Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 518
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate the superiority of Sotagliflozin versus placebo on hemoglobin A1c (HbA1c) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control with metformin.

Secondary Objectives:

* To compare Sotagliflozin versus placebo for.
* Change from baseline in 2-hour postprandial glucose (PPG) following a mixed meal.
* Change from baseline in fasting plasma glucose (FPG).
* Change from Baseline in systolic blood pressure (SBP) for participants with baseline SBP ≥130 millimeter of mercury (mmHg).
* Change from baseline in SBP for all participants.
* Change from baseline in body weight.
* Proportion of participants with HbA1c \<6.5% and \<7.0%.
* To evaluate the safety of Sotagliflozin versus placebo.

Detailed description:
The duration of the study period is up to 87 weeks, including a Screening Period consisting of a Screening phase of up to 2 weeks and a 2 week single blind Run-in phase, a 26 week double-blind Core Treatment Period, a 53-week double-blind Extension Period, a 4 week post treatment Follow-up period to collect safety information.

Arms:
arm 1: Following a 2-week run-in period, sotagliflozin 400 mg was administered as 2 tablets, once daily, before the first meal of the day plus metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks. arm 2: Following a 2-week run-in period, matching placebo was administered as 2 tablets, once daily, before the first meal of the day plus metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Interventions: intervention 1: Sotagliflozin (SAR439954) intervention 2: Placebo intervention 3: Metformin
Intervention descriptions: intervention 1: Pharmaceutical form: tablet. Route of administration: oral. intervention 2: Pharmaceutical form: tablet. Route of administration: oral. intervention 3: Pharmaceutical form: tablet. Route of administration: oral.

Protocol document:
Prot_000.pdf: 
Offi ci al Titl e:  A  R a n d o miz e d,  D o u bl e -bli n d,  Pl a c e b o -c o ntr oll e d,  P ar all el -gr o u p, 
M ulti c e nt er St u d y  t o E v al u at e t h e Effi c a c y a n d S af et y of S ot a glifl ozi n 
A d d e d t o M etf or mi n i n P ati e nts  wit h T y p e 2 Di a b et es M ellit us W h o H a v e 
I n a d e q u at e Gl y c e mi c C o ntr ol o n M etf or mi n  
N C T N u m b er:  N C T 0 2 9 2 6 9 5 0  
D o c u m e nt  D at e : Pr ot o c ol  V er si o n 2:  2 1- De c e m b er - 20 1 7 


 
 
A ny a n d all i nf or m ati o n pres e nt e d i n t his d oc u m e nt s h all b e tre at e d as c o nfi d e nti al a n d s h all r e m ai n t h e excl usiv e pr o p erty of S a n ofi ( or a ny of its 
affili at e d c o m p a ni es). T h e us e of s uc h c o nfi d e nti al i nf or m ati o n m ust b e r e strict e d t o t h e reci pi e nt f or t h e a gre e d p urp os e a n d m ust n ot b e 
discl os e d, p u blis h e d or ot h er wis e c o m m u nic at e d t o a ny u n a ut h oriz e d p ers o ns, f or a ny r e as o n, i n a ny f or m w h ats o ev er wit h o ut t h e pri or writt e n 
c o ns e nt of S a n ofi (or t h e c o nc ern e d affili at e d c o m p a ny); ‘ affili ate d c o m p a ny’ m e a ns a ny c orp orati o n, p art n ers hi p or ot h er e ntit y w hic h at t h e d at e 
of c o m m u nic ati o n or aft er w ar ds (i) c o ntr ols dir ectly or i n dir ectly S a n ofi, (ii) is dir ectly or i n dir ectly c o ntr oll e d by S a n ofi,  wit h ‘c o ntr ol’ m e a ni n g 
dir ect or i n dir ect o w n ers hi p of m or e t h a n 5 0 % of t h e c a pit al st ock or t h e v oti n g ri g hts i n s uc h c or p or ati o n, p art n ers hi p or ot h er e ntity 
 
 
P a g e 1  
 
A M E N D E D C LI NI C A L T RI A L P R O T O C O L N O. 0 2 
 
C O M P O U N D: s ot a glifl o zi n/ S A R 4 3 9 9 5 4 
A R a n d o mi z e d, D o u bl e- bli n d, Pl a c e b o- c o ntr o ll e d, P ar all el- gr o u p, M ulti c e nt er St u d y 
t o E v al u at e t h e Effi c a c y a n d S af et y of S ot a glifl o zi n A d d e d t o M etf or mi n i n P ati e nt s 
wit h T y p e 2 Di a b et e s M ellit u s W h o H a v e I n a d e q u at e Gl y c e mi c C o ntr ol o n 
M etf or mi n 
S T U D Y N U M B E R: E F C 1 4 8 3 4 
S T U D Y N A M E: S O T A- M E T ( S O T A glif l o zi n a d d e d t o M E Tf or mi n) 
V E R SI O N D A T E / S T A T U S: A p pr o v al d at e ( 1 9- D e c- 2 0 1 7) / A p pr o v e d 
Pr ot o c ol A m e n d m e nt 0 2 
V er si o n n u m b er: 1 ( el e ctr o ni c 1. 0)  
D at e : 1 9- D e c- 2 0 1 7 
A m e n d e d Cli ni c al Tri al Pr ot o c ol 0 1  
V er si o n n u m b er: 1 ( el e ctr o ni c 1. 0)  
D at e : 2 4- A pr- 2 0 1 7 
Pr ot o c ol A m e n d m e nt 0 1 
V er si o n n u m b er: 1 ( el e ctr o ni c 1. 0)  
D at e : 2 4- A pr- 2 0 1 7 
Cli ni c al Tri al Pr ot o c ol 
V er si o n n u m b er: 1 ( el e ctr o ni c 1. 0)  
D at e : 2 7- J ul- 2 0 1 6 
E u dr a C T  
2 0 1 6- 0 0 1 8 0 0- 4 9 
I N D N u m b er( s) 
 
V er si o n N u m b er:  
1  
W H O u ni v er s al tri al n u m b er:  
U 1 1 1 1- 1 1 8 1- 6 1 4 5 
D at e: 
1 9- D e c- 2 0 1 7  
T ot al n u m b er of p a g e s:  
1 2 7 
 
 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 
N A M E S A N D A D D R E S S E S O F 
C O O R DI N A TI N G 
I N V E S TI G A T O R 
 
N a m e: 
A d dr e s s: 
 
 
T el: 
F a x: 
E- m ail: 
 
 
M O NI T O RI N G T E A M’ S 
R E P R E S E N T A TI V E 
 
N a m e: 
A d dr e s s: 
 
 
 
T el: 
F a x: 
E- m ail: 
 
 
S P O N S O R 
 
C o m p a n y: 
A d dr e s s: 
 
 
 
 
 
 
O T H E R E M E R G E N C Y 
T E L E P H O N E N U M B E R S 
 
 
 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 
C LI NI C A L T RI A L S U M M A R Y 
 
C O M P O U N D: s ot a g lifl o zi n/ S A R 4 3 9 9 5 4 
S T U D Y N o.: E F C 1 4 8 3 4 
TI T L E 
A R a n d o miz e d, D o u bl e- bli n d, Pl ac e b o-c o ntr oll e d, Par all el- gr o u p, 
M ultic e nt er St u dy t o Ev al u at e t h e Effic acy a n d Saf ety of Sot a glifl ozi n 
A d d e d t o M etf or mi n i n P ati e nts wit h Ty p e 2 Di a b et es M ellit us W h o 
H av e I n a d e q u at e Glyc e mic C o ntr ol o n M etf or mi n 
I N V E S TI G A T O R/ T RI A L L O C A TI O N 
M ulti n ati o n al 
P H A S E O F D E V E L O P M E N T 
3 
S T U D Y O B J E C TI V E S 
 
Pri m ar y o bj e cti v e: 
T h e pri m ary o bj ectiv e of t his st u d y is t o d e m o nstr at e t h e s u p eri ority 
of s ot a glifl ozi n 4 0 0 m g v ers us pl ac e b o o n h e m o gl o bi n A1c ( H b A 1c) 
r e d ucti o n at W e ek 2 6 i n p ati e nts with ty p e 2 di a b et es m ellit us ( T 2 D) 
w h o h av e i n a d e q u at e glyc e mic c o ntr ol wit h m etf or mi n.  
S e c o n d ar y o bj e cti v e s: 
•  
T o c o m p ar e s ot a glifl ozi n 4 0 0 m g v ers us pl ac e b o f or:  
- 
C h a n g e fr o m Bas eli n e i n 2- h o ur p ost pr a n di al gl uc os e 
( P P G) f oll o wi n g a mix e d m e al at W e ek 2 6 
- 
C h a n g e fr o m Bas eli n e i n f asti n g pl as m a gl uc os e 
( F P G) at W e ek 2 6 
- 
C h a n g e fr o m Bas eli n e i n b o dy w ei g ht at W e ek 2 6 
- 
C h a n g e fr o m Bas eli n e i n syst olic bl o o d pr ess ur e 
( S B P) at W e ek 1 2 f or p ati e nts wit h B as eli n e S B P 
≥1 3 0 m m H g  
- 
C h a n g e fr o m Bas eli n e i n S B P at W e ek 1 2 f or all 
p ati e nts 
- 
Pr o p orti o n of p ati e nts wit h H b A1c < 6. 5 %, < 7. 0 % at 
W e ek 2 6 
•  
T o ev al u at e t h e s af ety of s ot a glifl ozi n 4 0 0 m g v ers us 
pl ac e b o t hr o u g h o ut t h e 7 9- w e ek tri al 
Ot h er: 
•  
T o c o m p ar e s ot a glifl ozi n v ers us pl ac e b o wit h r es p ect t o 
c h a n g e fr o m Bas eli n e i n t h e f oll o wi n g e n d p oi nts: 
- 
Uri n e al b u mi n-cr e ati ni n e r ati o ( A C R) 
- 
Uri n ary gl uc os e excr eti o n ( U G E) a n d uri n e 
gl uc os e-cr e ati ni n e r ati o ( G C R) 
- 
Esti m at e d gl o m er ul ar filtr ati o n r at e ( e G F R) 
- 
R e d ucti o n i n b o dy w ei g ht by ≥2 %, ≥5 %, a n d ≥1 0 % 
•  
T o c o m p ar e s ot a glifl ozi n v ers us pl ac e b o f or: 
- 
C h a n g e fr o m Bas eli n e i n H b A1c at W e ek 7 9 
- 
C h a n g e fr o m Bas eli n e i n F P G at W e ek 7 9 
- 
C h a n g e fr o m Bas eli n e i n S B P at W e ek 2 6 f or all 
p ati e nts a n d f or p ati e nts wit h Bas eli n e S B P 
≥1 3 0 m m H g 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 
- 
C h a n g e fr o m Bas eli n e i n S B P at W e ek 7 9 f or all 
p ati e nts a n d f or p ati e nts wit h Bas eli n e S B P 
≥1 3 0 m m H g 
- 
C h a n g e fr o m Bas eli n e i n b o dy w ei g ht at W e ek 7 9 
•  
T o c o m p ar e t h e us e of r esc u e m e dic ati o ns f or 
hy p er glyc e mi a i n t h e s ot a glifl ozi n a n d pl ac e b o tr e at m e nt 
gr o u ps 
•  
T o ass ess pl as m a c o nc e ntr ati o ns of s ot a glifl ozi n a n d its 
3- O- gl uc ur o ni d e m et a b olit e 
A m b ul at ory Bl o o d Pre s s ure M o ni t ori n g ( A B P M) s u b st u d y 
A s u bst u dy will b e u n d ert ak e n t o m o nit or a m b ul at ory bl o o d pr ess ur e 
(i n a d diti o n t o all ot h er st u dy ass ess m e nts) i n a s u bs et of t h e t ot al 
st u dy p o p ul ati o n w h o h av e m e a n S B P ≥1 3 0 m m H g at Scr e e ni n g. 
T h e pri m ary o bj ectiv e of t h e s u bst u dy is t o c o m p ar e t h e eff ect of 
s ot a glifl ozi n v ers us pl ac e b o i n a s u bs et of p ati e nts wit h m e a n S B P 
≥1 3 0 m m H g at Scr e e ni n g o n 2 4- h o ur  av er a g e S B P at W e ek 1 2. 
T h e s ec o n d ary o bj ectiv es of t h e A B P M s u bst u dy ar e t o c o m p ar e t h e 
eff ect of s ot a glifl ozi n v ers us pl ac e b o i n a s u bs et of p ati e nts wit h 
m e a n S B P ≥1 3 0 m m H g at Scr e e ni n g o n t h e f oll o wi n g: 
•  
2 4- h o ur av er a g e S B P at W e ek 2 6  
•  
2 4- h o ur av er a g e di ast olic bl o o d pr ess ur e ( D B P) at 
W e eks 1 2 a n d 2 6 
•  
Av er a g e a dj ust e d a w ak e ti m e bl o o d pr ess ur e ( B P) as 
m e as ur e d by S B P a n d D B P at W e eks 1 2 a n d 2 6 wit h 
a dj ust m e nt b as e d o n acti gr a p hy  
•  
Av er a g e a dj ust e d sl e e pi n g ti m e B P as m e as ur e d by S B P 
a n d D B P at W e eks 1 2 a n d 2 6 wit h a dj ust m e nt b as e d o n 
acti gr a p hy  
S T U D Y D E SI G N 
T his is a Ph as e 3, m ultic e nt er, r a n d o miz e d, d o u bl e- bli n d, 
pl ac e b o-c o ntr oll e d, p ar all el- gr o u p st u dy t h at is a ntici p at e d t o e nr oll 
a p pr oxi m at ely 5 0 0 p ati e nts. 
Pati e nts t aki n g m etf or mi n at a st a bl e d os a g e ≥1 5 0 0 m g/ d ay f or at 
l e ast 1 2 w e eks b ef or e e nr oll m e nt will b e eli gi bl e f or scr e e ni n g. 
Pati e nts o n m etf or mi n at a d os e < 1 5 0 0 m g/ d ay at t h e ti m e of 
e nr oll m e nt (st a bl e d os e f or at l e ast 1 2 w e eks b ef or e e nr oll m e nt) m ay 
b e eli gi bl e f or scr e e ni n g if d oc u m e nt ati o n of l ack of t ol er a nc e of a 
m etf or mi n d os e ≥1 5 0 0 m g/ d ay c a n b e pr ovi d e d.  
All p ati e nts will h av e a Scr e e ni n g P e ri o d c o nsisti n g of a Scr e e ni n g 
p h as e of u p t o 2 w e eks a n d a 2- w e ek si n gl e- bli n d R u n-i n p h as e pri or 
t o r a n d o miz ati o n. I n or d er t o q u alify f or r a n d o miz ati o n, p ati e nts m ust 
d e m o nstr at e c o m pli a nc e b as e d u p o n t a bl et c o u nt ( ≥8 0 %) d uri n g t h e 
R u n-i n p h as e. 
R a n d o miz ati o n will b e str atifi e d by:  
•  
H b A1c at Scr e e ni n g ( ≤8. 0 %, > 8. 0 %) 
•  
S B P at Scr e e ni n g ( < 1 3 0 m m H g, ≥1 3 0 m m H g)  
F oll o wi n g r a n d o miz ati o n, p ati e nts will h av e a 2 6- w e ek, d o u bl e- bli n d 
C or e Tr e at m e nt Peri o d, a 5 3- w e ek d o u bl e- bli n d ext e nsi o n, a n d a 
4- w e ek p ost-tr e at m e nt F oll o w- u p visit t o c oll ect s af ety i nf or m ati o n. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 
All p ati e nts will h av e P P G ass ess e d f oll o wi n g a M M T T at W e eks 0, 
2 6, a n d 7 9. 
A t ot al of 5 0 0 p ati e nts ≥1 8 y e ars of a g e will b e r a n d o mly assi g n e d 
1: 1 t o 1 of t h e f oll o wi n g 2 tr e at m e nt gr o u ps: 
•  
Sot a glifl ozi n 4 0 0 m g as t w o 2 0 0 m g t a bl ets, o nc e d aily  
•  
Pl ac e b o as t w o pl ac e b o t a bl ets (i d e ntic al t o s ot a glifl ozi n i n 
a p p e ar a nc e), o nc e d aily 
H e m o gl o bi n A 1c, F P G, a n d P P G (fr o m M M T T ass ess m e nt) will b e 
m ask e d t o st u dy sit es a n d p ati e nts aft er r a n d o miz ati o n u ntil st u dy 
e n d. T o pr ev e nt p arti al u n bli n di n g, U G E a n d uri n e G C R r es ults will 
b e m ask e d t o st u dy sit es a n d p ati e nts. Ad diti o n ally, uri n alysis by 
di pstick will n ot i ncl u d e t h e m e as ur e m e nt of uri n e gl uc os e. Uri n e 
gl uc os e, al b u mi n, c alci u m a n d cr e ati ni n e will b e m e as ur e d 
s e p ar at ely at all o n-sit e visits by t h e c e ntr al l a b or at ory. 
A m b ul at or y Bl o o d Pr e s s ur e M o nit ori n g s u b st u d y: 
Ap pr oxi m at ely 2 0 0 of t h e 5 0 0 e nr oll e d p ati e nts w h o h av e a m e a n 
Scr e e ni n g S B P ≥1 3 0 m m H g ar e ex p ect e d t o p artici p at e i n a n A B P M 
s u bst u dy. A m b ul at ory bl o o d pr ess ur e will b e ass ess e d f or 2 4 h o urs 
d uri n g t h e R u n-i n p h as e, W e ek  1 2, a n d W e ek 2 6. F or e ac h 
ass ess m e nt, t h e p ati e nts p artici p ati n g i n t h e s u bst u dy will att e n d a 
s p eci al s u bst u dy Visit pri or t o t h e sc h e d ul e d visit ( 1 w e ek pri or t o 
R a n d o miz ati o n, a n d 1 d ay pri or t o W e ek 1 2 a n d W e ek 2 6 visits) t o 
h av e t h e A B P M d evic e a p pli e d, as i n dic at e d i n t h e St u dy Fl o w C h art. 
T h e p ati e nts will r et ur n t h e f oll o wi n g d ay f or t h e r e g ul arly sc h e d ul e d 
st u dy visit. 
E arl y t er mi n ati o n: 
If a p ati e nt disc o nti n u es tr e at m e nt wit h i nv esti g ati o n al m e dici n al 
pr o d uct (I M P) e arly d uri n g t h e 2 6- w e ek C or e Tr e at m e nt Peri o d, t h e 
p ati e nt will h av e a Pr e m at ur e E n d- of- Tr e at m e nt ( E O T) Visit a n d a 
F oll o w- u p Visit 4 w e eks aft er t h e l ast d os e of I M P. I n a d diti o n, ev ery 
eff ort will b e m a d e t o h av e all p ati e nts r et ur n t o t h e sit e at t h e ti m e 
c orr es p o n di n g t o t h eir sc h e d ul e d visits, p artic ul arly t h e W e ek 2 6 
Visit. 
P ati e nts p artici p ati n g i n t h e A B P M s u bst u dy will n ot b e r e q uir e d t o 
disc o nti n u e t h e s u bst u dy i n t h e ev e nt t h at t h ey p er m a n e ntly 
disc o nti n u e tr e at m e nt i n t h e m ai n st u dy. Ev ery eff ort s h o ul d b e m a d e 
t o e ns ur e t h at disc o nti n u e d p ati e nts c o m pl et e t h e A B P M s u bst u dy, if 
t h ey ar e willi n g a n d a bl e t o d o s o. 
If a p ati e nt c o m pl et es t h e C or e Tr e at m e nt, b ut disc o nti n u es I M P 
d uri n g t h e ext e nsi o n, t h e p ati e nt will h av e a Pr e m at ur e E O T Visit 
a n d a F oll o w- u p Visit 4 w e eks aft er t h e l ast d os e of I M P. I n a d diti o n, 
ev ery eff ort will b e m a d e t o h av e all p ati e nts r et ur n t o t h e sit e at t h e 
ti m e c orr es p o n di n g t o t h eir q u art erly visits (i e, ev ery 1 3 w e eks) 
d uri n g t h e Ext e nsi o n Peri o d. If a p ati e nt d o es n ot a gr e e t o sit e visits, 
h e/s h e will b e c o nt act e d by t el e p h o n e t o i n q uir e a b o ut t h eir s af ety 
st at us, p artic ul arly at t h e ti m e of sc h e d ul e d W e ek 7 9 Visit. 
D o u bl e- bli n d E xt e n si o n P eri o d: 
P ati e nts still i n t h e st u dy at W e ek 2 6 will c o nti n u e d o u bl e- bli n d 
tr e at m e nt fr o m W e ek 2 7 t o 7 9 i n a 5 3- w e ek d o u bl e- bli n d Ext e nsi o n 
P eri o d. P ati e nts will c o nti n u e t o r ec eiv e t h e bli n d e d m e dic ati o n 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 
(s ot a glifl ozi n or pl ac e b o) t o w hic h t h ey w er e r a n d o miz e d o n D ay 1. 
Pati e nts w h o r ec eiv e d r esc u e m e dic ati o n d uri n g t h e 2 6- w e ek C or e 
Tr e at m e nt P eri o d will c o nti n u e o n t h e s a m e r esc u e m e dic ati o n 
d uri n g t h e d o u bl e- bli n d Ext e nsi o n Peri o d ( u nl ess t h e I nv esti g at or 
c o nsi d ers a c h a n g e n ec ess ary f or s af ety r e as o ns). T h e crit eri a f or 
i niti ati o n of r esc u e fr o m W e eks 2 6 t o 7 9 will b e as i n dic at e d i n t h e 
s ecti o n, “R e s c u e t h er a p y .” O p e n-l a b el r esc u e will r e m ai n at t h e 
discr eti o n of t h e I nv esti g at or.  
T h e st u dy d esi g n is pr es e nt e d gr a p hic ally at t h e e n d of t h e sy n o psis. 
S T U D Y P O P U L A TI O N  
M ai n s el e cti o n crit eri a 
I n cl u si o n crit eri a: 
•  
Pati e nts wit h Ty p e 2 Di a b et es c urr e ntly tr e at e d wit h di et 
a n d ex ercis e a n d o n m etf or mi n at a st a bl e d os e 
≥1 5 0 0 m g/ d ay f or at l e ast 1 2 w e eks. H o w ev er, p ati e nts o n 
m etf or mi n at a d os e < 1 5 0 0 m g/ d ay at t h e ti m e of 
e nr oll m e nt (st a bl e d os e f or at l e ast 1 2 w e eks b ef or e 
e nr oll m e nt) m ay b e eli gi bl e f or scr e e ni n g if d oc u m e nt ati o n 
of l ack of t ol er a nc e of a m etf or mi n d os e ≥1 5 0 0 m g/ d ay c a n 
b e pr ovi d e d 
•  
Si g n e d writt e n i nf or m e d c o ns e nt 
M aj or e x cl u si o n crit eri a: 
•  
Ag e < 1 8 y e ars at t h e Scr e e ni n g visit or <l e g al a g e of 
m aj ority, w hic h ev er is gr e at er 
•  
Ty p e 1 di a b et es m ellit us 
•  
Bo dy M ass I n d ex ( B MI) ≤2 0 or > 4 5 k g/ m 2 at Scr e e ni n g 
•  
H b A1c < 7 % or H b A1c > 1 0 % vi a c e ntr al l a b or at ory t est at 
Scr e e ni n g 
•  
F asti n g pl as m a gl uc os e > 1 5 m m ol/ L ( > 2 7 0 m g/ d L) 
m e as ur e d by t h e c e ntr al l a b or at ory at Scr e e ni n g ( Visit 1) 
a n d c o nfir m e d by a r e p e at t est ( > 1 5 m m ol/ L [ > 2 7 0 m g/ d L]) 
b ef or e r a n d o miz ati o n 
•  
W o m e n of c hil d b e ari n g p ot e nti al n ot willi n g t o us e hi g hly 
eff ectiv e m et h o d(s) of birt h c o ntr ol or w h o ar e u n willi n g or 
u n a bl e t o b e t est e d f or pr e g n a ncy (s e e Ap p e n dix A ), 
d uri n g t h e st u dy 
•  
Tr e at e d wit h a n a nti di a b etic p h ar m ac ol o gic al r e gi m e n 
ot h er t h a n m etf or mi n ≥1 5 0 0 m g per d ay ( or m axi m u m 
t ol er at e d d os e) wit hi n t h e 1 2 w e eks pr ec e di n g t h e 
scr e e ni n g visit 
•  
Pr evi o us us e of a ny ty p es of i ns uli n f or > 1 m o nt h ( at a ny 
ti m e, exc e pt f or tr e at m e nt of g est ati o n al di a b et es) 
•  
Hist ory of pri or g astric s ur gic al pr oc e d ur e, i ncl u di n g g astric 
b a n di n g, wit hi n 3 y e ars b ef or e t h e Scr e e ni n g Visit 
•  
Hist ory of di a b etic k et o aci d osis or n o nk et otic hy p er os m ol ar 
c o m a wit hi n 1 2 w e eks pri or t o t h e Scr e e ni n g Visit 
•  
M e a n of 3 s e p ar at e bl o o d pr ess ur e m e as ur e m e nts 
> 1 8 0 m m H g ( S B P) or > 1 0 0 m m H g ( D B P) 
•  
Hist ory of hy p ert e nsiv e e m er g e ncy wit hi n 1 2 w e eks pri or t o 
Scr e e ni n g ( 1 ) 
 
( el e ctr o ni c 
 
 
 
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( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 
•  
Pati e nts wit h s ev er e a n e mi a, s ev er e c ar di ov asc ul ar 
(i ncl u di n g c o n g estiv e h e art f ail ur e N e w York H e art 
Ass oci ati o n [ N Y H A] I V), r es pir at ory, h e p atic, n e ur ol o gic al, 
psyc hi atric, or activ e m ali g n a nt t u m or or ot h er m aj or 
syst e mic dis e as e or p ati e nts wit h s h ort lif e ex p ect a ncy 
m aki n g i m pl e m e nt ati o n of t h e pr ot oc ol or i nt er pr et ati o n of 
t h e st u dy r es ults diffic ult  
•  
As p art at e a mi n otr a nsf er as e a n d/ or al a ni n e 
a mi n otr a nsf er as e: > 3 ti m es t h e u p p er li mit of t h e n or m al 
l a b or at ory r a n g e 
•  
T ot al bilir u bi n: > 1. 5 ti m es t h e u p p er li mit of t h e n or m al 
l a b or at ory r a n g e ( exc e pt i n c as e of Gil b ert’s sy n dr o m e) 
•  
Us e of syst e mic gl uc oc ortic oi ds ( excl u di n g t o pic al or 
o p ht h al mic a p plic ati o n or i n h al e d f or ms) f or m or e t h a n 
1 0 c o ns ec utiv e d ays wit hi n 9 0 d ays pri or t o t h e Scr e e ni n g 
Visit 
•  
Pati e nt w h o h as t ak e n ot h er i nv esti g ati o n al dr u gs or 
pr o hi bit e d t h er a py f or t his st u dy wit hi n 1 2 w e eks or 
5 h alf-liv es fr o m scr e e ni n g or r a n d o miz ati o n, w hic h ev er is 
l o n g er 
•  
Pr e g n a nt (c o nfir m e d by s er u m pr e g n a ncy t est at 
Scr e e ni n g) or br e astf e e di n g w o m e n 
•  
P ati e nt is u n willi n g or u n a bl e t o p erf or m s elf- m o nit ori n g of 
bl o o d gl uc os e ( S M B G), c o m pl et e t h e p ati e nt di ary, or 
c o m ply wit h st u dy visits a n d ot h er st u dy pr oc e d ur es as 
r e q uir e d p er pr ot oc ol 
•  
C o ntr ai n dic ati o n t o m etf or mi n as p er l oc al l a b eli n g  
T ot al e x p e ct e d n u m b er of p ati e nt s 
5 0 0 
S T U D Y T R E A T M E N T S 
 
I n v e sti g ati o n al m e di ci n al pr o d u ct s 
•  
Sot a glifl ozi n 4 0 0 m g a d mi nist er e d as t w o 2 0 0 m g t a bl ets, 
o nc e d aily, b ef or e t h e first m e al of t h e d ay  
•  
Pl ac e b o a d mi nist er e d as t w o pl ac e b o t a bl ets (i d e ntic al t o 
s ot a glifl ozi n 2 0 0 m g t a bl ets i n a p p e ar a nc e), o nc e d aily, 
b ef or e t h e first m e al of t h e d ay  
N o ni n v e sti g ati o n al m e di ci n al pr o d u ct 
 
•  
M etf or mi n t a bl ets a d mi nist er e d as p er Pri nci p al 
I nv esti g at or 
N O T E: O n st u dy visit d ays occ urri n g o n D ay 1 ( Visit 3), W e ek 2 6 
( Visit 9), a n d W e ek 7 9 ( Visit 1 3), I M P a n d m etf or mi n s h o ul d b e 
a d mi nist er e d acc or di n g t o t h e sc h e d ul e o utli n e d i n Ap p e n dix C . 
T h e d os e of m etf or mi n s h o ul d b e st a bl e t hr o u g h o ut t h e st u dy u nl ess 
d o w n-titr ati o n is r e q uir e d f or s af ety r e as o ns. 
 
R e s c u e t h er a p y 
T h e t hr es h ol d v al u es ar e d efi n e d as f oll o ws, d e p e n di n g o n st u dy 
p eri o d: 
•  
F P G > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L) fr o m R a n d o miz ati o n u p 
t hr o u g h t h e sc h e d ul e d W e ek 8 visit 
 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 8 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 
•  
F P G > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) aft er t h e W e ek 8 visit u p 
t hr o u g h t h e sc h e d ul e d W e ek 1 2 visit 
•  
F P G > 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) aft er t h e W e ek 1 2 visit 
t hr o u g h t h e e n d of t h e 2 6- w e ek C or e Tr e at m e nt P eri o d  
•  
F P G > 1 7 0 m g/ d L ( 9. 4 m m ol/ L) or H b A1c ≥8. 0 % aft er t h e 
W e ek 2 6 Visit t hr o u g h t h e e n d of t h e tr e at m e nt p eri o d 
R o uti n e f asti n g S M B G a n d c e ntr al l a b or at ory al erts o n F P G ( a n d 
H b A1c at W e ek 2 6 a n d o n w ar d) ar e s et u p t o e ns ur e t h at glyc e mic 
p ar a m et er r es ults r e m ai n u n d er pr e d efi n e d t hr es h ol ds. 
•  
If o n e f asti n g S M B G v al u e exc e e ds t h e s p ecific glyc e mic 
li mit o n o n e d ay, t h e p ati e nt c h ecks it a g ai n d uri n g t h e t w o 
f oll o wi n g d ays. If all t h e v al u es i n t hr e e c o ns ec utiv e d ays 
exc e e d t h e s p ecific li mit, t h e p ati e nt s h o ul d c o nt act t h e 
I nv esti g at or a n d a c e ntr al l a b or at ory F P G m e as ur e m e nt 
( a n d H b A1c at W e ek 2 6 a n d o n w ar d) b e p erf or m e d as 
s o o n as p ossi bl e, pr ef er a bly wit hi n 7 d ays, t o c o nfir m t h e 
hy p er glyc e mi a.  
•  
U p o n r ec ei pt of a c e ntr al l a b or at ory r esc u e al ert, a c e ntr al 
l a b or at ory r e-t est m ust b e c o m pl et e d a n d c o nfir m e d as 
exc e e di n g t h e t hr es h ol d f or r esc u e b ef or e r esc u e t h er a py 
is i niti at e d. T h e r e-t est c o nfir m ati o n s h o ul d b e p erf or m e d 
as s o o n as p ossi bl e, b ut wit hi n 7 d ays of r ec ei pt, by 
u nsc h e d ul e d visit.  
I n t h e ev e nt t h at a c o nfir m at ory F P G a n d/ or H b A1c exc e e ds t h e 
t hr es h ol d, t h e I nv esti g at or s h o ul d e ns ur e t h at n o r e as o n a bl e 
ex pl a n ati o n exists f or i ns uffici e nt  gl uc os e c o ntr ol a n d i n p artic ul ar 
t h at: 
•  
T h e i ncr e as e d F P G h as b e e n t est e d at a f asti n g st at us (i e, 
n o f o o d i nt ak e f or ≥8 h o urs) 
•  
I nv esti g ati o n al m e dici n al pro d uct is giv e n at t h e pl a n n e d 
d os e 
•  
T h er e is n o i nt erc urr e nt dis e as e, w hic h m ay j e o p ar diz e 
glyc e mic c o ntr ol ( e g, i nf ecti o us dis e as e) 
•  
C o m pli a nc e t o tr e at m e nt is a p pr o pri at e 
•  
C o m pli a nc e t o di et a n d lif estyl e is a p pr o pri at e 
If a ny of t h e a b ov e c a n r e as o n a bly ex pl ai n t h e i ns uffici e nt glyc e mic 
c o ntr ol, t h e I nv esti g at or s h o ul d c o nsi d er n ot i niti ati n g r esc u e 
m e dic ati o n a n d s h o ul d u n d ert ak e a p pr o pri at e acti o n, i e: 
•  
Ass ess pl as m a gl uc os e i n f asti n g c o n diti o n (i e, aft er at 
l e ast 8 h o urs f ast) 
•  
I niti at e a n ev al u ati o n a n d tr e at m e nt of i nt erc urr e nt dis e as e 
(t o b e r e p ort e d i n A E/c o nc o mit a nt m e dic ati o n p arts of t h e 
e- C R F a n d t h e m e dic al r ec or d) 
•  
Str ess t h e a bs ol ut e n e e d t o b e c o m pli a nt wit h tr e at m e nt 
•  
Or g a niz e a s p ecific i nt ervi e w wit h t h e p ati e nt a n d a 
R e gist er e d Di etici a n or ot h er q u alifi e d n utriti o n 
pr of essi o n al t o r ei nf orc e t h e a bs ol ut e n e e d t o b e c o m pli a nt 
wit h di et a n d lif estyl e r ec o m m e n d ati o ns, a n d sc h e d ul e a 
F P G/ H b A 1c ass ess m e nt at t h e n ext visit 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 9 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 
If n o n e of t h e a b ov e m e nti o n e d r e as o ns c a n b e f o u n d, or if 
a p pr o pri at e acti o n f ails t o d ecr e as e F P G/ H b A1c u n d er t h e t hr es h ol d 
v al u es, r esc u e m e dic ati o n m ay b e i ntr o d uc e d. 
O p e n-l a b el r esc u e m e dic ati o n(s) t o  tr e at hy p er glyc e mi a will b e at t h e 
discr eti o n of t h e I nv esti g at or a n d i n acc or d a nc e wit h l oc al st a n d ar d 
of c ar e a n d pr escri bi n g pr actic e. Exc e pt f or s o di u m- gl uc os e 
c otr a ns p ort er ty p e 2 ( S G L T 2) i n hi bit ors, a ny a p pr ov e d m e dic ati o n(s) 
i ncl u di n g or al a nti di a b etic dr u gs or i ns uli n c a n b e pr escri b e d t o tr e at 
t h e hy p er glyc e mi a. F or p ati e nts wit h r e n al i m p air m e nt, 
c o ntr ai n dic ati o ns t o a nti hy p er glyc e mic dr u gs s h o ul d b e t ak e n i nt o 
c o nsi d er ati o n. If a p ati e nt re q uir es glyc e mic r esc u e, t h e I M P 
r ec eiv e d d uri n g t h e r a n d o miz e d, d o u bl e- bli n d Tr e at m e nt Peri o d 
s h o ul d c o nti n u e a n d m ust r e m ai n bli n d e d u ntil t h e e n d of t h e st u dy.  
E N D P OI N T S 
 
 
Pri m ar y effi c a c y e n d p oi nt: 
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n H b A1c 
S e c o n d ar y effi c a c y e n d p oi nt s: 
•  
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n 2- h o ur P P G f oll o wi n g 
a mix e d m e al ( M M) 
•  
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n F P G 
•  
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n b o dy w ei g ht 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 i n S B P f or p ati e nts wit h 
b as eli n e S B P ≥1 3 0 m m H g 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 i n S B P f or all p ati e nts 
•  
Pr o p orti o n of p ati e nts wit h H b A1c < 6. 5 %, < 7. 0 % at 
W e ek 2 6 
Ot h er effi c a c y e n d p oi nt s: 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 i n S B P f or p ati e nts wit h 
Bas eli n e S B P < 1 3 0 m m H g 
•  
Pr o p orti o n of p ati e nts wit h r e d ucti o n i n b o dy w ei g ht by 
≥2 %, ≥5 %, a n d ≥1 0 % fr o m Bas eli n e  
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 i n D B P 
•  
Pr o p orti o n of p ati e nts ac hi evi n g S B P < 1 3 0 m m H g f or 
t h os e wit h Bas eli n e S B P ≥1 3 0 m m H g 
•  
Pr o p orti o n of p ati e nts ac hi evi n g D B P < 8 0 m m H g f or t h os e 
wit h Bas eli n e D B P ≥8 0 m m H g 
•  
Pr o p orti o n of p ati e nts r e q uiri n g r esc u e f or hy p er glyc e mi a 
•  
C h a n g e fr o m Bas eli n e i n: 
- 
Ser u m cr e ati ni n e 
- 
Uri n e A C R 
- 
U G E, a n d uri n e G C R 
- 
e G F R 
•  
C h a n g e fr o m Bas eli n e t o W e ek 7 9 i n H b A1c 
•  
C h a n g e fr o m Bas eli n e t o W e ek 7 9 i n F P G 
•  
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n S B P f or all p ati e nts 
a n d f or p ati e nts wit h Bas eli n e S B P ≥1 3 0 m m H g 
 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 1 0 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 
•  
C h a n g e fr o m Bas eli n e t o W e ek 7 9 i n S B P f or all p ati e nts 
a n d f or p ati e nts wit h Bas eli n e S B P ≥1 3 0 m m H g 
•  
C h a n g e fr o m Bas eli n e t o W e ek 7 9 i n b o dy w ei g ht 
S af et y e n d p oi nt s: 
•  
Adv ers e ev e nts ( A Es), hy p o glyc e mi a ( all, s ev er e, a n d/ or 
d oc u m e nt e d sy m pt o m atic hy p o glyc e mi a), E O SI, A E SI, 
A Es l e a di n g t o disc o nti n u ati o n fr o m t h e I M P, S A Es, a n d 
d e at hs 
•  
Cli nic al l a b or at ory r es ults, i ncl u di n g f asti n g li pi ds, vit al 
si g ns, a n d el ectr oc ar di o gr a m ( E C G) r es ults 
•  
M ark ers of b o n e a n d c alci u m m et a b olis m 
•  
M ark ers of i nt esti n al tr a nsit a n d a bs or pti o n 
P h ar m a c o ki n eti c e n d p oi nt s:  
•  
Pl as m a c o nc e ntr ati o ns of s ot a glifl ozi n a n d its m et a b olit e 
pr e- d os e at W e eks 4, 1 8, 2 6, 5 2, 7 9 a n d 2 h o urs 3 0 
mi n ut es p ost- d os e at W e eks 2 6 a n d 7 9 
E n d p oi nt s of A B P M s u b st u d y: 
Pri m ary e n d p oi nt: 
•  
T h e pri m ary e n d p oi nt of t h e A B P M s u bst u dy is t h e c h a n g e 
fr o m B as eli n e t o W e ek 1 2 i n av er a g e 2 4-h o ur S B P i n a 
s u bs et of p ati e nts wit h m e a n S B P ≥1 3 0 m m H g at 
Scr e e ni n g 
Se c o n d ary e n d p oi nt s: 
•  
C h a n g e fr o m Bas eli n e t o W e ek 2 6 i n av er a g e 2 4- h o ur 
S B P 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 a n d 2 6 i n av er a g e 
2 4- h o ur D B P 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 a n d 2 6 i n av er a g e 
a dj ust e d a w ak e ti m e B P as m e as ur e d by S B P a n d D B P 
wit h a dj ust m e nt b as e d o n acti gr a p hy 
•  
C h a n g e fr o m Bas eli n e t o W e ek 1 2 a n d 2 6 i n av er a g e 
a dj ust e d sl e e p ti m e B P as m e as ur e d by S B P a n d D B P 
wit h a dj ust m e nt b as e d o n acti gr a p hy 
A S S E S S M E N T S C H E D U L E 
Se e St u dy Fl o w C h art Secti o n 1. 2  
S T A TI S TI C A L C O N SI D E R A TI O N S 
 
S a m pl e si z e d et er mi n ati o n: 
T h e s a m pl e siz e/ p o w er c alc ul ati o ns ar e b as e d o n t h e pri m ary 
v ari a bl e, c h a n g e fr o m Bas eli n e t o W e ek 2 6 i n H b A1c. 
Ass u mi n g a c o m m o n st a n d ar d d evi ati o n ( S D) of 1. 2 % a n d usi n g a 
2-si d e d t est at a 0. 0 5 α -l ev el, 2 5 0 p ati e nts p er ar m will h av e at l e ast 
9 9 % p o w er t o d et ect a tr e at m e nt diff er e nc e of 0. 6 % i n m e a n H b A 1c 
c h a n g e fr o m Bas eli n e t o W e ek 2 6 b et w e e n s ot a glifl ozi n 4 0 0 m g a n d 
pl ac e b o. 
T h e s a m pl e siz e/ p o w er c alc ul ati o ns f or A B P M s u bst u dy ar e b as e d 
o n t h e pri m ary v ari a bl e, c h a n g e fr o m Bas eli n e t o W e ek 1 2 i n 
av er a g e 2 4- h o ur S B P i n p ati e nts wit h m e a n S B P ≥1 3 0 m m H g at 
Scr e e ni n g. Ass u mi n g a c o m m o n S D of 1 5 m m H g a n d usi n g a 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 1 
2-si d e d t est at a 0. 0 5 α -l ev el, 1 0 0 p ati e nts p er ar m will pr ovi d e 
9 0 % p o w er t o d et ect a tr e at m e nt diff er e nc e of 7 m m H g i n av er a g e 
2 4- h o ur S B P c h a n g e fr o m B as e li n e t o W e ek 1 2 b et w e e n 
s ot a glifl ozi n 4 0 0 m g a n d pl ac e b o. 
A n al y si s p o p ul ati o n: 
Effic acy a n alys es will b e b as e d o n t h e i nt e nti o n t o tr e at (I T T) 
p o p ul ati o n, d efi n e d as all r a n d o miz e d p ati e nts, irr es p ectiv e of 
c o m pli a nc e wit h t h e st u dy pr ot oc ol a n d pr oc e d ur es. 
Pri m ar y a n al y si s: 
An alysis of t h e pri m ary effic acy e n d p oi nt (c h a n g e fr o m Bas eli n e t o 
W e ek 2 6 i n H b A1c) will b e p erf or m e d o n t h e I T T p o p ul ati o n, usi n g 
H b A1c m e as ur e m e nts o bt ai n e d d uri n g t h e st u dy, i ncl u di n g t h os e 
o bt ai n e d aft er I M P disc o nti n u ati o n or i ntr o d ucti o n of r esc u e t h er a py. 
T h e pri m ary effic acy e n d p oi nt of c h a n g e i n H b A1c fr o m b as eli n e t o 
W e ek 2 6 will b e a n alyz e d wit h missi n g v al u es i m p ut e d by 
c o ntr ol- b as e d m ulti pl e i m p ut ati o n m et h o d u n d er t h e missi n g n ot at 
r a n d o m fr a m e w ork.  
•  
F or pl ac e b o p ati e nts, missi n g d at a will b e i m p ut e d b as e d 
o n t h e pl ac e b o gr o u p d at a, 
•  
F or p ati e nts i n t h e s ot a glifl ozi n gr o u p, missi n g d at a will b e 
i m p ut e d as if t h e p ati e nts w er e o n pl ac e b o t hr o u g h o ut t h e 
st u dy. 
Eac h of t h e c o m pl et e d at as ets will b e a n alyz e d by a n An alysis of 
C ov ari a nc e ( A N C O V A) m o d el wit h tr e at m e nt gr o u ps (s ot a glifl ozi n, 
pl ac e b o), r a n d o miz ati o n str at u m of H b A1c ( ≤8. 0 %, > 8. 0 %), 
r a n d o miz ati o n str at u m of S B P ( < 1 3 0, ≥1 3 0 m m H g), a n d c o u ntry as 
fix e d eff ects, a n d b as eli n e H b A1c v al u e as a c ov ari at e. R es ults fr o m 
e ac h c o m pl et e d at as et will b e c o m bi n e d t o pr ovi d e t h e a dj ust e d 
m e a n c h a n g e i n H b A1c fr o m Bas eli n e t o W e ek 2 6 f or e ac h tr e at m e nt 
gr o u p, as w ell as t h e b et w e e n- gr o u p diff er e nc e (c o m p ari n g 
s ot a glifl ozi n vs pl ac e b o) a n d t h e 9 5 % c o nfi d e nc e i nt erv als ( CI) f or 
t h e diff er e nc e.  
Su m m ary st atistics (f or scr e e ni n g v al u e, b as eli n e v al u e, o bs erv e d 
v al u es, a n d o bs erv e d c h a n g es fr o m B as eli n e) at sc h e d ul e d visits will 
b e pr ovi d e d f or e ac h tr e at m e nt gr o u p. T h e s u m m ary will i ncl u d e t h e 
n u m b er of o bs erv ati o ns, m e a n, S D, st a n d ar d err or ( S E), mi ni m u m, 
m e di a n, a n d m axi m u m. Gr a p hic al pr es e nt ati o ns will als o b e us e d t o 
ex a mi n e tr e n ds ov er ti m e us i n g m e a n v al u es ( ± S E) a n d m e a n 
c h a n g es fr o m Bas eli n e ( ± S E) at e ach of t h e sc h e d ul e d visits ( usi n g 
o bs erv e d c as es [ O C]). 
A n al y si s of s e c o n d ar y effi c a c y e n d p oi nt s: 
T h e s ec o n d ary e n d p oi nts will b e a n alyz e d usi n g a si mil ar a p pr o ac h 
t o t h e pri m ary effic acy e n d p oi nt, wit h missi n g v al u es i m p ut e d by 
c o ntr ol- b as e d m ulti pl e i m p ut ati o n m et h o d u n d er t h e missi n g n ot at 
r a n d o m fr a m e w ork.  
F or e ac h of t h e c o nti n u o us s ec o n d ary e n d p oi nt, e ac h of t h e 
c o m pl et e d at as ets will b e a n alyz e d by t h e A N C O V A m o d el wit h 
tr e at m e nt gr o u ps (s ot a glifl ozi n, pl ac e b o), r a n d o miz ati o n str at u m of 
H b A 1c ( ≤8. 0 %, > 8. 0 %), r a n d o miz ati o n str at u m of S B P ( < 1 3 0 m m H g, 
≥1 3 0 m m H g), a n d c o u ntry as fix e d eff ects, a n d b as eli n e s ec o n d ary 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 2 
e n d p oi nt v al u e as a c ov ari at e. R es ults fr o m e ac h c o m pl et e d at as et 
will b e c o m bi n e d t o pr ovi d e t h e a dj ust e d m e a n c h a n g e fr o m B as eli n e 
t o W e ek 2 6 f or e ac h tr e at m e nt gr o u p, as w ell as t h e b et w e e n- gr o u p 
diff er e nc e (c o m p ari n g s ot a glifl ozi n vs pl ac e b o) a n d t h e 9 5 % CI f or 
t h e diff er e nc e. 
T h e c at e g oric al s ec o n d ary effic acy v ari a bl es of H b A1c < 6. 5 %, 
< 7 % at W e ek 2 6 will b e a n alyz e d usi n g a C oc hr a n- M a nt el- H a e nsz el 
m et h o d str atifi e d by r a n d o miz ati o n str at u m of H b A1c ( ≤8. 0 %, 
> 8. 0 %), a n d r a n d o miz ati o n str at u m of S B P ( < 1 3 0, ≥1 3 0 m m H g). 
A n al y si s of ot h er effi c a c y e n d p oi nt s:  
T h e a n alysis of ot h er e n d p oi nts will b e d escri ptiv e wit h n o f or m al 
t esti n g. S u m m ary st atistics at sc h e d ul e d visits usi n g O C will b e 
pr ovi d e d by e ac h tr e at m e nt gr o u p. Gr a p hic al pr es e nt ati o ns will als o 
b e us e d t o ill ustr at e tr e n ds ov er ti m e. 
A n al y s e s of s af et y d at a:  
All s af ety s u m m ari es will b e d escri ptiv e; n o st atistic al si g nific a nc e 
t ests will b e p erf or m e d o n s af ety d at a. T h es e a n alys es will b e b as e d 
o n t h e Saf ety Po p ul ati o n, w hic h is d efi n e d as all r a n d o miz e d p ati e nts 
w h o r ec eiv e at l e ast 1 d os e of d o u bl e- bli n d tr e at m e nt, r e g ar dl ess of 
t h e a m o u nt of tr e at m e nt a d mi nist er e d. Pati e nts will b e a n alyz e d f or 
s af ety a n alys es acc or di n g t o t h e tr e at m e nt act u ally r ec eiv e d. T h e 
s af ety a n alys es will b e pr ovi d e d f or t h e 2 6- w e ek c or e tr e at m e nt 
p eri o d a n d f or t h e e ntir e tr e at m e nt p eri o d. 
A n al y si s of A B P M s u b st u d y e n d p oi nt s: 
A B P M s u bst u dy e n d p oi nts will b e a n alyz e d usi n g a si mil ar a p pr o ac h 
as t h e pri m ary effic acy e n d p oi nt wit h missi n g v al u es i m p ut e d by 
c o ntr ol- b as e d m ulti pl e i m p ut ati o n m et h o d u n d er t h e missi n g n ot at 
r a n d o m fr a m e w ork. E ac h of t h e c o m pl et e d at as et will b e a n alyz e d 
usi n g A N C O V A m o d el i ncl u di n g f act ors f or tr e at m e nt (s ot a glifl ozi n, 
pl ac e b o), r a n d o miz ati o n str at u m of H b A1c ( ≤8. 0 %, > 8. 0 %) as fix e d 
eff ects, a n d t h e b as eli n e v al u e of t h e s p ecific d e p e n d e nt v ari a bl e as 
a c ov ari at e.  
D U R A TI O N O F S T U D Y P E RI O D ( p er 
p ati e nt)  
U p t o 8 7 w e eks, i ncl u di n g a Scr e e ni n g Peri o d c o nsisti n g of a 
Scr e e ni n g p h as e of u p t o 2 w e eks a n d a 2- w e ek si n gl e- bli n d R u n-i n 
p h as e, a 2 6- w e ek d o u bl e- bli n d C or e  Tr e at m e nt Peri o d, a 5 3- w e ek 
d o u bl e- bli n d Ext e nsi o n Peri o d, a 4- w e ek p ost tr e at m e nt F oll o w- u p 
p eri o d t o c oll ect s af ety i nf or m ati o n. 
S T U D Y C O M MI T T E E S 
St e eri n g c o m mitt e e:  
 Y es    
 N o 
D at a m o nit ori n g c o m mitt e e: 
 Yes    
 N o 
Cli ni c al E n d p oi nt C o m mitt e e s:  
 Yes    
 N o 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 3 
1  
F L O W C H A R T S 
1. 1  
G R A P HI C A L S T U D Y D E SI G N 
 
 
 
A b brevi ati o ns: A B P M: a m b ul at or y bl o o d press ure m o nit ori n g; H b A 1c: h e m o gl o bi n A 1c; R: ra n d o miz ati o n; T 2 D: ty p e 2 di a b et es m ellit us. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 4 
1. 2  
S T U D Y F L O W C H A R T 
S cr e e ni n g P eri o d  
 
S cr e e ni n g  
R u n-i n 
D o u bl e- Bli n d C or e Tr e at m e nt P eri o d a 
D o u bl e- Bli n d E xt e n si o n 
P eri o d b  
F oll o w-
u p  
VI SI T 
1  
2  
3 A ( A B P M 
pl a c e m e nt) c  
3 
( R a n d o m
-iz ati o n) 
4  
5  
6  
7 A ( A B P M 
pl a c e m e nt) c  
7  
8  
9 A ( A B P M 
pl a c e m e nt) c  
9  
1 0  
1 1  
1 2  
1 3 
1 4 d 
W e e k 
U p t o - 4  
- 2  
- 1  
0 
B a s eli n e 
1  
4  
8  
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3 
Da y ( wi n d o w [ d a y s])  
  
 
(- 7/ 
+ 3) 
- 7  
( ± 2) 
1  
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5 
( ± 7) 
5 5 1  
(-3 t o + 4) 
5 7 9 
( ± 3) 
I nf or m e d
 
c o ns e nt
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n
 
crit eri a
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Excl usi o n
 
crit eri a
  
X
 
 
 
 
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gra p hics
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al/ S ur gic al
 
Hist ory
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic ati o n
 
Hist ory
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H e p atitis
 
s er ol o gy
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o dy w ei g ht, h ei g ht e 
X
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
Vit al si g ns f 
X
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
P hysic al
 
Ex a mi n ati o n:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m pl et e
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
X
 
 
 
  X
 
 
 
A b brevi at e d
 
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
 
 
  X
 X
 X
 
 
  
X
 
Di et & ex ercis e i nstructi o n  
  
X  
  
X  
  
  
  
  
  
  
  
X  
  
X  
  
X  
 
I nstr ucti o n o n b asic 
g e nit o uri n ary hy gi e n e & 
hy dr ati o n 
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
 
( el e ctr o ni c 
 
 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 5 
S cr e e ni n g P eri o d  
 
S cr e e ni n g  
R u n-i n 
D o u bl e- Bli n d C or e Tr e at m e nt P eri o d a 
D o u bl e- Bli n d E xt e n si o n 
P eri o d b  
F oll o w-
u p  
VI SI T 
1  
2  
3 A ( A B P M 
pl a c e m e nt) c  
3 
( R a n d o m
-iz ati o n) 
4  
5  
6  
7 A ( A B P M 
pl a c e m e nt) c  
7  
8  
9 A ( A B P M 
pl a c e m e nt) c  
9  
1 0  
1 1  
1 2  
1 3 
1 4 d 
W e e k 
U p t o - 4  
- 2  
- 1  
0 
B a s eli n e 
1  
4  
8  
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3 
Da y ( wi n d o w [ d a y s])  
  
 
(- 7/ 
+ 3) 
- 7  
( ± 2) 
1  
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5 
( ± 7) 
5 5 1  
(-3 t o + 4) 
5 7 9 
( ± 3) 
I R T c o nt actg 
X
  
X
 
 
  
X
 
 
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
R a n d o miz ati o n
 
 
 
 
 
  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dis p e ns e gl uc os e m et er   
  
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Dis p e ns e
 
di ary
 
X
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
 
C oll ect/revi e w
 
di ary
 
 
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
I nstr ucti o n o n di a b etic 
k et o aci d osis sy m pt o ms, 
gl uc os e t esti n g 
 
 
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
 
Dis p e ns e
 
I M P
  
  
X
 
 
  
X
 
 
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
 
 
 
 
 
I M P acc o u nti n g & 
c o m pli a nc e 
 
 
 
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
C o nc o mit a nt
 
M e dic ati o n
  
X
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
S elf- m o nit ori n g of bl o o d 
gl uc os e h 
  
X
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
1 2-l e a d E C G i 
X
 
 
 
 
  
X
 
 
 
 
 
 
 
 
 
 
 
  
X
 
 
 
  X
 
 
 
St a n d ar d mix e d m e al 
t ol er a nc e t estj 
 
 
 
 
  
X
 
 
 
 
 
 
 
 
 
 
 
  
X
 
 
 
  X
 
 
 
L a b or at or y te sti n g k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F P G
 
X
 
 
 
 
  
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
 
( el e ctr o ni c 
 
 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 6 
S cr e e ni n g P eri o d  
 
S cr e e ni n g  
R u n-i n 
D o u bl e- Bli n d C or e Tr e at m e nt P eri o d a 
D o u bl e- Bli n d E xt e n si o n 
P eri o d b  
F oll o w-
u p  
VI SI T 
1  
2  
3 A ( A B P M 
pl a c e m e nt )c  
3 
( R a n d o m
-iz ati o n) 
4  
5  
6  
7 A ( A B P M 
pl a c e m e nt) c  
7  
8  
9 A ( A B P M 
pl a c e m e nt) c  
9  
1 0  
1 1  
1 2  
1 3 
1 4 d 
W e e k 
U p t o - 4  
- 2  
- 1  
0 
B a s eli n e 
1  
4  
8  
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3 
Da y ( wi n d o w [ d a y s])  
  
 
(- 7/ 
+ 3) 
- 7  
( ± 2) 
1  
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5 
( ± 7) 
5 5 1  
(-3 t o + 4) 
5 7 9 
( ± 3) 
H b A 1c
 
X
 
 
 
 
  
X
 
 
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
 
C h e mistry (i ncl u di n g 
a myl as e a n d li p as e) 
X
 
 
 
 
  
X
 
 
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
H e m at ol o gy
 
X
 
 
 
 
  
X
 
 
 
 
 
 
 
 
  
X
 
 
 
 
  
X
 X
 X
 X
  
X
 
 
 
F asti n g
 
li pi ds
  
X
 
 
 
 
  
X
 
 
 X
 X
 
 
  
X
 X
 
 
  
X
 
 
 
  X
 
 
 
Pr e g n a ncy t est 
( W O C B P)l 
X
 
 
 
 
  
X
 
 
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
 
 
S eru m f ollicl e 
sti m ul ati n g h or m o n e 
a n d estr a di ol 
( m e n o p a us al w o m e n 
o nly) l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pl as m a c o nc e ntr ati o n m  
 
 
 
 
 
 
X
 
 
 
 
 
 X
 
 
  
X
  
X 
 
X 
 
M ark ers of i nt esti n al 
tr a nsit & a bs orpti o nn 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X
 
 
 
  X
  
X
 
M ark ers of b o n e & 
c alci u m m et a b olis mo 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
  
X
 
 
 
  X
 
 
 
Uri n alysis ( di pstick a n d 
microsc o py) p 
X
 
 
 
 
  
X
 
 
 
 
 
 
 
 
 
 
 
  
X
 
 
 
  X
 
 
 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 7 
S cr e e ni n g P eri o d  
 
S cr e e ni n g  
R u n-i n 
D o u bl e- Bli n d C or e Tr e at m e nt P eri o d a 
D o u bl e- Bli n d E xt e n si o n 
P eri o d b  
F oll o w-
u p  
VI SI T 
1  
2  
3 A ( A B P M 
pl a c e m e nt) c  
3 
( R a n d o m
-iz ati o n) 
4  
5  
6  
7 A ( A B P M 
pl a c e m e nt) c  
7  
8  
9 A ( A B P M 
pl a c e m e nt) c  
9  
1 0  
1 1  
1 2  
1 3 
1 4 d 
W e e k 
U p t o - 4  
- 2  
- 1  
0 
B a s eli n e 
1  
4  
8  
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3 
Da y ( wi n d o w [ d a y s])  
  
 
(- 7/ 
+ 3) 
- 7  
( ± 2) 
1  
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5 
( ± 7) 
5 5 1  
(-3 t o + 4) 
5 7 9 
( ± 3) 
Uri n e al b u mi n, c alci u m, 
gl uc os e & cre ati ni n e 
 
 
 
X
  
X
  X
  X
 
 
  
X
 X
 
 
  
X
 X
 X
 X
  
X
  
X
 
A B P M pl ac e m e nt c 
 
 
X
 
 
 
 
 
 
  
X
 
 
 
  
X
 
 
  
 
 
 
 
 
 
A B P M r e m ov al a n d 
ass ess m e nt  
 
 
 
X
 
 
 
 
 
 
  
X
 
 
 
  
X
  
 
 
 
 
 
 
Ev al u at e f or glyc e mic 
r esc u e 
 
 
 
 
 
T o b e ass ess e d a n d r e p ort e d t hr o u g h o ut t h e tr e at m e nt p eri o d 
 
Hy p o glyc e mi a 
T o b e ass ess e d a n d r e p ort e d t hr o u g h o ut t h e st u dy 
A Es/ S A Es/ A E SIs/ E O SIs 
T o b e ass ess e d a n d r e p ort e d t hr o u g h o ut t h e st u dy s 
a  If a p ati e nt disc o nti n u es tr e at m e nt wit h i nv esti g ati o n al m e dici n al pr o d uct (I M P) e arly d uri n g t h e C or e Tr e at m e nt P eri o d, t h e p ati e nt will h av e a Pre mat ure E n d-of- Tre at m e nt ( E O T ) Visit, a n d a F oll o w-u p Visit 4 
we eks aft er t h e l ast d os e of I M P. I n a d diti o n, ev ery eff ort w ill b e m a d e t o h av e all p ati e nts ret urn t o t h e sit e at t h e ti m e c orres p o n di n g t o t h eir sc h e d ul e d visits, p artic ul arly t h e W e ek 2 6 Visit. If t h e p ati e nt d o es n ot 
a gre e t o a sit e visit, t h ey will b e c o nt act e d by t el e p h o n e t o i n q uire a b o ut s af ety st at us. If a p ati e nt disc o nti n u es ( or c o m pl et es) tre at m e nt a n d st u dy at t h e s a m e ti m e, a si n gl e visit will b e p erf or m e d usi n g t h e 
pr oc e d ur e n or m ally pl a n n e d f or t h e E O T visit. 
b  If a p ati e nt c o m pl et es t h e C ore Tre at m e nt, b ut disc o nti n u es I M P d uri n g t h e Ext e nsi o n P eri o d, t h e p ati e nt will h av e a Pre m at ure E O T Visit, a n d a F oll o w-u p Visit 4 we eks aft er t h e l ast d os e of I M P. Ev ery eff ort will 
b e m a d e t o h av e all p ati e nts r et ur n t o t h e sit e at t h e ti m e c orres p o n di n g t o t h eir q u art erly visits (i e, ev ery 1 3 w e eks) d uri n g  t h e Ext e nsi o n P eri o d. At t h e ti m e c orres p o n di n g t o t h eir W e ek 7 9 Visit, all att e m pts will b e 
m a d e t o c o nt act t h e p ati e nt t o i n q uir e a b o ut s af ety st at us. If a p ati e nt disc o nti n u es ( or c o m pl et es) tr e at m e nt a n d st u dy at t h e  s a m e ti m e, a si n gl e visit will b e p erf or m e d usi n g t h e proc e d ur e n or m ally pl a n n e d f or t h e 
E O T visit. 
c A m b ul at ory Bl o o d Press ur e M o nit ori n g ( A B P M) s u bst u dy visits f or a s u bs et of p ati e nts will occ ur 1 w e ek b ef ore t h e ra n d o miz ati o n  Visit; p ati e nts will r et urn t h e A B P M d evice by p ost aft er 2 4-h o ur m o nit ori n g is 
c o m pl et e. P ati e nts i n t h e A B P M s u bst u dy will als o h av e visits f or pl ac e m e nt of t h e A B P M d evic e t h e d ay b ef ore W e ek 1 2 a n d W e ek 2 6 visits. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 8 
d  F o ur w e eks aft er t h e l ast d os e of I M P. 
e  H ei g ht t o b e m e as ure d o nly at scre e ni n g. 
f 
Vit al si g n m e as ur e m e nts (sitti n g B P a n d h e art r at e): 3 s e p ar at e s e at e d B P a n d h e art r at e m e as ur e m e nts s h o ul d b e t ak e n wit h at l e ast 1 mi n ut e b et w e e n r e a di n gs, f oll o wi n g a 5- mi n ut e r est p eri o d a n d pri or t o 
p hl e b ot o my (s e e  S ecti o n 9. 2. 1. 4  a n d d et ail e d i nstr ucti o ns i n A p p e n dix E ). 
g  I nt er activ e r es p o ns e T ec h n ol o gy (I R T) c o nt act n ot r e q uir e d f or p ati e nts w h o disc o nti n u e I M P e arly aft er t h ey h av e att e n d e d t h e E O T Visit.  
h  S e e S ecti o n  9. 2. 1. 6  f or d et ails of S M B G m e as ur e m e nts. Gl uc os e m et ers us e d f or S M B G dis pl ay r es ults as pl as m a gl uc os e c o nc e ntr ati o n. P ati e nts s h o uld m e as ur e t h eir f asti n g pl as m a gl uc os e at l e ast 3 ti m es p er 
w e ek (i ncl u di n g o n d ay of e ac h o n-sit e st u dy visit). Aft er Visit 9 ( W e ek 2 6), if f asti n g S M B G v al u es ar e < 1 2 0 m g/ d L, ov er a 2- w e ek p eri o d, t h e I nv esti g at or c a n i nstr uct p ati e nts t o s elf- m o nit or bl o o d gl uc os e o nc e a 
w e ek ( o n d ay of o n-sit e st u dy visit f or w e eks wit h o n-sit e st u dy visits). 
i 
T h e 1 2-l e a d E C G rec ordi n gs s h o ul d b e o bt ai n e d pri or t o I M P a d mi nistrati o n. T h e E C G will b e ev al u at e d as “n or m al” or “a b n or m al”. 
j 
P ost pra n di al pl as m a gl uc os e will b e ass ess e d by c e ntral l a b orat ory at B as eli n e a n d 2 h o urs aft er c o ns u mi n g a st a n d ard mix e d li q ui d br e akf ast m e al a n d vi a a mix e d m e al t ol er a nc e t est ( M M T T) o n D ay 1, W e ek 
2 6, a n d W e ek 7 9. If a p ati e nt wit h dra ws fr o m I M P e arly, pl e as e s e e S ecti o n  1 0. 3. 4 . 
k All l a b or at ory ass ess m e nts occ ur pri or t o first d os e of d o u bl e- bli n d I M P. T h e first d os e of d o u bl e-bli n d I M P occ urs aft er s a m pl es f or t h e mix e d li q ui d m e al h av e b e e n c oll ect e d. A ll visit d at es will b e sc h e d ul e d b as e d 
o n t h e d at e of r a n d o miz ati o n wit h a ± 3 d ays visit wi n d o w all o w e d d uri n g t h e c or e tre at m e nt p eri o d. S er u m c h e mistry p ar a m et ers ( cli nic al c h e mistry [incl u di n g a myl as e a n d li p as e], h e m at ol o gy, a n d ot h er bl o o d 
p ar a m et ers) ar e list e d i n T a bl e 2.   
l 
S er u m pre g n a ncy t esti n g o nly at scr e e ni n g; uri n e pr e g n a ncy t esti n g s u bs e q u e ntly. S er u m pr e g n a ncy t est r es ults m ust b e r evi e w e d pri or t o b e gi n ni n g t h e R u n-i n p h as e f or all w o m e n of c hil d b e ari n g p ot e nti al 
( W O C B P) u nl ess t h er e is d oc u m e nt e d hist ory of m e n o p a us e (b as e d o n d oc u me nt e d f ollicl e-sti m ul a ti n g h or m o n e [ F S H] a n d estra di ol lev els – if res ults n ot d oc u m e nt e d t h e n F S H a n d estr a di ol will b e t est e d at 
Scr e e ni n g visit) or t h ey ar e s ur gic ally st eril e. A ny p ositiv e uri n e t est r es ults m ust b e c o nfir m e d b as e d o n s er u m pre g n a ncy t est. T h e I nv esti g at or m ay p erf or m a d diti o n al t ests at t h eir discr eti o n or as r e q uir e d by 
l oc al r e g ul ati o ns. 
m  Pl as m a c o nc e ntr ati o n s a m pl es (i e, f or s ot a glifl ozi n a n d S ot a glifl ozi n- 3- O- gl uc ur o ni d e) o n W e ek 4, W e ek 1 8, a n d W e ek 5 2 s h o ul d b e dra w n wit h t h e ot h er l a b or at ory ass ess m e nts. F or W e ek 2 6 a n d W e ek 7 9, 
pl as m a c o nc e ntr ati o n s a m pl es s h o ul d b e dra w n at Ti m e 0 a n d 1 5 0 mi n ut es ( 2 h o ur 3 0 mi n ut es) i m m e di at ely aft er t h e r es p ectiv e gl u c os e ass ess m e nts d uri n g t h e M M T T. P h ar m ac oki n etic ( P K) s a m pl es ( exc e pt t h e 
2 h o ur 3 0 mi n ut e s a m pl e d uri n g t h e M M T T) M U S T b e c oll ect e d b ef or e a d mi nistr ati o n of I M P. T h e d at e a n d ti m e of t h e l ast i nt ak e o f I M P pri or t o visits w h er e P K s a m pl es are t ak e n s h o ul d b e r ec or d e d by t h e 
p ati e nt i n t h e p ati e nt di ary. P ati e nts s h o ul d b e r e mi n d e d of t his at visits pr ec e di n g P K ti m e p oi nts t o e ns ur e t h es e d et ails ar e c a pt ur e d. I n t h e c as e of pr e m at ur e I M P disc o nti n u ati o n, P K s a m pl es s h o ul d n ot b e 
dr a w n at t h e Pr e m at ure E O T visit, n or at a ny s u bs e q u e nt visits. 
n  T h e m ark ers of i nt esti n al tr a nsit a n d a bs or pti o n i ncl u d e vit a mi ns B 6, B 1 2, K, E, a n d A, s er u m f ol at e, a n d f erriti n. 
o  M ark ers of b o n e a n d c alci u m m et a b olis m i ncl u d e: s eru m a n d uri n ary c alci u m, s eru m 2 5-hy droxyvit a min D, s eru m 1, 2 5-di hy droxyvit a m i n D, s er u m a n d uri n ary p h os p h or us, s er u m p ar at hyroi d h or m o n e, m ark ers of 
b o n e r es or pti o n  (ser u m N T X, s er u m β - C T X- 1), a n d b o n e f or m ati o n (s er u m P 1 N P). 
p  Uri n alysis i ncl u d es uri n e di pstick a n d microsc o py. Di pstick i ncl u d es ass ess m e nt of s p ecific gr avity, p H, pr ot ei n, bl o o d, k et o n e s, biliru bi n, uro bili n o g e n, nitrite, a n d l e uk ocyt e est eras e. Micr osc o py i n cl u d es d et ecti o n 
of f or m e d c ell ul ar el e m e nts, c asts, b act eri a, y e ast, p ar asit es, a n d cryst als i n c e ntrif u g e d uri n e s e di m e nt. I n t h e ev e nt of a b n or m al uri n alysis fi n di n gs s us pici o us of uri n ary tract i nf ecti o n, uri n e c ult ur e s h o ul d b e 
p erf or m e d. P ositiv e uri n e c ult ure d et er mi n ati o n will b e b as e d u p o n t h e crit eri a of t h e re p orti n g l a b orat ory. 
 
 
 
s All s eri o us a dv ers e ev e nts ( S A Es), a dv ers e ev e nts ( A Es), A Es of s p eci al i nt erest ( A E SI s), a n d Ev e nts of S p eci al I nt erest ( E O SIs) will b e c oll ect e d st arti n g wit h si g ni n g i nf or m e d c o ns e nt a n d c o nti n u e u ntil t h e e n d 
of t h e st u dy. All A Es t h at occ ur d uri n g tr e at m e nt s h o ul d b e f oll o w e d u ntil st u dy c o m pl eti o n ( or u ntil p ati e nts l e av e t h e st u dy)  or u ntil t h e ev e nt h as res olv e d, t h e c o n diti o n h as st a biliz e d, or t h e p ati e nt is l ost t o 
f oll o w-u p. All p ati e nts will h av e a f oll o w-u p visit 4 w e eks aft er t h e l ast d os e of I M P t o c oll ect s af ety i nf or m ati o n. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 9 
2  
T A B L E O F C O N T E N T S 
 
1  
F L O W C H A R T S.................................................................................................................... .........1 3  
1. 1  
G R A P HI C A L S T U D Y D E SI G N ...................................................................................................... 1 3  
1. 2  
S T U D Y F L O W C H A R T .................................................................................................................. 1 4  
2  
T A B L E O F C O N T E N T S ................................................................................................................ 1 9  
2. 1  
LI S T O F T A B L E S................................................................................................................. ..........2 5  
2. 2  
LI S T O F FI G U R E S......................................................................................................................... 2 5  
3  
LI S T O F A B B R E VI A TI O N S .......................................................................................................... 2 6  
4  
I N T R O D U C TI O N A N D R A TI O N A L E.............................................................................................2 8  
4. 1  
B A C K G R O U N D: S O T A G LI F L O ZI N A N D DI S E A S E ..................................................................... 2 8  
4. 2  
C LI NI C A L T RI A L S O F S O T A G LI F L O ZI N I N H U M A N S ................................................................ 2 9  
4. 3  
R A TI O N A L E F O R S E L E C TI O N O F D O S E ................................................................................... 3 0  
4. 4  
R A TI O N A L E F O R S T U D Y D E SI G N A N D C O N T R O L G R O U P S .................................................. 3 0  
4. 5  
R A TI O N A L E F O R A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y ................ 3 1  
4. 6  
B E N E FI T/ RI S K O F S O T A G LI F L O ZI N ........................................................................................... 3 1  
5  
S T U D Y O B J E C TI V E S ............................................................................................................... ....3 3  
5. 1  
P RI M A R Y........................................................................................................................ ...............3 3  
5. 2  
S E C O N D A R Y ...................................................................................................................... ..........3 3  
5. 3  
O T H E R........................................................................................................................................... 3 3  
5. 4  
A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y .............................................. 3 4  
6  
S T U D Y D E SI G N ................................................................................................................... .........3 5  
6. 1  
D E S C RI P TI O N O F T H E S T U D Y ................................................................................................... 3 5  
6. 1. 1  
S cr e e ni n g P eri o d............................................................................................................... .............3 5  
6. 1. 1. 1  
S cr e e ni n g p h a s e ( Vi sit 1) ...............................................................................................................3 5  
6. 1. 1. 2  
R u n-i n p h a s e ( Vi sit 2)..................................................................................................................... 3 6  
6. 1. 2  
D o u bl e- bli n d C or e Tr e at m e nt P eri o d ( W e e k 0 t o W e e k 2 6) .......................................................... 3 6  
6. 1. 3  
D o u bl e- bli n d E xt e n si o n P eri o d ( W e e k 2 7 t o W e e k 7 9).................................................................. 3 6  
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 0 
6. 1. 4  
A m b ul at or y bl o o d pr e s s ur e  m o nit ori n g s u b st u d y...........................................................................3 7  
 
3 7  
6. 1. 6  
F oll o w- u p p eri o d............................................................................................................... ..............3 7  
6. 2  
D U R A TI O N O F S T U D Y P A R TI CI P A TI O N .................................................................................... 3 7  
6. 2. 1  
D ur ati o n of st u d y p arti ci p ati o n f or e a c h p ati e nt ............................................................................. 3 7  
6. 2. 2  
D et er mi n ati o n of e n d of cli n i c al tri al ( all p ati e nt s) ..........................................................................3 8  
6. 3  
I N T E RI M A N A L Y SI S......................................................................................................................3 8  
6. 4  
S T U D Y C O M MI T T E E S ............................................................................................................... ...3 8  
6. 4. 1  
D at a m o nit ori n g c o m mitt e e ...................................................................................................... ......3 8  
6. 4. 2  
Cli ni c al e n d p oi nt c o m mitt e e( s)................................................................................................. ......3 8  
6. 4. 3  
S af et y a dj u di c ati o n of e v e nt s r e q uiri n g o n g oi n g m o nit ori n g .......................................................... 3 8  
6. 4. 4  
St e eri n g C o m mitt e e ............................................................................................................. ..........3 9  
7  
S E L E C TI O N O F P A TI E N T S.......................................................................................................... 4 0  
7. 1  
I N C L U SI O N C RI T E RI A..................................................................................................................4 0  
7. 2  
E X C L U SI O N C RI T E RI A ................................................................................................................ 4 0  
7. 2. 1  
E x cl u si o n crit eri a r el at e d t o st u d y m et h o d ol o g y ............................................................................ 4 0  
7. 2. 2  
E x cl u si o n crit eri a r el at e d t o di a b et e s hi st or y a n d tr e at m e nt .......................................................... 4 1  
7. 2. 3  
E x cl u si o n crit eri a r el at e d t o t h e c u rr e nt k n o wl e d g e of s ot a glifl o zi n ...............................................4 2  
7. 2. 4  
A d diti o n al e x cl u si o n crit eri a d ur i n g or at t h e e n d of t h e R u n-i n p h a s e b ef or e R a n d o mi z ati o n ......4 2  
8  
S T U D Y T R E A T M E N T S ............................................................................................................... ..4 4  
8. 1  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T S.............................................................................4 4  
8. 2  
N O NI N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T ....................................................................... 4 4  
8. 2. 1  
M etf or mi n ....................................................................................................................................... 4 4  
8. 2. 2  
R e s c u e t h er a p y .............................................................................................................................. 4 5  
8. 3  
B LI N DI N G P R O C E D U R E S............................................................................................................ 4 6  
8. 3. 1  
M et h o d s of bli n di n g ........................................................................................................................ 4 6  
8. 3. 2  
R a n d o mi z ati o n c o d e br e a ki n g d uri n g t h e st u d y............................................................................. 4 7  
8. 4  
M E T H O D O F A S SI G NI N G P A TI E N T S T O T R E A T M E N T G R O U P .............................................. 4 7  
8. 5  
P A C K A GI N G A N D L A B E LI N G ...................................................................................................... 4 8  
8. 6  
S T O R A G E C O N DI TI O N S A N D S H E L F LI F E ................................................................................ 4 8  
8. 7  
R E S P O N SI BI LI TI E S ............................................................................................................... .......4 8  
8. 7. 1  
Tr e at m e nt a c c o u nt a bi lit y a n d c om pli a n c e...................................................................................... 4 9  
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 1 
8. 7. 2  
R et ur n a n d/ or d e str u cti o n of tr e at m e nt s ........................................................................................ 4 9  
8. 8  
C O N C O MI T A N T M E DI C A TI O N..................................................................................................... 5 0  
8. 8. 1  
Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s ............................................................................... 5 0  
8. 8. 2  
C o n c o mit a nt di a b et e s t h er a p y ................................................................................................... ....5 1  
8. 9  
P O S T S T U D Y T R E A T M E N T .......................................................................................................... 5 1  
9  
A S S E S S M E N T O F I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T .............................................. 5 2  
9. 1  
E F FI C A C Y E N D P OI N T S ............................................................................................................. ..5 2  
9. 1. 1  
Pri m ar y effi c a c y e n d p oi nt...................................................................................................... .........5 2  
9. 1. 2  
S e c o n d ar y effi c a c y e n d p oi nt s ................................................................................................... .....5 2  
9. 1. 3  
Ot h er effi c a c y e n d p oi nt s ....................................................................................................... .........5 2  
9. 1. 4  
A s s e s s m e nt m et h o d s of effi c a c y e n d p oi nt s................................................................................... 5 3  
9. 1. 4. 1  
H e m o gl o bi n A 1 c................................................................................................................. ............5 3  
9. 1. 4. 2  
P o st pr a n di al gl u c o s e a n d mi x e d m e al t ol er a n c e t e st .................................................................... 5 3  
9. 1. 4. 3  
F a sti n g pl a s m a gl u c o s e m e a s ur e m e nt .......................................................................................... 5 4  
9. 1. 4. 4  
B o d y w ei g ht m e a s ur e m e nt ........................................................................................................ ....5 4  
9. 1. 4. 5  
Bl o o d pr e s s ur e e n d p oi nt m e a s ur e m e nt s ....................................................................................... 5 4  
9. 1. 4. 6  
Ki d n e y f u n cti o n p ar a m et er m e a s ur e m e nt...................................................................................... 5 5  
9. 1. 4. 7  
Pr o p orti o n of p ati e nt s r e q uiri n g r e s c u e f or h y p er gl y c e mi a ............................................................ 5 5  
9. 2  
S A F E T Y E N D P OI N T S ............................................................................................................... ....5 5  
9. 2. 1  
A s s e s s m e nt m et h o d s of s af et y e n d p oi nt s ..................................................................................... 5 6  
9. 2. 1. 1  
A d v er s e e v e nt s .............................................................................................................................. 5 6  
9. 2. 1. 2  
H y p o gl y c e mi a................................................................................................................... ..............5 6  
9. 2. 1. 3  
L a b or at or y s af et y v ari a bl e s .................................................................................................... ........5 7  
9. 2. 1. 4  
Vit al si g n s a n d p h y si c al e x a m.................................................................................................. ......5 9  
9. 2. 1. 5  
El e ctr o c ar di o gr a m v ari a bl e s .................................................................................................... ......5 9  
9. 2. 1. 6  
S elf- m o nit ori n g of  bl o o d gl u c o s e....................................................................................................5 9  
9. 2. 1. 7  
Di a b eti c k e t o a ci d o si s .....................................................................................................................6 0  
9. 3  
O T H E R E N D P OI N T S..................................................................................................................... 6 0  
9. 3. 1  
P h ar m a c o ki n eti c s............................................................................................................... ............6 0  
9. 3. 1. 1  
S a m pli n g ti m e ................................................................................................................................6 0  
9. 3. 1. 2  
P h ar m a c o ki n eti c s h a n dli n g pr o c e d ur e........................................................................................... 6 1  
9. 3. 1. 3  
Bi o a n al yti c a l m et h o d ......................................................................................................................6 1  
 
6 1  
9. 5  
A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y .............................................. 6 2  
 
