi n , t otal
m g/ d L
> 2 X U L N if Pre T x > U L N
Gl uc ose, Plas ma U ns pecifie d
m g/ d L
< 5 4 m g/ d L
> 3 5 0 m g/ d L
Na ( S o di u m)
m E q/ L
< 1 3 0 m E q/ L
> 1 5 0 m E q/ L
Na ( S o di u m)
m E q/ L
< 1 2 0 m E q/ L
K ( P otassi u m)
m E q/ L
2. 5 m E q/ L
6. 0 m E q/ L
Creati ni ne
m g/ d L
1. 5 X Pr e T x C R E A T
Creati ni ne
m g/ d L
2. 5 m g/ d L
Calci u m
m g/ d L
< 7. 5 m g/ d L
1 m g/ d L fr o m U L N a n d 
0. 5 m g/ d L fr o m Pr e T x C A
Ma g nesi u m
m E q/ L
< 1 m E q/ L
> 4 m E q/ L
P O 4 ( P h os p hate)
m g/ d L
A ge 1 7 -6 5: 1. 8 m g/ d L
A ge 1 7 -6 5: 5. 6 m g/ d L
Uri ne
U A C R ( Uri nar y Al b u mi n t o 
Creati ni ne Rati o)
m g/ g
> 1 8 0 0 m g/ g


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 6
St a n d ar d I nter n ati o n al U nits
M ar ke d A b n or m alit y Criteri a
Cli nic al L a b or at or y v ari a bles
U nits
L o w
Hi g h
He m at ol o g y
H ae mat ocrit
rati o
< 0. 2 0
> 0. 5 5
H ae mat ocrit
rati o
> 0. 6 0
Hae m o gl o bi n
g/ L
< 6 0 g/ L
> 1 8 0 g/ L
Hae m o gl o bi n
g/ L
> 2 0 0 g/ L
Bl o o d C he mistr y
P r otei n, t otal
g/ L
> 1 0 0 g/ L
A L P
u kat/ L
> 3 X U L N
A L T
u kat/ L
> 3 X U L N
A S T
u kat/ L
> 3 X U L N
A L T
u kat/ L
> 5 X U L N
A S T
u kat/ L
> 5 X U L N
A L T
u kat/ L
> 1 0 X U L N
A S T
u kat/ L
> 1 0 X U L N
A L T
u kat/ L
> 2 0 X U L N
A S T
u kat/ L
> 2 0 X U L N
Bilir u bi n , t otal
μ m ol/ L
> 1. 5 X U L N if Pre T x 
U L N
Bilir u bi n , t otal
μ m ol/ L
> 2 X U L N if Pre T x > 
U L N
Gl uc ose, Plas ma U ns pecifie d
m m ol/ L
< 3 m m ol/ L
> 1 9. 4 m m ol/ L
Na ( S o di u m)
m m ol/ L
< 1 3 0 m m ol/ L 
> 1 5 0 m m ol/ L
Na ( S o di u m)
m m ol/ L
< 1 2 0 m m ol/ L
K ( P otassi u m)
m m ol/ L
2. 5 m m ol/ L
6. 0 m m ol/ L
Creati ni ne
μ m ol/ L
1. 5 X Pre T x C R E A T
Creati ni ne
μ m ol/ L
2 2 1 µ m ol/ L
Calci u m
m m ol/ L
< 1. 8 8 m m ol/ L
0. 2 5 m m ol/ L fr o m 
U L N a n d 0. 1 3 
m m ol/ L f r om Pre T x 
C A
Ma g nesi u m
m m ol/ L
< 0. 5 m m ol/ L
> 2 m m ol/ L
P O 4 ( P h os p hate)
m m ol/ L
A ge 1 7 -6 5: 0. 5 8 
m m ol/ L
A ge 1 7 -6 5: 1. 8 1 
m m ol/ L
Uri ne
U A C R ( Uri nar y Al b u mi n t o 
Creati ni ne Rati o)
g/ m ol
> 2 0 3. 6 2 g/ m ol
Ele v ate d A T ( A L T a n d/ or A S T) a n d t ot al Bilir u bi n
T he f oll owi n g t hree crit eria will be s u m marise d i n e xa mi nati o n of  ele vate d A T ( A L T a n d/ or 
A S T) a n d t otal bilir u bi n :

( A S T or A L T > 3 X U L N) a n d ( Bilir u bi n > 1. 5 X U L N wit hi n 1 4 da ys o n or after A T ele vati o n),

( A S T or A L T > 3 X U L N) a n d ( Bilir u bi n > 2 X U L N wit hi n 1 4 da ys o n or after A T ele vati o n),






Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 3 9
8. 1 0
P u bert y st at us a n d hei g ht vel ocit y use d t o c ate g orise gr o wt h a n d 
m at ur ati o n m ar kers as well as b o ne bi o m ar kers
8. 1 0. 1
T a n ner st a gi n g
T a bl e 2 1 T a n ner st a gi n g criteri a
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 
ar eola 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 ver e 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 dia l 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 dia l s urface of t hi g hs
Mat ure; pr ojecti o n of pa pilla o nl y d ue t o 
r ecessi o n of t he are ola t o t he ge neral 
c o nt o ur of t he breast
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
4
Rese m bles a d ult t y pe b ut t he area 
c o ver e 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 dia l 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 dia l 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