6 3  
9. 7  
A P P R O P RI A T E N E S S O F  M E A S U R E M E N T S ..............................................................................6 3  
1 0  
S T U D Y P R O C E D U R E S ............................................................................................................... .6 5  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 2 
1 0. 1  
VI SI T S C H E D U L E................................................................................................................. .........6 5  
1 0. 1. 1  
S cr e e ni n g P eri o d............................................................................................................... .............6 5  
1 0. 1. 1. 1  S cr e e ni n g p h a s e ................................................................................................................ ............6 6  
1 0. 1. 1. 2  R u n-i n p h a s e.................................................................................................................................. 6 7  
1 0. 1. 2  
D o u bl e- bli n d r a n d o mi z e d C o r e Tr e at m e nt P eri o d .........................................................................6 8  
1 0. 1. 2. 1  Tr e at m e nt P eri o d ( D a y 1 t o W e e k 2 6) ........................................................................................... 6 8  
1 0. 1. 2. 2  A m b ul at or y bl o o d pr e s s ur e m o nit or pl a c e m e nt o n- sit e Vi sit 7 A a n d 9 A ( W e e k 1 2 a n d W e e k 
2 6) .................................................................................................................................................. 7 2  
1 0. 1. 3  
D o u bl e- bli n d e xt e n si o n p eri o d .................................................................................................. .....7 3  
1 0. 1. 3. 1  O n- sit e vi sit s at W e e k s 3 9, 5 2, a n d 6 5 ( Vi sit s 1 0 t o 1 2) ................................................................ 7 3  
1 0. 1. 3. 2  O n- sit e Vi sit 1 3 at W e e k 7 9 - E n d- of-tr e at m e nt ............................................................................. 7 4  
1 0. 1. 4  
P o st-tr e at m e nt F oll o w- u p p eri o d.................................................................................................... 7 5  
1 0. 1. 4. 1  O n- sit e f oll o w- u p Vi sit 1 4 ( W e e k 8 2).............................................................................................. 7 5  
1 0. 2  
D E FI NI TI O N O F S O U R C E D A T A.................................................................................................. 7 6  
1 0. 2. 1  
S o ur c e d at a t o b e f o u n d i n p ati e nt ’ s fil e.........................................................................................7 6  
1 0. 2. 2  
S o ur c e d at a v erifi c ati o n r e q u ir e m e nt s f or s cre e n f ail ur e s ............................................................. 7 7  
1 0. 3  
H A N D LI N G O F P A TI E N T T E M P O R A R Y O R P E R M A N E N T T R E A T M E N T 
DI S C O N TI N U A TI O N A N D O F P A TI E N T S T U D Y DI S C O N TI N U A TI O N....................................... 7 7  
1 0. 3. 1  
T e m p or ar y tr e at m e nt di s c o nti n u ati o n wit h  i n v e sti g ati o n al me di ci n al pr o d u ct( s) ........................... 7 7  
1 0. 3. 2  
P er m a n e nt tr e at m e nt di s c o nti n u ati o n wit h i n v e sti g ati o n al me di ci n al pr o d u ct( s) ........................... 7 8  
1 0. 3. 3  
Li st of crit eri a f or p er m a n e nt  tr e at m e nt di s c o nti n u ati o n.................................................................7 8  
1 0. 3. 4  
H a n dli n g of p ati e nt s aft er p er m a n e nt tr e at m e nt di s c o nti n u ati o n ................................................... 7 9  
1 0. 3. 5  
Pr o c e d ur e a n d c o n s e q u e n c e f or p ati e nt wit h dr a w al fr o m st u d y.................................................... 7 9  
1 0. 4  
O B LI G A TI O N O F T H E I N V E S TI G A T O R R E G A R DI N G S A F E T Y R E P O R TI N G .......................... 8 0  
1 0. 4. 1  
D efi niti o n s of a d v er s e e v e nt s.................................................................................................. .......8 0  
1 0. 4. 1. 1  A d v er s e e v e nt ................................................................................................................................ 8 0  
1 0. 4. 1. 2  S eri o u s a d v er s e e v e nt ................................................................................................................... 8 0  
1 0. 4. 1. 3  A d v er s e e v e nt of s p e ci al i nt er e st .............................................................................................. .....8 1  
1 0. 4. 1. 4  E v e nt s of s p e c i al i nt er e st ...............................................................................................................8 2  
1 0. 4. 2  
G e n er al g ui d eli n e s f or r e p orti n g a d v e r s e e v e nt s ...........................................................................8 3  
1 0. 4. 3  
I n str u cti o n s f or r e p orti n g s eri o u s a d v er s e e v e nt s ..........................................................................8 3  
1 0. 4. 4  
G ui d eli n e s f or r e p orti n g a d v er s e e v e nt s of s p e ci al i nt er e st ........................................................... 8 4  
1 0. 4. 5  
G ui d eli n e s f or r e p orti n g e v e nt s of s p e ci a l i nt er e st.........................................................................8 4  
1 0. 4. 6  
G ui d eli n e s f or m a n a g e m e nt of s p e cif i c l a b or at or y a b n or m aliti e s .................................................. 8 4  
1 0. 5  
O B LI G A TI O N S O F T H E S P O N S O R ............................................................................................. 8 4  
1 0. 6  
S A F E T Y I N S T R U C TI O N S ............................................................................................................ .8 5  
1 0. 6. 1  
H y p o gl y c e mi a................................................................................................................... ..............8 5  
1 0. 7  
A D V E R S E E V E N T S M O NI T O RI N G .............................................................................................. 8 7  
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 3 
1 1  
S T A TI S TI C A L C O N SI D E R A TI O N S .............................................................................................. 8 8  
1 1. 1  
D E T E R MI N A TI O N O F S A M P L E SI Z E........................................................................................... 8 8  
1 1. 2  
DI S P O SI TI O N O F P A TI E N T S ....................................................................................................... 8 8  
1 1. 3  
A N A L Y SI S P O P U L A TI O N S........................................................................................................... 8 9  
1 1. 3. 1  
Effi c a c y p o p ul ati o n s ........................................................................................................... ............8 9  
1 1. 3. 1. 1  I nt e nt-t o-tr e at p o p ul ati o n ................................................................................................................8 9  
1 1. 3. 2  
S af et y p o p ul ati o n .............................................................................................................. .............8 9  
1 1. 4  
S T A TI S TI C A L M E T H O D S ............................................................................................................ .9 0  
1 1. 4. 1  
E xt e nt of st u d y tr e at m e nt  e x p o s ur e a n d c o m pli a n c e.....................................................................9 0  
1 1. 4. 1. 1  E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e.................................................................... 9 0  
1 1. 4. 1. 2  C o m pli a n c e ..................................................................................................................... ...............9 1  
1 1. 4. 2  
A n al y s e s of effi c a c y e n d p oi nt s................................................................................................. ......9 1  
1 1. 4. 2. 1  A n al y si s of pri m ar y effi c a c y e n d p oi nt.......................................................................................... ...9 1  
1 1. 4. 2. 2  A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s ..................................................................................... 9 2  
1 1. 4. 2. 3  A n al y s e s of ot h er effi c a c y e n d p oi nt s ........................................................................................... ..9 3  
1 1. 4. 2. 4  A n al y si s of a m b ul at or y bl o o d pr e s s ur e m o nit ori n g s u b st u d y e n d p oi nt s........................................ 9 3  
1 1. 4. 2. 5  M ulti pli cit y c o n si d er ati o n s .................................................................................................... ..........9 3  
1 1. 4. 3  
A n al y s e s of s af et y d at a ........................................................................................................ ..........9 4  
1 1. 4. 3. 1  A n al y si s of a d v er s e e v e nt s ..................................................................................................... .......9 4  
1 1. 4. 3. 2  A n al y s e s of h y p o gl y c e mi a ....................................................................................................... ......9 6  
1 1. 4. 3. 3  A n al y s e s of a d v er s e e v e nt s of s p e ci a l i nt er e st..............................................................................9 6  
1 1. 4. 3. 4  A n al y s e s of e v e nt s of s p e ci al i nt er e st......................................................................................... ...9 6  
1 1. 4. 3. 5  A n al y s e s of l a b or at or y v ari a bl e s ............................................................................................... .....9 6  
1 1. 4. 3. 6  A n al y s e s of vit a l si g n v ari a bl e s ......................................................................................................9 6  
1 1. 4. 3. 7  A n al y s e s of 1 2 l e a d E C G st at u s ................................................................................................. ...9 7  
1 1. 4. 4  
A n al y s e s of p h ar m a c o ki n eti c v ari a bl e s.......................................................................................... 9 7  
1 1. 5  
I N T E RI M A N A L Y SI S......................................................................................................................9 7  
1 2  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S................................................................... 9 8  
1 2. 1  
E T HI C A L A N D R E G U L A T O R Y S T A N D A R D S .............................................................................. 9 8  
1 2. 2  
I N F O R M E D C O N S E N T .................................................................................................................9 8  
1 2. 3  
H E A L T H A U T H O RI TI E S A N D I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T 
E T HI C S C O M MI T T E E (I R B/I E C)................................................................................................... 9 8  
1 3  
S T U D Y M O NI T O RI N G............................................................................................................... ..1 0 0  
1 3. 1  
R E S P O N SI BI LI TI E S O F T H E I N V E S T I G A T O R..........................................................................1 0 0  
1 3. 2  
R E S P O N SI BI LI TI E S O F T H E S P O N S O R O R S E R VI C E  P R O VI D E R .......................................1 0 0  
1 3. 3  
S O U R C E D O C U M E N T R E Q UI R E M E N T S.................................................................................. 1 0 0  
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 4 
1 3. 4  
U S E A N D C O M P L E TI O N O F C A S E R E P O R T F O R M S ( C R F S) A N D A D DI TI O N A L 
R E Q U E S T .................................................................................................................................... 1 0 1  
1 3. 5  
U S E O F C O M P U T E RI Z E D S Y S T E M S........................................................................................ 1 0 1  
1 4  
A D DI TI O N A L R E Q UI R E M E N T S................................................................................................. 1 0 2  
1 4. 1  
C U R RI C U L U M VI T A E............................................................................................................... ...1 0 2  
1 4. 2  
R E C O R D R E T E N TI O N I N S T U D Y SI T E S .................................................................................. 1 0 2  
1 4. 3  
C O N FI D E N TI A LI T Y ..................................................................................................................... 1 0 2  
1 4. 4  
P R O P E R T Y RI G H T S................................................................................................................... 1 0 3  
1 4. 5  
D A T A P R O T E C TI O N ................................................................................................................ ...1 0 3  
1 4. 6  
I N S U R A N C E C O M P E N S A TI O N..................................................................................................1 0 4  
1 4. 7  
S P O N S O R A U DI T S A N D I N S P E C TI O N S B Y R E G U L A T O R Y A G E N CI E S ............................... 1 0 4  
1 4. 8  
P R E M A T U R E DI S C O N TI N U A TI O N O F T H E S T U D Y O R P R E M A T U R E C L O S E- O U T O F 
A SI T E ......................................................................................................................... .................1 0 4  
1 4. 8. 1  
B y t h e S p o n s or................................................................................................................. ............1 0 4  
1 4. 8. 2  
B y t h e I n v e sti g at or ............................................................................................................ ...........1 0 5  
1 4. 9  
C LI NI C A L T RI A L R E S U L T S ........................................................................................................ 1 0 5  
1 4. 1 0  
P U B LI C A TI O N S A N D C O M M U NI C A TI O N S ............................................................................... 1 0 5  
1 5  
C LI NI C A L T RI A L P R O T O C O L A M E N D M E N T S ........................................................................ 1 0 7  
1 6  
BI B LI O G R A P HI C R E F E R E N C E S............................................................................................... 1 0 8  
1 7  
A P P E N DI C E S.............................................................................................................................. 1 1 0  
A P P E N DI X A  G UI D A N C E O N C O N T R A C E P TI V E M E T H O D S A N D C O L L E C TI O N O F 
P R E G N A N C Y I N F O R M A TI O N .................................................................................................... 1 1 1  
A P P E N DI X B  A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y .................................. 1 1 4  
A P P E N DI X C  T W O- H O U R S T A N D A R DI Z E D MI X E D M E A L .................................................................. 1 1 7  
A P P E N DI X D  R E C O M M E N D A TI O N S O N B A SI C G E NI T O U RI N A R Y H Y GI E N E, M AI N T AI NI N G 
H Y D R A TI O N A N D R E C O G NI ZI N G DI A B E TI C K E T O A CI D O SI S............................................... 1 1 9  
A P P E N DI X E  M E A S U R E M E N T O F B L O O D P R E S S U R E A N D P U L S E R A T E ...................................... 1 2 2  
A P P E N DI X F  G E N E R A L G UI D A N C E F O R T H E F O L L O W- U P O F L A B O R A T O R Y 
A B N O R M A LI TI E S B Y S A N O FI.................................................................................................... 1 2 3  
 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 5 
2. 1  
LI S T O F T A B L E S 
T a bl e 1 - S u m m ar y of i n v e sti g ati o n al m e di ci n al pr o d u ct s........................................................................ .....4 4  
T a bl e 2 - S er u m c h e mi str y p ar a m et er s ........................................................................................... ..............5 7  
T a bl e 3 - S a m pl e s i d e ntifi cati o n ............................................................................................... .....................6 1  
 
2. 2  
LI S T O F FI G U R E S 
Fi g ur e 1 - H y p o gl y c e mi a cl a s si fi c ati o n i n Stu d y E F C 1 4 8 3 4....................................................................... ...8 6  
 
 
 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 6 
3  
LI S T O F A B B R E VI A TI O N S 
 
A B P M:  
a m b ulat or y bl o o d press ure m o nit ori n g 
A C R:
 al b u mi n-creati ni ne
 
rati o
 
A E:
 a d verse
 
e ve nt
 
A E SI:  
a d verse e ve nt of s p ecial i nterest 
A L T:
 ala ni ne
 
a mi n otra nsf eras e
 
A N C O V A:  
A nal ysis of C o varia nce 
A S T:
 as partate
 
a mi n otra nsferas e
 
B MI:  
b o d y mass i n de x 
B P:
 bl o o d
 
press ure
 
C E C:  
Cli nical E n d p oi nt C o m mittee 
CI:
 c o nfi de nce
 
i nter val
 
C R F:  
case r e p ort f or m 
C R O:  
c o ntract r esearc h or ga nizati o n 
C S R:  
cli nical st u d y r e p ort 
C V:
 car di o vas c ular
 
D B P:  
diast olic bl o o d press ure 
DI LI:  
dr u g-i n d uce d li ver i nj uri es 
D K A:
 dia betic
 
ket oaci d osis
 
D M C:  
Data M o nit ori n g C o m mittee 
D R F:  
Discre pa n c y Res ol uti o n F or m 
E C G:
 electr ocar di o gr a 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 O SI:  
e ve nts of s peci al i nterest 
E O T:
 E n d- of- Tr eat me nt
 
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 u c ose
 
F S H:  
f ollicle sti m ulati n g h or m o ne 
G C P:  
G o o d cli nical practice 
G C R:
 gl uc ose-cr eati ni ne
 
rati o
 
GI:
 gastr oi ntesti nal
 
G L P- 1:
 gl uca g o n-li ke
 
pe pti de- 1
 
H b A 1c:
 he m o gl o bi n
 
A 1c
 
H L G T:  
hi g h-le v el gr o u p ter m 
H L T:  
hi g h le vel ter m 
H R T:  
h or m o ne re place me nt t hera p y 
I B:
 I n v esti gat or's
 
Br oc h ure
 
I C F:  
i nf or me d c o nse nt f or m 
I C H:  
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C:  
i n de pe n de nt et hics c o m mittee 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 7 
I M P:
 I n v esti gati o nal me dici nal pr o d uct 
I R B:  
i nstit uti o nal re vie w b oar d 
I R T:  
I nteracti ve Res p o nse Tec h n ol o g y 
I T T:
 i nte nt-t o-treat
 
M A C E:  
maj or a d vers e car di o vasc ular e ve nts 
MI:
 m y ocar dial
 
i nfarcti o n
 
M M:
 mi x e d
 
meal
 
M M T T:  
mi x e d meal t olera nce test 
NI M P:
 n o ni n vesti gati o na l me dici nal pr o d uct 
O C:
 o bser ve d
 
cases
 
P C S A:
 p ote ntiall y
 
cli nicall y  si g nifica nt a b n or malit y 
P D:
 p har mac o d y n a mic
 
P- g p:
 P- gl yc o pr ot ei n
 
PI:
 Pri nci pal
 
I n v esti gat or
 
P K:
 p har mac o ki netic
 
P P G:
 p ost pra n dial
 
gl u c ose
 
P T:
 preferre d
 
t er m
 
P Y Y:
 pe pti de
 
Y Y
 
S A E:  
seri o us a d vers e e v e nt 
S A P:  
statistical a nal ysis pla n 
S B P:  
s yst olic bl o o d press ure 
S C:
 Steeri n g
 
C o m mittee
 
S D:
 sta n dar d
 
de viati o n
 
S E:
 sta n dar d
 
err or
 
S G L T:
 s o di u m- gl uc ose
 
c o-tra ns p orter
 
S G L T 1:  
s o di u m- gl uc ose c o ntra ns p orter t y pe 1 
S G L T 2:  
s o di u m- gl uc ose c otra ns p orter t y pe 2 
S M B G:  
self- m o nit ori n g of bl o o d gl uc ose 
S O C:  
s yste m or ga n class 
S U S A R:  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T 1 D:  
t y pe 1 dia b etes mellit us 
T 2 D:  
t y pe 2 dia b etes mellit us 
T E A E:  
treat me nt-e mer ge nt a d v erse e ve nts 
T G:
 tri gl yceri des
 
U G E:  
uri nar y gl uc ose e x creti o n 
U L N:  
u p per li mit of n or mal 
U S:
 U nite d
 
States
 
W O C B P:  
w o me n of c hil d- beari n g p ote ntial 
 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 8 
4  
I N T R O D U C TI O N A N D R A TI O N A L E 
4. 1  
B A C K G R O U N D: S O T A G LI F L O ZI N A N D DI S E A S E 
S ota glifl ozi n is a d ual i n hi bit or of t he s o di u m- g l u c ose c otra ns p orters t y pe 1 a n d 2 ( S G L T 1 a n d 
S G L T 2) b ei n g de vel o pe d f or use i n t y pe 2 dia bet es mellit us ( T 2 D), a meta b olic dis or der 
c haracterize d b y h y per gl yce mia t hat res ults fr o m a c o m bi nati o n of i ncreas e d i ns uli n resista nce 
a n d beta cell d ysf u ncti o n. T he mic r o vasc ul ar c o m plicati o ns of dia betes are well k n o w n a n d ca n 
res ult i n i m paire d re n al f u nctio n, reti n o pat h y a n d ne ur o pat h y. Ot her c o m or bi dities t hat are 
fre q ue ntl y ass o ciate d wit h dia betes are h y pert e nsi o n, o besit y, a n d car di o v asc ular ( C V) disease. 
Rece ntl y, t h e Ce nters f or Disease C o ntr ol a n d Pre ve nti o n releas e d a re p ort stati n g t hat if c urre nt 
tre n ds c o nti n ue, 1 i n 3 A merica ns will ha ve di a betes b y t he year 2 0 5 0. Acc or di n g t o t he m ost 
rece nt I nter nati o nal Di a b etes Fe d er ati o n Dia betes Atlas, t he esti mates i n 2 0 1 5 were t hat 1 i n 
1 1 a d ults ha ve dia betes, w hic h mea ns 4 1 5 milli o n pe o ple; esti mate d t o rise t o 6 4 2 milli o n b y 
2 0 4 0 ( 2 ). 
I n 2 0 1 0, 3 3 milli o n pe o ple i n t he E ur o pea n U ni o n had dia betes, 9 % of t he a d ult p o p ulati o n. T his 
n u m ber is pr ojecte d t o i n creas e t o 3 8 milli o n b y 2 0 3 0 ( 3 ). W hile t hese n u m bers i ncl u de b ot h 
pe o ple wit h T 2 D a n d t y p e 1 dia betes ( T 1 D), o ver 9 0 %  of a d ults wit h dia betes ha ve T 2 D. Di a betes 
is a m o n g t he lea di n g ca uses of deat h b y disease a n d is a lea di n g ca us e of h eart diseas e, str o ke, 
bli n d ness, ki d ne y diseas e, a n d a m p utati o n ( 2 , 3 ). Des pite t he fact t hat t he p o p ulati o n of pe o ple 
wit h dia betes is gr o wi n g, n o ne of t he c urre nt t her a pies is c urati ve a n d t he res ults of treat me nt are 
varia ble. 
Alt h o u g h lifest yle c h a n ges, i ncl u di n g diet, e x er cise, a n d e d u cati o n, are val u a ble c o m p o ne nts of 
dia betes treat me nt, t he vast maj orit y of pe o pl e wit h T 2 D re q uire p har mac ol o gical t hera p y t o 
c o ntr ol t he disease. I n t he U nite d States ( U S) a n d E ur o pe, metf or mi n is t he sta n dar d first-li ne 
t hera p y i n t he a bs e nce of a n y c o ntrai n dicati o ns or t olera bilit y iss ues as per g ui da n ce fr o m t he 
A merica n Ass o ciati o n of Dia betes ( 4 ).  
Des pite t he n u mer o us tr eat me nt o pti o ns a vaila ble, m o n ot hera p y fails i n ma n y patie nts as b eta-cell 
f u ncti o n c o nti n ues t o det eri orate l ea di n g t o pr o gressi vel y i ncreasi n g h y per gl yce mia. A g gressi ve 
gl yce mic c o ntr ol wit h t he c urre ntl y a vaila ble a ge nts ofte n lea ds t o si de effects, m ost n ota bl y 
wei g ht gai n a n d a n i ncrease d fr e q ue nc y of h y p o gl yce mia. T hes e c o ncer ns e m p hasize t he nee d t o 
de vel o p ne w a ge nts t hat effecti vel y a n d sa fel y l o wer gl uc ose i n dia b etic p atie nts. 
I n p atie nts wit h dia betes, it is desira ble t o mai ntai n bl o o d gl uc ose i n t he n or mal ra n ge wit h o ut 
e x ha usti n g t he a bilit y of t he pa ncr eatic b eta-cells t o pr o d uce i ns uli n. Gl uc ose is tra ns p orte d acr oss 
t he cell me m bra n e b y 2 differe nt t y pes of gl uc ose tra ns p orters: gl uc os e-facilitate d tra ns p orters a n d 
S G L T pr ot ei ns ( 5 ). I n t he ki d ne y, after bl o o d is filt ere d b y t he gl o mer ul us, gl uc ose passes i nt o t he 
uri ne, b ut 9 9 % is rea bs or be d, pri maril y via S G L T 2, w hic h is res p o nsi ble f or 9 0 % of gl uc ose 
rea bs or pti o n, w hile 1 0 % is rea bs or be d b y S G L T 1. W he n f u ncti o nal S G L T 2 is lac ki n g i n h u ma ns, 
a si g nifica nt a m o u nt of gl uc ose re mai ns i n  t he uri ne a n d is re m o ve d fr o m t he b o d y (6 ). T his wa y 
of re d uci n g bl o o d gl uc os e is n ot a n i ns uli n- de pe n de nt mec ha nis m; t heref ore h y p er gl yce mia ma y 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 2 9 
be re d uce d w hile t he p a n creas is s pare d fr o m a n i ncreas e d de ma n d f or i ns uli n pr o d ucti o n t hat is 
ca use d b y h y p er gl yce mia. Si nce o besit y is a si g nifica nt c o m or bi dit y i n T 2 D M, a n d i ns uli n 
resista nce is i ncr eas e d i n o besit y, t he cal oric l oss fr o m gl uc os e i n t he uri ne ma y re prese nt a n 
a d diti o nal be nefit res ulti n g i n decrease d w ei g ht, w hic h s h o ul d res ult i n decreas e d i ns uli n 
resista nce (6 ).  
T he S G L T 1 is e x presse d pre d o mi na ntl y i n t he gast r oi ntesti nal ( GI) tract; S G L T 1 is res p o nsi ble 
f or t he maj orit y of gl uc os e a bs or pti o n b y t he s mall i ntesti ne (7 ). I n hi biti o n of S G L T 1 i n t he GI 
tract pre v e nts gl u c ose fr o m bei n g a bs or be d. A d diti o nall y, t here is acc u m ulati n g e vi de n ce t hat 
S G L T 1 i n hi biti o n sti m ulates secr eti o n of gl uca g o n-li ke pe pti de- 1 ( G L P- 1) a n d pe pti de Y Y 
( P Y Y), g ut h or m o nes i n v ol ve d i n pa ncreatic beta-cell f u ncti o n a n d a p p etite c o ntr ol, res pecti vel y. 
Re d uce d gl uc ose a bs or pti o n i n t he pr o xi mal i ntesti ne lea ds t o m ore gl uc ose bei n g d eli vere d 
distall y, w hic h all o ws L cells i n b ot h t he ile u m a n d t he c ol o n t o se nse gl uc ose a n d its b y pr o d ucts, 
a n d as a r es ult, t he y s ecr ete G L P- 1 a n d P Y Y. A lt h o u g h a c o m plete lac k of f u ncti o nal S G L T 1 ma y 
be ass ociate d wit h s y m pt o ms of gl uc os e a n d galact ose mala bs or pti o n ( 8 ), p har mac ol o gic 
i n hi biti o n of S G L T 1 b y s ota glifl ozi n has n ot pro d uce d t hese effects i n precli nical m o dels or 
patie nts wit h T 2 D. Selecti ve i n hi bit ors of t he S G L T 1 tra ns p orter are i n earl y sta ges of 
de vel o p me nt. 
E xte nsi ve cli nical st u dies c o n d ucte d f or selecti ve S G L T 2 i n hi bit ors ha ve esta blis he d t his class as 
effecti ve a ge nts f or t he treat me nt of T 2 D ( 9 , 1 0 , 1 1 ) a n d ha ve l e d t o a p pr o v als b y t he U S F o o d 
a n d Dr u g A d mi nistrati o n ( F D A) a n d t he E ur o p ea n Me dici nes A ge n c y ( E M A). St u dies wit h 
s ota glifl ozi n, a p ote nt, d ual i n hi bit or of S G L T 2 a n d S G L T 1, ha v e s h o w n t h at t his a ge nt pr o d uces 
si g nifica nt gl uc os uria i n precli nical a ni mal mo dels, healt h y h u ma n v ol u nteers, a n d patie nts wit h 
T 2 D. Si n gle a n d m ulti ple- d ose a d mi nistrati o n of s ota glifl ozi n t o healt h y h u ma n patie nts has 
res ulte d i n d ose- de p e n de nt i ncreases i n gl uc os uri a. M ulti ple- d ose ( 2 8- da y) a d mi nistrati o n i n 
dia betic patie nts pr o d uce d i m pr o ve me nts i n se veral meta b olic para meters, i ncl u di n g uri nar y 
gl uc ose e x creti o n ( U G E), fasti n g plas ma gl u c ose ( F P G), he m o gl o bi n A 1c ( H b A 1c), G L P- 1, a n d 
P Y Y. T hese data s u g gest t hat s ota glifl ozi n s h o ul d be  of t hera pe utic be n efit t o patie nts wit h T 2 D.  
4. 2  
C LI NI C A L T RI A L S O F S O T A G LI F L O ZI N I N H U M A N S 
A p pr o xi matel y 7 8 0 s u bj ects ( 6 3 9 assi g n e d t o s o ta glifl ozi n a n d 1 4 1 assi g n e d t o place b o) ha v e 
partici pate d i n c o m plete d cli nical st u dies of s ota glifl ozi n. N o si g nifica nt safet y c o ncer ns ha ve 
bee n i de ntifie d i n t he s ot a glifl ozi n dr u g pr o gra m, a n d s ota glifl ozi n has bee n well-t olerate d i n all 
st u dies t o date. Seri o us a d verse e v e nts ( S A Es) a n d disc o nti n uati o ns d ue t o a d verse e ve nts ( A Es) 
ha ve bee n i nfre q u e nt a n d ha ve bee n bala n ce d bet wee n treat me nt a n d c o m parat or gr o u ps. R e p orts 
of treat me nt-e mer ge nt a d verse e v e nts ( T E A E) acr oss all s ota glifl ozi n st u dies f or w hic h d ata are 
a vaila ble w ere ge nerall y bala nce d  b et wee n treat m e nt a n d c o m parat or gr o u ps. T he m ost fre q ue ntl y 
re p orte d T E A Es (≥2. 0 %) were h ea dac he, n a usea, diarr hea, c o nsti pati o n, a n d dizzi ness, all of 
w hic h were re p orte d at a fre q ue n c y greater t h a n  place b o. H o we ver, m ost were des cri be d as mil d 
t o m o derate, a n d m ost res ol ve d s p o nta ne o usl y.  
I n c o m plete d a n d o n g oi n g cli nical trials, n o safet y iss ues i n a d diti o n t o t h ose alrea d y descri be d i n 
t he c urr e nt I n vesti gat or Br oc h ure w ere o bs er ved. I n ge neral, n o si g nifi ca nt i m bala nces of 
S A E/ A Es bet wee n s ota glifl ozi n a n d c o m parat ors were o bs er ve d i n c o m plete d st u dies.  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 0 
C u m ulati vel y, d uri n g t he cli nical trial pr o gra m 8 S A Es were re p orte d b y 6 patie nts ( 4 T 2 D a n d 
2 T 1 D), all of w hic h wer e assesse d as u nrelat e d t o st u d y dr u g; t h ose re p orte d b y 4 T 2 D p atie nts 
w h o recei ve d s ota glifl ozi n i ncl u de d p ul m o nar y e m b olis m, dee p vei n t hr o m b osis, bile d uct st o ne, 
c h ola n gitis a n d l o wer li m b fract ure, w hile a m y o car dial i nfarcti o n ( MI) was e x perie nce d b y a 
patie nt recei vi n g place b o. T w o S A Es of dia betic k et oaci d osis were re p orte d b y 2 T 1 D p atie nts 
recei vi n g 4 0 0 m g o nce d ail y s ota glifl ozi n i n t he P hase 2 T 1 D st u d y L X 4 2 1 1. 1- 2 0 3- TI D M; b ot h 
S A Es were assesse d as d ue t o fail ure  of i ns uli n deli ver y via i ns uli n p u m p. 
A dr u g i nteracti o n st u d y wit h di g o xi n, a se nsiti ve P- gl yc o pr ot ei n ( P- g p) s u bstrate, i n dicate d t hat 
s ota glifl ozi n acts as a w ea k P- g p i n hi bit or.  
M ore i nf or mati o n o n t he safet y of s ota glifl ozi n a n d o n t he cli nical pr o gra m ca n be f o u n d i n t he 
I n v esti gat or Br oc h ur e (I B). 
4. 3  
R A TI O N A L E F O R S E L E C TI O N O F D O S E 
T he pr o p ose d 4 0 0 m g o n ce dail y d ose is base d o n t he res ults of t he P hase 2 b st u d y 
L X 4 2 1 1. 1- 2 0 2- D M. I n t his st u d y d os es of 7 5 m g o nce dail y, 2 0 0 m g o nce d ail y, 2 0 0 m g t wice 
dail y, a n d 4 0 0 m g o n ce d ail y s ota glifl ozi n were  teste d o ver a 1 2- wee k, d o u ble- bli n d peri o d. T he 
4 0 0 m g o nce dail y d ose was c h ose n f or f urt h er e v al uati o n base d o n its H b A 1c l o weri n g effect a n d 
t he o verall safet y a n d t ol era bilit y o bs er ve d at t his d ose. At 1 2 wee ks, t he 4 0 0 m g d ose l o w ere d 
H b A 1c b y a mea n of 0. 9 3 %, w hile place b o l o w ere d H b A 1c b y a mea n of 0. 1 4 %. L o wer d os es 
were less eff ecti ve t ha n t he 4 0 0 m g d os e a n d di d n ot ha ve a n y a d v a nta ges i n safet y or t olera bilit y. 
T he o ver all i nci de nce of A Es i n patie nts recei vi n g 4 0 0 m g o nce dail y was si milar t o t hat see n wit h 
place b o. 
I n h ealt h y s u bjects s ota glifl ozi n was well-t olerate d f oll o wi n g si n g le d oses u p t o 2 0 0 0 m g, a n d i n 
m ulti ple d oses u p t o 8 0 0 m g o ver 1 0 da ys. F urt her m or e, si n gle d os es of s ot a glifl ozi n ( 8 0 0 m g a n d 
2 0 0 0 m g) w ere well-t oler ate d a n d di d n ot pr ol o n g t he Q T i nter val. A d diti o n all y, e v al uati o n of 
meta b olites i n uri ne a n d plas ma of healt h y s u bjects res ulte d i n n o safet y c o ncer ns f oll o wi n g si n gle 
d oses of 4 0 0 m g s ota glifl ozi n. Si n gle d oses of  4 0 0 m g i n c o m bi nati o n wit h sita gli pti n, a n d 
m ulti ple d oses u p t o 4 0 0 m g i n c o m bi nati o n wit h metf or mi n o ver 1 2 wee ks were als o 
well-t olerate d i n p atie nts wit h T 2 D. 
4. 4  
R A TI O N A L E F O R S T U D Y D E SI G N A N D C O N T R O L G R O U P S 
T his st u d y is desi g n e d t o de m o nstrate t he efficac y  a n d safet y of s ot a glifl ozi n w he n use d as a d d- o n 
t hera p y t o metf or mi n i n patie nts wit h T 2 D w h o ha ve i na de q u ate gl yce mic c o ntr ol. S ota glifl ozi n 
pl us metf or mi n will be c o m pare d t o place b o pl us metf or mi n. Bas e d o n t he st u d y desi g n, t he 
pr ot oc ol sti p ulates t hat patie nt s be pr o vi de d a nti di a betic a ge nt resc u e t hera p y acc or di n g t o a 
pre defi n e d al g orit h m. Safet y, t olera bilit y, p h ar mac o ki netic ( P K) a n d p h ar mac o d y na mic ( P D) 
effects of s ota glifl ozi n are s u p p orte d b y P hase 1 a n d P hase 2 st u dies a n d t o xic ol o g y dat a i n rats u p 
t o 2 6 wee ks a n d d o gs u p t o 3 9 wee ks as w ell as 2- year carci n o ge nicit y d ata i n rats. 
T o ac hie ve b ala nce d ra n d o miza ti o n f or assess me nt of t he pri mar y e n d p oi nt, ra n d o mizati o n will be 
stratifie d base d o n pree xisti n g meta b olic c o ntr ol ( Scree ni n g H b A 1 c ≤8. 0 % vers us > 8. 0 %). 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 1 
A n ot her stratificati o n fact or (s yst olic bl o o d press ure  [ S B P] < 1 3 0 m m H g vers us ≥1 3 0 m m H g) h as 
bee n a d d e d t o e ns ure b al a nce i n r a n d o mizati o n f o r a sec o n d ar y e n d p oi nt (c ha n ge fr o m Bas eli ne t o 
1 2- wee ks i n S B P f or pati e nts wit h baseli ne S B P ≥1 3 0 m m H g). 
A place b o c o ntr ol will be use d t o all o w f or a n u n bi ase d assess me nt of treat me nt effects a n d safet y 
data. Bias will be mi ni mize d b y ra n d o mizi n g t he p atie nts t o treat me nt gr o u ps, bli n di n g t he 
patie nts, t he I n vesti gat ors, a n d t he S p o ns or t o t he treat me nt all ocati o ns, a n d b y a dj u dicati n g t h e 
e n d p oi nts i n a bli n de d fas hi o n. 
A parallel- gr o u p, ra n d o mize d place b o c o ntr olle d d esi g n w as selecte d be ca use trial partici pa nts are 
e x p ose d t o a si n gle treat me nt a n d assi g n m e nt t o t hat treat me nt is base d s ol el y o n c ha nce.  T his 
desi g n is fr ee of t he li mitati o ns of c o m peti n g d esi g ns s uc h as cr oss o ver i n w hic h t here ma y b e a 
carr y o v er of eff ect fr o m o ne treat me nt t o t he sec o n d treat me nt. Alt h o u g h t his carr y o ver effect ca n 
be mi ni mize d wit h a was h o ut peri o d, it is p ossi ble t h at s o me l o n ger ter m effects ma y persist.  
W hile t he sa m ple size of t he pa rallel gr o u p d esi g n is lar ger t o acc o u nt f or m ore vari a bilit y w he n 
partici pa nts ca n n ot ser ve as t heir o w n c o ntr ol,  t he a b o ve- me nti o ne d li mitati o ns of t he cr oss o ver 
desi g n ha ve le d t he ra n d o mize d c o ntr olle d trial desi g n t o be t he sta n d ar d f or t hera pe utic 
c o nfir mat or y trials f or re g ulat or y a p pr o val s uc h as t his trial. 
4. 5  
R A TI O N A L E F O R A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y 
Data fr o m a P hase 2 trial of s ota glifl ozi n ( L X 4 2 1 1. 1- 2 0 2) s u g gest t hat s ota glifl ozi n re d uce d b ot h 
S B P a n d diast olic bl o o d press ure ( D B P) i n p atie nts wit h ele vate d S B P a n d D B P at baseli ne b ut 
n ot n or m ote nsi ve patie nts. I n or de r t o s yste maticall y assess t he S B P a n d D B P l o weri n g efficac y 
of s ota glifl ozi n, b ot h sitti n g bl o o d pr ess ure at  st u d y visits a n d a m b ulat or y bl o o d press ure 
m o nit ori n g ( A B P M) will be meas ur e d. A m b ulat or y bl o o d press ure m o nit ori n g is m ore cl osel y 
c orrel ate d wit h mar kers of or ga n da m a ge, a n d is a m ore se nsiti ve pre dict or of C V o utc o mes ( 1 2 ). 
It als o p er mits assess me nt of nig htti me a n d da yti m e bl o o d press ure ( 1 2 ), a n d has bee n s h o w n t o 
re d uce t h e “ w hite c oat” effect see n wit h sitti n g bl o o d press ure meas ure m e nts. 
4. 6  
B E N E FI T/ RI S K O F S O T A G LI F L O ZI N 
S ota glifl ozi n is c urre ntl y bei n g i n vesti gate d as  a n a dj u nct t o diet a n d e x ercise t o i m pr o ve 
gl yce mic c o ntr ol i n a d ults wit h T 2 D. T he st u d y pr o gra m will als o pr o vi de efficac y a n d safet y data 
f or s ota glifl ozi n i n c o m bi nati o n wit h ot her a nti dia betic me dicati o ns. I n a d diti o n t he st u d y pr o gra m 
will e val uate cli nical o ut c o mes i n patie nts wit h hi g h C V ris k a n d i n p atie nts wit h re nal 
i m pair me nt. T he use of s ota glifl ozi n i n t he treat me nt of T 1 D is als o bei n g st u die d i n a se parat e 
de vel o p me nt pr o gr a m. 
S ota glifl ozi n ma y be n efit a wi de vari et y of dia beti c patie nts base d o n m ulti ple p ote ntial be nefici al 
effects of d ual S G L T 2/ S G L T 1 i n hi biti o n, a n d its i ns uli n-i n de pe n de nt mec ha nis m of acti o n. 
I m pr o v e me nts i n H b A 1c, F P G, a n d p ost pra n dial gl uc ose ( P P G) were o bser ve d wit h s ota glifl ozi n 
i n m ulti ple st u dies. As a ntici pate d fr o m t he mec h a nis m of acti o n, treat me nt wit h s ota glifl ozi n 
res ulte d i n i ncrease d U G E (fr o m i n hi biti o n of S G L T 2) as well as i ncrease d i ncreti n le vels (fr o m 
i n hi biti o n of S G L T 1). I n a d diti o n, t he i m pr o ve ments i n b o d y wei g ht, bl o o d press ure ( B P), a n d 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 2 
tri gl yceri des ( T G) o bser v e d wit h s ota glifl ozi n treat me nt ha ve t he p ote ntial t o be nefit patie nts wit h 
dia betes t hr o u g h t heir effects o n c o m m o n dia betic c o m or bi dities. 
O verall, s ota glifl ozi n has bee n well-t olerate d i n all st u dies t o date, wit h t he maj orit y of e ve nts 
assesse d as mil d t o m o dera te; m ost of w hic h res ol ve d s p o nta ne o usl y. Se vere a d vers e e v e nts a n d 
disc o nti n uati o ns d ue t o A Es ha ve bee n li mite d a n d bala nce d b et wee n treat me nt a n d c o m parat or 
gr o u ps. Se v ere h y p o gl yc e mia, ge n ital m yc otic i nfecti o ns, uri nary tract i nfecti o ns, dia betic 
ket oaci d osis ( D K A), v ol u me de ple ti o n wit h seri o us c o nse q ue nce ( ort h ostasis, falls, fract ures), 
se vere di arr h ea, pa n creatitis, b o ne fract ures, ve n o us t hr o m b otic e ve nts, dr u g-i n d uce d li ver i nj uries 
( DI LIs), s e ver e r e nal e ve nts an d mali g na n cies of s pecial i nterest  ( breast, bl a d der, re nal cell, 
Le y di g cell, pa ncreatic, pr ostate , a n d t h yr oi d carci n o ma) are m o nit ore d cl osel y as i d e ntifie d a n d 
p ote ntial ris ks. 
T he i m pr o ve me nt i n gl yc e mic c o ntr ol, t he re d ucti o ns i n wei g ht a n d B P, a n d t he t olera bilit y a n d 
safet y pr ofile of s ota glifl ozin t o date, de m o nstrate a fa v ora b le be n efit-ris k assess me nt f or 
s ota glifl ozi n. 
 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 3 
5  
S T U D Y O B J E C TI V E S 
5. 1  
P RI M A R Y  
T he pri mar y o bjecti ve of t his st u d y is t o de m o nstrate t he s u peri orit y of s ota glifl ozi n 4 0 0 m g 
vers us place b o o n H b A 1 c re d ucti o n at Wee k 2 6 i n patie nts wit h T 2 D w h o ha ve i na de q u ate 
gl yce mic c o ntr ol wit h metf or mi n. 
5. 2  
S E C O N D A R Y  
•  T o c o m pare s ota glifl ozi n 4 0 0 m g vers us place b o f or:  
- 
C ha n ge fr o m Baseli ne i n 2- h o ur P P G f oll o wi n g a mi x e d meal ( M M) at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n F P G at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n b o d y w ei g ht at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or patie nts wit h Baseli ne S B P ≥1 3 0 m m H g  
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or all p atie nts 
- 
Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6 
•  T o e val uate t he s afet y of s ota glifl ozi n 4 0 0 m g vers us place b o t hr o u g h o ut t h e 7 9- wee k 
trial. 
5. 3  
O T H E R 
•  T o c o m pare s ota glifl ozi n vers us place b o wit h res p ect t o c ha n ge fr o m Baseli ne o n t he 
f oll o wi n g e n d p oi nts: 
- 
Uri ne al b u mi n-creati ni ne rati o ( A C R) 
- 
Uri nar y gl uc os e e x creti o n a n d uri ne gl uc ose-creati ni ne rati o ( G C R) 
- 
Esti mate d gl o mer ular filtrati o n rate (e G F R) 
- 
Re d ucti o n i n b o d y wei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 % 
•  T o c o m pare s ota glifl ozi n vers us place b o f or: 
- 
C ha n ge fr o m Baseli ne i n H b A 1c at Wee k 7 9 
- 
C ha n ge fr o m Baseli ne i n F P G at Wee k 7 9 
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 2 6 f or all p atie nts a n d f or patie nts wit h 
Baseli ne S B P ≥1 3 0 m m H g 
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 7 9 f or all p atie nts a n d f or patie nts wit h 
Baseli ne S B P ≥1 3 0 m m H g 
- 
C ha n ge fr o m Baseli ne i n b o d y w ei g ht at Wee k 7 9 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 4 
•  T o c o m pare t h e use of resc ue me dicati o ns f or h y p er gl yce mia i n t he s ota glifl ozi n a n d 
place b o tre at me nt gr o u ps 
•  T o assess plas ma c o n ce ntrati o ns of s ota glifl ozi n a n d its 3- O- gl u c ur o ni de m eta b olite. 
5. 4  
A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y 
T he pri mar y o bjecti ve of t he A B P M s u bst u d y is t o  c o m pare t he effect of s ot a glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h mea n S B P ≥1 3 0 m m H g at Scree ni n g o n 2 4- h o ur a vera ge S B P 
at Wee k 1 2. 
T he sec o n d ar y o bjecti ves of t he A B P M s u bst u d y are t o c o m pare t he effect of s ota glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h mea n S B P ≥1 3 0 m m H g at Scree ni n g o n t he f oll o wi n g: 
•  2 4- h o ur a vera ge S B P at Wee k 2 6 
•  2 4- h o ur a vera ge D B P at Wee ks 1 2 a n d 2 6 
•  A vera ge a dj uste d a wa ke ti me bl o o d press ure ( B P) as meas ure d b y S B P a n d D B P at Wee ks 
1 2 a n d 2 6 wit h a dj ust me nt base d o n acti gra p h y 
•  A vera ge a dj uste d slee pi n g ti me B P as m eas ure d b y S B P a n d D B P at Wee ks 1 2 a n d 2 6 
wit h a dj ust me nt base d o n acti gra p h y 
F ull details of t he A B P M s u bst u d y are pr o vi de d i n A p pe n di x B . 
 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 5 
6  
S T U D Y D E SI G N 
6. 1  
D E S C RI P TI O N O F T H E S T U D Y 
T his st u d y is a P hase 3, m ultice nter a n d m ulti nati o nal, 1: 1 ra n d o mize d, d o u ble- bli n d, 
place b o- c o ntr olle d, par allel- gr o u p st u d y t hat is a n tici pate d t o e nr oll a p pro xi matel y 5 0 0 p atie nts. 
T he st u d y will c o m prise a Scree ni n g Peri o d c o nsisti n g of a Scree ni n g p has e of u p t o 2 wee ks a n d 
a 2- wee k si n gl e- bli n d R u n-i n p hase, a d o u ble- bli n d C ore Treat me nt Peri o d, a d o u ble- bli n d 
E xte nsi o n Peri o d, a n d a F oll o w- u p Peri o d. A d diti o nall y, t here will be a n A B P M s u bst u d y f or a 
s u bset of patie nts wit h mea n Scree ni n g S B P ≥1 3 0 m m H g. Se parate i nf o r m e d c o nse nt will be 
ta ke n bef ore patie nts partici pate i n t he A B P M s u bst u d y. 
T he st u d y d esi g n is pr ese nte d gr a p hicall y at t he e n d of t he s y n o psis. 
6. 1. 1  S cr e e ni n g P eri o d 
6. 1. 1. 1  S cr e e ni n g p h a s e ( Vi sit 1) 
T he Scree ni n g p h ase will last u p t o 2 wee ks. T he p eri o d m ust be l o n g e n o u g h t o c ollect t he data 
re q uire d t o esta blis h w h et her t he patie nt satisfies t he i ncl usi o n/e x cl usi o n criteria. 
Patie nts ta ki n g metf or mi n at a sta ble d osa ge ≥1 5 0 0 m g/ da y f or at least 1 2 wee ks bef ore 
e nr oll me nt will be eli gi bl e f or scree ni n g. 
Patie nts o n metf or mi n at a d ose < 1 5 0 0 m g/ da y at t h e ti me of e nr oll me nt ( m ai ntai ne d f or at least 
1 2 wee ks bef ore e nr oll me nt) ma y be eli gi ble f or s cree ni n g if d o c u me ntati o n of lac k of t olera nce 
of a metf or mi n d ose ≥1 5 0 0 m g/ da y ca n be pr o vi d e d.  
At t he Scree ni n g Visit aft er si g ni n g of t he i nf or me d c o nse nt f or m (I C F), eli gi bilit y criteria will be 
assesse d a n d Scree ni n g assess me nts will be perf or me d. W o me n of c hil d beari n g p ote ntial 
( W O C B P) n ot willi n g t o use hi g hl y effecti ve met h o d(s) of birt h c o ntr ol d uri n g t he st u d y treat me nt 
peri o d a n d t he f oll o w- u p peri o d, or w h o are u n willi n g or  u n a ble t o be teste d f or pre g n a nc y will be 
e x cl u de d fr o m t he st u d y; g ui da n ce o n hi g hl y eff ecti ve c o ntrace pti ve met h o ds a n d c ollecti o n of 
pre g na nc y i nf or mati o n is pr o vi de d i n A p pe n di x A . If a n ot her c o ntrace pti ve met h o d is use d (s uc h 
as a barrier met h o d), it s h o ul d be use d i n c o m bi na ti o n wit h o ne of t he hi g hl y effecti ve met h o ds i n 
A p pe n di x A  (s uc h as a n oral c o ntrace pti ve). 
T he I nteracti ve Res p o nse Tec h n ol o g y (I R T; eit h er I nteracti ve V oice Res p o nse S yste m or 
I nteracti ve We b Res p o nse S yste m) will be c o ntact e d at Visit 1 f or n otificati o n of scree ni n g a n d 
f or patie nt n u m ber all ocati o n. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 6 
6. 1. 1. 2  R u n-i n p h a s e ( Vi sit 2) 
T he R u n-i n p hase will last 2 wee ks. Patie nts will be treate d i n a si n gl e- bli n d ma n ner wit h place b o 
( 2 ta blets) o nce d ail y d uri n g t he R u n-i n p hase, st arti n g fr o m Visit 2. Patie nts i ncl u de d i n t he 
A B P M s u bst u d y will als o atte n d Visit 3 A f or place me nt of t he A B P M. 
6. 1. 2  D o u bl e- bli n d C or e Tr e at m e nt P eri o d ( W e e k 0 t o W e e k 2 6) 
Eli gi ble patie nts will be r a n d o mize d o n Da y 1 ( V isit 3). I n or d er t o q ualif y f or ra n d o mizati o n, 
patie nts m ust de m o nstrate c o m plia nce d uri n g t h e si n gle- bli n d place b o R u n-i n p hase base d u p o n 
ta blet c o u nt (≥8 0 %).  
Ra n d o mizati o n will be stratifie d b y: 
•  H b A 1c at Scr ee ni n g ( ≤8. 0 %, > 8. 0 %) 
•  S B P at Scree ni n g ( < 1 3 0 m m H g, ≥1 3 0 m m H g)  
F oll o wi n g ra n d o mizati o n, patie nts will be treate d i n a d o u ble- bli n d ma n ner f or 2 6 wee ks. All 
patie nts will ha ve P P G assesse d f oll o wi n g a M M T T at Wee ks 0 a n d 2 6. A t otal of 5 0 0 patie nts 
≥1 8 years of a ge ( or ≥le gal a ge of maj orit y if great er) will be ra n d o ml y assi g ne d 1: 1 t o t he 
f oll o wi n g 2 treat me nt gr o u ps: 
•  S ota glifl ozi n 4 0 0 m g as t w o 2 0 0 m g ta blets, o nce dail y 
•  Place b o as t w o place b o t a blets (i de ntical t o  s ota glifl ozi n i n a p peara nce), o n ce dail y 
Fasti n g gl uc ose ( plas m a or ser u m), H b A 1 c, a n d P P G will be mas ke d t o st u d y sites a n d p atie nts 
after r a n d o mizati o n u ntil st u d y e n d. T o pre ve nt pa rtial u n bli n di n g, U G E a nd G C R res ults will be 
mas ke d t o i n vesti gati o nal sites a n d patie nts, a n d t he ce ntral la b orat or y uri ne di pstic k will n ot 
i ncl u de t he meas ur e me nt of uri ne gl uc ose. 
If a patie nt disc o nti n ues treat ment wit h i n vesti gati o nal me dici nal pr o d uct (I M P) earl y d uri n g t he 
2 6- wee k C or e Treat me nt Peri o d, t h e patie nt will ha ve a Pre m at ure E n d- of- Treat me nt ( E O T) Visit 
a n d a F oll o w- u p Visit 4 wee ks after t he last d ose of I M P. I n a d diti o n, e ver y eff ort will be ma d e t o 
ha ve all patie nts r et ur n t o t he s ite at t he ti me c orres p o n di n g t o t heir sc he d ul e d visits, partic ularl y 
t he Wee k 2 6 Visit. If t h e patie nt d oes n ot a gree t o site visits, t he y will be c o ntacte d b y tele p h o n e 
t o i n q uire a b o ut safet y st at us. 
6. 1. 3  D o u bl e- bli n d E xt e n si o n P eri o d ( W e e k 2 7 t o W e e k 7 9) 
Fr o m Wee k 2 7 t o 7 9, patie nts will be i n a 5 3- wee k d o u ble- bli n d E xte ns i o n Peri o d. Patie nts will 
c o nti n ue t o recei ve t he bli n de d me dicati o n (s ota glifl ozi n or place b o) t o w hi c h t he y were 
ra n d o mize d o n Da y 1. All patie nts will ha ve P P G assesse d f oll o wi n g a M M T T at Wee k 7 9. 
Patie nts w h o recei v e d res c ue me di cati o n d uri n g t h e 2 6- wee k C ore Treat me nt Peri o d will c o nti n ue 
o n t he sa me res c ue me di cati o n d ur i n g t h e d o u ble- bli n d E xte nsi o n Peri o d ( u nless t he I n vesti gat or 
c o nsi ders a c h a n ge n ecessar y f or s afet y reas o ns). 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 8 
6. 2. 2  D et er mi n ati o n of e n d of cli ni c al tri al ( all p ati e nt s) 
T he e n d of t he st u d y is d efi ne d as b ei n g t h e “las t patie nt last visit” pla n ne d wit h t he pr ot oc ol, 
i ncl u di n g f oll o w- u p visit. 
T he S p o ns or ca n ter mi nate t he trial pre mat urel y b ase d o n t he a d vice of t he i n de pe n de nt Dat a 
M o nit ori n g C o m mittee ( D M C) or ot her u nf oresee n de vel o p me nts. 
6. 3  
I N T E RI M A N A L Y SI S 
N o i nteri m a nal ysis is pla n ne d. 
6. 4  
S T U D Y C O M MI T T E E S 
6. 4. 1  D at a m o nit ori n g c o m mitt e e 
A D M C wit h me m bers w h o are i n de p e n de nt fr o m t h e S p o ns or a n d t he I n vesti gat ors will meet o n 
a re g ular basis, a n d will be res p o nsi ble f or: 
•  Re vie w of acc u m ulati n g cli nical trial safet y d ata b y treat me nt 
•  Ma ki n g a rec o m me n dati o n t o t he S p o ns or re gar di n g t he st u d y f oll o wi n g eac h meeti n g. 
Safet y d ata t o be re vie w e d will be u n bli n de d a n d i ncl u de e ve n ts a n d o ut c o mes descri be d b el o w 
f or a dj u dicati o n, as w ell as a n y a d diti o nal safet y d ata c o nsi dere d rel e va nt. Details descri bi n g t he 
D M C pr ocesses a n d pr oce d ures are o utli ne d i n a s e parat e D M C C harter. T o mai ntai n c o nti n u o us 
bli n di n g a n d st u d y i nte grit y, t he a n al ysis will be c o n d ucte d b y a n i n de p e n d e nt statisticia n, a n d 
meas ures will be ta k e n t o e ns ure t he v ali dit y of t he data. 
6. 4. 2  Cli ni c al e n d p oi nt c o m mitt e e( s) 
T he Cli nical E n d p oi nt C o m mittees ( C E C) is/are c o m prise d of e x perts i n car di ol o g y a n d 
ne p hr ol o g y (a n d ot her a p pr o priate  me dical s pecialties s uc h as ne ur ol o g y a n d e n d ocri n ol o g y, as 
nee de d) w h o ar e i n de pe n de nt of t he S p o ns or a n d t he c o ntract researc h or ga nizati o n ( C R O). T he 
C E Cs will re vie w a n d a dj u dicate all deat hs, maj or a d verse car di o v asc ular e ve nts 
( M A C E)/selecte d C V e v e nts ( MI, str o ke, u nsta ble a n gi n a lea di n g t o h os pitalizati o n, a n d heart 
fail ure lea di n g t o h os pitalizati o n), selecte d re nal e ve nts, b o ne fract ure, a n d D K A. 
T he details re gar di n g t he C E C pr ocesses a n d pr o ce d ures will be o utli ne d i n t he C E C C harter(s). 
6. 4. 3  S af et y a dj u di c ati o n of e v e nt s r e q uiri n g o n g oi n g m o nit ori n g 
T w o i n de pe n de nt c o m mittees will re vie w safet y e ve nts t hat re q uire o n g oi n g m o nit ori n g t o e ns ure 
ti mi n g pr ot oc ol a me n d m e nts i n case a s afet y si g n al is i de ntifie d. T hese e v e nts are: 1) p ote ntial 
cases of DI LI, a n d 2) cas es of a m p utati o ns. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 3 9 
T he t w o c o m mittees will re vie w t he cases i n a treat me nt- bli n de d ma n ner a n d will prese nt t heir 
assess me nt t o t he D M C. 
T he me m bers, r ol es a n d r es p o nsi bilities of t he t w o c o m mittees will be descri be d i n se parat e 
C harters. 
6. 4. 4  St e eri n g C o m mitt e e 
T he Steeri n g C o m mittee ( S C) is c o m p ose d of e x perts i n dia betes a n d s cie ntists wit h cli nical a n d 
met h o d ol o gical e x pertise. 
T his C o m mittee, le d b y a C hair, i n c olla b orati o n wit h t he S p o ns or, is res p o nsi ble f or pr o d uci n g 
a n d c o n d ucti n g a sci e ntificall y s o u n d st u d y a n d f or e ns uri n g acc urate re p orti n g of t he st u d y. I n 
t hat ca pacit y, t he S C m ust a d dress a n d res ol ve scie ntific iss ues e nc o u ntere d d uri n g t he st u d y. T he 
me m bers will re mai n bli n de d u ntil c o m pleti o n of t he st u d y. 
A m o n g its res p o nsi bilities, t he S C will recei ve bli n de d st u d y stat us re p orts fr o m S p o ns or, a n d will 
re vie w t he rec o m me n d ati o ns fr o m t he D M C t hr o u g h o ut t he st u d y. T he S C me m bers will 
partici pate i n face-t o-face meeti n gs at re g ul a r i nter vals t hr o u g h o ut t he st u d y a n d i n re g ularl y 
sc he d ule d telec o nfere nces. 
Detaile d acti vities a n d res p o nsi bilities of t he S C are pr o vi de d i n t he S C c harter. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 0 
7  
S E L E C TI O N O F P A TI E N T S 
N ote: A p atie nt s h o ul d n ot be ra n d o mize d m ore t ha n o n ce. I n cas es w here ori gi nal scree n fail ure 
was d ue t o reas o ns e x pecte d t o c ha n ge at resc ree ni n g a n d b ase d u p o n t he I n vesti gat or’s cli nical 
j u d g me nt, t he patie nt ca n be rescree n e d o nce pri or t o e nteri n g R u n-i n f or t his st u d y.  
7. 1  
I N C L U SI O N C RI T E RI A 
Patie nts meeti n g all of t h e f oll o wi n g i ncl usi o n criteria will be scree n e d: 
I 0 1. Patie nts wit h T 2 D c urre ntl y treat e d wit h diet  a n d e x ercise a n d o n metf or mi n at a sta ble 
d ose ≥1 5 0 0 m g/ da y f or at least 1 2 wee ks  
( Patie nts o n metf or mi n t hera p y at a d ose < 1 5 0 0 m g/ da y at t he ti me of e nr oll me nt ( mai ntai ne d f or 
at least 1 2 wee ks at a sta ble d ose bef ore e nr oll me nt) ma y b e eli gi ble f or s cree ni n g if 
d oc u me ntati o n of lac k of t olera nce of a metf or mi n d ose ≥1 5 0 0 m g/ da y ca n be pr o vi de d). 
I 0 2. Si g ne d writte n i nf or m e d c o nse nt 
7. 2  
E X C L U SI O N C RI T E RI A 
Patie nts w h o ha ve met all t he a b o ve i ncl us i o n crit eria liste d i n Secti o n  7. 1  will be scree n e d f or t h e 
f oll o wi n g e x cl usi o n criteria w hic h are s orte d a n d n u m bere d i n t he f oll o wi n g 4 s u bsecti o ns: 
7. 2. 1  E x cl u si o n crit eri a r el at e d t o st u d y m et h o d ol o g y 
E 0 1.  A ge < 1 8 years at t he ti m e of Scree ni n g or <le gal a ge of maj orit y, w hic h e v er is great er  
E 0 2.  T y pe 1 di a betes 
E 0 3.  B o d y mass i n de x ( B MI) ≤2 0 or > 4 5 k g/ m² at Scree ni n g 
E 0 4.  Pre vi o us use of a n y a nti dia betic dr u g ot her t h a n metf or mi n u nless t he a nti dia betic dr u g has 
bee n disc o nti n ue d f or a p eri o d of at le ast 1 2 wee ks bef ore t h e Scree ni n g Visit 
E 0 5.  Use of s yste mic gl uc oc ortic oi ds (e x cl u di n g t o pical or o p ht hal mic a p plicati o n, nasal s pra y 
or i n hale d f or ms) f or m or e t ha n 1 0 c o nsec uti v e da ys wit hi n 9 0 da ys pri or t o t he Scree ni n g 
Visit 
E 0 6.  Use of wei g ht l oss me dicati o ns wit hi n 1 2 wee ks or wei g ht c ha n ge of 5 k g or m ore d uri n g 
t he 1 2 wee ks b ef or e scr e e ni n g 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 1 
E 0 7.  Li keli h o o d of r e q uiri n g treat me nt d uri n g t he st u d y peri o d wit h dr u gs n ot per mitte d b y t he 
st u d y pr ot oc ol ( e g, l o n g-t er m s yste mic gl u c ocortic oi ds) a n d ref usi n g or u n a ble t o ta ke 
alter nati ve treat me nt 
E 0 8.  Patie nts w h o ha ve pre vi o usl y partici p ate d i n a n y cli nical  trial of s ota glifl ozi n/ L X 4 2 1 1 
E 0 9.  Patie nts wit h se vere a n e mia, se vere C V (i ncl u di n g c o n gesti ve heart fail ure Ne w Y or k 
Heart Ass o ciati o n I V), r es pirat or y, he patic, n e ur ol o gical, ps yc hiatric, or acti ve mali g na nt 
t u m or or ot her maj or s yst e mic disease or p atie nts wit h s h ort life e x pecta nc y ma ki n g 
i m ple me ntati o n of t he pr ot ocol or i nter pretati o n of t he st u d y res ults diffic ult 
E 1 0.  C urre nt dia g n osis of c hr o nic he patitis, He patitis B s urface a nti ge n p ositi ve, He patitis C 
a nti b o d y p ositi ve, a n d/ or ot her cli nicall y acti ve li v er disease re q uiri n g treat me nt 
E 1 1.  K n o w n prese n ce of fact ors t hat i nterfere wit h t he Ce ntral La b H b A 1 c meas ure me nt (e g, 
ge n etic H b varia nts) c o m pr o misi n g t he relia bilit y of H b A 1c assess me nt, or me dical 
c o n diti o ns t hat affect i nter pretati o n of H b A 1c res ults (e g, bl o o d tra nsf usi o n or se vere bl o o d 
l oss i n t he last 3 m o nt hs pri or t o ra n d o mizati o n, a n y c o n diti o n t hat s h orte ns er yt hr oc yte 
s ur vi val) 
E 1 2.  Hist or y of dr u g or al c o h ol a b use wit hi n 6 m o nt hs pri or t o scree ni n g 
E 1 3.  Patie nt is a n e m pl o yee of t he S p o ns or, or is  t he I n vesti gat or or a n y S u b-i n v esti gat or, 
researc h assista nt, p har macist, st u d y c o or di nat or, ot her staff or relati ve t h ere of directl y 
i n v ol ve d i n c o n d ucti n g t he st u d y 
E 1 4.  Patie nt w h o has ta ke n ot her i n vesti gati o nal dr u gs or pr o hi bite d t hera p y f or t his st u d y 
wit hi n 1 2 wee ks or 5 half-li ves, w hic he ver is l o n ger, pri or t o t he scree ni n g 
E 1 5.  Patie nts u n willi n g or u na ble t o perf or m se lf- m o nit ori n g of bl o o d gl uc os e ( S M B G), 
c o m plete t he patie nt diar y, or c o m pl y wit h st u d y visits a n d ot her st u d y pr o ce d ures as 
re q uire d p er pr ot oc ol 
E 1 6.  C o ntrai n dicati o n t o metf or mi n as per l ocal la b eli n g 
7. 2. 2  E x cl u si o n crit eri a r el at e d t o di a b et e s hi st or y a n d tr e at m e nt  
E 1 7.  He m o gl o bi n A 1 c < 7 % or > 1 0 % meas ure d b y  t he ce ntral la b orat or y at Scree ni n g 
E 1 8.  Fasti n g plas ma gl uc ose > 1 5 m m ol/ L ( > 2 7 0 m g/ d L)  meas ure d b y t h e ce ntral la b orat or y at 
Scree ni n g ( Visit 1), a n d c o nf ir me d b y a re peat test ( > 1 5 m m ol/ L [ > 2 7 0 m g/ d L]) bef ore 
ra n d o mizati o n 
E 1 9.  Pre vi o us use of a n y t y pes of i ns uli n f or > 1 m o nt h (at a n y ti me, e x ce pt f or treat me nt of 
gestati o nal dia b etes) 
E 2 0.  Hist or y of di a betic ket oaci d os is or n o n ket otic h y p er os m olar c oma wit hi n 1 2 wee ks pri or t o 
t he Scree ni n g Visit 
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1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 2 
7. 2. 3  E x cl u si o n crit eri a r el at e d t o t h e c urr e nt k n o wl e d g e of s ot a glifl o zi n 
E 2 1.  Pre g n a nt (c o nfir me d b y s er u m pre g n a nc y te st at S cree ni n g) or breast-fee di n g w o me n 
E 2 2.  W o me n of c hil d beari n g p ote ntial n ot willi n g t o use hi g hl y effecti ve met h o d(s) of birt h 
c o ntr ol or w h o are u n willi n g or u n a ble t o be teste d f or pre g n a nc y (s ee A p p e n di x A ), d uri n g 
t he st u d y. 
E 2 3.  Mea n of 3 se p arat e bl o o d press ure me as ure m e nts > 1 8 0 m m H g ( S B P) or > 1 0 0 m m H g 
( D B P) 
E 2 4.  Hist or y of h y p erte nsi ve e mer ge nc y w it hi n 1 2 wee ks pri or t o Scree ni n g (1 ) 
E 2 5.  Hist or y of gastric s ur ger y, i n cl u di n g gastric b a n di n g, wit hi n 3 years or i nfl a m mat or y b o wel 
disease 
E 2 6.  Diffic ult y s wall o wi n g s u c h t hat t he patie nt ca n n ot ta ke t he I M P 
E 2 7.  K n o w n aller gies, h y p erse nsiti vit y, or i nt o lera nce t o S G L T 2 i n hi bit or or a n y i nacti ve 
c o m p o ne nt of s ota glifl ozi n or place b o (i e,  micr ocr ystalli ne cell ul ose, cr oscar mell ose 
s o di u m [ disi nte gra nt], talc, silic o ne di o xi de, a n d ma g n esi um stearate [ n o n b o vi ne]), u nless 
t he reacti o n is dee me d irrele va nt t o t he st u d y b y t h e I n vesti gat or 
E 2 8.  La b orat or y fi n di n gs wit h t he ce ntral la b orat or y tests at Visit 1 
- 
Ala ni ne a mi n otra nsf eras e ( A L T) or as partate a mi n otra nsferase ( A S T)  > 3 × t he u p per 
li mit of t he n or mal la b orat or y ra n ge ( U L N) 
- 
T otal bilir u bi n > 1. 5 × U L N (e x ce pt i n case of Gil bert’s s y n dr o me) 
- 
Ne utr o p hils < 1, 5 0 0/ m m 3 ( or acc or di n g t o et h nic gr o u p; see A p pe n di x F  f or details) 
a n d/ or platelets < 1 0 0, 0 0 0/ m m 3 
- 
A m ylase a n d/ or li pase > 3 × U L N 
E 2 9.  Se vere r e nal diseas e as d efi ne d b y e G F R  of < 3 0 m L/ mi n/ 1. 7 3 m² at scree ni n g b y t he 
4 varia ble M o dificati o n of Diet i n  Re nal Diseas e ( M D R D) e q uati o n  
E 3 0.  A n y c o u ntr y-r elate d s pe cific re g ulati o n t hat w o ul d pre ve nt t he patie nt fr o m e nteri n g t he 
st u d y 
7. 2. 4  A d diti o n al e x cl u si o n crit eri a d uri n g or at t h e e n d of t h e R u n-i n p h a s e b ef or e 
R a n d o mi z ati o n 
E 3 1.  I nf or me d c o ns e nt wit h dra wal bef ore ra n d o mizati o n ( patie nt w h o is n ot willi n g t o c o nti n ue) 
or patie nt fails t o ret ur n. 
E 3 2.  A n y cli nicall y si g nifica nt a b n or malit y i de ntifie d o n p h ysical e x a mi nati o n, la b orat or y tests, 
E C G or vital si g ns at t he ti me of scree ni n g or a n y A E d uri n g Scree ni n g p eri o d w hic h, i n 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 3 
t he j u d g me nt of t he I n vesti gat or or a n y S u b-i n vesti gat or, w o ul d precl u de safe c o m pleti o n 
of t he st u d y or c o nstrai ns efficac y ass ess me nt. 
E 3 3.  Patie nt i ns ufficie ntl y c o m plia nt d uri n g R u n-i n  p hase base d o n t a blet c o u nt ( < 8 0 %) or i n 
t he o pi ni o n of t he I n vesti gat or. 
 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 4 
8  
S T U D Y T R E A T M E N T S 
8. 1  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T S 
T he I M Ps are s ota glifl ozi n 2 0 0 m g a n d mat c hi n g place b o. Patie nts will be pr o vi de d wit h 7 0 ta blet 
b ottle(s) of s ota glifl ozi n 2 0 0 m g or matc hi n g place b o. Ta ble 1  pr o vi d es a s u m mar y of eac h I M P. 
T a bl e 1 - S u m m ar y of i n v e sti g ati o n al m e di ci n al pr o d u ct s 
I M P: 
S ot a glifl ozi n 
Pl a c e b o 
N a m e of t h e I M P s 
S ot a glifl ozi n ( S A R 4 3 9 9 5 4)  
Pl ac e b o 
P h ar m a c e uti c al f or m 
S ot a glifl ozi n ( S A R 4 3 9 9 5 4) will b e s u p pli e d as 
2 0 0 m g t a bl ets 
Pl ac e b o will b e s u p pli e d as t a bl ets (i d e ntic al t o 
s ot a glifl ozi n i n a p p e ar a nc e) 
D o s e, ti mi n g a n d r o ut e of 
a d mi ni strati o n 
T w o 2 0 0 m g t a bl ets, t ak e n or ally o nc e d aily, 
b ef or e first m e al of t h e d ay a 
T w o 2 0 0 m g t a bl ets, t ak e n or ally o nc e d aily, 
b ef or e first m e al of t h e d ay a 
D ur ati o n of tr e at m e nt 
7 9 w e eks f oll o wi n g r a n d o miz ati o n i ncl u di n g a 
2 6- w e ek d o u bl e- bli n d C or e Tr e at m e nt P eri o d 
a n d a 5 3- w e ek d o u bl e- bli n d Ext e nsi o n 
7 9 w e eks f oll o wi n g r a n d o miz ati o n i ncl u di n g a 
2 6- w e ek d o u bl e- bli n d C or e Tr e at m e nt P eri o d 
a n d a 5 3- w e ek d o u bl e- bli n d Ext e nsi o n 
St ora g e c o n diti o n s  
St or e b et w e e n + 1 5° C a n d + 3 0° C  
( 5 9° F a n d 8 6° F) 
 St or e b et w e e n + 1 5° C a n d + 3 0° C  
( 5 9° F a n d 8 6° F) 
I M P: I nv esti g ati o n al m e dici n al pr o d uct 
a  O n st u dy visit d ays occ urri n g o n D ay 1 ( Visit 3), W e ek 2 6 ( Visit 9), a n d W e ek 7 9 ( Visit 1 3), I M P a n d m etf or mi n s h o ul d b e a d mi ni st er e d 
acc or di n g t o t h e sc h e d ul e o utli n e d i n A p p e n dix C . 
8. 2  
N O NI N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T 
8. 2. 1  M etf or mi n 
Patie nts are e nr olle d wit h a bac k gr o u n d t hera p y c o nsisti n g of metf or mi n. Bac k gr o u n d metf or mi n 
is c o nsi dere d as a n o ni n vesti gati o nal me dici n al pr o d uct ( NI M P). Metf or mi n (c o m merci al 
f or m ulati o ns) will be a d mi nistere d orall y acc or di n g t o t he l ocall y a p pr o ve d la bel. O n st u d y visit 
da ys, metf or mi n s h o ul d be ta ke n wit h t he first m eal after t he st u d y visit has c o ncl u de d, e x ce pt at 
Visits 3, 9, a n d 1 3 ( Da y 1, W ee ks 2 6 a n d 7 9), w h ere metf or mi n treat me nt s h o ul d be ta ke n 
acc or di n g t o t he i nstr ucti o ns i n A p pe n di x C . 
T he d ose of metf or mi n m ust be ≥1 5 0 0 m g/ da y a n d m ust be sta ble f or at least 1 2 wee ks bef ore 
e nr oll me nt, e x ce pt w her e d oc u me ntati o n of lac k of t olera nce of a m etf or mi n d ose ≥1 5 0 0 m g/ da y 
ca n be pr o vi d e d (see Secti o n  7. 1 ).  
T he d ose of metf or mi n s h o ul d be sta ble t hr o u g h o ut t he st u d y u nless d o w n-titrati o n is re q uire d f or 
safet y reas o ns. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 5 
Metf or mi n treat me nt is t o be re p ort e d i n t he elec tr o nic cas e re p ort f or m (e- C R F). T his i nf or mati o n 
s h o ul d i ncl u de s pecific dr u g n a me, d ose, r o ute of a d mi nistrati o n, a n d fre q u e nc y. 
T he c ost of t he bac k gr o u n d treat me nt metf or mi n  or resc u e t hera p y n ot c o v ere d b y healt h 
i ns ura nce will be rei m b urse d w here per mitte d b y l ocal re g ulati o ns. 
8. 2. 2  R e s c u e t h er a p y 
T he t hres h ol d val ues are defi ne d as  f oll o ws, d e pe n di n g o n st u d y peri o d: 
•  F P G > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L) fr o m Ra n d o mizati o n u p t hr o u g h t he s c he d ule d Wee k 8 
Visit 
•  F P G > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) after t he Wee k 8 visit u p t hr o u g h t he sc h e d ule d Wee k 1 2 
Visit 
•  F P G > 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) after t he Wee k 1 2 Visit t hr o u g h t he e n d of t he 2 6- wee k 
C ore Treat me nt Peri o d 
•  F P G > 1 7 0 m g/ d L ( 9. 4 m m ol/ L) or H b A 1c ≥8. 0 % after t he Wee k 2 6 Visit t hr o u g h t h e e n d 
of t he treat me nt p eri o d 
R o uti ne fasti n g S M B G (s ee Secti o n  9. 2. 1. 6 ) a n d ce ntral la b orat or y alerts o n F P G (a n d H b A 1c at 
Wee k 2 6 a n d o n war d) ar e set u p t o e ns ure t h at gl yce mic para mete r res ults re mai n u n der 
pre defi n e d t hres h ol ds.  
•  If o ne f asti n g S M B G val ue e x cee ds t he s pecific gl yce mic li mit o n o ne da y, t he patie nt 
c hec ks it a gai n d uri n g t h e t w o f oll o wi n g d a ys. If all t he val ues i n t hree c o nsec uti ve da ys 
e x cee d t he s pecific li mit, t he patie nt s h o ul d c o ntact t he I n v esti gat or a n d a ce ntral 
la b orat or y F P G meas ur e me nt (a n d H b A 1 c at Wee k 2 6 a n d o n war d) be perf or me d as s o o n 
as p ossi ble, prefera bl y wit hi n 7 da ys, t o c o nfir m t h e h y p er gl yce mia.  
•  U p o n recei pt of a ce ntral la b orat or y resc ue al ert, a ce ntral la b orat or y re-test m ust be 
c o m plete d a n d c o nfir me d as e x cee di n g t he t hres h ol d f or resc u e bef ore resc u e t hera p y is 
i nitiate d. T he re-test c o nfir matio n s h o ul d be perf or me d as s o o n as p ossi ble, b ut wit hi n 
7 da ys of recei pt, b y u nsc he d ule d visit.  
I n t he e ve nt t hat a c o nfir mat or y F P G a n d/ or H bA 1c e x cee ds t he t hres h ol d, t he I n v esti gat or s h o ul d 
e ns ure t hat n o r eas o na bl e e x pla nati o n e xists f or i n s ufficie nt gl uc ose c o ntr ol a n d i n partic ular t h at: 
•  T he i ncrease d F P G has b ee n teste d at a fasti n g stat us (ie, n o f o o d i nta ke f or ≥8 h o urs) 
•  I n v esti gati o nal me dicinal pr o d uct is gi ve n at t he pl a n ne d d ose 
•  T here is n o i nterc urre nt disease, w hic h ma y j e o par dize gl yce mic c o ntr ol (e g, i nfecti o us 
disease) 
•  C o m plia nce t o treat me nt is a p pr o priate 
•  C o m plia nce t o diet a n d lif est yl e is a p pr o priat e 
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1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 6 
If a n y of t he a b o ve ca n r eas o na bl y e x plai n t he i ns ufficie nt gl yce mic c o ntr ol, t he I n v esti gat or 
s h o ul d c o nsi der n ot i nitiati n g res c ue me dicati o n a n d s h o ul d u n derta ke a p pr o priate acti o n, ie: 
•  Assess plas ma gl uc ose i n fasti n g c o n d iti o n (ie, aft er at least 8 h o urs fast) 
•  I nitiate a n e val u ati o n a n d treat me nt of i nterc urre nt disease (t o be re p orte d i n 
A E/c o nc o mita nt me dicati o n parts of t he e- C R F a n d t he me dical rec or d) 
•  Stress t he a bs ol ute nee d t o be c o m plia nt wit h treat me nt 
•  Or ga nize a s pecific i nter vie w wit h t he patie nt a n d a Re gistere d Dietici a n or ot her q ualifie d 
n utriti o n pr ofessi o nal t o rei nf orce t he a bs ol ute nee d t o be c o m plia nt wit h diet a n d lifest yl e 
rec o m me n dati o ns, a n d s c he d ule a F P G/ H b A 1c ass ess me nt at t he ne xt visit. 
If n o ne of t he a b o ve me nti o ne d reas o ns ca n be f o u n d, or if a p pr o pri ate acti o n fails t o decrease 
F P G/ H b A 1c u n der t he t hres h ol d val ues, resc ue m e dicati o n ma y be i ntr o d u ce d. 
I nitiati o n of o pe n-la bel resc ue me dicati o n(s) t o treat h y per gl yce mia will be at t he discreti o n of t he 
I n v esti gat or a n d i n acc or da nce wit h l ocal sta n dar d of care a n d prescri bi n g practice. E x ce pt f or 
S G L T 2 i n hi bit ors, a n y a p pr o ve d me dicati o n(s) i ncl u di n g oral a nti dia b etic dr u gs or i ns uli n ca n be 
prescri be d t o treat t he h y per gl yce mia. T h e patie nt c o nti n ues t he st u d y treat me nt ( bli n de d) a n d 
sta ys i n t he st u d y i n or der t o c ollect efficac y a n d s afet y i nf or mati o n. T h e pla n ne d visits a n d 
assess me nts s h o ul d occ ur u ntil t he last sc he d ule d  visit. F or patie nts wit h re n al i m pair me nt, 
c o ntrai n dicati o ns t o a nti h y p er gl yce mic dr u gs s h o ul d be ta ke n i nt o c o ns i derati o n. If a patie nt 
re q uires gl yc e mic res c ue, t he I M P r ecei v e d d uri n g t he ra n d o mize d, d o u ble- bli n d Treat me nt 
Peri o d s h o ul d c o nti n ue a n d m ust re mai n  bli n de d u ntil t he e n d of t he st u d y. 
Resc ue t her a p y is c o nsi dere d a NI M P. Resc ue t h era p y is t o be  re p orte d i n t he e- C R F. T his 
i nf or mati o n s h o ul d i ncl u de s pecific dr u g na me, d ose, r o ute of a d mi nistrati o n, a n d fre q u e nc y. 
If n ot c o vere d b y healt h i ns ura nce, t h e c ost of t he resc ue t h era p y will be rei m b urse d w here 
per mitte d b y l ocal re g ulati o ns. 
8. 3  
B LI N DI N G P R O C E D U R E S 
8. 3. 1  M et h o d s of bli n di n g 
T o mai ntai n bli n di n g, s ota glifl ozi n a n d place b o ta blets a n d pac ka gi n g will be bli n de d a n d 
i n disti n g uis ha ble. 
D uri n g t h e d o u ble- bli n d treat me nt peri o d eac h trea t me nt pac ka ge will be labele d wit h a n u m ber, 
w hic h is ge nerate d b y a c o m p uter pr o gra m fr o m Sa n ofi. I n vesti gat ors will n ot ha ve access t o t he 
ra n d o mizati o n (treat me nt) c o de e x ce pt u n der circ u msta nces descri be d i n Secti o n  8. 3. 2 . 
T he ra n d o mizati o n a n d t he treat me nt all ocati o n will be perf or me d ce ntrall y b y a n I R T. T he st u d y 
bi ostatisticia n pr o vi des t he ra n d o mizati o n sc he me t o t he I R T. T h e n, t he I R T ge n erates t he patie nt 
ra n d o mizati o n list fr o m w hic h it all ocates treat me nt ar ms t o t he patie nts. 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 8 
 At Visit 3 ( Bas eli ne), ass ess me nt res ults are re vie we d a n d baseli ne assess me nts 
are c o m plet e d, t he I R T is c o ntacte d f or ra n d o mi zati o n a n d all ocati o n of treat me nt pac ka ge.  
F or eac h ra n d o mize d patie nt, t he I R T will all ocat e a treat me nt pac ka ge n u m ber c orres p o n di n g t o 
t he treat me nt gr o u p assi g ne d. After Visit 3 ( Bas eli ne) t he I R T is c o ntacte d a gai n eac h ti me ne w 
treat me nt pac k a ge(s) all o cati o n is re q uire d b y t he pr ot oc ol. Treat ment p ac k a ges are all ocate d b y 
t he I R T usi n g t heir treat me nt kit n u m ber. 
A ra n d o mize d patie nt is defi ne d as  a patie nt w h o is re gistere d an d assi g n e d wit h a treat me nt kit 
n u m ber fr o m t he I R T, as d oc u me nte d i n I R T. 
A patie nt ma y n ot be e nr olle d i n t his st u d y m ore t ha n o nce (i e, bei n g ra n d o mize d t wice). I n cas es 
w here ori gi n al scree n fail ure was d u e t o reas o ns e x pecte d t o c ha n ge at rescree ni n g a n d b ase d u p o n 
t he I n v esti gat or’s cli nical j u d g me nt, t he patie nt ca n be rescree n e d pri or t o e nteri n g R u n-i n o nce 
f or t his st u d y. I n t hes e cases, a patie nt will nee d t o si g n a ne w I C F, b e re gistere d as a re-scree ne d 
patie nt i n I R T a n d assi g n e d a ne w p atie nt n u m ber i n I R T (first Scree ni n g Visit is t o be re gistere d 
as scree n fail ur e i n I R T), a n d a gai n c o m p let e Scree ni n g Visit pr oce d ures/ assess me nts. 
8. 5  
P A C K A GI N G A N D L A B E LI N G 
Pac ka gi n g will be u n dert a ke n i n acc or da n ce wit h t he a d mi nistrati o n sc he d ule. T he c o nte nt of t h e 
la beli n g is i n acc or d a nce wit h t he l ocal re g ulat or y s pecificati o ns a n d re q uire me nts. 
T he a p pr o pri ate n u m ber of pac ka ges will be dis pe nse d t o c o ver u p t o t he n e xt dis pe nsi n g visit 
( please r ef er t o Secti o n  1. 2 ). St ora ge c o n diti o ns a n d use- b y-e n d d ate are p art of t he la b el te xt. 
Treat me nt la bels will i n dicate t he treat me nt n u m ber ( use d f or treat me nt all ocati o n a n d re p orte d i n 
t he e- C R F). 
8. 6  
S T O R A G E C O N DI TI O N S A N D S H E L F LI F E 
I n v esti gat ors or ot her a ut h orize d pers o ns (e g, p h armacists) are res p o nsi ble f or st ori n g t he I M P i n a 
sec ure a n d saf e place i n acc or da n ce wit h l ocal re g ulati o ns, la beli n g s pecificati o ns, p olicies, a n d 
pr oce d ur es. 
C o ntr ol of I M P st ora ge c o n diti o ns, es peciall y c o nt r ol of te m perat ure a n d i nstr ucti o ns f or ha n dli n g 
t he Sa n ofi c o m p o u n d s h o ul d be ma na ge d acc or di n g t o t he r ules pr o vi de d b y t he S p o ns or. 
T he e x pir y dat e a n d st ora ge c o n diti o ns are writte n o n t he I M P la b els. T he I M P s h o ul d be st ore d 
bet wee n + 1 5° C a n d + 3 0° C ( 5 9° F a n d 8 6° F). 
8. 7  
R E S P O N SI BI LI TI E S 
T he I n vesti gat or, t he h os pital p har macist, or ot he r pers o n nel all o we d t o st ore a n d dis pe ns e t he 
I M P will be r es p o nsi ble f or e ns uri n g t hat t he I M P use d i n t he cli nical trial is sec urel y mai ntai ne d 
as s pecifie d b y t he S p o ns or a n d i n acc or da n ce wit h a p plica ble re g ulat or y re q uire me nts. 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 4 9 
All I M Ps will be dis pe ns e d i n acc or da nce wit h t he I n v esti gat or's pres cri pti o n a n d it is t he 
I n v esti gat or's res p o nsi bilit y t o e ns ure t h at a n acc urate rec or d of I M P iss ue d a n d ret ur n e d is 
mai ntai ne d. 
A n y q u alit y iss ue n otice d wit h t he recei pt or us e of a n I M P ( defici e nc y i n c o n diti o n, a p peara n ce, 
pertai ni n g d o c u me ntati o n, la beli n g, e x pirati o n date, etc) s h o ul d be pr o m ptl y n otifie d t o t he 
S p o ns or or Dele gat e. S o me deficie n cies ma y be rec or de d t hr o u g h a c o m pl ai nt pr oce d ure. 
A p ote ntial defect i n t he q ualit y of I M P ma y be s u bject t o i nitiati o n of a recall pr oce d ure b y t he 
S p o ns or. I n t his cas e, t he I n v esti gat or will be res p o nsi ble f or pr o m ptl y a d dressi n g a n y re q u est 
ma de b y t he S p o ns or or Dele ga te, i n or d er t o recall t he I M P a n d eli mi nate p ote ntial hazar ds. 
U n der n o circ u msta nces will t he I n vesti gat or s u p pl y I M P t o a t hir d part y (e x ce pt f or 
direct-t o- patie nt s hi p me nt, f or w h ic h a c o urier c o m pa n y h as bee n a p pr o ve d b y t he S p o ns or), all o w 
t he I M P t o be us e d ot her t ha n as direct e d b y t his cli nical trial pr ot oc ol, or dis p ose of I M P i n a n y 
ot her ma n ner. 
8. 7. 1  Tr e at m e nt a c c o u nt a bilit y a n d c o m pli a n c e 
Acc o u nti n g a n d c o m plia nce f or I M Ps will be perf or me d at Visit 3 a n d all s u bse q ue nt visits 
(e x cl u di n g A B P M place me nt Visits).  
T he I n vesti gat or will c h ec k t he c o m plia nce t o t he I M P d ose sc h e d ule bas e d o n t he patie nt diar y 
a n d will t he n c o m plete t he a p pr o pri ate Site treat m e nt a n d patie nt treat me nt l o g f or ms. Ret ur n e d 
I M P s h o ul d be c o u nt e d b y site staff. I n a d ditio n t he d osi n g i nf or mati o n will be rec or de d o n t he 
a p pr o priate p a ges of t h e e- C R F. 
F or NI M P metf or mi n, na me, start a n d e n d d ate of treat me nt, t otal dail y d os e, etc, will be 
d oc u me nte d i n t he s o urce d oc u me nts. C o m plia nce t o metf or mi n will be c h ec ke d b y i nter vi e wi n g 
t he patie nt a n d re vi e wi n g diar y at eac h visit an d be d oc u me nte d i n t he s o urce d oc u me nts a n d i n 
t he e- C R F. 
If c o m plia nce is i na de q u ate as deter mi ne d b y t he Pri nci pal I n v esti gat or ( PI), patie nts will be 
trai ne d a gai n a n d me nt ore d. If s u b o pti mal c o m plia nce c o nti n ues after trai ni n g a n d me nt ori n g, 
patie nts ma y b e disc o nti n ue d at t he discreti o n of  t he PI after dis c ussi o n wit h t he S p o ns or’s 
me dical m o nit or. 
8. 7. 2  R et ur n a n d/ or d e str u cti o n of tr e at m e nt s 
Patie nts are t o ret ur n all I M P ( u n use d, i n use or e m pt y b ottle[s]) at eac h o n-site visit (e x ce pt 
A B P M visits f or w hic h I M P acc o u nti n g is n ot re q uire d, as descri be d i n Secti o n 1. 2 ).  
At Visit 4 ( Wee k 1), beca use n o I M P re-s u p pl y is pl a n ne d d uri n g t his visit, patie nts will be se nt 
h o me after t his visit wit h t he i n- use b ottle(s) dis pe nse d at ra n d o mizati o n. 
Patie nts are t o ret ur n all t he use d, i n- use a n d u n use d I M P at Visit 1 3 ( or fi n al assess me nt 
o n-treat me nt visit i n case of per m a n e nt pre mat ure disc o nti n uati o n).  
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 0 
All use d, partiall y- use d or u n use d I M Ps will be retrie ve d b y t he S p o ns or or Dele gate. A detaile d 
site a n d patie nt treat me nt l o g of t he ret ur ne d I M P will be esta blis he d wit h t he I n vesti gat or ( or t he 
p har macist) a n d c o u ntersi g ne d b y t he I n vesti gat or a n d t he m o nit ori n g tea m. 
8. 8  
C O N C O MI T A N T M E DI C A TI O N 
A c o nc o mita nt me dicati o n is a n y treat me nt recei v e d b y t h e patie nt c o n c o mita ntl y t o a n y I M P(s). 
T he I M P i ncl u des place b o a n d s ota glifl ozi n 4 0 0 m g. 
All c o nc o mita nt me di cati o ns s h o ul d be d oc u me nte d o n t he Me dicati o ns pa ge of t he e- C R F. T his 
i ncl u des all NI M P treat m e nts t hat are ta k e n b y t he patie nts at a n y ti me d uri n g t he cli nical trial, 
be gi n ni n g at Visit 1.  
A d diti o nall y, all me dicati o ns ta ke n i n t he 3 m o nt hs pri or t o Visit 1 a n d pri or use of S G L T 2 
i n hi bit ors s h o ul d be re p orte d. 
8. 8. 1  Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s 
D uri n g t h e st u d y tr eat me nt peri o d, t he f oll o wi n g me dicati o ns are pr o hi bite d: 
•  I nitiati o n of a n y a nti dia betic a ge nts, i ncl u di n g oral or i njecta ble a nti h y per gl yce mic a ge nts 
ot her t ha n t he I M P is n ot all o we d bef ore t he resc u e t hera p y 
•  S yste mic use of gl uc o c ortic oi ds is n ot all o we d f or m ore t ha n 1 0 c o nsec uti ve da ys (t o pical, 
o p ht hal mic, nasal s pra y or i n hale d a p plicati o ns are all o we d) 
•  I nitiati o n of a n y wei g ht l oss dr u gs (e g, p he nter mi ne, orlistat)  
•  I n v esti gati o nal me dicinal pr o d ucts i n a n y ot her cli nical st u d y 
•  S G L T 2 i n hi bit ors (e g, ca na glifl ozi n, da pa glifl o zi n, or e m pa glifl ozi n) are n ot all o we d f or 
resc ue 
Re d ucti o n of di g o xi n d ose s h o ul d be c o nsi dere d b eca use s ot a glifl ozi n acts as a wea k P- g p 
i n hi bit or a n d i ncreases s yste mic e x p os ure t o di g o xi n. Patie nts ta ki n g s ota glifl ozi n wit h 
c o nc o mita nt di g o xi n s h o ul d ha ve di g o xi n c o nce ntrati o ns m o nit ore d a n d d oses re d uce d as nee de d. 
I n a d diti o n, ot her P- g p s u bstrates ma y be affecte d a n d t he la bels of P- g p s u bstrate dr u gs s h o ul d be 
c o ns ulte d wit h re gar ds t o m o nit ori n g a n d d ose a dj ust me nts. 
Ot her me dicati o ns w hic h are u nli kel y t o i nterfer e wit h t he P K or P D of t he I M P or c o nf o u n d 
i nter pretati o n of t he st u d y e n d p oi nts are all o w ed as nee de d f oll o wi n g disc ussi o n bet wee n t he 
I n v esti gat or a n d t he S p o ns or. H o we ver, d oses of c hr o nicall y a d mi niste re d me dici nes s h o ul d be 
ke pt fi x e d d uri n g t he trial if at all p ossi ble. 
After pr e mat ure p er ma n e nt disc o nti n uati o n of t he I M Ps, a n y treat me nts ( ot her t ha n S G L T 2 
i n hi bit ors) are per mitte d, as dee me d n ecess ar y b y t he I n vesti gat or. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 1 
T he d ose of all a nti h y perte nsi ve a ge nts s h o ul d be ke pt c o nsta nt d uri n g t he 1 2 wee ks f oll o wi n g 
ra n d o mizati o n a n d n o a nti h y pert e nsi ve a ge nts sh o ul d be a d de d or wit h dra w n f or t he 1 2 wee ks 
f oll o wi n g r a n d o mizati o n u nless it is c o nsi dere d necessar y f or safet y reas o ns. 
8. 8. 2  C o n c o mit a nt di a b et e s t h er a p y 
F or patie nts i n b ot h gr o u ps, bac k gr o u n d metf or mi n  s h o ul d be sta ble t hr o u g h o ut t he st u d y u nless 
d o w n-titrati o n is re q uire d f or safet y reas o ns. 
N o n-I M P treat me nt is defi ne d as t he resc ue m e dicati o n(s) t hat will be use d t o treat h y p er gl yce mia 
w he n a patie nt’s h y p er gl yce mia reac h es t he res c u e t hres h ol d. E x ce pt f or S G L T 2 i n hi bit ors, a n y 
a p pr o ve d me dicati o n(s) i ncl u di n g or al a nti dia betic dr u gs or i ns uli n ca n be prescri be d at t he 
I n v esti gat or’s discreti o n t o treat t he h y per gl yce mia. T he re gi me n of t h e res c ue me dicati o ns will be 
i n acc or d a nce wit h l ocal sta n dar d of care a n d pres cri bi n g practice. 
8. 9  
P O S T S T U D Y T R E A T M E N T 
Beca use s ota glifl ozi n ma y re d uce B P, a dj ust me nt of a nti h y p erte nsi ve me di cati o n ma y be nee de d 
d uri n g t he st u d y i n patie nts wit h h y perte nsi o n. C o n versel y, m o nit ori n g f or a n i ncrease i n B P 
s h o ul d be perf or m e d after wit h dra wal of st u d y me dicati o n. If t he B P is ele v ate d after wit h dra w al 
of st u d y tr eat me nt, t he I n vesti gat or s h o ul d c o nsi d er a d di n g or a dj usti n g a nti h y perte nsi ve 
me dicati o n. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 2 
9  
A S S E S S M E N T O F I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T 
9. 1  
E F FI C A C Y E N D P OI N T S 
9. 1. 1  Pri m ar y effi c a c y e n d p oi nt 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c ( %). 
9. 1. 2  S e c o n d ar y effi c a c y e n d p oi nt s 
T he c o nti n u o us sec o n dar y efficac y e n d p oi nts are: 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n 2- h o ur P P G f oll o wi n g a M M 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n F P G 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or all patie nts 
•  Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6. 
9. 1. 3  Ot h er effi c a c y e n d p oi nt s 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P < 1 3 0 m m H g 
•  Pr o p orti o n of patie nts wit h re d ucti o n i n b o d y w ei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 % fr o m 
Baseli ne  
•  C ha n ges fr o m Baseli ne t o Wee k 1 2 i n D B P 
•  Pr o p orti o n of patie nts ac hie vi n g S B P < 1 3 0 m m H g f or t h ose wit h Baseli ne 
S B P ≥1 3 0 m m H g 
•  Pr o p orti o n of patie nts ac hie vi n g D B P < 8 0 m m H g f or t h ose wit h Baseli ne D B P ≥8 0 m m H g 
•  Pr o p orti o n of patie nts re q uiri n g  resc ue f or h y per gl yce mia 
•  C ha n ge fr o m Baseli ne i n: 
- 
Uri ne A C R, U G E, a n d uri ne G C R 
- 
Ser u m creati ni ne 
- 
e G F R 
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n H b A 1c 
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n F P G 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 3 
•  
C ha n ge fr o m Baseli ne t o Wee k 2 6 i n S B P f or all patie nts a n d f or patie nts wit h Baseli ne 
S B P ≥1 3 0 m m H g 
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n S B P f or all patie nts a n d f or patie nts wit h Baseli ne 
S B P ≥1 3 0 m m H g 
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n b o d y w ei g ht. 
9. 1. 4  A s s e s s m e nt m et h o d s of effi c a c y e n d p oi nt s 
9. 1. 4. 1  H e m o gl o bi n A 1 c 
He m o gl o bi n A 1 c will be assesse d at Scree ni n g ( Visit 1) a n d all o n-site visits d uri n g t he 
d o u ble- bli n d treat me nt p eri o d wit h t he e x ce pti o n of  Wee k 1 ( Visit 4) a n d t he A B P M place me nt 
Visits 3 A, 7 A, a n d 9 A. 
F or t he eli gi bilit y a n d efficac y ass ess me nts of t he st u d y, H b A 1 c is meas ure d b y a certifi e d le vel I 
“ Nati o nal Gl yc o h e m o gl o bi n Sta n dar dizati o n Pr o gra m” ce ntral la b orat or y t o all o w esti mati o n of 
t he c ha n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c a n d t he pr o p orti o n of patie nts wit h H b A 1c 
< 6. 5 %, < 7. 0 % at Wee k 2 6. 
If a patie nt n ee ds t o recei ve resc u e a nti diabetic me dicati o n, assess me n t of H b A 1c s h o ul d be 
perf or me d b ef or e t he i ntr o d ucti o n of t he resc u e m e dicati o n. 
9. 1. 4. 2  P o st pr a n di al gl u c o s e a n d mi x e d m e al t ol er a n c e t e st 
Patie nts will u n der g o ass ess me nt of P P G at Bas eli ne ( Visit 3) a n d Wee k 2 6 ( Visit 9) via a mi x e d 
meal t olera nc e test ( M M T T) t o all o w esti mati o n of c ha n ge fr o m Baseli ne t o Wee k 2 6 i n 2- h o ur 
P P G f oll o wi n g a M M. A n M M T T will als o be perf or me d at Wee k 7 9 ( Visit 1 3). F ull details of t he 
M M T T pr oce d ur e at Bas eli ne, Wee k 2 6, a n d Wee k 7 9 are prese nte d i n A p pe n di x C . 
At Baseli ne ( Visit 3), Wee k 2 6 ( Visit 9), a n d We e k 7 9 ( Visit 1 3), P P G will  be assesse d b y M M T T 
at baseli ne (f asti n g) a n d 2 h o ur s after c o ns u mi n g a sta n dar d mi x e d li q ui d brea kfast meal. 
T he first d ose of d o u ble- bli n d I M P a n d metf or mi n o n Da y 1 ( Baseli ne; Visit 3) will be gi ve n after  
c o m pleti o n of t he 2- h o ur P P G c ollecti o n. 
F or t he Wee k 2 6 ( Visit 9) a n d Wee k 7 9 ( Visit 1 3) sta n dar dize d M M, t he patie nt s h o ul d ta ke t he 
d ose of d o u ble- bli n d I M P i m me diatel y after t he fasti n g bl o o d sa m ples are o btai ne d, a n d 
a p pr o xi matel y 3 0 mi n utes bef ore  i n gesti o n of t he sta n dar dize d M M be gi ns. At Wee k 2 6 a n d 
Wee k 7 9, metf or mi n is gi ve n after  c o m pleti o n of t he 2- h o ur P P G c ollecti o n. 
Plas ma c o nce ntr ati o n sa m ples at  Wee k 2 6 a n d Wee k 7 9 s h o ul d be ta ke n at t he sa me ti mes as t he 
fasti n g bl o o d sa m ple a n d t he 2- h o ur ce ntral la b orat or y plas ma P P G c ollecti o n (see 
Secti o n  9. 3. 1. 1 ). 
T he c o m p ositi o n a n d t he q ua ntit y of t he sta n d ar d mi x e d li q ui d brea kfast m eal m ust be i de ntical 
t hr o u g h o ut t he st u d y; see A p pe n di x C  f or f urt her details. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 4 
A n y p atie nt w h o re q uir es t he a d diti o n of resc u e me dicati o n pri or t o Wee k 2 6 or Wee k 7 9 s h o ul d 
still ha ve t he sta n dar dize d M M perf or me d as sc he d ule d. 
I n case of per m a ne nt disc o nti n uati o n of t he treat me nt wit h I M P bef ore Wee k 2 6 a n d/ or Wee k 7 9, 
e ver y eff ort will be ma d e t o ha ve t he patie nt ret ur n t o t he site at t he ti me of t heir Wee k 2 6 a n d 
Wee k 7 9 visits; h o we ver t he M M T T s h o ul d n ot be pe rf or me d at t hese or a ny ot her visit f oll o wi n g 
a Pre mat ure E O T visit. 
O n t he da ys of t he M M T T, patie nts will c o me t o t he i n vesti gati o nal site i n t he m or ni n g, i n fasti n g 
c o n diti o ns f or at least 8 h o urs a n d m ust n ot eat  a n y f o o d or dri n k, e x ce pt w ater, bef ore t he 
sc he d ule d sta n dar diz e d meal test. 
T he e x act ti mes of t he I M P a d mi nistrati o n, sta n dar d  mi x e d li q ui d brea kfast meal i nta ke, a n d t he 
bl o o d dra ws ar e t o be d o c u me nte d. 
9. 1. 4. 3  F a sti n g pl a s m a gl u c o s e m e a s ur e m e nt 
Plas ma gl uc ose is meas ure d i n t he fasti n g state at Scree ni n g ( Visit 1) a n d all o n-site visits d uri n g 
t he treat me nt peri o d wit h t he e x ce pti o n of t he A B P M place me nt Visits 3 A, 7 A, a n d 9 A. F or t he 
eli gi bilit y a n d efficac y assess me nts of t he st u d y, F P G is meas ure d at a ce ntral la b orat or y t o all o w 
esti mati o n of c ha n ge fr o m Baseli ne t o Wee k 2 6 i n F P G. 
9. 1. 4. 4  B o d y w ei g ht m e a s ur e m e nt 
B o d y wei g ht is meas ur e d at all o n-site Visits, wit h t he e x ce pti o n of t he A B P M place me nt 
Visits 3 A, 7 A, a n d 9 A. B o d y w ei g ht will be meas ure d t o all o w t he esti mati o n of c ha n ge fr o m 
Baseli ne t o Wee k 2 6 i n b o d y w ei g ht a n d re d u cti o n i n b o d y wei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 % fr o m 
Baseli ne. 
B o d y wei g ht s h o ul d be o btai ne d wit h t he patie nt  weari n g u n der gar m e nts or ver y li g ht cl ot hi n g 
a n d n o s h oes, a n d wit h a n e m pt y bla d d er. 
T he sa me scale s h o ul d be use d t hr o u g h o ut t he st u d y, a n d cali brat e d o n a re g ular basis as 
rec o m me n de d b y t h e ma n ufact ur er. Cali brati o n sh o ul d be d oc u me nte d i n s o urce d oc u m e nts. T he 
use of bala n ce scales is r ec o m me n de d. T h e fl o or s u rface o n w hic h t he s cale rests m ust be har d a n d 
s h o ul d n ot be car pet e d or c o vere d wit h ot her s oft material. T he sc ale s h o ul d be bala nce d wit h b ot h 
wei g hts at zer o a n d t he b ala nce b ar ali g ne d. T h e p a tie nt s h o ul d sta n d i n t he ce nter of t he platf or m 
as sta n di n g off- ce nter m a y affe ct meas ure me nt.  T h e wei g hts are m o ve d u ntil t he bea m bala nces 
(t he arr o ws ar e ali g ne d). T he wei g ht is rea d a n d rec or de d i n t he e- C R F a n d S o urce Data. S elf-
re p orte d w ei g hts are n ot acce pta ble; patie nts m ust n ot rea d t he scales t he msel ves. 
9. 1. 4. 5  Bl o o d pr e s s ur e e n d p oi nt m e a s ur e m e nt s 
S yst olic B P a n d D B P will be assesse d at all o n-site visits, wit h t he e x ce pti o n of t he A B P M 
place me nt Visits 3 A, 7 A, a n d 9 A.  Bl o o d press ure meas ure me nts m ust  be ta ke n as descri be d i n 
Secti o n  9. 2. 1. 4  wit h details pr o vi de d i n A p pe n di x E.  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 5 
9. 1. 4. 6  Ki d n e y f u n cti o n p ar a m et er m e a s ur e m e nt 
Ser u m creati ni ne a n d uri ne al b u mi n, creati ni ne, a n d gl uc os e are assesse d at Baseli ne ( Visit 3) a n d 
all s u bse q ue nt o n-site Visits wit h t he e x ce ptio n of A B P M place m e nts Visits 3 A, 7 A, a n d 9 A. A 
ce ntral la b orat or y will a n al yze sa m ples a n d esti mate c ha n ge fr o m Baseli ne i n uri ne A C R, U G E, 
uri ne G C R, ser u m creati ni ne, a n d e G F R ( b y t he 4 varia ble M D R D e q uati o n). T o pre ve nt p artial 
u n bli n di n g, U G E, a n d G C R res ults will be mas ke d t o i n vesti gati o nal sites a n d patie nts. 
9. 1. 4. 7  Pr o p orti o n of p ati e nt s r e q uiri n g r e s c u e f or h y p er gl y c e mi a 
T he use of r esc ue m e dicati o ns f or h y p er gl yce mia  will be assesse d a n d rep orte d t hr o u g h o ut t he 
treat me nt peri o d. R o uti ne alerts o n F P G a n d/ or H bA 1c will be se nt t o t he I n vesti gat or fr o m t he 
ce ntral la b orat or y t o e ns ure t hat gl yce mic p ara met er res ults re m ai n wit hi n pre defi n e d t hres h ol ds. 
F or details a n d f urt her acti o ns s h o ul d F P G a n d/ or  H b A 1c val ues fall a b o ve t hres h ol ds, ref er t o 
Secti o n  8. 2. 2 . 
9. 2  
S A F E T Y E N D P OI N T S 
Assess me nts f or saf et y i ncl u de A Es, S M B G, cli nical la b orat or y assess me nts, p h ysical 
e x a mi nati o n, electr ocar di o gr a m ( E C G), w ei g ht, a n d vital si g ns. A n i n de pe n de nt D M C will meet 
o n a re g ular basis t o re vi e w acc u m ulati n g cli nical trial safet y data. 
A dj u dicati o n of all deat hs, M A C E/ ot her selecte d C V  e ve nts ( MI, str o ke, u nsta ble a n gi na lea di n g 
t o h os pitalizati o n, a n d heart fail ure l ea di n g t o h os pitalizati o n), selecte d re n al e ve nts, b o ne 
fract ure, a n d D K A will b e perf or me d i n a bli n de d ma n ner b y a C E C(s) c o m prise d of e x perts. 
Details will be pr o vi de d i n t he c harter of t h e C E C(s). F urt her details are a v aila ble i n Secti o n  6. 4 . 
T w o e x pert c o m mittees will re vie w all p ote ntial cases of DI LIs a n d cases of a m p utati o n i n a 
treat me nt- bli n de d ma n ner t o e val uate ca usalit y. 
T he f oll o wi n g s afet y e n d p oi nts will be assesse d: 
•  A d verse e ve nts, A Es lea di n g t o disc o nti n uati o n fr o m t he I M P, a d v erse e ve nts of s pecial 
i nterest ( A E SIs), e ve nts of s pecial i nterest ( E O SIs), S A Es a n d deat hs 
•  H y p o gl yce mia (all, se v er e, a n d/ or d oc u me nt e d s y m pt o matic h y p o gl yce mia) 
•  Cli nical la b orat or y res ults (i ncl u di n g fasti n g li pi ds; see Secti o n  9. 2. 1. 3 ), vital si g ns, a n d 
E C G res ults 
•  Mar kers of b o ne a n d calci u m meta b olis m  
•  Mar kers of i ntesti nal tra nsit a n d a bs or pti o n 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 6 
O bser v ati o n peri o d of s afet y e n d p oi nts  
T he o bser vati o n peri o d of safet y dat a will be di vi de d i nt o 3 se g me nts: 
•  T he pre-treat me nt peri o d is defi ne d as t he ti me bet wee n t he d ate of t he i nf or me d c o nse nt 
a n d t he first d ose of d o u ble- bli n d I M P.  
•  T he o n-treat me nt peri o d ( T E A E peri o d) is defi ne d as t he ti me fr o m t he first d ose of 
d o u ble- bli n d I M P u p t o 1 0 da ys ( 1 da y f or h y p o gl yce mia) after t he l ast d ose of d o u ble-
bli n d I M P, re gar dless of t he i n tr o d ucti o n of resc u e t hera p y. T he 1 0- da y i nt er val is c h ose n 
base d o n t he half-life of t he I M P (a p pr o xi matel y 5 ti mes t he half-life of s ot a glifl ozi n) i n 
patie nts wit h m o derate r e nal d ysf u n cti o n. 
•  T he p ost-treat me nt p eri o d is defi ne d as t he ti me st arti n g 1 1 d a ys after t he last d ose of 
d o u ble- bli n d I M P ( after t he o n-treat me nt peri o d).  
T he baseli ne v al ue f or s afet y e n d p oi nts i n t he safe t y p o p ulati o n is t he last a vaila ble val ue ( or t he 
a vera ge of all val ues f or creati ni ne or e G F R) pri o r t o t he first a d mi nistrati o n of d o u ble- bli n d I M P. 
9. 2. 1  A s s e s s m e nt m et h o d s of s af et y e n d p oi nt s 
9. 2. 1. 1  A d v er s e e v e nt s 
A d verse e ve nts i ncl u di n g S A E, A E SI, a n d E O SI will be assesse d. Refer t o Secti o n  1 0. 4  t o 
Secti o n  1 0. 7  f or details. 
9. 2. 1. 1. 1  A d v er s e e v e nt s of s p e ci al i nt er e st 
A d verse e ve nts of s pecial i nterest are liste d i n Secti o n  1 0. 4. 1. 3 , re p orti n g re q uire me nts f or A E SI 
are pr ese nte d i n Secti o n  1 0. 4. 4 . 
9. 2. 1. 1. 2  E v e nt s of s p e ci al i nt er e st 
E ve nts of s pecial i nter est are se p arat e fr o m A E SIs.  F or a list of e v e nts defi ne d as E O SIs a n d t heir 
re p orti n g re q uire me nts see Secti o n  1 0. 4. 1. 4  a n d Secti o n  1 0. 4. 5, res pecti vel y. 
9. 2. 1. 2  H y p o gl y c e mi a 
H y p o gl yce mia will be assesse d fr o m Visit 2 o n war ds a n d c o nti n ue u ntil 4 wee ks after t he last 
d ose of I M P ( n ote: f or p atie nts w h o disc o nti n ue treat me nt bef ore Wee k 7 9, safet y data will be 
c ollecte d u ntil sc he d ule d st u d y e n d). Patie nts will als o c o m plete t he h y p o gl yce mia l o g (as p art of 
t he patie nt diar y) fr o m Visit 2 o n war ds, w hic h will be re g ularl y re vie w e d b y I n v esti gat ors. See 
Secti o n  1 0. 6. 1  f or f urt her details. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 7 
9. 2. 1. 3  L a b or at or y s af et y v ari a bl e s 
T he cli nical la b orat or y d ata c o nsist of bl o o d a nal ys is (i ncl u di n g he mat ol o g y, cli nical c he mistr y, 
a m ylas e, li pase, li pi d pr ofile) a n d uri nal ysis, acc or di n g t o t he sc he d ul e pres e nte d i n Secti o n  1. 2 . 
Cli nical la b orat or y val ues will be a nal yze d after c o n versi o n i nt o sta n da r d i nter nati o nal u nits. 
I nter nati o nal u nits will be use d i n all listi n gs a n d t a bles. Ta ble 2  lists t he he mat ol o g y, cli nical 
c he mistr y, a n d ot her bl o o d safe t y para meters t o be assessed b y t he ce ntral l a b orat or y. 
Alerts t o t he I n vesti gat or are set u p f or s peci fic la b orat or y a b n or m alities. I n vesti gat ors s h o ul d 
re vie w t hes e alerts a n d f oll o w- u p if nee de d as per his/ her me dical j u d ge me nt. Re-tests at ce ntral 
la b orat or y are acce pta ble if nee de d. 
I n a d diti o n, f or W O C B P a ser u m pre g n a nc y test is perf or me d at Scree ni n g, a n d uri ne pre g na nc y 
tests are ta ke n at all o n-site visits d uri n g t he d o u ble- bli n d treat me nt peri o d e x cl u di n g Visit 4 
( W ee k 1) a n d A B P M place me nt Visits 3 A, 7 A, a n d 9 A. A n y p ositi ve uri n e test res ults m ust be 
c o nfir me d b y a s er u m pr e g n a nc y test. T h e I n vest i gat or m a y perf or m a d diti o nal tests at t heir 
discreti o n or as r e q uire d b y l ocal re g ulati o ns. 
Ser u m f ollicle sti m ulati n g h or m o n e ( F S H) a n d estra di ol will be  meas ure d i n me n o pa usal w o me n 
at scree ni n g ( Visit 1, Wee k - 4) (s ee A p p e n di x A  f or defi niti o n of me n o pa usal w o me n). 
T a bl e 2 - S er u m c h e mi str y p ar a m et er s 
Cli ni c al c h e mi str y 
H e m at ol o g y 
Ot h er bl o o d p ar a m et er s 
S o di u m 
C o m pl et e bl o o d c o u nt ( C B C) 
Li pi d pr ofil e 
P ot assi u m 
Diff er e nti al 
T ot al c h ol est er ol ( T C) 
C hl ori d e 
Pl at el et c o u nt 
Hi g h- d e nsity li p o pr ot ei n c h ol est er ol ( H D L- C) 
C ar b o n di oxi d e ( bic ar b o n at e) 
H e m o gl o bi n 
L o w- d e nsity li p o pr ot ei n c h ol est er ol ( L D L- C) will b e 
c alc ul at e d by Fri e d w al d e q u ati o n 
Bl o o d ur e a nitr o g e n ( B U N) 
H e m at ocrit 
N o n- H D L C will b e c alc ul at e d as t h e diff er e nc e 
b et w e e n T C a n d H D L C 
Cr e ati ni n e ( e G F R will b e 
c alc ul at e d) 
 Tri glyc eri d es
 ( T G)
Gl uc os e (s er u m) 
 