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 0
8. 1 0. 2
Hei g ht vel ocit y
T he hei g ht vel ocit y is defi ne d as t he c ha n ge fr o m baseli ne , or t he pre vi o us meas ure me nt,
t o 
Wee k t i n hei g ht (c m) sta n dar dise d t o 2 6 wee ks ( 1 8 3 d a y s) or 5 2 wee ks ( 3 6 5 da ys) . F or e xa m ple, 
c ha n ge fr o m Wee k 5 2 t o Wee k 1 0 4 . 
T he n u m ber of act ual da ys bet wee n baseli ne, or t he pre vi o us meas ure me nt, a n d Wee k t will be 
use d t o deri ve hei g ht vel ocit y.
I n case of missi n g Wee k t ( Wee k 2 6, 5 2, or 1 0 4) hei g ht , a n a vera ge c ha n ge i n hei g ht ( i n da ys) 
will be deri ve d base d o n t he act ual da y of  the t w o cl o sest n o n-missi n g o bser vat i ons ( Wee k a
a n d Wee k b, w here Wee k a is t he earlier of  the t w o visit s) t o t he pl a n ne d visit . F or missi n g 
Wee k 1 0 4, t hi s will be t he pre vi o us t wo o b ser vati o ns c ollecte d. T he a vera ge c ha n ge i n h ei g ht 
per da y will be m ult i plie d b y t he n u m ber of  da ys bet wee n t he da y of  the Wee k a a n d Wee k t 
tar get date, a n d a d de d t o t he hei g ht val ue of Wee k a t o deri ve a n i m p ute d Wee k t val ue.
8. 1 0. 3
P u bert y st at us
P u bert y stat us will be defi ne d, b y visit, usi n g t he Ta n ner sta ge at t hat visit alo n g wi t h hei g ht 
vel ocit y (as defi ne d Sect i on 8. 1 0. 1 ) as f oll ow:

Earl y/ m i d p u bert y: Ta n ner sta ge 1 or Ta n ner sta ge 2 or Ta n ner sta ge 3 , or Ta n ner sta ge 
4 wi t h hei g ht velo ci t y ≥1. 5 c m / 2 6 wee ks = ≥3 c m/ 5 2 wee ks ,

Late p u bert y a n d y o u n g a d ult: Ta n ner sta ge 4 wi t h hei g ht vel ocity < 1. 5 c m/ 2 6 wee ks = 
< 3 c m/ 5 2 wee ks, or Ta n ner sta ge 5.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 1
8. 1 1
Ge o gr a p hic al re gi o ns
T a ble 2 2 Ge o gr a p hic Re gi o ns
Ge o gr a p hic Re gi o n
C o u ntries
N ort h A merica
Ca na da
U nite d States
Lati n A merica
Ar ge nti na, C ol o m bia
Brazil, Me xic o
C hile
E ur o pe
U krai ne, R ussia
P ola n d, Ital y
U nite d Ki n g d o m
Fi nla n d, R o ma nia 
Israel, T ur ke y
As ia/ Pacific
A ustralia , Tai wa n,
P hili p pi nes , S o ut h K orea
I n dia, T haila n d
Mala ysia, Ne w Zeala n d 
8. 1 2
Re p orti n g c o n ve nti o ns
Re p orti n g c o n ve nt i ons will f o ll ow A Z's st yle g ui de, w here ver a p plica ble.
F or s u m mar y statist ics, t he mea n a n d me dia n will be dis pla ye d t o o ne deci mal place greater 
t ha n t he origi nal  val ue a n d t he meas ure of varia bilit y (e. g. S D, sta n dar d err or [ S E]) will be 
di s pla ye d t o t w o deci mal places greater t ha n t he ori gi nal v alue. Mi ni m u m  a n d ma xi m u m will 
be re p orte d t o t he sa me deci mal places as t he ori gi nal val ue. Least -s q uare mea n est i mates will 
be r o u n de d t o t w o deci mal places greater t ha n t he ori gi nal val ue. O d ds rati os will be r o u n de d 
t o o ne deci mal place. 
All v al ues will be prese nte d t o a ma xi m u m 4 deci mal places.
P- val ues ≥0. 0 0 1 will be re p orte d t o t hree deci mal places; p -val ues less t ha n 0. 0 0 1 will be 
re p orte d as < 0. 0 0 1. F or fre q ue nc y ta b ulati ons, perce nta ges will be prese nte d wit h o ne deci mal 
pl ace. Perce nta ges less t ha n 0. 1 % will be prese nte d as ‘ < 0. 1 %’. If t he fre q ue nc y a n d 
perce nta ge are zer o t he y will be prese nte d as ' 0' (i nstea d of 0 ( 0. 0)). N o n -esti ma ble S Ds or 
S Es will be re place d wit h a das h ('- '). C o nfi de nce i nter vals will be re p orte d t o t he sa me 
n u m ber of deci mal places as t he ass ociate d esti mate. T he n o mi nal al p ha defi ne d f or t he st u d y  
is 0. 0 5 (t w o-si de d). 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 2. 0
Date 0 7 D E C 2 0 2 2
8. 1 3
Tre at me nt prese nt ati o n f or t a bles a n d fi g ures
Tre at me nt l a bel
E x pl a n ati o n
A n al ysis p ur p ose
First r a n d o mis e d / act u al tre at me nt ( D a y 1)
Di s p ositio n , D e mo gra p hics, 
S af et y , E x p os ure
T ot al  Da pa glifl ozi n
All s u bjects 1st ra n d omise d 
t o / act ual treat me nt t o 
da pa glifl ozi n 5 m g
T ot al  Sa xa gli pti n
All s u bjects 1st ra n d omise d 
t o / act ual treat me nt 
sa xa gli pti n 2. 5 m g
Pl ace b o
All s u bjects 1st ra n d omise d 
t o / act ual treat me nt place b o
Tre at me nt re gi me n
B y  re gi me n o ut p uts:
Di s p ositio n , Efficac y
Da pa glifl ozi n 5 m g/ 1 0 m g
L o w/ hi g h d ose re gi me n 
da pa glifl ozi n
Da pa glifl ozi n 5 m g
L o w d ose re gi me n 
da pa glifl ozi n
Sa xa gli pt i n
2. 5 m g/ 5 m g
L o w/ hi g h d ose re gi me n 
sa xa gli pti n
Sa xa gli pt i n 2. 5 m g
L o w d ose re gi me n 
sa xa gli pti n
Pl ace b o
All s u bjects 1st ra n d omise d 
t o place b o
Sec o n d r a n d o mis ati o n ( Wee k 1 4)
U p -titratio n s u bjects a nal ysis 
set o ut p uts: Dis p ositi on, 
De m o gra p hics, Efficac y
Da pa glifl ozi n 5 m g
All s u bjects ra n d omise d at 
Wee k 1 4 t o re mai n o n 
da pa glifl ozi n 5 m g
Da pa glifl ozi n 1 0 m g
All s u bjects ra n d omise d at 
Wee k 1 4 t o u p -titrate t o 
da pa glifl ozi n 1 0 m g
Sa xa gli pt i n 2. 5 m g
All s u bjects ra n d omise d at 
Wee k 1 4 t o re mai n o n 
sa xa gli pti n 2. 5 m g
Sa xa gli pt i n 5 m g
All s u bjects ra n d omise d at 
Wee k 1 4 t o u p -titrate t o 
sa xa gli pti n 5 m g
T hir d r a n d o mis ati o n ( Wee k 3 2 or 4 0)
Ra n d o mise d wit h dra wal
s u bjects a nal ysis set o ut p uts: 
Di s p ositio n , D e mo gra p hics, 
Efficac y, Safet y