Bl o o d M ark ers of I nt e sti n al Tra n sit a n d 
A b s or pti o n a 
Al a ni n e a mi n otr a nsf er as e ( A L T) 
 
Vit a mi ns: B 6, B 1 2, K, E, A 
As p art at e a mi n otr a nsf er as e ( A S T) 
 
Ser u m f ol at e 
T ot al bilir u bi n ( T B) 
 
F erriti n 
Alk ali n e p h os p h at as e ( A L P) 
 
M ark ers of b o n e a n d c al ci u m met a b oli s m b 
Uric aci d  
  
C alci u m 
C alci u m
 
  
2 5- hy dr oxyvit a mi n
 
D
P h os p h or us
 
  
1, 2 5- di hy dr oxyvit a mi n
 
D
 
T ot al pr ot ei n 
 
Ph os p h or us 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 8 
Cli ni c al c h e mi str y 
H e m at ol o g y 
Ot h er bl o o d p ar a m et er s 
Al b u mi n 
 
Par at hyr oi d h or m o n e ( P T H) 
M a g n esi u m 
 
M ark ers of b o n e r es or p ti o n: N-t er mi n al t el o p e pti d e 
( N T X), b et a- C-t er mi n al t el o p e pti d e (β - C T X- 1) 
Cr e ati n e p h os p h oki n as e ( C P K) 
 
M ark er of b o n e f or m ati o n: ty p e 1 pr oc oll a g e n 
N-t er mi n al ( P 1 N P) 
L actic aci d d e hy dr o g e n as e ( L D H)  
 
 
A myl as e
 
 
 
Li p as e
 
 
 
All ass ess m e nts t o b e p erf or m e d by c e ntr al l a b or at ory. All ass ess m e nt m e as ur e d i n s er u m. 
a  T o b e c oll ect e d at B as eli n e ( Visit 3), W e ek 2 6 ( Visit 9), W e ek 7 9 ( Visit 1 3), a n d F oll o w- u p Visit ( Visit 1 4). 
b  T o b e c oll ect e d at B as eli n e ( Visit 3), W e ek 2 6 ( Visit 9), a n d W e ek 7 9 ( Visit 1 3). Uri n e m ark ers of b o n e a n d c alci u m m et a b olis m ar e list e d 
i n S ecti o n  9. 2. 1. 3 . 
9. 2. 1. 3. 1  Uri n al y si s 
Uri nal ysis ( uri ne di pstic k wit h micr osc o p y) will be perf or me d b y ce ntral la b orat or y at Scree ni n g 
( Visit 1), Bas eli ne ( Visit 3), Wee k 2 6 ( Visit 9), a n d Wee k 7 9 ( Visit 1 3). T o pre ve nt partial 
u n bli n di n g, U G E res ults will be bli n de d t o i n vesti gati o nal sites a n d p atie nts, a n d t he ce ntral 
la b orat or y U A di pstic k will n ot i ncl u de t he meas ure me nt of uri ne gl uc os e. Ce ntral uri nal ysis 
i ncl u des: 
•  Uri ne di pstic k i ncl u des: s pecific gra vit y, p H, pr otei n, bl o o d, ket o nes, bilir u bi n, 
ur o bili n o ge n, nitrite, a n d le u k oc yt e esterase 
•  Uri ne micr osc o p y i ncl u d es, b ut is n ot li mite d t o: detecti o n of f or m e d cell ul ar ele me nts, 
casts, bacteria, yeast, par asites, a n d cr ystals i n ce ntrif u ge d uri ne se di me nt. 
I n t he e ve nt of a b n or mal uri nal ysis fi n di n gs s us pici o us of uri nar y tract i nfecti o n, uri ne c ult ure 
s h o ul d be perf or m e d. P ositi ve uri ne c ult ure deter mi nati o n will be base d u p o n t he criteria of t he 
re p orti n g la b orat or y. 
If t he uri ne di pstic k is p ositi ve f or bl o o d, t he ce ntr al la b orat or y will perf or m refle xi ve testi n g t o 
i ncl u de micr osc o p y. A d diti o nal testi n g will be perf or me d acc or di n g t o t he j u d g me nt of t he 
I n v esti gat or. Referral t o ur ol o g y/ ur ol o gic e val uati o n is rec o m me n de d f or n e w or u ne x plai ne d 
cases of c o nfir me d h e mat uria ( ur ol o g y/ ur ol o gic e val uati o n is n ot re q uire d w here h e mat uria is 
c o nsi dere d t o be relate d t o dia betic ne p hr o p at h y). 
I n a d diti o n, uri ne al b u mi n, calci u m, gl uc ose, a n d creati ni ne will be assesse d as Bas eli ne ( Visit 3) 
a n d all s u bse q ue nt o n-sit e visits.  
Uri ne mar k ers of b o n e a n d calci u m meta b olis m will be assesse d at Baseli ne ( Visit 3), Wee k 2 6 
( Visit 9), a n d Wee k 7 9 ( Visit 1 3), a n d i ncl u de: calci u m a n d p h os p h or us. Se r u m mar kers of b o ne 
a n d calci u m meta b olis m are liste d i n Ta ble 2 . 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 5 9 
9. 2. 1. 4  Vit al si g n s a n d p h y si c al e x a m 
A c o m plete p h ysical e x a m (i ncl u di n g sitti n g bl o o d press ure a n d heart rate, te m perat ure a n d 
res pirat or y rate) will be perf or me d at Visit 1 ( Scree ni n g), Visit 9 ( Wee k 2 6), a n d Visit 1 3 
( Wee k 7 9). A b br e viate d p h ysical e x a ms (i ncl u di n g sitti n g bl o o d press ure an d heart rate) will be 
perf or me d at all ot her o n-site visits. T he a b bre viat e d p h ysical e x a m s h o ul d f oc us o n car diac a n d 
res pirat or y s yste ms, as w ell as a n y areas i m p orta nt f or assess me nt of A Es if necessar y. T hree 
se parat e seate d B Ps a n d heart r ate meas ure me nts s h o ul d be ta ke n wit h at least 1 mi n ute bet wee n 
meas ure me nts f oll o wi n g a 5- mi n ute rest peri o d, a n d pri or t o p hle b ot o m y. F ull details a n d 
directi o ns f or t he meas ure me nt of  bl o o d press ure are prese nte d i n A p p e n di x E . 
9. 2. 1. 5  El e ctr o c ar di o gr a m v ari a bl e s 
T he E C G assess me nt of “ n or mal” or “a b n or m al” will be a nal yze d. 
A 1 2-lea d E C G r ec or d is perf or me d l o call y at Scree ni n g ( Visit 1), Bas eli ne ( Visit 3), Wee k 2 6 
( Visit 9), a n d Wee k 7 9 ( Visit 1 3). 
T he 1 2-lea d E C G s h o ul d be perf or me d  after at least 1 0 mi n utes i n s u pi ne p ositi o n a n d pri or t o t he 
m or ni n g I M P a d mi nistrati o n. T he I n vesti gat or  s h o ul d re vie w t he E C G a n d d oc u me nt t he 
i nter pretati o n, si g n a n d d ate it o n t he E C G pri nt o ut a n d re p ort it i n t he e- C R F. Eac h E C G trace is 
a nal yz e d i n c o m paris o n wit h t he scree ni n g rec or d e d  trace. All ori gi nal traces are k e pt as s o urce 
data. 
N ote: A n y n e w E C G a b n or malit y s h o ul d be r ec hec ke d f or c o nfir mati o n a n d re p orte d as 
a p pr o priate f or t hat fi n di n g. 
9. 2. 1. 6  S elf- m o nit ori n g of bl o o d gl u c o s e 
A meter f or s elf- assess me nt of bl o o d gl uc os e will be  dis pe nse d at t he R u n-i n visit ( Visit 2). I n 
a d diti o n t o h o me meas ur e me nts of self- m o nit ore d bl o o d gl uc ose, s elf- m o nit ori n g of bl o o d gl uc ose 
will be perf or me d at Bas eli ne ( Visit 3) a n d all s u bse q ue nt o n-site visits. Gl uc ose meters us e d f or 
S M B G dis pla y res ults as plas ma gl uc os e c o n ce ntrati o n. 
Patie nts will als o recei ve a patie nt diar y at a ll o n-site visits wit h t he e x ce pti o n of F oll o w- u p 
Visit 1 4. T he diar y will be re vie w e d at all o n-site visits fr o m Visit 2 t o Visit 1 4 wit h t he e x ce pti o n 
of t he A B P M place me nts visits ( 3 A, 7 A, a n d 9 A). Self-assesse d bl o o d gl uc ose le vels will be 
e ntere d i n t he p atie nt diar y.  
Patie nts will be as ke d t o self-assess bl o o d gl uc ose levels at least 3 ti mes a wee k fr o m t he r u n-i n 
Visit ( Visit 2) t o t he e n d of t he Treat me nt Peri o d i ncl u di n g o n da y of eac h o n-site st u d y visit. 
After Visit 9 ( Wee k 2 6), if S M B G val ues are < 1 2 0 m g/ d L o ver a 2- w ee k p eri o d, t he I n vesti gat or 
ca n (at t heir o w n discreti o n) i nstr uct patie nts t o self- m o nit or bl o o d gl uc ose o nce a w ee k ( o n d a y 
of o n-site st u d y visit f or wee k s wit h o n-site st u d y visits). 
Patie nts will be re q ueste d t o self-assess bl o o d gl u c ose le vels i n t he faste d state a n d w he n e ver t h e y 
e x perie nce a n y ill nesses (e g, c ol d, fl u), or s y m pt o ms of h y per gl yce mia or h y p o gl yce mia. 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 0 
S y m pt o ms of h y p o gl yce mia ma y i ncl u d e s ha ki ness,  dizzi ness, s weati n g, h u n ger, hea d ac h e, pale 
s ki n c ol or, s u d de n m o o di ness or beha vi or c ha n ges (s uc h as cr yi n g f or n o a p pare nt reas o n), cl u ms y 
or jer k y m o ve me nts, seiz ure, diffic ult y pa yi n g atte nti o n or c o nf usi o n, or ti n gli n g se nsati o ns 
ar o u n d t he m o ut h. Patie nts will be i nstr ucte d t o rec o r d t he prese nce or a bs e nce of h y p o gl yce mic 
e pis o des or h y p o gl yce mi c s y m pt o ms i n t he patie nt diar y pr o vi de d. 
Patie nts will als o be i nstr ucte d t o rec or d S M B G v al ues t hat are ≤7 0 m g/ d L ( ≤3. 9 m m ol/ L) i n t he 
patie nt diar y. Patie nts s h o ul d be i nstr ucte d t o c o nt act t he site if fasti n g S M B G val ues o v er 
3 c o nsec uti ve da ys are:  
•  > 2 7 0 m g/ d L ( 1 5. 0 m m ol/ L) fr o m Ra n d o mizati o n u p t hr o u g h t he s c he d ule d Wee k 8 Visit 
•  > 2 4 0 m g/ d L ( 1 3. 3 m m ol/ L) after t he Wee k 8 visit u p t hr o u g h t he s c he d ule d Wee k 1 2 Visit 
•  > 2 0 0 m g/ d L ( 1 1. 1 m m ol/ L) after t he Wee k 1 2 Vi sit a n d t hr o u g h t he e n d of t he 2 6- wee k 
d o u ble- bli n d Treat me nt Peri o d 
•  > 1 7 0 m g/ d L ( 9. 4 m m ol/ L) after t he Wee k 2 6 Visit t hr o u g h t he e n d of t he E xte nsi o n 
treat me nt peri o d 
9. 2. 1. 7  Di a b eti c k et o a ci d o si s 
Patie nts will be pr o vi de d wit h i nstr ucti o ns o n h o w t o rec o g nize t he s y m pt o ms of D K A a n d 
i nstr ucte d t o c o ntact t he site ( or see k e mer ge nc y m e dical ser vi ces if after b usi ness h o urs) if t hese 
s y m pt o ms de vel o p.  Patie nts s h o uld ha ve a f ull cli nical e val uati o n wit h la b orat or y testi n g f or 
p ossi ble D K A b y t h e i n vesti gat or or e mer ge nc y m e di cal ser vi ces p h ysicia n If s uc h e v al uati o n a n d 
la b orat or y testi n g c o nfir m t he prese nce of meta b olic aci d osis, t he n a p pr o priate treat me nt s h o ul d 
be i m ple me nte d a n d t he “ P ossi ble D K A” e- C R F s h o ul d be c o m plete d. See A p pe n di x D  f or f urt her 
details. 
9. 3  
O T H E R E N D P OI N T S 
9. 3. 1  P h ar m a c o ki n eti c s 
T he P K e n d p oi nt is: 
•  Plas ma c o nce ntr ati o ns of s ota glifl ozi n a n d its meta b olite pre- d ose at Wee k 4, 1 8, 2 6, 5 2, 
7 9 a n d 2 h o urs 3 0 mi n utes p ost- d ose at Wee k 2 6 a n d 7 9 
9. 3. 1. 1  S a m pli n g ti m e 
At Wee ks 4, 1 8, a n d 5 2 ( Visits 5, 8, a n d 1 1 res pecti v el y), P K sa m ples are t o be dra w n wit h t he 
ot her la b orat or y assess m e nts i m me diatel y bef ore  I M P a d mi nistrati o n. At Wee k 2 6 a n d Wee k 7 9 
( Visits 9 a n d 1 3, res pecti vel y), P K s a m ples sh o ul d be dra w n pre- d os e a n d 2 h o urs 3 0 mi n utes 
p ost- d ose, i m me diatel y after t he res pecti ve gl uc ose assess me nts d uri n g t he M M T T. 
P har mac o ki netic sa m ples ( wit h t he e x ce pti o n of t he 2 h o urs 3 0 mi n ute sa m ple d uri n g t he 
Wee k 2 6 a n d Wee k 7 9 M M T T) m ust  be c ollecte d bef ore a d mi nistrati o n of I M P. See Ta ble 3 f or 
t he i de ntificati o n of sa m ples. 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 4 
patie nts wit h D B P > 8 0 m m H g.  Alt h o u g h effects o n B P i n P hase 2 data were o bser ve d wit h t he 
4 0 0 m g d ose at 1 2 wee ks, t he eff ects will be e x a mi ne d at Wee ks 1 2, 2 6, a n d 7 9. 
E vi de nce t hat s ota glifl ozi n re d uces ele vat e d S B P a n d D B P is descri be d i n S ecti o n  4. 5 . T o f urt her 
assess t hese effects, A B P M will be meas ure d i n a s u bset of patie nts wit h mea n S B P ≥1 3 0 m m H g 
at Scree ni n g, i n a d diti o n t o sitti n g B P meas ure d i n all patie nts. A B P M ma y re d uce t h e “ w hite 
c oat” effect see n wit h sitti n g bl o o d press ure m eas ure me nts, is m ore cl osel y c orrel ate d wit h 
mar kers of or ga n d a ma ge, a n d is a m ore se nsiti ve pre dict or of C V o utc o m es ( 1 2 ). It als o per mits 
assess me nt of ni g htti me a n d da yti me bl o o d press ure ( 1 2 ). 
E n d p oi nts f or e val uati n g re nal f u n cti o n i ncl u de e G F R, base d o n ser u m creati ni ne, a n d uri ne 
al b u mi n t o creati ni ne rati o as well as r o uti ne m o nit ori n g of uri ne via di pstic k a n d micr osc o p y.  
U G E, uri ne G C R ar e ot h er vali d mar k ers of re na l f u ncti o n, a n d will be assesse d at a p pr o pri ate 
ti me p oi nts i n t his st u d y. 
Bec a use of p ot e ntial eff e cts o n b o ne a n d calci u m meta b olis m, s pecific bi o mar kers f or b o ne a n d 
calci u m meta b olis m will be assesse d at re g ular ti me p oi nts. I n vie w of t he S G L T 1 i n hi bit or y 
effects i n t he GI tract, s p ecific mar kers of i ntesti n al tra nsit a n d a bs or pti o n will als o be meas ure d. 
T he ot her efficac y a n d s afet y assess me nts i n  t his st u d y are sta n dar d, well-esta blis he d 
meas ure me nts f or a P has e 3 st u d y e val uati n g t he treat me nt of T 2 D i n a d ult patie nts.  
T he le n gt h of t he st u d y is c o ns i dere d a p pr o priat e f or detecti o n of t he pri mar y e n d p oi nt gi ve n t he 
p o wer esti mates (s ee Secti o n  1 1 ). 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 5 
1 0  
S T U D Y P R O C E D U R E S 
1 0. 1  VI SI T S C H E D U L E 
T he visit sc he d ule a n d pr oce d ures/ assess me nts are liste d i n t he “ St u d y Fl o w C hart” (Secti o n  1. 2 ). 
T he ai m of t his secti o n is t o pr o vi de details o n h o w s o me of t he pr o ce d ures /assess me nts s h o ul d be 
perf or me d. 
T his is a n o ut- patie nt st u d y a n d c o nsists of 1 4 o n- site visits ( 1 7 o n-site visits f or patie nts e nr olle d 
i n t he A B P M s u bst u d y), alt h o u g h o pti o nal o n-site a n d/ or tele p h o ne visits ca n be sc he d ul e d at a n y 
ti me f or a n y reas o n d uri n g t he st u d y w h e ne ver c o nsi dere d necessar y b y t he I n v esti gat or. 
T he patie nts nee d t o b e f asti n g f or o n-site visits Visit 1 t hr o u g h Visit 1 3 ( Wee k - 4 t hr o u g h 
Wee k 7 9), u nless i nstr ucte d ot her wise b y t he I n vesti gat or. T hr o u g h o ut t he st u d y, “fasti n g” is 
defi ne d as 8 h o urs wit h o ut f o o d. N ote:  If t he p atie nt is n ot fasti n g at t he visits s pecifie d a b o ve, t he 
bl o o d sa m ple will n ot be c ollecte d  a n d a ne w a p p oi nt me nt s h o ul d be gi ve n t o t he patie nt f or t he 
f oll o wi n g da y if p ossi ble, wit h i nstr ucti o n t o be faste d. Patie nts i n t he A B P M s u bst u d y d o n ot 
nee d t o be f asti n g f or visits Visit 3 A, Visit 7 A, a n d Visit 9 A, d uri n g w hic h A B P M de vice 
place me nt will occ ur. 
T he R u n-i n visit ( Visit 2) ca n be p erf or m e d as s o o n as t he res ults of all scree ni n g tests are 
a vaila ble a n d t he patie nt is c o nfir me d t o be eli gi ble f or partici pati o n i n t he st u d y. T he visit 
wi n d o w f or Visit 4 t hr o u g h Visit 9, a n d Visit 1 4 s h o ul d occ ur wit hi n ± 3 da ys. Visits 1 0, 1 1 a n d 
1 2 s h o ul d occ ur wit hi n ± 7 da ys. Visit 1 3 ( E O T) s h o ul d occ ur d uri n g D a y 5 4 8 t o 5 5 5. F or F oll o w-
u p Visit V 1 4, t he visit wi n d o w s h o ul d occ ur wit hi n +  3 da ys, 4 wee ks aft er Visit 1 3. F or patie nts 
i n t he A B P M s u bst u d y, t he Visits 3 A, 7 A, a n d 9 A s h o ul d occ ur wit hi n ± 2 da ys. 
If o ne visit date is c ha n ge d, t he ne xt visit s h o uld occ ur acc or di n g t o t he ori gi nal sc he d ul e, ie 
calc ulate d fr o m t he date of Bas eli ne visit ( Visit 3, Wee k 0). 
F or a c o m plete list of pr o ce d ures s c he d ule d f or eac h st u d y visit please refer t o t he St u d y Fl o w 
C hart ( Secti o n  1. 2 ), w hic h details t he pr oce d ures t o be perf or me d. 
All data o btai ne d d uri n g t he trial visits are re vie w e d b y t h e I n vesti gat or a n d s u b-i n vesti gat ors w h o 
are q ualifi e d i n treat me nt of T 2 D a n d are trai ne d o n t he st u d y. 
1 0. 1. 1 S cr e e ni n g P eri o d 
T he Scree ni n g p eri o d is u p t o 4 wee ks a n d i ncl u d es t he Scree ni n g p h ase a n d t he R u n-i n p hase. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 7 
•  Meas ure me nt of b o d y hei g ht a n d w ei g ht 
•  C o m plete p h ysical e x a mi nati o n i ncl u di n g vita l si g ns ( S B P a n d D B P, te m perat ure, h eart 
rate, a n d res pirat or y rate). T hree se p arate seat e d B Ps a n d heart rate meas ure me nts s h o ul d 
be ta ke n wit h at least 1 mi n ute bet wee n me as ure m e nts f oll o wi n g a 5- mi n ute rest peri o d, 
a n d pri or t o p hle b ot o m y (see A p p e n di x E  f or details of B P pr oce d ure) 
•  1 2-lea d E C G 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
Fasti n g plas ma gl uc ose 
- 
H b A 1c 
- 
He patitis ser ol o g y 
- 
Ser u m pre g na n c y testi n g f or W O C B P 
- 
ser u m F S H a n d estra di ol (p ost me n o pa usal w o me n o nl y) 
- 
He mat ol o g y 
- 
Cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e 
- 
Fasti n g li pi ds 
- 
Uri nal ysis ( di pstic k a n d micr osc o p y) 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site f or Visit 2 ( Wee k - 2) i n a faste d state 
1 0. 1. 1. 2 R u n-i n p h a s e 
T he R u n-i n p hase is 2 wee ks a n d i ncl u des Visit 2 ( Wee k - 2) a n d, f or patie nts w h o c o nse nte d t o 
t he A B P M s u bst u d y, Visit 3 A ( W ee k - 1).  
1 0. 1. 1. 2. 1 O n- sit e Vi sit 2 ( R u n-i n, W e e k - 2) 
T he f oll o wi n g pr oce d ures/assess me nts will be perf or me d at Visit 2 ( Wee k - 2): 
•  Meas ure me nt of b o d y wei g ht 
•  A b bre viate d p h ysical e x a mi nati o n i ncl u di n g vital si g ns perf or me d after t he patie nt has 
bee n seat e d f or at least 5 mi n utes ( S B P a n d D B P, a n d heart rate). Bl o o d press ure a n d h eart 
rate will be assess e d 3 ti mes wit h at least 1 mi n ute bet wee n eac h meas ure me nt (see 
A p pe n di x E  f or details) 
•  Diet a n d e x ercise i nstr ucti o n 
•  Bl o o d gl uc ose meter is dis pe nse d a n d i nstr ucti o ns/trai ni n g are pr o vi d e d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  I R T t o be n otifie d 
•  Patie nt diar y is c ollecte d/re vie we d. A ne w di ar y,  i ncl u di n g h y p o gl yce mia l o g, is dis pe nse d 
a n d i nstr ucti o ns/trai ni n g are pr o vi d e d as nee de d 
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A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 8 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d, i ncl u di n g t h ose occ urri n g 
si nce Visit 1 
•  R u n-i n kit/ place b o is dis pe nse d  
•  C o nc o mita nt me dicati o n 
•  Fasti n g S M B G is assess e d 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site i n t he fasti n g state f or Visit 3 ( Ra n d o mizati o n) 
or, f or patie nts e nr olle d i n t he A B P M s u bst u d y, at Visit 3 A 
1 0. 1. 1. 2. 2 A m b ul at or y bl o o d pr e s s ur e m o nit or pl a c e m e nt o n- sit e vi sit 3 A, ( W e e k - 1) 
T he f oll o wi n g pr oce d ures will be perf or me d at t hese visits o nl y f or p atie nts i n t he A B P M 
s u bst u d y: 
•  Place me nt of t he A B P M de vice 
Patie nts d o n ot nee d t o be fasti n g f or Visit 3 A. After t he patie nt has w or n t he A B P M de vice f or 
2 4 h o urs after pl ace m e nt, t he y will re m o v e it a n d p ost it t o t he i n vesti gati ve site usi n g a p pr o priate 
pac ka gi n g pr o vi de d b y t h e site. Data will be re vie we d t o assess q ualit y; p atie nts wit h A B P M data 
n ot of s ufficie nt q ualit y s h o ul d n ot be ra n d o mize d  u ntil t he Baseli ne A B P M rec or di n g h as bee n 
re peat e d (see A p pe n di x B ). 
1 0. 1. 2 D o u bl e- bli n d r a n d o mi z e d C or e Tr e at m e nt P eri o d 
1 0. 1. 2. 1 Tr e at m e nt P eri o d ( D a y 1 t o W e e k 2 6) 
U p o n s uccessf ul c o m pleti o n of t he R u n-i n p hase, patie nts will be ra n d o ml y all ocate d t o eit her 
s ota glifl ozi n 4 0 0 m g or place b o f or t he d o u ble- bli n d treat me nt peri o d lasti n g 2 6 w ee ks. All 
ra n d o mize d patie nts will be f oll o we d at re g ular o n-site visits f or t he d urati o n of t he treat me nt 
peri o d. 
I n a d diti o n t o r o uti ne la b orat or y testi n g, t h e f oll o wi n g will be perf or me d at s pecifie d ti me p oi nts: 
plas ma c o nce ntrati o n; mar kers of  i ntesti nal tra nsit a n d a bs or ptio n; mar kers of b o ne a n d calci u m 
meta b olis m; uri ne al b u mi n, calci u m, gl u c ose, a n d creati ni ne. 
T he date a n d ti me of t he last i nta ke of I M P pri or t o visits w her e P K sa m ples are ta k e n s h o ul d be 
rec or d e d b y t he patie nt i n t he patie nt diar y. Patients s h o ul d be re mi n de d of t h is at visits prece di n g 
P K ti me p oi nts t o e ns ure t hese details are ca pt ure d. 
I n t he e ve nt of a b n or mal uri nal ysis fi n di n gs s us pici o us of uri nar y tract i nfecti o n, uri ne c ult ure 
s h o ul d be perf or m e d. P ositi ve uri ne c ult ure deter mi nati o n will be base d u p o n t he criteria of t he 
re p orti n g la b orat or y. 
I n a d diti o n, P P G will be assesse d at Baseli ne a n d 2 h o urs after c o ns u mi n g a sta n dar d mi x e d li q ui d 
brea kf ast meal vial a M M T T o n Da y 1 a n d at Wee k 2 6. 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 6 9 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 6 9 
F or patie nts w h o h a ve c o nse nte d t o t he A B P M s u bst u d y, t here will be 2 a d diti o nal o n-site visits 
f or place me nt of t he A B P M de vice, w hic h will occ ur at Da y 8 3 ( Visit 7 A) a n d Da y 1 8 1 
( Visit 9 A). Pr oce d ur es f or Visits 7 A a n d 9 A are s p ecifie d i n Secti o n  1 0. 1. 2. 2 . 
1 0. 1. 2. 1. 1 O n- sit e R a n d o mi z ati o n Vi sit o n D a y 1 ( B a s eli n e; W e e k 0; Vi sit 3) 
T he f oll o wi n g pr oce d ures will be perf or me d at t his visit: 
•  E x cl usi o n criteria are t o be re vie w e d, i ncl u di n g assess me nt of c o m plia nce d uri n g R u n-i n 
p hase 
•  C o nc o mita nt me dicati o ns are ass esse d 
•  Meas ure me nt of b o d y wei g ht 
•  A b bre viate d p h ysical e x a mi nati o n i ncl u di n g vital si g ns perf or me d after t he patie nt has 
bee n seat e d f or at least 5 mi n utes. S yst olic a n d di ast olic B P a n d heart rate will be assesse d 
3 ti mes wit h at least 1 mi n ute bet wee n eac h meas ure me nt (see A p pe n di x E  f or details) 
•  I M P acc o u nti n g a n d c o m plia nce f or si n gle- bli n d place b o R u n-i n p hase 
•  I R T t o be n otifie d a n d ra n d o mizati o n will occ ur 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Diet a n d e x ercise i nstr ucti o n 
•  Patie nt diar y, i ncl u di n g h y p o gl yce mia l o g,  is c ollecte d/re vie we d a n d dis pe nse d a n d 
i nstr ucti o ns/trai ni n g ar e pr o vi de d as nee de d  
•  I nstr u cti o n o n D K A s y m pt o ms (see A p pe n di x D ) is pr o vi de d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  1 2-lea d E C G, pri or t o I M P a d mi nistrati o n 
•  Fasti n g S M B G is assess e d 
•  Sta n dar d M M T T ( 2- h o ur p ost pra n dial gl u c ose meas ure me nts) 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
Fasti n g plas ma gl uc ose 
- 
H b A 1c 
- 
Uri ne pre g n a nc y testi n g f or W O C B P (a n y p ositi ve uri ne test res ults m ust be c o nfir me d 
b y a s er u m pr e g na nc y test) 
- 
He mat ol o g y 
- 
Cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e 
- 
Fasti n g li pi ds 
- 
Uri nal ysis ( di pstic k a n d micr osc o p y) 
- 
Uri ne a nal ysis f or al b u mi n, calci u m, gl uc ose, a n d creati ni ne 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 0 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 0 
•  A d diti o nal la b orat or y testi n g at t his visit: 
- 
Mar kers of i ntesti nal tra nsit a n d a bs or p ti o n ( vita mi ns B 6, B 1 2, K, E, a n d A, ser u m 
f olate, a n d ferriti n) 
- 
Mar kers of b o ne a n d calci u m meta b olis m (ser u m a n d uri nar y calci u m, ser u m 
2 5- h y dr o x y vita mi n D, ser u m 1, 2 5- di h y dr o x y vita mi n D, ser u m a n d uri nar y 
p h os p h or us, ser u m P T H, mar kers of b o n e res or pti o n [ser u m N T X, ser u m β - C T X- 1], 
a n d b o ne f or m ati o n [ser u m P 1 N P]) 
 
 
 
 
•  I M P is dis pe nse d 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site i n t he fasti n g state f or Visit 4 ( Wee k 1). 
•  F or acc o u nta bilit y a n d c o m plia nce p ur p oses, patie nt s are i nstr ucte d t o ret ur n t o t he site 
wit h t heir i n- use b ottle(s) dis pe nse d d uri n g Visit 3. 
1 0. 1. 2. 1. 2 O n- sit e vi sit s at W e e k s 1, 4, 8, 1 2, a n d 1 8 ( Vi sit s 4 t o 8) 
T he f oll o wi n g will be perf or me d at t hese visits: 
•  Re m o val of A B P M de vic e ( o nl y at Wee k 1 2 [ Visit 7] a n d o nl y f or p atie nts i n t he A P B M 
s u bst u d y) 
•  I R T t o be n otifie d (all visits e x ce pt Visit 4) 
•  I M P acc o u nti n g a n d c o m plia nce 
•  Patie nt diar y, i ncl u di n g h y p o gl yce mia l o g,  is c ollecte d/re vie we d a n d dis pe nse d a n d 
i nstr ucti o ns/trai ni n g ar e pr o vi de d as nee de d 
•  C o nc o mita nt me dicati o ns are ass esse d 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Patie nts are e v al uate d f or gl yce mic res c ue (s ee Secti o n  9. 1. 4. 7 ) 
•  Meas ure me nt of b o d y wei g ht 
•  A b bre viate d p h ysical e x a mi nati o n i ncl u di n g vital si g ns perf or me d after t he patie nt has 
bee n seat e d f or at least 5 mi n utes. S yst olic a n d di ast olic B P a n d heart rate will be assesse d 
3 ti mes wit h at least 1 mi n ute bet wee n eac h meas ure me nt (see A p pe n di x E  f or details) 
•  I nstr u cti o n o n D K A s y m pt o ms (see A p pe n di x D ) is pr o vi de d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  Fasti n g S M B G is assess e d 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
Fasti n g plas ma gl uc ose (f or all visits) 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 1 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 1 
- 
H b A 1c (all visits e x ce pt Visit 4) 
- 
Uri ne pre g n a nc y testi n g f or W O C B P (all visits e x ce pt Visit 4; a n y p ositi ve uri ne test 
res ults m ust be c o nfir me d b y a s er u m pre g na nc y t est) 
- 
He mat ol o g y ( Visit 7 o nl y) 
- 
Cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e ( Visits 5, 6, 7, a n d 8) 
- 
Fasti n g li pi ds (all visits e x ce pt Visit 4) 
- 
Uri ne a nal ysis f or al b u mi n, calci u m, gl uc ose, a n d creati ni ne (f or all visits) 
•  Pre- d ose plas ma c o nce ntrati o n sa m ples are c ollect e d a n d se nt t o t he a p pr o priate la b orat or y 
( Visits 5 a n d 8 o nl y) 
•  Patie nts s h o ul d be re mi n de d t o r ec or d t he ti me of I M P i nta ke o n t he d a y bef ore t heir n e xt 
visit (re mi n ders at Visits 4, 7 a n d 8 o nl y) 
•  I M P is dis pe nse d (all visits e x ce pt Visit 4) 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site i n t he fasti n g state f or t h eir ne xt visit. 
•  F or acc o u nta bilit y a n d c o m plia nce p ur p oses, patie nt s are i nstr ucte d t o ret ur n t o t he site 
wit h t heir b ottle(s) at t he ne xt visit 
N B: F or patie nts i n t he A B P M s u bst u d y, it is n ot re q uire d t o ret ur n t h eir b ottle(s) at 
A B P M visits). 
1 0. 1. 2. 1. 3 O n- sit e Vi sit 9 at W e e k 2 6  
T he f oll o wi n g will be perf or me d at t his visit: 
•  Re m o val of A B P M de vic e ( o nl y f o r patie nts i n t he A P B M s u bst u d y) 
•  I R T t o be n otifie d 
•  I M P acc o u nti n g a n d c o m plia nce  
•  Patie nt diar y, i ncl u di n g h y p o gl yce mia l o g,  is c ollecte d/re vie we d a n d dis pe nse d a n d 
i nstr ucti o ns/trai ni n g ar e pr o vi de d as nee de d 
•  C o nc o mita nt me dicati o ns are ass esse d 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Patie nts are e v al uate d f or gl yce mic res c ue (s ee Secti o n  9. 1. 4. 7 ) 
•  Meas ure me nt of b o d y wei g ht 
•  C o m plete p h ysical e x a mi nati o n i ncl u di n g vita l si g ns ( S B P a n d D B P, te m perat ure, h eart 
rate, a n d res pirat or y rate). T hree se p arate seat e d B Ps a n d heart rate meas ure me nts s h o ul d 
be ta ke n wit h at least 1 mi n ute bet wee n me as ure m e nts f oll o wi n g a 5- mi n ute rest peri o d, 
a n d pri or t o p hle b ot o m y (see A p p e n di x E  f or details of B P pr oce d ure)  
•  Diet a n d e x ercise i n str ucti o n is pr o vi de d 
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2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 2 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 2 
•  I nstr u cti o n o n D K A s y m pt o ms (see A p pe n di x D ) is pr o vi de d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  1 2-lea d E C G, pri or t o t he m or ni n g I M P a d mi nistrati o n 
•  Fasti n g S M B G is assess e d 
•  Sta n dar d M M T T ( 2- h o ur p ost pra n dial gl u c ose meas ure me nts) 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
Fasti n g plas ma gl uc ose 
- 
H b A 1c 
- 
Uri ne pre g n a nc y testi n g f or W O C B P (a n y p ositi ve uri ne test res ults m ust be c o nfir me d 
b y a s er u m pr e g na nc y test) 
- 
He mat ol o g y 
- 
Cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e 
- 
Fasti n g li pi ds 
- 
Uri nal ysis ( di pstic k a n d micr osc o p y) 
- 
Uri ne a nal ysis f or al b u mi n, calci u m, gl uc ose, a n d creati ni ne 
•  A d diti o nal la b orat or y testi n g at t his visit: 
- 
Mar kers of i ntesti nal tra nsit a n d a bs or p ti o n ( vita mi ns B 6, B 1 2, K, E, a n d A, ser u m 
f olate, a n d ferriti n) 
- 
Mar kers of b o ne a n d calci u m meta b olis m (ser u m a n d uri nar y calci u m, ser u m 
2 5- h y dr o x y vita mi n D, ser u m 1, 2 5- di h y dr o x y vita mi n D, ser u m a n d uri nar y 
p h os p h or us, ser u m P T H, mar kers of b o n e res or pti o n [ser u m N T X, ser u m β - C T X- 1], 
a n d b o ne f or m ati o n [ser u m P 1 N P]) 
 