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 3
Tre at me nt l a bel
E x pl a n ati o n
A n al ysis p ur p ose
Da pa glifl ozi n 1 0 m g 
m o n ot hera p y
All s u bjects ra n d omise d at 
Wee k 3 2/ 4 0 t o wit h dra w 
bac k gr o u n d metf or mi n a n d 
eit her u p-titrate t o 
da pa glifl ozi n 1 0 m g (if 
pre vi o usl y ra n d o mise d t o 
da pa glifl ozi n 5 m g) or t o sta y  
o n da pa glifl ozi n 1 0 m g (if 
pre vi o usl y u p -titr atio n 
ra n d omise d t o hi g h -d ose) or 
s witc h fr o m place b o t o 
da pa glifl ozi n 1 0 m g
Da pa glifl ozi n 5 m g or 1 0 m g 
+ Metf or mi n
All 1 st ra n d omisat i on 
da pa glifl ozi n s u bjects 
ra n d omise d at Wee k 3 2/ 4 0 
t o re mai n o n bac k gr o u n d 
met f or mi n
Sa xa gli pt i n 5 m g 
m o n ot hera p y
All s u bjects ra n d omise d at 
Wee k 3 2/ 4 0 t o wit h dra w 
bac k gr o u n d metf or mi n a n d 
eit her u p-titrate t o 
sa xa gli pti n 5 m g (if 
pre vi o usl y ra n d o mise d t o 
sa xa gli pti n 2. 5 m g) or t o sta y  
o n sa xa gli pt i n 5 m g (if 
pre vi o usl y u p -titr atio n 
ra n d omise d t o hi g h -d ose) or 
s wit c h fr o m place b o t o 
sa xa gli pti n 5 m g
Sa xa gli pt i n
2 . 5 mg or 5 m g + Metf or mi n
All 1 st ra n d omisat i on 
sa xa gli pti n s u bjects 
ra n d omise d at Wee k 3 2/ 4 0 
t o re mai n o n bac k gr o u n d 
met f or mi n
Pl ace b o + Metf or mi n
All 1 st ra n d omisat i on 
pl ace b o s u bjects ra n d o mise d 
at Wee k 3 2/ 4 0 t o re mai n o n 
bac k gr o u n d metf or mi n
L ast r a n d o mise d/ act u al tre at me nt
Di s p ositio n , D e mo gra p hics, 
S af et y
Da pa glifl ozi n 1 0 m g 
m o n ot hera p y
All s u bjects w h ose last 
ra n d omise d/act ual treat me nt 
was da pa glifl ozi n a n d t he 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 4
Tre at me nt l a bel
E x pl a n ati o n
A n al ysis p ur p ose
s u bject was ra n d o mise d t o 
wi t hdra w bac k gr o u n d 
met f or mi n
Da pa glifl ozi n 5 m g or 1 0 m g
All s u bjects w h ose last 
ra n d omise d/act ual treat me nt 
was da pa glifl ozi n a n d t he 
s u bject re mai ne d o n 
bac k gr o u n d metf or mi n (if 
eli gi ble f or t hir d 
ra n d omisat i on)
Sa xa gli pt i n 5 m g 
m o n ot hera p y
All s u bjects w h ose last 
ra n d omise d/act ual treat me nt 
was sa xa gli pt i n a n d t he 
s u bject was ra n d o mise d t o 
wi t hdra w bac k gr o u n d 
met f or mi n
Sa xa gli pt i n 2. 5 m g or 5 m g
All s u bjects w h ose last 
ra n d omise d/act ual treat me nt 
was sa xa gli pt i n a n d t he 
s u bject re mai ne d o n 
bac k gr o u n d metf or mi n (if 
eli gi ble f or t hir d 
ra n d omisat i on)
Pl ace b o
All s u bjects w h ose last 
ra n d omise d/act ual treat me nt 
was pl ace b o a n d t he s u bject 
r e mai ne d o n bac k gr o u n d 
met f or mi n (if eli gi ble f or 
t hir d ra n d o misati on)
D ose at o nset / act u al d ose a n d tre at me nt t a ke n
D ose at o nset o ut p uts: Safet y 
(e x p os ure, A Es, la bs)
Da pa glifl ozi n 5 m g
All s u bjects o n da pa glifl ozi n 
5 m g per treat m e nt 
assi g n me nts i n Secti o n  4. 1. 6
Da pa glifl ozi n 1 0 m g
All s u bjects o n da pa glifl ozi n 
1 0 m g per treat m e nt 
assi g n me nts i n Secti o n  4. 1. 6
T ot al  Da pa glifl ozi n
All s u bjects w h o t o o k 
Da pa glifl ozi n base d o n all 
t hree ra n d o misati o ns
Sa xa gli pt i n 2. 5 m g
All s u bjects o n sa xa gli pti n 
2. 5 m g per treat m e nt 
assi g n me nts i n Secti o n  4. 1. 6


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 5
Tre at me nt l a bel
E x pl a n ati o n
A n al ysis p ur p ose
Sa xa gli pt i n 5 m g
All s u bjects o n sa xa gli pti n 
5 m g per treat m e nt 
assi g n me nts i n Secti o n  4. 1. 6
T ot al  Sa xa gli pti n
All s u bjects w h o t o o k 
Sa xa gli pt i n base d o n all 
t hree ra n d o misati o ns
Pl ace b o
All s u bjects o n place b o per 
treat me nt assig n me nts i n 
Secti o n  4. 1. 6
Hi g hest d ose t a ke n i n S T peri o d
P K o ut p uts
Da pa glifl ozi n 5 m g
All s u bjects w h ose hi g hest 
act ual d ose i n t he S T peri o d 
was da pa glifl ozi n 5 m g
Da pa glifl ozi n 1 0 m g
All s u bjects w h ose hi g hest 
act ual d ose i n t he S T peri o d 
was da pa glifl ozi n 1 0 m g 
Sa xa gli pt i n 2. 5 m g
All s u bjects w h ose hi g hest 
act ual d ose i n t he S T peri o d 
was sa xa gli pti n 2. 5 m g
Sa xa gli pt i n 5 m g
All s u bjects w h ose hi g hest 
act ual d ose i n t he S T peri o d 
was sa xa gli pti n 5 m g
8. 1 4
O ver vie w of pri m ar y a n d se nsiti vit y effic ac y a n al yses
T a ble 2 3 O ver vie w of pri m ar y a n d se nsiti vit y effic ac y a n al yses
S u b gr o u p i ncl u des race, et h nicity, se x, a ge gr o u p usi n g t he ra n d omisati o n strata , ge o gra p hical 
r e gio n, baseli ne a nt i dia betic treat me nt, baseli ne H b A 1c, baseli ne B MI.
S h ort ter m peri o d


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 6
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
H b A 1c 
C ha n ge 
fr om 
baseli ne t o 
Wee k 2 6
P 1, pri m ar y
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 1, pri m ar y
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 2, pri m ar y
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 9, pri m ar y
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset
P 1, 
s u p p orti ve
Fi g ure L S 
mea ns b y 
visit u p t o 
Wee k 2 6
MI f o ll owe d 
b y A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 1, 
s u p p orti ve
Fi g ure L S 
mea ns b y 
visit u p t o 
Wee k 2 6
MI f o ll owe d 
b y wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 2, S A 1
Pri or resc ue 
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 9, S A 1
Pri or resc ue 
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
A N C O V A
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset
P 1, S A 1
Pri or resc ue 
or 
S 1, S A 1
Pri or resc ue 
or 
S 2, 
s u b p o p ul ati o
n
S 9, 
s u b p o p ul ati o
n


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 7
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
di sc o nti n uati
o n
MI ( M A R) 
f oll owe d b y 
A N C O V A
Ra n d o mise d 
S u bjects 
Dataset
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R 
U p -titratio n 
Ra n d o mise d 
S u bjects 
Dataset
P 1, S A 2
Pri or resc ue 
or 
di sc o nti n uati
o n or R P D 
o nset
MI ( M A R) 
f oll owe d b y 
A N C O V A
E val ua ble 
S u bjects 
Dataset
S 1, 
s u b gr o u p 
a n al ysis
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R 
Ra n d o mise d 
S u bjects 
Dataset
P 1, S A 3
Ti p pi n g p oi nt 
a nal ysis
S 1, 
s u b p o p ul ati o
n


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 8
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
MI f o ll owe d 
b y A N C O V A 
(sa me as P 1)
Ra n d o mise d
S u bjects 
Dataset
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R 
Ra n d o mise d 
S u bjects 
Dataset
P 1, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
P 1, 
s u b gr o u p 
a n al ysis
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 4 9
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
Ra n d o mise d
S u bjects 
Dataset
P r o p ortio n
of  s u bjects 
wi t 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 2 6
S 6, pri m ar y
MI f o ll owe d 
b y L o gi stic 
re gressi o n
I T T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 7, pri m ar y
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
I T T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 8, pri m ar y
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
I T T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 1 1, 
pri m ar y
MI f o ll owe d 
b y l ogist ic 
re gressi o n
I T T esti ma n d 
M N A R
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset
S 6, S A 1
Re gar dless of 
baseli ne 
val ue
MI f o ll owe d 
b y L o gi stic 
re gressi o n
I T T esti ma n d
S 7, S A 1
Re gar dless of 
baseli ne 
val ue
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
I T T esti ma n d
S 8, S A 1
Re gar dless of 
baseli ne 
val ue
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
I T T esti ma n d


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 0
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
Ra n d o mise d
S u bjects 
Dataset
Ra n d o mise d
S u bjects 
Dataset
Ra n d o mise d
S u bjects 
Dataset
S 6, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y L o gi stic 
re gressi o n
I T T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 7, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
I T T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 8, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y wei g hte d 
L o gist ic 
re gressi o n
IT T esti ma n d
Ra n d o mise d
S u bjects 
Dataset
S 1 1, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y l ogist ic 
re gressi o n
I T T esti ma n d 
M N A R
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset
F P G
C ha n ge 
fr om 
baseli ne t o 
Wee k 2 6
S 3, pri m ar y
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 4, pri m ar y
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 5, pri m ar y
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mise d
S u bjects 
Dataset
S 1 0, 
pri m ar y
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
U p -titratio n 
Ra n d o mise d


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 1
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
S u bjects 
Dataset
S 3, 
s u p p orti ve
Fi g ure L S 
mea ns b y 
visit u p t o 
Wee k 2 6
MI f o ll owe d 
b y A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 4, 
s u p p orti ve
Fi g ure L S 
mea ns b y 
visit u p t o 
Wee k 2 6
MI f o ll owe d 
b y wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 5, S A 1
Pri or resc ue 
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 1 0, S A 1
Pri or resc ue 
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
A N C O V A
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset
S 3, S A 1
Pri or resc ue
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 4, S A 1
Pri or resc ue 
or 
di sc o nti n uati
o n
MI ( M A R)
f oll owe d b y 
wei g hte d 
A N C O V A
Ra n d o mise d
S u bjects 
Dataset
S 5, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y wei g hte d 
A N C O V A
I T T esti ma n d 
M N A R
Ra n d o mi se d
S u bjects 
Dataset
S 1 0, 
s u b p o p ul ati o
n
MI f o ll owe d 
b y A N C O V A
I T T esti ma n d 
M N A R
U p -titratio n 
Ra n d o mise d
S u bjects 
Dataset