 
•  Plas ma c o nce ntrati o n sa m ples ( pre- d os e a n d 2 h o urs 3 0 mi n utes p ost- d ose) are c ollecte d 
a n d se nt t o t he a p pr o pri ate la b orat or y 
•  I M P is dis pe nse d 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site i n t he fasti n g state i n 1 3 wee ks f or Visit 1 0. 
•  F or acc o u nta bilit y a n d c o m plia nce p ur p oses, patie nt s are i nstr ucte d t o ret ur n t o t he site 
wit h t heir b ottle(s) at Visit 1 0. 
1 0. 1. 2. 2 A m b ul at or y bl o o d pr e s s ur e m o nit or pl a c e m e nt o n- sit e Vi sit 7 A a n d 9 A ( W e e k 1 2 
a n d W e e k 2 6) 
T he f oll o wi n g pr oce d ures will be perf or me d at t hese visits o nl y f or p atie nts i n t he A B P M 
s u bst u d y: 
•  
Place me nt of t he A B P M de vice 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 3 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 3 
•  
Patie nts are i nstr ucte d t o ret ur n t o t he site i n a fasti n g state i n 2 4 h o urs 
•  
Patie nts s h o ul d be re mi n de d t o rec or d t he ti me of I M P i nta ke o n t he d a y bef ore Visit 9 
(re mi n der at Visit 9 A o nl y). 
1 0. 1. 3 D o u bl e- bli n d e xt e n si o n p eri o d 
U p o n c o m pleti o n of t he d o u ble- bli n d c ore treat m e nt peri o d, patie nts will re mai n o n t he sa me 
bli n de d treat me nt t hr o u g h o ut a 5 3- wee k d o u ble- bli n d e xte nsi o n peri o d f or a t otal treat me nt 
d urati o n of 7 9 wee ks. 
T he d o u ble- bli n d e xte nsi o n peri o d will c o nsist of  4 visits, occ urri n g at Wee k 3 9 ( Visit 1 0), 
Wee k 5 2 ( Visit 1 1), Wee k 6 5 ( Visit 1 2), a n d a n e n d- of-treat me nt visit at Wee k 7 9 ( Visit 1 3). 
I n t he e ve nt of a b n or mal uri nal ysis fi n di n gs s us pici o us of uri nar y tract i nfecti o n, uri ne c ult ure 
s h o ul d be perf or m e d. P ositi ve uri ne c ult ure deter mi nati o n will be base d u p o n t he criteria of t he 
re p orti n g la b orat or y. 
1 0. 1. 3. 1 O n- sit e vi sit s at W e e k s 3 9, 5 2, a n d 6 5 ( Vi sit s 1 0 t o 1 2) 
T he f oll o wi n g will be perf or me d at t hese visits: 
•  I R T t o be n otifie d 
•  I M P acc o u nti n g a n d c o m plia nce 
•  Patie nt diar y, i ncl u di n g h y p o gl yce mia l o g,  is c ollecte d/re vie we d a n d dis pe nse d a n d 
i nstr ucti o ns/trai ni n g ar e pr o vi de d as nee de d 
•  C o nc o mita nt me dicati o ns are ass esse d 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Patie nts are e v al uate d f or gl yce mic res c ue (s ee Secti o n  9. 1. 4. 7 ) 
•  Meas ure me nt of b o d y wei g ht 
•  A b bre viate d p h ysical e x a mi nati o n i ncl u di n g vital si g ns perf or me d after t he patie nt has 
bee n seat e d f or at least 5 mi n utes. S yst olic a n d di ast olic B P a n d heart rate will be assesse d 
3 ti mes wit h at least 1 mi n ute bet wee n eac h meas ure me nt (see A p pe n di x E  f or details) 
•  Diet a n d e x ercise i nstr ucti o n is pr o vi de d ( Visit 1 1 o nl y) 
•  I nstr u cti o n o n D K A s y m pt o ms (see A p pe n di x D ) is pr o vi de d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  Fasti n g S M B G is assess e d 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
Fasti n g plas ma gl uc ose 
- 
H b A 1c 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 7 4 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 4 
- 
Uri ne pre g n a nc y testi n g f or W O C B P (a n y p ositi ve uri ne test res ults m ust be c o nfir me d 
b y a s er u m pr e g na nc y test) 
- 
He mat ol o g y 
- 
Cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e 
- 
Uri ne a nal ysis f or al b u mi n, calci u m, gl uc ose, a n d creati ni ne 
•  Pre- d ose plas ma c o nce ntrati o n sa m ples are c ollect e d a n d se nt t o t he a p pr o priate la b orat or y 
( Visit 1 1 o nl y)  
•  Patie nts s h o ul d be re mi n de d t o r ec or d t he ti me of I M P i nta ke o n t he d a y bef ore t heir n e xt 
visit ( Visits 1 0 a n d 1 2 o nl y) 
•  I M P is dis pe nse d 
•  Patie nts are i nstr ucte d t o ret ur n t o t he site i n t he fasti n g state f or t h eir ne xt visit. 
•  F or acc o u nta bilit y a n d c o m plia nce p ur p oses, patie nt s are i nstr ucte d t o ret ur n t o t he site 
wit h t heir b ottle(s) at t he ne xt visit. 
1 0. 1. 3. 2 O n- sit e Vi sit 1 3 at W e e k 7 9 - E n d- of-tr e at m e nt 
T he f oll o wi n g will be perf or me d at t his visit: 
•  I R T t o be n otifie d (if E O T visit is als o last visit, I R T s h o ul d be n otifie d f or e n d of st u d y) 
•  I M P acc o u nti n g a n d c o m plia nce 
•  Patie nt diar y, i ncl u di n g h y p o gl yce mia l o g,  is c ollecte d/re vie we d a n d dis pe nse d a n d 
i nstr ucti o ns/trai ni n g ar e pr o vi de d as nee de d 
•  C o nc o mita nt me dicati o ns are ass esse d 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Patie nts are e v al uate d f or gl yce mic res c ue (s ee Secti o n  9. 1. 4. 7 ) 
•  Meas ure me nt of b o d y wei g ht 
•  C o m plete p h ysical e x a mi nati o n i ncl u di n g vita l si g ns ( S B P a n d D B P, te m perat ure, h eart 
rate, a n d res pirat or y rate). T hree se p arate seat e d B Ps a n d heart rate meas ure me nts s h o ul d 
be ta ke n wit h at least 1 mi n ute bet wee n me as ure m e nts f oll o wi n g a 5- mi n ute rest peri o d, 
a n d pri or t o p hle b ot o m y (see A p p e n di x E  f or details of B P pr oce d ure) 
•  Diet a n d e x ercise i n str ucti o n is pr o vi de d 
•  I nstr u cti o n o n D K A s y m pt o ms (see A p pe n di x D ) is pr o vi de d 
•  I nstr u cti o n o n basic G U h y gie n e a n d h y drati o n (see A p pe n di x D ) 
•  1 2-lea d E C G, pri or t o t he m or ni n g I M P a d mi nistrati o n 
•  Fasti n g S M B G is assess e d 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 6 
•  A Es/ S A Es/ A E SI/ E O SI a n d h y p o gl yce mia (if a n y) are re p orte d 
•  Meas ure me nt of b o d y wei g ht  
•  A b bre viate d p h ysical e x a mi nati o n i ncl u di n g vital si g ns perf or me d after t he patie nt has 
bee n seat e d f or at least 5 mi n utes. S yst olic a n d di ast olic B P a n d heart rate will be assesse d 
3 ti mes wit h at least 1 mi n ute bet wee n eac h meas ure me nt (see A p pe n di x E  f or details) 
•  Scree ni n g a n d c urr e nt B P rea di n gs are re vie we d, a n d p osttreat me nt a nti h y perte nsi ve 
me dicati o n is a d de d or a dj uste d as per i nstr ucti o ns gi ve n i n Secti o n  8. 9.  
•  S M B G is perf or m e d 
•  T he f oll o wi n g l a b orat or y testi n g ( b y t he ce ntral la b orat or y): 
- 
cli nical c he mistr y t o i ncl u de a m yl ase a n d li pas e 
- 
uri ne a nal ysis f or al b u mi n, calci u m, gl uc ose, a n d creati ni ne 
•  A d diti o nal la b orat or y testi n g at t his visit: 
- 
Mar kers of i ntesti nal tra nsit a n d a bs or p ti o n ( vita mi ns B 6, B 1 2, K, E, a n d A, ser u m 
f olate, a n d ferriti n) 
•  T he patie nt is i nstr ucte d t o sc he d ule f ut ure  f oll o w- u p wit h t heir o w n pers o n al p h ysicia n. 
1 0. 2  
D E FI NI TI O N O F S O U R C E D A T A 
1 0. 2. 1 S o ur c e d at a t o b e f o u n d i n p ati e nt’ s fil e 
E val uati o ns rec or de d i n t he e- C R F m ust be  s u p p orte d b y a p pr o priat el y si g n e d s o urce 
d oc u me ntati o n relate d b ut n ot li mite d t o t he f oll o wi n g: 
•  A gree me nt a n d si g n at ure of I C F wit h t he st u d y i de ntificati o n 
•  St u d y i d e ntificati o n ( na m e) 
•  Patie nt n u m ber, c o nfir mati o n of ra n d o mizati o n, treat me nt batc h n u m ber, d ates a n d d oses 
of st u d y me dicati o n a d mi nistrati o n 
•  Me dical, s ur gical, dia b et es hist or y, i ncl u di n g i nf or mati o n o n: 
- 
De m o gra p h y, i ncl usi o n a n d e x cl usi o n criteria 
- 
Last p artici pati o n i n a cli nical trial 
- 
C o ntrace pti o n met h o d f or W O C B P 
- 
Pre vi o us a n d c o nc o mita nt me dicati o n 
•  Dates a n d ti mes of visits a n d assess me nts i ncl u di n g e x a mi nati o n res ults 
•  Vital si g ns, hei g ht, b o d y wei g ht, la b orat or y re p orts, I n v esti gati o n res ults (e g, E C G traces, 
i ma gi n g re p orts) 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 7 
•  A d verse e ve nts a n d f oll o w- u p: 
- 
I n case of S A E, t he site s h o ul d file i n t he s o urce d oc u me nts at least c o pies of t he 
h os pitalizati o n re p orts a n d a n y rele v a nt e x a mi nati o n re p orts d oc u me nti n g t he 
f oll o w- u p of t he S A E. 
•  Date of pr e mat ure treat m e nt di sc o nti n uati o n (if a n y) a n d reas o n 
•  Date of pr e mat ure st u d y disc o nti n uati o n (if a n y) a n d reas o n 
•  N ursi n g n otes 
•  Dieticia n’s n otes 
•  P h ysicia n’s n otes. 
1 0. 2. 2 S o ur c e d at a v erifi c ati o n r e q uir e m e nt s f or s cr e e n f ail ur e s 
F or scree n fail ure p atie nts, t he f oll o wi n g s o urce d ata m ust be verifie d: p atie nt's i de ntificati o n 
details, t he i nf or me d c o nse nt si g ne d b y t he p atie nt, t he st u d y i de ntificati o n ( na me), d ates of st u d y 
visits a n d t he mai n reas o ns f or scree n fail ure. 
1 0. 3  
H A N D LI N G O F P A TI E N T T E M P O R A R Y O R P E R M A N E N T T R E A T M E N T 
DI S C O N TI N U A TI O N A N D O F P A TI E N T S T U D Y DI S C O N TI N U A TI O N  
T he I M P s h o ul d be c o nti n ue d w he ne v er p ossi bl e. I n case t h e I M P is st o p pe d, it s h o ul d be 
deter mi ne d w het h er t he st o p ca n be ma d e te m p or aril y; per m a ne nt I M P disc o nti n uati o n s h o ul d be 
a last res ort. A n y I M P disc o nti n uati o n s h o ul d be f ull y d oc u me nte d i n t he e- C R F. I n a n y case, t he 
patie nt s h o ul d re mai n i n t he st u d y a n d f oll o we d f or t he re mai n d er of t he st u d y d urati o n t o c ollect 
vital safet y stat us  a n d e n d p oi nt data. 
1 0. 3. 1 T e m p or ar y tr e at m e nt di s c o nti n u ati o n wit h i n v e sti g ati o n al m e di ci n al pr o d u ct( s) 
Te m p orar y tr eat me nt dis c o nti n uati o n ma y b e c o nsi dere d b y t he I n v esti gat or beca us e of s us pecte d 
A Es. L o wer e xtre mit y c o m plicati o ns (s uc h as s k i n ulcers, i nfecti o n, oste o m yelitis, a n d ga n gre ne) 
re q uiri n g treat me nt s h o ul d lea d t o te m p orar y disc o nti n uati o n of I M P. Rei nitiati n g treat me nt wit h 
t he I M P will be d o ne u n d er cl ose a n d a p pr o priate cli nical a n d/ or la b orat or y m o nit ori n g o nce t he 
I n v esti gat or will ha ve c o nsi dere d acc or di n g t o his/ her best me dical j u d g me nt t hat t he occ urre nce 
of t he c o ncer ne d e ve nt w as u nli kel y t o be relate d t o t he I M P. 
It is i n t he i nterest of t h e patie nt t o m o nit or bl o o d gl uc ose d uri n g t he te m p orar y disc o nti n uati o n 
peri o d, t heref ore re g ular deter mi nati o n of S M B G is t o be  perf or me d a n d d oc u me nte d. 
F or all te m p or ar y treat me nt disc o nti n uati o ns, d urati o n s h o ul d be rec o r d e d b y t he I n vesti gat or i n 
t he a p pr o priat e pa ges of t he e- C R F w h e n c o nsi dere d as c o nfir m e d. 
Te m p orar y tr eat me nt dis c o nti n uati o n deci de d b y t he I n vesti gat or c orres p o n ds t o m ore t ha n 1 d ose 
n ot a d mi nistere d t o t he patie nt. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 7 8 
Use of a n y differ e nt a nti- h y per gl yce mic me di cati o n d uri n g t he ti me of t e m p orar y treat me nt 
disc o nti n uati o n (ie, i ns uli n d uri n g a h os pitalizati o n) is rec or d e d as c o nc o mita nt me dicati o n wit h 
t he na me a n d d oses rec or de d i n t he e- C R F. 
1 0. 3. 2 P er m a n e nt tr e at m e nt di s c o nti n u ati o n wit h i n v e sti g ati o n al m e di ci n al pr o d u ct( s) 
Per ma ne nt treat me nt disc o nti n uati o n is a n y tr eat me nt disc o nti n uati o n ass ociate d wit h t he 
defi niti ve decisi o n fr o m t he I n vesti gat or or t h e patie nt n ot t o re-e x p ose t he patie nt t o t he I M P at 
a n y ti me. 
1 0. 3. 3 Li st of crit eri a f or p er m a n e nt tr e at m e nt di s c o nti n u ati o n 
T he patie nts ma y wit h dra w fr o m treat me nt wit h t h e I M P at a n y ti me f or a n y reas o n or t his ma y be 
t he I n v esti gat or’s decisi o n. Patie nts s h o ul d disc uss st o p pi n g st u d y me di cati o n wit h t he site bef ore 
d oi n g s o i n or der t hat q uesti o ns ca n be a d dre sse d, gl yce mic t hera p y a dj uste d, a n d a f oll o w- u p 
assess me nt arr a n ge d. All eff ort s s h o ul d be ma d e t o d oc u me nt t he reas o ns f or treat me nt 
disc o nti n uati o n a n d t his s h o ul d be d oc u me nte d i n t he e- C R F. 
T he f oll o wi n g reas o ns lea d t o per ma ne nt disc o nti n uati o n: 
•  At t he patie nt’s o w n re q u est (ie, w it h dra w al of c o nse nt f or treat me nt) 
•  If, i n t he I n vesti gat or's o pi ni o n, c o nti n uati o n wit h t he a d mi nistrati o n of t he st u d y treat me nt 
w o ul d be detri me ntal t o t he patie nt's well- bei n g 
•  I nter-c urre nt c o n diti o n t hat re q uires p er ma n e nt disc o nti n uati o n of t he st u d y treat me nt as 
l o n g as t he a b n or malit y p ersists a n d if t he cas u al relati o ns hi p of t he c o ncer ne d e ve nt a n d 
t he I M P is p ossi ble (acc or di n g t o t he I nv esti gat or’s best me dical j u d g m e nt) 
•  Pre g n a nc y (i n fe male p atie nts) 
•  S pecific re q u est of t he S p o ns or. 
A n y a b n or mal la b or at or y val ue w ill be i m me diatel y rec hec ke d f or c o nfir mati o n bef ore ma ki n g a 
decisi o n of per ma n e nt disc o nti n uati o n of  t he I M P f or t he c o n cer n e d patie nt. 
F or patie nts w h o pre mat urel y dis c o nti n ue t he I M P, t he assess me nts pla n ne d at E O T visit 
(Secti o n  1 0. 1. 3. 2 ) will be perf or me d at t he Pre mat ure E O T Visit, sc he d ule d prefera bl y pri or t o 
treat me nt disc o nti n uati o n or as s o o n as p ossi ble aft er ti me of disc o nti n uati o n (t he latest at t he ne xt 
o n-site visit). Reas o n f or I M P disc o nti n uati o n will be clearl y s p ecifie d. T his Pre mat ure E O T 
assess me nt ma y occ ur at a re g ularl y s c he d ul e d visit or at a n u nsc he d ule d visit. 
Patie nts partici pati n g i n t he A B P M s u bst u d y will n ot be re q uire d t o disc o nti n ue t he s u bst u d y i n 
t he e ve nt t hat t he y per ma ne ntl y disc o nti n ue treat ment i n t he mai n st u d y. E v er y eff ort s h o ul d be 
ma de t o e ns ure t h at disc o nti n ue d patie nts c o m plete t he A B P M s u bst u d y, if t he y are willi n g a n d 
a ble t o d o s o. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 0 
All st u d y wit h dra w als s h o ul d be rec or de d b y t he I n vesti gat or i n t he a p pr o priate scree ns of t he 
e- C R F a n d i n t he patie nt’s me dical rec or ds w he n c o nsi dere d as c o nfir me d. I n t he me dical rec or d, 
at least t he date of t he wit h dra wal  a n d t he reas o n s h o ul d be d oc u me nte d. 
F or patie nts w h o fail t o r et ur n t o t he site, u nle ss t he patie nt wit h dra ws c o nse nt f or f oll o w- u p, t he 
I n v esti gat or s h o ul d ma ke t he best eff ort t o reco ntact t he patie nt (e g, c o ntact patie nt’s fa mil y or 
pri vate p h ysicia n, r e vie w a vaila ble r e gistries or healt h care d ata bas es), a n d t o deter mi ne his/ her 
healt h stat us, i ncl u di n g at least his/ her vital stat us. Atte m pts t o c o ntact s uc h patie nts ( 3 p h o ne call 
atte m pts f oll o we d b y a certifie d letter) m ust be d o c u me nte d i n t he patie nt’s rec or ds (e g, ti mes a n d 
dates of atte m pte d tele p h o ne  c o ntact, recei pt f or s e n di n g a re gistere d letter). 
Patie nts w h o ha ve wit h dr a w n fr o m t he st u d y ca n n ot be rera n d o mize d (treat e d) i n t he st u d y. T h eir 
i ncl usi o n a n d treat me nt n u m bers m ust n ot be re use d.  
1 0. 4  
O B LI G A TI O N O F T H E I N V E S TI G A T O R R E G A R DI N G S A F E T Y R E P O R TI N G 
1 0. 4. 1 D efi niti o n s of a d v er s e e v e nt s  
1 0. 4. 1. 1 A d v er s e e v e nt 
A n a d verse e v e nt  ( A E) is a n y u nt o w ar d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt a d mi nistere d a p h ar mace u tical pr o d uct a n d w hic h d oes n ot necessaril y ha v e t o ha ve a 
ca usal relati o ns hi p wit h t his treat me nt. 
1 0. 4. 1. 2 S eri o u s a d v er s e e v e nt 
A seri o us a d verse e v e nt ( S A E) is a n y u nt o war d me dical occ urre n ce t hat at a n y d ose: 
•  Res ults i n deat h, or 
•  Is life-t hreate ni n g, or 
N ote : T he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
patie nt was at ris k of d eat 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 v e ca use d d eat h if it were m ore se vere. 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of  e xisti n g h os pitalizati o n, or 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y, or 
•  Is a c o n ge nital a n o mal y/ birt h defect 
•  Is a me dicall y i m p orta nt e ve nt 
Me dical a n d sci e ntific j u d g me nt  s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g 
is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
patie nt or ma y re q uir e m e dical or s ur gical i n ter ve nti o n (ie, s pecific meas ures or c orrecti ve 
treat me nt) t o pre v e nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 1 
N ote : T he f oll o wi n g list of me dicall y i m p orta nt e ve nts is i nte n de d t o ser ve as a g ui deli ne f or 
deter mi ni n g w hi c h c o n diti o n has t o  be c o nsi dere d as a me dically i m p orta nt e ve nt. T he list is 
n ot i nte n de d t o be e x ha usti ve: 
•  I nte nsi v e treat me nt i n a n e mer ge n c y r o o m or at h o me f or: 
- 
Aller gi c br o nc h os p as m  
- 
Bl o o d d ys crasias (ie, a gra n ul oc yt osis, a pl astic a ne mia, b o ne marr o w a plasi a, 
m yel o d ys plasia, p a nc yt o pe nia, etc),  
- 
C o n v ulsi o ns (seiz ures, e pile ps y, e pile ptic fit, a bse nce, etc). 
•  De vel o p me nt of dr u g d e pe n de nce or dr u g a b use 
•  A L T > 3 × U L N + t otal bilir u bi n > 2 × U L N or as y m pt o matic A L T i ncreas e > 1 0 × U L N 
•  S uici de atte m pt or a n y e v e nt s u g gesti ve of s uici dalit y 
•  S y nc o pe, l oss of c o nsci o us ness (e x ce pt if  d oc u me nte d as a c o ns e q ue nce of bl o o d 
sa m pli n g) 
•  B ull o us c uta ne o us er u pti o ns  
•  Ca ncers dia g n os e d d uri n g t he st u d y or a g gra v ate d d uri n g t he st u d y 
•  C hr o nic ne ur o de ge ner ati ve diseases ( n e wl y dia g n ose d) or a g gra vat e d d uri n g t he st u d y  
1 0. 4. 1. 3 A d v er s e e v e nt of s p e ci al i nt er e st 
A n A E SI is a n A E (seri o us or n o n-seri o us) of s cie ntific a n d me dical c o n cer n s pecific t o t he 
S p o ns or’s pr o d uct or pr o gr a m, f or w hi c h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he 
I n v esti gat or t o t he S p o ns or ma y b e a p pr o priate. S uc h e ve nts ma y re q uire f urt her i n vesti gati o n i n 
or der t o c h aracterize a n d u n dersta n d t he m. A E SI s ma y b e a d de d or re m o v e d d uri n g a st u d y b y 
pr ot oc ol a me n d me nt. 
T he A E SI f or t his st u d y are: 
•  Pre g n a nc y of a fe m ale patie nt e ntere d i n a st u d y as well as pre g n a nc y occ urri n g i n a 
fe male part ner of a male patie nt e ntere d i n a st u d y wit h I M P/ NI M P: 
- 
Pre g n a nc y occ urri n g i n a fe male patie nt i ncl u d e d i n t he cli nical trial or i n a fe male 
part ner of a male p atie nt e ntere d i n t he cli nical trial. It will be q ualifie d as a n S A E o nl y 
if it f ulfills o ne of t he seri o us ness criteria (s ee Secti o n  1 0. 4. 1. 2 ), 
- 
I n t he e ve nt of pre g na n c y i n a fe male p atie nt, I M P s h o ul d be disc o nti n ue d,  
- 
F oll o w- u p of t he pre g na n c y i n a fe mal e patie nt or i n a fe male p art ner of a m ale patie nt 
is ma n dat or y u ntil t he o utc o me has bee n d eter mi n e d. 
•  S y m pt o matic o v er d ose wit h I M P/ NI M P: 
- 
A s y m pt o matic o ver d ose (acci d e ntal or i nte nti o nal) wit h t he I M P/ NI M P is a n e ve nt 
s us pecte d b y t he I n v esti gat or or s p o nta ne o usl y n otifie d b y t he p atie nt a n d res ulti n g i n 
cli nical s y m pt o ms a n d/ or si g ns acc o m pa nie d b y a d mi nistrati o n of m ore t ha n t wice t he 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 2 
i nte n de d dail y d os e wit hi n a 2 4- h o ur peri o d. It will be rec or de d i n t he e- C R F as a n 
A E SI wit h i m me diate n otificati o n “ S y m pt o matic O V E R D O S E (acci de ntal or 
i nte nti o nal)” i n all cases a n d will be q ualifie d as a n S A E o nl y if it f ulfills t he S A E 
criteria. 
( Please n ote t hat a n As y m pt o matic o verd ose wit h t he I M P/ NI M P, acci de nt al or 
i nte nti o nal, defi ne d a d mi nistrati o n of m ore t ha n t wice t he i nte n de d d ail y d ose wit hi n a 
2 4- h o ur peri o d, wit h o ut cli nical s y m pt o ms a n d/ or si g ns, eit her s us p ecte d b y t he 
I n v esti gat or or s p o nta ne o usl y n otifie d b y t he patie nt, n ot base d o n acc o u nt a bilit y 
assess me nt. It will be rec or de d as a n A E “ As y m pt o matic O V E R D O S E, acci de ntal or 
i nte nti o nal.”) 
•  A L T i n crease > 3 X U L N (ref er t o rel ate d fl o w c hart, A p pe n di x F ). 
1 0. 4. 1. 4 E v e nt s of s p e ci al i nt er e st 
A n E O SI is a seri o us or n o n-seri o us A E of s cie ntific a n d me dical c o ncer n s pecific t o t he 
S p o ns or’s pr o d uct or pr o gr a m, f or w hi c h o n g oi n g m o nit ori n g ma y be a p pr o priate. S uc h e ve nts 
ma y r e q uire f urt her i n v esti gati o n i n or der t o c haracterize a n d u n dersta n d t he m. T hese e v e nts 
s h o ul d be re p orte d o n t he s pecific e- C R F pa ge ( w h ere a p plica ble) a n d will o nl y q ualif y f or 
e x pe dite d re p orti n g w he n seri o us (f ulfilli n g S A E criteria). 
T he E O SI f or t his st u d y are: 
•  Maj or a d vers e car di o vas c ular e v e nts ( M A C E [car di o vasc ular deat h, MI, or str o ke]) a n d 
ot her s pecific C V e ve nts (e g, heart fail ure lea di n g t o h os pitalizati o n) 
•  Se vere h y p o gl yce mia (see Secti o n  1 0. 6. 1 ) 
•  Ge nital m yc otic i nfecti o ns (t o i ncl u de v ul v o va gi nal ca n di dias is i n fe males a n d ca n di dal 
bala nitis i n males) 
•  Uri nar y tract i nfe cti o ns 
•  Cli nicall y rele v a nt v ol u me de pleti o n a n d e v e nts rel ate d/ p ossi bl y rel ate d t o v ol u me 
de pleti o n 
•  Diarr he a 
•  Pa ncreatitis 
•  B o ne fract ures 
•  Ve n o us t hr o m b otic e ve nts t o i ncl u de dee p ve n o us t hr o m b osis a n d t hr o m b oe m b olis m (t o 
i ncl u de p ul m o nar y e m b olis m) 
•  Dia betic ket oaci d osis 
•  Re nal e ve nts t o i ncl u de 5 0 % decli ne i n e G F R, e n d sta ge ki d n e y disease, re n al deat h 
•  Mali g na n cies of s pecial i nterest ( breast, bla d der, re nal cell, Le y di g cell, pa ncreatic, 
pr ostate, a n d t h yr oi d c arci n o ma) 
•  A d verse e ve nt lea di n g t o a n a m p utati o n 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 3 
1 0. 4. 2 G e n er al g ui d eli n e s f or r e p orti n g a d v er s e e v e nt s 
•  All A Es, re gar dl ess of seri o us ness or rela ti o ns hi p t o I M P/ NI M P, s pa n ni n g fr o m t he 
si g nat ure of t he I C F u ntil t he e n d of t he st u d y as d efi ne d b y t he pr ot o c ol f or t hat patie nt, 
are t o be rec or de d o n t he c orres p o n di n g p a ge(s) or scree n(s) of t he e- C R F. 
•  W he ne ver p ossi ble, dia g n osis or si n gle s y n dr o me s h o ul d be re p orte d i nstea d of s y m pt o ms. 
T he I n vesti gat or s h o ul d s pecif y t he dat e of o ns et, i nte nsit y, acti o n ta k e n wit h res pect t o 
I M P, c orrecti ve treat me nt/t hera p y gi v e n, a d diti o nal i n vesti gati o ns perf or m e d, o utc o me, 
a n d his/ her o pi ni o n as t o w het her t here is a reas o n a ble p ossi bilit y t h at t he A E was ca use d 
b y t he I M P or b y t h e st u d y pr o ce d ure(s).  
•  I n t his st u d y, t he use of c o nc o mita nt me dicati o ns i ncl u di n g a nti dia b etic me dicati o ns ma y 
ma ke it diffic ult t o assess t he ca usal relati o ns hi p, partic ularl y f or h y p o gl yce mia. Gl o bal 
Safet y Officer wit h i n p ut fr o m ot her a p pr o pr iate st u d y tea m me m bers will d eter mi ne t he 
ca usal r elati o ns hi p w he n it is n ot clearl y pr o vi d e d b y t he I n vesti gat or. 
•  T he I n vesti gat or s h o ul d t a ke a p pr o priate meas ur es t o f oll o w all A Es u ntil cli nical rec o v er y 
is c o m plete a n d la b orat or y res ults ha ve ret ur ne d t o n or mal, or u ntil pr o gressi o n has bee n 
sta bilize d, or u ntil deat h, i n or der t o e ns ure t he safet y of t h e patie nts. T his ma y i m pl y t hat 
o bser vati o ns will c o nti n ue be y o n d t he last pla n ne d visit per pr ot oc ol , a n d t hat a d diti o nal 
i n vesti gati o ns ma y be r e q ueste d b y t he m o nit ori n g tea m u p t o as n otice d b y t he S p o ns or. 
•  W he n treat me nt is pre mat urel y disc o nti n ue d, t h e p atie nt’s o bser vati o ns will c o nti n ue u ntil 
t he e n d of t he st u d y as defi ne d b y t h e pr ot oc ol f or t hat patie nt. 
•  La b orat or y, vital si g ns or E C G a b n or malities are t o be rec or de d as A Es if t he y are 
me dicall y rele v a nt base d o n t he I n ves ti gat or’s me dical j u d ge me nt, e g,:  
- 
S y m pt o matic a n d/ or  
- 
Re q uiri n g eit her c orrecti ve trea t me nt or c o ns ultati o n, a n d/ or  
- 
Lea di n g t o I M P disc o nti n uati o n or m o dificati o n of d osi n g, a n d/ or  
- 
F ulfilli n g a s eri o us ness criteri o n, a n d/ or  
- 
Defi ne d as a n A E SI or E O SI. 
1 0. 4. 3 I n str u cti o n s f or r e p orti n g s eri o u s a d v er s e e v e nt s 
I n t he cas e of occ urr e nce of a n S A E, t he I n v esti gat or or a n y desi g nees m ust i m me diatel y: 
•  E N T E R ( wit hi n 2 4 h o urs) t he i nf or mati o n rel ate d t o t he S A E i n t he a p pr o priate scree ns of 
t he e- C R F; t he s yste m will a ut o maticall y se n d t he n otificati o n t o t he M o nit ori n g tea m a n d 
P har mac o vi gila nce after a p pr o val of t he I n vesti gat or wit hi n t he e- C R F: 
•  S E N D ( pref er a bl y b y fa x or e- mail) a p h ot o c o p y of all e x a mi nati o ns carrie d o ut a n d t he 
dates o n w hic h t hese e x a mi nati o ns  were perf or me d, t o t he re pres e ntati ve of t he m o nit ori n g 
tea m w h ose na me, fa x n u m ber, a n d e mail a d dress a p pear o n t h e cli n ical trial pr ot oc ol. 
Care s h o ul d be ta ke n t o e ns ure  t hat t he patie nt's i d e ntit y is pr otect e d a n d t h e patie nt's 
i de ntifiers i n t he cli nical trial are pr o p erl y me nti o ne d o n a n y c o p y of a s o urce d oc u m e nt 
pr o vi de d t o t he S p o ns or. F or la b orat or y res ults, i ncl u de t he la b orat or y n or mal ra n ges. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 4 
•  All f urt her data u p d ates s h o ul d be rec or de d  i n t he e- C R F as a p pr o priate, a n d f urt her 
d oc u me ntati o n as well as a d diti o nal i nf or mati o n (f or la b orat or y d ata, c o n c o mita nt 
me dicati o ns, patie nt stat us, etc)  s h o ul d be se nt ( b y fa x or e-mail) t o t he m o nit ori n g tea m 
wit hi n 2 4 h o urs of k n o wle d ge of t he S A E. I n a d diti o n, e ver y eff ort s h o ul d b e ma de t o 
f urt her d oc u m e nt a n y S A E t hat is fatal or life t hreate ni n g wit hi n a w ee k ( 7 d a ys) of t he 
i nitial n otificati o n. 
•  A bac k- u p pla n ( usi n g a pa per C R F pr o cess) is a v aila ble a n d s h o ul d be use d w he n t he 
e- C R F s yste m d oes n ot w or k. 
A n y S A E br o u g ht t o t he atte nti o n of t he I n vesti gat or at a n y ti me after t he e n d of t he st u d y f or t he 
patie nt a n d c o nsi der e d b y hi m/ her  t o be ca use d b y t he I M P wit h a reas o n a ble p ossi bilit y, s h o ul d 
be re p ort e d t o t he m o nit ori n g tea m. 
1 0. 4. 4 G ui d eli n e s f or r e p orti n g a d v er s e e v e nt s of s p e ci al i nt er e st  
F or A E SIs, t he S p o ns or m ust be i nf or me d i m me diatel y (i e, wit hi n 2 4 h o urs), as per S A E 
n otificati o n g ui deli nes descri be d i n Secti o n  1 0. 4. 3 , e ve n if n ot f ulfilli n g a seri o us ness criteri o n, 
usi n g t he c orres p o n di n g pa ges of t he e- C R F (t o b e se nt) or scree ns i n t he e- C R F. 
1 0. 4. 5 G ui d eli n e s f or r e p orti n g e v e nt s of s p e ci al i nt er e st 
If a n E O SI f ulfills t he criteria of a n S A E, re p orti n g s h o ul d be p erf or m e d acc or di n g t o t he 
i nstr ucti o ns f or re p orti n g of S A Es (see Secti o n  1 0. 4. 3 ). Ot her wise, re p orti n g s h o ul d f oll o w t he 
i nstr ucti o ns f or a n A E (s ee Secti o n  1 0. 4. 2 ). 
1 0. 4. 6 G ui d eli n e s f or m a n a g e m e nt of s p e cifi c l a b or at or y a b n or m aliti e s 
Decisi o n trees f or t he ma na ge me nt of certai n la b orat or y a b n or m alities b y S a n ofi are pr o vi de d i n 
A p pe n di x F . 
T he f oll o wi n g l a b orat or y a b n or malities s h o ul d be m o nit ore d, d oc u m e nte d, a n d ma na ge d 
acc or di n g t o t he relate d fl o w c hart i n pr ot oc ol a p p e n dices.  
•  Ne utr o pe nia 
•  T hr o m b oc yt o p e nia 
•  I n crease i n A L T 
•  Ac ute re n al i ns ufficie n c y 
•  S us pici o n of r ha b d o m y ol ysis 
1 0. 5  
O B LI G A TI O N S O F T H E S P O N S O R 
D uri n g t h e c o urs e of t he st u d y, t he S p o ns or will re p ort i n a n e x pe dite d ma n ner: 
•  All S A Es t hat are b ot h u ne x pecte d a n d at leas t reas o na bl y relat e d t o t he I M P (s us pecte d 
u ne x pecte d seri o us a d verse reacti o n [ S U S A R]), t o t he re g ulat or y a ut h orities, i n de pe n de nt 
et hics c o m mittees (I E Cs)/i nstit uti o nal re vie w b oar ds (I R Bs) as a p pr o pri ate a n d t o t he 
I n v esti gat ors. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 5 
•  All S A Es t hat are e x pect e d a n d at least reas o n a bl y relate d t o t he I M Ps t o t he re g ulat or y 
a ut h orities, acc or di n g t o l ocal re g ulati o ns. 
•  T he f oll o wi n g A E SIs t o t h ose re g ulat or y a ut h orities w h o re q uire s uc h re p orti n g: 
- 
Pre g n a nc y 
- 
S y m pt o matic o v er d ose 
- 
A L T i n cre ase > 3 X U L N 
A d verse e ve nts t hat ar e c o nsi dere d e x pecte d will be s pecifie d b y t h e refere nce safet y i nf or mati o n 
pr o vi de d i n t he c urr e nt I B.  
If re q uir e d, u n bli n di n g of S U S A Rs will be t he res p o nsi bilit y of t he S p o ns or. 
T he S p o ns or will re p ort all safet y  o bs er vati o ns ma de d uri n g t he co n d uct of t he trial i n t he C S R. 
1 0. 6  S A F E T Y I N S T R U C TI O N S 
1 0. 6. 1 H y p o gl y c e mi a 
D uri n g t h e st u d y, p atie nts are i nstr ucte d t o d o c u me nt a n y h y p o gl yce mic e pis o des i n t heir st u d y 
diar y. T he h y p o gl yce mia will be re p orte d i n t he s p ecific e- C R F pa ge wit h o nset date a n d ti me, 
s y m pt o ms a n d/ or si g ns, t he S M B G val ue if a vaila ble, a n d t he treat me nt. If t he e ve nt f ulfills S A E 
criteria, h y p o gl yce mia will als o be re p orte d as a n S A E. 
H y p o gl yce mia is cate g orize d acc or di n g t o t he A D A w or k gr o u p o n h y p o gl yce mia classificati o n 
(1 3 , 1 4 ) a n d s u m marize d i n Fi g ure 1 . 
I n a d diti o n t o t he t hres h ol d of ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L), h y p o gl yce mia e pis o des wit h a plas ma 
gl uc ose of < 3. 0 m m ol/ L ( < 5 4 m g/ d L) will be a nal yz e d se paratel y. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 6 
Fi g ur e 1 - H y p o gl y c e mi a cl a s sifi c ati o n i n St u d y E F C 1 4 8 3 4 
 
Se vere h y p o gl yce mi a 
Se vere h y p o gl yce mia is a n e ve nt r e q uiri n g assista nce of a n ot h er pers o n t o acti vel y a d mi nister 
car b o h y dr ate, gl uca g o n, i ntra ve n o us gl uc ose or ot her res us citati ve acti o ns. T hese e pis o des ma y b e 
ass ociate d wit h s uffici e nt ne ur o gl yc o pe nia t o i n d u ce seiz ure, u nc o ns ci o us ness or c o ma. 
Self- m o nit ore d plas ma gl uc ose val ues ma y n ot b e a vaila ble, b ut ne ur ol o gical  rec o v er y attri b uta ble 
t o t he rest orati o n of plas ma gl ucos e t o n or mal is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt w as 
i n d uce d b y a l o w plas ma gl uc ose c o nce ntrati o n. 
N ote : “re q uiri n g assista nce of a n ot h er pers o n” mea ns t hat t he patie nt c o ul d n ot hel p hi mself or 
herself t o treat t he h y p o gl yce mia. Assisti n g a p atie nt o ut of ki n d ness, w he n assista nce is n ot 
re q uire d, s h o ul d n ot be c o nsi dere d a “re q uires assista nce” i nci de nt. 
A n y h y p o gl yce mic e v e nt w hic h lea ds t o u nc o ns ci o us ness, c o ma, or seiz ure s h o ul d als o be 
re p orte d as a n S A E.  
D oc u me nte d s y m pt o m atic h y p o gl yce mi a 
D oc u me nte d s y m pt o matic h y p o gl yce mia is a n e v e nt d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl yce mia acc o m pa nie d b y a meas ure d plas m a gl u c ose c o n ce ntrati o n of ≤3. 9 m m ol/ L 
(≤7 0 m g/ d L).  
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 7 
Cli nical s y m pt o ms t hat are c o nsi der e d t o res ult fr o m a h y p o gl yce mic e pis o de are e g, i ncrease d 
s weati n g, ner v o us n ess, ast he nia/ wea k ness, tre m or, dizzi ness, i ncrease d a p p etite, pal pitati o ns, 
hea dac he, slee p dis or d er, c o nf usi o n, seiz ures, u nc o nsci o us ness, or c o ma. 
As y m pt o m atic h y p o gl yce mi a 
As y m pt o matic h y p o gl yce mia is a n e ve nt n ot acc o m pa nie d b y t y pical s y m pt o ms of h y p o gl yce mia 
b ut wit h a meas ure d plas ma gl uc os e c o nce ntrati o n ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L).   
N ote:  l o w plas ma gl u c os e val ues wit h o ut s y m pt o ms or si g ns s h o ul d n ot be re p orte d m ore t ha n 
o nce wit hi n 3 0 mi n utes.  Re peate d l o w gl uc os e va l ues wit hi n a s h ort peri o d c o ul d be d ue t o 
malf u ncti o n of t he de vice, err or te sti n g or f oll o wi n g u p a l o w gl u c ose rea di n g. T he I n vesti gat or 
s h o ul d tr y n ot t o d oc u me nt false l o w S M B G val u es or re d u n da nt l o w gl uc ose val ues as 
as y m pt o matic h y p o gl yce mic e ve nt. F urt h er cl arifi cati o n wit h t he patie nts is nee de d. 
Pr o b a ble s y m pt o m atic h y p o gl yce mi a 
Pr o ba ble s y m pt o matic h y p o gl yce mia is a n e ve nt d u ri n g w hi c h s y m pt o ms of h y p o gl yce mia are n ot 
acc o m pa ni e d b y a plas m a gl u c ose deter mi nati o n, ( b ut t hat was pres u ma bl y ca use d b y a pl as ma 
gl uc ose c o nce ntrati o n ≤3. 9 m m ol/ L [ ≤7 0 m g/ d L]), ie, s y m pt o ms treate d wit h oral car b o h y drate 
wit h o ut  a test of plas ma gl uc ose.  
Rel ati ve h y p o gl yce mi a 
Relati ve h y p o gl yce mia, r ece ntl y ter me d “ pse u d o- h y p o gl yce mia” (1 5 ) is a n e ve nt d uri n g w hic h t he 
patie nt re p orts t y pical s y m pt o ms of h y p o gl yce mia, a n d i nter prets t he s y m pt o ms as i n dicati ve of 
h y p o gl yc e mia, b ut wit h a meas ure d plas ma gl u c os e c o nce ntrati o n > 3. 9 m m ol/ L ( > 7 0 m g/ d L). 
1 0. 7  
A D V E R S E E V E N T S M O NI T O RI N G 
All e ve nts will be ma na ge d a n d re p orte d i n c o m plia nce wit h all a p plica bl e re g ulati o ns, a n d 
i ncl u de d i n t he fi nal C S R. 
 
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 8 8 
1 1  
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 1. 1  
D E T E R MI N A TI O N O F S A M P L E SI Z E 
T he sa m ple size/ p o wer calc ula ti o ns are b ase d o n t he pri mar y varia ble, c h a n ge fr o m Baseli ne t o 
Wee k 2 6 i n H b A 1c. Ass u mi n g a c o m m o n sta n dar d de viati o n ( S D) of 1. 2 %  a n d usi n g a 2-si de d 
test at a 0. 0 5 α -le v el, 2 5 0 patie nts per ar m will ha v e at least 9 9 % p o w er t o d etect a treat me nt 
differe n ce of 0. 6 % i n mea n H b A 1c c ha n ge fr o m Baseli ne t o Wee k 2 6 b et wee n s ota glifl ozi n 
4 0 0 m g a n d place b o. 
T he sa m ple siz e/ p o wer c alc ulati o ns f or A B P M  s u bst u d y are bas e d o n t he pri mar y varia bl e, 
c ha n ge fr o m Baseli ne t o Wee k 1 2 i n a ver a ge 2 4- h o ur S B P i n patie nts wit h mea n 
S B P ≥1 3 0 m m H g at Scr ee ni n g. Ass u mi n g a c o m m o n S D of 1 5 m m H g a n d usi n g a 2-si d e d test at 
a 0. 0 5 α -le v el, 1 0 0 patie nts per ar m will pr o vi de 9 0 % p o wer t o det ect a treat me nt differe n ce of 
7 m m H g i n a vera ge 2 4- h o ur S B P c ha n ge fr o m Baseli ne t o Wee k 1 2 bet wee n s ota glifl ozi n 4 0 0 m g 
a n d place b o. 
1 1. 2  
DI S P O SI TI O N O F P A TI E N T S 
T he t otal n u m ber of patie nts f or eac h of t he f oll o wi n g cate g ories will be prese nte d i n t he C S R: 
•  Scree ne d p atie nts: patie nts w h o ha ve si g n e d t he I C F 
•  R u n-i n patie nts 
•  Ra n d o mize d patie nts: patie nts wit h a treat me nt  kit n u m ber all ocate d a n d rec or de d i n I R T 
data base, a n d re gar dless of w het her t h e treat me nt kit was use d or n ot 
•  T he safet y p o p ulati o n (i e, ra n d o mize d a n d treat e d patie nts) 
•  T he i nte nt-t o-treat (I T T) p o p ulati o n (as defi ne d i n Secti o n  1 1. 3. 1. 1  a n d a nal yz e d as 
ra n d o mize d) 
•  T he ra n d o mizati o n strata ( H b A 1c at Scree ni n g [≤8. 0 %, > 8. 0 %], a n d S B P 
[ < 1 3 0, ≥1 3 0 m m H g]). T he discre p a nc y bet w ee n t h e strata assi g ne d b y I R T a n d t he 
i nf or mati o n re p orte d o n e- C R F will be liste d f or all ra n d o mize d patie nts 
•  Patie nts w h o ha ve c o m pl ete d t he 2 6- wee k mai n treat me nt peri o d 
•  Patie nts w h o disc o nti n ue d t he I M P d uri n g t he 2 6- wee k mai n treat me nt peri o d, a n d t he 
reas o ns f or treat me nt dis c o nti n uati o n 
•  Patie nts w h o ha ve c o m pl ete d t he e ntire treat me nt peri o d 
•  Patie nts w h o disc o nti n ue d t he I M P d uri n g t he e ntire treat me nt peri o d, a n d t he reas o ns f or 
treat me nt disc o nti n uati o n 
•  Patie nts w h o ha ve c o m pl ete d t he st u d y 
•  Patie nts w h o disc o nti n ue d t he st u d y, a n d t he reas o ns f or st u d y disc o nti n uati o n 
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P a g e 8 9 
F or all cate g ories of patie nts e x ce pt scree ne d, p erce nta ges will be calc ulate d usi n g t he n u m ber of 
ra n d o mize d patie nts as de n o mi nat or f or eac h treat me nt gr o u p. 
A list of patie nts pre mat urel y dis c o nti n ue d fr o m t h e treat me nt, al o n g wit h reas o ns f or 
disc o nti n uati o n, will be pr o vi de d. Si milarl y, a list of patie nts pre mat urel y disc o nti n ue d fr o m t he 
st u d y, al o n g wit h reas o ns f or disc o nti n uati o n, w ill be pr o vi de d. 
Patie nts treate d b ut n ot ra n d o miz e d, patie nts ra n d o mize d b ut n ot treate d a n d patie nts ra n d o mize d 
b ut n ot treate d as ra n d o mize d will be i de ntifie d a n d descri be d i n se p arat e listi n gs. T he safet y 
e x perie nce of p atie nts treate d a n d n ot ra n d o mize d will be re p orte d se p aratel y, a n d t h ese patie nts 
will n ot be i n t he safet y p o p ulati o n. 
F or a n y p atie nt ra n d o mize d m ore t ha n o nce, o nl y t h e data ass o ciate d wit h t he first ra n d o mizati o n 
will be use d i n a n y a nal ysis p o p ulati o n. T he sa fet y e x perie n ce ass o ciate d wit h a n y lat er 
ra n d o mizati o n will be assesse d se paratel y. 
1 1. 3  
A N A L Y SI S P O P U L A TI O N S 
1 1. 3. 1 Effi c a c y p o p ul ati o n s 
Efficac y a nal ys es will be base d o n t he treat me nt  gr o u p all ocate d b y t he I R T acc or di n g t o t he 
ra n d o mizati o n sc he d ule at ra n d o mizati o n visit (as ra n d o mize d), irres pecti ve of t he treat me nt 
act uall y recei ve d. 
1 1. 3. 1. 1 I nt e nt-t o-tr e at p o p ul ati o n 
Efficac y a nal ys es will be base d o n t he I T T p o p ul ati o n, defi ne d as a ll ra n d o mize d patie nts, 
irres pecti ve of c o m plia nce wit h t he st u d y pr ot o c ol a n d pr oce d ures. Patie nts will be a nal yze d f or 
efficac y a n al ys es acc or di n g t o t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d. 
1 1. 3. 2 S af et y p o p ul ati o n 
Safet y a nal yses will be base d o n t he safet y p o p ulati o n, defi ne d as all ra n d o mize d patie nts w h o 
recei v e at least 1 d ose of d o u ble- bli n d I M P (re gardless of t he a m o u nt of treat me nt a d mi nistere d). 
Patie nts will be a nal yze d f or saf et y a nal yses  acc or di n g t o t he treat me nt act u all y recei v e d. 
I n a d diti o n: 
•  N o nra n d o mize d b ut treat e d patie nts will n ot be part of t he safet y p o p ul ati o n, b ut t heir 
safet y data will be prese nte d se paratel y 
•  Ra n d o mize d patie nts f or w h o m it is u nclear w het h er t he y t o o k t he st u d y me dicati o n will 
be i ncl u de d i n t he saf et y p o p ulati o n as ra n d o mize d 
•  W he n a patie nt is e x p ose d t o b ot h s ota glifl ozi n a n d place b o, t he p atie nt will be a nal yz e d i n 
t he s ota glifl ozi n gr o u p  
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P a g e 9 0 
•  Ra n d o mize d patie nts will be e x cl u de d fr o m t he safet y p o p ulati o n o nl y if t here is 
d oc u me nte d e vi de n ce (i e, all st u d y dates rec o r de d as n o me dicati o n ta ke n) t hat patie nts 
ha ve n ot ta ke n t he st u d y me dicati o n 
1 1. 4  
S T A TI S TI C A L M E T H O D S 
C o nti n u o us data will be s u m ma rize d b y treat me nt gr o u p usi n g t he n u m ber of o bser vati o ns 
a vaila ble, mea n, S D, mi ni m u m, me dia n, a n d ma xi m u m. Cate g orical data will be s u m marize d b y 
treat me nt gr o u p usi n g c o u nt a n d perce nta ge. 
I n ge neral, descri pti ve statistics of q ua ntitati ve efficac y a n d s afet y p ara met ers (res ult a n d c ha n ge 
fr o m Bas eli ne) b y sc h e d ule d visits will be pr o vi de d o n o bser ve d cas es ( O C), ie, i ncl usi o n of o nl y 
patie nts ha vi n g n o n- missi n g asse ss me nts at a s pecific visit. 
T he baseli ne v al ue is defi ne d ge ner all y as t he last a vaila ble val ue b ef ore t h e first d ose of 
d o u ble- bli n d I M P or t he l ast a vaila ble val u e pri or t o ra n d o mizati o n f or patie nts w h o were 
ra n d o mize d b ut ne ver e x p ose d t o I M P. 
F or ser u m creati ni ne a n d e G F R, t he Bas eli ne val ue is  defi ne d as t he a v era ge of all val ues bef ore 
t he first d ose of d o u ble- bli n d I M P f or t h ose ra n d omize d a n d e x p ose d or bef ore ra n d o mizati o n f or 
t h ose w h o wer e ra n d o mi ze d b ut ne ver e x p ose d t o I M P. 
A nal ysis of d e m o gra p hics a n d baseli ne c h aracteristics, pri or a n d c o nc o mita nt me dicati o ns will be 
pr o vi de d i n detail i n t he statis tical a nal ysis pla n ( S A P). 
1 1. 4. 1 E xt e nt of st u d y tr e at m e nt e x p o s ur e a n d c o m pli a n c e 
T he e xte nt of st u d y treat me nt e x p os ure a n d c o m plia nce will be assess e d a n d s u m marize d b y 
act ual treat me nt recei ve d i n t he safet y p o p ulati o n. 
1 1. 4. 1. 1 E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e 
T he e xte nt of st u d y treat me nt e x p os ure will be assesse d b y t he d urati o n of treat me nt e x p os ure 
d uri n g t he st u d y.  
T he d urati o n of treat me nt e x p os ure will be t he t otal n u m ber of da ys of a d mi nistrati o n of t he 
d o u ble- bli n d I M P, r e gar dless of u n pla n ne d i nter m itte nt disc o nti n uati o ns. T he d urati o n of I M P 
e x p os ure will be calc ulat e d as: 
( Date of t h e last d o u ble- bli n d I M P ta ke n – D ate of t he first d o u ble- bli n d I M P ta ke n) + 1. 
T he n u m ber ( %) of p atie nts ra n d o mize d a n d e x p os e d t o d o u ble- bli n d I M P will be prese nte d b y 
s pecific ti me peri o ds f or eac h tr eat me nt gr o u p. T h e ti me peri o ds of i nterest will be defi ne d i n t he 
S A P. 
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P a g e 9 1 
Descri pti ve statistics of d urati o n of treat me nt  e x p os ure ( n u m ber, m ea n, S D, mi ni m u m, me dia n, 
a n d ma xi m u m) a n d c u m ulati ve e x p os ure i n patie nt year will als o be prese nte d b y treat me nt gr o u p 
i n t he safet y p o p ulati o n. 
1 1. 4. 1. 2 C o m pli a n c e  
A gi ve n a d mi nistrati o n will be c o nsi dere d n o nc o m plia nt if t he pa tie nt di d n ot ta ke t he pla n ne d 
d ose of treat me nt as re q uire d b y t h e pr ot oc ol. N o i m p utati o n will be ma de f or patie nts wit h 
missi n g or i nc o m plete data.  
Treat me nt c o m plia nce, a b o ve- p la n ne d a n d u n der- pla n ne d d osi n g p erce nta ges will be s u m marize d 
descri pti vel y ( N, mea n, S D, me di a n, mi n, a n d ma x). T he perce nta ge  of p atie nts wit h c o m plia nce 
< 8 0 % will be s u m marize d. I n a d diti o n, t he n u m ber a n d perce nta ge of patie nts wit h at least 
1 a b o ve- pla n n e d d osi n g a d mi nistra ti o n will be gi ve n, as well as t he n u m b er a n d perce nta ge of 
patie nts wit h 0, > 0 t o 2 0 % , a n d > 2 0 % u n d er- pl a n ne d d osi n g a d mi nistrati o ns. 
1 1. 4. 2 A n al y s e s of effi c a c y e n d p oi nt s 
Efficac y a nal ys es will be perf or me d o n t he I T T p o p ulati o n. 
Statistical testi n g will be perf or me d f or pri mar y  e n d p oi nt a n d sec o n dar y e n d p oi nts at Wee k 2 6 ( or 
Wee k 1 2 f or S B P). All efficac y v aria bles after Wee k 2 6 will o nl y be s u m m arize d b y d escri pti ve 
statistics wit h o ut f or mal statistical testi n g. 
1 1. 4. 2. 1 A n al y si s of pri m ar y effi c a c y e n d p oi nt 
T he statistical test will be t w o-si de d tests at a n o mi nal 5 % si g nifica nce le vel. 
A nal ysis of t h e pri mar y efficac y e n d p oi nt (c h a n ge fr o m Bas eli ne t o Wee k 2 6 i n H b A 1c; see 
Secti o n  9. 1. 1 ) will be perf or me d o n t he I T T p o p ul atio n, usi n g H b A 1 c meas ure me nts o btai ne d 
fr o m visits d uri n g t he st u d y, i ncl u di n g t h ose o btaine d after I M P disc o nti n uati o n or i ntr o d ucti o n of 
resc ue t h era p y. 
T he pri mar y efficac y e n d p oi nt of c ha n ge i n H b A 1 c fr o m baseli ne t o Wee k 2 6 will be a nal yze d 
wit h missi n g val ues i m p ute d b y c o ntr ol- base d m ulti ple i m p utati o n met h o d u n der t he missi n g n ot 
at ra n d o m fr a me w or k.  
•  F or place b o patie nts, missi n g data will be i m p ute d base d o n t he place b o gr o u p data. 
•  F or patie nts i n t he s ota glifl ozi n gr o u p, missi n g da t a will be i m p ute d as if t he patie nts were 
o n place b o t hr o u g h o ut t h e st u d y. 
Eac h of t he c o m plete dat asets will be a nal yz e d b y a n A nal ysis of C o varia n ce ( A N C O V A) m o del 
wit h treat me nt gr o u ps (s ota glifl ozi n, pl ace b o), ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), 
ra n d o mizati o n strat u m of S B P ( < 1 3 0, ≥1 3 0 m m H g), a n d c o u ntr y as fi x e d effects, a n d b aseli ne 
H b A 1c val ue as a c o vari ate. Res ults fr o m eac h c o m plete dataset will be c o m bi ne d t o pr o vi de t he 
a dj uste d mea n c h a n ge i n H b A 1c fr o m Bas eli ne t o  Wee k 2 6 f or eac h treat me nt gr o u p, as well as 
t he bet wee n- gr o u p diff er e nce ( c o m pari n g s ota glifl ozi n vs place b o) a n d t he 9 5 % c o nfi de n ce 
i nter val ( CI) f or t he diff ere nce.  
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P a g e 9 2 
S u m mar y statistics (f or s cree ni n g v al ue, bas eli n e val ue, o bser v e d val ues, a n d o bser ve d c h a n ges 
fr o m Bas eli ne) at s c he d ule d visits will be pr o vi de d f or eac h treat me nt gr o u p. T he s u m mar y will 
i ncl u de t he n u m ber of o bser vati o ns, mea n, S D, sta n dar d err or ( S E), mi ni m u m, me dia n, a n d 
ma xi m u m. Gra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds o ver ti me usi n g mea n 
val ues ( ± S E) a n d mea n c ha n ges fr o m Bas eli ne ( ± S E) at eac h of t he sc h e d ule d visits ( usi n g O C). 
Assess me nt of tre at me nt eff ect b y s u b gr o u p  
Descri pti ve a n al ys es will be perf or me d o n t he pri mar y e n d p oi nt t o s u m marize t he treat me nt 
effects acr oss s u b gr o u ps defi ne d b y t he f o ll o wi n g Baseli ne or Scree ni n g fact ors: 
•  Race 
•  Et h nicit y ( His pa nic, N ot His pa nic) 
•  A ge gr o u p ( < 5 0 years, ≥5 0 t o < 6 5 years, ≥6 5 years) 
•  Ge n der 
•  Baseli ne B MI le v el ( < 3 0, ≥3 0 k g/ m²) 
•  Baseli ne H b A 1c ( ≤8. 0 %, > 8. 0 %)  
•  Baseli ne H b A 1c ( ≤8. 5 %, > 8. 5 %)  
•  Baseli ne S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g)  
•  C o u ntr y 
T he treat me nt effects acr oss t he s u b gr o u ps d efi ne d f or eac h of t hes e fact ors will be esti mate d f or 
t he c ha n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c i n t he I T T p o p ulati o n, a n d usi n g a si milar 
a p pr oac h t o t he a nal ysis f or t he pri mar y effica c y e n d p oi nt. T he a dj uste d esti mates of treat me nt 
mea n differe nces (s ota glifl ozi n vers us place b o) wit h S E a n d 9 5 % CIs will b e pr o vi de d as 
a p pr o priate acr oss t he s u b gr o u ps. 
I n t he cas e t hat t he s u b gr o u p fact or is i de ntical or si milar t o a ra n d o mizati o n strata fact or (e g, 
baseli ne H b A 1 c cate g or y), o nl y t he s u b gr o u p fact or  will be i ncl u de d i n t he m o del i n or der t o 
a v oi d t he iss ue of c olli nearit y i n t he a nal ysis. 
1 1. 4. 2. 2 A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s 
T he sec o n d ar y e n d p oi nts (see Secti o n  9. 1. 2 ) will be a nal yz e d usi n g a si milar a p pr o ac h t o t he 
pri mar y efficac y e n d p oi nt wit h missi n g val ues  i m p ute d b y c o ntr ol- base d m ulti ple i m p utati o n 
met h o d u n der t he missi n g n ot at r a n d o m fra m e w or k.  
•  F or place b o patie nts, missi n g data will be i m p ute d base d o n t he place b o gr o u p data. 
•  F or patie nts i n t he s ota glifl ozi n gr o u p, missi n g da t a will be i m p ute d as if t he patie nts were 
o n place b o gr o u p t hr o u g h o ut t he st u d y. 
F or eac h of t h e c o nti n u o us sec o n dar y e n d p oi nts, eac h  of t h e c o m plete d atasets will be a nal yze d b y 
a n A N C O V A m o del wit h treat me nt gr o u ps (s ota g lifl ozi n, place b o), ra n d omizati o n strat u m of 
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P a g e 9 3 
H b A 1c ( ≤8. 0 %, > 8. 0 %), ra n d o miz ati o n st rat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g), a n d c o u ntr y 
as fi x e d effects, a n d baseli ne sec o n dar y e n d p oi nt val ue as a c o vari ate. Res ults fr o m eac h c o m plet e 
dataset will be c o m bi ne d t o pr o vi de t he a dj uste d m ea n c h a n ge fr o m Bas eli ne t o Wee k 2 6 ( or 
Wee k 1 2 f or S B P) f or eac h treat me nt gr o u p, as w ell as t he bet wee n- gr o u p differe n ce (c o m pari n g 
s ota glifl ozi n vs place b o) a n d t he 9 5 % CI f or t he differe nce.  
T he cate g orical sec o n dar y efficac y varia bles of H b A 1c < 6. 5 %, < 7 % at Wee k 2 6 will be a nal yz e d 
usi n g a C oc hra n- M a ntel- Hae nszel met h o d stra tifie d b y ra n d o mizati o n strat u m of H b A 1c (≤8. 0 %, 
> 8. 0 %), a n d ra n d o miz ati o n st rat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g). T he pr o p orti o n i n eac h 
treat me nt gr o u p will be pr o vi de d, as well as t he differe nce of pr o p orti o ns b et wee n s ota glifl ozi n 
a n d place b o wit h ass ociate d 2-si de d 9 5 % CI . F or H b A 1c res p o n ders at Wee k 2 6 ( < 6. 5 %, 
< 7 % res p ecti vel y), all val ues at Wee k 2 6 will be use d t o deter mi ne w h et her a patie nt is a 
res p o n der or n ot, e ve n if t he y are meas ure d after I M P disc o nti n uati o n or resc ue me dicati o n use. 
Patie nts w h o ha ve n o H b A 1c meas ur e me nt at Wee k 2 6 will be treate d as n o n-res p o n ders. 
F or all sec o n dar y e n d p oi nts, s u m ma r y statistics at sc he d ule d visits will be pr o vi de d f or eac h 
treat me nt gr o u p. T he s u m mar y will i ncl u de t he n um ber of o bser v ati o ns, mea n, S D, S E, mi ni m u m, 
me dia n, a n d ma xi m u m. Gra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds o ver ti me 
usi n g mea n v al ues ( ± S E) a n d mea n c h a n ges fr o m baseli ne ( ± S E) at eac h of t he sc he d ule d visits 
( usi n g O C). 
1 1. 4. 2. 3 A n al y s e s of ot h er effi c a c y e n d p oi nt s 
T he a nal ysis of ot her e n d p oi nts (see Secti o n  9. 1. 3 ) will be descri pti ve wit h n o f or mal testi n g. 
S u m mar y statistics at sc h e d ule d visits usi n g O C will be pr o vi de d b y eac h treat me nt gr o u p. 
Gra p hical prese ntati o ns will als o be use d t o ill ustrate tre n ds o v er ti me. 
1 1. 4. 2. 4 A n al y si s of a m b ul at or y bl o o d pr e s s ur e m o nit ori n g s u b st u d y e n d p oi nt s 
A B P M s u bst u d y e n d p oi nts will be a nal yze d usi n g a si milar a p pr oac h as t he pri mar y efficac y 
e n d p oi nt wit h missi n g val ues i m p ute d b y c o ntr ol- base d m ulti ple i m p utati o n met h o d u n der t he 
missi n g n ot at ra n d o m fra me w or k. E ac h of t h e c o m plete dataset will be a n al yze d usi n g 
A N C O V A m o del i ncl u di n g f act ors f or treat me nt (s ota glifl ozi n, place b o), ra n d o mizati o n strat u m 
of H b A 1c ( ≤8. 0 %, > 8. 0 %) as fi x e d effects, a n d t he baseli ne val u e of t he s pecific de p e n de nt 
varia ble as a c o v ariate.  
1 1. 4. 2. 5 M ulti pli cit y c o n si d er ati o n s 
T o c o ntr ol t he fa mil y- wise t y pe I err or, a fi x e d se q ue nce testi n g pr o ce d ure will be a p plie d. O nce 
t he mai n st u d y pri mar y v aria ble (c ha n ge fr o m Bas eli ne t o Wee k 2 6 i n H b A 1c) is statisticall y 
si g nifica nt at α = 0. 0 5 ( 2-si de d), a hierarc hi cal testi n g pr o ce d ure will be perf or me d t o test t he 
f oll o wi n g mai n st u d y sec o n dar y efficac y vari a bles a n d A B P M s u bst u d y pri mar y e n d p oi nt b y t h e 
f oll o wi n g pri oritize d or d er. T he testi n g will sto p as s o o n as a n e n d p oi nt is f o u n d t o be n ot 
statisticall y si g nifica nt at α = 0. 0 5 ( 2-si d e d). 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n 2- h o ur P P G f oll o wi n g a n M M 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n F P G 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 4 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or all patie nts 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n a vera ge 2 4- h o ur S B P i n patie nts fr o m A B P M 
s u bst u d y (t he pri mar y e n d p oi nt of t he A B P M s u bst u d y) 
•  Pr o p orti o n of patie nts wit h H b A 1c < 7. 0 % at Wee k 2 6. 
N o m ulti plicit y a dj ust me nt will be  ma de o n ot her sec o n dar y efficac y v aria bles t ha n me nti o ne d 
a b o ve. 
1 1. 4. 3 A n al y s e s of s af et y d at a 
Safet y e n d p oi nts are pres e nte d i n Secti o n  9. 2. T he s u m mar y of safet y res ults will be prese nte d b y 
treat me nt gr o u p. T he s af et y d ata will be s u m mari ze d f or t he 2 6- we e k C ore Treat me nt Peri o d a n d 
t he e ntire treat me nt peri o d se parat el y, u nl ess s pecifie d ot her wise. All safet y a nal ys es will be 
perf or me d o n t h e Safet y p o p ulati o n as defi ne d i n Secti o n  1 1. 3. 2  usi n g t he f oll o wi n g c o m m o n 
r ules: 
T he f oll o wi n g d efi niti o ns will be a p plie d t o la b orat or y para met ers a n d vital si g ns: 
•  T he p ote ntiall y cli nicall y si g nifica nt a b n or ma lit y ( P C S A) val ues f or cli nical la b orat or y 
tests a n d vital si g ns ar e d efi ned as a b n or mal val ues c o nsi dere d  me dicall y i m p orta nt b y t he 
S p o ns or’s Gl o bal P har mac o vi gila nce a n d E pi de mi ol o g y de part me nt a n d i n effect at t he 
ti me of t he fi nal S A P a p pr o val. P C S A criteria f or para meters n ot cite d i n t he pr ot oc ol as 
safet y para meters will n ot be a nal yz e d, 
•  P C S A criteria will deter mi ne w hic h patie nts ha d at least 1 P C S A d uri n g t h e o n-treat me nt 
peri o d, ta ki n g i nt o acc o u nt all e val uati o ns  perf or me d d uri n g t he o n-treat me nt peri o d, 
i ncl u di n g u nsc he d ul e d or re peat e d e val u ati o ns. T he n u m ber of all s uc h patie nts will be t he 
n u merat or f or t he o n-tr eat me nt P C S A perce nta ge. 
T he “ o bser v ati o n peri o ds ” defi ne d i n Secti o n  9. 2. 1  are a p plica ble f or classificati o n of A Es, 
deter mi nati o n of o n-tr eat me nt P C S A val ues a n d t he last o n-treat me nt v al ue f or t he la b orat or y, 
vital si g n a n d E C G para meters. 
1 1. 4. 3. 1  A n al y si s of a d v er s e e v e nt s 
Pre-t re at me nt A Es  are A Es t hat de vel o pe d or w orse ne d or b eca m e seri o us d uri n g t he 
pre-treat me nt peri o d. 
Tre at me nt-e mer g e nt A Es  are A Es t hat de v el o pe d or w orse n e d (acc or di n g t o t he I n v esti gat or’s 
o pi ni o n) or beca m e seri o us d uri n g t he o n-treat me nt peri o d. 
P ost-tre at me nt A Es  ar e A Es t hat de vel o pe d or w orse ne d or b eca m e seri o us d uri n g t he 
p ost-treat me nt peri o d. 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 5 
T he pri mar y f o c us of A E re p orti n g i n t he C S R will be o n T E A Es. Pre- a n d p ost-treat me nt A Es 
will be descri be d se p aratel y. 
All a d verse e ve nts 
A d verse e ve nt i nci de n ce ta bles will prese nt b y s yste m or ga n class ( S O C) (s orte d b y 
i nter nati o nall y a gree d or der), hi g h-le v el gr o u p ter m ( H L G T), hi g h le vel ter m ( H L T) a n d preferre d 
ter m ( P T) s orte d i n al p ha betical or der f or eac h treat me nt gr o u p, t h e n u m ber ( n) a n d p erce nta ge 
( %) of p atie nts e x perie nci n g a n A E. M ulti ple occ urrences of t he sa m e e ve nt i n t he sa me patie nt 
will be c o u nte d o nl y o n ce i n t he ta bles w it hi n a treat me nt p hase. T h e de n o mi nat or f or 
c o m p utati o n of perce nta ges is t he safe t y p o p ulati o n wit hi n eac h treat me nt gr o u p.  
S u m maries of all T E A Es i n eac h  treat me nt gr o u p will i ncl u de: 
•  T he o ver vie w of A Es, s u m marizi n g n u m ber ( %) of patie nts wit h a n y 
- 
T E A E 
- 
Seri o us T E A E 
- 
T E A E lea di n g t o deat h 
- 
T E A E lea di n g t o per m a n e nt treat me nt disc o nti n uati o n 
•  T he n u m ber ( n) a n d perce nta ge ( %) of p atie nt s wit h at least o ne T E A E b y pri mar y S O C, 
H L G T, H L T a n d P T 
•  S u m mar y of T E A Es b y ma xi mal se verit y (se v ere, m o derate, mil d), pres e nte d b y pri mar y 
S O C a n d P T 
•  S u m mar y of T E A Es p ossi bl y relat e d t o I M P, prese nte d b y pri mar y S O C, H L G T, H L T a n d 
P T. 
A detaile d listi n g of T E A E s u m maries will be pr o vi de d i n t he S A P. 
De at h a n d seri o us a d verse e ve nts 
Deat h a n d treat me nt-e m er ge nt S A Es will be s u m marize d a n d prese nt e d as n u m ber a n d perce nt of 
patie nts i n eac h tr eat me nt gr o u p. 
T he f oll o wi n g d eat hs s u m maries will be ge nerate d: 
•  N u m ber ( %) of patie nts w h o die d b y st u d y p e ri o d ( o n-st u d y, o n-treat me nt, p ost-st u d y) 
s u m marize d o n t he safet y p o p ulati o n b y treat me nt recei ve d. 
•  Deat h i n n o nra n d o mize d patie nts or ra n d o mize d a n d n ot treate d patie nts 
•  T E A E lea di n g t o deat h ( deat h as a n o utc o m e o n t he A E e- C R F p a ge as re p orte d b y t h e 
I n v esti gat or) b y pri mar y S O C, H L G T, H L T a n d P T s h o wi n g n u m ber ( %) of patie nts 
s orte d b y i nter nati o nall y a gree d or der of S O C a n d al p ha betic or d er of H L G T, H L T, a n d 
P T. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 6 
A d verse e v e nts le a di n g t o per m a ne nt tre at me nt disc o nti n u ati o n 
Treat me nt-e mer ge nt A Es lea di n g t o p er ma ne nt treat me nt disc o nti n uati o n will be s u m marize d a n d 
prese nte d as n u m ber a n d perce nt of  patie nts i n eac h treat me nt gr o u p. 
1 1. 4. 3. 2 A n al y s e s of h y p o gl y c e mi a 
T he n u m ber ( %) of p atie nts a n d rate  i n patie nt years ( 2 t y pes: t he n u m ber of patie nts wit h e ve nts 
or t he t otal n u m ber of e v e nts pe r 1 0 0 patie nt- year) of all, se vere, a n d d o c u me nte d s y m pt o matic 
h y p o gl yce mia will be s u m marize d b y treat me nt gr o u p res pecti vel y. T heir patter n of occ urre nce 
o ver ti me will als o be ass esse d, as a p pr o priate. 
1 1. 4. 3. 3 A n al y s e s of a d v er s e e v e nt s of s p e ci al i nt er e st 
Pre g n a nc y a n d o ver d os e will be i ncl u de d i n o verall A E s u m maries if a n y are re p ort e d. A L T 
i ncreas e > 3 × U L N is i ncl u de d i n la b orat or y P C S A s u m mar y if a n y. 
1 1. 4. 3. 4 A n al y s e s of e v e nt s of s p e ci al i nt er e st 
T he n u m ber ( %) of p atie nts wit h eac h E O SI e v e nt will be s u m marize d b y treat me nt gr o u p. All 
e ve nts re p ort e d b y t he I n vesti gat ors o n t he A E f or ms f or s pecial i nterests will be liste d al o n g wit h 
t he a dj u dicati o n o utc o me (if a p plica ble). 
1 1. 4. 3. 5 A n al y s e s of l a b or at or y v ari a bl e s 
T he n u m ber a n d p erce nta ge of patie nts wit h P C S A  or b y t he pre- defi ne d cat e g ories (if n o P C S A 
criteri o n is defi ne d) at a n y e v al uati o n d uri n g t he o n-treat me nt peri o d will be s u m marize d f or eac h 
cli nical la b orat or y test wit hi n eac h treat me nt gr o u p. T he s u m maries will i ncl u de patie nts i n t he 
safet y p o p ulati o n w h o ha ve at least o ne la b orat or y test perf or me d d uri n g t h e o n-treat me nt peri o d 
a n d, w he n r e q uire d b y t h e defi niti o n of t he a b n or malit y, wit h a n a v aila ble baseli ne val ue a n d 
a vaila ble la b or at or y n or mal ra n ges. 
Descri pti ve statistics will be use d t o s u m marize t he la b orat or y res ults a n d t he c ha n ges fr o m 
baseli ne b y visit a n d f or t he last o n-treat me nt v al ue wit hi n eac h treat me nt gr o u p. S hift ta bles a n d 
ot her ta b ular a n d gra p hical met h o ds  ma y b e use d t o prese nt t he res ults f or la b orat or y tests of 
i nterest. Listi n gs will be pr o vi de d wit h fla gs i n dicati n g t he o ut of la b orat or y ra n ge val u es as w ell 
as t he P C S A val ues. 
T he li ver f u ncti o n tests, na mel y A L T, A S T, al kali ne p h os p hatase, a n d t ota l bilir u bi n, are use d t o 
assess p ossi ble dr u g-i n d u ce d li ver t o xicit y. T he pr o p orti o n of patie nts wit h P C S A val ues at a n y 
p ost baseli ne visit b y baseli ne stat us will be di s pla ye d b y treat me nt gr o u p f or eac h p ara met er. 
1 1. 4. 3. 6 A n al y s e s of vit al si g n v ari a bl e s 
T he n u m ber a n d p erce nta ge of patie nts wit h P C S A at a n y e val u ati o n d uri n g t he o n-treat me nt 
peri o d will be s u m marize d f or eac h vital si g n  p ara meter wit hi n eac h treat m e nt gr o u p. T he 
s u m maries will i ncl u de patie nts i n t he safet y p o p ulati o n w h o ha ve at least o ne para m eter t o be 
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E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 7 
a nal yze d d uri n g t h e o n-tr eat me nt peri o d. Descri pt i ve statistics will be use d t o s u m marize t he 
res ults a n d t he c ha n ges fr o m baseli ne b y visit a n d f or t he last o n-treat me nt val ue wit hi n eac h 
treat me nt gr o u p. Ta b ul ar a n d gra p hical met h o ds ma y b e use d t o prese nt t he res ults f or para meters 
of i nterest. Listi n gs will be pr o vi de d wit h fla gs i n dicati n g t he P C S A val ues. 
1 1. 4. 3. 7 A n al y s e s of 1 2 l e a d E C G st at u s 
A s hift ta ble will be pr o vi de d t o prese nt t he E C G o n-treat me nt stat us acc or di n g t o t he baseli ne 
stat us wit hi n eac h treat m e nt gr o u p. 
1 1. 4. 4 A n al y s e s of p h ar m a c o ki n eti c v ari a bl e s 
T he P K e n d p oi nt is prese nte d i n Secti o n  9. 3. 1 . I n di vi d ual plas ma c o nce ntrati o ns of s ota glifl ozi n 
a n d of its 3- O- gl uc ur o ni de at n o mi nal sa m pli n g ti mes will be liste d.  
C o nce ntrati o n data will b e s u m marize d b y visit a n d, if a p pr o priate, wit hi n visit b y n o mi nal 
sa m pli n g ti mes ( pre- d ose, 2 h o ur 3 0 mi n ute p ost-d ose), usi n g d escri pti ve st atistics b y N, 
ge o m etric mea n, c oeffici e nt of  variati o n, me dia n, mi ni m u m a n d ma xi m u m at eac h visit/ n o mi nal 
sa m pli n g ti me p oi nt f or s ota glifl ozi n-treate d p atie nts. 
1 1. 5  I N T E RI M A N A L Y SI S 
N o f or mal i nteri m a nal ysis f or efficac y is pla n n e d f or t his st u d y. T he st u d y will n ot be ter mi nate d 
earl y f or e x celle nt effi cac y. 
A n i n de pe n de nt D M C will m o nit or a n d assess t he safet y of patie nts fr o m t his trial t hr o u g h 
peri o dic re vi e w of t he acc u m ulate d safet y d ata  pr o vi de d b y a n i n de pe n d e nt statistical gr o u p. 
Relate d details ar e pr o vi de d i n se par ate d oc u me nts ( D M C c harter a n d D M C S A P). 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 9 9 
T he cli nical trial (st u d y n u m ber, cli nical trial pr ot o c ol title a n d versi o n n u m ber), t he d o c u me nts 
re vie we d (cli nical trial pr ot oc ol, I C F, I B wit h a n y a d de n da or l a beli n g d oc u me nts (s u m mar y of 
pr o d uct c haract eristics, pac ka ge i nsert), I n v esti gat or’s c urric ul u m vitae, etc) a n d t he date of t he 
re vie w s h o ul d be clearl y state d o n t he writte n (I R B/I E C) a p pr o val/fa v ora ble o pi ni o n. 
T he I M P will n ot be release d at t he st u d y site a n d t he I n v esti gat or will n ot start t he st u d y b ef ore 
t he writte n a n d date d a p pro val/fa v or a ble o pi ni o n is recei v e d b y t he I n vesti gat or a n d t he S p o ns or. 
D uri n g t h e cli nical trial, a n y a me n d me nt or m o dificati o n t o t he cli nical trial pr ot oc ol s h o ul d be 
s u b mitte d t o t he healt h a ut h orities (c o m pete nt re g ulat or y a ut h orit y), as re q uire d b y l o cal 
re g ulati o n, i n a d diti o n t o t he I R B/I E C, bef ore i m pl e me ntati o n, u nless t he c h a n ge is necessar y t o 
eli mi nate a n i m me diate h azar d t o t he patie nts, i n w hic h case t h e healt h a ut h orities (c o m pete nt 
re g ulat or y a ut h orit y) a n d t he I R B/I E C s h o ul d be i nf or me d as s o o n as p ossi ble. T he y s h o ul d als o 
be i nf or me d of a n y e ve nt li kel y t o affect t he s a fet y of patie nts or t he c o nti n ue d c o n d uct of t he 
cli nical trial, i n partic ular a n y c ha n ge i n safet y. All u p dates t o t he I B or la beli n g i nf or mati o n, will 
be se nt t o t he I R B/I E C a n d t o healt h a ut h orities (c o m pete nt re g ulat or y a ut h orit y), as re q uire d b y 
l ocal re g ulati o n. 
A pr o gress r e p ort is se nt t o t he I R B/I E C at least a n n uall y a n d a s u m mar y of t he cli nical trial’s 
o utc o me at t he e n d of t h e cli nical trial. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 0 
1 3  
S T U D Y M O NI T O RI N G 
1 3. 1  
R E S P O N SI BI LI TI E S O F T H E I N V E S TI G A T O R 
T he I n vesti gat or is r e q uir e d t o e ns ure c o m plia nce w it h all pr oce d ures re q uire d b y t he cli nical trial 
pr ot oc ol a n d wit h all st u d y pr o ce d ur es pr o vi de d b y t he S p o ns or (i ncl u di n g s ec urit y r ules). T h e 
I n v esti gat or a grees t o pr o vi de relia ble dat a a n d all i nf or mati o n re q ueste d b y t he cli nical trial 
pr ot oc ol ( wit h t he hel p of t he C R F, Discre p a nc y R es ol uti o n F or m [ D R F] or ot her a p pr o pri ate 
i nstr u me nt) i n a n acc urat e a n d le gi ble ma n n er acc or di n g t o t he i nstr ucti o ns pr o vi de d a n d t o e ns ure 
direct access t o s o urce d o c u me nts b y S p o ns or re prese ntati ves. 
If a n y cir c uit i ncl u des tra nsfer of d ata partic ul ar atte nti o n s h o ul d be pai d t o t he c o nfi de ntialit y of 
t he patie nt's d ata t o be tra nsferr e d. 
T he I n vesti gat or ma y a p p oi nt s uc h ot her i n di vi d uals as he/s he ma y dee m a p pr o priate as 
S u bi n vesti gat ors t o assist i n t he c o n d uct of t he cli nical trial i n acc o r da nce wit h t he cli nical trial 
pr ot oc ol. All S u bi n vesti gat or s s hall be a p p oi nte d a n d liste d i n a ti mel y m a n ner. T he 
S u bi n vesti gat ors will be s u per vise d b y a n d w or k  u n der t he res p o nsi bilit y of t he I n vesti gat or. T h e 
I n v esti gat or will pr o vi de t he m wit h a c o p y of t he cli nical trial pr otoc ol a n d all necessar y 
i nf or mati o n. 
1 3. 2  
R E S P O N SI BI LI TI E S O F T H E S P O N S O R O R S E R VI C E P R O VI D E R 
T he S p o ns or a n d/ or ser vi ce pr o vi der of t his cli nical tria l is res p o nsi ble t o re g ulat or y a ut h orities f or 
ta ki n g all r eas o na bl e ste ps t o e ns ure t he pr o p er c o n d uct of t he cli nical trial as re gar ds et hics, 
cli nical trial pr ot oc ol c o m plia nce, a n d i nte grit y a n d vali dit y of t he dat a rec or de d o n t he C R Fs. 
T h us, t he mai n d ut y of t h e m o nit ori n g tea m is t o h el p t he I n vesti gat or a n d t he S p o ns or mai ntai n a 
hi g h le vel of et hical, scie ntific, tec h nical a n d re g ul at or y q u alit y i n all as p ects of t he cli nical trial. 
At re g ular i nter v als d uri n g t he cli nical trial, t he site will be c o ntacte d, t hr o u g h m o nit ori n g visits, 
letters or tele p h o ne calls, b y a repr ese ntati ve of t he m o nit ori n g tea m t o re vie w st u d y pr o gress, 
I n v esti gat or a n d patie nt c o m plia nce wit h cli nical trial pr ot oc ol re q uireme nts a n d a n y e mer ge nt 
pr o ble ms. T hese m o nit ori n g visits will i ncl u de b ut n ot be li mite d t o re vie w of t he f oll o wi n g 
as pects: patie nt i nf or me d c o nse nt, patie nt recr uit me nt a n d f oll o w-u p, S A E d oc u me ntati o n a n d 
re p orti n g, A E SI d oc u me ntati o n a n d re p orti n g, A E a n d E O SI d oc u me ntati o n, I M P all ocati o n, 
patie nt c o m plia nce wit h t he I M P re gi me n, I M P acc o u nta bilit y, c o n c o mita nt t hera p y use a n d 
q ualit y of dat a. 
1 3. 3  S O U R C E D O C U M E N T R E Q UI R E M E N T S 
Acc or di n g t o t he I C H G C P, t he m o nit ori n g tea m m ust c hec k t he C R F e ntri es a gai nst t he s o urce 
d oc u me nts, e x ce pt f or t h e pre-i d e ntifie d s o urce data directl y rec or de d i n t h e C R F. T he I C F will 
i ncl u de a state me nt b y w hic h t he patie nt all o ws t he S p o ns or’s d ul y a ut h ori ze d pers o n nel, t he 
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P a g e 1 0 1 
et hics c o m mittee (I R B/I E C), a n d t he re g ul at or y a u t h orities t o ha ve direct access t o ori gi nal 
me dical rec or ds w hic h s u p p ort t he data o n t he C R F s (e g, p atie nt's me dical file, a p p oi nt me nt 
b o o ks, ori gi nal la b or at or y r ec or ds, etc). T h ese pers o n nel, b o u n d b y pr ofessi o nal secrec y, m ust 
mai ntai n t he c o nfi de ntialit y of all pers o nal i de ntit y or p ers o nal me dical i nf or mati o n (acc or di n g t o 
c o nfi de ntialit y a n d pers o nal  data pr otecti o n r ules). 
1 3. 4  
U S E A N D C O M P L E TI O N O F C A S E R E P O R T F O R M S ( C R F S) A N D A D DI TI O N A L 
R E Q U E S T 
It is t he r es p o nsi bilit y of t he I n v esti gat or t o mai ntai n a de q uat e a n d acc urat e case re p ort f or ms 
( C R Fs) (acc or di n g t o t he tec h n ol o g y us e d) desi g ne d b y t he S p o ns or/ser vi ce pr o vi der t o rec or d 
(acc or di n g t o S p o ns or i nstr ucti o ns) all o bser vati o ns a n d ot her data p erti ne nt t o t he cli nical 
i n vesti gati o n i n a ti mel y ma n ner. All C R Fs s h o ul d be c o m plete d i n t heir e ntiret y i n a n eat, le gi ble 
ma n ner t o e ns ur e acc ur ate  i nter pret ati o n of data. 
S h o ul d a c orrecti o n be ma de, t he c orrecte d i nf or m ati o n will be e n tere d i n t he e- C R F o v er writi n g 
t he i nitial i nf or mati o n. A n a u dit trail all o ws i de ntif yi n g t he m o dificati o n.  
Data ar e a v aila ble wit hi n t he s yste m t o t he S p o ns or as s o o n as t he y are e ntere d i n t he e- C R F. 
T he c o m p uterize d ha n dli n g of t he data b y t he S p o ns or/ser vice pr o vi der ma y ge n erat e a d diti o nal 
re q uests ( D R F) t o w hic h t he I n v esti gat or is o bli ge d t o res p o n d b y c o nfir mi n g or m o dif yi n g t he 
data q uesti o ne d. T he re q uests wit h t heir re s p o nses will be ma na ge d t hr o u g h t he e- C R F. 
1 3. 5  
U S E O F C O M P U T E RI Z E D S Y S T E M S 
T he c o m plete list of c o m p uterize d s yste ms use d f or t he st u d y is pr o vi de d i n a se parate d oc u m e nt 
w hic h is mai ntai ne d i n t he S p o ns or/ser vi ce pr o vi der a n d I n v esti gat or st u d y files. 
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P a g e 1 0 2 
1 4  
A D DI TI O N A L R E Q UI R E M E N T S 
1 4. 1  
C U R RI C U L U M VI T A E 
A c urr e nt c o p y of t he c urric ul u m  vitae descri bi n g t he e x perie nce, q u alificati o n a n d trai ni n g of 
eac h I n v esti gat or a n d S u bi n vesti gat or will be si g n e d, date d a n d pr o vi de d t o t he S p o ns or/ser vice 
pr o vi der pri or t o t he b e gi n ni n g of t he cli nical trial. 
1 4. 2  
R E C O R D R E T E N TI O N I N S T U D Y SI T E S 
T he I n vesti gat or m ust mai ntai n  c o nfi de ntial all st u d y d oc u m e ntati o n, a n d t a ke meas ures t o 
pre ve nt acci de ntal or pre mat ure destr ucti o n of t h ese d oc u me nts. 
T he I n vesti gat or s h o ul d r etai n t he st u d y d o c u me nts at least 1 5 years after t he c o m pleti o n or 
disc o nti n uati o n of t he cli nical trial. 
H o we ver, a p plica ble re g ulat or y re q uire m e nts s h o ul d be ta ke n i nt o acc o u nt i n t he e ve nt t hat a 
l o n ger p eri o d is re q uir e d. 
T he I n vesti gat or m ust n otif y t he S p o ns or pri or t o destr o yi n g a n y st u d y ess e ntial d oc u me nts 
f oll o wi n g t he cli nical trial c o m pleti o n or disc o nti n uati o n. 
If t he I n vesti gat or's p ers o nal sit uati o n is s uc h t hat arc hi vi n g ca n n o l o n ger b e e ns ure d b y hi m/ her, 
t he I n v esti gat or s hall i nf or m t he S p o ns or a n d t he rele va nt rec or ds s h all be tra nsferre d t o a 
m ut uall y a gr ee d u p o n desi g nee. 
1 4. 3  
C O N FI D E N TI A LI T Y 
All i nf or mati o n discl ose d or pr o vi de d b y t he S p o ns or ( or a n y c o m pa n y/i nstit uti o n acti n g o n t heir 
be half), or pr o d uce d d uri n g t he cli nical trial, i ncl u di n g, b ut n ot li mite d t o, t he cli nical trial 
pr ot oc ol, pers o nal dat a i n  relati o n t o t he patie nts, t he C R Fs, t he I B a n d t he res ults o btai ne d d uri n g 
t he c o urse of t h e cli nical trial, is c o nfi de ntial, pri or t o t he p u blicati o n of res ults. T he I n v esti gat or 
a n d a n y pers o n u n d er his/ her a ut h orit y a gree t o u n de rta ke t o kee p c o nfi de ntial a n d n ot t o discl ose 
t he i nf or mati o n t o a n y t hir d part y wit h o ut t he pri or writte n a p pro val of t h e S p o ns or. 
H o we ver, t he s u b missi o n of t his cli nical trial pr ot oc ol a n d ot her necessar y d oc u me ntati o n t o t he 
et hics c o m mittee (I R B/I E C) is e x pressl y per mitte d, t he I R B/I E C me m bers ha vi n g t he s a me 
o bli gati o n of c o nfi de ntialit y. 
T he S u bi n vesti gat ors s hall be b o u n d b y t he sa m e o bli gati o n as t he I n v esti gat or. T he I n v esti gat or 
s hall i nf or m t he S u bi n vesti gat ors of t he c o nfi de ntial nat ure of t he cli nical trial. 
T he I n vesti gat or a n d t he S u bi n vesti gat ors s hall us e t he i nf or mati o n s olel y f or t he p ur p oses of t h e 
cli nical trial, t o t he e x cl usi o n of a n y us e f or t h eir o w n or f or a t hir d part y's acc o u nt. 
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 4 
1 4. 6  I N S U R A N C E C O M P E N S A TI O N 
T he S p o ns or certifies t h at it has ta ke n o ut a lia bilit y i ns ura n ce p olic y c o veri n g all cli nical tri als 
u n der its s p o ns ors hi p. T his i ns ura nce p olic y is i n  acc or da n ce wit h l ocal la ws a n d re q uire m e nts. 
T he i ns ura nce of t he S p o ns or d oes n ot relie ve t h e I n v esti gat or a n d t he c olla b orat ors fr o m a n y 
o bli gati o n t o mai ntai n t heir o w n lia bilit y i ns u ra n ce p olic y. A n i ns ura nce certificate will be 
pr o vi de d t o t he I E Cs/I R Bs or r e g ulat or y a ut h or iti es i n c o u ntries re q uiri n g t his d oc u me nt. 
1 4. 7  S P O N S O R A U DI T S A N D I N S P E C TI O N S B Y R E G U L A T O R Y A G E N CI E S 
F or t he p ur p os e of e ns uri n g c o m plia n ce wit h t he cli n ical trial pr ot oc ol, g o o d cli nical practice, a n d 
a p plica ble r e g ulat or y r e q uire me nts, t he I n vesti gat or s h o ul d per mit a u diti n g b y  or o n t h e be half of 
t he S p o ns or a n d i ns pecti o n b y r e g ulat or y a ut h orities. 
T he I n vesti gat or a grees t o all o w t he a u dit ors/i n s pect ors t o ha ve direct access t o his/ her st u d y 
rec or ds f or r e vie w, bei n g u n derst o o d t hat t hese pers o n nel is b o u n d b y pr ofessi o nal secrec y, a n d as 
s uc h will n ot discl ose a n y pers o nal i de ntit y or pers o nal me dical i nf or mati o n. 
T he I n vesti gat or will ma ke e ver y eff ort t o hel p wit h t he perf or ma n ce of t he a u dits a n d i ns pecti o ns, 
gi vi n g access t o all necessar y facilities, data, a n d d oc u me nts. 
As s o o n as t he I n vesti gat or is n otifie d of a pl a n ne d i ns pecti o n b y t he a ut h orities, he/s he will 
i nf or m t he S p o ns or a n d a ut h orize t he S p o nsor t o partici pate i n t his i ns pecti o n. 
T he c o nfi de ntialit y of t he data verifi e d a n d t he pr otecti o n of t he patie nts s h o ul d be res pecte d 
d uri n g t hes e i ns pecti o ns. 
A n y res ult a n d i nf or mati o n arisi n g fr o m t he i ns pecti o ns b y t he re g ulat or y a ut h orities will be 
i m me diatel y c o m m u nicat e d b y t h e I n vesti gat or t o t he S p o ns or. 
T he I n vesti gat or s hall ta k e a p pr o pri ate meas ures re q uire d b y t he S p o ns or t o ta ke c orrecti ve 
acti o ns f or all pr o ble ms f o u n d d ur i n g t he a u dit or i ns pecti o ns. 
1 4. 8  P R E M A T U R E DI S C O N TI N U A TI O N O F T H E S T U D Y O R P R E M A T U R E C L O S E- O U T O F 
A SI T E 
1 4. 8. 1 B y t h e S p o n s or  
T he S p o ns or has t he ri g ht t o ter mi nat e t he partici p ati o n of eit her a n i n di vi d ual site or t he st u d y at 
a n y ti me, f or a n y r eas o n, i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g:  
•  T he i nf or mati o n o n t he pr o d uct lea ds t o d o u bt as t o t he be nefit/ris k rati o 
•  Patie nt e nr oll me nt is u nsatisfact or y 
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 5 
•  T he I n vesti gat or h as recei ve d fr o m t he S p o ns or all I M P, mea ns, a n d i nf or m ati o n necessar y 
t o perf or m t he cli nical trial a n d has n ot i ncl u de d a n y patie nt after a reas o na ble peri o d of 
ti me m ut uall y a gree d u p o n 
•  N o nc o m plia nce of t h e I n vesti gat or or S u bi n ve sti gat or, dele gat e d staff wit h a n y pr o visi o n 
of t he cli nical trial pr ot oc ol, a n d breac h of t he a p plica ble la ws  a n d re g ulati o ns or breac h of 
t he I C H G C P 
•  T he t otal n u m ber of patie nts are i ncl u de d earlier t ha n e x pecte d. 
I n a n y cas e t he S p o ns or will n otif y t h e I n vesti gat or of its decisi o n b y writte n n otice. 
1 4. 8. 2 B y t h e I n v e sti g at or 
T he I n vesti gat or ma y t er mi nate his/ her partici pat i o n u p o n t hirt y ( 3 0) d a ys' pri or writte n n otice if 
t he st u d y site or t he I n vesti gat or f or a n y reas o n bec o mes u na ble t o perf or m or c o m plete t he 
cli nical trial.  
I n t he e ve nt of pre mat ur e disc o nti n uati o n of t he st u d y or pre mat ure cl ose- o ut of a site, f or a n y 
reas o n w h ats oe ver, t h e a p pr o priate I R B/I E C a n d re g ul at or y a ut h orities s h o ul d be i nf or me d 
acc or di n g t o a p plica ble r e g ul at or y re q uire me nts. 
1 4. 9  
C LI NI C A L T RI A L R E S U L T S 
T he S p o ns or will be res p o nsi ble f or pre p ari n g a C S R a n d t o pr o vi de a s u m mar y of st u d y res ults t o 
t he I n v esti gat or. 
1 4. 1 0  P U B LI C A TI O N S A N D C O M M U NI C A TI O N S 
T he I n vesti gat or u n d erta kes n ot t o ma ke a n y p u blica ti o n or release pertai ni n g t o t he st u d y a n d/ or 
res ults of t he st u d y pri or t o t he S p o ns or’s written c o nse nt, bei n g u n derst o o d t hat t he S p o ns or will 
n ot u nreas o na bl y wit h h ol d its a p pr o val. 
As t he st u d y is bei n g c o n d ucte d at m ulti ple site s, t he S p o ns or a grees t hat, c o nsiste nt wit h 
scie ntific sta n dar ds, a pri mar y prese nt ati o n or p u blicati o n of t he st u d y res ults base d o n gl o b al 
st u d y o utc o mes s hall be s o u g ht. H o w e ver, if n o m ultice nter p u blicati o n is s u b mitte d, u n der wa y, 
or pla n ne d wit hi n t wel ve ( 1 2) m o nt hs of t he c o m pl eti o n of t his st u d y at all sites, t he I n v esti gat or 
s hall ha ve t he ri g ht t o p u blis h or prese nt i n de pe n d e ntl y t he res ults of t his st u d y i n a gree me nt wit h 
ot her I n vesti gat ors a n d st a ke h ol de rs. T h e I n vesti gat or s hall pr o vi de t he S p o ns or wit h a c o p y of 
a n y s u c h pres e ntati o n or p u blicati o n f or re vie w a n d c o m me nt at least 3 0 da ys i n a d v a nce of a n y 
prese ntati o n or s u b missi o n f or p u blicati o n. I n a d diti o n, if re q ueste d b y t he S p o ns or, a n y 
prese ntati o n or s u b missi o n f or p u blicati o n s hall be dela ye d f or a li mite d ti me, n ot t o e x cee d 
9 0 da ys, t o all o w f or fili n g of a pa te nt a p plicati o n or s uc h ot her j ustifie d meas ures as t he S p o ns or 
dee ms a p pr o priate t o esta blis h a n d preser v e its pr o prietar y ri g hts.  
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P a g e 1 0 6 
T he I n vesti gat or s hall n ot use t he na me(s) of t he S p o ns or a n d/ or its e m pl o yees i n a d vertisi n g or 
pr o m oti o nal material or p u blicati o n wit h o ut t he pri or writte n c o nse nt of t h e S p o ns or. T he S p o ns or 
s hall n ot use t he na me(s) of t he I n vesti gat or a n d/ or t he c olla b orat ors i n a d v ertisi n g or pr o m oti o nal 
material or p u blicati o n wit h o ut ha vi n g recei ve d  his/ her a n d/ or t heir pri or writte n c o nse nt(s). 
T he S p o ns or has t he ri g ht at a n y ti me t o p u blis h t he res ults of t he st u d y. 
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V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 7 
1 5  
C LI NI C A L T RI A L P R O T O C O L A M E N D M E N T S 
All a p pe n dices attac he d heret o a n d re ferre d t o herei n are ma d e part of t his cli nical  trial pr ot oc ol. 
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 fr o m, or c ha n ges t o t he cli nical trial pr ot oc ol 
wit h o ut a gr ee me nt b y t he S p o ns or a n d pri or re vi e w a n d d oc u me nte d a p pr o val/fa v ora bl e o pi ni o n 
fr o m t he I R B/I E C a n d/ or n otificati o n/a p pr o val of healt h a ut h orities (c o m pete nt re g ulat or y 
a ut h orit y) of a n a m e n d me nt, as re q uire d b y l o cal re g ul ati o n, e x ce pt w here necessar y t o eli mi nate 
a n i m me diate hazar d(s) t o cli nical trial patie nts, or w he n t he c h a n ge(s) i n v ol ves o nl y l o gistical or 
a d mi nistrati ve as pects of t he trial. A n y c ha n ge  a gree d u p o n will be rec or d e d i n writi n g, t he 
writte n a me n d me nt will be si g ne d b y t he I n vest i gat or a n d b y t he S p o ns or a n d t he si g ne d 
a me n d me nt will be file d wit h t his cli nical trial pr ot oc ol. 
A n y a me n d me nt t o t he cli nical trial pr ot oc ol re q uires writte n a p pr o val/fa v ora ble o pi ni o n b y t h e 
I R B/I E C pri or t o its i m ple me ntati o n, u nless t here are o verri di n g safet y reas o ns. 
I n case of s u bsta ntial a m e n d me nt t o t he cli nical trial pr ot oc ol, a p pr o val fr o m t he healt h a ut h orities 
(c o m pete nt r e g ulat or y a ut h orit y) will be s o u g ht bef ore i m ple me ntati o n. 
I n s o me i nsta n ces, a n a m e n d me nt ma y re q uire a c ha n ge t o t he I C F. T h e I n vesti gat or m ust recei v e 
a n I R B/I E C a p pr o val/fa v ora ble o pi ni o n c o ncer ni n g t he re vise d I C F pri or t o i m ple me ntati o n of t he 
c ha n ge a n d patie nt si g n at ure s h o ul d be re-c ollecte d if necessar y. 
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Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 0 8 
1 6  
BI B LI O G R A P HI C R E F E R E N C E S 
1.  Cre mer A, A mr a o ui F, Li p G Y, M orales E, R u bi n S, Se g ura J, et al. Fr o m mali g na nt 
h y perte nsi o n t o h y p erte nsi o n- M O D: a m o der n defi niti o n f or a n ol d b ut still da n ger o us 
e mer ge n c y. J H u m H y perte ns. 2 0 1 6; 3 0( 8): 4 6 3- 4 6 6. 
2.  I nter nati o nal Dia b etes Fe derati o n Dia bet es Atlas 7t h E diti o n.  
htt p:// w w w. dia betesatlas. or g/r es o urces/ 2 0 1 5-atlas. ht ml. Accesse d 1 5 J ul y 2 0 1 6 
3.  A merica n Di a betes Ass o ciati o n. A merica n Dia bet es Ass oci ati o n A p pla u ds T w o- Year Re 
A ut h orizati o n of S pecial Dia betes Pr o gra m. A merica n Dia bet es Ass ociati o n. A vaila ble fr o m: 
htt p:// w w w. dia betes. or g/ ne wsr o o m/ press-releas es/ 2 0 1 0/re-a ut h orizati o n-s pecial- dia b etes-
pr o gra m. ht ml. Accesse d J ul y 1 2, 2 0 1 6. 
4.  A merica n Di a betes Ass o ciati o n. Sta n dar ds of Me dical Care i n Di a b etes – 2 0 1 3. Dia betes 
Care. 2 0 1 3 J a n; 3 6( S u p pl 1): S 1 1- S 6 6. 
5.  Casta ne da- Sce p pa C, Casta ne da F. S o di u m- d e pe n de nt gl uc os e tra ns p ort er pr otei n as a 
p ote ntial t hera pe utic tar get f or i m pr o vi n g gl yce mi c c o ntr ol i n dia betes. N utr Re v. 2 0 1 1 Dec; 
6 9( 1 2): 7 2 0- 7 2 9. 
6.  M u dalier S. S o di u m – Gl uc ose C otra ns p orter I n hi bit ors: Effects o n Re nal a n d I ntesti nal 
Gl uc ose Tra ns p ort; Fr o m Be nc h t o Be dsi de. Dia betes Care. 2 0 1 5; 3 8: 2 3 4 4 – 5 3. 
7.  He di ger H A. E x pressi o n cl o ni n g a n d c D N A s e q ue nci n g of t h e Na +/ gl u c ose c o-tra ns p ort er. 
Nat ure. 1 9 8 7; 3 3 0: 3 7 9- 8 1. 
8.  Wri g ht E M. I. Gl uc ose galact ose mala bs or pti o n. A m J P h ysi ol. 1 9 9 8; 2 7 5: G 8 7 9- G 8 8 2. 
9.  K o m or os ki B, Vac h har aj a ni N, Fe n g Y, Li L, K or n ha user D, Pfister M. D a pa glifl ozi n, a 
n o vel, selecti ve S G L T 2 i n hi bit or, i m pr o ve d gl y ce mic c o ntr ol o ver 2 w ee ks i n patie nts wit h 
t y pe 2 dia b etes mellit us. Cli nical P har mac ol o g y & T hera p e utics. 2 0 0 9 Ma y; 8 5( 5): 5 1 3- 9. 
1 0. List J F, W o o V, M orales E, Ta n g W, Fie d ore k  F T. S o di u m- gl uc ose c otra ns p ort i n hi biti o n wit h 
da pa glifl ozi n i n t y p e 2 dia betes. Dia b etes care. 2 0 0 9 A pr; 3 2( 4): 6 5 0- 7. 
1 1. I nz ucc hi S E, Ber ge nstal R M, B use J B, Dia m a nt M, Ferra n ni ni E, Na u c k M, et al. 
Ma na ge me nt of h y p er gl yce mia i n t y p e 2 di a betes: a patie nt-ce ntere d a p pr o ac h p ositi o n 
state me nt of t he A meri ca n Dia betes Ass oci ati o n ( A D A) a n d t h e E ur o pea n Ass ociati o n f or t he 
St u d y of Dia b etes ( E A S D). Di a betes care. 2 0 1 2 J u n; 3 5( 6): 1 3 6 4- 7 9. 
1 2. Ma ncia G, Fa gar d R, Nar k ie wicz K, Re d o n J, Za n c hetti A, B ö h m M, et al. 2 0 1 3 E S H/ E S C 
g ui deli nes f or t he ma na ge me nt of art erial h y pe rt e nsi o n: t he Tas k F orce f or t he Ma na ge me nt of 
Arterial H y p erte nsi o n of t he E ur o pea n S oci et y of H y p erte nsi o n ( E S H) a n d of t he E ur o pea n 
S ociet y of Car di ol o g y ( E S C). E ur Heart J. 2 0 1 3; 3 4( 2 8): 2 1 5 9 – 2 1 9. 
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P a g e 1 0 9 
1 3. W or k gr o u p o n H y p o gl yce mia, A merica n Dia b et es Ass ociati o n. Defi ni n g a n d re p orti n g 
h y p o gl yce mia i n dia betes: a re p ort fr o m t h e A meri ca n Dia b etes Ass ociati o n W or k gr o u p o n 
H y p o gl yce mia. Dia b etes Care. 2 0 0 5 Ma y; 2 8( 5): 1 2 4 5- 9. 
1 4. F D A G ui da n ce f or I n d ustr y:  Dia b etes Mellit us - De vel o pi n g Dr u gs a n d T hera pe utic Bi ol o gics 
f or Treat me nt a n d Pre v e nti o n. Li nes 1 1 4 4 – 1 2 1 5. A vaila ble fr o m: 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ 
Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/ U C M 0 7 1 6 2 4. p df. Accesse d 
J ul y 1 2, 2 0 1 6 
1 5. Sea q uist E R, A n ders o n J, C hil ds B, Cr yer P, Da g o ga-J ac 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 meri ca n Dia b etes Ass ociati o n a n d T he E n d ocri ne 
S ociet y. Dia b etes Car e. 2 0 1 3; 3 6( 5): 1 3 8 4- 9 5 
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P a g e 1 1 1 
A p p e n di x A  
G ui d a n c e o n c o ntr a c e pti v e m et h o d s a n d c oll e ct i o n of pr e g n a n c y 
i nf or m ati o n 
D E FI NI TI O N S 
N o nre pr o d ucti ve p ote nti al 
1.  Pre me n o pa usal f e male wit h 1 of t he f oll o wi n g: 
- 
D oc u me nte d h yster ect o m y 
- 
D oc u me nte d bilateral sal pi n gect o m y 
- 
D oc u me nte d bilater al o o p h orect o m y. 
2.  P ost me n o pa usal 
- 
A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e. A hi g h F S H le vel i n t he p os t me n o pa usal ra n ge ma y be use d t o c o nfir m 
a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o ne 
re place me nt t hera p y ( H R T). H o we v er, i n t he a bs e nce of 1 2 m o nt hs of a me n orr hea, a 
si n gle F S H meas ur e me nt is i ns ufficie nt.  
- 
Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 1 of 
t he hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T d uri n g 
t he st u d y. Ot her wise, t he y m ust disco nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr ol me nt. 
Re pr o d ucti ve p ote nti al  ( W O C B P) 
A w o ma n is c o nsi der e d of re pr o d u cti ve p ote ntial ( W O C B P), ie, fertile, f oll o wi n g me n arc h e a n d 
u ntil bec o mi n g p ost me n o pa usal u nless per ma n e ntl y  sterile. Per ma ne nt sterilizati o n met h o ds 
i ncl u de h ysterect o m y, bil ateral sal pi n gect o m y a n d bilateral o o p h orect o m y. 
C O N T R A C E P TI V E G UI D A N C E 
W o me n of re pr o d ucti ve p ote ntial ( W O C B P) m ust us e a hi g hl y effecti ve m et h o d of c o ntrace pti o n 
d uri n g t he tr eat me nt peri o d a n d t he p ost-treat me nt f oll o w u p perio d ( 2 8 ± 3 da ys). If a n ot her 
c o ntrace pti ve met h o d is use d (s uc h as a barrier m et h o d), it s h o ul d be use d i n c o m bi nati o n wit h 
o ne of t he hi g hl y eff ecti v e met h o ds (s uc h as a n oral c o ntrace pti ve). 
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P a g e 1 1 2 
Fe m ale p atie nts: 
Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds T h at Are User De pe n de nt 
F ail ure r ate of < 1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly a 
•  C o m bi ne d (estr o ge n- a n d pr o gest o ge n-c o ntai ni n g ) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n 
− oral 
− i ntra va gi nal 
− tra ns der mal 
•  Pr o gest o ge n- o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
− oral 
− i njecta ble 
Hi g hl y Effecti ve Met h o ds T h at Are User I n de pe n de nt 
•  I m pla nta ble pr o gest o ge n- o nl y h or m o ne c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
•  I ntra uteri ne de vice (I U D) 
•  I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) 
•  Bilateral t u bal occl usi o n 
•  Vasect o mize d part ner 
( V asect o mize d p art ner is a hi g hly effective c o ntr ace ptive met h o d pr ovi de d t h at t he p art ner is t he 
s ole sex u al p art ner of t he w o m a n of c hil d be ari n g p ote nti al a n d t he a bse nce of s per m h as bee n 
c o nfir me d. If n ot, a n a d diti o n al hi g hly effective met h o d(s) of c o ntr ace pti o n s h o ul d be use d. 
S per m at o ge nesis cycle is a p pr oxi m ately 9 0 d ays.)  
•  Se x ual a bsti ne nce 
( Sex u al a bsti ne nce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m 
heter osex u al i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy dr u g. T he 
reli a bility of sex u al a bsti ne nce nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy a n d 
t he preferre d a n d us u al lifestyle of t he p atie nt.) 
N O T E: 
a)  T y pical use fail ure rates ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be 
c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or patie nts 
partici pati n g i n cli nical st u dies. 
 