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 2
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
Gl yc ae mic 
resc ue 
me dic ati o n 
or 
disc o nti n ui
n g st u d y 
me dic ati o n 
d ue t o l ac k 
of effic ac y
Pr o p orti o n 
of  s u bjects
E 1
L o gist ic 
re gressi o n
Ra n d o mise d 
S u bjects 
Dataset
E 1, 
s u b p o p ul ati o
n
L o gist ic 
re gressi o n
Ra n d o mise d 
S u bjects 
Dataset
Ti me t o 
Gl ycae mic 
resc ue 
me dicat i on 
or 
di sc o nti n ui
n g st u d y  
me dicat i on 
E 2
C o x 
pr o p orti o nal 
hazar ds
Ra n d o mise d 
S u bjects 
Dataset


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 3
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
d ue t o l ac k 
of  efficac y
E 2
Ka pla n -
Meier
Ra n d o mise d 
S u bjects 
Dataset
E 2, 
s u b p o p ul ati o
n
C o x 
pr o p orti o nal 
hazar ds
Ra n d o mise d 
S u bjects 
Dataset
E 2, 
s u b p o p ul ati o
n
Ka pla n -
Meier
Ra n d o mise d 
S u bjects 
Dataset


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 4
P ar a meter
Assess me nt
O ver all dr u g 
tre at me nt 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -
d ose / Hi g h-
d ose
re gi me n 
d a p a glifl ozi n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose 
re gi me n 
d a p a glifl oz i n 
( or 
s a x a gli pti n) 
vs pl ace b o
L o w -d ose vs 
hi g h -d ose 
d a p a glifl ozi n 
( or 
s a x a gli pti n)
Perce nta ge 
of  s u bjects 
w h o i nit iate
resc ue 
me dicat i on
E 2, 
s u p p orti ve
Descri pt i ve 
statistics
Ra n d o mise d 
S u bjects 
Dataset
E 2, 
s u b p o p ul ati o
n
Descri pt i ve 
statistics
Ra n d o mise d 
S u bjects 
Dataset
P = Pri mar y. S = Sec o n dar y . S A = Se nsitivit y A nal ysis. E = E x pl orat or y .
S u b p o p ul at i on: s u b gr o u p of s u bjects o n bac k gr o u n d me dicat i on met f or mi n +/- i ns uli n.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 5
S h ort ter m + l o n g ter m peri o d
P ar a meter
Assess me nt
O ver all dr u g tre at me nt [ d a p a glifl ozi n or s a x a gli pti n] vs 
pl ace b o
Wit h o ut c o nsi deri n g t he 
t hir d r a n d o mis ati o n ( u p 
t o Wee k 5 2)
E xcl u di n g s u bjects 
r a n d o mise d t o wit h dr a w al
( u p t o Wee k 5 2)
H b A 1c
Mea n c ha n ge 
fr om 
baseli ne t o 
Wee k 5 2
E 3
MI M A R f o ll owe d b y 
A N C O V A
Ra n d o mise d S u bjects 
Dataset
E 3, s u p p orti ve
MI M A R f o ll owe d b y 
wei g hte d A N C O V A
Ra n d o mise d S u bjects Dataset 
e xcl u di n g s u bjects 
ra n d omise d t o wit hdra wal
E 3, s u p p orti ve
Li ne pl ot b y  visit
MI M A R f o ll owe d b y 
A N C O V A
Ra n d o mise d S u bjects 
Dataset
Pr o p orti o n of  
s u bjects w h o 
ha d baseli ne 
≥7 % w h o 
ac hie ve a n 
H b A 1c le vel 
< 7 % at 
Wee k 5 2
E 4
MI M A R f oll owe d b y 
l ogist ic re gressi on
Ra n d o mise d S u bjects 
Dataset
E 4, s u p p orti ve
MI M A R f o ll owe d b y 
l ogist ic re gressi on
Ra n d o mise d S u bjects Dataset 
e xcl u di n g s u bjects 
ra n d omise d t o wit hdra wal
F P G
Mea n c ha n ge 
fr om 
E 3
E 3, s u p p orti ve


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 6
P ar a meter
Assess me nt
O ver all dr u g tre at me nt [ d a p a glifl ozi n or s a x a gli pti n] vs 
pl ace b o
Wit h o ut c o nsi deri n g t he 
t hir d r a n d o mis ati o n ( u p 
t o Wee k 5 2)
E xcl u di n g s u bjects 
r a n d o mise d t o wit h dr a w al
( u p t o Wee k 5 2)
baseli ne at 
Wee k 5 2
MI M A R f o ll owe d b y 
A N C O V A b y visit
Ra n d o mise d S u bjects 
Dataset
MI M A R f o ll owe d b y 
wei g hte d A N C O V A
Ra n d o mise d S u bjects Dataset 
e xcl u di n g s u bjects 
ra n d omise d t o wit hdra wal
E 3, s u p p orti ve
Li ne pl ot b y  visit
MI M A R f o ll owe d b y 
A N C O V A
Ra n d o mise d S u bjects 
Dataset
Gl yc ae mic
resc ue 
me dic ati o n 
or 
disc o nti n ui n g 
st u d y 
me dic ati o n 
d ue t o l ac k of 
effic ac y
Pr o p orti o n of  
s u bjects at 
Wee k 5 2
E 1
L o gist ic re gressi on
Ra n d o mise d S u bjects 
Dataset
Ti me t o 
Gl ycae mic
resc ue 
me dicat i on 
or 
E 2
C o x pr o p orti o nal hazar ds


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 7
P ar a meter
Assess me nt
O ver all dr u g tre at me nt [ d a p a glifl ozi n or s a x a gli pti n] vs 
pl ace b o
Wit h o ut c o nsi deri n g t he 
t hir d r a n d o mis ati o n ( u p 
t o Wee k 5 2)
E xcl u di n g s u bjects 
r a n d o mise d t o wit h dr a w al
( u p t o Wee k 5 2)
di sc o nti n ui n g 
st u d y 
me dicat i on 
d ue t o l ac k 
of  efficac y
Ra n d o mise d S u bjects 
Dataset
E 2
Ka pla n -Meier
Ra n d o mise d S u bjects 
Dataset
Perce nta ge 
of  s u bjects 
w h o i nit iate 
resc ue 
me dicat i on at 
Wee k 5 2
E 2, s u p p orti ve
Descri pt i ve statistics
Ra n d o mise d S u bjects 
Dataset
E 2, s u b p o p ul ati o n
Descri pt i ve statistics
Ra n d o mise d S u bjects 
Dataset
E = E x pl or at or y .
S u b p o p ul at i on: s u b gr o u p of s u bjects o n bac k gr o u n d me dicat i on met f or mi n +/- i ns uli n.


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 8
R a n d o mise d w it h dr a w al peri o d
P ar a meter
Assess me nt
F or s u bjects i niti all y 
r a n d o mise d t he 
d a p a glifl ozi n ( or 
s a x a gli pti n) gr o u p:
D a p a glifl ozi n ( or 
s a x a gli pti n) vs 
D a p a glifl ozi n ( or 
s a x a gli pti n) + Metf or mi n
F or s u bjects i niti all y 
r a n d o mise d t o t he pl ace b o 
gr o u p: 
Hi g h -d os e d a p a glifl ozi n 
( or s a x a gli pti n) vs Pl ace b o 
+ Metf or mi n
H b A 1c
Mea n c ha n ge 
fr om 
wi t hdra wal  
baseli ne t o 
Wee k 5 2
E 5
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E 5
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
Perce nta ge 
of  s u bjects 
w h o ac hie ve 
a n H b A 1c 
le vel < 7 % at 
Wee k 5 2
E 5, s u p p orti ve
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E 5, s u p p orti ve
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
F P G
Mea n c ha n ge 
fr om 
wi t hdra wal  
baseli ne t o 
Wee k 5 2
E 5
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E 5
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 5 9
P ar a meter
Assess me nt
F or s u bjects i niti all y 
r a n d o mise d t he 
d a p a glifl ozi n ( or 
s a x a gli pti n) gr o u p:
D a p a glifl ozi n ( or 
s a x a gli pti n) vs 
D a p a glifl ozi n ( or 
s a x a gli pti n) + Metf or mi n
F or s u bjects i niti all y 
r a n d o mise d t o t he pl ace b o 
gr o u p: 
Hi g h -d os e d a p a glifl ozi n 
( or s a x a gli pti n) vs Pl ace b o 
+ Metf or mi n
Gl yc ae mic
resc ue 
me dic ati o n 
or 
disc o nti n ui n g 
st u d y 
me dic ati o n 
d ue t o l ac k of 
effic ac y
Ti me t o 
Gl ycae mic
resc ue 
me dicat i on 
or 
di sc o nti n ui n g 
st u d y 
me dicat i on 
d ue t o l ac k 
of  efficac y
E 5, s u p p orti ve
Ka pla n -Meier
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E 5, s u p p orti ve
Ka pla n -Meier
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
Perce nta ge 
of  s u bjects 
w h o i nit iate 
resc ue 
me dicat i on at 
Wee k 5 2
E 5, s u p p orti ve
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E 5, s u p p orti ve
Descri pt i ve statistics
N o i m p ut ati o n
Ra n d o mise d Wit h dra wal  
S u bjects Dataset
E = E x pl or at or y .


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 0
8. 1 5
O ver vie w of pri m ar y a n d se nsiti vit y s afet y a n al yses
T a ble 2 4 O ver vie w of pri m ar y a n d se nsiti vit y s afet y a n al yses


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 1
S u b gr o u p i ncl u des race, et h nicity, se x, a ge gr o u p usi n g t he ra n d omisati o n strata , re gi o n, baseli ne a nti dia betic treat me nt, baseli ne 
H b A 1c, baseli ne B MI.
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
A Es
O verall A Es
Descri pti ve statistics + 
i nci de nce rates
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics + 
i nci de nce rates
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics + i nci de nce 
rates
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Se nsiti vit y
Descri pti ve statistics + 
i nci de nce rates
Pri o r t o resc ue
Treate d S u bjects Data Set
Se nsiti vit y
Descri pti ve statistics + 
i nci de nce rates
Pri o r t o resc ue
Treate d S u bjects Data 
Set
Se nsiti vit y
Descri pti ve statistics + i nci de nce 
rates
Pri o r t o resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi m e ns 1, 2 a n d 3
U p t o Wee k 3 2
Descri pti ve statistics + 
i nci de nce rates
Re gar dless of resc ue


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 2
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Treate d S u bjects Data 
Set
E xcl u di n g s u bjects 
r a n d o mise d t o 
wit h dr a w al
Wei g hte d a nal ysis
Treate d S u bjects Data 
Set
S u b gr o u p
Descri pti ve statistics + 
i nci de nce rates
Re gar dless of resc ue
Treate d S u bjects Data 
Set
S u b gr o u p -
Se nsiti vit y
Descri pti ve statistics + 
i nci de nce rates
Pri o r t o resc ue
Treate d S u bjects Data 
Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 3
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
S u b p o p ul ati o n
Descri pti ve statistics + 
i nci de nce rates
Re gar dless of resc ue
Treate d S u bjects Data 
Set
B y tre at me nt at o nset 
of A E
I nci de nce rates
Re gar dless of resc ue
Base d o n treat me nt 
recei ve d at o nset of A E
Treate d S u bjects Data 
Set
A n y  A E b y 
S O C + P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Descri pti ve 
statistics
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 4
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
Se nsiti vit y
Descri pti ve statistics 
Pri o r t o resc ue
Treate d S u bjects Data 
Set
U p t o Wee k 3 2
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
E xcl u di n g s u bjects 
r a n d o mise d t o 
wit h dr a w al
Descri pti ve statistics 
wei g hte d a nal ysis
Re gar dless of resc ue
Treate d S u bjects Data 
Set
S u b gr o u p [ O nl y f or s u b gr o u ps: a ge 
gr o u p, s e x, r ace, b aseli ne a nti di a betic 
tre at me nt]
S u b gr o u p [ O nl y f or 
s u b gr o u ps: a ge gr o u p, s e x, r ace, 
b aseli ne a nti di a betic tre at me nt]
S u b gr o u p [ O nl y f or s u b gr o u ps: age gr o u p, s e x, 
r ace, b aseli ne a nti di a betic tre at me nt]
Descri pti ve statistics