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P a g e 1 1 3 
C O L L E C TI O N O F P R E G N A N C Y I N F O R M A TI O N 
M ale p atie nts wit h p art ners of re pr o d ucti ve p ote nti al w h o bec o me pre g n a nt  
•  T he I n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y fe mal e part ner of a 
male st u d y patie nt w h o b ec o mes pre g na nt w hile p artici pati n g i n t his st u d y. T his a p plies 
o nl y t o patie nts w h o r ecei ve st u d y treat me nt. 
•  After o btai ni n g t he necessar y si g n e d i nf or me d  c o nse nt fr o m t he pre g n a nt fe male part ner 
directl y, t h e I n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o pri ate f or m a n d 
s u b mit it t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of t he part ner’s pre g n a nc y  
•  Part ner will als o be f oll o we d t o deter mi ne t he o ut c o me of t he pre g na n c y. I nf or mati o n o n 
t he stat us of t he m ot her a n d c hil d will be f or war d e d t o t he S p o ns or.  
•  Ge ner all y, f oll o w- u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t he esti mate d deli ver y 
date. A n y ter mi nati o n of t he pre g na n c y will be re p orte d re gar dless of fetal stat us ( prese n ce 
or a bse nce of a n o m alies) or i n dicati o n f or pr o ce d ure  
Fe m ale p atie nts w h o bec o me pre g n a nt  
•  T he I n vesti gat or will c oll ect pre g n a nc y i nf or m ati o n o n a n y fe male p atie nt, w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y  
•  I nf or mati o n will be rec or de d o n t he a p pr o priate f or m a n d s u b mitte d t o t he S p o ns or wit hi n 
2 4 h o urs of lear ni n g of a patie nt's pre g na n c y.  
•  Patie nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g n a nc y. T he I n vesti gat or will 
c ollect f oll o w- u p i nf or m ati o n o n patie nt a n d ne o n ate, w hic h will be f or war de d t o t he 
S p o ns or. Ge ner all y, f oll o w- u p w ill n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t he 
esti mate d deli ver y date.  
•  A n y ter mi nati o n of pre g n a nc y will be re p orte d, re gar dless of fetal stat us ( prese nce or 
a bse nce of a n o malies) or i n dicati o n f or pr oce d ure.  
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be  a n A E or S A E, a n y pre g na n c y c o m plicati o n 
or electi ve ter mi nati o n of a pre g na n c y will be re p orte d as a n A E or S A E.  
•  A s p o nta ne o us a b orti o n is al wa ys c o nsi dere d t o  be a n S A E a n d will be re p orte d as s uc h. 
A n y S A E o cc urri n g as a res ult of a p ost-st u d y pre g na n c y w hic h is c o nsi dere d reas o n a bl y relat e d 
t o t he st u d y treat me nt b y t he I n v esti gat or, will be re p orte d t o t he Sp o ns or as descri be d i n 
Secti o n  1 0. 4. 1. 2 . W hile t he I n vesti gat or is n ot o bli gat e d t o acti vel y see k t his i nf or mati o n i n 
f or mer st u d y patie nts, he or s he ma y lear n of a n S A E t hr o u g h s p o nt a ne o us re p orti n g.  
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P a g e 1 1 4 
A p p e n di x B  
A m b ul at or y bl o o d pr e s s ur e m o nit ori n g s u b st u d y 
B ac k gr o u n d 
A P hase 2 trial of s ota glifl ozi n ( L X 4 2 1 1. 1- 2 0 2) pr o vi de d e vi de nce t hat s ot a glifl ozi n re d uce d b ot h 
S B P a n d D B P i n patie nts wit h el e vate d S B P a n d D B P at Baseli ne b ut n ot n or m ote nsi ve patie nts. 
I n t his s u bst u d y of a p pr o xi matel y 2 0 0 patie nts wit h mea n Scree ni n g S B P ≥1 3 0 m m H g, patie nts 
will ha ve A B P M assess e d f or 2 4 h o urs at Baseli n e, Wee k 1 2, a n d Wee k 2 6 t o pr o vi de a m ore 
s yste matic assess me nt of t he S B P a n d D BP l o weri n g efficac y of s ota glifl ozi n. 
S u b-st u d y pr oce d ures 
Patie nts wit h mea n Scree ni n g S B P ≥1 3 0 m m H g will pr o vi de d wit h i nf or mati o n o n t he A B P M 
s u bst u d y, a n d se p arat e i nf or me d c o nse nt ta ke n bef ore A B P M s u bst u d y-s pecific pr oce d ures are 
perf or me d.  
Patie nts i n t he A B P M s u bst u d y w ill ha ve 3 a d diti o nal visits t o t he site f or place me nt of t he A B P M 
de vice. T hes e will be Visits 3 A, 7 A a n d 9 A. Visit 3 A will occ ur at Wee k - 1, 1 wee k bef ore 
ra n d o mizati o n. Visits 7 A a n d 9 A will occ ur t he d a y bef ore Visit 7 ( Wee k 1 2) a n d Visit 9 
( Wee k 2 6).  
Patie nts d o n ot nee d t o be fasti n g f or Visits 3 A, 7 A a n d 9 A. O nce t he A B P M de vice has b ee n 
place d at Visit 3 A, patie nts will be i nstr ucte d t o re m o ve it 2 4 h o urs later a n d re t ur n it t o t he site b y 
p ost i n a p pr o priate pac ka gi n g pr o vi de d b y t he site. T we nt y-f o ur h o urs aft er Visits 7 A a n d 9 A, 
patie nts will ret ur n t o t he site i n a fasti n g stat e at Visits 7 a n d 9, res pecti vel y, a n d t he d e vice will 
be re m o ve d. All A B P M data will be re vie we d f oll o wi n g ret ur n of t he d e vice t o e ns ure q u alit y of 
t he rec or di n g; p atie nts wit h A B P M data n ot of s ufficie nt q ualit y will be as k e d t o re peat t he 
pr ocess as s o o n as p ossi ble. Patie nts wit h A B P M data n ot of s uffici e nt q ualit y at Visit 3 A s h o ul d 
n ot be ra n d o mize d u ntil t he Bas eli ne A B P M rec or di n g has b ee n re peat e d. 
A m b ulat or y bl o o d pr ess ure m o nit ori n g will be p erf or me d wit h a vali dat e d de vice pr o vi de d b y t h e 
S p o ns or or S p o ns or re prese ntati ve. Eac h rec or di n g will start i n t he m or ni n g prefera bl y bet w ee n 
8: 0 0 a n d 1 0: 0 0 i m me diatel y after t h e a d mi nistrati o n of st u d y me dicati o n, a n d will e n d after at 
least 2 4 h o urs of r ec or di n g o n t he f oll o wi n g day. T he bl o o d press ure c uff will be a p plie d 
prefere ntiall y o n t he n o n- d o mi na nt ar m. T he m o nit or will be pr o gra m me d t o meas ure bl o o d 
press ure e ver y 2 0 mi n utes bet wee n 0 8: 0 0 a n d 2 1: 5 9, a n d e ver y 3 0 mi n utes bet wee n 2 2: 0 0 a n d 
0 7: 5 9. Patie nts will re mai n b li n de d t o all c ollecte d A B P M val ues b y s witc hi n g off t h e dis pla y of 
t he de vice. T h e y will be i nstr ucte d t o f oll o w t heir us ual dail y r o uti nes, b ut t o re mai n still a n d 
a v oi d ar m m o ve me nt d uri n g eac h a ut o mate d m eas ure me nt. Patie nts will be as ke d t o a v oi d 
stre n u o us acti vit y, b at hi n g, or ta ki n g a s h o wer a n d t o rec or d t he ti me of sl ee p a n d a n y u n us ual 
e ve nts or p o or slee p q ualit y d uri n g t he A B P M rec or di n g peri o d i n t heir st u d y l o g. 
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P a g e 1 1 5 
S u b-st u d y o bjecti ves 
T he pri mar y o bjecti ve of t he A B P M s u bst u d y is t o  c o m pare t he effect of s ot a glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h mea n S B P ≥1 3 0 m m H g at Scree ni n g o n 2 4- h o ur a vera ge S B P 
at Wee k 1 2. 
T he sec o n d ar y o bjecti ves of t he A B P M s u bst u d y are t o c o m pare t he effect of s ota glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h mea n S B P ≥1 3 0 m m H g at Scree ni n g o n t he f oll o wi n g: 
•  2 4- h o ur a vera ge S B P at Wee k 2 6 
•  2 4- h o ur a vera ge D B P at Wee ks 1 2 a n d 2 6 
•  A vera ge a dj uste d a wa ke ti me bl o o d press ure ( B P) as meas ure d b y S B P a n d D B P at Wee ks 
1 2 a n d 2 6 wit h a dj ust me nt base d o n acti gra p h y 
•  A vera ge a dj uste d slee pi n g ti me B P as m eas ure d b y S B P a n d D B P at Wee ks 1 2 a n d 2 6 
wit h a dj ust me nt base d o n acti gra p h y. 
S u b-st u d y e n d p oi nts 
T he pri mar y e n d p oi nt of t he s u bst u d y is: 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n a vera ge 2 4- h o ur S B P i n a s u bset of patie nts wit h 
mea n S B P ≥1 3 0 m m H g at Scree ni n g. 
T he sec o n d ar y e n d p oi nts of t he s u bst u d y are: 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n a vera ge 2 4- h o ur S B P 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n A vera ge 2 4- h o ur D B P  
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d a w a ke ti me B P as meas ure d 
b y S B P a n d D B P wit h a dj ust me nt base d o n acti gra p h y 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d slee p ti me B P as meas ure d 
b y S B P a n d D B P wit h a dj ust me nt base d o n acti gra p h y. 
St atistic al a n al yses 
T he q ualit y of a visit rec or di n g will be c o nsi d ere d i ns ufficie nt if t he visit rec or di n g d oes n ot meet 
t he criteria b el o w: 
1.  Visit rec or di n g d oes n ot c o ntai n great er t ha n  or e q ual t o 1 7 n o n-c o nsec uti v e h o urs of dat a 
w here eac h h o ur has at least o ne vali d B P meas ure me nt. 
2.  Visit rec or di n g has less t ha n 4 4 t otal meas ure m e nts. 
A B P M s u bst u d y e n d p oi nts will be a nal yze d usi n g a si milar a p pr oac h as t he pri mar y efficac y 
e n d p oi nt wit h missi n g val ues i m p ute d b y c o ntr ol- base d m ulti ple i m p utati o n met h o d u n der t he 
missi n g n ot at ra n d o m fr a me w or k. E ac h of t h e c o m plete dataset will be a n al yze d usi n g 
A N C O V A m o del i ncl u di n g f act ors f or treat me nt (s ota glifl ozi n, place b o), ra n d o mizati o n strat u m 
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2. 0)
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1. 0)
Pa ge 1 1 6 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 1 6 
of H b A 1c ( ≤8. 0 %, > 8. 0 %) as fi x e d effects, a n d t he baseli ne val u e of t he s pecific de p e n de nt 
varia ble as a c o v ariate. 
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2. 0)
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1. 0)
Pa ge 1 1 7 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 1 7 
A p p e n di x C  
T w o- h o ur st a n d ar di z e d mi x e d m e al 
A 2- h o ur P P G will be o btai ne d after a sta n dar d ize d M M i n all patie nts at Baseli ne ( D a y 1, 
Visit 3), at Wee k 2 6 ( Visit 9), a n d at Wee k 7 9 ( Vis it 1 3) or earlier if t he patie nt ter mi nates st u d y 
partici pati o n bef or e Wee k 2 6. A n y p atie nt w h o re q uires t he a d diti o n of res c ue me dicati o n pri or t o 
Wee k 2 6 a n d/ or Wee k 7 9 (see Secti o n 9. 1. 4. 2 ) s h o ul d still ha ve t he sta n dar dize d M Ms perf or me d 
at Wee k 2 6 a n d Wee k 7 9. 
T he sta n dar dize d M M m ust n ot be d o ne w hile pa tie nts are te m p oraril y off I M P; t he Me dical 
M o nit or will a d dress a n y e pis o des o n a case- b y-case basis a n d t he sta n dar dize d M M will be 
resc he d ul e d w he n t he p atie nt ca n res u m e I M P, if a p plica ble. 
T he first d ose of d o u ble- bli n d I M P a n d metf or mi n o n Da y 1 ( Visit 3) will be gi v e n after  
c o m pleti o n of t he 2- h o ur P P G c ollecti o n. F or t h e Wee k 2 6 a n d Wee k 7 9 sta n dar dize d M M, t he 
patie nt s h o ul d ta ke t he d ose of  d o u ble- bli n d I M P i m me diatel y after t he fasti n g bl o o d sa m ples are 
o btai ne d, a n d a p pr o x i matel y 3 0 mi n utes bef ore  i n gesti o n of t he sta n d ar dize d M M be gi ns. At 
Wee k 2 6, metf or mi n is gi ve n after  c o m pleti o n of t he 2- h o ur P P G c ollecti o n. 
St a n d ar d Me al f or t he St a n d ar dize d Mi xe d Me al: 
T he sta n dar d ( brea kfast) meal will be pr o vi de d b y t he S p o ns or as a li q ui d n utriti o n dri n k ( B o ost ® , 
E ns ure ® , or si milar), wit h ~ 4 0 g car b o h y drate a n d ~ 2 4 0 cal ories per b ottle ( ~ 8 o u nces). T he 
cal oric c o m p ositi o n of t h e meal is ~ 6 5 % car b o h y drate, ~ 1 5 % pr otei n, a n d ~ 2 0 % fat. T he a m o u nt 
gi ve n is 6 m L/ k g b o d y w ei g ht u p t o a ma xi m u m of 3 6 0 m L. T h eref ore f or patie nts ≥6 0 k g, t he 
sta n dar d meal c o nsists of ~ 6 0 g car b o h y drate a n d 3 6 0 cal ories.  
Patie nts are i nstr ucte d t o c o m pletel y c o ns u me t h e meal wit hi n 1 5 mi n utes, a n d e ver y eff ort s h o ul d 
be ma de t o c o m plete t he meal wit hi n 2 0 mi n utes after it is starte d. Water or n o ncaffei nate d, 
zer o-cal orie b e vera ges m a y b e c o ns u me d a d li b it u m. N o ot her f o o d ma y be c o ns u me d u ntil t he 
2- h o ur p ost pra n dial plas ma gl uc os e sa m ple has b ee n c ollecte d. If t he p atie nt is u na ble t o c o ns u me 
at least 5 0 % of t he sta n d ar d meal d uri n g t he M M T T at Bas eli ne ( D a y 1, Visit 3), t he patie nt 
s h o ul d n ot be ra n d o mize d. If a M M T T after ra n d o mizati o n is n ot t olerate d, eff ort s h o ul d be ma d e 
t o re peat t he testi n g at t h e discreti o n of t he In vesti gat or. If t he p atie nt  ca n n ot t olerate M M T T u p o n 
re peat testi n g, t his s h o ul d be d oc u me nte d i n t he e- C R F wit h t he reas o n a n d t he patie nt s h o ul d 
c o nti n ue i n t he st u d y. If t he patie nt is a ble  t o c o ns u me > 5 0 % of t he sta n d ar dize d M M, t he 
a p pr o xi mate a m o u nt s h o ul d be rec or de d, a n d a n e q ui vale nt a m o u nt  s h o ul d be c o ns u me d at t he 
s u bse q ue nt sta n dar diz e d M M. 
B aseli ne Visit ( D a y 1, Visi t 3) St a n d ar dize d M M: 
1.  Rec or d t he a m o u nt a n d bra n d na me of t he sta n dar d meal li q ui d n utriti o n dri n k t he patie nt 
is i nstr ucte d t o c o ns u me i n t he s o urce d o c u me nts 
2.  Fasti n g bl o o d sa m ples ar e o btai ne d, i ncl u di n g Ti me 0 fasti n g F P G 
3.  Rec or d t he ti me of bl o o d sa m ple c ollecti o n i n t he s o urce d oc u m e nts 
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Pa ge 1 1 8 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 1 8 
4.  I m me diat el y after t he fasti n g bl o o d sa m ples are c ollecte d, t he patie nt starts c o ns u mi n g t he 
sta n dar d meal 
5.  Rec or d t he ti me t he meal i n gesti o n starts i n t he s o urce d oc u m e nts 
6.  T he 2- h o ur c o u nt d o w n f or t he 2- h o ur plas ma P P G starts i m me diatel y after t he patie nt 
be gi ns i n gesti o n of t he st a n dar d meal 
7.  T he patie nt is i nstr ucte d t o i n gest t he prescri b e d a m o u nt wit hi n 1 5 t o 2 0 mi n utes. 
8.  Rec or d t he ti me i n gesti o n is c o m plete d, meas ure t he p orti o n of t he meal n ot i n geste d (if 
a n y), a n d r ec or d t h e assesse d perce nt of pr escri be d a m o u nt i n geste d i n t he s o urce 
d oc u me nts 
9.  N o bl o o d sa m ples f or P K are c ollecte d at t his visit 
1 0.  T w o h o urs after t he meal i n gesti o n starts , t he 2- h o ur plas ma P P G is c ollecte d 
1 1.  Rec or d t he ti me t he 2- h o ur plas ma P P G is c ollecte d i n s o urce d o c u me nts 
1 2.  D o u ble- bli n d I M P a n d metf or mi n are a d mi nistere d after  t he bl o o d sa m ple is dra w n at 
1 2 0 mi n utes 
1 3.  Rec or d t he ti me t he d o u ble- bli n d I M P is a d mi nistere d i n t he s o urce d oc u me nts. 
Wee k 2 6 Visit ( Visit 9) a n d Wee k 7 9 ( Visit 1 3) St a n d ar dize d M M: 
1.  Rec or d t he a m o u nt a n d bra n d na me of t he sta n dar d meal li q ui d n utriti o n dri n k t he patie nt 
is i nstr ucte d t o c o ns u me i n t he s o urce d o c u me nts 
2.  Fasti n g bl o o d sa m ples ar e o btai ne d, i ncl u di n g  Ti me 0 F P G a n d pre- d ose P K sa m ples 
3.  Rec or d t he ti me of bl o o d sa m ple c ollecti o n i n t he s o urce d oc u m e nts 
4.  D o u ble- bli n d I M P is a d mi nistere d after  t he fasti n g bl o o d sa m ples are o bt ai ne d 
5.  Rec or d t he ti me t he d o u ble- bli n d I M P is a d mi nistere d i n t he s o urce d oc u me nts 
6.  T hirt y mi n utes aft er t he d o u ble- bli n d I M P is a d mi nistere d, t he patie nt starts c o ns u mi n g t he 
sta n dar d meal 
7.  Rec or d t he ti me t he meal i n gesti o n starts i n t he s o urce d oc u m e nts 
8.  T he 2- h o ur c o u nt d o w n f or t he 2- h o ur P P G star ts i m me diatel y after t he p atie nt be gi ns 
i n gesti o n of t he sta n d ar d meal 
9.  T he patie nt is i nstr ucte d t o i n gest t he prescri b e d a m o u nt wit hi n 1 5 t o 2 0 mi n utes 
1 0.  Rec or d t he ti me i n gesti o n is c o m plete d, meas ure t he p orti o n of t he meal n ot i n geste d 
(if a n y), a n d rec or d t he assesse d perce nt of prescri be d a m o u nt i n geste d i n t he s o urce 
d oc u me nts 
1 1.  T w o h o urs after t he meal i n gesti o n starts , t he 2- h o ur P P G a n d 2- h o ur 3 0 mi n ute P K 
sa m ples are c ollecte d 
1 2.  Metf or mi n is a d mi nistere d after  t he bl o o d sa m ple is dra w n at 1 2 0 mi n utes 
1 3.  Rec or d t he ti me t he 2- h o ur p ost pra n dial bl o o d sa m ples are c ollecte d i n t he s o urce 
d oc u me nts. 
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Pa ge 1 1 9 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 1 9 
A p p e n di x D  
R e c o m m e n d ati o n s o n b a si c g e nit o uri n ar y h y gi e n e, m ai nt ai ni n g 
h y dr ati o n a n d r e c o g ni zi n g di a b eti c k et o a ci d o si s 
Patie nts wit h T 2 D are at ris k f or de vel o pi n g G U i nfecti o ns. T he f oll o wi n g g ui deli nes s h o ul d be 
c o m m u nicate d t o fe mal es a n d u ncirc u mcise d m ales re gar di n g G U i nfecti o ns. Patie nt 
c o m m u nicati o n car ds will be pri nte d wit h t he f oll o wi n g: 
F or fe males: 
“ T he f oll o wi n g a d vice m a y b e usef ul i n hel pi n g y o u t o kee p y o ur bla d der a n d uret hra free fr o m 
i nfecti o n: 
•  G o t o t he t oilet as s o o n as y o u feel t he nee d t o uri nate, rat her t ha n h ol di n g it i n.  
•  Wi pe fr o m fr o nt t o bac k after g oi n g t o t he t oilet.  
•  Practice g o o d h y gie n e b y was hi n g y o ur ge nitals e v er y da y, a n d b ef ore ha vi n g se x.  
•  E m pt y y o ur bla d d er after ha vi n g s e x.”  
F or u ncirc u mcise d males: 
“ T he f oll o wi n g a d vice m a y b e usef ul i n hel pi n g y o u t o kee p t he f ores ki n free fr o m i nfecti o n: 
•  Was h t he e n d of y o ur pe nis a n d f ores ki n wit h  s oa p a n d water ( d o n ot let s oa p get i n t he 
o pe ni n g).  
•  After y o ur s h o w er or b at h, dr y t he e n d of y o ur  pe nis a n d f ores ki n pr o p erl y a n d re place t he 
f ores ki n.  
•  Als o, w he n y o u uri nate, sli de t he f ores ki n bac k e n o u g h s o t hat uri ne d o es n ot get o n t he 
f ores ki n-t his hel ps t o kee p it clea n.” 
M ai nt ai ni n g H y dr ati o n: 
S o di u m- gl uc ose c otr a ns p orter t y pe 2 i n hi bit ors are ass ociate d wit h os m otic di uresis a n d v ol u me 
de pleti o n, w hic h ma y lea d t o dizz i ness or h y p ote nsi o n, es peciall y i n t he el d erl y. Bef ore i nitiati n g 
st u d y dr u g ( at Scree ni n g, R u n-i n a n d Ra n d o mizati o n) a n d d uri n g all o n-site stu d y visits t hereaft er, 
assess v ol u me stat us i n patie nts wit h  re nal i m pair me nt, t he el derl y, i n patie nts wit h l o w S B P, or if 
recei vi n g di ur etics, a n gi ote nsi n-c o n verti n g-e nz y m e i n hi bit ors, or a n gi ote nsi n rece pt or bl oc kers. 
All patie nts will be a d vise d t o mai ntai n pr o per fl ui d i nta ke a n d t o c o nsi der i ncreasi n g it if t he y 
se nse greater t hirst, m ore uri ne pr o d uctio n, or if t h e y feel dizz y or fai nt. 
Patie nt c o m m u nicati o n car ds will be pri nte d wit h t he f oll o wi n g f or patie nts wit h T 2 D: 
“ T he f oll o wi n g a d vice m a y b e usef ul i n hel pi n g y o u t o mai ntai n pr o pe r h y drati o n a n d pre v e nt 
de h y drati o n: 
•  De h y drati o n is w he n y o ur b o d y l oses t o o m u c h fl ui d, fre q ue ntl y d ue t o diarr hea or 
i ncreas e d uri nati o n 
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Pa ge 1 2 0 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 2 0 
•  C o nsi der i ncreasi n g t he a m o u nt of fl ui ds y o u dri n k if: 
- 
Y o u se nse gr eater t hirst t ha n us ual 
- 
Y o u ha ve a dr y m o ut h or crac k e d li ps 
- 
Y o u ha ve a fe ver 
- 
Y o u ha ve diarr hea or v o miti n g  
- 
Y o u uri nate m ore fre q u e ntl y or i n lar ger a m o u nts t ha n us ual 
- 
Y o u get u p i n t he mi d dle of t he ni g ht t o uri nat e ( m ore t ha n us ual) 
- 
Y o u feel dizz y or li g ht- h ea de d 
- 
Y o u e x ercise, or w h e n it is h ot o utsi de”.  
Rec o g nizi n g D K A 
P ote ntial GI a d v erse e ve nts occ urri n g wit h s ota glifl ozi n ma y m as k pres e nti n g s y m pt o ms of D K A. 
Patie nt c o m m u nicati o n car ds will be pri nte d wit h t he f oll o wi n g: 
“If y o u ha v e a n y of t hese s y m pt o ms o n t he list, t he n c o ntact y o ur st u d y site i m me diatel y f or 
assista nce wit h ma na gi n g y o ur dia betes: 
•  I n a bilit y t o mai ntai n oral i nta ke 
•  Ge ner alize d wea k ness 
•  A b d o mi nal ( bell y) pai n 
•  I n crease d w ei g ht l oss 
•  Fe ver 
•  Fre q u e nt uri nati o n, i ncl u di n g at ni g ht 
•  Fr uit y-sce nte d breat h 
•  C o nf usi o n 
•  Ac ute ill ness 
•  C o nsiste ntl y el e vate d bl o o d gl uc os e 
•  Feeli n g ver y t hirst y or dri n ki n g a l ot 
•  Na usea or v o miti n g 
•  Ha vi n g tr o u ble t hi n ki n g clearl y or feeli n g tire d. 
It is p ossi ble t o ha ve D K A e ve n if y o ur bl o o d gl u c ose is n ot ele vate d. Re gar dless of y o ur bl o o d 
gl uc ose l e vel, if y o u ha v e a n y of t hes e s y m pt o ms o n t he list, t he n c o ntact y o ur st u d y site 
re gar di n g t he n ee d t o be e val uate d f or p ossi ble D K A, w hic h will i ncl u de s pecific bl o o d testi n g. If 
y o ur st u d y site is cl ose d a n d y o ur st u d y d o ct or is  n ot a vaila ble, g o t o t he n earest e mer ge n c y r o o m 
f or e val u ati o n. 
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1. 0)
Pa ge 1 2 1 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 2 1 
If y o u ar e sc he d ul e d f or a pr oce d ure or s ur ger y t hat re q uires y o u t o n ot ta k e a n y f o o d or li q ui ds, 
please c o ntact y o ur st u d y d oct or f or i nstr ucti o ns o n c o nti n ui n g st u d y dr u g. I n s u c h cas es y o ur 
st u d y d oct or ma y a d vise y o u N O T t o ta ke y o ur stu d y dr u g fr o m t he da y pri or t o t he pr oce d ure or 
s ur ger y u ntil after t h e pr o ce d ure or s ur ger y is c om plete, a n d y o u are ta ki n g f o o d a n d li q ui ds as 
y o u n or m all y d o.” 
W he ne ver A E d ata is c ollecte d or t he p atie nt  re p orts D K A or i nterc urre nt ill ness (i ncl u di n g 
i nfecti o ns), ge neralize d wea k ness, i ncreas e d wei g ht l oss, GI s y m pt o ms i ncl u di n g na us ea, 
v o miti n g, or a b d o mi nal p ai n or ot her s y m pt o ms or  si g ns t hat t he I n vesti gat or belie ves ma y b e 
c o nsiste nt wit h D K A, t he n t he site will deter mi ne if a n assess me nt f or D K A is a p pr o priate. If 
la b orat or y testi n g c o nfir ms prese nce of meta b olic aci d osis, t he n t he “ P ossi ble D K A” e- C R F will 
be c o m plete d. 
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Pa ge 1 2 2 of 3 6 0


A m e n d e d Cli ni c al Tri al Pr ot o c ol N o. 0 2  
1 9- D e c- 2 0 1 7 
E F C 1 4 8 3 4 - s ot a glifl o zi n 
V er si o n n u m b er: 1 
Pr o p ert y of t h e S a n ofi Gr o u p - stri ctl y c o nfi d e nti al 
P a g e 1 2 2 
A p p e n di x E  
M e a s ur e m e nt of Bl o o d Pr e s s ur e a n d P ul s e R at e 
T he B P meas ure me nt de vice s h o ul d be cali brate d acc or di n g t o ma n ufact urer i nstr ucti o ns.  
E q ui p me nt 
1.  Bl o o d press ur e meas ure me nts will be ta ke n b y  a n a ut o mate d bl o o d press ure m o nit or or a 
ma n ual s p h y g m o ma n o m eter 
2.  Bla d der Le n gt h – S h o ul d nearl y or c o m pletel y e ncircle t he patie nt’s ar m. F or ma n y a d ults, 
t he sta n dar d “a d ult” size bla d der is n ot lo n g e n o u g h a n d t he “lar ge” size bla d der is 
rec o m me n de d 
3.  Bla d der Wi dt h – S h o ul d be at l east 4 0 % of t h e bla d der le n gt h. 
P ati e nt F act o rs 
E xtra ne o us varia bles ass ociate d  wit h t he meas ure me nt of B P s h o ul d be mi ni mize d. T hese i ncl u de: 
1.  F o o d i nta ke, caff ei ne- c o ntai ni n g be v era ges,  ci garette s m o ki n g, or stre n u o us e x ercise 
wit hi n 2 h o urs pri or t o meas ure m e nt 
2.  F ull uri nar y bla d d er 
3.  T he patie nt s h o ul d n ot be all o we d t o tal k w hile B P is bei n g meas ure d 
4.  T he patie nt s h o ul d be place d i n t he e x a mi nati o n r o o m a n d t he c uff s h o ul d b e place d o n t h e 
patie nt’s n o n d o mi na nt ar m. T he pr o per size d c uff s h o ul d fit s n u gl y wit h t he l o wer e d ge 2 
t o 3 c m a b o ve t he a nt ec u bital f ossa. 
5.  T he patie nt s h o ul d be all o we d t o sit q uietl y i n a c o mf orta bl y war m place (t e m perat ure 
ar o u n d 2 5° C or 7 7° F) f or 5 mi n utes wit h t he ar m s u p p orte d at heart le vel, prefera bl y wit h 
t he c uff i n place a n d wit h n o restricti ve clot hi n g o n t he ar m. T he p atie nt s h o ul d be 
e nc o ura ge d n ot t o te nse his or her m uscles. 
N o n d o mi n a nt Ar m 
T he patie nt’s n o n d o mi na nt ar m s h o ul d be t he ar m d eclare d b y t he patie nt as bei n g n o n d o mi na nt. 
T he n o n d o mi na nt ar m s h o ul d t he n be use d f or all s eate d B P meas ure m e nts t hr o u g h o ut t he st u d y. 
Me as ure me nt Tec h ni q ue 
F oll o wi n g t he 5- mi n ute r est peri o d, 3 se parate seate d B Ps s h o ul d be meas ure d wit h at least 
1 mi n ute bet wee n B P meas ure me nts a n d wit h t he c uff f ull y deflate d bet w ee n meas ure me nts. 
All 3 B Ps will be rec or d e d i n t he patie nt’s e- C R F. T he mea n of t h e 3 seate d B Ps will c o nstit ute 
t he B P val ue f or t hat visit. 
T hree seate d p ulse rate m eas ure m e nts will be o btai ne d. T he mea n of t he 3 s eate d p ulse rate 
meas ure me nts will c o nstit ute t he p ulse rate v al ue f or t hat visit. 
( el e ctr o ni c 
 
 
 
2. 0)
( el e ctr o ni c 
 
 
 
1. 0)
Pa ge 1 2 3 of 3 6 0













SAP_001.pdf: 
Offi ci al Titl e:  A  R a n d o miz e d,  D o u bl e -bli n d,  Pl a c e b o -c o ntr oll e d,  P ar all el -gr o u p, 
M ulti c e nt er St u d y  t o E v al u at e t h e Effi c a c y a n d S af et y of S ot a glifl ozi n 
A d d e d t o M etf or mi n i n P ati e nts  wit h T y p e 2 Di a b et es M ellit us W h o H a v e 
I n a d e q u at e Gl y c e mi c C o ntr ol o n M etf or mi n  
N C T N u m b er:  N C T 0 2 9 2 6 9 5 0  
D o c u m e nt  D at e : S A P V er si o n 3:  13 - De c e m b er - 20 1 9 


C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 of 9 9  
 
L e xi c o n P h ar m a c e uti c al s, I n c. 
 
Pr ot o c ol N o.: E F C 1 4 8 3 4 
A R a n d o mi z e d, D o u bl e -bli n d, Pl a c e b o -c o ntr oll e d, P ar all el -gr o u p, M ulti c e nt er St u d y 
t o E v al u at e t h e Effi c a c y a n d S af et y of S ot a glifl o zi n A d d e d t o M etf or mi n i n P ati e nt s 
wit h T y p e 2 Di a b et e s M ellit u s W h o H a v e I n a d e q u at e Gl y c e mi c C o ntr ol o n 
M etf or mi n  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
St ati sti c al A n al y si s Pl a n   
 
V er si o n: 3  
D A T E O F I S S U E: 1 0  D e c e m b er 2 0 1 9  
A ut h or: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Le xic o n P h ar m a ce utic als, I nc.  
8 8 0 0 Tec h n ol o g y F orest Place 
T he  W o o dla n ds, T X 7 7 3 8 1- 1 1 6 0 
C o v a nce Cli nic al De vel o p me nt Ser vices  
2 0 6 Car ne gie Ce nter 
Pri ncet o n, NJ 0 8 5 4 0- 6 2 3 3 
 




St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 of 9 9  
 
V E R SI O N HI S T O R Y  
Versi o n St at us  
Versi o n D ate  
 Fi nal 1. 0 
 2 9 Ma y 2 0 1 8 
 Fi nal 2. 0  
0 3 Ma y 2 0 1 9 
 Fi nal 3. 0 
1 0 Dece m b er 2 0 1 9 
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 of 9 9  
 
 
T A B L E O F C O N T E N T S  
A P P R O V A L S  .................................................................................................................................................. 2 
V E R SI O N HI S T O R Y  ....................................................................................................................................... 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 A N D D E FI NI TI O N O F T E R M S  .......................................................................... 7 
1  
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N  ................................................................................ 9 
1. 1  
S T U D Y D E SI G N A N D R A N D O MI Z A TI O N  ...................................................................................... 9 
1. 2  
O B J E C TI V E S  ................................................................................................................................... 9 
1. 2. 1  
Pri m ar y o bj e cti v e s  ............................................................................................................................ 9 
1. 2. 2  
S e c o n d ar y o bj e cti v e s  ..................................................................................................................... 1 0  
1. 2. 3  
Ot h er o bj e cti v e s  ............................................................................................................................. 1 0  
1. 2. 4  
O bj e cti v e s of A B P M s u b st u d y  ........................................................................................................ 1 0  
1. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E  ........................................................................................... 1 1  
1. 4  
S T U D Y P L A N  ................................................................................................................................. 1 1  
1. 5  
M O DI FI C A TI O N S T O T H E S T A TI S TI C A L S E C TI O N O F T H E P R O T O C O L  ................................ 1 2  
1. 6  
S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E S T A TI S TI C A L A N A L Y SI S P L A N  ..................... 1 3  
2  
S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S  .................................................................... 1 8  
2. 1  
A N A L Y SI S E N D P OI N T S  ............................................................................................................... 1 8  
2. 1. 1  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  .................................................................................... 1 8  
2. 1. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  ................................................................................................... 2 0  
2. 1. 2. 1  
R e s c u e t h er a p y  .............................................................................................................................. 2 0  
2. 1. 2. 2  
Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s  ............................................................................... 2 0  
2. 1. 3  
Effi c a c y e n d p oi nt s  .......................................................................................................................... 2 1  
2. 1. 3. 1  
Pri m ar y effi c a c y e n d p oi nt  ............................................................................................................... 2 1  
2. 1. 3. 2  
S e c o n d ar y effi c a c y e n d p oi nt s  ........................................................................................................ 2 1  
2. 1. 3. 3  
Ot h er effi c a c y e n d p oi nt s  ................................................................................................................ 2 2  
2. 1. 3. 4  
A B P M s u b st u d y effi c a c y e n d p oi nt( s)  ............................................................................................. 2 2  
2. 1. 4  
S af et y e n d p oi nt s  ............................................................................................................................ 2 3  
2. 1. 4. 1  
H y p o gl y c e mi a  ................................................................................................................................. 2 4  
2. 1. 4. 2  
A E s v ari a bl e s  ................................................................................................................................. 2 6  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 of 9 9  
 
2. 1. 4. 3  
D e at h s  ............................................................................................................................................ 2 9  
2. 1. 4. 4  
L a b or at or y  s af et y v ari a bl e s  ............................................................................................................ 2 9  
2. 1. 4. 5  
Vit al si g n s v ari a bl e s  ....................................................................................................................... 3 1  
2. 1. 4. 6  
P h y si c al e x a mi n ati o n  ..................................................................................................................... 3 1  
2. 1. 4. 7  
El e ctr o c ar di o gr a m v ari a bl e s  .......................................................................................................... 3 1  
2. 1. 5  
P h ar m a c o ki n eti c v ari a bl e s  ............................................................................................................. 3 1  
2. 2  
DI S P O SI TI O N O F P A TI E N T S  ....................................................................................................... 3 1  
2. 2. 1  
R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s  ......................................................................... 3 4  
2. 3  
A N A L Y SI S P O P U L A TI O N S  ........................................................................................................... 3 5  
2. 3. 1  
Effi c a c y p o p ul ati o n s  ....................................................................................................................... 3 5  
2. 3. 1. 1  
I T T p o p ul ati o n ................................................................................................................................ 3 5  
2. 3. 1. 2  
A B P M s u b st u d y p o p ul ati o n  ............................................................................................................ 3 6  
2. 3. 2  
S af et y p o p ul ati o n  ........................................................................................................................... 3 6  
2. 3. 3  
P K p o p ul ati o n  ................................................................................................................................. 3 6  
2. 4  
S T A TI S TI C A L M E T H O D S  ............................................................................................................. 3 6  
2. 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  .................................................................................. 3 7  
2. 4. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  ................................................................................................... 3 7  
2. 4. 3  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pli a n c e  ......................................... 3 8  
2. 4. 3. 1  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e  .................................................................... 3 8  
2. 4. 3. 2  
C o m pli a n c e  .................................................................................................................................... 3 8  
2. 4. 4  
A n al y s e s of effi c a c y e n d p oi nt s  ....................................................................................................... 3 9  
2. 4. 4. 1  
A n al y si s of pri m ar y effi c a c y e n d p oi nt( s)  ........................................................................................ 3 9  
2. 4. 4. 2  
A n al y s e s of s e c o n d ar y effi c a c y e n d p oi n t s ..................................................................................... 4 2  
2. 4. 4. 3  
A n al y s e s of ot h er effi c a c y e n d p oi nt s  ............................................................................................. 4 3  
2. 4. 4. 4  
A n al y si s of A B P M s u b st u d y effi c a c y e n d p oi nt s  ............................................................................. 4 4  
2. 4. 4. 5  
M ulti pli cit y i s s u e s  ........................................................................................................................... 4 4  
2. 4. 5  
A n al y s e s of s af et y d at a  .................................................................................................................. 4 5  
2. 4. 5. 1  
A n al y s e s of h y p o gl y c e mi a  ............................................................................................................. 4 6  
2. 4. 5. 2  
A n al y s e s of A E s  ............................................................................................................................. 4 6  
2. 4. 5. 3  
D e at h s  ............................................................................................................................................ 5 0  
2. 4. 5. 4  
A n al y s e s of l a b or at or y v ari a bl e s  .................................................................................................... 5 1  
2. 4. 5. 5  
A n al y s e s of vit al si g n v ari a bl e s  ...................................................................................................... 5 2  
2. 4. 5. 6  
A n al y s e s of el e ctr o c ar di o gr a m v ari a bl e s  ....................................................................................... 5 2  
2. 4. 5. 7  
A n al y s e s of p h y si c al e x a mi n ati o n v ari a bl e s  .................................................................................. 5 3  
2. 4. 6  
A n al y s e s of p h ar m a c o ki n eti c v ari a bl e s  .......................................................................................... 5 3  
2. 5  
D A T A H A N D LI N G C O N V E N TI O N S  .............................................................................................. 5 3  
2. 5. 1  
G e n er al c o n v e nti o n s  ...................................................................................................................... 5 3  
2. 5. 2  
D at a h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s  ......................................................... 5 4  
2. 5. 3  
Mi s si n g d at a  ................................................................................................................................... 5 4  
2. 5. 4  
Wi n d o w s f or ti m e p oi nt s/ M e a s ur e m e nt s f or a n al y s e s  ................................................................... 5 7  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 of 9 9  
 
2. 5. 5  
U n s c h e d ul e d vi sit s  ......................................................................................................................... 6 0  
2. 5. 6  
P o oli n g of c e nt er s f or st ati sti c al a n al y s e s  ...................................................................................... 6 0  
2. 5. 7  
St ati sti c al t e c h ni c al i s s u e s  ............................................................................................................. 6 0  
3  
I N T E RI M A N A L Y SI S ..................................................................................................................... 6 1  
4  
D A T A B A S E L O C K ........................................................................................................................ 6 2  
5  
S O F T W A R E D O C U M E N T A TI O N  ................................................................................................. 6 3  
6  
R E F E R E N C E S  ............................................................................................................................... 6 4  
7  
LI S T O F A P P E N DI C E S  ................................................................................................................. 6 5  
A P P E N DI X A  M A P PI N G O F I N C L U SI O N  A N D E X C L U SI O N C RI T E RI A U N D E R T H E O RI GI N A L 
P R O T O C O L A N D A M E N D M E N T 1  ............................................................................................... 6 6  
A P P E N DI X B  S A M P L E S A S ® C O D E F O R  A N A L Y S E S O F E F FI C A C Y E N D P OI N T S  ............................ 6 7  
A P P E N DI X C  A M B U L A T O R Y B L O O D P R E S S U R E M O NI T O RI N G S U B S T U D Y  .................................... 7 3  
A P P E N DI X D  A B P M S U B S T U D Y E F FI C A C Y V A RI A B L E D E RI V A TI O N  ................................................. 7 5  
A P P E N DI X E  P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S C RI T E RI A  ...................... 7 7  
A P P E N DI X F  LI S T O F P T S F O R S E L E C T E O SI S ( M E D D R A V 2 1 . 1) ...................................................... 8 3  
A P P E N DI X G  S U M M A R Y O F S T A TI S TI C A L A N A L Y S E S  ........................................................................ 9 1  
A P P E N DI X H  S T U D Y F L O W C H A R T  ........................................................................................................ 9 5  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 of 9 9  
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
 
A B P M:   
a m b ulat or y bl o o d press ure m o nit ori n g 
A E:  
a d verse e ve nt  
A E SI:  
a d verse e ve nt of s p ecial i nterest  
A L T:  
ala ni ne a mi n otra nsferas e  
A S T:  
as partate a mi n otra nsferas e  
A T C:  
a nat o mical t her a pe utic c he mical  
B MI:   
b o d y mass i n de x 
C E C:  
Cli nical E n d p oi nt C o m mittee(s)  
CI:  
c o nfi de nce i nter val 
C M H:  
C oc hra n -Ma nt el -Hae nszel  
C V:  
car di o vas c ular  
D B P:   
diast olic bl o o d press ure 
DI LI:   
dr u g-i n d uce d li ver i nj ur y  
E C G:  
electr ocar di o gr a 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 O SI:  
e ve nt of s pecial i nterest  
F P G:  
fasti n g plas ma gl u c ose 
G C R:   
gl uc ose-cr eati ni ne rati o  
H b A 1c:   
He m o gl o bi n A 1 c 
H D L - C:  
hi g h de nsit y li p o pr otei n c h olester ol 
I F C C: 
I nter nati o nal Fe derati o n of Cli nical C he mistr y a n d La b orat or y M e dici ne  
I M P: 
i n vesti gati o nal me dici nal pro d uct 
I R T:  
i nteracti ve r es p o nse tec h n ol o g y 
K M:  
Ka pla n -Mei er  
L D L - C:  
l o w de nsit y li p o pr otei n c h olester ol  
Me d D R A:  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI:  
m ulti ple i m p utati o n  
M M:  
mi x e d meal  
M N A R:   
missi n g n ot at ra n d o m 
NI M P:  
n o ni n vesti gati o nal me dici n al pr o d uct 
P C S A:  
p ote ntiall y cli nicall y si g nifica nt a b n or malit y  
P K:  
p har mac o ki netic 
P P G:   
p ost pra n dial gl u c ose 
P R A C:  
P har mac o vi gila nce Ris k Assess me nt C o m mittee  
S A E:  
seri o us a d vers e e v e nt 
S B P:   
s yst olic bl o o d press ure 
S D:  
sta n dar d de viati o n 
S O C:  
s yste m or ga n class  
T C : 
t otal c h olester ol 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 of 9 9  
 
T E A E:  
treat me nt-e mer ge nt a d v erse e ve nt  
T G : 
tri gl yceri des 
U A C R:   
uri ne al b u mi n-cr eati ni ne rati o  
U G E:  
uri nar y gl uc ose e x creti o n  
U L N:   
u p per li mit of n or mal 
W H O -D D:  
W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 of 9 9  
 
1 
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N  
1. 1  
S T U D Y D E SI G N A N D R A N D O MI Z A TI O N  
T his is a P hase 3, m ultice nter  a n d m ulti nati o nal, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 
parallel - gr o u p st u d y t o e val uate t he efficac y a n d s afet y of s ota glifl ozi n a d d e d t o metf or mi n i n 
patie nts wit h t y pe 2 dia b etes  mellit us  ( T 2 DM) w h o ha ve i na de q u ate gl yce mic c o ntr ol o n 
metf or mi n . 
All patie nts will ha ve a Scree ni n g Peri o d c o nsisti n g of a Scree ni n g p hase of u p t o 2 wee ks a n d a 
2- wee k si n gle - bli n d R u n-i n p hase pri or t o ra n d o mi zati o n. I n or der t o q ualif y f or ra n d o mizati o n, 
patie nts m ust de m o nstrate c o m plia nce b ase d u p o n pill c o u nt ( ≥8 0 %) d uri n g t he R u n-i n p hase. 
Ra n d o mizati o n will be perf or me d  vi a i nteracti ve res p o nse tec h n ol o g y (I R T), w here f orce d 
ra n d o mizati o n is n ot all o we d , a n d stratifie d b y: 
•  He m o gl o bi n A 1 c ( H b A 1 c ) at Scree ni n g (≤8. 0 %, > 8. 0 %)  
•  Mea n s yst olic bl o o d p ress ure (S B P ) at Scree ni n g ( < 1 3 0 m m H g, ≥1 3 0 m m H g) 
F oll o wi n g ra n d o mizati o n, patie nts will ha ve a 2 6- wee k, d o u ble- bli n d C ore Treat me nt Peri o d, a 
5 3- wee k d o u bl e- bli n d e xte nsi o n, a n d a 4- w ee k p ost -treat me nt F oll o w- u p p eri o d t o c ollect safet y 
i nf or mati o n ( patie nts w h o pre mat urel y disc o nti n u e t he st u d y treat me nt are e x pecte d t o c o nti n ue i n 
t he st u d y). 
A t otal of 5 0 0 patie nts ≥1 8 years of a ge will be ra n d o ml y assi g ne d 1: 1 t o 1 of t he f oll o wi n g 
2 treat me nt gr o u ps: 
•  s ota glifl ozi n 4 0 0 m g  
•  Place b o  
A m b ul at or y Bl o o d Press ure M o nit ori n g s u bst u d y ( A B P M s u bst u d y) 
A p pr o xi matel y 2 0 0 of t h e 5 0 0 e nr olle d patie nts w h o ha ve a mea n S B P ≥1 3 0 m m H g at scree ni n g 
are e x pecte d t o p artici pat e i n a n A B P M s u bst u d y  w here p atie nts will ha ve bl o o d press ure 
meas ure d b y a vali date d A B P M de vice .  
1. 2  
O B J E C TI V E S  
1. 2. 1  Pri m ar y o bj e cti v e s  
T he pri mar y o bjecti ve of t his st u d y is t o de m o nstrate t he s u peri orit y of s ota glifl ozi n 4 0 0 m g 
vers us place b o o n H b A 1 c re d ucti o n at Wee k 2 6 i n patie nts wit h T 2 D M w h o ha ve i na de q u ate 
gl yce mic c o ntr ol wit h metf or mi n . 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 0  of 9 9  
 
1. 2. 2  S e c o n d ar y o bj e cti v e s  
•  T o c o m pare s ota glifl ozi n 4 0 0 m g vers us place b o f or:  
- 
C ha n ge fr o m Baseli ne i n 2 - h o ur p ost pra n dial gl uc ose (P P G ) f oll o wi n g a mi x e d meal 
( M M) at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n fasti n g plas ma gl u c ose ( F P G ) at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n b o d y w ei g ht at Wee k 2 6 
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or patie nts wit h Baseli ne S B P ≥1 3 0 m m H g  
- 
C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or all p atie nts  
- 
Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6; 
•  T o e val uate t he s afet y of s ota glifl ozi n 4 0 0 m g vers us place b o t hr o u g h o ut t h e 7 9- wee k 
trial. 
1. 2. 3  Ot h er o bj e cti v e s  
•  T o c o m pare s ota glifl ozi n vers us place b o wit h res p ect t o C ha n ge fr o m Bas eli ne o n t he 
f oll o wi n g e n d p oi nts: 
- 
Uri ne al b u mi n -cr eati ni ne rati o ( U A C R ) 
- 
Uri nar y gl uc os e e x creti o n  ( U G E) a n d uri ne gl uc ose-creati ni ne rati o ( G C R ) 
- 
Esti mate d gl o mer ular filtrati o n rate (e G F R ) 
- 
Re d ucti o n i n b o d y wei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 %; 
•  T o c o m pare s ota glifl ozi n vers us place b o f or: 
- 
C ha n ge fr o m Baseli ne  i n H b A 1c at Wee k 7 9 
- 
C ha n g e fr o m Baseli ne i n F P G at Wee k 7 9 
- 
C ha n ge fr o m B aseli ne i n S B P at Wee k 2 6 f or all p atie nts a n d f or patie nts wit h 
Baseli ne S B P ≥1 3 0 m m H g 
- 
C ha n ge fr o m B aseli ne i n S B P at Wee k 7 9 f or all p atie nts a n d f or patie nts wit h 
Baseli ne S B P ≥1 3 0 m m H g 
- 
C ha n ge fr o m B aseli ne i n b o d y w ei g ht at Wee k 7 9; 
•  T o c o m pare t h e use of r esc ue me dicati o ns f or h y p er gl yce mia i n t he s ota glifl ozi n a n d 
place b o treat me nt gr o u ps; 
•  T o assess plas ma c o n ce ntrati o ns of s ota glifl ozi n a n d its 3 - O- gl u c ur o ni de m eta b olite. 
1. 2. 4  O bj e cti v e s of A B P M s u b st u d y  
T he p ri mar y o bjecti ve of t he A B P M s u bst u d y is t o c o m pare t he effect of s ot a glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h mea n S B P ≥1 3 0 m m H g at Scree ni n g o n 2 4- h o ur a vera ge S B P 
at Wee k 1 2.  






St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 3  of 9 9  
 
A m e n d m e nt  
N u m b er  
D at e  
A p pr o v e d  
R ati o n al e  
D e s cri pti o n of st ati sti c al c h a n g e s  
2 
1 9 -D ec -2 0 1 7  
5 h alf -liv es of s ot a glifl ozi n pr ol o n g e d 
t o 1 0 d ays c o nsi d eri n g p ati e nts  wit h 
m o d er at e r e n al dysf u ncti o n  
5 h alf -liv es of I M P u p d at e d fr o m 5 d ays t o 
1 0  d ays; T E A E p eri o d u p d at e d acc or di n gly  
2 
1 9 -D ec -2 0 1 7  
B as eli n e e G F R d efi n e d as 
r ec o m m e n d e d by C DI S C 
T h er a p e utic Ar e a D at a St a n d ar ds 
Us er G ui d e f or Di a b etic Ki d n ey 
Dis e as e  
F or s er u m cr e ati ni n e a n d e G F R, t h e b as eli n e 
v al u e is d efi n e d as t h e av er a g e of all v al u es 
b ef or e t h e first d os e of d o u bl e bli n d I M P f or 
t h os e r a n d o miz e d a n d ex p os e d or b ef or e 
r a n d o miz ati o n f or t h os e w h o w er e 
r a n d o miz e d b ut n ev er ex p os e d t o I M P. 
2 
1 9 -D ec -2 0 1 7  
Ur g e nt c or o n ary r ev asc ul ariz ati o n 
n ot a dj u dic at e d by C E C t o b e 
c o nsist e nt wit h o utc o m e tri als 
Ur g e nt c or o n ary r ev asc ul ariz ati o n n ot 
i ncl u d e d i n a dj u dic ati o n r el at e d a n alys es. 
2 
1 9 -D ec -2 0 1 7  
T h e eff ect i n b o dy w ei g ht is 
c o nsi d er e d m or e cl os ely ass oci at e d 
wit h t h e pl a n n e d i n dic ati o n.  
C h a n g e i n t h e or d er of s ec o n d ary o bj ectiv es, 
e n d p oi nts , a n d m ulti plicity a dj ust m e nt 
1. 6  
S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E S T A TI S TI C A L A N A L Y SI S P L A N  
T he statistical a nal ysis pla n hist or y ta bl e bel o w gi ves t he ti mi n g, rati o nale, a n d ke y details f or 
maj or c ha n ges t o t he statistical a nal ysis feat ures i n t he statistical a nal ysis pl a n. C ha n ges als o 
i nc or p orate d i n a pr ot oc ol a me n d me nt are cr oss-refere n ce d t o Ta bl e  1. 
T a bl e 2 - St ati sti c al a n al y si s pl a n st ati sti c al c h a n g e s  
S A P 
v er si o n  
n u m b er  
D at e 
a p pr o v e d  
R ati o n al e  
D e s cri pti o n of st ati sti c al c h a n g e s  
1  
2 9 -M ay -2 0 1 8  
T o b e c o nsist e nt wit h t h e Ve n d or 
( 
)’s d evic e’s s etti n g a n d pr o p erty  
T w o s ec o n d ary e n d p oi nts of A B P M s u bst u dy 
u p d at e d*:  
“C h a n g e fr o m Bas eli n e  t o W e ek 1 2 a n d 2 6 i n 
av er a g e d ayti m e B P ( a w ak e) as m e as ur e d by S B P 
a n d D B P b et w e e n 0 9: 0 0 a n d 2 0: 5 9” t o  
“C h a n g e fr o m Bas eli n e  t o W e eks 1 2 a n d 2 6 i n 
av er a g e a dj ust e d a w ak e ti m e B P as m e as ur e d by 
S B P a n d D B P wit h a dj ust m e nt b as e d o n 
acti gr a p hy”;  
“C h a n g e fr o m Bas eli n e  t o W e ek 1 2 a n d 2 6 i n 
av er a g e ni g htti m e (sl e e p) B P as m e as ur e d by 
S B P a n d D B P b et w e e n 0 1: 0 0 a n d  0 5: 5 9” t o  
“C h a n g e fr o m Bas eli n e  t o W e eks 1 2 a n d 2 6 i n 
av er a g e a dj ust e d sl e e pi n g ti m e B P as m e as ur e d 
by S B P a n d D B P wit h a dj ust m e nt b as e d o n 
acti gr a p hy”   






St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 6  of 9 9  
 
T he statistical met h o ds detaile d i n t his secti o n will be perf or m e d i n a d diti o n t o t h ose s pecifie d i n 
ot her secti o ns of t he S A P. T he maj orit y of t hese a d diti o nal assess me nts will ser ve as se nsiti vit y 
a nal ys es a n d will be use d t o s u p p ort/ q ualif y t he r o b ust ness of res ults fr o m t he ori gi n all y pla n n e d 
a nal ys es.  
F or t he pri mar y a n d c o nti n u o us sec o n dar y effi cac y e n d p oi nts, missi n g data at Wee k  2 6 ( or Wee k 
1 2 f or S B P) visit will be i m p ute d usi n g a m o del b uilt se paratel y i n eac h treat me nt gr o u p a n d 
esti mate d fr o m t he patie nts i n t he sa me treat me nt gr o u p w h o pre mat urel y disc o nti n ue t he I M P 
bef ore t h e Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha ve t he meas ure me nt f or t he e n d p oi nt ( ie, 
retrie ve d dr o p o uts). T he i m p utati o n m o del will i ncl u de t he ra n d o mizati o n strata a n d t h e 
c orres p o n di n g b aseli ne v al ue. I n cases of n o n-c o n ver ge nce d uri n g t he i m p utati o ns, t he offe n di n g 
strat u m will be i de ntifie d a n d t he n will be dr o p pe d fr o m t he m o del. C o nsi deri n g t hat t he n u m ber 
of retrie v e d dr o p o ut patie nts i n eac h treat me nt gr o u p is e x pecte d t o be s mall, a si m ple i m p utati o n 
m o del base d o n re gressi o n will be use d wit h baseli ne meas ure me nt i ncl u de d as t he pre dict or.  
A n alter nati ve ( bac k - u p) i m p utati o n met h o d will be use d if t he n u m ber of p atie nts w h o 
pre mat urel y disc o nti n ue t he I M P bef ore t he Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha ve t he 
meas ure me nt f or t he e n d p oi nt is <  5 i n a n y treat me nt gr o u ps (ie, a n i ns ufficie nt n u m ber of 
retrie ve d dr o p o uts t o s u p p ort t he i m p utati o n met h o d descri be d a b o ve). T his criteri o n will be 
assesse d f or eac h pri mar y or c o nti n u o us sec o n dar y efficac y e n d p oi nt.  
I n t he b ac k- u p i m p utati o n met h o d, missi n g p ost- baseli ne e n d p oi nt val ues at Wee k 2 6 ( or Wee k 1 2 
f or S B P) will be i m p ute d b y t he w as h o ut M ulti ple I m p utati o n ( MI) met h o d u n der t he missi n g n ot 
at ra n d o m ( M N A R) fr a m e w or k.  
Missi n g e n d p oi nt data at t he Wee k 2 6 ( or Wee k 1 2 f or S B P) i n all treat me nt gr o u ps (s ota glifl ozi n 
4 0 0 m g a n d place b o) ar e i m p ute d fr o m a m o del esti mate d fr o m patie nts i n t he place b o gr o u p w h o 
ha ve t he e n d p oi nt dat a a v aila ble.  
F or patie nts i n t he s ota glifl ozi n 4 0 0 m g wit h missi n g dat a at Wee k 2 6 ( or Wee k 1 2 f or S B P), t heir 
missi n g val ues will be i m p ute d usi n g o bser ve d bas eli ne a n d t he o bser ve d pri mar y e n d p oi nt data 
fr o m place b o c o m pleters; n o i nter mitte nt val ues fr o m eit her place b o or t he acti ve treat me nt gr o u ps 
will be use d.  
F or place b o patie nts, missi n g data will be i m p ute d base d o n t he place b o gr o u p data. I nter mitte nt 
o bser ve d val u es will be use d w hile i m p uti n g missi n g val u es at Wee k 2 6 ( or Wee k 1 2 f or S B P) . I n 
cases t hat a n o n - m o n ot o ne missi n g data p atter n occ urs at t he i nter me di ate visits, t hese data p oi nts 
will be first i m p ute d i n t he place b o gr o u p usi n g t h e Mar k o v C hai n M o nte Carl o ( M C M C) o pti o n 
i n P R O C MI t o ac hie ve a m o n ot o ne missi n g patter n f or all place b o patie nts. T he Wee k 2 6 ( or 
Wee k 1 2  f or S B P) e n d p oi nt val ues will be s u bse q ue ntl y i m p ute d fr o m t he m ulti ple c o pies of t he 
ori gi nal dat aset w here eac h c o p y will ha ve a m o n ot o ne missi n g patter n. 
T he i m p utati o n m o dels f or t he was h o ut MI met h o d will i ncl u de t he ra n d o mizati o n strata a n d t he 
c orres p o n di n g b aseli ne v al ue. Missi n g data will be i m p ute d usi n g t he re gressi o n met h o d. I n cases 
of n o n-c o n ver ge n ce d uri n g t he i m p utati o ns, es peciall y f or t h e M C M C a p plicati o n i n t he place b o 
n o n- m o n ot o ne datasets, gr a p hical meas ures (e g, trace a n d a ut oc orrel at i o n pl ots) will be use d t o 
i de ntif y t he offe n di n g varia ble a n d o nce detecte d, t hat varia ble(s) will be dr o p pe d fr o m t he m o del 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 7  of 9 9  
 
a n d t he i m p utati o ns will be re -r u n. T hese re-r u n m o dels will use t he sa me see d n u m ber a n d 
n u m ber of i m p utati o ns as use d i n t he ori gi n al m o dels.          
Eac h of t he c o m plete d datasets after t h e i m p utati o n will be a nal yze d usi n g t he A nal ysis of 
C o varia nce ( A N C O V A) m o del wit h treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, place b o), 
ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), ra n d o mizati o n strat u m of S B P ( < 1 3 0 m m H g, 
≥1 3 0 m m H g), a n d c o u ntr y as fi x e d fact ors, a n d b aseli ne val ue of t he effi cac y e n d p oi nt as a 
c o variate.  
Res ults fr o m eac h a n al ysis will be c o m bi ne d usi n g R u bi n’s f or m ula, t o pr o vi de t he a dj uste d mea n 
c ha n ge i n H b A 1 c fr o m Baseli ne t o Wee k 2 6 ( or Wee k 1 2 f or S B P) f or eac h treat me nt gr o u p, as 
well as t he bet wee n - gr o u p differe n ce (c o m pari n g s ota glifl ozi n 4 0 0 m g vers us place b o) a n d its 
ass ociate d 9 5 % c o nfi de n ce i nter val ( CI).  
F or A B P M s u bst u d y, t he pri mar y a n d sec o n dar y efficac y e n d p oi nts will be a nal yze d usi n g a 
si milar a p pr oac h as descri be d a b o ve wit h p ost- bas eli ne missi n g val ues i m p ute d b y t he retrie v e d 
dr o p o uts met h o d or b y t h e was h o ut i m p utati o n met h o d acc or di n g t o t he criteri o n s pecifie d a b o ve. 
Patie nts i n t his st u d y ha v e u n der g o n e s a m pli n g f or plas ma le vels of s ota glifl ozi n a n d its mai n 
acti ve meta b olite i n or der t o perf or m p o p ulati o n P K a nal ysis. Patie nts treat e d wit h s ota glifl ozi n 
4 0 0 m g w h o ha v e n o det ecta ble le v els of acti ve st u d y dr u g or meta b olite i n t heir sa m ples (ie, 
Bel o w  L o w er Li mit of Q ua ntificati o n or B L L O Q) ma y b e i de ntifie d as a n o mal o us.  I n a d diti o n, 
patie nts ra n d o mize d t o t he place b o ar m ma y als o b e i de ntifie d as ha vi n g P K a n o malies if t here is 
a detect a ble le vel of acti v e st u d y dr u g a n d/ or meta b olite i n t heir s yste m  (i.e., a b o ve li mit of 
detecti o n). W he n sa m ple a nal ysis h as bee n c o m plete d a n d t he st u d y h as bee n u n bli n de d, 
e x pla nati o ns f or s o me of t hese a n o malies ma y b e f o u n d: k n o w n n o n-c o m plia nce or s a m pli n g 
occ urri n g after tr eat me nt ha d bee n disc o nti n ue d. I n ot her cas es, dr u g i nta ke hist or y relati ve t o t he 
ra n d o mizati o n assi g n me nt ma y n ot be f ull y e x plai ne d. T he I T T-b ase d a nal ys es s p ecifie d i n t his 
d oc u me nt pr o vi des f or a c o nser vati ve assess me nt of t he effi cac y d ata s h o ul d patie nts ha ve bee n 
s u bjecte d t o t hese u ne x plai ne d n o n-c o m plia nce fi n di n gs or P K ‘a n o malies’. T o pr o vi de a br o a der 
pers pecti ve o n t h e i m pact of t hese a p pare nt err ors i n c o m plia nce, a d diti o nal se nsiti vit y a nal yses of 
t he pri mar y efficac y e n d p oi nt a n d c o nti n u o us effi cac y e n d p oi nts will be c o n d ucte d. T he nee d t o 
perf or m s uc h a nal yses, t h eir s pecifics, a n d res ults ma y b e pr o vi de d i n t he Cli nical St u d y Re p ort 
( C S R), if a p plica ble. T he a nal ysis met h o ds a p plie d t o t he patie nt s u b p o p ulati o ns defi ne d b y t he 
occ urr e nce of t he P K a n o malies (e g, e x cl usi o n of pati e nts wit h P K a n o malies fr o m t he I T T 
dataset) will i ncl u de t he A N C O V A m o del usi n g t he retrie v e d dr o p o ut or w as h o ut MI m et h o ds 
pre vi o usl y s p ecifie d i n t his secti o n. 
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 8  of 9 9  
 
2 
S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S  
2. 1  
A N A L Y SI S E N D P OI N T S  
2. 1. 1  D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  
T he baseli ne v al ue ( wit h t he e x ce pti o n of ser u m creati ni ne a n d e G F R) is defi ne d as t he last 
a vaila ble val ue b ef or e t h e first d ose of d o u ble- bli n d i n vesti gati o nal me dici nal pr o d uct (I M P ) or 
t he last a vaila ble val u e pri or t o ra n d o mizati o n f or patie nts w h o were ra n d o mize d b ut ne ver 
e x p ose d t o I M P. 
F or ser u m creati ni ne a n d e G F R, t he b aseli ne val ue is defi ne d as t he a v era ge of all val ues bef ore 
t he first d ose of d o u ble-bli n d I M P  f or t h ose ra n d o mize d a n d e x p ose d or bef ore ra n d o mizati o n f or 
t h ose w h o wer e ra n d o mi ze d b ut ne ver e x p ose d t o I M P. 
B aseli ne s afet y a n d efficac y par a meters are pres e nte d al o n g wit h t he s u m mar y st atistics i n t he 
safet y a n d efficac y secti o ns (Secti o n  2. 4. 5  a n d Secti o n  2. 4. 4 ). 
De m o gr a p hic c h ar acteristics   
De m o gra p hic c har acteristics t o be s u m marize d are:  
•  A ge ( years):  Y ear of i nf or me d c o nse nt - Year of birt h , 
•  A ge cat e g ories:  ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 t o < 7 5, ≥7 5 years) , 
•  Ge n der ( Male, Fe male),  
•  Race ( W hite, Blac k or Africa n A m erica n, Asia n, A merica n I n dia n or Alas ka nati ve, 
Nat i ve Ha w aiia n or ot her pacific isla n der, M ulti ple, U n k n o w n) 
•  Et h nicit y ( His pa nic  or Lati n o , N ot His pa nic or Lati n o, U n k n o w n), 
•  H b A 1c ( %) at scree ni n g visit,  
•  Ra n d o mizati o n strata of H b A 1c ( ≤8 %, > 8 %) at scree ni n g visit ( data fr o m I R T), 
•  M ea n S B P at scr ee ni n g visit,  
•  Ra n d o mizati o n strata of mea n S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g) at scree ni n g visit ( data 
fr o m I R T), 
•  Baseli ne b o d y m ass i n de x ( B MI ) ( k g/ m2) deri ve d as: ( Wei g ht i n k g)/( H ei g ht i n meters)2, 
•  Baseli ne B MI cate g o ries ( < 3 0, ≥3 0 k g/ m2), 
•  C o u ntr y. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 1 9  of 9 9  
 