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 5
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
S u b p o p ul ati o n
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
S u b p o p ul ati o n
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
S u b p o p ul ati o n
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
B y tre at me nt at o nset 
of A E
I nci de nce rates
Re gar dless of resc ue
Base d o n treat me nt 
recei ve d at o nset of A E
Treate d S u bjects Data 
Set
A n y  A E b y 
S O C, P T a n d 
Descri pti ve statistics
Re gar dless of resc ue
Descri pti ve statistics
Re gar dless of resc ue
Descri pti ve statistics
Re gar dless of resc ue


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 6
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
ma xi m u m 
i nte nsit y
Treate d S u bjects Data Set
Treate d S u bjects Data 
Set
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
A n y  A E relate d 
t o st u d y dr u g b y 
S O C a n d P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
A n y  A E b y 
S O C a n d P T f or 
c o m m o n P Ts 
> 5 %
Descri pti ve statistics + 
n u m ber of e ve nts
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics + 
n u m ber of e ve nts
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics + n u m ber of 
e ve nts
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
S u b p o p ul ati o n
Descri pti ve statistics + 
n u m ber of e ve nts
Re gar dless of resc ue
Treate d S u bjects Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 7
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
A n y  n o n-seri o us 
A E b y  S O C a n d 
P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Lea di n g t o 
disc o nti n uati o n 
of st u d y 
me dicati o n
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data 
Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
A E O SI b y P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 8
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
S A Es
A n y  S A E b y 
S O C a n d P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Descri pti ve 
statistics
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data 
Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
U p t o Wee k 3 2
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
B y tre at me nt at o nset 
of A E
Descri pti ve statistics


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 6 9
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Re gar dless of resc ue
Base d o n treat me nt 
recei ve d at o nset of A E
Treate d S u bjects Data 
Set
A n y  S A E 
relate d t o st u d y 
dr u g b y S O C 
a n d P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
A n y  S A E
lea di n g t o 
disc o nti n uati o n 
of st u d y 
me dicati o n b y 
S O C a n d P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1, 2 a n d 3
Descri pti ve 
statistics
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set
A m p ut ati o n
A n y  
a m p utati ons
Descri pti ve statistics
Re gar dless of resc ue


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 0
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Treate d S u bjects Data 
Set
A dj u dic ate d D K A
A n y  a dj u dicate d 
D K A e ve nts b y 
a dj u dicati o n 
cate g or y
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1 a n d 2
A n y  a dj u dicate d 
D K A e ve nts, 
si g ns, s ym pt o ms 
a n d ris k fact ors 
b y a dj u dicati o n 
cate g or y
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1 a n d 2
A n y  a dj u dicate d 
D K A e ve nts 
lea di n g t o 
disc o nti n uati o n 
b y a dj u dicati o n 
cate g or y 
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 1
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
A n y  seri o us 
a dj u dicate d 
D K A e ve nts b y 
a dj u dicati o n 
cate g or y a n d P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me ns 1 a n d 2
H y p o gl yc ae mi a
A n y  
h y p o gl ycae mic
e ve nts
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
F or tre at me nt re gi me n s 1, 2, a n d 3
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data 
Set
U p t o Wee k 3 2
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 2
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
U p t o Wee k 3 2, 
Se nsiti vit y
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data 
Set
La bs
La b tests o ver 
ti m e
O bser ve d a n d c ha n ge 
fr o m baseli ne
Re gar dless of resc ue
Treate d S u bjects Data 
Set
O bser ve d a n d c ha n ge fr o m baseli ne
Re gar dless of resc ue
Ra n d o mise d S u bjects Data Set
F or tre at me nt re gi me ns 1 a n d 2
U p t o Wee k 3 2
Descri pti ve statistics
O bser ve d a n d c ha n ge 
fr o m baseli ne
Re gar dless of resc ue
Treate d S u bjects Data 
Set
S hift ta ble
Base d o n L O C F val ues
S hift ta ble
Base d o n L O C F val ues


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 3
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Treate d S u bjects Data Set
Treate d S u bjects Data 
Set
e G F R o ver ti me 
b y a ge gr o u p
O bser ve d a n d c ha n ge 
fr o m baseli ne
Re gar dless of resc ue
Treate d S u bjects Data 
Set
O bser ve d a n d c ha n ge fr o m baseli ne
Re gar dless of resc ue
Ra n d o mise d S u bjects Data Set
F or tre at me nt re gi me ns 1 a n d 2
Ele vate d li ver 
f u ncti o n tests
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d S u bjects Data Set
F or tre at me nt re gi me ns 1 a n d 2
He patic A Es b y  
P T
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d S u bjects Data Set
F or tre at me nt re gi me ns 1 a n d 2
M A la bs
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
I nci de nce rate
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data Set
F or tre at me nt re gi me n 1, 2 a n d 3
Se nsiti vit y
Se nsiti vit y
Se nsiti vit y


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 4
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
Descri pti ve statistics
I nci de nce rate
Pri o r t o resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Pri o r t o resc ue
Treate d S u bjects Data Set
F or tre at me nt re gi me n 1, 2 a n d 3
U p t o Wee k 3 2
Descri pti ve statistics
Treate d S u bjects Data 
Set
E xcl u di n g s u bjects 
r a n d o mise d t o 
wit h dr a w al
Wei g hte d a nal ysis
Re gar dless of resc ue
Treate d S u bjects Data 
Set
B y tre at me nt at o nset 
of M A
I nci de nce rates
Re gar dless of resc ue