Dise ase c h ar acteristics at scree ni n g  or b aseli ne   
Disease hist or y:  
•  D urati o n of dia bet es ( years): ( Date of i nf or me d c o nse nt – Date of dia g n osis of 
dia betes + 1)/ 3 6 5. 2 5, 
•  D urati o n of dia bet es cate g ories:  ( < 1 0, ≥1 0 years ), 
•  A ge  at dia g n osis of dia betes ( years): Year of dia g n osis of dia betes – Year of  Birt h , 
•  D urati o n of metf or mi n tr eat me nt ( years): ( d ate of i nf or me d c o nse nt - d ate of first i nta ke of 
metf or mi n  + 1)/ 3 6 5. 2 5, 
•  Dail y d o s e of metf or mi n( m g) at b aseli ne, 
•  Cate g orize d dail y d ose of metf or mi n at baseli ne ( < 1 5 0 0, ≥1 5 0 0 t o < 2 5 0 0, ≥2 5 0 0 m g), 
•  Baseli ne di a betic micr o v asc ular c o m plicati o ns ( Y es, N o) (ie, di a betic reti n o pat h y, dia b etic 
ne ur o pat h y, dia betic n e p hr o pat h y, dia betic peri p h eral ne ur o pat h y (se ns or y or m ot o r), 
dia betic a ut o n o mic ne ur o pat h y, a n d dia betic f o ot i nfecti o n), 
•  Baseli ne U A C R cate g ori es ( < 3 0 m g/ g  [ N or mal], ≥3 0 t o < 3 0 0 m g/ g  [ Micr oal b u mi n uria], 
a n d ≥3 0 0 m g/ g  [ Macr o al b u mi n uria]), 
•  e G F R at scree ni n g ( m L/ mi n / 1. 7 3 m2), 
•  e G F R cate g ories at scree ni n g ( < 1 5 m L/ m i n/ 1. 7 3 m2 [ E n d sta ge re nal disease], ≥1 5 t o 
< 3 0  m L/ mi n / 1. 7 3 m2 [ Se vere decrease i n G F R], ≥3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m2 [ M o derate 
decrease i n G F R], ≥6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m 2 [ Mil d decreas e i n G F R], a n d 
≥9 0 m L/ mi n / 1. 7 3 m2 [ N or mal]), 
•  Pri or a nti h y perte nsi ve m e dicati o n i de ntifie d b y t h era pe utic class as a ge nts acti n g o n t h e 
re ni n-a n gi ote nsi n s yste m, beta bl oc ki n g a ge nts, di uretics (a s u b-cate g or y: l o o p di uretics 
i de ntifie d p har mac ol o gical class as hi g h-ceili n g di uretics) , calci u m c ha n n el bl oc kers, a n d 
a nti h y perte nsi ves acc or di n g t o W orl d Healt h Or ga nizati o n- Dr u g Dicti o nar y ( W H O -D D ). 
Me dic al or s ur gic al hist ory 
Me dical hist or y a n d me dical fi n di n gs i ncl u d e: 
•  P h ysical e x a mi nati o n,  
•  Me dica l or s ur gical hist or y, 
•  Me dical hist or y car di o vasc ular,  
•  S ur gical hist or y a m p utati o n , 
•  Alc o h ol ha bits, 
•  T o bacc o s m o ki n g ha bit s. 
Me dical a n d s ur gical hist or y will be c o de d t o a “l o wer le vel ter m ( L L T)”, “ preferre d t er m ( P T)”, 
“ hi g h le v el ter m ( H L T)”, “ hi g h le v el gr o u p ter m ( H L G T)”, a n d ass oci ate d pri mar y “s yste m or ga n 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 0  of 9 9  
 
class ( S O C )” usi n g t he v ersi o n of Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) 
c urre ntl y i n effect at Sa n ofi at t he ti me of data bas e l oc k.  
A n y tec h nical d etails relate d t o c o m p utati o n, dates, a n d i m p utati o ns f or missi n g dates are 
descri be d i n  Secti o n  2. 5 . 
2. 1. 2  Pri or or c o n c o mit a nt m e di c ati o n s  
All me dicati o ns ta ke n wit hi n 3 m o nt hs bef ore scree ni n g visit (a n y ti me f or pri or S G L T 2 us e) a n d 
u ntil t he e n d of t he st u d y are t o be re p orte d i n t he electr o nic case re p ort f or m  (e-C R F ). 
All me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n - Dr u g Dicti o nar y usi n g t h e 
versi o n c urr e ntl y i n eff ect at Sa n ofi at t he ti me of data base l oc k . 
•  Pri or me dicati o ns are t h ose t he patie nt use d pri or t o first a d mi nistrati o n  of t he d o u ble-
bli n d I M P .  Pri or me dicati o ns ca n be disc o nti n ue d bef ore first a d mi nistrati o n or ca n be 
o n g oi n g d uri n g treat me nt p hase.   
•  C o nc o mita nt me dicati o ns are a n y treat me nts recei ve d b y t h e patie nt c o n c o mita ntl y t o t he 
I M P fr o m t he first a d mi nistrati o n  of d o u ble- bli n d I M P t o t he date of t he  last a d mi nistrati o n 
of d o u ble- bli n d I M P  + 1 0 da ys.  A gi ve n me dicati o n ca n be classifie d b ot h as a pri or 
me dicati o n a n d as a c o nc o mita nt me dicati o n.   
•  P osttreat me nt me dicati o ns are t h ose t he p atie nt t o o k i n t he peri o d r u n ni n g fr o m t he 
1 1 t h da y after t h e last a d mi nistrati o n of d o u ble-bli n d I M P u p t o t he e n d of t he st u d y. 
Bac k gr o u n d metf or mi n is c o nsi dere d as a n o ni n vesti gati o nal me dici nal pr o d uct ( NI M P). 
Metf or mi n (c o m mer cial f or m ulati o ns) will be a d mi nistere d orall y acc or di n g t o t he l ocall y 
a p pr o ve d la b el.  
2. 1. 2. 1  R e s c u e t h er a p y  
E x ce pt f or S G L T 2 i n hi bit ors, a n y a p pr o v e d me dicati o n(s) i ncl u di n g oral a nti dia betic dr u gs or 
i ns uli n ca n be prescri be d at t he I n vesti gat or’s discreti o n t o treat t he h y per gl yce mia. Resc u e 
t hera p y is c o nsi der e d a NI M P.  
2. 1. 2. 2  Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s  
D uri n g t h e st u d y tr eat me nt peri o d, t he f oll o wi n g me dicati o ns are pr o hi bite d: 
•  I nitiati o n of a n y a nti dia betic a ge nts, i ncl u di n g oral or i njecta ble a nti h y per gl yce mic a ge nts 
ot her t ha n t he I M P is n ot all o we d bef ore t he resc u e t hera p y , 
•  S yste mic use of gl uc o c ortic oi ds is n ot all o we d f or m ore t ha n 1 0 c o nsec uti ve da ys (t o pical, 
o p ht hal mic, nasal s pra y or i n hale d a p plicati o ns are all o we d), 
•  I nitiati o n of a n y wei g ht l oss dr u gs (e g, p he nter mi ne, orlistat), 
•  I n v esti gati o nal me dici nal pr o d ucts i n a n y ot her cli nical st u d y, 
•  S G L T 2 i n hi bit or (e g, ca n a glifl ozi n, da pa glifl ozi n, or e m pa glifl ozi n) are n ot all o we d f or 
resc ue. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 1  of 9 9  
 
Re d ucti o n of di g o xi n d ose s h o ul d be c o nsi dere d b eca use s ot a glifl ozi n acts as a wea k 
P- gl yc o pr ot ei n i n hi bit or a n d i ncreases s yste mic e x p os ure t o di g o xi n. 
Ot her me dicati o ns w hic h are u nli kel y t o i nterfere wit h t he p har mac o ki netic ( P K ) or 
p har mac o d y n a mics  (P D ) of t he I M P or c o nf o u n d i nter pretati o n of t he st u d y e n d p oi nts are all o w e d 
as nee de d f oll o wi n g disc ussi o n bet wee n t he I n v esti gat or a n d t h e S p o ns or. H o we ver, d oses of 
c hr o nicall y a d mi nistere d me dici nes s h o ul d be ke pt fi x e d d uri n g t he trial if at all p ossi ble. 
After pr e mat ure p er ma n e nt disc o nti n uati o n of t he I M Ps, a n y treat me nts ( ot her t ha n S G L T 2 
i n hi bit ors) are per mitte d, as dee me d n ecess ar y b y t he I n vesti gat or. 
T he d ose of all a nti h y perte nsi ve a ge nts s h o ul d be ke pt c o nsta nt d uri n g t he 1 2 wee ks f oll o wi n g 
ra n do mizati o n a n d n o a nti h y pert e nsi ve a ge nts s h o ul d be a d de d or wit h dra w n f or t he 1 2 wee ks 
f oll o wi n g r a n d o mizati o n u nless it is c o nsi dere d necessar y f or safet y reas o ns. 
2. 1. 3  Effi c a c y e n d p oi nt s  
All efficac y meas ure me nts c ollecte d d uri n g t he st u d y will be c o nsi dere d f or a nal yses, i ncl u di n g 
t h ose o btai ne d after I M P disc o nti n uati o n or i ntr o d ucti o n of resc u e t hera p y (see Secti o n  2. 5. 4 ).  
Efficac y v ari a bles H b A 1 c, 2- h o ur P P G, F P G , U A C R, U G E, U G C R, ser u m creati ni ne, a n d e G F R 
will be meas ure d/calc ulat e d  b y a ce ntral la b orat or y (see st u d y fl o wc h art i n  A p pe n di x H ).  B o d y 
wei g ht, S B P a n d D B P (s ee Secti o n  2. 1. 4. 5 ) will b e meas ure d at o n -site visits b y t he i n vesti gat or. 
Patie nts re q uiri n g resc u e are i de ntifie d as t h ose wit h t he reas o n f or treat me nt tic ke d “res c ue 
t hera p y” i n e-C R F “ Me di cati o n” pa ge.  
Efficac y vari a bles will be s u m marize d i n b ot h sta n dar d i nter nati o nal u nits a n d c o n ve nti o nal u nits 
w he n a p plica bl e.  
2. 1. 3. 1  Pri m ar y effi c a c y e n d p oi nt  
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n H b A 1c ( %). 
2. 1. 3. 2  S e c o n d ar y effi c a c y e n d p oi nt s  
T he c o nti n u o us sec o n dar y efficac y e n d p oi nts are: 
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n 2- h o ur P P G f oll o wi n g a M M 
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n F P G 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht 
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g  
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n S B P f or all patie nts 
•  Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 2  of 9 9  
 
2. 1. 3. 3  Ot h er effi c a c y e n d p oi nt s  
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P < 1 3 0 m m H g  
•  Pr o p orti o n of patie nts wit h re d ucti o n i n b o d y w ei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 % fr o m 
baseli ne  
•  C ha n ges fr o m bas eli ne t o Wee k 1 2 i n D B P 
•  Pr o p orti o n of patie nts ac hie vi n g S B P < 1 3 0 m m H g f or t h ose wit h baseli ne  
S B P ≥1 3 0 m m H g  
•  Pr o p orti o n of patie nts ac hie vi n g D B P < 8 0 m m H g f or t h ose wit h baseli ne  D B P ≥8 0 m m H g 
•  Pr o p orti o n of patie nts re q uiri n g resc ue f or h y per gl yce mia 
•  C ha n ge fr o m Baseli ne  i n: 
- 
U A C R, U G E, a n d U G C R  
- 
Ser u m creati ni ne  
- 
e G F R  
•  C ha n ge fr o m Baseli ne t o Wee k 7 9 i n H b A 1c 
•  C ha n ge fr o m Baseli ne t o Wee k 7 9 i n F P G 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n S B P f or all patie nts a n d f or patie nts wit h b aseli ne 
S B P ≥1 3 0 m m H g 
•  C ha n ge fr o m Baseli ne t o Wee k 7 9 i n S B P f or all patie nts a n d f or patie nts wit h b aseli ne 
S B P ≥1 3 0 m m H g 
•  C ha n ge fr o m Baseli ne t o Wee k 7 9 i n b o d y w ei g ht. 
2. 1. 3. 4  A B P M s u b st u d y effi c a c y e n d p oi nt( s)  
Pri m ar y  e n d p oi nts  
T he pri mar y e n d p oi nt of t he s u bst u d y is: 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n a vera ge 2 4- h o ur S B P i n a s u bset of patie nts wit h 
mea n S B P ≥1 3 0 m m H g at Scree ni n g. 
Sec o n d ar y e n d p oi nts  
T he sec o n d ar y e n d p oi nts of t he s u bst u d y are: 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n a vera ge 2 4- h o ur S B P 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge 2 4- h o ur D B P 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d a w a ke ti me B P  as meas ure d 
b y S B P a n d D B P wit h a dj ust me nt base d o n acti gra p h y  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 3  of 9 9  
 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d slee p ti me B P  as meas ure d 
b y  S B P a n d D B P wit h  a dj ust me nt base d o n acti gra p h y. 
2. 1. 4  S af et y e n d p oi nt s  
T he safet y a nal ysis will be base d o n t he re p orte d a d verse e v e nts ( A E s), h y p o gl yce mia, a n d ot her 
safet y i nf or mati o n, s uc h as cli nical la b orat or y dat a, vital si g ns, electr ocar di o gra m ( E C G ), a n d 
p h ysical e x a mi nati o n , etc.  
O bserv ati o n peri o d   
T he o bser vati o n peri o d will be di vi de d i nt o 4 e p oc hs:  
•  T he scree ni n g e p oc h is defi ne d as t he ti me fr o m t he si g ne d i nf or me d c o ns e nt date u p t o 
t he first a d mi nistrati o n of t he d o u ble- bl i n d I M P.  
•  T he treat me nt e p o c h is d efi ne d as t he ti me fr o m t he first a d mi nistrati o n of d o u ble- bli n d 
I M P t o t he last a d mi nistrati o n of d o u ble- bli n d I M P. T his e p oc h i ncl u des t he 2 6-wee k 
d o u ble- bli n d c ore tr eat m e nt peri o d a n d t he 5 3- wee k d o u ble- bli n d e xte nsi o n treat me nt 
peri o d. T he 2 6- wee k d o u ble- bli n d c ore treat me nt peri o d is t he ti me fr o m t he first 
a d mi nistrati o n of d o u ble- bli n d I M P t o t he last a d mi nistrati o n of d o u ble- bli n d I M P o n or 
bef ore Visit 9/ Wee k 2 6 ( or Da y 1 8 2 if Visit 9/ Wee k 2 6 date is missi n g) . 
•  T he resi d u al tre at me nt  e p oc h is defi ne d as t he ti me fr o m t he last a d mi nistrati o n of 
d o u ble- bli n d I M P t o t he l ast a d mi nistrati o n of d o u ble- bli n d I M P + 1 0 d a ys ( 1 da y f or 
h y p o gl yce mia).  
T he treat me nt -e mer ge nt a d verse e ve nt ( T E A E) peri o d f or t he 7 9- w ee k d o u ble- bli n d e ntire 
treat me nt peri o d will i ncl u de b ot h tre at me nt a n d resi d u al tre at me nt  e p oc hs ( See t he T E A E 
peri o d f or t he 2 6- wee k d o u ble- bli n d c ore treat me nt peri o d i n Secti o n  2. 5. 4 ). 
•  T he p osttre at me nt  e p oc h is defi ne d as t he peri o d of ti me starti n g t he d a y after t he e n d of 
t he treat me nt-e m er ge nt a d verse e v e nt peri o d u p t o t he last pr ot oc ol- pla n ne d visit or t he 
res ol uti o n/sta bilizati o n of all seri o us a d verse e v e nts ( S A E), a d vers e e ve nts of s pecial 
i nterest ( A E SI) a n d e ve nts of s pecial i nterest ( E O SI), w hic he v er is later. 
T he  o n-st u d y o bser v ati o n peri o d is defi ne d as t h e ti me fr o m start of d o u ble- bli n d treat me nt u ntil 
t he e n d of t he st u d y ( defi ne d as t he last sc he d ul e d visit f or t h ose w h o c o m plete d t he st u d y a n d t he 
date c ollecte d o n e - C R F pa ge “ C o m pleti o n of E n d of St u d y/ F oll o w- u p ” f or t h ose w h o di d n ot 
c o m plete t he st u d y).  
T he p ost-st u d y o bs er vati o n peri o d is defi ne d as t h e ti me fr o m t he da y after t he e n d of t he st u d y 
u ntil t he res ol uti o n/sta bilizati o n of all S A E, A E SI a n d E O SI if a p plica bl e.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 4  of 9 9  
 
2. 1. 4. 1  H y p o gl y c e mi a  
H y p o gl yce mia will be  i d e ntifie d as e v e nts rec or de d o n t he de dicate d e-C R F “ H y p o gl yce mic 
E ve nt i nf or mati o n” pa ge, a n d will be cate g orize d as f oll o ws (see pr ot oc ol f or f urt her d etails):  
Severe hy p o glyce mi a  
Se vere h y p o gl yce mia is a n e ve nt r e q uiri n g assista nce of a n ot h er pers o n  t o acti vel y a d mi nister 
car b o h y dr ate, gl uca g o n, i ntra ve n o us gl uc ose or ot her res us citati ve acti o ns. T hese e pis o des ma y b e 
ass ociate d wit h s uffici e nt ne ur o gl yc o pe nia t o i n d u ce seiz ure, u nc o ns ci o us ness or c o ma. 
Self - m o nit ore d plas ma gl uc ose val ues ma y n ot b e a vaila ble, b ut ne ur ol o gical rec o v er y attri b uta ble 
t o t he rest orati o n of plas ma gl uc os e t o n or mal is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt w as 
i n d uce d b y a l o w plas ma gl uc ose c o nce ntrati o n. 
Se vere h y p o gl yce mia is i de ntifie d i n e C R F “ H y p o gl yce mic E v e nt I nf or mati o n ” pa ge as t h ose 
d oc u me nte d as,  
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n ”, tic ke d t he o pti o n “ S u bject was N ot 
Ca pa ble of Tr eati n g Self a n d Re q uire d Assista nce”, a n d  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”.  
D oc u m e nte d sy m pt o m atic hy p o glyce mi a  
D oc u me nte d s y m pt o matic h y p o gl yce mia is a n e v e nt d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl yce mia acc o m pa nie d b y a meas ure d plas m a gl u c ose c o n ce ntrati o n of ≤3. 9 m m ol/ L 
( 7 0 m g/ d L). 
Cli nical s y m pt o ms t hat are c o nsi der e d t o res ult fr o m a  h y p o gl yce mic e pis o de are e g , i ncrease d 
s weati n g, ner v o us n ess, ast he nia/ wea k ness, tre m or, dizzi ness, i ncrease d a p p etite, pal pitati o ns, 
hea dac he, slee p dis or d er, c o nf usi o n, seiz ures, u nc o nsci o us ness, or c o ma. 
D oc u me nte d s y m pt o matic h y p o gl yce mia is i de ntifie d i n e C R F “ H y p o gl yce mic E ve nt 
I nf or mati o n” pa ge as t h ose d oc u me nte d as: 
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n ”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”, a n d  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure ≤3. 9 m m ol/ L ( 7 0 m g/ d L).  
Asy m pt o m atic hy p o glyce mi a   
As y m pt o matic h y p o gl yce mia is a n e ve nt n ot acc o m pa nie d b y t y pical s y m pt o ms of h y p o gl yce mia 
b ut wit h a meas ure d plas ma gl uc os e c o nce ntrati o n ≤3. 9 m m ol/ L ( 7 0 m g/ d L). 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 5  of 9 9  
 
As y m pt o matic h y p o gl yce mia is i de ntifie d i n e C R F “ H y p o gl yce mic E ve nt I nf or mati o n ” pa ge as 
t h ose d oc u me nte d as:  
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n ”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d  Re q uire d Assist a nce”, a n d  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ N o”, a n d  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure ≤3. 9 m m ol/ L ( 7 0 m g/ d L).  
 
Pr o b a ble sy m pt o m atic hy p o glyce mi a 
Pr o ba ble s y m pt o matic h y p o gl yce mia is a n e ve nt d uri n g w hi c h s y m pt o ms of h y p o gl yce mia are n ot 
acc o m pa ni e d b y a plas m a gl u c ose deter mi nati o n, ( b ut t hat was pres u ma bl y ca use d b y a pl as ma 
gl uc ose c o nce ntrati o n ≤3. 9 m m ol/ L [ 7 0 m g/ d L]), i e, s y m pt o ms treat e d wit h oral car b o h y drate 
wit h o ut a test of plas ma gl uc ose.  
Pr o ba ble s y m pt o matic h y p o gl yce mia is i de ntifie d i n e -C R F “ H y p o gl yce mic E ve nt I nf or mati o n ” 
pa ge as t h ose d o c u me nte d as, 
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce” , a n d 
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d 
3.  Wit h n o plas ma gl uc ose val ue bef ore c o u nt er meas ure, a n d  
4.  T o t he q uesti o n “ Di d t his c o u nter meas ure lea d a si g nifica nt i m pr o ve me nt or pr o m pt 
rec o ver y? ” tic ke d “ Yes”. 
Rel ative hy p o glyce mi a  
Relat i ve h y p o gl yce mia, r ece ntl y ter me d “ pse u d o-h y p o gl yce mia”  is a n e v e nt d uri n g w hic h t he 
patie nt re p orts t y pical s y m pt o ms of h y p o gl yce mia, a n d i nter prets t he s y m pt o ms as i n dicati ve of 
h y p o gl yce mia, b ut wit h a meas ure d plas ma gl u c os e c o nce ntrati o n > 3. 9 m m ol/ L ( 7 0 m g/ d L). 
Relati ve h y p o gl yce mia is i de ntifie d i n e C R F “ H y p o gl yce mic E ve nt I nf or mati o n ” pa ge as t h ose 
d oc u me nte d as, 
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n ”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure > 3. 9 m m ol/ L ( 7 0 m g/ d L).  
I n a d diti o n of t he t hres h ol d of ≤3. 9 m m ol/ L ( 7 0 m g/ d L), h y p o gl yce mia e pis o des wit h a plas ma 
gl uc ose of < 3. 0 m m ol/ L ( 5 4 m g/ d L) will be a nal yze d se paratel y.  
A n y h y p o gl yce mic e v e nt f ulfilli n g t he criteria of a S A E or lea di n g t o u nc o nsci o us ness, c o ma, or 
seiz ure will als o be rec or de d as a S A E (Secti o n  2. 1. 4. 2 ).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 6  of 9 9  
 
2. 1. 4. 2  A E s v ari a bl e s  
A E  o bserv ati o n peri o d  
•  Pre -treat me nt A E s ar e A E s t hat de vel o pe d or w orse ne d or beca me s eri o us fr o m t he si g n e d 
i nf or me d c o nse nt dat e u p t o first d ose of d o u ble- bli n d I M P 
•  Treat me nt -e mer ge nt A Es  are A Es  t hat d e vel o pe d or w orse n e d or beca me s eri o us d uri n g 
t he treat me nt-e m er ge nt A E  peri o d.  
•  P osttreat me nt A E  are A Es  t hat de vel o pe d or w orse ne d or beca me seri o us d uri n g t he 
p osttreat me nt peri o d . 
All a d verse e ve nts (i ncl u di n g S A Es , A E SI  a n d E O SI) will be c o de d t o a l o wer-le v el ter m (L L T ), 
preferre d t er m ( P T ), hi g h -le vel ter m (H L T ), hi g h -l e vel gr o u p ter m (H L G T ), a n d ass ociate d 
pri mar y s yst e m or ga n cl ass ( S O C ) usi n g t he versi o n of Me d D R A c urre ntl y i n effect at Sa n ofi at 
t he ti me of data bas e l oc k. 
T he occ urre n ce of A E s (i ncl u di n g S A Es, A E SI a n d E O SI ) will be rec or de d fr o m t he ti me of 
si g ne d i nf or me d c o nse nt u ntil t he e n d of t he st u d y (see Secti o n  2. 1. 4 ) or t he 
res ol uti o n/sta bilizati o n of all S A E, A E SI a n d E O SI.  
A E SI  
•  Pre g n a nc y  
•  S y m pt o matic o v er d ose wit h I M P/ NI M P  
•  Ala ni ne a mi n otra nsf eras e ( A L T ) i n crease > 3 ti mes u p per li mit of n or mal ( U L N ) 
E O SI  
•  Maj or a d vers e car di o vas c ular e v e nts ( M A C E) [car di o vasc ular d eat h, m y ocar dial 
i nfarcti o n, or str o ke]) a n d ot her s pecific car di o vasc ular ( C V) e ve nts (e g, h eart fail ure 
re q uiri n g h os pitalizati o n)  
•  Se vere h y p o gl yce mia  
Ge nital m yc otic i nfecti o ns (t o i ncl u de v ul v o va gi nal ca n di diasis i n fe males a n d ca n di da 
bala n itis i n males) 
•  Uri na r y tract i nfecti o ns 
•  Cli nicall y rele v a nt v ol u me de pleti o n a n d e v e nts rel ate d/ p ossi bl y rel ate d t o v ol u me 
de pleti o n 
•  Diarr hea  
•  Pa ncreatitis  
•  B o ne fract ures  
•  Ve n o us t hr o m b otic e ve nts, t o i ncl u de dee p ve n o us t hr o m b osis a n d t hr o m b oe m b olis m (t o 
i ncl u de p ul m o nar y e m b olis m)  
•  Dia betic ket oaci d osis  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 7  of 9 9  
 
•  Re nal e ve nts, t o i ncl u de 5 0 % decli ne i n e G F R, e n d sta ge ki d n e y disease, re nal deat h 
•  Mali g na n cies of s pecial i nterest ( breast, bla d der, re nal cell, Le y di g cell, pa ncreatic, 
pr ostate, a n d t h yr oi d ca n cer) 
•  A E  lea di n g t o a n a m p utati o n. 
A Cli nical E n d p oi nt C o m mittee(s) ( C E C) will , i n a bli n de d ma n ner re vie w a n d a dj u dicat e all 
deat hs, m y o car di a l i nfar cti o n, str o ke, u nsta ble a n gi na re q uiri n g h os pitaliz ati o n, a n d heart f ail ure 
re q uiri n g h os pitalizati o n, selecte d r e nal e v e nts, b o ne fract ure, a n d dia betic ket oaci d osis. 
T w o i n de pe n de nt c o m mittees will re vie w safet y e ve nts t hat re q uire o n g oi n g m o nit ori n g t o e ns ure 
ti mi n g pr ot oc ol a me n d m e nts i n case a s afet y si g n al is i de ntifie d. T hese e v e nts are: 1) p ote ntial 
cases of dr u g-i n d uce d li ver i nj ur y ( DI LI), a n d 2) cases of a m p utati o ns. T he t w o c o m mittees will 
re vie w t he cases i n a treat me nt- bli n de d ma n ner a n d will prese nt t heir assess me nt t o t he D M C.  
A E SI a n d E O SI will be i de ntifie d base d o n criteri a i n Ta ble  3.  
T a bl e  3 - Crit eri a f or A E SI a n d E O SI  
A E Gr o u pi n g  
Crit eri a  
A E SI  
 
Pr e g n a ncy  
e C R F  “ Pr e g n a ncy” 
Sy m pt o m atic ov er d os e wit h 
I M P/ NI M P 
“ Ov er d os e of I M P” or “ Ov er d os e of NI M P ” c h eck e d a n d “ Sy m pt o m atic ov er d os e” 
c h eck e d i n e C R F “ Ov er d os e” 
 A L T i ncr e as e > 3 X U L N  
e C R F “ AL T i ncr e as e” 
E O SI  a dj u di c at e d  
 
C ar di ov asc ul ar D e at h  
P ositiv ely a dj u dic at e d by C E C: “ C ar di ov asc ul ar” or “ U n d et er mi n e d” as t h e pri m ary c a us e 
of d e at h  
My oc ar di al i nf arcti o n, U nst a bl e 
A n gi n a  r e q uiri n g h os pit aliz ati o n  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of 
a n MI f or t his st u dy ?”, or Yes t o t h e q u esti o n “If ev e nt is n ot a n MI, d o es t h e ev e nt m e et 
t h e d efi niti o n of a n U A R e q uiri n g a d missi o n t o h os pit al or e m er g e ncy r o o m, f or t his 
st u dy ?” 
Str ok e  
P ositiv ely a d j u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of 
a Str ok e f or t his st u dy ?”  
H e art f ail ur e r e q uiri n g  h os pit aliz ati o n  P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of 
a H e art F ail ur e Ev e nt f or t his st u dy ?”  
B o n e fr act ur es  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ Di d t h e Fr act ur e occ ur ?”  
Di a b etic k et o aci d osis  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t his ev e nt m e et t h e crit eri a t o 
b e a D K A ev e nt ?”  
E O SI R e n al e v e nt s w h er e s el e ct e v e nt s a dj u di c at e d  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 8  of 9 9  
 
A E Gr o u pi n g  
Crit eri a  
S ust ai n e d ≥5 0 % d ecr e as e i n e G F R  
( 1) F or ≥5 0 % d ecr e as e i n e G F R fr o m b as eli n e,  
( 1 a)  c o nfir m e d ≥5 0 % d ecr e as e i n G F R f or ≥3 0 d ays wit h n o r ev ersi bl e c a us e as 
r ec or d e d i n e C R F “e G F R d ecr e as e”, O R  
( 1 b)  p ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e s u bj ect m e et t h e 
crit eri a of C K D pr o gr essi o n” f or ≥5 0 % d ecr e as e i n e G F R.  
S ust ai n e d e G F R < 1 5 m L/ mi n/ 1. 7 3 m 2 ( 2) F or e G F R < 1 5 m L/ mi n/ 1. 7 3 m2, 
( 2 a)  c o nfir m e d e G F R < 1 5 m L/ mi n/ 1. 7 3 m 2 f or ≥3 0 d ays wit h n o r ev ersi bl e  c a us e as 
r ec or d e d i n e C R F “e G F R d ecr e as e”, O R 
( 2 b)  p ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e s u bj ect m e et t h e 
crit eri a of C K D pr o gr essi o n”. 
C hr o nic di alysis  
( 3) F or di alysis,  
( 3 a)  di alysis l ast e d f or ≥9 0 d ays ( e g, e n d d at e – st art d at e + 1 ≥9 0) as r ec or d e d i n 
e C R F “ R e n al Ev e nt – Di alysis”, O R  
( 3 b)  p ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “. D o es t h e s u bj ect m e et t h e 
crit eri a f or E S R D”. 
R e n al tr a ns pl a nt  * 
( 4) “ R e n al tr a ns pl a nt” c a pt ur e d i n e C R F “ Ot h er pr oc e d ur e f or m”, w h er e a dj u dic ati o n is 
n ot r e q uir e d. P Ts of R e n al tr a ns pl a nt ( 1 0 0 3 8 5 3 3), R e n al a n d p a ncr e as tr a ns pl a nt 
( 1 0 0 5 2 2 7 8), R e n al a n d liv er tr a ns pl a nt ( 1 0 0 5 2 2 7 9) b as e d o n M e d D R A v 2 1. 1. 
R e n al d e at h  
( 5) R e n al d e at h as p ositiv ely a dj u dic at e d by C E C: “ D e at h - N o n -C ar di ov asc ul ar ( R e n al)” 
as t h e pri m ary c a us e of d e at h  
E O SI  n ot a dj u di c at e d  * 
 
S ev er e hy p o glyc e mi a  
al g orit h m s p ecifi e d i n S ecti o n  2. 1. 4. 1  b as e d o n e C R F “ Hy p o glyc e mic Ev e nts” 
G e nit al myc otic i nf ecti o ns  
P Ts i n  A p p e n dix F  
Uri n ary tr act i nf ecti o ns  
P Ts i n A p p e n dix F  
Cli nic ally r el ev a nt v ol u m e d e pl eti o n 
a n d ev e nts r el at e d/ p ossi bly r el at e d t o 
v ol u m e d e pl eti o n 
P Ts i n A p p e n dix F  
Di arr h e a  
N arr o w s e arc h o n “ N o ni nf ecti o us di arr h o e a ( S M Q)” [ 2 0 0 0 0 2 1 8] pl us t h e f oll o wi n g P Ts 
(M e d D R A v 2 1. 1):  G astr o e nt eritis ( 1 0 0 1 7 8 8 8), Anti di arr h o e al s u p p ortiv e c ar e 
( 1 0 0 5 5 6 6 0), Ent eritis ( 1 0 0 1 4 8 6 6), Ent eritis l e uk o p e nic ( 1 0 0 1 4 8 7 7), Ent er oc olitis 
( 1 0 0 1 4 8 9 3), Ent er oc olitis h a e m orr h a gic ( 1 0 0 1 4 8 9 6) 
P a ncr e atitis  
P Ts i n A p p e n dix F  
V e n o us t hr o m b otic ev e nts  
P Ts i n A p p e n dix F  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 2 9  of 9 9  
 
A E Gr o u pi n g  
Crit eri a  
M ali g n a nci es of s p eci al i nt er est  
Br e ast c a nc er: N arr o w s e arc h o n “ Br e ast c a nc er: N arr o w s e arc h o n “ Br e ast n e o pl as ms, 
m ali g n a nt a n d u ns p ecifi e d ( S M Q)” [ 2 0 0 0 0 1 4 9]  
Pr ost at e c a nc er: N arr o w s e arc h o n “ Pr ost at e n e o pl as ms, m ali g n a nt a n d u ns p ecifi e d 
( S M Q)” [ 2 0 0 0 0 1 5 2] 
L ey di g -c ell c a nc er: P Ts of L ey di g c ell t u m o ur of t h e t estis ( 1 0 0 2 4 4 0 7) a n d Ov ari a n 
S ert oli -L ey di g c ell t u m o ur ( 1 0 0 7 3 2 7 0) b as e d o n M e d D R A v 2 1. 1  
T hyr oi d c a nc er: P Ts i n Ap p e n dix F   
R e n al c ell c a nc er: P Ts i n A p p e n dix F  
P a ncr e atic c a nc er: P Ts i n Ap p e n dix F  
Bl a d d er c a nc er: P Ts i n Ap p e n dix F  
E O SI A E l e a di n g t o a n a m p ut ati o n  
A E l e a di n g t o a n a m p ut ati o n  
“ A E C orr ecti o n” as t h e r e as o n f or a m p ut ati o n i n e C R F “ Ot h er Pr oc e d ur es r el at e d t o 
A m p ut ati o n”  
A E p ot e nti ally  l e a di n g t o a n 
a m p ut ati o n  * 
P Ts i n A p p e n dix F  
* S e arc h t er ms will b e u p d at e d usi n g t h e M e d D R A v ersi o n c urr e ntly i n eff ect at S a n ofi at t h e ti m e of d at a b as e l ock f or E O SI id e ntifi e d by t h e m.  
A E p ot e nti ally l e a di n g t o a n a m p ut ati o n: n ot a n E O SI p er i n divi d u al prot oc ol; a n alyz e d d u e t o t h eir rel ev a nc e t o l o w er li m b c o m plic ati o n a n d 
a m p ut ati o ns as a re q uire m e nt fr o m h e alt h a ut h oriti es.  
2. 1. 4. 3  D e at h s  
T he deat hs o bser vati o n p eri o d ar e per t he o bs er vati o n peri o ds defi ne d a b o v e.  
•  Deat h o n-st u d y:  deat hs o cc urri n g d uri n g t he o n-st u d y o bser vati o n peri o d  
•  Deat h o n -tr eat me nt:  deat hs occ urri n g d uri n g t he treat me nt-e mer ge nt A E p eri o d   
•  Deat h p ost- st u d y:  d eat hs occ urri n g after t h e e n d of t he st u d y.  
2. 1. 4. 4  L a b or at or y s af et y v ari a bl e s  
Cli nical la b orat or y d ata c o nsists of bl o o d a nal ysis (i ncl u di n g he m at ol o g y, cli nical c he mistr y, 
a m ylas e, li pase, li pi d pr ofile ) a n d uri nal ysis.  Cli nical la b orat or y v al ues will be s u m marize d i n 
b ot h sta n dar d i nter nati o n al u nits a n d c o n ve nti o nal u nits w he n a p plica ble.  
Bl o o d sa m ples f or cli nical la b orat ories will be ta k e n at desi g nate d visits as s pecifie d i n pr ot oc ol 
(see st u d y fl o wc h art i n A p pe n di x H ).  Cli nical la b orat or y val ues will be s u m marize d b y t he 
f oll o wi n g gr o u ps:  
•  He mat ol o g y  
- 
Re d bl o o d cells a n d pl atelets : he m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, platelet 
c o u nt  
- 
W hite bl o o d cells:   w hite bl o o d cell c o u nt, differe ntial c o u nt ( ne utr o p hils, 
l y m p h oc ytes, m o n oc ytes, bas o p hils, e osi n o p hils) 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 0  of 9 9  
 
•  Cli nical c he mistr y  
- 
Met a b olis m:  gl uc ose (s er u m), creati ne p h os p h o ki nase ( C P K) 
- 
Electr ol ytes  a n d mi ner als :  s o di u m, p otassi u m, c hl ori de, bicar b o n ate (ie, car b o n 
di o xi de), calci u m, p h os p h or us, ma g n esi u m  
- 
Re n al f u ncti o n :  bl o o d urea nitr o ge n ( B U N), creati ni ne, uric aci d  
- 
Li ver f u ncti o n :  t otal pr otei n, al b u mi n, ala ni ne a mi n otra nsferas e ( A L T), as partate 
a mi n otra nsfer ase ( A S T ), al kali ne p h os p hatase ( A L P), t otal bilir u bi n,  lactic aci d 
de h y dr o ge nas e ( L D H ) 
•  Li pi d par a meters (fasti n g) 
- 
T otal c h olester ol (T C ) 
- 
Hi g h de nsit y li p o pr otei n c h olester ol ( H D L - C) 
- 
L o w d e nsit y li p o pr otei n c h olester ol (L D L - C) (cal c ulate d b y Frie d wal d e q u ati o n) 
- 
N o n -H D L C (calc ulate d as t he differe nce b et wee n T C a n d H D L C)  
- 
Tri gl yceri des ( T G). 
•  Pa ncreatic e nz y mes: li pase, a m yl ase.  
•  Bl o o d Mar k ers of I nt esti nal Tra nsit a n d A bs or pti o n  
- 
Vita mi ns: B 6, B 1 2, K, E a n d A 
- 
Ser u m f olate  
- 
Ferriti n  
•  Mar kers of b o ne a n d calci u m meta b olis m 
- 
Calci u m,  
- 
2 5- h y dr o x y vita mi n D,  
- 
1, 2 5- di h y dr o x y vita mi n D,  
- 
P h os p h or us,  
- 
Parat h yr oi d h or m o ne ( P T H ),  
- 
Mar kers of b o ne r es or pti o n: N- ter mi nal tel o pe pti de (N T X ), beta- C-t er mi nal 
tel o pe pti de ( β-C T X - 1),  
- 
Mar ker of b o ne f or mati o n: t y pe 1 pr o c olla ge n N- ter mi nal ( P 1 N P). 
Uri ne sa m ples will be c ollecte d at desi g nat e d visits (see st u d y fl o wc h art i n  A p pe n di x H ) a n d 
meas ure d b y ce ntral la b orat or y : 
•  Uri ne di pstic k i ncl u des: s pecific gra vit y, p H, pr otei n, bl o o d, ket o nes, bilir u bi n, 
ur o bili n o ge n, nitri te, a n d le u k oc yt e esterase 
•  Uri ne micr osc o p y i ncl u d es, b ut is n ot li mite d t o: detecti o n of f or m e d cell ul ar ele me nts, 
casts, bacteria, yeast, par asites, a n d cr ystals i n ce ntrif u ge d uri ne se di me nt  
•  Uri ne mar k ers of b o n e a n d calci u m met a b olis m: calci u m a n d p h os p h or us 
•  Uri ne al b u mi n, calci u m, gl uc ose a n d creati ni ne. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 1  of 9 9  
 
Ser u m gl uc os e, U G E, cal c ulate d U A C R a n d calc ulate d  UG C R will be pres e nte d as efficac y 
para meters i n  Secti o n  2. 4. 4  . F or creati ni ne a n d cal c ulate d e G F R, P C S A s u m maries will be 
prese nte d i n t he safet y secti o n w hile descri pti ve s u m maries i n t he effi cac y secti o n.  
Tec h nical f or m ulas ar e d escri be d i n  Secti o n  2. 5. 1 . 
2. 1. 4. 5  Vit al si g n s v ari a bl e s  
Vital si g ns i ncl u de:  heart rate, s yst olic a n d diast olic bl o o d press ure, te m p erat ure, a n d res pirat or y 
rate (see st u d y fl o wc h art i n A p pe n di x H  f or desi g n ate d visits). T he y will be perf or me d after t he 
patie nt has bee n s eate d f or at least 5 mi n utes. B l o o d press ure a n d heart rat e will be meas ure d 
3 ti mes  wit h at least 1 mi n ute bet wee n eac h meas ure me nt. T he mea n of t h e 3 meas ure me nts will 
be a nal yz e d f or eac h vital si g n varia bl e  ( Heart rate, S B P, a n d D B P). 
2. 1. 4. 6  P h y si c al e x a mi n ati o n  
A c o m plete p h ysical e x a m will be perf or me d at Visit 1/ Scree ni n g, Visit 9/ Wee k 2 6, a n d 
Visit  1 3/ Wee k 7 9. “ N or mal”, “ A b n or mal ”, “ N ot d o ne” as det er mi ne d b y t he I n vesti gat or will be 
re p orte d i n t he e-C R F b y b o d y s yste m.  
2. 1. 4. 7  El e ctr o c ar di o gr a m v ari a bl e s  
1 2- lea d E C Gs will be perf or me d at Visit 1/ Scree ni n g, Visit 3 / Ra n d o mizati o n, Visit 9/ Wee k 2 6, 
a n d Visit 1 3 / Wee k 7 9 . E C G stat us of “ n or mal” or “a b n or mal” will be re p orte d i n t he e C R F as 
deter mi ne d b y t he I n v esti gat or .  
2. 1. 5  P h ar m a c o ki n eti c v ari a bl e s  
P har mac o ki netic varia bles i ncl u de t he c o nce ntrati o n of s ota glifl ozi n a n d its 3- O- gl uc ur o ni d e 
meta b olite i n t he s ota glifl ozi n gr o u p.  
2. 2  
DI S P O SI TI O N O F P A TI E N T S  
T his secti o n descri bes p atie nt dis p ositi o n f or b ot h patie nt st u d y stat us a n d t he patie nt a nal ysis 
p o p ulati o ns. 
Scree ne d p atie nts ar e defi ne d as all patie nts w h o si g ne d t he i nf or me d c o ns e nt.   
Ra n d o mize d patie nts c o nsist of all patie nts wit h a si g ne d i nf or me d c o nse nt f or m w h o ha ve h a d a 
treat me nt kit n u m ber all o cate d a n d rec or de d i n t he I R T dat a base, re gar dless of w het her t h e 
treat me nt kit was use d or not. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 2  of 9 9  
 
F or patie nt st u d y stat us, t he t otal n u m ber of patie nts i n eac h of t he f oll o wi n g cate g ories will be 
prese nte d i n t he cli nical st u d y re p ort usi n g a fl o wc hart dia gra m or s u m mar y ta bles:  
•  Scree ne d p atie nts  
•  R u n i n patie nts: patie nts w h o ha d a r u n-i n rec or d i n I R T  
•  Scree n f ail ure patie nts (i ncl u di n g fail ures  d uri n g r u n-i n) a n d reas o ns f or s cree n fail ure 
(see A p p e n di x A  f or details o n t he ma p pi n g of i ncl usi o n a n d e x cl usi o n criteria u n der t he 
ori gi nal pr ot o c ol a n d A m e n d me nt 1) 
•  N o nra n d o mize d b ut treat e d patie nts 
•  Ra n d o mize d patie nts 
•  Ra n d o mize d b ut n ot treate d patie nts 
•  Ra n d o mize d a n d treate d patie nts 
•  Patie nts w h o ha ve c o m pl ete d t he 2 6- w ee k d o u ble- bli n d c ore treat me nt peri o d 
(see Secti o n  2. 5. 4 ) as per pr ot oc ol 
•  Patie nts w h o di d n ot c o m plete t he 2 6- wee k d o u ble- bli n d c ore treat me nt peri o d 
(see Secti o n  2. 5. 4 ) as per pr ot oc ol a n d t he reas o ns f or per ma n e nt treat me nt disc o nti n uati o n 
•  Patie nts w h o ha ve c o m pl ete d t he 7 9- w ee k d o u ble- bli n d e ntire treat me nt peri o d  as per 
pr ot oc ol ( d o u ble- bli n d c ore treat me nt peri o d a n d e xte nsi o n treat me nt peri o d)  
•  Patie nts w h o di d n ot c o m plete t he 7 9- wee k d o u ble- bli n d e ntire treat me nt  p eri o d as per 
pr ot oc ol, a n d t he r eas o ns f or per ma n e nt treat me nt disc o nti n uati o n  
•  Patie nts w h o ha ve c o m pl ete d t he st u d y as per pr ot oc ol 
•  Patie nts w h o  di d n ot c o m plete t he st u d y as per pr ot oc ol a n d t he reas o ns f or st u d y 
disc o nti n uati o n 
•  Patie nts’ e n d of st u d y stat us (c o m plete d, n ot c o m plete d) a n d c orres p o n di n g e n d of e ntire 
treat me nt stat us (c o m plet e d, n ot c o m plete d)  
•  Stat us at last st u d y c o ntact . 
F or scree n e d, r u n-i n, scree n fail ure, a n d n o nra n d o mize d b ut treate d patie nts, perce nt a ges will be 
calc ulate d usi n g t he n u m ber of scree n e d patie nts as t he de n o mi nat or. All ot her cat e g ories of 
patie nts will be prese nte d b y treat me nt gr o u p a n d t he pe rce nta ges will be calc ulate d usi n g t he 
n u m ber of ra n d o mize d patie nts wit hi n eac h treat me nt gr o u p as t he de n o mi nat or.  Reas o ns f or 
treat me nt disc o nti n uati o n will be s u p plie d i n ta bles gi vi n g n u m bers a n d p erce nta ges b y treat me nt 
gr o u p.  Patie nts pr e mat ur el y disc o nti n ue d fr o m treat me nt a n d/ or st u d y, al o n g wit h reas o ns f or 
disc o nti n uati o n, will als o be liste d.  
A s u m mar y of t he distri b uti o n of patie nts b y c o u ntr y a n d ce nt er will als o be pr o vi de d ( o verall 
n u m ber of patie nts scr ee ne d, r u n-i n, ra n d o mize d, a n d trea te d, as well as n u m ber of patie nts 
ra n d o mize d, disc o nti n ue d fr o m st u d y treat me nt, a n d disc o nti n ue d fr o m st u d y f or eac h treat me nt 
gr o u p).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 3  of 9 9  
 
Patie nts treate d b ut n ot ra n d o mize d, patie nts ra n d o mize d b ut n ot treate d a n d patie nts ra n d o mize d 
b ut n ot treate d as r a n d o mize d will be i de ntifie d a n d descri be d i n se p arat e listi n gs. T he patie nts of 
t he t hir d cate g or y (ra n d o mize d a n d n ot treate d as ra n d o mize d) will be part of efficac y a n d safet y 
a nal ys es (Secti o n  2. 3 ). P atie nts ra n d o mize d b ut n ot treate d will be i ncl u de d i n efficac y a n al ysis. 
Safet y d ata of p atie nts treate d b ut n ot ra n d o mize d will be re p orte d se p aratel y . 
T he ra n d o mizati o n strata [ H b A 1c at Scree ni n g ( ≤8. 0 %, > 8. 0 %) a n d mea n S B P ( < 1 3 0, 
≥1 3 0 m m H g)] assi g n e d b y I R T will be s u m marize d. T he perce nta ges will be calc ul ate d usi n g t h e 
n u m ber of ra n d o mize d patie nts as t he de n o mi nat or. T he discre pa nc y b et wee n t he strata assi g n e d 
b y I R T a n d t he i nf or mati o n re p orte d o n e C R F will be liste d f or all ra n d o mi ze d patie nts. 
Ka pla n -Mei er ( K M ) pl ots of t he c u m ulati ve i nci d e nce of d o u bl e- bli n d I M P disc o nti n uati o n d ue t o 
a n y reas o n a n d d ue t o A E will be pr o vi de d f or t h e e ntire 7 9-wee k d o u bl e- bli n d treat me nt peri o d 
se parat el y (see Secti o n  2. 5. 4 ). A listi n g of t hese p atie nts, al o n g wit h t he reas o n f or disc o nti n uati o n 
treat me nt, st u d y c o m pleti o n stat us a n d t he reas o n f or disc o nti n uati o n st u d y, will be pr o vi de d.  
F or A B P M s u b-st u d y, t h e n u m ber of p atie nts i n eac h of t he f oll o wi n g cate g ories will be 
s u m marize d.  
•  Patie nts w h o c o nse nte d t o A B P M s u b st u d y  
•  Patie nt s n ot e nteri n g A B P M s u bst u d y a n d t he reas o n f or n ot e nteri n g  
•  Patie nt s w h o ra n d o mize d a n d e ntere d A B P M s u bst u d y (ie, A B P M s u bst u d y p o p ulati o n, 
see Secti o n  2. 3. 1. 2 ) 
•  Patie nts w h o c o m plete d A B P M s u bst u d y  
•  Patie nts w h o disc o nti n ue d A B P M s u bst u d y a n d t he reas o n f or disc o nti n uati o n: 
- 
A d verse E v e nt  
- 
St u d y Ter mi nate d b y S p o ns or 
- 
At patie nt’s o w n re q u est 
- 
L ost t o f oll o w- u p 
- 
P o or c o m plia nce t o Pr ot oc ol 
- 
Ot her  
•  Patie nts wit h g o o d q ualit y  (s ee A p p e n di x C ) A B P M meas ure me nts at eit her 
Visit  7 A/ Wee k 1 2, or Visit 9 A/ Wee k 2 6 or b ot h visits. 
F or patie nts w h o c o nse nt e d b ut di d n ot e nteri n g A B P M s u bst u d y , perce nt a ges will be calc ulat e d 
usi n g t he n u m ber of patie nts c o nse nte d t o s u bst u d y as t he d e n o mi nat or. All ot her cate g ories of 
patie nts will be prese nte d b y treat me nt gr o u p a n d t he perce nta ges will be calc ulate d usi n g t he 
n u m ber of patie nts r a n d o mize d a n d e ntere d s u bst u d y wit hi n eac h treat me nt gr o u p as t he 
de n o mi nat or.  Reas o ns f or A B P M s u bst u d y dis c o nti n uati o n will be s u p plie d i n ta bles gi vi n g 
n u m bers a n d perce nta ges b y treat me nt gr o u p. Pati e nts pre mat urel y disc o nti n ue d t he s u bst u d y, 
al o n g wit h r eas o ns f o r disc o nti n uati o n, will als o be liste d. Patie nts w h o c o nse nte d b ut di d n ot 
e nter A B P M s u bst u d y, al o n g wit h r eas o ns f or n ot e nteri n g, will als o be prese nte d .  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 4  of 9 9  
 
All i m p orta nt de viati o ns i ncl u di n g ra n d o mizati o n a n d dr u g -dis pe nsi n g irre g ularities will be 
s u m marize d i n ta bles gi vi n g n u m bers a n d perce nt a ges of de vi ati o ns b y ra n d o mize d treat me nt 
gr o u p. 
A d diti o nall y, t he a n al ysis p o p ulati o ns f or safet y, efficac y, A B P M s u bst u d y, a n d p h ar mac o ki netics 
defi ne d i n Secti o n  2. 3  will be s u m marize d i n a ta ble b y n u m ber of patie nts i n t he ra n d o mize d 
p o p ulati o n.  
•  Efficac y p o p ulati o n: i nte nt- t o-treat (I T T) p o p ulati o n  
•  Efficac y p o p ulati o n f or s u bst u d y: A B P M s u bst u d y p o p ulati o n 
•  Safet y p o p ulati o n 
•  P K p o p ulati o n. 
2. 2. 1  R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s  
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities occ ur w h e ne ver: 
1.  A ra n d o mizati o n is n ot i n acc or d a nce wit h t he pr ot oc ol- defi ne d ra n d o mizati o n met h o d, 
s uc h as a) a n i neli gi ble p atie nt is ra n d o mize d, b) a patie nt is ra n d o mize d base d o n a n 
i nc orrect strat u m, or c) a patie nt is ra n d o mize d t wice , or d) i n a d y na mic ra n d o mizati o n 
sc he me t he tr eat me nt assi g n me nt is, i n fact, n ot ra n d o m, d ue t o a c o m p uter pr o gra m 
err or.   
 
O R  
2.  A patie nt is dis pe nse d a n I M P kit n ot all ocate d b y t he pr ot oc ol- defi n e d ra n d o mizati o n, 
s uc h as a) a patie nt at a n y ti me i n t he st u d y is dis pe nse d a differe nt treat m e nt kit t ha n as 
ra n d o mize d ( w hic h ma y or ma y n ot c o ntai n t he c orrect -as-ra nd o mize d I M P), 
or b) a n o nr a n d o mize d patie nt is treate d wit h I M P reser v e d f or ra n d o mize d patie nts. 
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities will be m o nit ore d t hr o u g h o ut t he st u d y a n d 
re vie we d o n a n o n g oi n g basis.  
All ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ulariti es will be d oc u me nte d i n t he cli nical st u d y 
re p ort.  If t h e n u m ber of irre g ularities is lar ge e n o u g h t o ma ke a ta b ular s u m mar y us ef ul, t he 
irre g ularities will be cate g orize d a n d s u m marize d a m o n g ra n d o mize d patie nts ( n u m ber a n d 
perce nt a ges).  N o nra n d o mize d, treate d patie nts will be descri be d se p arat el y.  Listi n gs wit h 
a d diti o nal, rele va nt det ails will be pr o vi de d i n a n a p pe n di x.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 5  of 9 9  
 
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities t o be pr os pecti vel y i de ntifie d i ncl u de b ut are 
n ot li mite d t o:  
 
R a n d o mi z ati o n a n d dr u g all o c ati o n irr e g ul ariti e s  
Kit dis p e ns ati o n wit h o ut I R T tr a ns acti o n  
Err o n e o us kit dis p e ns ati o n  
Kit n ot av ail a bl e  
R a n d o miz ati o n by err or  
P ati e nt r a n d o miz e d t wic e  
Str atific ati o n err or  
P ati e nt s witc h e d t o a n ot h er sit e  
2. 3  
A N A L Y SI S P O P U L A TI O N S  
Patie nts treate d wit h o ut bei n g r a n d o mize d will n ot be c o nsi dere d ra n d o mize d a n d will n ot be 
i ncl u de d i n a n y efficac y p o p ulati o n.  
T he ra n d o mize d p o p ulati o n i ncl u des a n y patie nt w h o has bee n all ocate d t o a ra n d o mize d 
treat me nt re gar dless of w het her t he treat me nt kit was use d. 
F or a n y p atie nt ra n d o mize d m ore t ha n o nce, o nl y t he data ass o ciate d wit h t he first ra n d o mizati o n 
will be use d i n a n y a nal ysis p o p ulati o n.  T he safet y e x perie n ce ass o ciate d wit h a n y lat er 
ra n d o mizati o n will be assesse d se paratel y. 
T he safet y e x perie nce of patie nts treate d a n d n ot ra n d o mize d will be re p ort e d se paratel y, a n d 
t hese patie nts will n ot be i n t he safet y p o p ulati o n. 
2. 3. 1  Effi c a c y p o p ul ati o n s   
Efficac y a nal ys es will be base d o n t he treat me nt gr o u p all ocate d b y t he I R T acc or di n g t o t he 
ra n d o mizati o n sc he d ule at ra n d o mizati o n visit (as ra n d o mize d), irres pecti ve of t he treat me nt 
act uall y recei ve d . 
2. 3. 1. 1  I T T p o p ul ati o n 
Efficac y a nal ys es will be base d o n t he I T T p o p ul ati o n, defi ne d as all ra n d o mize d patie nts, 
irres pecti ve of c o m plia nce wit h t he st u d y pr ot o c ol a n d pr oce d ures. Patie nts will be a nal yze d f or 
efficac y acc or di n g t o t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 6  of 9 9  
 
2. 3. 1. 2  A B P M s u b st u d y p o p ul ati o n  
A B P M effi cac y a nal ysis will be base d o n A B P M s u bst u d y p o p ulati o n w hic h defi ne d as all 
ra n d o mize d patie nts ha vi n g: 
1.  si g ne d t he i nf or me d c o ns e nt f or A B P M s u bst u d y 
2.  Eli gi ble scr ee ni n g S B P  ≥1 3 0 m m H g  
3.  B aseli ne A B P M meas ure me nt at Visit 3 A wit h G o o d Q ualit y ( s ee A p p e n di x D ) 
4.  At least o ne p ost- baseli n e A B P M visit rec or di n g .  
2. 3. 2  S af et y p o p ul ati o n  
Safet y a nal yses will be base d o n t he safet y p o p ulati o n, defi ne d as all ra n d o mize d patie nts w h o 
recei v e at least o ne d os e o f d o u ble- bli n d I M P  (re gar dless of t he a m o u nt of treat me nt 
a d mi nistere d) . Patie nts will be a nal yze d acc or di n g t o t he treat me nt act u all y recei v e d.  
I n a d diti o n:  
•  N o nra n d o mize d b ut treat e d patie nts will n ot be part of t he safet y p o p ul ati o n; h o we ver, 
t heir safet y dat a will be prese nte d se p aratel y 
•  Ra n d o mize d patie nts f or w h o m it is u nclear w het h er t he y t o o k t he I M P will be i ncl u de d i n 
t he safet y p o p ulati o n as r a n d o mize d 
•  W he n a patie nt is e x p ose d t o b ot h s ota glifl ozi n a n d place b o, t he p atie nt will be a nal yz e d i n 
t he s ota glifl ozi n gr o u p  
•  Ra n d o mize d patie nts will be e x cl u de d fr o m t he safet y p o p ulati o n o nl y if t here is 
d oc u me nte d e vi de n ce (i e, all st u d y dates rec or de d as n o me dicati o n ta ke n) t hat patie nts 
ha ve n ot ta ke n t he st u d y treat me nt. If a patie nt is dis pe nse d d o u ble- bli n d I M P a n d is l ost t o 
f oll o w- u p wit h o ut a n y d o c u me nte d e vi de n ce, t he p atie nt will be c o nsi dere d e x p ose d. 
2. 3. 3  P K p o p ul ati o n  
F or P K a n al ys es, t he P K p o p ulati o n is defi ne d as all safet y p atie nts  w h o c o ntri b ute wit h at least 
1 vali d plas ma c o nce ntrati o n of s ota glifl ozi n  or its 3 - O-gl uc ur o ni d e meta b olite . P K data will be 
a nal yze d acc or di n g t o t he treat me nt act uall y recei ve d.  
2. 4  
S T A TI S TI C A L M E T H O D S  
Descri pti ve statistics ( n u m ber, mea n, sta n d ar d de viati o n ( S D), me dia n, mi ni m u m, a n d ma xi m u m) 
will be prese nte d f or c o nti n u o us varia ble b y  treat me nt gr o u p.  T he n u m ber a n d perce nt a ge of 
patie nts i n eac h cate g or y will be prese nte d f or cate g orical vari a bles b y treat me nt gr o u p.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 7  of 9 9  
 
2. 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  
Para meters will be s u m m arize d i n t he ra n d o mize d p o p ulati o n a nal yze d i n t h e treat me nt gr o u p t o 
w hic h t he y were r a n d o mize d. A nal yses f or t he s afet y p o p ulati o n will be i ncl u de d i n t he 
a p pe n dices if t h e size of t he safet y p o p ulati o n is differe nt ( > 1 0 %) fr o m t he size of t hat i n t he 
pri mar y a nal ysis p o p ulati o n f or a n y treat me nt gr o u p. 
Para meters d escri be d i n  Secti o n  2. 1. 1  will be s u m marize d b y treat me nt gr o u p a n d o verall ( p o ol e d 
acr oss treat me nt gr o u ps) gr o u ps usi n g des cri pti ve statistics.   
De m o gra p hic a n d diseas e c har acter istics will be s u m marize d f or A B P M s u bst u d y p o p ulati o n b y 
treat me nt gr o u p a n d o v er all ( p o ole d acr oss treat m e nt gr o u ps) gr o u ps usi n g descri pti ve statistics.  
P- val ues o n t he treat me nt differe n ce f or de m o gra p hic a n d baseli ne c haracteristic data will n ot be 
calc ulate d.  
I n ge ner al, n o s pecifi c descri pti o n of t he safet y p ara meters will be pr o vi de d at baseli ne.  If 
rele va nt, t he b aseli ne val ues will be descri be d al o n g wit h eac h safet y a n al ysis. 
I n ge ner al, n o s pecifi c descri pti o n of t he effi cac y para meters will be pr o vi de d at baseli ne.  If 
rele va nt, t he b aseli ne val ues will be descri be d al o n g wit h eac h efficac y a n al ysis. 
2. 4. 2  Pri or or c o n c o mit a nt m e di c ati o n s  
T he pri or, c o n c o mita nt a n d p osttreat me nt me dicati o ns will be prese nte d i n t he ra n d o mize d 
p o p ulati o n f or eac h treat me nt gr o u p (a n d o verall f or t he s u m mar y of pri or me dicati o ns), usi n g 
c o u nts a n d per ce nta ges. N o statistical test f or t he bet wee n - gr o u p differe n ce will be perf or me d. 
Me dicati o ns will be s u m marize d b y treat me nt gr o u p acc or di n g t o t he W H O - D D dicti o nar y, 
c o nsi deri n g t he first di git of t he A n at o mical T h era pe utic C he mical  ( A T C) class (a nat o mic 
cate g or y) a n d t he first 3 di gits of t he A T C class (t hera pe utic cate g or y).  A gi ve n me di cati o n ma y 
be classifie d i n m ore t h a n 1 A T C class.  All A T C c o des c orres p o n di n g t o a me dicati o n will be 
s u m marize d, a n d a patie nt will be c o u nte d o nce wit hi n eac h A T C cate g or y (a nat o mic or 
t hera pe utic) li n ke d t o t he me dicati o n. T heref ore a patie nt ma y b e c o u nte d s e veral ti mes f or t he 
sa me me dicati o n.  
Pri o r me dicati o ns will be prese nte d b y a nat o mic a n d t hera pe utic cate g ori es a n d s orte d b y 
decreasi n g fr e q ue nc y of A T C base d o n t he o verall i nci de nce acr oss treat me nt gr o u ps.  I n case of 
e q ual fr e q ue nc y re gar di n g A T Cs ( a nat o mic or t hera pe utic cate g ories), al p h a betical or d er will be 
use d. 
C o nc o mita nt a n d p osttreat me nt me dicati o ns will be ta b ulate d b y a n at o mic a n d t hera p e utic 
cate g ories a n d s orte d b y decreasi n g fre q ue nc y i n t he s ota glifl ozi n gr o u p. I n case of e q ual 
fre q ue n c y re gar di n g A T Cs (a nat o mic or t hera pe utic cate g ories), al p ha b etical or der will be use d.  
Pri or a n d c o nc o mita nt m e dicati o ns will als o be prese nte d f or t h e A B P M s u bst u d y p o p ulati o n f or 
eac h tr eat me nt gr o u p, usi n g c o u nts a n d perce nta ges.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 8  of 9 9  
 
2. 4. 3  E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pl i a n c e  
T he e xte nt of I M P e x p os ure a n d c o m plia n ce will be assesse d a n d s u m mari ze d b y act ual treat me nt 
wit hi n t he safet y p o p ulati o n ( Secti o n  2. 3. 2 ) a n d A B P M s u bst u d y p o p ulati o n (see Secti o n  2. 3. 1. 2 ).  
2. 4. 3. 1  E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e  
T he e xte nt of I M P e x p os ure will be assess e d b y t he d urati o n of I M P e x p os ure. 
D urati o n of I M P e x p os ure is defi ne d as  
( Date of l ast d o u ble-bli n d I M P  d ose) – (date of first d o u ble- bli n d I M P  d ose) + 1 da y, 
re gar dl ess of u n pla n ne d i nt er mitte nt disc o nti n uati o ns (see  Secti o n  2. 5. 3  f or calc ulati o n i n cas e of 
missi n g or i nc o m plete data).  
D urati o n of I M P e x p os ure will be s u m marize d descri pti vel y as a q ua ntitati v e varia ble ( n u m ber  of 
patie nts e x p ose d , mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m).  I n a d diti o n, d urati o n of 
treat me nt e x p os ure will als o be s u m marize d cate g oricall y b y n u m b ers a n d perce nt a ges f or eac h of 
t he f oll o wi n g cate g ori es a n d c u m ulati vel y acc or di n g t o t hese cate g ories:  
•  1 t o 2 8 da ys 
•  2 9 t o 5 6 da ys 
•  5 7 t o 8 4 da ys 
•  8 5 t o 1 2 6 da ys  
•  1 2 7 t o 1 8 2 da ys 
•  1 8 3 t o 3 6 4 da ys  
•  3 6 5 t o 5 5 1 da ys 
•  > 5 5 1 da ys  
A d diti o nall y, t he c u m ulati ve d urati o n of treat me nt e x p os ure will be pr o vi de d, defi ne d as t he s u m 
of t he d urati o n of tr eat me nt e x p os ure f or all patie nts, a n d will be e x presse d i n patie nt years. 
N u m ber a n d p erce nta ge of patie nts b y fi nal d ose at t he e n d of t he treat me nt will als o be prese nte d 
b y eac h tr eat me nt gr o u p.  
2. 4. 3. 2  C o m pli a n c e  
A gi ve n a d mi nistrati o n will be c o nsi dere d n o nc o m plia nt if t he patie nt di d n ot ta ke t he pla n ne d 
d ose of treat me nt as re q uire d b y t h e pr ot oc ol. N o i m p utati o n will be ma de f or patie nts wit h 
missi n g or i nc o m plete data.  
Perce nta ge of c o m plia n ce f or  a p atie nt will be defi ne d as t he n u m ber of d a ys t hat t he patie nt w as 
c o m plia nt di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was pla n ne d t o ta ke d uri n g t he 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 3 9  of 9 9  
 
treat me nt e p oc h d efi ne d i n Secti o n  2. 1. 4  (ie, fr o m t he first date t o t he last d ate of d o u ble- bli n d 
I M P a d mi nistrati o n).  
A b o ve- pla n ne d d osi n g p erce nt a ge f or a patie nt will be defi ne d as t he n u m b er of da ys t hat t he 
patie nt t o o k a hi g h er d os e t ha n pla n ne d di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was 
pla n ne d t o ta ke d uri n g t h e treat me nt e p o c h.  
U n der- pla n n e d d osi n g perce nta ge f or a patie nt will be defi ne d as t h e n u m ber of da ys t hat t he 
patie nt t o o k a l o wer d ose t ha n pla n ne d di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was 
pla n ne d t o ta ke d uri n g t h e treat me nt e p o c h.  
Treat me nt c o m plia nce, a b o ve- pla n ne d, a n d u n der- pla n ne d d osi n g perce nta ges will be s u m marize d 
descri pti vel y as q ua ntitati ve varia bles ( n u m b er, m ea n, S D, me dia n, mi ni m u m, a n d ma xi m u m). 
T he per ce nta ge of patie nts w h ose c o m plia nce is < 8 0 % will be s u m marize d. I n a d diti o n, n u m bers 
a n d perce nta ges of patie nts wit h at least 1 da y a b o ve- pla n ne d d os e will be pr o vi de d, as well as 
n u m bers a n d perce nta ges of patie nts wit h ( 0, 2 0 %], a n d > 2 0 % of d a ys u n der- pla n ne d d os e. 
Cases of o ver d os e (see st u d y pr ot o c ol f or f urt her d etails) will c o nstit ute A Es / S A Es a n d will be 
a nal yze d as s uc h. M or e ge nerall y, d osi n g irre g ularities will be liste d i n  Secti o n  2. 2. 1 . 
2. 4. 4  A n al y s e s of effi c a c y e n d p oi nt s  
Efficac y a nal ys es will be perf or me d o n t he I T T p o p ulati o n usi n g effi cac y assess me nt c ollecte d 
d uri n g t he st u d y, i ncl u di n g t h ose o btai ne d after I M P disc o nti n uati o n or i ntr o d ucti o n of resc u e 
t hera p y, u nless ot her wise s pecifie d. 
Statistical testi n g will be perf or me d f or pri mar y e n d p oi nt a n d s o me sec o n dar y e n d p oi nts at 
Wee k  2 6 ( or Wee k 1 2 f or S B P) as s pecifie d i n t he f oll o wi n g s u bsecti o ns. All efficac y varia bl es 
after Wee k 2 6 will o nl y be s u m marize d b y d escri pti ve statistics wit h o ut f or mal statistical testi n g.  
Missi n g data f or efficac y a nal ys es is i de ntifie d t hr o u g h ste ps des cri be d i n S e cti o n 2. 5. 4 . 
2. 4. 4. 1  A n al y si s of pri m ar y effi c a c y e n d p oi nt( s)  
T he statistical test will be t w o -si de d at a n o mi nal 5 % si g nifica nce l e vel. 
Pri m ar y a n al ysis 
T he pri mar y efficac y e n d p oi nt c ha n ge i n H b A 1c fr o m baseli ne t o Wee k 2 6 will be a nal yze d b y a n 
A N C O V A m o del usi n g H b A 1c val ues m eas ure d at baseli ne a n d Wee k 2 6 ( o bser ve d or i m p ute d). 
T he missi n g data at e n d p oi nt will be i m p ute d b y m ulti ple i m p utati o n ( MI) m et h o ds i n 2 parts as 
detaile d bel o w. T o be c o ncise, t he f oll o wi n g te xts relate d t o i m p utati o n are ge n eralize d t o 
acc o m m o date pri mar y as well as c o nti n u o us sec o n dar y efficac y e n d p oi nts.  
1.  Missi n g e n d p oi nt data f or patie nts w h o pre mat urel y disc o nti n ue t he I M P b ef ore t h e 
Wee k  2 6 ( or Wee k 1 2 f or S B P) visit will be i m p ute d usi n g a m o del b uilt s e parat el y i n 
eac h tr eat me nt gr o u p a n d esti mate d fr o m t he patie nts i n t he sa me treat me nt gr o u p w h o 
pre mat urel y disc o nti n ue t he I M P bef ore t he Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha ve 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 0  of 9 9  
 
t he meas ure m e nt f or t he e n d p oi nt (retrie v e d dr o p o uts). C o nsi deri n g t hat t he n u m ber of 
patie nts i n eac h tr eat me nt gr o u p w h o disc o nti n ue t he I M P b ut ha ve t he meas ure me nt f or 
t he e n d p oi nt is e x pecte d t o be s mall, a si m ple i m p utati o n m o del base d o n re gressi o n will 
be use d wit h baseli ne meas ure me nt i ncl u de d as t he pre dict or. E ac h treat me nt gr o u p will 
ha ve t heir o w n i m p utati o n m o del. 
2.  Missi n g e n d p oi nt data f or all patie nts w h o sta y o n t he I M P u ntil t he Wee k 2 6 ( or Wee k 1 2 
f or S B P) visit, i ncl u di n g t h ose i n t he s ota glifl ozi n 4 0 0 m g gr o u p, will be i m p ute d 
se parat el y. T h e was h- o ut i m p utati o n met h o d will be use d, w here missi n g e n d p oi nt data i n 
t he s ota glifl ozi n 4 0 0 m g gr o u p, as well as i n t he place b o gr o u p are i m p ute d fr o m a m o del 
esti mate d fr o m patie nt s i n t he place b o gr o u p w h o sta y o n t he I M P u ntil t he Wee k 2 6 ( or 
Wee k 1 2 f or S B P) visit a n d ha ve t he e n d p oi nt dat a a vaila ble. T h e i m p utati o n m o del will 
i ncl u de t he ra n d o mizati o n strata a n d t he c orres p o n di n g bas eli ne val ue. Missi n g data will 
be i m p ute d usi n g t he r e gr essi o n met h o d. 
A n alter nati ve ( bac k - u p) i m p utati o n met h o d will be use d if t he n u m ber of p atie nts w h o 
pre mat urel y disc o nti n ue t he I M P bef ore t he Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha ve t he 
meas ure me nt f or t he e n d p oi nt is < 5 i n a n y treat me nt gr o u ps (ie, n ot s uffici e nt retrie v e d dr o p o uts 
t o s u p p ort t he i m p utati o n met h o d descri be d a b o ve). T his criteri o n will be assesse d f or eac h 
pri mar y or c o nti n u o us sec o n dar y efficac y e n d p oi nt se paratel y.  
I n t he b ac k- u p i m p utati o n met h o d, missi n g p ost-baseli ne v al ues will be i m p ute d b y c o ntr ol- base d 
c o p y ref ere n ce MI m et h o d u n der t he missi n g n ot at ra n d o m ( M N A R ) fra me w or k. 
•  F or place b o patie nts, missi n g data will be i m p ute d base d o n t he place b o gr o u p data, 
•  F o r patie nts i n t he s ota glifl ozi n 4 0 0 m g gr o u p, missi n g data will be i m p ute d as if t he 
patie nts were o n pl ace b o t hr o u g h o ut t he st u d y , w h ere all patie nts’ m eas ure me nts i ncl u di n g 
t he o n-treat me nt meas ure me nts will be c o nsi dere d as if t he meas ure me nts w ere fr o m t he 
place b o gr o u p i n t he i m p utati o n m o del. 
Usi n g eit her i m p utati o n met h o d, missi n g e n d p oi nt data will be i m p ute d m ulti ple ti mes t o ge nerat e 
m ulti ple data sets wit h c o m plete data (see sa m ple c o de Part 1a or Part 2a of A p pe n di x B ). T he 
c ha n ge fr o m baseli ne t o Wee k 2 6 will be deri ve d fr o m o bser ve d a n d i m p ute d H b A 1c v al ues at 
Wee k 2 6. Eac h of t h e c o m plete d datasets aft er t he i m p utati o n will be a nal yze d usi n g t he 
A N C O V A m o de l wit h t he treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, place b o), ra n d o mizati o n 
strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), ra n d o mizati o n strat u m of S B P ( < 1 3 0, ≥1 3 0 m m H g), a n d 
c o u ntr y as fi x e d fact ors, a n d baseli ne H b A 1c val u e as a c o v ariat e (see sa m ple c o de Part 4 of 
A p pe n di x B ). T he r es ults fr o m eac h a nal ysis will be c o m bi ne d usi n g R u bi n’s f or m ula, t o pr o vi de 
t he a dj uste d mea n c h a n ge i n H b A 1c fr o m Baseli ne t o Wee k 2 6 f or eac h treat ment gr o u p, as well 
as its bet wee n - gr o u p diff ere nce ( c o m pari n g s ota glifl ozi n 4 0 0 m g vs place b o) a n d t he 
c orres p o n di n g 9 5 % c o nfi de nce i nter v al ( CI ) f or t h e differe nce(see sa m ple c o de Part 5 of 
A p pe n di x B ).  
Se nsiti vit y a n al yses 
Ti p pi n g p oi nt a nal ysis base d o n t he sa me MI met h o d as a p plie d t o t he pri m ar y a nal ysis will be 
perf or me d t o e x a mi ne t he r o b ust ness of t he res ults fr o m t he pri mar y a n al ysis. Patie nts w h o were 
ra n d o mize d t o s ota glifl ozi n 4 0 0 m g gr o u p a n d h a d n o H b A 1c data at Wee k 2 6 will be gi ve n a 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 1  of 9 9  
 
pe nalt y. T h e pe n alt y will be gra d uall y i ncreas e d t o e val uate a t w hic h le vel t he c o ncl usi o n of t he 
a nal ys es i n ter ms of statistical si g nifica n ce is c h a n ge d. T h e ti p pi n g p oi nt is t he pe nalt y l e vel, at 
w hic h t he ma g nit u de of efficac y re d u cti o n i n patie nts wit h o ut H b A 1c data at Wee k 2 6 creat es a 
s hift i n t he treat me nt eff ect of s ota glifl ozi n 4 0 0 m g fr o m bei n g statisticall y si g nifica ntl y better 
t ha n place b o t o a n o n-statisticall y si g nifica nt effect. L S mea n differe nce b et wee n s ota glifl ozi n 
4 0 0 m g a n d place b o a n d its ass ociate d p- val ue will be pr o vi de d f or eac h p e nalt y le v el. T he ste ps 
t o perf or m t he ti p pi n g p oi nt a nal ysis are as f oll o ws: 
1.  Missi n g data will be i m p ute d usi n g t he sa m e MI met h o d as a p plie d t o t he pri mar y a nal ysis  
(see sa m ple c o de Part 3 i n A p pe n di x B ), 
2.  T he i m p ute d H b A 1c val u e at Wee k 2 6 i n t he s ota glifl ozi n 4 0 0 m g gr o u p will be pe nalize d  
b y a d di n g a pe nalt y δ ( e g, δ = 0. 1 %) i n eac h c o m plete dataset (s ee sa m ple c o de Part 3 i n 
A p pe n di x B ), 
3.  C ha n ge fr o m Baseli ne  at Wee k 2 6 i n H b A 1c will be a nal yz e d usi n g t h e sa me A N C O V A 
m o del as s pecifie d i n t he pri mar y a nal ysis i n eac h c o m plete dataset (s ee s a m ple c o de 
Part  4 i n A p pe n di x B ),  
4.  Res ults will be c o m bi ne d acr oss c o m plete d atasets usi n g R u bi n’s r ule (s ee s a m ple c o de 
Part 5 i n A p pe n di x B ), 
5.  Ste ps 2 t o 4 will be re peate d wit h i ncre me ntal pe n alt y at δ (ie, δ, 2 δ, 3 δ, etc) u ntil t he  
p- val ue f or treat me nt eff ect of s ota glifl ozi n 4 0 0 m g c o m pare d t o place b o esti mate d i n 
Ste p  4 is > 0. 0 5. 
T he ti p pi n g p oi nt a nal ysis will be perf or me d o nl y if t he pri mar y varia ble (C ha n ge fr o m Bas eli ne 
t o Wee k 2 6 i n H b A 1c) is statisticall y si g nifica nt at α = 0. 0 5 ( 2-si de d). 
If t he retrie ve d dr o p o ut i m p utati o n is a p plie d t o t he pri mar y a n al ysis, t he a nal ysis bas e d o n t he 
c o ntr ol- base d i m p utati o n (ie, t he bac k u p i m p utati o n met h o d) will be prese nte d as a se nsiti vit y 
a nal ysis.  
Assess me nt of tre at me nt eff ect b y s u b gr o u p  
Descri pti ve a n al ys es will be perf or me d o n t he pri mar y e n d p oi nt t o s u m marize t he treat me nt 
effects acr oss s u b gr o u ps defi ne d b y t he f oll o wi n g Basel i ne or Scree ni n g fact ors: 
•  Race ( W hite, Blac k or Africa n A m erica n, Asia n, Ot her ) (a n y race gr o u ps wit h fe wer t h a n 
5 patie nts ma y b e c o m bi ne d wit h “ Ot her” cat e g or y as a p pr o priat e),   
•  Et h nicit y ( His pa nic, N ot His pa nic), 
•  A ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 years) ( a n y cate g or y wit h fe wer t ha n 5 p atie nts ma y b e 
c o m bi ne d wit h a n ot her cate g or y as a p pr o priat e), 
•  Ge n der ( Male, Fe male),  
•  Baseli ne B MI le v el ( < 3 0, ≥3 0 k g/ m²), 
•  Baseli ne H b A 1c ( ≤8. 0 %, > 8. 0 %), 
•  Baseli ne H b A 1c ( ≤8. 5 %, > 8. 5 %), 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 2  of 9 9  
 
•  Baseli ne m ea n S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g ), 
•  Baseli ne e G F R ( ≥3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m2 [ M o derate d ecrease i n G F R], ≥6 0 t o 
< 9 0  m L/ mi n/ 1. 7 3 m2 [ Mil d decrease i n G F R], a n d ≥9 0 m L/ mi n/ 1. 7 3 m2 [ N or mal]), 
•  D urati o n of dia bet es ( < 1 0, ≥1 0 years), 
•  C o u ntr y. 
T he treat me nt effects acr oss t he s u b gr o u ps d efi ne d a b o ve will be esti mate d f or t he C ha n ge fr o m 
Baseli ne t o Wee k 2 6 i n H b A 1c i n t he I T T p o p ulati o n usi n g t he sa me MI met h o d as a p plie d t o t he 
pri mar y a nal ysis . T he A N C O V A m o del will i ncl u de treat me nt (s ota glifl o zi n 4 0 0 m g , place b o), 
ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), ra n d o mizati o n strat u m of S B P ( < 1 3 0, 
≥1 3 0 m m H g), s u b gr o u p f act or, treat me nt-b y -s u b gr o u p fact or, a n d c o u ntr y as fi x e d fact ors a n d  
baseli ne H b A 1 c as a c o v ariate  (s ee sa m ple c o de P art 4 of A p pe n di x B ). T h e a dj uste d esti mates of 
treat me nt mea n differ e nces (s ota glifl ozi n 4 0 0 m g vers us place b o) wit h sta n dar d err or (S E ) a n d 
9 5 % CIs will be pr o vi de d as a p pr o priat e acr oss t he s u b gr o u ps. A gra p hi cal prese ntat i o n of t he 
res ults (ie, f or est pl ot) will als o be pr o vi de d.  
I n t he cas e t hat t he s u b gr o u p fact or is i de ntical or si milar t o a ra n d o mizati o n strata fact or 
(e g, baseli ne H b A 1c or b aseli ne mea n S B P cate g or y),  o nl y t h e s u b gr o u p v aria ble (as si n gl e fact or 
or a n i nteracti o n ter m ) will be i ncl u de d i n t he m o del i n or der t o a v oi d t he iss ue of c olli nearit y i n 
t he a nal ysis. T he c orres p o n di n g strata fact or will n ot be i ncl u de d i n t he m o del. 
S u m m ar y st atistics at s c he d ule d visits  
S u m mar y statistics (f or s cree ni n g v al u e, bas eli ne val ue, o bser v e d p ost- bas eli ne val ue a n d its 
C ha n ge fr o m Baseli ne ) at sc he d ule d visits will be pr o vi de d f or eac h treat m e nt gr o u p. T he 
s u m mar y will i ncl u de t he n u m ber of o bser v ati o ns, mea n, S D, sta n dar d err or ( S E), mi ni m u m, 
me dia n, a n d ma xi m u m. G ra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds o ver ti me 
usi n g mea n v al ues ( ± S E) a n d mea n c h a n ges fr o m baseli ne ( ± S E) at eac h of t he sc he d ule d visits .  
Si milar prese ntati o ns will be pr o vi de d e x cl u di n g meas ure me nts after resc u e t hera p y d uri n g t h e 
e ntire 7 9- w ee k d o u ble- bli n d treat me nt peri o d. 
2. 4. 4. 2  A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s  
F or c o nti n u o us sec o n dar y e n d p oi nts wit h missi n g data at baseli ne, missi n g data will be i m p ute d 
usi n g MI u n der t he missi n g at r a n d o m ( M A R) ass u m pti o n. Missi n g data at b aseli ne will be 
i m p ute d usi n g re gr essi o n met h o d t hat i ncl u des ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), 
ra n d o mizati o n strat u m of S B P ( < 1 3 0, ≥1 3 0 m m H g), a n d baseli ne v al ue i n t he i m p utati o n m o del 
(see sa m ple c o de Part 1 b or Part 2 b i n A p pe n di x B ). 
T he c o nti n u o us sec o n dar y e n d p oi nts ( Secti o n  2. 1. 3. 2 ) will be a nal yz e d usi n g si milar A N C O V A 
m o del i ncl u di n g c orres p o n di n g meas ure me nts at b aseli ne a n d e n d p oi nt ( o bs er ve d or i m p ute d) as 
descri be d i n Secti o n  2. 4. 4. 1 . T he missi n g data at e n d p oi nt will be i m p ute d b y t he retrie v e d 
dr o p o uts & was h o ut i m p utati o n met h o d or b y t he c o ntr ol- base d c o p y refere nce i m p uta ti o n met h o d 
acc or di n g t o t he criteri o n descri be d i n Secti o n  2. 4. 4. 1  . After i m p utati o n, eac h of t he c o m plete 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 3  of 9 9  
 
datase ts will be a nal yze d b y a n A N C O V A m o del wit h treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, 
place b o), ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %), ra n d o mizati o n strat u m of S B P ( < 1 3 0, 
≥1 3 0 m m H g), a n d c o u ntr y as fi x e d effects, a n d c orres p o n di n g baseli ne v al ue as a c o v ariat e. F or 
t he a nal ysis of S B P i n patie nts wit h baseli ne S B P ≥1 3 0 m m H g, t he ra n d o mizati o n strat u m of S B P 
will n ot be i ncl u de d i n t he A N C O V A m o del.  Res ults fr o m eac h c o m plet e dataset will be 
c o m bi ne d usi n g R u bi n’s f or m ula t o pr o vi de t he a dj uste d mea n C ha n ge fr o m Baseli ne t o Wee k 2 6 
( or Wee k 1 2 f or S B P) f or eac h tr eat me nt gr o u p, as well as t he bet wee n-gr o u p differe n ce 
(c o m pari n g s ota glifl ozi n 4 0 0 m g vs place b o) a n d t he 9 5 % CI f or t h e differe nce.  
F or all c o nti n u o us sec o n dar y e n d p oi nts, s u m mar y statistics at sc he d ule d visits will be pr o vi de d f or 
eac h tr eat me nt gr o u p. T h e s u m mar y will i ncl u de t he n u m ber of o bs er vati o ns, mea n, S D, S E, 
mi ni m u m, me dia n, a n d ma xi m u m. Gra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds 
o ver ti me usi n g mea n val u es ( ± S E) a n d mea n c ha n ges fr o m baseli ne ( ± S E) at eac h of t he 
sc he d ule d visits. I n a d diti o n, S B P will be s u m marize d descri pti vel y at eac h visit f or t h ose wit h 
baseli ne S B P ≥1 4 0 m m H g. 
T he bi nar y efficac y varia bles of H b A 1c ( < 6. 5 %, < 7 % at Wee k 2 6 res p ecti v el y) will be a nal yz e d 
usi n g a C oc hra n -M a ntel -Hae nszel (C M H ) met h o d stratifie d b y ra n d o mizati o n strat u m of H b A 1c 
( ≤8. 0 %, > 8. 0 %), a n d r a n d o mizati o n strat u m of S B P ( < 1 3 0, ≥1 3 0 m m H g). T he pr o p orti o n i n eac h 
treat me nt gr o u p, as w ell as t he differe nce of pr o p orti o ns bet wee n s ota glifl ozi n 4 0 0 m g a n d 
place b o wit h ass oci ate d 2 -si de d 9 5 % CI will be pr o vi de d. F or H b A 1c res p o n ders at Wee k 2 6 
( < 6. 5 %, < 7 % res p ecti vel y), all val ues at W ee k 2 6 will  be use d t o deter mi ne w het her a p atie nt is a 
res p o n der or n ot, e ve n if t he y are meas ure d after I M P disc o nti n uati o n or resc ue me dicati o n use. 
Patie nts w h o ha ve n o H b A 1c meas ur e me nt at W ee k 2 6 will be treate d as n o n -res p o n ders.  
S u m mar y ta bles a n d gra p hs will als o be pr o vi de d b y treat me nt gr o u p at sc h e d ule d visits. 
F or bet w ee n - gr o u p c o m p aris o n, a se nsiti vit y a n al ysis will be perf or me d se p aratel y f or 
H b A 1c  < 6. 5 % res p o n d er (e x cl u di n g patie nts wit h baseli ne H b A 1 c < 6. 5 %) a n d f or H b A 1 c  < 7 % 
res p o n der (e x cl u di n g pati e nts wit h baseli ne H bA 1 c val ues < 7 %) b y usi n g t he sa me C M H test as 
t hat use d f or t he a b o v e bi nar y vari a bles. T he s u m mar y b y visit ma y als o b e pr o vi de d b y e x cl u di n g 
t h ose patie nts wit h H b A 1c < 6 . 5% or < 7 % res pecti vel y . 
2. 4. 4. 3  A n al y s e s of ot h er effi c a c y e n d p oi nt s  
T he a nal ysis of ot her e n d p oi nts (see Secti o n  2. 1. 3. 3 ) will be descri pti ve wit h n o f or mal testi n g. 
S u m mar y statistics at sc h e d ule d visits usi n g o bser ve d val ues  will be pr o vi d e d b y eac h treat me nt 
gr o u p. Gra p hical pres e ntati o ns will als o be use d t o ill ustrate tre n ds o ver ti me.  
T he n u m ber ( %) of patie nts w h o use d resc ue t hera p y will be s u m marize d b y treat me nt gr o u p  d uri n g 
t he c ore (see Secti o n  2. 5. 4 ) a n d t he e ntire d o u ble-bli n d treat me nt peri o ds. A K M c ur ve will be 
pr o vi de d f or t he c u m ulati ve i nci de nce of resc ue t hera p y  d uri n g t he e ntire d o u ble-bli n d treat me nt 
peri o d . T he list of patie nts w h o use d resc ue t hera p y will als o be pr o vi de d (see Secti o n  2. 5. 4 ). 
U A C R will be l o g -tra nsf or me d at patie nt le vel. S u m mar y statistics of U A C R i n l o g scale will t he n 
be calc ul ate d f or eac h treat me nt gr o u p at eac h visit a n d bac k -tra nsf or me d t o pr o vi de t he ge o metri c 
mea n a n d its ass ociate d p erce nt c ha n ge of U A C R fr o m baseli ne.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 4  of 9 9  
 
S hift ta bles will be pr o vi de d f or U A C R at Wee k 2 6  a n d Wee k 7 9 usi n g t he pre- defi ne d cate g ories. 
T hat is, t he n u m ber ( %) of patie nts wit h pr o gressi o n fr o m o ne cate g or y at baseli ne t o a n ot her 
cate g or y at Wee k 2 6 a n d Wee k 7 9 will be pr o vi de d b y treat me nt gr o u p res pecti vel y. T he pre-
defi ne d cate g ories are, f or uri ne A C R, < 3 0 m g/ g creati ni ne [ N or mal], ≥3 0 t o < 3 0 0 m g/ g 
creati ni ne [ Micr oal b u mi n uria], a n d ≥3 0 0 m g/ g creati ni ne [ Macr oal b u mi n uria]. 
2. 4. 4. 4  A n al y si s of A B P M  s u b st u d y effi c a c y e n d p oi nt s  
A nal ys es of A B P M s u bst u d y efficac y e n d p oi nts will be perf or me d o n t he A B P M p o p ulati o n usi n g 
all assess me nt c ollecte d  u p t o Wee k 2 6, i ncl u di n g t h ose o btai ne d after I M P disc o nti n uati o n or 
i ntr o d ucti o n of resc u e t hera p y, u nless ot her wise s pecifie d.  
F or A B P M s u bst u d y, pri mar y a n d sec o n dar y efficac y e n d p oi nts will be a nal yz e d usi n g a si milar 
a p pr oac h as i n t he mai n -st u d y wit h p ost- baseli ne missi n g val ues i m p ute d b y t he retrie v e d 
dr o p o uts & was h o ut i m p utati o n met h o d or b y t he c o ntr ol- base d c o p y refere nce i m p utati o n met h o d 
acc or di n g t o t he criteri o n descri be d i n Secti o n  2. 4. 4. 1 . Eac h of t he c o m plete dataset will be 
a nal yze d usi n g A N C O V A m o del i ncl u di n g fact ors f or treat me nt (s ot a glifl ozi n  4 0 0 m g, place b o), 
ra n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %) as fi x e d fact or, a n d t h e b aseli ne val ue of t he 
s pecific de p e n de nt varia ble as a c o v ariate. Res ults fr o m eac h c o m plete dat aset will be c o m bi ne d 
usi n g R u bi n’s f or m ula t o pr o vi de t he a dj uste d mea n f or eac h treat me nt gr o u p, as well as t he 
bet wee n - gr o u p diff ere n ce a n d t he ass o ciate d 9 5 % CI.  
All A B P M s u bst u d y effi cac y e n d p oi nts will als o be s u m marize d b y d escri pti ve statistics b y 
sc he d ule d visits ( Visit 3/ Ra n d o mizati o n, Visit 7/ Wee k 1 2 a n d Visit 9/ Wee k 2 6). T he d escri pti ve 
statistics will i ncl u de n u m ber, mea n, S E, sta n dar d de viati o n, mi ni m u m, ma xi m u m .  
Please ref er t o A p p e n di x C  a n d A p pe n di x D  f or A B P M s u bst u d y efficac y v aria ble deri vati o n.   
2. 4. 4. 5  M ulti pli cit y i s s u e s  
T o c o ntr ol t he fa mil y- wise t y pe I err or, a fi xe d-se q ue nce testi n g pr o ce d ure will be a p plie d. 
O nce t he pri mar y vari a ble ( C ha n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c) is statisticall y 
si g nifica nt at α = 0. 0 5 ( 2-si de d), t he f oll o wi n g m ai n sec o n dar y effi cac y v ari a bles a n d A B P M 
s u bst u d y pri mar y e n d p oi nt will be teste d i n t he f oll o wi n g pri oritize d or der. T he testi n g will st o p 
as s o o n as a n e n d p oi nt is f o u n d n ot t o be statisticall y si g nifica nt at α = 0. 0 5 ( 2-si de d). 
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n 2- h o ur P P G f oll o wi n g a n M M 
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n F P G 
•  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht 
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or all patie nts 
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n a vera ge 2 4- h o ur S B P i n patie nts fr o m A B P M 
s u bst u d y (t he pri mar y e n d p oi nt of t he A B P M s u bst u d y) 
•  Pr o p orti o n of patie nts wit h H b A 1c < 7. 0 % at W ee k 2 6. 
N o m ulti plicit y a dj ust me nt will be ma de o n effi cac y v aria bles ot h er t ha n t h ose me nti o ne d a b o ve. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 5  of 9 9  
 
 
2. 4. 5  A n al y s e s of s af et y d at a  
Safet y e n d p oi nts are pres e nte d i n  Secti o n  2. 1. 4 . T he s u m mar y of safet y res ults will be prese nte d 
b y treat me nt gr o u p. T he safet y data will be s u m marize d f or t he 2 6- wee k c ore treat me nt peri o d  a n d 
t he 7 9- wee k e ntire tr eat me nt peri o d se paratel y, u nless ot her wise s pecifie d.  
T he “ o bser v ati o n peri o d” defi ne d i n Secti o n  2. 1. 4  is a p plica ble i n all safet y a nal ys es f or t h e 
classificati o n of A Es, d eter mi nati o n of treat me nt-e mer ge nt P ote ntiall y Cli nicall y Si g nifica nt 
A b n or malit y ( P C S A ) val ues a n d t he last o n-treat me nt val ue f or t he l a b orat or y, vital si g n a n d 
E C G.   
Ge ner al c o m m o n r ules  
All safet y a nal yses will be perf or me d o n t he Safet y p o p ulati o n usi n g t h e f oll o wi n g c o m m o n r ules:  
•  Safet y d ata i n patie nts w h o d o n ot bel o n g t o t he s afet y p o p ulati o n (e g, e x p ose d b ut n ot 
ra n d o mize d) will be liste d se parat el y. 
•  T he baseli ne v al ue  ( wit h t he e x ce pti o n of ser u m creati ni ne a n d e G F R) is defi ne d as t he 
last a vaila ble val ue b ef or e t he first d ose of d o u ble-bli n d I M P. F or creati ni ne a n d e G F R, 
t he baseli ne val ue is d efi ne d as t he a v era ge of all val ues bef ore t he first d ose of d o u ble-
bli n d I M P.  
•  P C S A val ues are defi n e d as a b n or mal val u es c o nsi dere d me dicall y i m p orta nt b y t he 
S p o ns or acc or di n g t o pr e defi ne d criteria/t hres h ol ds base d o n literat ure re vi e w a n d defi ne d 
b y t he S p o ns or f or cli nical la b orat or y tests, vital si g ns,  a n d E C G (A p pe n di x E ). 
•  P C S A criteria will deter mi ne w hic h patie nts ha d at least 1 P C S A d uri n g t h e  treat me nt-
e mer ge nt A E  p eri o d, ta ki n g i nt o acc o u nt all e val u ati o ns perf or me d d uri n g t he treat me nt-
e mer ge nt A E  p eri o d, i ncl u di n g n o nsc h e d ule d or re peate d e v al uati o ns. T he n u m ber of all 
s uc h patie nts will be t he n u merat or f or t he treat me nt-e mer ge nt  P C S A perce nta ge . 
•  T he treat me nt - e mer ge nt P C S A de n o mi nat or b y gr o u p f or a gi ven p ara met er will be base d 
o n t he n u m ber of patie nts assesse d f or t h at gi v e n p ara meter d uri n g t he treat me nt- e mer ge nt 
A E peri o d b y treat me nt gr o u p i n t he safet y p o p ulati o n. 
•  F or la b or at or y para meters cite d i n t he pr ot oc ol as efficac y e n d p oi nts (i ncl u di n g H b A 1 c 
a n d plas ma gl uc ose,  etc),  P C S A s u m maries will n ot be pr o vi de d. T hese p ara meters will be 
s u m marize d i n Secti o n  2. 4. 4 . F or ser u m cr eati ni ne, a n d e G F R, P C S A s u m maries will be 
prese nte d i n safet y Secti o n  2. 4. 5 , w hile descri pti v e s u m maries i n effi cac y Secti o n  2. 4. 4 . 
•  F or q ua nti tati ve safet y para meters b ase d o n ce ntral la b orat or y/rea di n g meas ure me nts, 
descri pti ve statistics will be use d t o s u m marize res ults a n d c ha n ge fr o m Baseli ne val ues b y 
visit a n d treat me nt gr o u p f or t he 7 9- w ee k e ntire treat me nt peri o d  o nl y. S u m maries will 
i ncl u de t he last o n-treat me nt val ue. T he last o n -treat me nt val ue is c o m m o nl y defi ne d as 
t he val ue c ollect e d at t he sa me da y/ti me of t he last a d mi nistrati o n of I M P f or t he 7 9- wee k 
e ntire treat me nt peri o d . If t his val ue is missi n g, t his last o n- treat me nt val ue will be t he 
cl osest val ue pri or t o t he last a d mi nistrati o n of I M P d uri n g t he 7 9- w ee k e ntire treat me nt 
peri o d. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 6  of 9 9  
 
•  T he a nal ysis of t he safet y varia bles will be ess e ntiall y des cri pti ve a n d n o st atistical testi n g 
is pla n ne d.  Relati ve ris ks ver s us place b o a n d t heir 9 5 % CIs ma y be pr o vi d e d, if rele v a nt. 
•  Selecte d saf et y a nal yses will be s u m marize d b y a ge, ge n der, race , a n d ot h er perti ne nt 
s u b gr o u ps (s ee d etails i n Secti o n  2. 4. 5. 1  a n d Secti o n  2. 4. 5. 2 ). 
2. 4. 5. 1  A n al y s e s of h y p o gl y c e mi a  
A nal ys es of h y p o gl yce mia will be perf or me d o n t h e treat me nt-e mer ge nt A E  peri o ds as defi n e d i n 
Secti o n  2. 1. 4 . H y p o gl yce mia will be classifie d as se vere h y p o gl yce mia, d o c u me nte d s y m pt o matic 
h y p o gl yce mia, as y m pt o matic h y p o gl yce mia, pr o ba ble s y m pt o matic h y p o gl yce mia or relati ve 
h y p o gl yce mia  Secti o n  2. 1. 4 .  
T he n u m ber ( %) of patie nts wit h a n y h y p o gl yce mia , se vere h y p o gl yce mia, a n d d oc u me nte d 
s y m pt o matic h y p o gl yce mia will be s u m marize d res pecti vel y b y treat me nt gr o u p d uri n g t he treat me nt -
e mer ge nt A E peri o d, as well as t he i nci de nce rate i n patie nt years. T w o t y pes of i nci de nce rates will be 
prese nte d: t he n u m ber of patie nts wit h at least 1 e ve nt per 1 0 0 patie nt -years (calc ulate d as t he n u m ber 
of patie nts wit h at least 1 e ve nt / t otal e x p os ure i n 1 0 0 patie nt -years), a n d t he n u m ber of e ve nts per 
1 0 0 patie nt -years (calc ulate d as t he t otal n u m ber of e ve nts / (t otal e x p os ure i n 1 0 0 patie nt -years)). 
N ote: here e x p os ure i n days is d urati o n of treat me nt-e mer ge nt A E peri o d, ie, d urati o n o f I M P 
treat me nt i n da ys + 1 (Secti o n  2. 1. 4 ). 
T he s u m ma r y of fre q ue n c y a n d i nci de n ce rate i n patie nt years f or se vere h y p o gl yce mia or 
d oc u me nte d s y m pt o mati c h y p o gl yce mia will be pr o vi de d as a p pr o priate b y ge n d er ( M ale, 
Fe male), a ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 years) a n d race ( W hite, Blac k or Africa n A merica n, 
Asia n, O t her).  
A K M c ur ve will als o be pr o vi de d b y treat me nt gr o u p f or t he ti me t o first se vere h y p o gl yce mia or 
d oc u me nte d s y m pt o mati c h y p o gl yce mia d uri n g t he treat me nt-e mer ge nt A E  peri o d f or t he  
7 9- wee k e ntire treat me nt peri o d o nl y (see Secti o n  2. 5. 4 ). 
D oc u me nte d s y m pt o matic h y p o gl yce mia ma y b e prese nte d b y ≤3. 9 m m ol/ L ( 7 0 m g/ d L) a n d 
< 3. 0 m m ol/ L ( 5 4 m g/ d L) res pecti vel y, as a p pr o pri ate.  
A listi n g of patie nts f or all e ve nts re p orte d o n t he de dicate d e C R F “ H y p o gl yce mic e v e nt 
i nf or mati o n” pa ge will be pr o vi de d wit h fla g ge d cate g or y (ie, s e vere h y p o gl yce mia, d oc u me nte d 
s y m pt o matic h y p o gl yce mia, as y m pt o matic h y p o gl yce mia, pr o ba ble s y m pt o matic h y p o gl yce mia 
or relati ve h y p o gl yce mia).  
2. 4. 5. 2  A n al y s e s of A E s 
Ge ner alities  
T he pri mar y f o c us of A E  re p orti n g will be o n treat me nt-e mer ge nt A Es .  Pretreat me nt a n d 
p osttreat me nt A Es  will be descri b e d se paratel y.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 7  of 9 9  
 
If a n A E  d ate/ti me of o ns et ( occ urre n ce, w orse ni n g, or b ec o mi n g seri o us) is i nc o m plete, a n 
i m p utati o n al g orit h m will be use d t o classif y t he A E  as pretreat me nt, treat me nt -e mer ge nt, or 
p osttreat me nt.  T he al g orit h m f or i m p uti n g date/ti me of o nset will be c o nser vati ve a n d will 
classif y a n A E  as treat me nt e mer ge nt u nless t here is defi niti ve i nf or mati o n t o deter mi ne it is 
pretreat me nt or p osttreat me nt.  Details o n classifi cati o n of A E s wit h missi n g or p artial o nset dates 
are pr o vi d e d i n Secti o n  2. 5. 3 . 
A d verse e ve nt i nci de n ce ta bles will be prese nte d  b y S O C, H L G T, H L T, a n d P T, s orte d b y t he 
i nter nati o nall y a gree d or der f or S O Cs a n d al p ha b etic or der f or H L G T, H L T a n d P T wit hi n a S O C, 
t he n u m ber ( n) a n d per ce nta ge ( %) of patie nts e x perie nci n g a n a d verse e v e nt.  M ulti ple 
occ urr e nces of t he sa me e ve nt  b y P T  i n t he sa me patie nt will be c o u nte d o nl y o nce i n t he ta bles 
wit hi n a treat me nt p hase.  T he de n o mi nat or f or c o m p utati o n of perce nt a ges is t he safet y 
p o p ulati o n wit hi n eac h tr eat me nt gr o u p. 
S orti n g wit hi n ta bles e ns ures t he sa me prese ntati o n f or t he set of all a d vers e e ve nts wit hi n t he 
o bser vati o n peri o d ( pretr eat me nt, treat me nt- e mer ge nt, a n d p osttreat m e nt).  F or t hat p ur p os e, t he 
ta ble of all treat me nt-e m er ge nt a d v erse e ve nts prese nte d b y pri mar y S O C a n d P T s orte d b y t he 
i nter nati o nall y a gree d S O C or der a n d d ecreasi n g fre q ue n c y of P Ts wit hi n S O Cs i n t he 
s ota glifl ozi n gr o u p will d efi ne t he pr ese ntati o n or d er f or all ot her si milar ta bles u nless ot her wise 
s pecifie d. I n case of e q ual fre q ue n c y re gra di n g P Ts, al p ha betical or d er will be use d. 
A n alysis of all tre at m e nt -e m er ge nt A Es  
T he f oll o wi n g tr eat me nt -e mer ge nt A E  s u m maries will be ge n erat e d d uri n g t he  2 6-wee k c ore a n d 
t he 7 9- wee k e ntire tr eat me nt peri o d s res pecti vel y i n t he safet y p o p ulati o n. 
•  O ver vie w of treat me nt -e mer ge nt A Es , s u m marizi n g n u m ber ( %) of patie nts wit h a n y 
- 
Treat me nt -e mer ge nt A E  
- 
Seri o us treat me nt-e m er ge nt A E  
- 
Treat me nt -e mer ge nt  A E lea di n g t o d eat h 
- 
Treat me nt -e mer ge nt A E lea di n g t o p er ma ne nt treat me nt disc o nti n uati o n. 
•  All treat me nt -e mer ge nt A Es  b y pri mar y S O C , s h o wi n g n u m ber ( %) of patie nts wit h at 
least 1 treat me nt-e mer ge nt A E , s orte d b y i nter nati o nall y a gree d or der of pri mar y S O C . 
•  All treat me nt -e mer ge nt A Es  b y pri mar y S O C, H L G T, H L T, a n d P T, s h o wi n g n u m ber ( %) 
of patie nts wit h at least 1 treat me nt -e mer ge nt A E  s orte d b y t h e S O C i nter nati o nall y a gree d 
or der.  T he ot h er le v els ( H L G T, H L T, P T) will be prese nte d i n al p h a betical or der. 
•  N u m ber ( %) of patie nts e x perie nci n g Treat me nt -e mer ge nt A Es prese nte d b y P T, s orte d b y 
decreasi n g i nci de nce of P T i n t he s ota glifl ozi n gr o u p. 
•  All treat me nt -e mer ge nt A E s b y pri mar y S O C a n d P T, s h o wi n g t he n u m b er ( %) of patie nts 
wit h at least 1 treat me nt -e mer gent A E , s orte d b y t he i nter nati o nall y a gree d S O C or der a n d 
b y decreasi n g i nci de nce of P Ts wit hi n eac h S O C  i n t he s ota glifl ozi n gr o u p.  T his s orti n g 
or der will be a p plie d t o all ot her si milar ta bles, u nless ot her wise s pecifie d . 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 8  of 9 9  
 
•  All treat me nt -e mer ge nt A E s re gar dless of relati o ns hi p a n d relate d t o I M P b y pri mar y 
S O C, H L G T, H L T a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h at least 1 treat me nt-
e mer ge nt A E , s orte d b y t he i nter nati o nall y a gree d S O C or der.  T he ot her le vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betical or der . 
•  All treat me nt -e mer ge nt A E s b y ma xi mal se verit y, prese nte d b y pri mar y S O C a n d P T, 
s h o wi n g t he n u m ber ( %) of patie nts wit h at least 1 treat me nt-e mer ge nt A E  b y se v erit y 
(ie, mil d, m o derate, or s e vere), s orte d b y t he s orti n g or d er defi ne d a b ov e . 
•  C o m m o n treat me nt-e mer ge nt A Es ( P Ts wit h a n i nci de nce ≥2 % i n a n y treat me nt gr o u p) b y 
pri mar y S O C, H L G T, H L T, a n d P T, s orte d b y i nter nati o nall y a gree d or d er of S O Cs. T he 
ot her le vels ( H L G T, H L T, P T) will be prese nte d i n al p ha betic or d er.  
•  S u m maries of c o m m o n treat me nt -e mer ge nt A Es ( P Ts wit h a n i nci de nce ≥2 % i n a n y 
treat me nt gr o u p) will be pr o vi de d as a p pr o priate b y pri mar y S O C  a n d P T a n d b y 
de m o gr a p hic f act ors i ncl u di n g ge n d er ( M ale, Fe male), a ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, 
≥6 5 years of a ge), race ( W hite, Blac k or Africa n A merica n, Asi a n, Ot her), baseli ne S B P 
cate g or y ( < 1 3 0 m m H g, ≥1 3 0 m m H g), a n d baseli n e e G F R cate g or y ( ≥3 0 t o 
< 6 0  m L/ mi n / 1. 7 3 m2  [ M o derate d ecrease i n G F R], ≥6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m2 [ Mil d 
decrease i n G F R], a n d ≥9 0 m L/ mi n/ 1. 7 3 m 2  [ N or mal]). S O C will be s orte d b y 
i nter nati o nall y a gree d or der a n d t he P T b y decreasi n g i nci de nce wit hi n eac h S O C i n t he 
s ota glifl ozi n 4 0 0 m g gr o u p, as descri b e d a b o ve. 
•  T E A Es ( P Ts wit h a n i nci de nce ≥5 % i n a n y treat m e nt gr o u p) b y pri mar y S O C, H L G T, 
H L T, a n d P T, s orte d b y i nter nati o nall y a gree d or d er of S O Cs. T he ot her l e vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betic or d er. 
A n alysis of all tre at m e nt e m er ge nt S A E (s) 
•  All treat me nt -e mer ge nt S A E s b y pri mar y S O C, H L G T, H L T, a n d P T, s h o wi n g t he 
n u m ber ( %) of patie nts wit h at least 1 seri o us treat me nt-e mer ge nt A E , s orte d b y t he 
i nter nati o nall y a gree d S O C or der.  T he ot h er le v els ( H L G T, H L T, P T) will be prese nte d i n 
al p ha betical or d er . 
•  All treat me nt -e mer ge nt S A E s re gar dless of relati o ns hi p a n d relate d t o I M P, b y pri mar y 
S O C, H L G T, H L T, a n d P T, s h o wi n g t he n u m ber ( %) of p atie nts wit h at least 1 treat me nt-
e mer ge nt S A E , s orte d b y t he i nter nati o nall y a gree d S O C or der.  T he ot her le vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betical or der . 
A n alysis of all tr e at m e nt-e m er ge nt A E (s) le a di n g t o tre at m e nt disc o nti n u ati o n 
•  All treat me nt -e mer ge nt a d verse e v e nts lea di n g t o treat me nt disc o nti n uati o n, b y pri mar y 
S O C, H L G T, H L T, a n d P T, s h o wi n g t he n u m ber ( %) of p atie nts s orte d b y t he 
i nter nati o nall y a gree d S O C or der.  T he ot h er le v els ( H L G T, H L T, P T) will be prese nte d i n 
al p ha betical or d er . 
A n alysis of a dverse eve nts of s peci al i nterest  
T he s u m maries of A E SI will be prese nte d f or t he 7 9- wee k e ntire treat me nt peri o d o nl y i n t he 
safet y p o p ulati o n. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 4 9  of 9 9  
 
Pre g n a nc y a n d o ver d os e will be i ncl u de d i n o verall A E s u m maries if a n y are re p ort e d. A L T 
i ncreas e > 3 x U L N is i ncl u de d i n la b orat or y P C S A s u m mar y if a n y.  
I n a d diti o n, t he n u m ber ( %) of patie nts wit h a n A E SI will be s u m marize d b y P T a n d b y treat me nt 
gr o u p d uri n g t h e 7 9- w ee k e ntire treat me nt peri o d o nl y. C orres p o n di n g listi n gs will be pr o vi de d as 
a p pr o priatel y. 
A n alysis of eve nts of s peci al i nterest   
T he s u m maries of E O SI will be prese nte d f or t he 7 9- wee k e ntire treat me nt peri o d o nl y i n t he 
safet y p o p ulati o n. 
C V eve nts, b o ne fr act ure a n d D K A  
F or E O SIs t hat are a dj u dicate d (ie, d eat hs, m y ocar dial i nfarcti o n, str o ke, a n d u nsta ble a n gi na 
re q uiri n g h os pitalizati o n, heart f ail ure re q uiri n g  h os pitalizati o n, b o ne fract ure, a n d dia b etic 
ket oaci d osis), t he n u m ber ( % ) of patie nts wit h a n E O SI p ositi vel y a dj u dicate d b y C E C will be 
s u m marize d b y treat me nt gr o u p. All E O SIs s e nt f or a dj u dicati o n a n d/ or re p orte d b y t h e 
i n vesti gat ors i n t he s pecific A E f or ms will be liste d al o n g wit h t he a dj u dicati o n o utc o me. 
Re n al eve nts  
F or t he E O SI re nal e ve nts w here s electe d e ve nts are a dj u dicat e d, t he n u m b er ( %) of patie nts wit h 
a n y re nal e ve nts i de ntifie d i n Ta ble  3 i n Secti o n  2. 1. 4. 2  will be s u m marize d b y treat me nt gr o u p.  
T he f oll o wi n g re nal e ve nts will be liste d al o n g wit h t he a dj u dicati o n o utc o me if a p plica ble, 
i ncl u di n g e v e nts,  
i. 
rec or d e d i n e C R F “ G F R decrease”,  
ii. 
rec or d e d i n e C R F “ Re n al E ve nt – Dial ysis”,  
iii. 
i de ntifie d as “ Re nal tr a ns pla nt” i n e C R F “ Ot her pr oce d ure”,  
Re nal deat h will be part of all deat hs s pecifie d a b o ve.  
Ot her E O SIs  
F or E O SIs t hat are n ot a dj u dicate d, t he n u m ber ( %) of patie nts wit h at least o ne e ve nt will be 
s u m marize d b y treat me nt gr o u p a n d b y P T (as i de ntifie d i n Ta ble  3 i n Secti o n  2. 1. 4. 2 ).  
Se vere h y p o gl yce mia will be i ncl u de d i n t he s u m mar y of h y p o gl yce mia ( See Secti o n  2. 4. 5. 1 ). 
A E lea di n g t o a n a m p utati o n is descri be d i n t he secti o n bel o w. 
A n alysis of A m p ut ati o n 
T he n u m ber ( %) of p atie nts wit h a m p utati o n will be s u m marize d b y treat m e nt gr o u p a n d b y P T 
a n d L L T d uri n g t he st u d y (ie, re gar dless of o n- or p ost- treat me nt). A m p utati o n is a pr oce d ure 
rec or d e d i n e C R F f or m “ Ot her Pr oce d ures relate d t o A m p utati o n”. Patie nts w h o ha d a pr o ce d ure 
relate d t o a m p utati o n will be liste d.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 0  of 9 9  
 
T he n u m ber ( %) of p atie nts wit h a n “ A E lea di n g t o a n a m p utat i o n” will be s u m marize d b y 
treat me nt gr o u p a n d b y P T. T he “ A E lea di n g t o a n a m p utati o n” is deter mi ne d b y t h e A E i de ntifier 
rec or d e d i n e C R F “ Ot her Pr oce d ures relate d t o A m p utati o n” w he n “ A E c orrecti o n” is c h os e n as 
t he reas o n f or t he a m p utati o n pr oce d ure.  
I n a d diti o n, t he n u m ber ( %) of patie nts wit h a n “ A E p ote ntiall y lea di n g t o a n a m p utati o n” will be 
s u m marize d b y treat me nt gr o u p a n d b y P T (as i de ntifie d i n Ta ble  3 i n Secti o n  2. 1. 4. 2 ). T hese P Ts 
i n Ta ble  3 wer e re q u este d b y t he E ur o pea n M e dici nes A ge nc y ( E M A)/ P har mac o vi gila nce Ris k 
Assess me nt C o m mittee ( P R A C ) Assess me nt Re p ort, 9 Fe br u ar y 2 0 1 7).T h e a ss ociate d list will be 
pr o vi de d as well, wit h patie nts w h o ha d a n a m p utati o n pr oce d ure fla g ge d. “ A E p ote ntiall y lea di n g 
t o a n a m p utati o n” re pres e nts t he c o n diti o n t hat ma y p ot e ntiall y lea d t o  t he a m p utati o n pr oce d ure, 
b ut n ot i n all cases a n a m p utati o n has occ urre d. 
A n alysis of pretre at m e nt  a n d p osttre at m e nt A E s  
•  All pretreat me nt A E s b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h at 
least 1 pretreat me nt A E , s orte d b y t h e i nter nati o nall y a gree d S O C or der a n d decreasi n g 
i nci de nce of P Ts wit hi n eac h S O C i n t he sota glifl o zi n gr o u p 
•  All p ost treat me nt A E s b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h 
at least 1 p osttreat me nt A E , s orte d b y t he i nter nati o nall y a gree d S O C or d er a n d decreasi n g 
i nci de nce of P Ts wit hi n eac h S O C i n t he sota glifl o zi n gr o u p . 
Listi n gs  
S u p p orti n g A E listi n gs will be pr o vi de d f or all A Es, S A Es, deat h, A Es lea di n g t o treat me nt 
disc o nti n uati o n a n d/ or deat h, a n d E O SI if a p pr o pri ate.  
Listi n g of all A Es, S A Es, deat hs, a n d A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n, s orte d 
b y treat me nt, p atie nt I D, o nset date , will i ncl u de t he f oll o wi n g i nf or mati o n: treat me nt, patie nt I D, 
c o u ntr y, a ge, s e x, race, B MI, pri mar y S O C, P T, re p orte d ter m, o nset date, st u d y da y (relati ve d a y 
t o t he start date of d o u ble- bli n d treat me nt), A E d urati o n, d urati o n of e x p os ure, i nte nsit y, 
c orrecti ve treat me nt, acti o n ta ke n wit h I M P, date of treat me nt disc o nti n uati o n (if rele va nt), 
relati o ns hi p t o I M P/ NI M P, o utc o me, date of deat h if a n y, s eri o us ness, seri o us ness criteria, a n d A E 
stat us ( “E ” f or a T E A E; “ P” f or a n o n- st ud y  p ost-treat me nt A E). 
2. 4. 5. 3  D e at h s  
T he f oll o wi n g s u m maries of deat hs will be ge nerate d . 
•  N u m ber ( %) of patie nts w h o die d b y st u d y p eri o d ( o n-st u d y, o n- treat me nt, p ost-st u d y) 
•  Deat hs i n n o nra n d o mize d patie nts or ra n d o mize d b ut n ot treate d patie nts 
•  Treat me nt -e mer gent A E s lea di n g t o d eat h ( deat h as a n o utc o me o n t he a d v erse e ve nt case 
re p ort f or m p a ge as re p orte d b y t he I n vesti gat or) b y pri mar y S O C , H L G T, H L T, a n d P T 
s h o wi n g n u m ber ( %) of patie nts s orte d b y i nter nati o nall y a gree d S O C or der, wit h H L G T, 
H L T, a n d P T pr es e nte d i n al p ha betical or d er wit hi n eac h S O C.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 1  of 9 9  
 
2. 4. 5. 4  A n al y s e s of l a b or at or y v ari a bl e s  
La b orat or y p ara m eters will be gr o u pe d a n d s u m marize d b y bi ol o gical f u ncti o n as descri be d i n 
Secti o n  2. 1. 4. 4 . 
T he s u m mar y statistics (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3, sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of all la b orat or y vari a bles (ce ntral la b orat or y val u es, c ha n ges fr o m baseli ne) will 
be calc ul ate d f or eac h a p plica ble visit or st u d y ass ess me nt (scree ni n g, baseli ne, p ost baseli ne ti me 
p oi nts, last o n-treat me nt val ue) b y treat me nt gr o u p d uri n g t he e ntire treat me nt peri o d o nl y. 
T he i nci de nce of P C S As (list pr o vi de d i n A p pe n di x E ) at a n y ti me d uri n g t he treat me nt-e mer ge nt 
a d verse e ve nt peri o d will be s u m marize d f or eac h la b orat or y test b y bi ol o gi cal f u ncti o n a n d 
treat me nt gr o u p w h ate ver t he baseli ne le v el a n d/ or acc or di n g t o t he f oll o wi n g bas eli ne stat us 
cate g ories:  
•  N or mal/ missi n g  
•  A b n or mal acc or di n g t o P C S A criteri o n or criteria . 
F or para meters f or w hi c h n o P C S A criteria are d efi ne d, si milar ta ble(s) usi n g t he n or m al ra n ge 
will be pr o vi de d. 
All m eas ure me nts c ollecte d d uri n g t he treat me nt-e mer ge nt A E peri o d, i ncl u di n g val ues fr o m 
u nsc he d ule d visits, will be c o nsi der e d f or t he P C S A s u m maries. T hese s u m maries will i ncl u de 
patie nts i n t he safet y p o p ulati o n w h o ha ve at least 1 assess me nt perf or me d d uri n g t he treat me nt -
e mer ge nt A E p eri o d. W he n a P C S A defi niti o n i n v ol ves a C ha n ge fr o m Bas eli ne val ue, patie nts 
m ust als o ha ve a baseli ne val ue t o be i ncl u de d i n t he s u m maries, a n d w h e n re q uire d b y t he 
defi niti o n of t he a b n or malit y, p atie nts m ust als o ha ve a vaila ble la b orat or y n or mal ra n ges.  
A listi n g of patie nts wit h at least 1 p ost - baseli ne P C S A ( or o ut of n or mal ra n ge w he n n o P C S A 
criteri o n is defi ne d) will be pr o vi de d a n d will dis pla y t he e ntire patie nts’ pr ofile acr oss ti me f or all 
para meters bel o n gi n g t o t he c orr es p o n di n g bi ol o gi cal f u ncti o n. I n di vi d ual d ata listi n gs will 
i ncl u de fla gs w he n a p plica ble: 
•  Baseli ne v al ues will be fl a g ge d “ B”.  
•  N or mal la b orat or y ra n ges, a vaila ble f or m ost la b orat or y para meters, will be i de ntifie d as 
U L N a n d L L N. Bas eli ne, las t o n-treat me nt val ue, a n d i n di vi d ual data will be fla g ge d “ L” 
if t he val ue is bel o w t he L L N a n d will be fla g ge d “ H” if it is a b o ve t he U L N. 
•  La b orat or y P C S A criteri a will be use d f or t he c orres p o n di n g l a b orat or y p ara meters. 
Val ues reac hi n g a P C S A li mit will  be fla g ge d ( +, + +, -, or -- de p e n di n g u p o n t he directi o n 
a n d le vel of t he a b n or malit y). Fla gs f or W B C a n d differe ntial c o u nts will be deter mi ne d 
usi n g data e x presse d i n i nter nati o nal u nits. 
F or para meters w h ose P C S A criteria are m ulti ples of t he U L N, t he p ara meter’s val ue will als o be 
e x presse d as a m ulti ple of t he U L N i n t he i n di vi d ual data pr o vi de d. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 2  of 9 9  
 
Dr u g -i n d uce d liver i nj ury 
T he li ver f u ncti o n tests, na mel y A S T, A L T, al kali ne p h os p hatase, a n d t otal bilir u bi n, are use d t o 
assess p ossi ble dr u g-i n d u ce d li ver t o xicit y.  T he pr o p orti o n of patie nts wit h P C S A val ues at a n y 
p ost- baseli ne visit b y bas eli ne stat us will be dis pla ye d b y treat me nt gr o u p f or eac h p ara meter.  
T he pr o p orti o n of patie nts wit h P C S A val ues at a n y p ost- bas eli ne visit will als o be dis pla ye d b y 
d urati o n of e x p os ure f or eac h tr eat me nt gr o u p ( o nl y if a ta b ul ati o n s u m mar y is necessar y).  
Listi n g of p ossi ble H y’s l a w cas es i de ntifie d b y treat me nt gr o u p (e g, p atie nts wit h a n y ele vate d 
A L T > 3  x U L N, a n d ass o ciate d wit h a n i ncrease i n bilir u bi n ≥2 x U L N) wit h A L T, A S T, al kali ne 
p h os p hatase, t otal bilir u bi n, a n d t he f oll o wi n g c o m ple me ntar y para meters (if a vaila ble):  
c o nj u gate d bilir u bi n a n d pr ot hr o m bi n ti me /i nter nati o nal n or malize d rati o, creati ne p h os p h o ki nase, 
ser u m creati ni ne, c o m plete bl o o d c o u nt, a nti-H A V I g M, a nti - H Bc I g M, a nti-H C V a n d H C V 
R N A , a nti- C M V I g M a n d a nti- H E V I g M a nti b o di es, a ut o-a nti b o dies: a nti-n uclear, a nti -D N A, 
a nti-s m o ot h m uscle, E pstei n- Barr vir us, h er pes vir uses, a n d a nti-L K M.   
2. 4. 5. 5  A n al y s e s of vit al si g n v ari a bl e s  
T he s u m mar y statisti cs (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3 , sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of heart r ate, te m per at ure a n d res pirat or y rate ( o bser v e d val ues or mea n of 
o bser ve d val u es, a n d c h a n ges fr o m baseli ne) will be calc ul ate d f or eac h a p plica ble visit  or st u d y 
assess me nt  ( baseli ne, p ost-baseli ne ti me p oi nt s, last o n-treat me nt val ue) b y treat me nt gr o u p 
d uri n g t he e ntire treat me nt peri o d o nl y. 
T he i nci de nce of P C S As at a n y ti me d uri n g t h e treat me nt -e mer ge nt a d verse e ve nt peri o d will be 
s u m marize d b y treat me nt gr o u p f or S B P, D B P a n d H R. All meas ure me nts c ollecte d d uri n g t he 
treat me nt-e mer ge nt A E p er i o ds, i ncl u di n g v al ues fr o m u nsc he d ule d visits, will be c o nsi dere d f or 
t he P C S A s u m maries. T he s u m maries will i ncl u de patie nts i n t he safet y p o p ulati o n w h o ha ve at 
least 1 assess me nt perf or me d d uri n g t he treat me nt-e mer ge nt A E peri o d. W he n a P C S A defi niti o n 
i n v ol ves a C ha n ge fr o m Baseli ne v al ue, patie nts  m ust als o ha ve a baseli ne val ue t o be i ncl u de d i n 
t he s u m maries. 
A listi n g of patie nts wit h at least 1 p ost - baseli ne P C S A will be pr o vi de d a n d will dis pla y t h e 
patie nt’s pr ofile o ver ti me of all vital si g n p ara met ers. I n di vi d ual data listi n gs will i ncl u de  t he 
f oll o wi n g fla gs: 
•  Baseli ne v al ues will be fl a g ge d “ B”,  
• Para meter val ues reac hi n g a P C S A li mit will be fla g ge d ( +, or - de pe n di n g of t he directi o n).  
2. 4. 5. 6  A n al y s e s of el e ctr o c ar di o gr a m v ari a bl e s  
S hift ta bles will be pr o vi de d t o prese nt E C G stat us acc or di n g t o bas eli ne stat us ( N or mal/ Missi n g, 
A b n or mal) f or eac h treat me nt gr o u p d uri n g t h e treat me nt- e mer ge nt A E peri o d. S u p p orti ve listi n gs 
of patie nts wit h a b n or mal E C G stat us at a n y p ost- baseli ne visi t will be pr o vi de d. 




St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 4  of 9 9  
 
Uri ne A C R  
Sta n da r d u nit: UA C R ( m g/ g ) = 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐻𝐻𝜇𝜇𝐻𝐻𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶 (𝑆𝑆𝐴𝐴/ 𝑑𝑑𝐿𝐿) / (𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐷𝐷𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑆𝑆 (𝑆𝑆𝑆𝑆𝜇𝜇𝜇𝜇/ 𝐿𝐿)   ×
1 1 .3 1 )  × 1 0 0 0  
C o n ve nti o nal u nit: U A C R ( m g/ g) =  𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐻𝐻𝜇𝜇𝐻𝐻𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶 (𝑆𝑆𝐴𝐴/ 𝑑𝑑𝐿𝐿) / 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐷𝐷𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑆𝑆 (𝑆𝑆𝐴𝐴/ 𝑑𝑑𝐿𝐿) 𝑥𝑥 1 0 0 0  
Uri ne G C R  
Sta n da r d u nit: Uri ne G C R = 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐺𝐺𝜇𝜇𝑆𝑆𝑐𝑐𝜇𝜇𝐺𝐺𝑆𝑆 (𝑆𝑆𝑆𝑆𝜇𝜇𝜇𝜇/ 𝐿𝐿) / 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐷𝐷𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑆𝑆 (𝑆𝑆𝑆𝑆𝜇𝜇𝜇𝜇/ 𝐿𝐿) 
C o n ve nti o nal u nit: Uri ne G C R = 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐺𝐺𝜇𝜇𝑆𝑆𝑐𝑐𝜇𝜇𝐺𝐺𝑆𝑆 (𝑆𝑆𝐴𝐴/ 𝑑𝑑𝐿𝐿) / 𝑈𝑈𝑆𝑆𝐶𝐶𝐶𝐶𝑆𝑆 𝐷𝐷𝑆𝑆𝑆𝑆𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝑆𝑆 (𝑆𝑆𝐴𝐴/ 𝑑𝑑𝐿𝐿). 
C alc ul ati o n of L D L - C 
W he n  T G is l o wer t ha n or e q ual t o 4. 5 2 m m ol/ L ( 4 0 0 m g/ d L), L D L-C is calc ulate d usi n g t he 
Frie de wal d e q u ati o n as:  
•  i n Sta n dar d u nit(m m ol/ L ), T C – H D L -C – T G/ 2. 1 7; 
•  i n C o n ve nti o nal u nit (m g/ d L ), T C – H D L -C – T G/ 5 . 
2. 5. 2  D at a h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s  
Sc he d ule d meas ur e me nts  Secti o n  2. 5. 4  of c o nti n u o us efficac y varia bles c ollecte d d uri n g t he st u d y 
will be use d i n t he a nal ys es i ncl u di n g t h ose o btai n e d after I M P disc o nti n uati o n or i ntr o d ucti o n of 
resc ue t h era p y. C o nti n u o us sec o n dar y efficac y e n d p oi nts will be a nal yz e d wit h missi n g val ues 
i m p ute d b y t he r etrie ve d dr o p o uts & was h o ut i m p utati o n met h o d or b y t he c o ntr ol-base d c o p y 
refere nce i m p utati o n met h o d acc or di n g t o t he criteri o n descri be d i n Sec ti o n 2. 4. 4. 1 . 
F or t he cate g ori cal sec o n dar y efficac y e n d p oi nts, data ha n dli n g c o n ve nti o ns are des cri be d i n 
Secti o n  2. 4. 4. 2 . 
2. 5. 3  Mi s si n g d at a  
F or cate g orical varia bl es, patie nts wit h missi n g data are n ot i ncl u d e d i n calc ulati o ns of 
perce nt a ges u nless ot her wise s pecifie d.  W he n rel e va nt, t he n u m ber of pati e nts wit h missi n g data 
is prese nte d. 
Deri ve d varia bles will be c o nsi dere d missi n g if a n y of t he ori gi nal varia bl es re q uire d t o calc ulate 
t he m are missi n g. F or e x a m ple, if eit her a baseli n e assess me nt or a n e n d p oi nt assess me nt is 
missi n g f or a p artic ular p atie nt, t he n C ha n ge fr o m Baseli ne at e n d p oi nt will be missi n g. 
De pe n di n g u p o n t he ass ess me nt, a nal ys es ma y n ot i ncl u de all patie nts i n t he a nal ysis p o p ulati o n, 
beca use certai n patie nts i n t he i nte n de d p o p ulati o n ma y h a ve missi n g d ata.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 5  of 9 9  
 
I nc o m plete d ate of first a d mi nistr ati o n of d o u ble- bli n d I M P 
Date/ti me of first a d mi nistrati o n is t he first n o n -missi n g start date/ti me of d o u ble -bli n d I M P 
c o m plete d i n t he e C R F “ First d ose I M P” m o d ule. 
F or patie nts w h o are ra n d o mize d a n d dis pe nse d a d o u ble- bli n d treat me nt kit b ut w h o are l ost t o 
f oll o w-u p j ust after Visit 3 (e g , o nl y t he treat me nt kit n u m ber is re p orte d i n t he e C R F “ E x p os ure - 
treat me nt peri o d” m o d ul e wit h o ut a n y d os e i nf or mati o n), t he date of first a d mi nistrati o n will be 
i m p ute d usi n g t he date of ra n d o mizati o n. W he n a patie nt is ra n d o mize d b ut n ot e x p ose d, “ N ot 
ta ke n” s h o ul d be tic ke d i n t he e C R F “ First d ose I M P” m o d ule.  
H a n dli n g of c o m p ut ati o n of tre at m e nt d ur ati o n if I M P e n d of tre at m e nt d ate is missi n g   
F or t he calc ulati o n of t he treat me nt d urati o n, t he d ate of t he last d ose of d o u ble- bli n d I M P is e q ual 
t o t he date of last a d mi nistrati o n re p orte d o n t he e C R F “ Treat me nt stat us li brar y” p a ge.  If t his 
date is missi n g, t he e x p os ure d urati o n s h o ul d be l eft as missi n g.  
T he last d ose i nta ke s h o ul d be clearl y i de ntifie d i n t he case re p ort f or m a n d s h o ul d n ot be 
a p pr o xi mate d b y t he last ret ur ne d p ac ka ge date.  
H a n dli n g of missi n g d at a f or c o nti n u o us effic acy e n d p oi nts 
Please see  Secti o n  2. 4. 4. 1  a n d Secti o n  2. 4. 4. 2 . 
H a n dli n g of missi n g d at a f or c ate g oric al sec o n d ary effic a cy e n d p oi nts  
Please see Secti o n  2. 4. 4. 2 . 
H a n dli n g of m e dic ati o n missi n g/ p arti al d ates  
N o i m p utati o n of me dicati o n start/e n d dates or ti mes will be perf or me d.  If a me dicati o n date or 
ti me is missi n g or partiall y missi n g a n d it ca n n ot b e deter mi ne d w h et her it was ta ke n pri or or 
c o nc o mita ntl y, it will be c o nsi dere d a pri or, c o n c o mita nt, a n d p ost- treat me nt me dicati o n. 
H a n dl i n g of a dverse eve nts/ hy p o glyce mi a wit h missi n g or p arti al d ate/ti me of o nset  
Missi n g or partial a d v ers e e ve nt / h y p o gl yce mia o nset dates a n d ti mes will be i m p ute d  s o t hat if t he 
partial a d verse e v e nt / h y p o gl yce mia o nset date/ti me  i nf or mati o n d oes n ot i n dicate t hat t he 
A E/ h y p o gl yce mia starte d pri or t o treat me nt or after t he treat me nt -e mer ge nt A E , t he a d verse 
e ve nt/ h y p o gl yce mia will be classifie d as treat me nt -e mer ge nt.   
N o i m p utati o n of a d verse e ve nt e n d dat es/ti mes will be perf or me d. T hese d ata i m p utat i o ns are f or 
cate g orizati o n p ur p ose o nl y a n d will n ot be use d i n listi n gs.  N o i m p utati o n is pla n ne d f or 
date/ti me of a d vers e e v e nt res ol uti o n. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 6  of 9 9  
 
H a n dli n g of a dverse eve nts / hy p o glyce mi a w he n d ate a n d ti m e of first I M P a d mi nistr ati o n is 
missi n g  
W he n t he date a n d ti me of t he first d o u ble- bli n d I M P a d mi nistrati o n is missi n g, t he da y of 
ra n d o mizati o n s h o ul d be c o nsi dere d as t he start date of T E A E peri o d (see S ecti o n  2. 1. 4 ) T he 
e x p os ure d urati o n s h o ul d be ke pt as missi n g. 
H a n dli n g of a dverse eve nts/ hy p o glyce mi a w he n I M P e n d of tre at m e nt d ate is missi n g  
F or t he p ur p os e of defi ni n g treat me nt-e mer ge nt A E peri o d, t he date of t he l ast a d mi nistrati o n of 
d o u ble- bli n d I M P is e q ual t o t he date of t he last a d mi nistrati o n re p orte d o n t he e- C R F “ Treat me nt 
Stat us Li brar y” pa ge. If t he date of last a d mi nistrati o n re p orte d o n t he e- C R F “ Treat me nt Stat us 
Li br ar y” p a ge is :  
•  Part iall y missi n g, it will be i m p ute d wit h a date as late as p ossi ble bef ore or o n t he date of 
last a vaila ble i nf or mati o n o n e C R F “ C o m pleti o n of E n d of St u d y/ F oll o w- u p”.  
•  C o m pletel y missi n g, it will be i m p ute d wit h t he date of last a v aila ble i nf or mati o n o n e C R F 
“ C o m pleti o n of E n d of St u d y/ F oll o w- u p ” pa ge.  
If t he date of last a vaila bl e i nf or mati o n o n e C R F “ C o m pleti o n of E n d of St u d y/ F oll o w- u p” pa ge 
is:  
•  Partiall y missi n g, it will be i m p ute d wit h a date as late as p ossi ble.  
•  C o m pletel y missi n g, all a d verse e v e nts  occ urre d o n or after t h e first a d mi nistrati o n of 
d o u ble- bli n d I M P will be c o nsi dere d as treat me nt e mer ge nt a d v erse e ve nts.  
H a n dli n g of missi n g assess m e nt of rel ati o ns hi p of a dverse eve nts t o I M P 
If t he assess me nt of t he r elati o ns hi p t o I M P is missi n g, t he relati o ns hi p t o I M P has t o be ass u me d 
a n d t he a d verse e v e nt c o nsi dere d as s uc h i n t he fre q ue nc y ta bl es of p ossi bl y relate d a d v erse 
e ve nts, b ut n o i m p utati o n s h o ul d be d o ne at t he dat a le vel. 
H a n dli n g of missi n g severity/ gr a des of a dvers e eve nts  
If t he se verit y/ gr a de is missi n g f or 1 of t h e treat m e nt-e mer ge nt occ urre n ces of a n a d verse e v e nt, 
t he ma xi mal se verit y o n t he re mai ni n g occ urre nces will be c o nsi dere d.  If t he se verit y is missi n g 
f or all t he occ urr e nces, a “ missi n g” cate g or y will be a d de d i n t he s u m mar y ta ble. 
H a n dli n g of p ote nti ally cli nic ally si g nific a nt a b n or m alities  
If a patie nt h as a missi n g baseli ne he will be gr o u p e d i n t he cate g or y “ n or m al/ missi n g at 
baseli ne.”  
F or P C S As wit h 2 c o n diti o ns, o ne base d o n a C ha n ge fr o m Baseli ne  v al ue or a n or mal ra n ge a n d 
t he ot her o n a t hr es h ol d val ue, wit h t he first c o n diti o n bei n g missi n g, t he P C S A will be base d o nl y 
o n t he sec o n d c o n diti o n. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 7  of 9 9  
 
F or a P C S A defi ne d o n a t hres h ol d a n d/ or a n or m al ra n ge, t his P C S A will be deri ve d usi n g t his 
t hres h ol d if t he n or mal ra n ge is missi n g; e g, f or e osi n o p hils t he P C S A is > 0. 5 GI G A/ L or > U L N 
if U L N ≥0. 5 GI G A/ L.  W he n U L N is missi n g, t he val ue 0. 5 s h o ul d be us e d. 
Meas ure me nts fla g ge d as i n vali d b y t he la b orat or y will n ot be s u m marize d or ta ke n i nt o acc o u nt 
i n t he c o m p utati o n of P C S A val ues.   
Li n ke d a dverse eve nts t h at w orse ne d or bec a m e seri o us  
A n A E t hat w orse n e d or beca me s eri o us will ha ve a se parate rec or d i n t he data fr o m t he ori gi nal 
e ve nt rec or d wit h a n A E i de ntificati o n n u m ber t hat li n ks t he ne w rec or d t o t he ori gi n al rec or d. A n 
A E t hat w orse n e d or beca me seri o us will be c o nsi dere d a n e w rec urri n g A E i n t he s u m mar y of 
rec urre nt e v e nts or i n t he s u m mar y of e ve nts b y ti me i nter vals. 
2. 5. 4  Wi n d o w s f or ti m e p oi nt s / M e a s ur e m e nt s f or a n al y s e s  
T he f oll o wi n g ste ps will deci de h o w t he s c he d ule d a n d/ or u nsc he d ule d visits will be use d i n 
efficac y a n al ys es a n d  b y -visit s u m mar y a nal yses f or safet y varia bles (cli nical la b orat or y d ata i n 
Secti o n  2. 1. 4. 4  a n d vital si g ns i n  Secti o n  2. 1. 4. 5 ). 
Ste p 1 A sc he d ule d meas ure me nt will be use d if it is a vaila ble; ot her wise, a n u nsc he d ule d 
meas ure me nt (i n cl u di n g t he e n d of tr eat me nt/st u d y visit f or t h ose pre mat urel y disc o nti n ue d) will 
be use d if it ha p pe ns t o b e o n t he sa me dat e as t he date of t he sc h e d ule d visit. 
Ste p 2 After Ste p 1, if t he re are still n o meas ure m e nt f or a gi ve n p ara m eter at a sc he d ule d visit, 
t he a nal ysis wi n d o w bel o w (Ta ble  4) will be a p plie d t o re-all ocate a p ost -b ase li ne u nsc he d ul e d 
meas ure me nt t o a s c he d ule d meas ure m e nt.  
T a bl e  4 - A n al y s e s wi n d o w d efi niti o n  
S c h e d ul e d vi sit p o st b a s eli n e  
T ar g et e d st u d y d a y  
A n al y si s wi n d o w i n st u d y 
d a y s  
W e ek 1 ( Visit 4)  
7 
2 t o 1 7 
W e ek 4 ( Visit 5)  
2 8  
1 8 t o 4 1  
W e ek 8 ( Visit 6)  
5 6  
4 2 t o 6 9  
W e ek 1 2 ( Visit 7)  
8 3/ 8 4  
7 0 t o 1 0 4 
W e ek 1 8 ( Visit 8)  
1 2 6  
1 0 5 t o 1 5 3  
W e ek 2 6 ( Visit 9)  
 1 8 1/ 1 8 2  
1 5 4 t o 2 2 7  
W e ek 3 9  ( Visit 1 0) 
W e ek 5 2 ( Visit 1 1)  
W e ek 6 5 ( Visit 1 2)  
W e ek 7 9 ( Visit 1 3)  
2 7 3  
3 6 5 
4 5 5  
5 5 1  
2 2 8 t o 3 1 8  
3 1 9  t o 4 0 9  
4 1 0 t o 5 0 2  
> 5 0 2   
St u dy d ays are c alc ul at e d fro m t h e d ay of first a d mi nistrati o n of d o u bl e -bli n d I M P; t h e d ay of first a d mi nistrati o n of I M P ( or t h e d ay of 
ra n d o mizati o n if n ot ex p os e d) is D ay 1.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 8  of 9 9  
 
 
After a p pl yi n g a b o v e visit wi n d o ws, if m ulti ple assess me nts are ass ociate d t o t he sa me ti me p oi nt, 
t he cl osest fr o m t he tar gete d st u d y da y will be use d. I n case of e q ualit y, t he last meas ure me nt will 
be use d. Re-all ocate d sc h e d ule d visits (ie, visit n u m ber) s h o ul d be se q u e ntial if or dere d b y t he 
date of  meas ure me nt.  
After Ste p 2, if t her e ar e still n o meas ure me nt f or a gi v e n para meter at a sc he d ule d visit, data is 
c o nsi dere d missi n g f or efficac y a nal yses, w h ere m ulti ple i m p utati o n w o ul d be a p plie d as 
a p pr o priatel y as descri b e d i n Secti o n  2. 4. 4 .  
F or A B P M s u bst u d y, a n a nal ysis wi n d o w of 7 0 t o 1 3 3 was use d f or Visit 7 A, a n d 1 3 4- 2 2 7 f or 
Visit 9 A.  
Refere nce d a y  
T he ref er e nce d a y f or t h e calc ulati o n of e xte nt of e x p os ure, ti me t o o nset, a n d relati ve da ys will be 
t he da y of t he first a d mi nistrati o n of d o u ble- bli n d I M P or t he d a y of ra n d o mizati o n if n ot e x p ose d 
t o d o u ble- bli n d I M P, de n ote d as Da y 1. 
B aseli ne defi niti o n f or effic acy/s afety d at a  
F or t he safet y a n al ys es, t he baseli ne f or a gi ve n p ara meter is defi ne d as t he last a vaila ble 
meas ure me nt ( or t he a v er a ge of all meas ure me nts f or creati ni ne a n d e G F R), i ncl u di n g 
u nsc he d ule d ass ess me nts, assesse d pri or t o t he first a d mi nistrati o n of d o u ble- bli n d I M P. F or t he 
efficac y a n al ys es, t he bas eli ne f or a gi v e n para met er is defi ne d as t he last a vaila ble meas ure me nt 
( or t he a v era ge of all meas ure me nts f or creati ni ne a n d e G F R), i ncl u di n g u nsc he d ule d ass ess me nts, 
assesse d pri or t o t he first a d mi nistrati o n  of d o u ble-bli n d I M P or t he last a v aila ble val ue ( or t he 
a vera ge of all meas ure m e nts f or cr eati ni ne a n d e G F R) bef ore ra n d o mizati o n if n ot treate d wit h 
d o u ble- bli n d I M P.  
S u m m ary st atistics by visit f or c o nti n u o us effic acy e n d p oi nts  
S u m mar y statistics ( n u m b er, mea n, S D, S E, mi ni m u m, me dia n, ma xi m u m) of c o nti n u o us efficac y 
e n d p oi nts ( o bser ve d d ata a n d C ha n ge fr o m Bas eli ne ) will be pr o vi de d at sc he d ule d visits as per 
pr ot oc ol. S u m maries s h o wi n g dat a b y visit will be prese nte d acc or di n g t o t he visit n u m ber ( or 
re-all ocate d visit n u m ber) a n d la bele d wit h t he tar get e d a p pr o xi mate da y/ w ee k.  
L ast o n-tre at m e nt v al ue f or l a b or at ory v ari a bles a n d vit al si g ns 
T he last o n -treat me nt val ue is t he fi nal meas ure me nt assesse d d uri n g t he treat me nt e p oc h, 
re gar dl ess of t he i ntr o d ucti o n of resc ue t hera p y, i n cl u di n g meas ure me nts at u nsc he d ule d visits. 
Please see d etails i n Secti o n  2. 1. 4  a n d Secti o n  2. 4. 5 .  
Dis pl ay of s afety d at a by visit (l a b or at ory v ari a bles a n d vit al si g ns)  
Descri pti ve statistics ( n u m ber , mea n, S D, mi ni m u m, me dia n, ma xi m u m) of q ua ntitati ve 
la b orat or y varia bles a n d vital si g ns ( o bser v e d data a n d c ha n ge fr o m bas eli ne) d uri n g t he T E A E 
peri o d will be pr o vi de d at sc he d ule d visits. I n a d diti o n, t hese s u m maries will als o i ncl u de a r o w 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 5 9  of 9 9  
 
f or t he ‘last val u e o n -treat me nt’ t o descri be t he last a vaila ble o n-treat me nt val ue (see a b o ve). 
S u m maries s h o wi n g data b y visit will be prese nte d acc or di n g t o t he visit n u m ber ( or re -all ocate d 
visit n u m ber, see Secti o n  2. 5. 4 ) a n d la bele d wit h t he tar gete d a p pr o xi mate da y/ w ee k. 
As s pecifie d i n t he st u d y pr ot oc ol, la b orat or y d ata fr o m sc he d ule d visits are re p orte d b y ce ntral 
la b orat ories. T h e l ocal r es ults will n ot be use d i n t he effi cac y a nal yses or i n t he defi niti o n of 
baseli ne f or b ot h safet y a n d efficac y a n al ys es. I n t he safet y a nal yses, f or para meters wit h P C S A 
defi ne d bas e d o n n or mal ra n ge, l ocal res ults will o nl y be us e d i n t he P C S A s u m mary if t he y are 
acc o m pa ni e d b y a l ocal l a b orat or y n or m al ra n ge.  F or para meters wit h P C S A n ot defi ne d bas e d o n 
n or mal ra n ge, l o cal res ults will be use d i n t he P C S A s u m mar y a s a p pr o priat e. 
W he n a patie nt has m ore t ha n 1 meas ure m e nt fr o m t he ce ntral la b orat or y f or t he sa me la b or at or y  
para meter o n t he sa me d ate, t he a ver a ge of t he meas ure me nts will be use d. F or t he sa m e 
la b orat or y para meter, if a patie nt has m ore t ha n 1 meas ure me nt o n differe nt dates f or t he sa m e 
sc he d ule d visit, t he val ue cl osest t o t he date of t he visit will be use d f or t he sc he d ule d visit. W he n 
t he val ues f or t he s a me s c he d ule d visit are e q ui dista nt, t he last val ue s h o ul d be use d f or t h e 
sc he d ule d visit. 
2 6- wee k d o u ble bli n d c ore tre at m e nt peri o d  
T he 2 6- wee k d o u ble- bli n d c ore tr eat me nt peri o d is t he ti me fr o m first a d mi nistrati o n of d o u ble-
bli n d I M P t o t he last a d mi nistrati o n of d o u ble- bli n d I M P o n or b ef ore Visit 9/ Wee k 2 6 
( or Da y  1 8 2 if Visit 9/ Wee k 2 6 date is missi n g). T his is f or a nal yzi n g selecte d efficac y para meters 
(e g, res c ue d patie nts) d uri n g c or e treat me nt peri o d.  
T E A E peri o d f or t he 2 6- wee k c ore tre at m e nt peri o d  
T he T E A E peri o d f or c or e treat me nt peri o d is ( 1) t he ti me fr o m t he first a d mi nistrati o n of t he 
d o u ble- bli n d I M P u p t o 1 0 da ys ( 1 da y f or h y p o gl yce mia) after t he l ast a d mi nistrati o n of I M P if 
t he patie nt disc o nti n ue d treat me nt o n or b ef ore Visit 9 ( or Da y  1 8 2 if Visit 9 date is missi n g) , or 
( 2) t he ti me fr o m t he first a d mi nistrati o n of t he d o u ble-bli n d I M P  t o t he a d mi nistrati o n at 
Visit  9/ Wee k 2 6 ( or Da y 1 8 2 if Visit 9/ Wee k 2 6 date is missi n g) if t he pati e nt disc o nti n ue d 
treat me nt after Visit 9/ Wee k 2 6. T his is f or t he p ur p ose of safet y a n al ys es d uri n g t he c ore 
treat me nt peri o d. 
Ti m e t o eve nt a n alysis  
F or ti me t o e ve nt a n al ysis/ K M pl ot, ti me t o e ve nt (e g, treat me nt disc o nti n uati o n, resc ue t h era p y, 
h y p o gl yce mia, etc) is d efi ne d as t he n u m ber of d a ys fr o m t he date of t h e first a d mi nistrati o n of 
d o u ble- bli n d I M P ( or t he date of r a n d o mizati o n if n ot e x p ose d ) t o t he start date of t he first 
occ urr e nce of t he e v e nt d uri n g t he 7 9- wee k d o u ble- bli n d treat me nt peri o d.  
Patie nts w h o di d n ot e x perie nce a n y e v e nt d uri n g t he 7 9- wee k d o u ble- bli n d treat me nt peri o d are 
c o nsi dere d ce ns or e d o bser vati o ns. F or ti me t o treat me nt disc o nti n uati o n/resc ue t hera p y, ce ns ori n g 
date is t he date of E O T. F or ti me t o se vere or d o c u me nte d h y p o gl yce mia, ce ns ori n g date is dat e of 
E O T + 1 or d ate of E O S, w hic he ver is t he earliest. Date of E O S will be use d if date of E O T is n ot 
a vaila ble. Last co ntact date will be use d if date of E O S is n ot a vaila ble.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 0  of 9 9  
 
2. 5. 5  U n s c h e d ul e d vi sit s  
U nsc he d ule d visit meas ure me nts  of la b orat or y dat a, vital si g ns, a n d E C G will be use d f or 
c o m p utati o n of baseli ne, t he last o n- treat me nt val u e, P C S As  a n d t he s hift s u m maries f or safet y or 
efficac y. T he y will be i ncl u de d i n t he b y-visit s u m maries if t he y are re -all ocate d t o sc he d ul e d visit 
(see Secti o n  2. 5. 4 ). 
2. 5. 6  P o oli n g of c e nt er s f or st ati sti c al a n al y s e s  
Ce nter will n ot be i ncl u d e d i n t he statistical m o dels f or efficac y a n al ysis. H o we ver, all data fr o m 
t he ce nters wit hi n eac h c o u ntr y will be p o ol e d, a n d t he c o u ntr y will be i ncl u de d as fi x e d fact ors if 
para metri c  statistical m o del ( A N C O V A m o del, etc) are us e d f or pri mar y a n d sec o n dar y efficac y 
e n d p oi nts. C o u ntries wit h fe w er t h a n 5 ra n d o mize d patie nts will be gr o u p e d , if n u m ber of patie nts 
fr o m gr o u pe d c o u ntri es are still fe wer t ha n 5, t he y will t he n be f urt her gr o u pe d wit h t he c o u ntr y 
wit h t he l o we st n u m ber of patie nts t hat is 5 or m ore.  
2. 5. 7  St ati sti c al t e c h ni c al i s s u e s  
N ot a p plica ble.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 1  of 9 9  
 
3 
I N T E RI M A N A L Y SI S 
N o f or mal i nteri m a nal ysis f or efficac y is pla n n e d f or t his st u d y. T he st u d y will n ot be ter mi nate d 
earl y f or e x celle nt effi cac y.  
A n i n de pe n de nt D ata M o nit ori n g C o m mittee ( D M C) will be use d t o m o nit or a n d assess t he s afet y 
of patie nts fr o m t his trial t hr o u g h p eri o dic re vi e w of t he acc u m u late d safet y dat a pr o vi de d b y a n 
i n de pe n de nt statistical gr o u p. Relate d details are pr o vi de d i n se parate d oc u me nts ( D M C c harter 
a n d D M C S A P).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 2  of 9 9  
 
4 
D A T A B A S E L O C K  
T he data bas e is pla n ne d t o be l oc ke d a p pr o xi matel y 4 w ee ks after t he last p atie nt last visit. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 3  of 9 9  
 
5 
S O F T W A R E D O C U M E N T A TI O N  
All s u m maries a n d statistical a nal yses will be ge nerate d usi n g S A S ®  versi o n 9. 2 or hi g h er. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 4  of 9 9  
 
6 
R E F E R E N C E S  
 
1.  O' Brie n E, Parati G, Ster gi o u G, As mar R, Beili n L, Bil o G, et al. E ur o p ea n S ociet y of 
H y p erte nsi o n P ositi o n Pa per o n A m b ulat or y Bl o o d Press ure M o nit ori n g. J H y p erte ns. 
2 0 1 3; 3 1( 9): 1 7 3 1- 6 8. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 5  of 9 9  
 
7 
LI S T O F A P P E N DI C E S  
 
A p pe n di x A : 
Ma p pi n g of i n cl usi o n a n d e x cl usi o n criteria u n der t he ori gi nal pr ot oc ol a n d 
A me n d me nt 1  
A p pe n di x B : 
Sa m ple  S A S ® c o de f or a nal yses of efficac y e n d p oi nts   
A p pe n di x C : 
A m b ulat or y bl o o d press ure m o nit ori n g s u bst u d y  
A p pe n di x D : 
A B P M s u bst u d y efficac y varia ble deri vati o n  
A p pe n di x E : 
P ote ntiall y cli nicall y si g nifica nt a b n or malities crit eria  
A p pe n di x F : 
List of P Ts f or sel ect E O SIs ( Me d D R A v 2 1. 1)  
A p pe n di x G : 
S u m mar y of statistical a n al yses  
A p pe n di x H : 
St u d y Fl o w C hart  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 6  of 9 9  
 
A p p e n di x A  
M a p pi n g of i n cl u si o n a n d e x cl u si o n crit eri a u n d er t h e ori gi n al 
pr ot o c ol a n d A m e n d m e nt 1  
 
Or d er  
Ori gi n al Pr ot o c ol  
A m e n d m e nt 1  
C S R Di s pl a y  
1  
I 0 1 
 
I 0 1 
2  
I 0 2 
 
I 0 2 
3  
E 0 1  
 
E0 1  
4  
E 0 2  
 
E0 2  
5  
E 0 3  
 
E0 3  
6  
E 0 4  
 
E0 4  
7  
E 0 5  
 
E0 5  
8  
E 0 6  
 
E0 6  
9  
E 0 7  
 
E0 7  
1 0  
E 0 8  
 
E0 8  
1 1  
E 0 9  
 
E0 9  
1 2  
E 1 0  
 
E1 0  
1 3  
E 1 1  
 
E1 1  
1 4  
E 1 2  
 
E1 2  
1 5  
E 1 3  
 
E1 3  
1 6  
E 1 4  
 
E1 4  
1 7  
E 1 5  
 
E1 5  
1 8  
E 1 6  
E3 3  
E1 6/ E3 3 A1  
1 9  
E 1 7  
E1 6  
E1 7/ E1 6 A1  
2 0  
E 1 8  
E1 7  
E1 8/ E1 7 A1  
2 1  
E 1 9  
E1 8   
E1 9/ E1 8 A1  
2 2  
E 2 0  
E1 9  
E2 0/ E1 9 A1  
2 3  
E 2 1  
E2 0  
E2 1/ E2 0 A1  
2 4  
E 2 2  
E2 1  
E2 2/ E2 1 A1  
2 5  
E 2 3  
E2 2  
E2 3/ E2 2 A1  
2 6  
E 2 4  
E2 3  
E2 4/ E2 3 A1  
2 7  
E 2 5  
E2 4  
E2 5/ E2 4 A1  
2 8  
E 2 6  
E2 5  
E2 6/ E2 5 A1  
2 9  
E 2 7  
E2 6  
E2 7/ E2 6 A1  
3 0  
E 2 8  
E2 7  
E2 8/ E2 7 A1  
3 1  
E 2 9  
E2 7  
E2 9/ E2 7 A1  
3 2  
E 3 0  
E2 8   
E3 0/ E2 8 A1  
3 3  
E 3 1  
E2 9  
E3 1/ E2 9 A1  
3 4  
E 3 2  
 
E3 2  
3 5  
E 3 3  
E3 0   
E3 3/ E3 0 A1  
3 8  
  
E3 1  
E3 1 A1  
3 9  
  
E3 2  
E3 2 A1  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 7  of 9 9  
 
A p p e n di x B  
S a m pl e S A S ® c o d e f or a n al y s e s of effi c a c y e n d p oi nt s  
 
* V A RI A B L E S;  
* tr e at - tr e at m e nt; 
* str at a 1 - str atifi c ati o n f a ct or 1;  
* str at a 2 - str atifi c ati o n f a ct or 2; 
* v al u e 0 - v al u e at b a s eli n e;  
* v al u e 1  … v al u e n - v al u e at e a c h p o st -b a s eli n e vi sit f or a t ot al of n vi sit s;  v al u e n f or t h e e n d p oi nt vi sit;  
* c h a n g e - c h a n g e fr o m b a s eli n e;  
***************************************************************************************************************** ; 
****P art 1: Pr ef err e d i m p ut ati o n m et h o d: t h e r etri e v e d dr o p o ut s a n d w a s h o ut i m p ut ati o n *****; 
***************************************************************************************************************** ; 
/* P art 1 a, f or p ar a m et er s wit h n o mi s si n g d at a at b a s eli n e */; 
* MI i n p ati e nt s w h o pr e m at ur el y di s c o nti n u e d I M P b ef or e t h e e n d p oi nt u si n g t h e e n d p oi nt d at a fr o m it s 
o w n gr o u p (r etri e v e d dr o p o ut s);  
      pr o c s ort d at a = a d s;  
 
b y tr e at pti d;  
      r u n;  
    pr o c mi d at a = a d s o ut =  di s c _ mi  ni m p ut e = 2 0 0 0 s e e d = 9 7 5 3 1;  
 
w h er e di s c o nti n u e = “ Y";  
 
b y tr e at;  
 
v ar v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = v al u e 0 );  
    r u n; 
* MI i n p ati e nt s w h o st a y o n t h e I M P u ntil t h e e n d p oi nt vi sit u si n g t h e e n d p oi nt d at a fr o m t h e pl a c e b o gr o u p 
( w a s h-o ut MI);  
      pr o c s ort d at a = a d s;  
 
b y pti d;  
      r u n;  
    pr o c mi d at a = a d s o ut =  c o m p _ mi  ni m p ut e = 2 0 0 0 s e e d = 7 5 3 1 9;  
w h er e di s c o nti n u e =" N" a n d (tr e at = 1 or (tr e at n e 1 a n d v al u e n =. )); * 1 d e n ot e s pl a c e b o gr o u p;  
 
cl a s s str at a 1 str at a 2;  
 
v ar str at a 1 str at a 2 v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = str at a 1 str at a 2  v al u e 0 );  
    r u n; 
* R e p e at d at a s et wit h t h e s a m e n u m b er of r e pli c ati o n s f or r e m ai ni n g p ati e nt s w h o h a v e c o m pl et e d at a at 
t h e e n d p oi nt vi sit; 
    d at a c o m p _trt;  
s et a d s ( w h er e =( di s c o nti n u e =" N" a n d  tr e at n e 1 a n d v al u e n n e .));  
_i m p ut ati o n _ = 0;  
d o i = 1 t o 2 0 0 0;  
_i m p ut ati o n _ = _i m p ut ati o n _ + 1;  
o ut p ut;  
e n d;  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 8  of 9 9  
 
    r u n; 
* C o m bi n e t hr e e s u b s et s of p ati e nt s; 
    d at a mi _ 1;  
 
s et di s c _ mi c o m p _ mi c o m p _trt;  
    r u n; 
/* P art 1 b, f or p ar a m et er s wit h mi s si n g d at a at b a s eli n e */ 
* I m p ut e t h e mi s si n g d at a at b a s eli n e; 
      pr o c s ort d at a = a d s;  
 
b y pti d;  
      r u n;  
    pr o c mi  d at a = a d s o ut = mi _ b a s e ni m p ut e = 2 0 0 0 s e e d = 1 3 5 7 9;  
cl a s s str at a 1 str at a 2;  
             v ar str at a 1 str at a 2 v al u e 0;  
             m o n ot o n e r e gr e s si o n;  
    r u n; 
* MI i n p ati e nt s w h o pr e m at ur el y di s c o nti n u e d I M P b ef or e t h e e n d p oi nt u si n g t h e e n d p oi nt d at a fr o m it s  
o w n gr o u p (r etri e v e d dr o p o ut s);  
      pr o c s ort d at a = mi _ b a s e;  
 
b y _i m p ut ati o n _ tr e at pti d;  
      r u n;  
    pr o c mi d at a = mi _ b a s e o ut =  di s c _ mi  ni m p ut e = 1 s e e d = 9 7 5 3 1;  
 
w h er e di s c o nti n u e = “ Y";  
 
b y _i m p ut ati o n _ tr e at;  
 
v ar v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = v al u e 0 );  
    r u n; 
* MI i n p ati e nt s w h o st a y o n t h e I M P u ntil t h e e n d p oi nt vi sit u si n g t h e e n d p oi nt d at a fr o m t h e pl a c e b o gr o u p 
( w a s h-o ut MI);  
      pr o c s ort d at a = mi _ b a s e;  
 
b y _i m p ut ati o n _ pti d;  
      r u n;  
    pr o c mi d at a = mi _ b a s e o ut =  c o m p _ mi   ni m p ut e = 1 s e e d = 7 5 3 1 9;  
w h er e di s c o nti n u e =" N" a n d (tr e at = 1 or (tr e at n e 1 a n d v al u e n =. )); * 1 d e n ot e s pl a c e b o gr o u p;  
b y _i m p ut ati o n _;  
 
cl a s s str at a 1 str at a 2;  
 
v ar str at a 1 str at a 2 v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = str at a 1 str at a 2  v al u e 0 );  
    r u n; 
 
* C o m bi n e s u b s et s of p ati e nt s; 
    d at a mi _ 1;  
 
s et di s c _ mi c o m p _ mi mi _ b a s e ( w h er e =( di s c o nti n u e " N" a n d (tr e at n e 1 a n d v al u e n ^ =.));  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 6 9  of 9 9  
 
    r u n; 
 
*****************************************************************************************;  
************P art 2: B a c k -u p i m p ut ati o n m et h o d: C o ntr ol -b a s e d MI ************; 
*****************************************************************************************;  
/* P art 2 a, f or p ar a m et er s wit h n o mi s si n g d at a at b a s eli n e*/; 
* P arti al i m p ut ati o n s t o r e n d er m o n ot o n e mi s si n g d at a; 
      pr o c s ort d at a = a d s;  
             b y tr e at str at a 1 str at a 2 pti d;               
      R u n;  
    pr o c mi d at a = a d s o ut = m o n ot o n e ni m p ut e = 2 0 0 0 s e e d = 9 7 5 3 1;  
 
b y tr e at str at a 1 str at a 2;  
             v ar v al u e:;  
             m c m c c h ai n = m ulti pl e i m p ut e = m o n ot o n e;  
r u n; 
     
      * P arti al i m p ut ati o n s t o r e n d er m o n ot o n e mi s si n g d at a; Dr o p str at a if i m p ut ati o n c o ul d n ot c o n v er g e;  
      pr o c s ort d at a = a d s;  
             b y tr e at pti d;               
      R u n;  
      pr o c mi d at a = a d s o ut = m o n ot o n e ni m p ut e = 2 0 0 0 s e e d = 9 7 5 3 1;  
             b y tr e at;               
             v ar v al u e:;   
             m c m c c h ai n = m ulti pl e i m p ut e = m o n ot o n e;  
      r u n; 
 
* T o i m p ut e t h e mi s si n g d at a at p o st-b a s eli n e vi sit s;  
      pr o c s ort  d at a = m o n ot o n e;  
             b y _i m p ut ati o n _ pti d;  
      r u n; 
    pr o c mi d at a = m o n ot o n e o ut = mi _ 1 ni m p ut e = 1 s e e d = 7 5 3 1 9;  
             b y _i m p ut ati o n _;  
             cl a s s tr e at str at a 1 str at a 2;  
             m o n ot o n e r e g (  / d et ail s);  
             m n ar m o d e l ( v al u e: / m o d el o b s =(tr e at =' 1')); * 1 d e n ot e s pl a c e b o gr o u p; 
             v ar str at a 1 str at a 2 v al u e:;  
    r u n; 
/* P art 2 b, f or p ar a m et er s wit h mi s si n g d at a at b a s eli n e */ 
* T o i m p ut e t h e mi s si n g d at a at b a s eli n e; 
      pr o c s ort d at a = a d s;  
 
b y pti d;  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 0  of 9 9  
 
      r u n;  
    pr o c mi d at a = a d s o ut = m i _ b a s e ni m p ut e = 20 0 0 s e e d = 1 3 5 7 9;  
cl a s s str at a 1 str at a 2;  
             v ar str at a 1 str at a 2 v al u e 0;  
             m o n ot o n e r e gr e s si o n;  
    r u n; 
* P arti al i m p ut ati o n t o r e n d er m o n ot o n e mi s si n g; 
      pr o c s ort d at a = mi _ b a s e ; 
             b y _i m p ut ati o n _ tr e at str at a 1 str at a 2 pti d;               
      R u n;  
 
    pr o c mi d at a = mi _ b a s e o ut = m o n ot o n e ni m p ut e = 1 s e e d = 3 5 7 9 1;  
             b y _i m p ut ati o n _ tr e at str at a 1 str at a 2;  
             v ar v al u e:;  
             m c m c c h ai n = m ulti pl e i m p ut e = m o n ot o n e;  
    r u n; 
 
* N ot e f or p arti al i m p ut ati o n s t o r e n d er m o n ot o n e mi s si n g d at a, dr o p str at a 1 a n d str at a 2 if i m p ut ati o n c o ul d 
n ot c o n v er g e, s a m e a s i n P art 2 a.  
* T o i m p ut e t h e mi s si n g d at a at p o st-b a s eli n e vi sit s;  
      pr o c s ort  d at a = m o n ot o n e;  
             b y _i m p ut ati o n _ pti d;  
      r u n; 
    pr o c mi d at a = m o n ot o n e o ut = mi _ 1 ni m p ut e = 1 s e e d = 5 7 9 1 3;  
             b y _i m p ut ati o n _;  
             cl a s s tr e at str at a 1 str at a 2;  
             m o n ot o n e r e g (  / d et ail s);  
             m n ar m o d el ( v al u e: / m o d el o b s =(tr e at = ' 1')); * 1 d e n ot e s pl a c e b o gr o u p; 
             v ar str at a 1 str at a 2 v al u e:;  
    r u n; 
 