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 5
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Base d o n treat me nt 
recei ve d at o nset of 
M A
Treate d S u bjects Data 
Set
Fasti n g li pi d 
pa nel
O bser ve d a n d c ha n ge 
fr o m baseli ne
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Vit al si g ns
Vital si g ns o ver 
ti m e
O bser ve d a n d c ha n ge 
fr o m baseli ne
Re gar dless of resc ue
Treate d S u bjects Data 
Set
O bser ve d a n d c ha n ge fr o m baseli ne
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
E C G
E C Gs 
i nter pretati o n 
o ver ti me
Descri pti ve statistics
Re gar dless of resc ue
Base d o n L O C F val ues


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 6
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Treate d S u bjects Data 
Set
E xcl u di n g s u bjects 
r a n d o mise d t o 
wit h dr a w al
Descri pti ve statistics
Wei g hte d a nal ysis
Re gar dless of resc ue
Base d o n L O C F val ues
Treate d S u bjects Data 
Set
B o d y wei g ht, 
hei g ht a n d B MI
B o d y wei g ht, 
hei g ht a n d B MI 
(i ncl u di n g 
n or malise d
val ues) o ver 
ti m e
Descri pti ve statistics
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Descri pti ve 
statistics
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 7
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Me as ures of 
gr o wt h a n d 
m at urit y
Ta n ner sta ges
Descri pti ve statistics
Base d o n L O C F val ues 
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Base d o n L O C F val ues 
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Descri pti ve 
statistics
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Base d o n L O C F
val ues Re gar dless 
of resc ue
Treate d S u bjects 
Data Set
S hift ta ble fr o m baseli ne t o 
Wee k 2 6
Re gar dless of resc ue
Treate d S u bjects Data Set
S hift ta ble fr o m 
baseli ne t o Wee k 5 2
Base d o n L O C F val ues 
Re gar dless of resc ue
Treate d S u bjects Data 
Set
S hift ta ble fr o m wit h dra wal 
baseli ne t o Wee k 5 2
Base d o n L O C F val ues Re gar dless 
of resc ue
Treate d S u bjects Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
S hift ta ble fr o m 
baseli ne t o Wee k 
1 0 4
Base d o n L O C F
val ues Re gar dless 
of resc ue
Treate d S u bjects 
Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 8
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Cate g orical c ha n ge 
fr o m Wee k 2 6 t o Wee k 
5 2 b y  baseli ne stat us
Base d o n L O C F val ues 
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Cate g orical c ha n ge fr o m 
wit h dra wal baseli ne t o Wee k 5 2 b y 
baseli ne stat us
Base d o n L O C F val ues 
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Cate g orical c ha n ge 
fr o m Wee k 5 2 t o 
Wee k 1 0 4 b y 
baseli ne stat us
Base d o n L O C F
val ues 
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set
E xcl u di n g s u bjects 
r a n d o mise d t o 
wit h dr a w al
Descri pti ve statistics
Wei g hte d a nal ysis
Base d o n L O C F val ues
Re gar dless of resc ue
Treate d S u bjects Data 
Set 


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 7 9
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
Gr o wt h a n d 
mat urit y 
mar kers
Descri pti ve statistics
Base d o n L O C F val ues 
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Base d o n L O C F val ues
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Descri pti ve 
statistics
Re gar dless of 
resc ue
Base d o n L O C F
val ues
Treate d S u bjects 
Data Set
Cate g orical c ha n ge fr o m 
wit h dra wal baseli ne b y a ge a n d 
p u bert y stat us
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Cate g orical c ha n ge 
fr o m baseli ne b y 
a ge a n d p u bert y 
stat us
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 8 0
P ar a meter
Assess me nt
S h ort ter m peri o d
S h ort ter m + L o n g 
ter m peri o d
Wit h dr a w al peri o d:
1)
F or s u bjects i niti all y r a n d o mise d
t he d a p a glifl ozi n ( or s a x a gli pti n) 
gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Hi g h-d ose 
d a p a glifl ozi n ( or s a x a gli pti n) + 
Metf or mi n
2)
F or s u bjects i niti all y r a n d o mise d t o 
t he pl ace b o gr o u p:
Hi g h -d ose d a p a glifl ozi n ( or 
s a x a gli pti n) vs Pl ace b o + Metf or mi n
3)
B ase d o n t hir d r a n d o mis ati o n
(re g ar dless of pri or tre at me nts)
P ost -st u d y visit 
Wee k 1 0 4
B o ne 
bi o mar kers
Descri pti ve statistics
Base d o n L O C F val ues 
Re gar dless of resc ue
Treate d S u bjects Data 
Set
Descri pti ve statistics
Re gar dless of resc ue
Base d o n L O C F val ues
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Descri pti ve 
statistics
Re gar dless of 
resc ue
Base d o n L O C F
val ues
Treate d S u bjects 
Dat a Set
Cate g orical c ha n ge fr o m 
wit h dra wal baseli ne b y a ge a n d 
p u bert y stat us
Re gar dless of resc ue
Ra n d o mise d Wit h dra wal S u bjects 
Data Set
Tre at me nt re gi me ns 1 a n d 2
S h ort ter m + L o n g 
ter m + Wee k 1 0 4: 
Cate g orical c ha n ge 
fr o m baseli ne b y 
a ge a n d p u bert y 
stat us
Re gar dless of 
resc ue
Treate d S u bjects 
Data Set


Statistical A nal ysis Pla n 
St u d y C o de C V 1 8 1 3 7 5/ D 1 6 8 0 C 0 0 0 1 9
E diti o n N u m ber 5. 0
Date 0 7 D E C 2 0 2 2
1 8 1
S u b p o p ul at i on: s u b gr o u p of s u bjects o n bac k gr o u n d me dicat i on met f or mi n +/- i ns uli n.

Prot_000.pdf: 
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.