*****************************************************************************************;  
************ P art 3: M ulti pl e i m p ut ati o n f or ti p pi n g -p oi nt a n al y si s ************; 
*****************************************************************************************;  
/* P art 3 a, Pri m ar y i m p ut ati o n m et h o d: f or p ar a m et er s wit h n o mi s si n g d at a at b a s eli n e */; 
* MI i n p ati e nt s w h o pre m at ur el y di s c o nti n u e d I M P b ef or e t h e e n d p oi nt;  
pr o c s ort d at a = a d s;  
 
b y tr e at pti d;  
    r u n; 
    pr o c mi d at a = a d s o ut =  di s c _ mi  ni m p ut e = 2 0 0 0 s e e d = 9 7 5 3 1;  
 
w h er e di s c o nti n u e = “ Y";  
 
b y tr e at;  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 1  of 9 9  
 
 
 
v ar v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = v al u e 0 );  
             m n ar a dj u st ( v al u e n / s hift = 0. 1 a dj u st o b s =(tr e at = ' 2')); * 2 d e n ot e s t e st dr u g gr o u p; 
    r u n; 
* MI i n p ati e nt s w h o st a y o n t h e I M P u ntil t h e e n d p oi nt vi sit u si n g t h e e n d p oi nt d at a fr o m t h e pl a c e b o gr o u p 
( w a s h-o ut MI) ;  
    pr o c s ort d at a = a d s;  
 
b y pti d;  
    r u n; 
    pr o c mi d at a = a d s o ut =  c o m p _ mi  ni m p ut e = 2 0 0 0 s e e d = 7 5 3 1 9;  
w h er e di s c o nti n u e =" N" a n d (tr e at = 1  or (tr e at n e 1  a n d v al u e n =. )); * 1 d e n ot e s pl a c e b o gr o u p;  
 
cl a s s tr e at str at a 1 str at a 2;  
 
v ar tr e at str at a 1 str at a 2 v al u e 0 v al u e n;  
 
m o n ot o n e r e gr e s si o n ( v al u e n = str at a 1 str at a 2  v al u e 0 ); 
             m n ar a dj u st ( v al u e n / s hift = 0. 1 a dj u st o b s =(tr e at = '2' )); * 2 d e n ot e s t e st dr u g gr o u p; 
    r u n; 
/* P art 3 b, B a c k-u p i m p ut ati o n m et h o d, f or p ar a m et er s wit h n o mi s si n g d at a at b a s eli n e*/;  
* P arti al i m p ut ati o n t o r e n d er m o n ot o n e mi s si n g d at a; 
      pr o c s ort d at a = a d s;  
             b y tr e at str at a 1 str at a 2 pti d;               
      r u n; 
    pr o c mi d at a = a d s o ut = m o n ot o n e ni m p ut e = 2 0 0 0 s e e d = 9 7 5 3 1;  
 
b y tr e at str at a 1 str at a 2;  
             v ar v al u e:;  
             m c m c c h ai n = m ulti pl e i m p ut e = m o n ot o n e;  
    r u n; 
 
* N ot e f or p arti al i m p ut ati o n s t o r e n d er m o n ot o n e mi s si n g d at a, dr o p str at a 1 a n d str at a 2 if i m p ut ati o n c o ul d 
n ot c o n v er g e, s a m e a s i n P art 2 a.  
* T o i m p ut e t h e mi s si n g d at a at p o st-b a s eli n e vi sit s wit h p e n alt y i n t e st dr u g gr o u p ;  
      pr o c s ort d at a = m o n ot o n e;  
             b y _i m p ut ati o n _ pti d;  
      r u n; 
    pr o c mi d at a = m o n ot o n e o ut = mi _ 1 ni m p ut e = 1 s e e d = 7 5 3 1 9;  
             b y _i m p ut ati o n _;  
             cl a s s tr e at str at a 1 str at a 2;  
             m o n ot o n e r e g (  / d et ail s);  
             m n ar m o d el ( v al u e: / m o d el o b s =(tr e at = ' 1')); * 1 d e n ot e s c o ntr ol gr o u p; 
             m n ar a dj u st ( v al u e n / s hift = 0. 1 a dj u st o b s =(tr e at = ' 2')); * 2 d e n ot e s t e st dr u g gr o u p; 
             v ar str at a 1 str at a 2 v al u e:;  
    r u n; 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 2  of 9 9  
 
*****************************************************************************************;  
********************************* P art 4: A N C O V A ***********************************; 
*****************************************************************************************;  
/* F or t h e c o m p ari s o n b et w e e n pl a c e b o a n d s ot a glifl o zi n 4 0 0 m g; */ 
    pr o c mi x e d d at a = mi _ 2;  
             b y _i m p ut ati o n _;  
             cl a s s tr e at str at a 1 str at a 2 c o u ntr y;  
             m o d el c h a n g e = tr e at str at a 1 str at a 2 c o u ntr y v al u e 0;  
             l s m e a n s tr e at / diff cl e;  
l s m e sti m at e  tr e at " A 1 Pl a c e b o"   1 0  / cl; 
l s m e sti m at e  tr e at " A 2 T e st dr u g"    0 1   / cl; 
l s m e sti m at e  tr e at " B 1 T e st dr u g v s Pl a c e b o"   -1 1  / cl; 
o d s o ut p ut L S M E sti m at e s =l s m e sti m at e s;  
    r u n; 
 
* S u b gr o u p a n al y s e s u si n g g e n d er a s a n e x a m pl e;  
    pr o c mi x e d d at a = mi _ 2;  
             b y _i m p ut ati o n _;  
             cl a s s tr e at str at a 1 str at a 2 c o u ntr y g e n d er;  
             m o d el c h a n g e = str at a 1 str at a 2 c o u ntr y v al u e 0 tr e at* g e n d er;  
             l s m e a n s tr e at* g e n d er / diff cl;  
             l s m e sti m at e tr e at* g e n d er " S A 1 1 Pl a c e b o - F e m al e"   1 0 0 0 / cl;  
             l s m e sti m at e tr e at* g e n d er " S A 1 2 Pl a c e b o - M al e"        0 1 0 0 / cl;  
             l s m e sti m at e tr e at* g e n d er “ S A 2 1 T e st dr u g - F e m al e” 0 0 1 0 / cl;  
             l s m e sti m at e tr e at* g e n d er “ S A 2 2 T e st dr u g - M al e”     0 0 0 1 / cl;  
             l s m e stim at e tr e at* g e n d er “ S B 1 T e st dr u g v s Pl a c e b o - F e m al e” -1 0 1 0 / cl;  
             l s m e sti m at e tr e at* g e n d er “ S B 2 T e st dr u g v s Pl a c e b o - M al e”     0 -1 0 1 / cl;  
             o d s o ut p ut L S M E sti m at e s =l s m e sti m at e s;  
    r u n; 
 
*****************************************************************************************;  
*************** P art 5: C o m bi ni n g r e s ult s u si n g R u bi n’ s f or m ul a *************; 
*****************************************************************************************;  
    pr o c s ort d at a =l s m e sti m at e s;  
             b y l a b el _i m p ut ati o n _;  
    r u n; 
 
    pr o c mi a n al y z e d at a =l s m e sti m at e s;  
             b y l a b el;  
             m o d el eff e ct s e sti m at e;  
             st d err st d err;  
             o d s o ut p ut p ar a m et er e sti m at e s = a n c o v a;  
    r u n; 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 3  of 9 9  
 
A p p e n di x C  
A m b ul at or y bl o o d pr e s s ur e m o nit ori n g s u b st u d y   
B ac k gr o u n d 
A P hase 2 trial of s ota glifl ozi n ( L X 4 2 1 1. 1- 2 0 2) pr o vi de d e vi de nce t hat s ot a glifl ozi n re d uce d b ot h 
S B P a n d D B P i n patie nts wit h ele vate d S B P a n d D B P at baseli ne b ut n ot n or m ote nsi ve patie nts. 
I n t his s u bst u d y of a p pr o xi matel y 2 0 0 patie nts wit h mea n S B P ≥1 3 0 m m H g at scree ni n g, p atie nts 
will ha ve A B P M assess e d f or 2 4 h o urs at bas eli ne , Wee k 1 2, a n d Wee k 2 6 t o pr o vi de a m ore 
s yste matic assess me nt of t he S B P a n d D B P l o weri n g efficac y of s ota glifl ozi n. 
S u b- st u d y pr oce d ures 
Patie nts wit h S B P ≥1 3 0 m m H g at scree ni n g will be pr o vi de d wit h i nf or mati o n o n t he A B P M 
s u bst u d y, a n d se p arat e i nf or me d c o nse nt ta ke n bef ore A B P M s u bst u d y-s pecific pr oce d ures are 
perf or me d.  
Patie nts i n t he A B P M s u bst u d y will ha ve 3 a d dit i o nal visits t o t he site f or place me nt of t he A B P M 
de vice, na m el y  Visits 3 A, 7 A a n d 9 A. Visit 3 A will occ ur at Wee k - 1, 1 wee k bef ore 
ra n d o mizati o n. Visits 7 A a n d 9 A will occ ur, res pecti vel y, o n t he d a y bef ore Visit 7 ( Wee k 1 2) 
a n d Visit 9 ( Wee k  2 6).  
Pati e nts d o n ot nee d t o be fasti n g f or Visits 3 A, 7 A a n d 9 A. O nce t he A B P M de vice has b ee n 
place d at Visit 3 A, patie nts will be i nstr ucte d t o re m o ve it after 2 4 h o urs a n d ret ur n it t o t he site 
b y p ost i n a p pr o priate pac ka gi n g pr o vi de d b y t he site. T we nt y -f o ur h o urs after Visits 7 A a n d 9 A, 
patie nts will ret ur n t o t he site i n a fasti n g stat e at Visits 7 a n d 9, res pecti vel y, a n d t he d e vice will 
be re m o ve d. A ll A B P M data will be re vie we d f oll o wi n g ret ur n of t he d e vice t o e ns ure q u alit y of 
t he rec or di n g; Patie nts wi t h A B P M data n ot of s ufficie nt q ualit y will be as ke d t o re peat t he 
pr ocess as s o o n as p ossi ble. Patie nts wit h A B P M data n ot of s uffici e nt q ualit y at Visit 3 A s h o ul d 
n ot be ra n d o mize d u ntil t he baseli ne A B P M rec or di n g has b ee n re peat e d.  
A m b ulat or y bl o o d pr ess ure m o nit ori n g will be p erf or me d wit h a vali dat e d de vice pr o vi de d b y t h e 
S p o ns or or S p o ns or re prese ntati ve. Eac h rec or di n g will start i n t he m or ni n g prefera bl y bet w ee n 
8: 0 0 a n d 1 0: 0 0 i m me diatel y after t h e a d mi nistrati o n of st u d y me dicati o n, a n d will e n d after at 
least 2 4 h o urs of r ec or di n g o n t he f oll o wi n g da y. T he bl o o d press ure c uff will be a p plie d 
prefere ntiall y o n t he n o n- d o mi na nt ar m. T he m o nit or will be pr o gra m me d t o meas ure bl o o d 
press ure e ver y 2 0 mi n utes bet wee n 0 8: 0 0 a n d 2 1: 5 9, a n d e ver y 3 0 mi n utes bet wee n 2 2: 0 0 a n d 
0 7: 5 9. Patie nts will re mai n bli n de d t o all c ollecte d A B P M val ues b y s witc hi n g off t h e dis pla y of 
t he de vice. Patie nts will be i nstr ucte d t o f oll o w t heir us ual dail y r o uti nes, b ut t o re mai n still a n d 
a v oi d ar m m o ve me nt d uri n g eac h a ut o mate d meas ure me nt. Patie nts will be as ke d t o a v oi d 
stre n u o us acti vit y, b at hi n g, or ta ki n g a s h o wer a n d t o rec or d t he ti me of sl ee p a n d a n y u n us ual 
e ve nts or p o or slee p q ualit y d uri n g t he A B P M rec or di n g peri o d i n t heir st u d y l o g. 
S u b -st u d y o bjecti ves 
T h e pri mar y o bjecti ve of t he A B P M s u bst u d y is t o c o m pare t he effect of s ot a glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h S B P ≥1 3 0 m m H g at scree ni n g o n 2 4- h o ur a vera ge S B P at 
Wee k 1 2. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 4  of 9 9  
 
T he sec o n d ar y o bjecti ves of t he A B P M s u bst u d y are t o c o m pare t he effect of s ota glifl ozi n vers us 
place b o i n a s u bset of p atie nts wit h S B P ≥1 3 0 m m H g at scree ni n g o n t he f oll o wi n g: 
•  2 4- h o ur a vera ge S B P at Wee k 2 6 
•  2 4- h o ur a vera ge D B P at Wee ks 1 2 a n d 2 6 
•  A vera ge a dj uste d a wa ke ti me B P as meas ure d b y S B P a n d D B P at Wee ks 1 2 a n d 2 6 wit h 
a dj ust me nt base d o n acti gr a p h y 
•  A vera ge a dj uste d slee p ti me  B P as meas ure d b y S B P a n d D B P at Wee ks 1 2 a n d 2 6  wit h 
a dj ust me nt base d o n acti gr a p h y. 
S u b -st u d y e n d p oi nts 
T he pri mar y e n d p oi nt of t he s u bst u d y is: 
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 i n a vera ge 2 4- h o ur S B P i n a s u bset of patie nts wit h 
S B P ≥1 3 0 m m H g at scr ee ni n g. 
T he sec o n d ar y e n d p oi nts of t he s u bst u d y are: 
•  C ha n ge fr o m Baseli ne  t o Wee k 2 6 i n a vera ge 2 4- h o ur S B P 
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 a n d 2 6 i n a vera ge 2 4- h o ur D B P  
•  C ha n ge fr o m Baseli ne  t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d a w a ke ti me B P as meas ure d 
b y S B P a n d D B P wit h a dj ust me nt base d o n acti gra p h y 
•  C ha n ge fr o m Baseli ne t o Wee k 1 2 a n d 2 6 i n a vera ge a dj uste d slee p ti me B P as meas ure d 
b y S B P a n d D B P wit h a dj ust me nt base d o n acti gra p h y. 
St atistic al a n al yses 
T he q ualit y of a visit rec or di n g will be c o nsi d ere d i ns ufficie nt if t he visit rec or di n g d oes n ot meet 
t he criteria b el o w (1 ):  
1.  Visit Rec or di n g d oes n ot c o ntai n great er t ha n or e q ual t o 1 7 n o n-c o nsec uti v e h o urs of dat a 
w here eac h h o ur has at least o ne vali d B P meas ure me nt.  
2.  Visit Rec or di n g has l ess t ha n 4 4 t otal meas ure m e nts.  
A B P M s u bst u d y e n d p oi nts will be a nal yze d usi n g a s i milar a p pr oac h as t he pri mar y efficac y 
e n d p oi nt wit h missi n g val ues i m p ute d b y t he retrie ve d dr o p o uts & w as h o ut i m p utati o n met h o d or 
t he c o ntr ol- base d m ulti ple i m p utati o n met h o d u n der t he missi n g n ot at ra n d o m fra me w or k . Eac h 
of t he c o m plete dat aset will  be a nal yze d usi n g A N C O V A m o del i ncl u di n g fact ors f or treat me nt 
(s ota glifl ozi n, place b o), r a n d o mizati o n strat u m of H b A 1c ( ≤8. 0 %, > 8. 0 %) as fi x e d effects, a n d t he 
baseli ne val ue of t he s pecific de pe n d e nt varia bl e as a c o variate.  




St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 6  of 9 9  
 
S u m mi n g o ver all s uccessf ul i ncl u de d s yst olic/ diast olic meas ure me nts c oll ecte d d uri n g t he ti me 
i nter val ( 2 4- h o ur, acti gra p h y r e p orte d slee p ti me or acti gra p h y re p ort e d wa ke ti me), t he n di vi de 
t he t otal b y n u m ber of s u ccessf ul i ncl u de d m eas ure me nts. 
T he acti gr a p h y ca n d etect t he patie nt’s slee p or w a ke ti me base d o n t he p atie nt’s acti vit y i nte nsit y. 
If t he patie nt has i nterr u pti ve slee p peri o ds, t he acti gra p h y will re p ort t he first i nacti vit y p eri o d of 
t he patie nt as t he patie nt’s slee p ti me. Wa ke ti me will be t he ti me o utsi de t he slee p i nter v al. Eac h 
patie nt will o nl y ha ve o n e slee p ti me a n d o ne wa k e ti me re p orte d b y t h e de vice.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 7  of 9 9  
 
A p p e n di x E  
P ot e nti all y cli ni c all y si g nifi c a nt a b n or m aliti e s crit eri a  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
Cli ni c al C h e mi stry  
A L T  
By distri b uti o n a n alysis :  
> 3 U L N  
> 5 U L N  
> 1 0 U L N  
> 2 0 U L N  
Enzy m es activiti es m ust b e ex pr ess e d i n U L N, n ot i n 
I U/ L.  
C o nc e pt p a p er o n DI LI – F o o d a n d Dr u g Ad mi nistr ati o n 
( F D A) dr aft G ui d a nc e Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e m e nti o ni n g 
z er o c a n b e d el et e d. 
A S T  
By distri b uti o n a n alysis :  
> 3 U L N  
> 5 U L N  
> 1 0 U L N  
> 2 0 U L N  
Enzy m es activiti es m ust b e ex pr ess e d i n U L N, n ot i n 
I U/ L.  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e Oct  2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e m e nti o ni n g 
z er o c a n b e d el et e d. 
Alk ali n e P h os p h at as e  
> 1. 5 U L N  
Enzy m es activiti es m ust b e ex pr ess e d i n U L N, n ot i n 
I U/ L. 
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e Oct  2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
T ot al Bilir u bi n  
> 1. 5 U L N  
> 2 U L N  
M ust b e ex pr ess e d i n U L N, n ot i n µ m ol/ L or m g/ L. 
C at e g ori es ar e c u m ul ativ e.  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e Oct  2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
C o nj u g at e d Bilir u bi n  
> 3 5 % T ot al Bilir u bi n a n d T BI LI > 1. 5 U L N  C o nj u g at e d bilir u bi n d os e d o n a c as e -by -c as e b asis. 
A L T a n d T ot al Bilir u bi n  
A L T > 3 U L N a n d T BI LI > 2 U L N  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e Oct  2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
T o b e c o u nt e d wit hi n a s a m e tr e at m e nt p h as e, w h at ev er 
t h e i nt erv al b et w e e n m e as ur e m e nt. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 8  of 9 9  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
C P K  
> 3 U L N  
> 1 0 U L N  
F D A F e b 2 0 0 5.  
A m J C ar di ol Apr  2 0 0 6.  
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e m e nti o ni n g 
z er o c a n b e d el et e d.  
C Lcr ( m L/ mi n)  
( Esti m at e d cr e ati ni n e cl e ar a nc e 
b as e d o n t h e C okcr oft -G a ult 
e q u ati o n)  
< 1 5 ( e n d st a g e r e n al dis e as e)  
≥1 5 - < 3 0 (s ev er e d ecr e as e i n G F R)  
≥3 0 - < 6 0 ( m o d er at e d ecr e as e i n G F R)  
≥6 0 - < 9 0 ( mil d d ecr e as e i n G F R)  
≥ 9 0 ( n or m al G F R)  
F D A dr a ft G ui d a nc e 2 0 1 0 
Ph ar m ac oki n etics i n p ati e nts wit h i m p air e d r e n al 
f u ncti o n-st u dy d esi g n, d at a a n alysis, a n d i m p act o n 
d osi n g a n d l a b eli n g  
e G F R ( m L/ mi n/ 1. 7 3  m2) 
( Esti m at e of G F R b as e d o n a n 
M D R D e q u ati o n)  
 
< 1 5 ( e n d st a g e r e n al dis e as e)  
≥1 5 - < 3 0 (s ev er e d ecr e as e i n G F R)  
≥3 0 - < 6 0 ( m o d er at e d ecr e as e i n G F R)  
≥6 0 - < 9 0 ( mil d d ecr e as e i n G F R)  
≥ 9 0 ( n or m al G F R)  
F D A dr aft G ui d a nc e 2 0 1 0  
Ph ar m ac oki n etics i n p ati e nts wit h i m p air e d r e n al 
f u ncti o n-st u dy d esi g n, d at a a n alysis, a n d i m p act o n 
d osi n g a n d l a b eli n g  
Cr e ati ni n e  
≥1 5 0 μ m ol/ L ( A d ults)  
≥3 0 % c h a n g e fr o m b as eli n e  
≥1 0 0 % c h a n g e fr o m b as eli n e  
Be nic h o u C, 1 9 9 4.  
 
Uric Aci d  
Hy p er uric e mi a  
Hy p o uric e mi a  
 
> 4 0 8 μ m ol/ L  
< 1 2 0 μ m ol/ L  
H arris o n - Pri nci pl es of i nt er n al M e dici n e 1 7 th E d., 2 0 0 8.  
Bl o o d Ur e a Nitr o g e n  
≥1 7 m m ol/ L  
 
C hl ori d e  
< 8 0 m m ol/ L  
> 1 1 5 m m ol/ L  
 
S o di u m  
≤1 2 9 m m ol/ L  
≥1 6 0 m m ol/ L  
 
P ot assi u m  
< 3 m m ol/ L 
≥5. 5 m m ol/ L  
F D A F e b 2 0 0 5.  
T ot al C h ol est er ol  
≥7. 7 4 m m ol/ L  
T hr es h ol d f or t h er a p e utic i nt erv e nti o n.  
Tri glyc eri d es  
≥4. 6 m m ol/ L  
T hr es h ol d f or t h er a p e utic i nt erv e nti o n.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 7 9  of 9 9  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
Li p as e mi a  
≥3 U L N  
 
A myl as e mi a  
≥3 U L N  
 
Gl uc os e 
Hy p o glyc a e mi a  
Hy p er glyc a e mi a  
 
≤3. 9 m m ol/ L a n d < L L N  
≥1 1. 1 m m ol/ L ( u nf ast e d); ≥7 m mol/ L 
(f ast e d) 
 
A D A M ay 2 0 0 5.  
A D A J a n 2 0 0 8.  
H b A 1c  
> 8 %  
 
Al b u mi n  
≤2 5 g/ L  
 
C R P  
> 2 U L N or > 1 0 m g/ L (if U L N n ot pr ovi d e d)   F D A Se p 2 0 0 5.  
H e m at ol o g y  
W B C  
< 3. 0 Gi g a/ L ( N o n -Bl ack); < 2. 0 Gi g a/ L 
( Bl ack) 
≥1 6. 0 Gi g a/ L  
I ncr e as e i n W B C: n ot r el ev a nt. 
T o b e i nt er pr et e d o nly if n o diff er e nti al c o u nt av ail a bl e.  
Ly m p h ocyt es  
> 4. 0 Gi g a/ L  
 
N e utr o p hils  
< 1. 5 Gi g a/ L ( N o n -Bl ack); < 1. 0 Gi g a/ L 
( Bl ack) 
I nt er n ati o n al C o ns e ns us m e eti n g o n dr u g-i n d uc e d bl o o d 
cyt o p e ni as, 1 9 9 1. 
F D A crit eri a.  
M o n ocyt es  
> 0. 7 Gi g a/ L  
 
B as o p hils  
> 0. 1 Gi g a/ L  
 
E osi n o p hils  
> 0. 5 Gi g a/ L or > U L N (if U L N ≥0. 5 Gi g a/ L)  H arris o n - Pri nci pl es of i nt er n al M e dici n e 1 7 th E d., 2 0 0 8.  
H e m o gl o bi n  
≤1 1 5 g/ L ( M al e); ≤9 5 g/ L ( F e m ale)  
≥1 8 5 g/ L ( M al e); ≥1 6 5 g/ L ( F e m al e) 
 
D ecr e as e fr o m B as eli n e ≥2 0 g/ L  
Crit eri a b as e d u p o n d ecr e as e fr o m b as eli n e ar e m or e 
r el ev a nt t h a n b as e d o n a bs ol ut e v al u e. Ot h er c at e g ori es 
f or d ecr e as e fr o m b as eli n e c a n b e use d ( ≥3 0  g/ L, 
≥4 0  g/ L, ≥5 0  g/ L). 
H e m at ocrit  
≤0. 3 7 v/v ( M al e)  ; ≤0. 3 2 v/v ( F e mal e) 
≥0. 5 5 v/v ( M al e)  ; ≥0. 5 v/v ( F e m al e)  
 
R B C  
≥6 T er a/ L  
U nl ess s p ecific ally r e q uir e d f or p artic ul ar dr u g 
d ev el o p m e nt, t h e a n alysis is r e d u n d a nt wit h t h at of H b.  
Ot h er wis e, c o nsi d er F D A crit eri a. 
Pl at el ets  
< 1 0 0 Gi g a/ L  
≥7 0 0 Gi g a/ L  
I nt er n ati o n al C o ns e ns us m e eti n g o n dr u g-i n d uc e d bl o o d 
cyt o p e ni as, 1 9 9 1. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 0  of 9 9  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
Uri n al y si s  
p H  
≤4. 6  
≥8  
 
Vit al si g n s  
H R  
≤5 0 b p m a n d d ecr e as e fr o m b as eli n e 
≥2 0 b p m  
≥1 2 0 b p m a n d i ncr e as e fr o m b as eli n e  
≥2 0  b p m  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g missi n g) exc e pt 
S T A N DI N G.  
S B P  
≤9 5 m m H g a n d d ecr e as e fr o m b as eli n e 
≥2 0  m m H g  
≥1 6 0 m m H g a n d i ncr e as e fr o m b as eli n e 
≥2 0 m m H g  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g missi n g) exc e pt 
S T A N DI N G.  
D B P  
≤4 5 m m H g a n d d ecr e as e fr o m b as eli n e 
≥1 0 m m H g  
≥1 1 0 m m H g a n d i ncr e as e fr o m b as eli n e 
≥1 0 m m H g  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g missi n g) exc e pt 
S T A N DI N G.  
Ort h ost atic Hy p ot e nsi o n  
Ort h ost atic S D B  
Ort h ost atic D B P  
 
≤- 2 0 m m H g  
≤- 1 0 m m H g  
 
W ei g ht  
≥5 % i ncr e as e fr o m b as eli n e  
≥5 % d ecr e as e fr o m b as eli n e  
F D A F e b 2 0 0 7.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 1  of 9 9  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
E C G  
R ef.: I nt er n ati o n al C o u ncil f or H ar m o nis ati o n (I C H) E 1 4 
g ui d a nc e ( 2 0 0 5) a n d E1 4 Q & A ( 2 0 1 2), a n d C ar di ac 
Saf ety R es e arc h C o ns orti u m W hit e Pa p er o n P R a n d 
Q R S ( N a d a et al. A m H e art J. 2 0 1 3; 1 6 5( 4) : 4 8 9 -5 0 0)  
H R  
< 5 0 b p m  
< 5 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 
b p m  
< 4 0 b p m  
< 4 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 
b p m  
< 3 0 b p m  
< 3 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 
b p m  
 
> 9 0 b p m  
> 9 0 b p m a n d i ncr e as e fr o m b as eli n e 
≥2 0 b p m  
> 1 0 0 b p m  
> 1 0 0 b p m a n d i ncr e as e fr o m b as eli n e 
≥2 0 b p m  
> 1 2 0 b p m  
> 1 2 0 b p m a n d i ncr e as e fr o m b as eli n e 
≥2 0 b p m  
C at e g ori es ar e c u m ul ativ e  
 
 
 
 
 
 
C at e g ori es ar e c u m ul ativ e  
 
P R  
> 2 0 0 ms  
> 2 0 0 ms a n d i ncr e as e fr o m b as eli n e 
≥2 5 %  
> 2 2 0 ms  
> 2 2 0 ms a n d i ncr e as e fr o m b as eli n e 
≥2 5 %  
> 2 4 0 ms  
> 2 4 0 ms a n d i ncr e as e fr o m b as eli n e 
≥2 5 %  
C at e g ori es ar e c u m ul ativ e  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 2  of 9 9  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
 
P ar a m et er  
P C S A  
C o m m e nt s  
Q R S  
> 1 1 0 ms  
> 1 1 0 ms a n d i ncr e as e fr o m b as eli n e 
≥2 5 %  
> 1 2 0 ms  
> 1 2 0 ms a n d i ncr e as e fr o m b as eli n e 
≥2 5 %  
C at e g ori es ar e c u m ul ativ e  
Q T 
> 5 0 0 ms  
 
Q Tc 
 
A bs ol ut e v al u es ( ms)  
 
 
> 4 5 0 ms  
> 4 8 0 ms  
> 5 0 0 ms  
 
I ncr e as e fr o m b as eli n e 
I ncr e as e fr o m b as eli n e ]3 0 -6 0 ] ms  
I ncr e as e fr o m b as eli n e > 6 0 ms 
T o b e a p pli e d t o a ny ki n d of Q T c orr ecti o n f or m ul a.  
Abs ol ut e v al u es c at e g ori es ar e c u m ul ativ e  
 
Q Tc > 4 8 0 ms a n d ∆Q Tc > 6 0 ms ar e t h e 2 P C S A 
c at e g ori es t o b e i d e ntifi e d i n i n divi d u al s u bj ects/ p ati e nts 
listi n gs. 
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 3  of 9 9  
 
A p p e n di x F  
Li st of P T s f or s el e ct E O SI s ( M e d D R A v 2 1. 1 )  
E O SI  
Pr ef err e d 
T er m C o d e  
Pr ef err e d T er m  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 0 4 0 7 4  
B al a niti s c a n di d a  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 1 8 1 4 3  
G e nit al c a n di di a si s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 4 7 7 8 4  
V ul v o v a gi n al c a n di di a si s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 1 1 8 0  
G e nit al i nf e cti o n f u n g al  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 4 8 9 9  
V ul v o v a gi n al m y c oti c i nf e cti o n  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 5 5 8 2  
Ur o g e nit al i nf e cti o n f u n g al  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 7 1 2 0 9  
C a n di d a c er vi citi s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 7 9 5 2 1  
F u n g al b al a niti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 8 1  
C y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 9 0  
C y stiti s e s c h eri c hi a  
Uri n ar y tr a ct i nf e cti o n s 
1 0 0 1 1 7 9 7  
C y stiti s kl e b si ell a  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 9 9  
C y stiti s p s e u d o m o n al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 7 5 2 5  
F u n g al c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 8 1 8 5  
G e nit o uri n ar y c hl a m y di a i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 2 3 4 2 4  
Ki d n e y i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 8 4  
P y eliti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 9 6  
P y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 9 7  
P y el o n e p hriti s a c ut e  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 0 1  
P y el o n e p hriti s c hr o ni c  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 0 3  
P y el o n e p hriti s m y c o pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 5 3  
P y o n e p hr o si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 8 3 5 1  
R e n al a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 4 8 2 8  
T u b er c ul o si s of g e nit o uri n ar y s y st e m  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 2 4  
Ur et hr al a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 0  
Ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 2  
Ur et hriti s c hl a m y di al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 3  
Ur et hriti s g o n o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 9 0  
Ur et hriti s ur e a pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 5 7 1  
Uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 5 7 2  
Uri n ar y tr a ct i nf e cti o n e nt er o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 7 0 4  
Ur o g e nit al tri c h o m o ni a si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 3 0 2  
T u b ul oi nt er stiti al n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 7 0 9  
Ur o s e p si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 8 3 7  
C y stiti s gl a n d ul ari s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 9 0 5 9  
Uri n ar y tr a ct i nf e cti o n f u n g al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 9 1 0 0  
P y el o c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 1 2 5 0  
Ur et eriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 1 3 5 0  
C yt o m e g al o vir u s uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 1 9 5 9  
Uri n ar y bl a d d er a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 2 2 3 8  
E s c h eri c hi a uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 4 0 8 8  
Uri n ar y tr a ct i nf e cti o n b a ct eri al  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 4  of 9 9  
 
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 6 3 5 1  
E m p h y s e m at o u s c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 8 5 2 3  
Bl a d d er c a n di di a si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 8 5 9 6  
R e n al c y st i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 9 5 1 7  
B a ct eri al p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 1 1 8 1  
G e nit o uri n ar y tr a ct g o n o c o c c al i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 1 1 8 2  
G e nit o uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 1 3 9 5  
Ur et er a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 2 2 7 9  
Uri n ar y tr a ct i nf e cti o n p s e u d o m o n al  
Uri n ar y tr a ct i nf e cti o n s 
1 0 0 6 2 2 8 0  
Uri n ar y tr a ct i nf e cti o n st a p h yl o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 4 8 2 5  
Uri n ar y tr a ct i nf e cti o n vir al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 4 9 2 1  
Uri n ar y tr a ct i nfl a m m ati o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 1 9 7  
C y stiti s vir al  
Uri n ar y tr a ct i nf e cti o n s 
1 0 0 6 5 1 9 8  
C y stiti s b a ct eri al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 1 9 9  
C y stiti s h el mi nt hi c  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 2 1 3  
P y el o n e p hriti s vir al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 2 1 4  
P y el o n e p hriti s f u n g al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 5 8 2  
Ur o g e nit al i nf e cti o n f u n g al 
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 5 8 3  
Ur o g e nit al i nf e cti o n b a ct eri al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 6 7 5 7  
Uri n ar y tr a ct a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 8 8 2 2  
E m p h y s e m at o u s p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 0 3 0 0  
Str e pt o c o c c al uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 1 7 3 6  
A c ut e f o c al b a ct eri al n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 4 4 0 9  
E s c h eri c hi a p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 5 0 6 3  
Ur et hriti s m y c o pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 8 6 6 5  
B a ct eri al ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 8 1 1 6 3  
F u n g al ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 8 1 2 6 2  
C a n di d a ur et hriti s  
V ol u m e d e pl eti o n  
1 0 0 0 5 6 9 7  
Bl o o d o s m ol arit y i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 1  
Bl o o d pr e s s ur e a m b ul at or y d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 4  
Bl o o d pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 7  
Bl o o d pr e s s ur e di a st oli c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 4 8  
Bl o o d pr e s s ur e i m m e a s ur a bl e  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 5 8  
Bl o o d pr e s s ur e s y st oli c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 6 1  
Bl o o d pr e s s ur e s y st oli c i n s pir at or y d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 7 9 7 9  
C e ntr al v e n o u s pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 9 1 9 2  
Cir c ul at or y c oll a p s e  
V ol u m e d e pl eti o n  
1 0 0 1 2 1 7 4  
D e h y dr ati o n  
V ol u m e d e pl eti o n  
1 0 0 1 3 5 7 8  
Di z zi n e s s p o st ur al  
V ol u m e d e pl eti o n  
1 0 0 2 1 0 9 7  
H y p ot e n si o n  
V ol u m e d e pl eti o n  
1 0 0 2 1 1 3 7  
H y p o v ol a e mi a  
V ol u m e d e pl eti o n  
1 0 0 2 1 1 3 8  
H y p o v ol a e mi c s h o c k  
V ol u m e d e pl eti o n  
1 0 0 2 6 9 8 3  
M e a n art eri al pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 3 1 1 2 7  
Ort h o st ati c h y p ot e n si o n  
V ol u m e d e pl eti o n  
1 0 0 3 6 6 5 3  
Pr e s y n c o p e  
V ol u m e d e pl eti o n  
1 0 0 3 7 3 2 7  
P ul m o n ar y art eri al w e d g e pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 2 7 7 2  
S y n c o p e  
V ol u m e d e pl eti o n  
1 0 0 4 6 6 4 0  
Uri n e fl o w d e cr e a s e d  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 5  of 9 9  
 
V ol u m e d e pl eti o n  
1 0 0 4 7 2 3 5  
V e n o u s pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 7 2 3 9  
V e n o u s pr e s s ur e j u g ul ar d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 7 6 8 9  
V ol u m e bl o o d d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 0 7 6 0  
Bl o o d ur e a nitr o g e n/ cr e ati ni n e r ati o i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 0 9 0 5  
D e cr e a s e d v e ntri c ul ar pr el o a d  
V ol u m e d e pl eti o n  
1 0 0 5 3 3 5 6  
Bl o o d pr e s s ur e ort h o st ati c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 9 8 9 5  
Uri n e o ut p ut d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 0 0 8 9  
L eft v e ntri c ul ar e n d -di a st oli c pr e s s ur e 
d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 0 2 3 1  
P ul m o n ar y art eri al pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 3 0 8 0  
P o st ur al ort h o st ati c t a c h y c ar di a s y n dr o m e  
V ol u m e d e pl eti o n  
1 0 0 6 3 9 2 7  
Ort h o st ati c i nt ol er a n c e  
V ol u m e d e pl eti o n  
1 0 0 6 6 0 7 7  
Di a st oli c h y p ot e n si o n  
V ol u m e d e pl eti o n  
1 0 0 6 9 4 3 1  
Ort h o st ati c h e art r at e r e s p o n s e i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 9 5 8 3  
P ul s e v ol u m e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 7 2 3 7 0  
Pr er e n al f ail ur e  
P a n cr e atiti s  
1 0 0 3 3 6 2 5  
P a n cr e ati c h a e m orr h a g e  
P a n cr e atiti s  
1 0 0 3 3 6 3 5  
P a n cr e ati c p s e u d o c y st  
P a n cr e atiti s  
1 0 0 3 3 6 3 6  
P a n cr e ati c p s e u d o c y st dr ai n a g e  
P a n cr e atiti s  
1 0 0 3 3 6 4 5  
P a n cr e atiti s  
P a n cr e atiti s  
1 0 0 3 3 6 4 7  
P a n cr e atiti s a c ut e  
P a n cr e atiti s  
1 0 0 3 3 6 4 9  
P a n cr e atiti s c hr o ni c  
P a n cr e atiti s  
1 0 0 3 3 6 5 0  
P a n cr e atiti s h a e m orr h a gi c  
P a n cr e atiti s  
1 0 0 3 3 6 5 4  
P a n cr e atiti s n e cr oti si n g  
P a n cr e atiti s  
1 0 0 3 3 6 5 7  
P a n cr e atiti s r el a p si n g  
P a n cr e atiti s  
1 0 0 4 8 9 8 4  
P a n cr e ati c a b s c e s s  
P a n cr e atiti s  
1 0 0 5 2 4 0 0  
O e d e m at o u s p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 6 2 7 7  
P a n cr e at or e n al s y n dr o m e  
P a n cr e atiti s  
1 0 0 5 6 9 7 5  
P a n cr e ati c p hl e g m o n  
P a n cr e atiti s  
1 0 0 5 6 9 7 6  
H er e dit ar y p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 6 9 7 7  
Al c o h oli c p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 8 0 9 6  
P a n cr e ati c n e cr o si s  
P a n cr e atiti s  
1 0 0 6 5 1 8 9  
P a n cr e atiti s h el mi nt hi c  
P a n cr e atiti s  
1 0 0 6 6 1 2 7  
I s c h a e mi c p a n cr e atiti s 
P a n cr e atiti s  
1 0 0 6 9 0 0 2  
A ut oi m m u n e p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 7 4 8 9 4  
Tr a u m ati c p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 7 6 0 5 8  
H a e m orr h a gi c n e cr oti c p a n cr e atiti s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 3 1 9 2  
Art eri o v e n o u s fi st ul a t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 3 8 8 0  
A xill ar y v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 6 5 3 7  
B u d d -C hi ari s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 7 8 3 0  
C a v er n o u s si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 8 1 3 8  
C er e br al v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 1 4 5 2 2  
E m b oli s m v e n o u s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 1 9 7 1 3  
H e p ati c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 2 3 2 3 7  
J u g ul ar v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 2 7 4 0 2  
M e s e nt eri c v ei n t hr o m b o si s 
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 4 2 7 2  
P el vi c v e n o u s t hr o m b o si s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 6  of 9 9  
 
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 4 3 2 4  
P e nil e v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 6 2 0 6  
P ort al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 3 7 7  
P ul m o n ar y e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s 
1 0 0 3 7 4 2 1  
P ul m o n ar y mi cr o e m b oli  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 4 3 7  
P ul m o n ar y t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 4 5 9  
P ul m o n ar y v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 5 4 7  
R e n al v ei n e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 5 4 8  
R e n al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 9 0 8  
R eti n al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 1 6 5 9  
S pl e ni c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 2 5 6 7  
S u p eri or s a gitt al si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 7 0  
T hr o m b o p hl e biti s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 8 1  
T hr o m b o p hl e biti s mi gr a n s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 9 5  
T hr o m b o p hl e biti s s u p erfi ci al  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 6 0 5  
T hr o m b o s e d v ari c o s e v ei n  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 4 4 5 7  
Tr a n s v er s e si n u s t hr o m b o si s 
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 7 1 9 3  
V e n a c a v a e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 7 1 9 5  
V e n a c a v a t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 7 2 4 9  
V e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 8 5 9 1  
P o st t hr o m b oti c s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 9 4 4 6  
S u b cl a vi a n v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 0 2 1 6  
P a g et -S c hr o ett er s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 0 9 0 2  
P o st o p er ati v e t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 1 0 5 5  
D e e p v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 3 1 8 2  
Art eri o v e n o u s gr aft t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 1 2 5 1  
I ntr a cr a ni al v e n o u s si n u s t hr o m b o si s 
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 1 4 0 8  
V e n o u s t hr o m b o si s li m b  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 3 3 6 3  
Br a c hi o c e p h ali c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 3 9 0 9  
P o st pr o c e d ur al p ul m o n ar y e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 6 8 8 1  
D e e p v ei n t hr o m b o si s p o st o p er ati v e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 7 2 7 0  
T hr o m b o si s c or p or a c a v er n o s a  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 9 9 0 9  
M et a st ati c p ul m o n ar y e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s 
1 0 0 7 2 0 5 9  
O v ari a n v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 4 3 4 9  
O p ht h al mi c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 7 6 2 3  
P ort o s pl e n o m e s e nt eri c v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 7 8 2 9  
Vi s c er al v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 8 8 1 0  
H e p ati c v ei n e m b oli s m  
T h yr oi d c a n c er  
1 0 0 0 2 2 4 0  
A n a pl a sti c t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 1 6 9 3 5  
F olli c ul ar t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 2 7 1 0 5  
M e d ull ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 3 3 7 0 1  
P a pill ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 4 3 7 4 4  
T h yr oi d n e o pl a s m  
T h yr oi d c a n c er  
1 0 0 5 5 1 0 7  
T h yr oi d c a n c er m et a st ati c  
T h yr oi d c a n c er  
1 0 0 6 6 1 3 6  
H u ert hl e c ell c ar ci n o m a  
T h yr oi d c a n c er  
1 0 0 6 6 4 7 4  
T h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 7 0 5 6 7  
T h yr oi d c a n c er st a g e 0  
T h yr oi d c a n c er  
1 0 0 7 1 0 2 7  
T h yr oi d c a n c er st a g e I  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 7  of 9 9  
 
T h yr oi d c a n c er  
1 0 0 7 1 0 2 8  
T h yr oi d c a n c er st a g e II  
T h yr oi d c a n c er  
1 0 0 7 1 0 2 9  
T h yr oi d c a n c er st a g e III  
T h yr oi d c a n c er  
1 0 0 7 1 0 3 0  
T h yr oi d c a n c er st a g e I V  
T h yr oi d c a n c er  
1 0 0 7 2 1 6 2  
T h yr oi d c a n c er r e c urr e nt  
T h yr oi d c a n c er  
1 0 0 7 2 6 1 3  
T h yr oi d B -c ell l y m p h o m a  
T h yr oi d c a n c er  
1 0 0 7 3 1 5 3  
F a mili al m e d ull ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 7 6 6 0 3  
P o orl y diff er e nti at e d t h yr oi d c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 3 8 3 8 9  
R e n al c a n c er  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 0  
R e n al c a n c er r e c urr e nt  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 1  
R e n al c a n c er st a g e I  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 2  
R e n al c a n c er st a g e II  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 3  
R e n al c a n c er st a g e III  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 4  
R e n al c a n c er st a g e I V  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 0  
R e n al c ell c ar ci n o m a r e c urr e nt  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 1  
R e n al c ell c ar ci n o m a st a g e I  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 2  
R e n al c ell c ar ci n o m a st a g e II  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 3  
R e n al c ell c ar ci n o m a st a g e III  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 4  
R e n al c ell c ar ci n o m a st a g e I V  
R e n al c ell c a n c er  
1 0 0 5 0 0 1 8  
R e n al c a n c er m et a st ati c  
R e n al c ell c a n c er  
1 0 0 5 0 5 1 3  
M et a st ati c r e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 6 1 4 8 2  
R e n al n e o pl a s m  
R e n al c ell c a n c er  
1 0 0 6 7 9 4 4  
H er e dit ar y l ei o m y o m at o si s r e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 6 7 9 4 6  
R e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 7 3 2 5 1  
Cl e ar c ell r e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 7 8 4 9 3  
P a pill ar y r e n al c ell c ar ci n o m a  
P a n cr e ati c c a n c er  
1 0 0 1 8 4 0 4  
Gl u c a g o n o m a  
P a n cr e ati c c a n c er  
1 0 0 2 2 4 9 8  
I n s uli n o m a 
P a n cr e ati c c a n c er  
1 0 0 2 5 9 9 7  
M ali g n a nt n e o pl a s m of i sl et s of  L a n g er h a n s  
P a n cr e ati c c a n c er  
1 0 0 2 9 3 4 1  
N e ur ot e n si n o m a  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 0 9  
P a n cr e ati c c ar ci n o m a  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 1 0  
P a n cr e ati c c ar ci n o m a m et a st ati c  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 1 3  
P a n cr e ati c c ar ci n o m a r e c urr e nt  
P a n cr e ati c c a n c er  
1 0 0 4 1 3 2 9  
S o m at o st ati n o m a  
P a n cr e ati c c a n c er  
1 0 0 4 7 4 3 0  
Vi p o m a  
P a n cr e ati c c a n c er  
1 0 0 5 1 7 0 9  
G a stri n o m a m ali g n a nt  
P a n cr e ati c c a n c er  
1 0 0 5 2 7 4 7  
A d e n o c ar ci n o m a p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 5 5 0 0 6  
P a n cr e ati c s ar c o m a  
P a n cr e ati c c a n c er  
1 0 0 5 5 0 0 7  
C ar ci n oi d t u m o ur of t h e p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 0  
P a n cr e ati c c ar ci n o m a st a g e 0  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 1  
P a n cr e ati c c ar ci n o m a st a g e I  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 2  
P a n cr e ati c c ar ci n o m a st a g e II  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 3  
P a n cr e ati c c ar ci n o m a st a g e III  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 6  
P a n cr e ati c c ar ci n o m a st a g e I V  
P a n cr e ati c c a n c er  
1 0 0 6 1 9 0 2  
P a n cr e ati c n e o pl a s m  
P a n cr e ati c c a n c er  
1 0 0 6 7 5 1 7  
P a n cr e ati c n e ur o e n d o cri n e t u m o ur  
P a n cr e ati c c a n c er  
1 0 0 6 8 9 0 9  
P a n cr e ati c n e ur o e n d o cri n e t u m o ur m et a st ati c  
P a n cr e ati c c a n c er  
1 0 0 6 9 3 4 5  
S oli d p s e u d o p a pill ar y t u m o ur of t h e p a n cr e a s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 8  of 9 9  
 
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 3  
A ci n ar c ell c ar ci n o m a of p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 4  
D u ct al a d e n o c ar ci n o m a of p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 5  
I ntr a d u ct al p a pill ar y-m u ci n o u s c ar ci n o m a of 
p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 7  
P a n cr e at o bl a st o m a  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 6  
Bl a d d er a d e n o c ar ci n o m a r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 7  
Bl a d d er a d e n o c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 8  
Bl a d d er a d e n o c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 9  
Bl a d d er a d e n o c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 0 4 9 9 0  
Bl a d d er a d e n o c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 0 4 9 9 1  
Bl a d d er a d e n o c ar ci n o m a st a g e I V  
Bl a d d er c a n c er  
1 0 0 0 4 9 9 2  
Bl a d d er a d e n o c ar ci n o m a st a g e u n s p e cifi e d  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 3  
Bl a d d er c a n c er  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 5  
Bl a d d er c a n c er r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 6  
Bl a d d er c a n c er st a g e 0, wit h c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 7  
Bl a d d er c a n c er st a g e 0, wit h o ut c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 8  
Bl a d d er c a n c er st a g e I, wit h c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 9  
Bl a d d er c a n c er st a g e I, wit h o ut c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 0  
Bl a d d er c a n c er st a g e II  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 1  
Bl a d d er c a n c er st a g e III  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 2  
Bl a d d er c a n c er st a g e I V  
Bl a d d er c a n c er  
1 0 0 0 5 0 5 6  
Bl a d d er n e o pl a s m  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 5  
Bl a d d er s q u a m o u s c ell c ar ci n o m a r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 6  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 7  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 8  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 9  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 0 5 0 8 0  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e I V  
Bl a d d er c a n c er  
1 0 0 0 5 0 8 1  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e 
u n s p e cifi e d  
Bl a d d er c a n c er  
1 0 0 0 5 0 8 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a  
Bl a d d er c a n c er  
1 0 0 5 1 6 9 0  
Uri n ar y bl a d d er s ar c o m a  
Bl a d d er c a n c er  
1 0 0 5 7 3 5 2  
M et a st ati c c ar ci n o m a of t h e bl a d d er  
Bl a d d er c a n c er  
1 0 0 6 6 7 4 9  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 0  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a r e c urr e nt 
Bl a d d er c a n c er  
1 0 0 6 6 7 5 1  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 2  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e I V  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 3  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 7 1 6 6 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a m et a st ati c  
Bl a d d er c a n c er  
1 0 0 7 8 3 4 1  
N e ur o e n d o cri n e c ar ci n o m a of t h e bl a d d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 0 8 4  
Ar efl e xi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 1 7 8  
Art eri al t hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 2 1 0  
Art eri o s cl er o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 2 2 2  
Art eri o s cl er oti c g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 6 7 8 4  
B ur ni n g s e n s ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 0 4  
C ell uliti s e nt er o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 0 5  
C ell uliti s g a n gr e n o u s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 8 9  of 9 9  
 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 2 1  
C ell uliti s st a p h yl o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 2 2  
C ell uliti s str e pt o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 1 7 4  
D e h y dr ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 6 6 5  
Di a b eti c g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 6 7 9  
Di a b eti c n e ur o p at hi c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 6 8 0  
Di a b eti c n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 7 7 1 1  
G a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 0 9 3 7  
H y p o a e st h e si a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 1 1 3 7  
H y p o v ol a e mi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 1 5 1 9  
I m p air e d h e ali n g  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 1 7 8 4  
I nf e ct e d s ki n ul c er 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 2 5 6 2  
I nt er mitt e nt cl a u di c ati o n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 4 7 7 4  
L o c ali s e d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 8 8 6 2  
N e cr o si s i s c h a e mi c  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 9 3 3 1  
N e ur o p at h y p eri p h er al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 1 4 9  
O st eiti s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 2  
O st e o m y eliti s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 3  
O st e o m y eliti s a c ut e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 6  
O st e o m y eliti s c hr o ni c  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 6 2  
O st e o m y eliti s s al m o n ell a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 6 4  
O st e o n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 3 7 7 5  
P ar a e st h e si a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 5 6 8  
P eri p h er al c ol d n e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 5 7 6  
P eri p h er al i s c h a e mi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 6 2 0  
P eri p h er al s e n s or y n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 6 3 6  
P eri p h er al v a s c ul ar di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 6 1 5 5  
P o or p eri p h er al cir c ul ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 6 4 1 0  
P o st o p er ati v e w o u n d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 0 2 6  
S e n s or y di st ur b a n c e  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 4 0 8 4 0  
S ki n er o si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 8 7 2  
S ki n i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 9 4 3  
S ki n ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 2 3 4 3  
S u b c ut a n e o u s a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 3 6 0 7  
T hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 8 0 3 1  
W o u n d d e hi s c e n c e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 8 0 3 8  
W o u n d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 9 9 2 7  
Dr y g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 0 4 7 3  
A b s c e s s li m b  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 0 5 0 2  
N e ur o p at hi c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 1 5 4 8  
B ur n i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 2 4 2 8  
W o u n d  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 2 9 4 9  
Art eri al t h er a p e uti c pr o c e d ur e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 3 6 9 2  
W o u n d c o m pli c ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 3 7 1 6  
W o u n d n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 4 0 4 4  
Di a b eti c mi cr o a n gi o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 3 4 0  
Di a b eti c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 4 1 8  
Art eri al b y p a s s o p er ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 6 7 3  
P eri p h er al s e n s ori m ot or n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 7 5 1 8  
P eri p h er al art er y a n gi o pl a st y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 7 5 2 5  
P eri p h er al art er y o c cl u si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 8 0 4 1  
W o u n d s e p si s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 0  of 9 9  
 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 8 0 4 2  
W o u n d a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 2 4 5  
A n gi o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 3 8 5  
E xtr e mit y n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 4 4 2  
W o u n d i nf e cti o n st a p h yl o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 4 4 4  
W o u n d i nf e cti o n p s e u d o m o n a s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 7 3 4  
Di a b eti c f o ot  
P ot e nti all y l e a di n g t o  a m p ut ati o n  
1 0 0 6 0 8 0 3  
Di a b eti c f o ot i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 9 6 3  
Art eri al di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 9 6 5  
Art eri al st e n o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 2 7  
A m p ut ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 5 5  
Art eri al gr aft  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 5 7  
Art eri al st e nt i n s erti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 6 6  
A ut o n o mi c n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 8 1 5  
Di a b eti c v a s c ul ar di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 6 2 1 9 8  
Mi cr o a n gi o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 2 5 5  
S oft ti s s u e i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 5 8 5  
P eri p h er al art eri al o c cl u si v e di s e a s e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 5 9 9  
Art eri al o c cl u si v e di s e a s e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 6 1 0  
I s c h a e mi c li m b p ai n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 9 3 2  
W o u n d tr e at m e nt  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 4 2 5 0  
St a p h yl o c o c c al o st e o m y eliti s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 4 6 0 1  
Ili a c art er y o c cl u si o n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 3 7  
O st e o m y eliti s b a ct eri al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 3 9  
O st e o m y eliti s f u n g al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 4 0  
W o u n d i nf e cti o n b a ct eri al  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 6 5 2 4 2  
W o u n d i nf e cti o n f u n g al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 8 6 5 3  
B o n e a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 9 3 7 9  
P eri p h er al art eri al r e o c cl u si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 1 7 0  
S ki n w o u n d  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 7 2 5 5 7  
P eri p h er al art er y r e st e n o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 0  
P eri p h er al e n d art er e ct o m y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 1  
P eri p h er al art er y b y p a s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 2  
P eri p h er al art er y st e nt i n s erti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 3  
P eri p h er al art er y st e n o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 4  
P eri p h er al art er y t hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 4 3 9 6  
P e n etr ati n g at h er o s cl er oti c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 7 5 1 1 8  
S u b p eri o st e al a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 5 7 1 4  
V a s c uliti c ul c er  
 
 
 
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 1  of 9 9  
 
A p p e n di x G  
S u m m ar y of st ati sti c al a n al y s e s  
E F FI C A C Y A N A L Y SI S  
 
E n d p oi nt  
A n al y si s  
p o p ul ati o n  
Pri m ar y  a n al y si s  
S u p p orti v e  a n al y si s  
S u b gr o u p  a n al y si s  
Ot h er  a n al y s e s  
Pri m ar y e n d p oi nt  
 
 
 
 
 
H b A 1c: C h a n g e fr o m B as eli n e at 
W e ek 2 6  
I T T 
A N C O V A ( wit h missi n g v al u es i m p ut e d 
by t h e r etri ev e d dr o p o uts & w as h o ut 
i m p ut ati o n m et h o d or by c o ntr ol-b as e d 
c o py r ef er e nc e MI  m et h o d u n d er M N A R 
ass u m pti o n): tr e at m e nt, r a n d o miz ati o n 
str at u m ( H b A1c / S B P at scr e e ni n g), a n d 
c o u ntry as fix e d eff ects, a n d b as eli n e 
H b A1c v al u e as a c ov ari at e  
Ti p pi n g p oi nt a n alysis; 
A N C O V A ( wit h miss i n g 
v al u es i m p ut e d by t h e 
r etri ev e d dr o p o uts & w as h o ut 
i m p ut ati o n m et h o d or by 
c o ntr ol-b as e d c o py r ef er e nc e 
MI m et h o d u n d er M N A R 
ass u m pti o n)  
S u b gr o u ps:  
r ac e,  
et h nicity,  
a g e gr o u p,  
g e n d er,  
b as eli n e B MI, b as eli n e 
H b A 1c, b as eli n e S B P,  
B as eli n e e G F R,  
D ur ati o n of di a b et es,  
a n d c o u ntry.  
S u m m ary st atistics f or 
o bs erv e d v al u es a n d 
c h a n g es fr o m b as eli n e by 
visit. 
Gr a p hic al pr es e nt ati o ns f or 
m e a n c h a n g es fr o m b as eli n e 
( ± S E) a n d m e a n v al u es 
( ± S E) by visit. 
By -visit s u m m ary a n d gr a p h 
excl u di n g m e as ur e m e nts 
af t er r esc u e t h er a py. 
S e c o n d ar y e n d p oi nt s  
 
 
 
 
 
2- h o ur P P G, F P G, b o dy w ei g h t: 
C h a n g e fr o m B as eli n e t o 
W e ek  2 6;  
S B P (f or p ati e nts wit h b as eli n e 
S B P ≥1 3 0  m m H g, all p ati e nts): 
C h a n g e fr o m B as eli n e t o W e ek 1 2  
I T T 
A N C O V A ( wit h missi n g v al u es i m p ut e d 
by t h e r etri ev e d dr o p o uts & w as h o ut 
i m p ut ati o n m et h o d or by c o ntr ol-b as e d 
c o py r ef er e nc e MI m et h o d u n d er M N A R 
ass u m pti o n): tr e at m e nt, r a n d o miz ati o n 
str at u m ( H b A1c / S B P at scr e e ni n g), a n d 
c o u ntry as fix e d eff ects, a n d b as eli n e 
e n d p oi nt v al u e as a c ov ari at e  
N o  
N o  
S u m m ary st atistics f or 
o bs erv e d v al u es a n d 
c h a n g es fr o m b as eli n e by 
visit. 
Gr a p hic al pr es e nt ati o ns f or 
m e a n c h a n g es fr o m b as eli n e 
( ± S E) a n d m e a n v al u es 
( ± S E) by visit. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 2  of 9 9  
 
E n d p oi nt  
A n al y si s  
p o p ul ati o n  
Pri m ar y  a n al y si s  
S u p p orti v e  a n al y si s  
S u b gr o u p  a n al y si s  
Ot h er  a n al y s e s  
Pr o p orti o n of p ati e nts wit h H b A 1c 
< 6. 5 %, < 7. 0 % at W e ek 2 6  
I T T 
C M H m et h o d str atifi e d  o n r a n d o miz ati o n 
str at a ( H b A1c / S B P at scr e e ni n g) 
C M H m et h o d str atifi e d o n 
r a n d o miz ati o n str at a ( H b A 1c 
/ S B P at scr e e ni n g): 
excl u di n g p ati e nts wit h 
b as eli n e H b A1c v al u es 
< 6. 5 % (f or < 6 . 5 % 
r es p o n d ers) or < 7 % (f or 
< 7 %  r es p o n d ers) 
r es p ectiv ely 
N o  
By -visit s um m ary a n d gr a p hs 
of H b A 1c r es p o n d ers 
( < 6. 5 %, < 7 %). 
By -visit fr e q u e ncy s u m m ary 
a n d gr a p hs of H b A 1c 
r es p o n d ers ( < 6. 5 %, < 7 %) 
excl u di n g p ati e nts wit h 
b as eli n e H b A 1c v al u es 
< 6. 5 % or < 7 % r es p ectiv ely.  
Ot h er e n d p oi nt s  
 
 
 
 
 
U A C R, U G E, a n d U G C R, s er u m 
cr e ati ni n e, e G F R: C h a n g e fr o m 
B as eli n e  
 
S B P (f or p ati e nts wit h b as eli n e 
S B P < 1 3 0 m m H g), D B P: C h a n g e 
fr o m B as eli n e t o W e ek 1 2 
I T T 
Su m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
 
 
S u m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
N o  
 
 
 
N o  
N o  
 
 
 
N o  
Gr a p hic al pr es e nt ati o ns f or 
m e a n c h a n g es fr o m b as eli n e 
( ± S E) a n d m e a n v al u es 
( ± S E) by visit as a p pr o pri at e. 
 
Gr a p hic al pr es e nt ati o ns f or 
m e a n c h a n g es fr o m b as eli n e 
( ± S E) a n d m e a n v al u es 
( ± S E) by visit as a p pr o pri at e. 
 
S B P (f or all p ati e nts a n d p ati e nts 
wit h b as eli n e S B P ≥1 3 0 m m H g): 
C h a n g e fr o m B as eli n e  t o W e ek 2 6 
 
Su m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
N o  
N o  
N o  
H b A 1c, F P G, S B P (f or all p ati e nts 
a n d p ati e nts wit h b as eli n e 
S B P ≥1 3 0 m m H g), b o dy w ei g ht: 
C h a n g e fr o m B as eli n e  t o W e ek 7 9 
 
Su m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
N o  
N o  
N o  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 3  of 9 9  
 
E n d p oi nt  
A n al y si s  
p o p ul ati o n  
Pri m ar y  a n al y si s  
S u p p orti v e  a n al y si s  
S u b gr o u p  a n al y si s  
Ot h er  a n al y s e s  
Pr o p orti o n of p ati e nts: ac hi evi n g 
S B P < 1 3 0 m m H g f or t h os e wit h 
b as eli n e S B P ≥1 3 0 m m H g, 
ac hi evi n g D B P < 8 0 m m H g f or 
t h os e wit h b as eli n e D B P 
≥8 0  m m H g, wit h r e d ucti o n i n b o dy 
w ei g ht by ≥2 %, ≥5 %, a n d ≥1 0 % 
fr o m b as eli n e 
I T T 
By -visit fr e q u e ncy s u m m ary 
N o  
N o  
By -visit gr a p hic al 
pr es e nt ati o n as a p pr o pri at e  
Pr o p orti o n of p ati e nts r e q uiri n g 
r esc u e f or hy p er glyc e mi a 
I T T 
Su m m ary st atistics  
N o  
N o  
K M pl ot, List of p ati e nts 
r esc u e d 
A B P M S u b st u d y  
A B P M  
p o p ul ati o n  
 
 
 
 
Pri m ary e n d p oi nt 
 
 
 
 
 
C h a n g e fr o m B as eli n e t o W e ek 1 2 
i n av er a g e 2 4-h o ur S B P i n a 
s u bs et of p ati e nts wit h S B P 
≥1 3 0  m m H g at Scr e e ni n g  
A B P M p o p ul ati o n    A N C O V A ( wit h missi n g v al u es i m p ut e d 
by t h e r etri ev e d dr o p o uts & w as h o ut 
i m p ut ati o n m et h o d or by c o ntr ol-b as e d MI 
m et h o d u n d er M N A R ass u m pti o n): 
tr e at m e nt, r a n d o miz ati o n str at u m 
( H b A1c), a n d c o u ntry as fix e d eff ects, 
a n d b as eli n e S B P v al u e as a c ov ari at e  
N o  
N o  
S u m m ary st atistics f or 
o bs erv e d v al u es a n d 
c h a n g es fr o m b as eli n e by 
visit. 
 
Sec o n d ary e n d p oi nt  
 
 
 
 
 
A v er a g e 2 4-h o ur S B P: C h a n g e 
fr o m B as eli n e t o W e ek 2 6 
Av er a g e 2 4 -h o ur D B P, av er a g e 
a dj ust e d a w ak e ti m e B P as 
m e as ur e d by S B P a n d D B P wit h 
a dj ust m e nt b as e d o n acti gr a p hy, 
av er a g e a dj ust e d sl e e p ti m e B P 
as m e as ur e d by S B P a n d D B P 
wit h a dj ust m e nt b as e d o n 
acti gr a p hy: C h a n g e fr o m B as eli n e 
t o W e ek 1 2 a n d 2 6 
A B P M p o p ul ati o n    A N C O V A ( wit h missi n g v al u es i m p ut e d 
by t h e r etri ev e d dr o p o uts & w as h o ut 
i m p ut ati o n m et h o d or by c o ntr ol-b as e d MI 
m et h o d u n d er M N A R fr a m e w ork): 
tr e at m e nt, r a n d o miz ati o n str at u m 
( H b A1c), a n d c o u ntry as fix e d eff ects, 
a n d b as eli n e S B P v al u e as a c ov ari at e  
 
N o  
N o  
S u m m ary st atistics f or 
o bs erv e d v al u es a n d 
c h a n g es fr o m b as eli n e by 
visit. 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 4  of 9 9  
 
 
S A F E T Y A N A L Y S E S  
 
E n d p oi nt  
A n al y si s 
P o p ul ati o n  
Pri m ar y  a n al y si s  
S u p p orti v e A n al y si s  
S u b gr o u p  a n al y si s  
Ot h er  a n al y s e s  
hy p o glyc e mi a  
S af ety  
F oll o w s af ety g ui d eli n es  
N u m b er ( %) of p ati e nts wit h a ny 
hy p o glyc e mi a, s ev er e 
hy p o glyc e mi a, d oc u m e nt e d 
sy m pt o m atic hy p o glyc e mi a d uri n g 
T E A E p eri o d, a n d i nci d e nc e r at es i n 
1 0 0 p ati e nt -y e ars. 
 
Sev er e hy p o glyc e mi a or 
d oc u m e nt e d sy m pt o m atic 
hy p o glyc e mi a by s u b gr o u ps: 
r ac e, a g e gr o u p, g e n d er 
K M pl ot ti m e t o first ev e nt of s ev er e 
hy p o glyc e mi a or d oc u m e nt e d sy m pt o m atic 
hy p o glyc e mi a  
D oc u m e nt e d sy m pt o m atic hy p o glyc e mi a m ay b e 
pr es e nt e d by < 5 4 m g/ d L ( 3. 0 m m ol/ L) as 
a p pr o pri at e.  
A dv ers e Ev e nts  
S af ety  
F oll o w s af ety g ui d eli n es  
N o  
C o m m o n T E A Es by 
s u b gr o u ps: r ac e, a g e, g e n d er, 
b as eli n e S B P, b as eli n e e G F R  
 
Cli nic al l a b or at ory 
d at a  
S af ety  
F oll o w s af ety g ui d eli n es  
D escri ptiv e  
N o  
N o  
Vit al si g ns  
S af ety  
F oll o w s af ety g ui d eli n es  
D escri ptiv e  
N o  
N o  
E C G, P hysic al 
ex a mi n ati o n  
S af ety  
F oll o w s af ety g ui d eli n es  
Fr e q u e ncy s u m m ary  
N o  
N o  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 5  of 9 9  
 
A p p e n di x H  
St u d y Fl o w C h art  
 
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w
-u p  
S cr e e ni n g  
R u n -i n 
VI SI T  
1 
2 
3 A ( A B P M 
pl a c e m e nt)
c  
3 
( R a n d o m
-iz ati o n) 
4 
5 
6 
7 A ( A B P M 
pl a c e m e nt) c  
7 
8 
9 A ( A B P M 
pl a c e m e nt)
c  
9 
1 0  
1 1  
1 2  
1 3 
1 4 d  
W e e k  
U p t o -4 
-2 
-1 
0 
B a s eli n e  
1 
4 
8 
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3  
Da y ( wi n d o w [ d a y s])  
 
(-7/  
+ 3)  
-7  
( ± 2) 
1 
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 7 9  
( ± 3) 
I nf or m e d c o ns e nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n crit eri a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Excl usi o n crit eri a  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al/ S urgic al Hist ory  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic ati o n Hist ory  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
He p atitis s erol o gy  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o dy wei g ht, h ei g ht e 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vit al si g ns f 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
P hysic al Ex a mi n ati o n:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co m pl et e  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
A b brevi at e d  
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
 
X 
Di et & ex ercis e 
i nstructi o n 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
I nstructi o n o n b asic 
g e nit o uri n ary hy gi e n e & 
hy drati o n  
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 6  of 9 9  
 
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w
-u p  
S cr e e ni n g  
R u n -i n 
VI SI T  
1 
2 
3 A ( A B P M 
pl a c e m e nt)
c  
3 
( R a n d o m
-iz ati o n) 
4 
5 
6 
7 A ( A B P M 
pl a c e m e nt) c  
7 
8 
9 A ( A B P M 
pl a c e m e nt)
c  
9 
1 0  
1 1  
1 2  
1 3 
1 4 d  
W e e k  
U p t o -4 
-2 
-1 
0 
B a s eli n e  
1 
4 
8 
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3  
Da y ( wi n d o w [ d a y s])  
 
(-7/  
+ 3)  
-7  
( ± 2) 
1 
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 7 9  
( ± 3) 
I R T c o nt actg 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Ra n d o miz ati o n  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dis p e ns e gl uc os e m et er  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dis p e ns e d i ary 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Coll ect/re vi e w di ary 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
I nstructi on o n di a b etic 
k et o aci d osis sy m pt o ms, 
gl uc os e t esti n g  
 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Dis p e ns e I M P  
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
I M P acc o u nti n g & 
c o m pli a nc e 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Co nc o mit a n t M e dic ati o n 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
S elf -m o nit ori n g of bl o o d 
gl uc os e h 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
1 2 -l e a d E C Gi 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
St a n d ar d mix e d m e al 
t ol era nc e t estj 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
L a b or at or y te sti n g k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F P G 
X 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 7  of 9 9  
 
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w
-u p  
S cr e e ni n g  
R u n -i n 
VI SI T  
1 
2 
3 A ( A B P M 
pl a c e m e nt)
c  
3 
( R a n d o m
-iz ati o n) 
4 
5 
6 
7 A ( A B P M 
pl a c e m e nt) c  
7 
8 
9 A ( A B P M 
pl a c e m e nt)
c  
9 
1 0  
1 1  
1 2  
1 3 
1 4 d  
W e e k  
U p t o -4 
-2 
-1 
0 
B a s eli n e  
1 
4 
8 
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3  
Da y ( wi n d o w [ d a y s])  
 
(-7/  
+ 3)  
-7  
( ± 2) 
1 
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 7 9  
( ± 3) 
Hb A 1c  
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Ch e mistry (i ncl u di n g 
a myl as e a n d li p as e)  
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
He m at ol o gy  
X 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
F asti n g li pi ds  
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
X 
 
Pre g n a ncy t est 
( W O C B P)l 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
S eru m f oll icl e 
sti m ul ati n g h or m o n e 
a n d estra di ol 
( m e n o p a us al w o m e n 
o nly) l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pl as m a c o n c e ntrati o nm  
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
M ark ers of i nt esti n al 
tra nsit & a bs orpti o nn  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
M ark ers of b o n e & 
c alci u m m et a b olis mo 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Uri n alysis (di pstick a n d 
microsc o py) p  
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 8  of 9 9  
 
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w
-u p  
S cr e e ni n g  
R u n -i n 
VI SI T  
1 
2 
3 A ( A B P M 
pl a c e m e nt)
c  
3 
( R a n d o m
-iz ati o n) 
4 
5 
6 
7 A ( A B P M 
pl a c e m e nt) c  
7 
8 
9 A ( A B P M 
pl a c e m e nt)
c  
9 
1 0  
1 1  
1 2  
1 3 
1 4 d  
W e e k  
U p t o -4 
-2 
-1 
0 
B a s eli n e  
1 
4 
8 
1 2  
1 2  
1 8  
2 6  
2 6  
3 9  
5 2  
6 5  
7 9  
8 3  
Da y ( wi n d o w [ d a y s])  
 
(-7/  
+ 3)  
-7  
( ± 2) 
1 
7 
( ± 3) 
2 8 
( ± 3) 
5 6 
( ± 3) 
8 3  
( ± 2) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 1  
( ± 2) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 5 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 7 9  
( ± 3) 
Uri n e al b u mi n, c alci u m, 
gl uc os e & cre ati ni n e  
 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
A B P M pl ac e m e nt c 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
A B P M re m ov al a n d 
ass ess m e nt  
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Ev al u at e f or glyc e mic 
resc u e 
 
 
 
 
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e tre at m e nt p eri o d  
 
Hy p o glyc e mi a  
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e st u dy  
A Es/ S A Es/ A E SIs/ E O SIs 
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e st u dy s 
a  If a p ati e nt disc o nti n u es tre at m e nt wit h i nv esti g ati o n al m e dici n al pro d uct (I M P) e arly d uri n g t h e C ore Tr e at m e nt P eri o d, t h e p ati e nt will h av e a Pre m at ure E n d-of -Tre at m e nt ( E O T) Visit, a n d a  F oll o w -u p Visit 4 
we eks aft er t h e l ast d os e of I M P. I n a d diti o n, ev ery eff ort will b e m a d e t o h av e all p ati e nts ret urn t o t h e sit e at t h e ti m e c orres p o n di n g t o t h eir sc h e d ul e d visits, p artic ul arly t h e W e ek 2 6 Visit. If t h e p ati e nt d o es n ot 
a gre e t o a sit e  visit, t h ey will b e c o nt act e d by t el e p h o n e t o i n q uire a b o ut s af ety st at us. If a p ati e nt disc o nti n u es ( or c o m pl et es) tre at m e nt  a n d st u dy at t h e s a m e ti m e, a si n gl e visit will b e p erf or m e d usi n g t h e 
proc e d ure n or m ally pl a n n e d f or t h e E O T visit . 
b  If a p ati e nt c o m pl et es t h e C ore Tre at m e nt, b ut disc o nti n u es I M P d uri n g t h e Ext e nsi o n P eri o d, t h e p ati e nt will h av e a Pre m at ure E O T Visit, a n d a F oll o w -u p Visit 4 we eks aft er t h e l ast d os e of I M P. Ev ery eff ort will 
b e m a d e t o h av e all p ati e nts ret urn t o t h e sit e at t h e  ti m e c orres p o n di n g t o t h eir q u art erly visits (i e, ev ery 1 3 w e eks) d uri n g t h e Ext e nsi o n P eri o d. At t h e ti m e c orres p o n di n g t o t h eir W e ek 7 9 Visit, all att e m pts will b e 
m a d e t o c o nt act t h e p ati e nt t o i n q uire a b o ut s af ety st at us. If a p ati e nt disc o nti n u es (or  c o m pl et es) tre at m e nt a n d st u dy at t h e s a m e ti m e, a si n gl e visit will b e p erf or m e d usi n g t h e proc e d ur e n or m ally pl a n n e d f or t h e 
E O T visit . 
c A m b ul at ory Bl o o d Press ur e M o nit ori n g ( A B P M) s u bst u dy visits f or a s u bs et of p ati e nts will occ ur 1 w e ek b ef ore t h e ra n d o miz ati o n Visit; p ati e nts will r et urn t h e A B P M d evic e by p ost aft er 2 4 -h o ur m o nit ori n g is 
c o m pl et e. P ati e nts i n t h e A B P M s u bst u dy will als o h av e visits f or pl ac e m e nt of t h e A B P M d evic e t h e d ay b ef ore W e ek 1 2 a n d W e e k 2 6 visits. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 0  D e c e m b er 2 0 1 9  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 4   
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 0 5 2 5  
C O V A N C E I N C. C O N FI D E N TI A L  
 
 
P a g e 9 9  of 9 9  
 
d  F o ur we eks aft er t h e l ast d os e of I M P.  
e  Hei g ht t o b e m e as ure d o nly at scre e ni n g.  
f 
Vit al si g n m e as ure m e nts (sitti n g B P a n d h e art rat e): 3 s e p arat e s e at e d B P a n d h e art r at e m e as ure m e nts s h o ul d b e t ak e n wit h at  l e ast 1 mi n ut e b et we e n re a di n gs, f oll o wi n g a 5-mi n ut e rest p eri o d a n d pri or t o 
p hl e b ot o my (s e e  S ecti o n 9. 2. 1. 4 a n d d et ail e d i nstructi o ns i n  A p p e n dix E) . 
g  I nt eractiv e r es p o ns e T ec h n ol o gy (I R T) c o nt act n ot re q uir e d f or p ati e nts w h o disc o nti n u e I M P e arly aft er t h ey h av e att e n d e d t he E O T Visit.  
h  S e e S ecti o n 9. 2. 1. 6 f or d et ails of S M B G m e as ure m e nts. Gl uc os e m et ers us e d f or S M B G dis pl ay res ults as pl as m a gl uc os e c o nc e ntr ati o n. P ati e nts s h o ul d m e as ur e t h eir f asti n g pl as m a gl uc os e at l e ast 3 ti m es p er 
we ek (i ncl u di n g o n d ay of e ac h o n -sit e st u dy visit). Aft er Visit 9 ( W e ek 2 6), if f asti n g S M B G v al u es are < 1 2 0 m g/ d L, ov er a 2 -w e ek p eri o d, t h e I nv esti g at or c a n i nstruct p ati e nts t o s elf -m o nit or bl o o d gl uc os e o nc e a 
we ek (o n d ay of o n -sit e st u dy visit f or w e eks wit h o n-sit e st u dy visits). 
i 
T h e 1 2 -l e a d E C G rec ordi n gs s h o ul d b e o bt ai n e d pri or t o I M P a d mi nistrati o n. T h e E C G will b e ev al u at e d as “n or m al” or “a b n or m al”.  
j 
P ost pra n di al pl as m a gl uc os e will b e ass ess e d by c e ntral l a b orat ory at B as eli n e a n d 2 h o urs aft er c o ns u mi n g a st a n d ard mix e d li q ui d bre akf ast m e al a n d vi a a mix e d m e al t ol era nc e t est ( M M T T) o n Day 1, 
W e ek  2 6, a n d W e ek 7 9. If a p ati e nt wit h dra ws fro m I M P e arly, pl e as e s e e S ecti o n  1 0. 3. 4 . 
k All l a b orat ory ass ess m e nts occ ur pri or t o first d os e of d o u bl e -bli n d I M P. T h e first d os e of d o u bl e -bli n d I M P occ urs aft er s a m pl es f or t h e mix e d li q ui d m e al  h av e b e e n c oll ect e d. All visit d at es will b e sc h e d ul e d b as e d 
o n t h e d at e of ra n d o miz ati o n wit h a ± 3 d ays visit wi n d o w all o w e d d uri n g t h e c ore tre at m e nt p eri o d. S eru m c h e mistry p ara m et ers  (cli nic al c h e mistry [incl u di n g a myl as e a n d li p as e], h e m at ol o gy, a n d ot h er bl o o d 
p ara m et ers) ar e list e d i n  T a bl e 2 . 
l 
S eru m pre g n a ncy t esti n g o nly at scr e e ni n g; uri n e pre g n a ncy t esti n g s u bs e q u e ntly. S eru m pr e g n a ncy t est res ults m ust b e revi e w e d pri or t o b e gi n ni n g t h e Ru n -i n p h as e f or all wo m e n of c hil d b e ari n g p ot e nti al 
( W O C B P) u nl ess t h er e is d oc u m e nt e d hist ory of m e n o p a us e (b as e d o n d oc u m e nt e d f ollicl e-sti m ul ati n g h or m o n e [ F S H] a n d estra di ol l ev els – if res ults n ot d oc u m e nt e d t h e n F S H a n d estr a di ol will b e t est e d at 
Scre e ni n g visit) or t h ey ar e s urgic ally st eril e. A ny p ositiv e uri n e t est res ults m ust b e c o nfir m e d b as e d o n s eru m pre g n a ncy t est. T h e I nv esti g at or m ay p erf or m a d diti o n al t ests at t h eir discr eti o n or as re q uire d by 
l oc al re g ul ati o ns. 
m  Pl as m a c o nc e ntrati o n s a m pl es (i e, f or s ot a glifl ozi n a n d S ot a glifl ozi n - 3- O-gl uc uro ni d e) o n W e ek 4, W e ek  1 8, a n d W e ek 5 2 s h o ul d b e dra wn wit h t h e ot h er l a b orat ory ass ess m e nts. F or W e ek 2 6 a n d W e ek  7 9, 
pl as m a c o nc e ntr ati o n s a m pl es s h o ul d b e dra w n at Ti m e 0 a n d 1 5 0 mi n ut es (2 h o ur 3 0 mi n ut es) i m m e di at ely aft er t h e res p ectiv e gl uc os e ass ess m e nts d uri n g t h e M M T T. P h ar m ac oki n etic ( P K) s a m pl es (exc e pt t h e 
2 h o ur 3 0 mi n ut e s a m pl e d uri n g t h e M M T T) M U S T b e c oll ect e d b ef ore a d mi nistrati o n of I M P. T h e d at e a n d ti m e of t h e l ast i nt ak e of I M P pri or t o visits wh ere P K s a m pl es are t ak e n s h o ul d b e r ec ord e d  by t h e 
p ati e nt i n t h e p ati e nt di ary. P ati e nts s h o ul d b e re mi n d e d of t his at visits prec e di n g P K ti m e p oi nts t o e ns ur e t h es e d et ails are c a pt ure d. I n t h e c as e of pre m at ure I M P disc o nti n u ati o n, P K s a m pl es s h o ul d n ot b e 
dra wn at t h e Pre m at ure E O T visit, n or at a ny s u bs e q u e nt visits.  
n  T h e m ark ers of i nt esti n al tra nsit a n d a bs orpti o n i ncl u d e vit a mi ns B 6, B 1 2, K, E, a n d A, s eru m f ol at e, a n d f erriti n.  
o  M ark ers of b o n e a n d c alci u m m et a b olis m i ncl u d e: s eru m a n d uri n ary c alci u m, s eru m 2 5 -hy droxyvit a mi n D, s eru m 1, 2 5 -di hy droxyvit a mi n D, s eru m a n d uri n ary p h os p h orus, s eru m p arat hyroi d h or m o n e, m ark ers of 
b o n e r es orpti o n (s er u m N T X, s eru m β -C T X -1), a n d b o n e f or m ati o n (s er u m P 1 N P).  
p  Uri n alysis i ncl u d es uri n e di pstick a n d microsc o py. Di pstick i ncl u d es ass ess m e nt of s p ecific gravity, p H, pr ot ei n, bl o o d, k et o n es, biliru bi n, uro bili n o g e n, nitrit e, a n d l e uk ocyt e est eras e. Micr osc o py i ncl u d es d et ecti o n  
of f or m e d c ell ul ar el e m e nts, c asts, b act eri a, y e ast, p arasit es, a n d cryst als i n c e ntrif u g e d uri n e s e di m e nt. I n t h e ev e nt of a b n or m al uri n alysis fi n di n gs s us pici o us of uri n ary tract i nf ecti o n, uri n e c ult ure s h o ul d b e 
p erf or m e d. P ositiv e uri n e c ult ure d et er mi n ati o n will b e b as e d u p o n t h e crit eri a of t h e re p orti n g l a b orat ory.  
 
 
 
 
s All s eri o us a dv ers e ev e nts ( S A Es), a dv ers e ev e nts ( A Es), A Es of s p eci al i nt erest ( A E SIs), a n d Ev e nts of S p eci al I nt erest ( E O SIs) will b e c oll ect e d st arti n g wit h si g ni n g i nf or m e d c o ns e nt a n d c o nti n u e u ntil t h e e n d 
of t h e st u dy. All A Es t h at occ ur d uri n g tre at m e nt s h o ul d b e f oll o w e d u ntil st u dy c o m pl eti o n ( or u ntil p ati e nts l e av e t h e st u dy)  or u ntil t h e ev e nt h as res olv e d, t h e c o n diti o n h as st a biliz e d, or t h e p ati e nt is l ost t o 
f oll o w-u p.  All p ati e nts will h av e a f oll o w -u p visit 4 w e eks aft er t h e l ast d os e of  I M P t o c oll ect s af ety i nf or m ati o n.