Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 diabetes mellitus Blood glucose Anti-diabetic Bile acid sequestrant Colesevelam HCl Oral suspension Pediatric Add-on therapy Add-on to metformin Metformin Adolescent Lipid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 236
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of the study drug in treating type 2 diabetes in children 10 to 17 years old.

The groups will be low-dose (0.625 g Welchol) and high-dose (3.75 g Welchol). The children will have a 2 in 5 chance of being assigned to the low-dose group. They will have a 3 in 5 chance of being assigned to the high-dose group.

We believe the study drug will be safe, well tolerated, and improve blood sugar control in children 10 to 17 years old.

Detailed description:
Colesevelam oral suspension will be studied as treatment of type 2 diabetes mellitus (T2DM) to evaluate clinical safety and efficacy in patients aged 10-17 years. The patients may have been treated with Metformin or have had no antidiabetic drug treatment in the previous three months.

Study Hypothesis: Colesevelam oral suspension for pediatric subjects with T2DM is safe, well tolerated, and shows improved blood sugar control (as evidenced by a significant change from baseline in hemoglobin A1C \[HbA1c\]).

Arms:
arm 1: High-dose colesevelam suspended in a drink for oral administration once daily with dinner arm 2: Low-dose colesevelam suspended in a drink for oral administration once daily with dinner

Interventions: intervention 1: High-dose colesevelam intervention 2: Low-dose colesevelam
Intervention descriptions: intervention 1: 3.75 grams colesevelam hydrochloride in oral suspension intervention 2: 0.625 grams colesevelam hydrochloride in oral suspension

Protocol document:
Prot_SAP_000.pdf: 
C LI NI C A L S T U D Y P R O T O C O L 
 
 
C O L E S E V E L A M O R A L S U S P E N SI O N A S 
M O N O T H E R A P Y O R A D D - O N T O M E T F O R MI N 
T H E R A P Y I N P E DI A T RI C S U B J E C T S WI T H 
T Y P E 2 DI A B E T E S M E L LI T U S 
 
 
W E L- A- U 3 0 7 
 
 
V E R SI O N: 2. 0 , 3 0  A U G 2 0 1 1 
 
 
Pre vi o us versi o n : 1. 0, 3 0 J ul y 2 0 1 0 
 
 
D aiic hi S a n k y o P h ar m a De vel o p me nt  
3 9 9 T h or n all Street 
E dis o n, N J 0 8 8 3 7 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T 
I nf or mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n k y o P har ma 
De vel o p me nt ( D S P D).  T he i nf or mati o n is pr o vi de d t o y o u i n c o nfi de nce w hic h is 
req ueste d u n d er a n a gree d- u p o n a n d si g n e d C o nfi de ntialit y a n d Discl os ur e A gree me nt.  
D o n ot gi ve t his d oc u me nt or a n y c o p y of it or re veal a n y pr o prietar y i nf or mati o n 
c o ntai ne d i n it t o a n y t hir d part y ( ot her t ha n t h os e i n y o ur or ga nizati o n w h o are assisti n g 
y o u i n t his w or k a n d are b o u n d b y t he C o nfi de ntialit y a n d Discl os ure A gree me nt) 
wit h o ut t he pri or writte n per missi o n of a n a ut h orize d re prese ntati ve of D S P D. 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 of 6 4 
P R O T O C O L S Y N O P SI S 
E u dra C T/I N D N u m b er:   
I N D 6 8, 4 6 6 
Pr ot oc ol N u m ber:   
W E L -A -U 3 0 7  
I n v esti gati o nal Pr o d uct:  
Wel ch ol ®  (colese vela m h y dr oc hl ori de ) f or Oral S us pe nsi o n  
Acti ve I n gre die nt(s)/I N N:   
C olese vela m h y dr oc hl ori de  
St u d y Title:  
C olese vela m Oral S us pe nsi o n as M o n ot hera p y or A d d -o n 
t o Metf or mi n T hera p y i n Pe diatric S u bjects wit h T y p e 2 
Dia betes Mellit us  
St u d y P has e:  
P hase 3 b/ 4  
I n dicati o n U n der 
I n v esti gati o n: 
Pe diatric t y p e 2 dia betes mellit us  
St u d y O bjecti ves:   
T he pri mar y o bjecti ve of t he st u d y is t o de m o nstrate t he 
effects of  c olese vela m h y dr oc hl ori de ( H Cl) oral s us pe nsi o n 
as m o n ot hera p y or  as a n a d d-o n t hera p y t o metf or mi n o n 
mea n c ha n ge i n he m o gl o bi n H b A 1c  fr o m baseli ne o ver a 6-
m o nt h d o u ble -bli n d  treat me nt peri o d i n pe diatric s u bjects 
wit h t y pe 2 dia betes mellit us.  
T he sec o n d ar y o bjecti ves of t he  st u d y are: 
 T o de m o nstrate t he safet y a n d t olera bilit y of 
c olese velam H Cl oral s us pe nsi o n as a n a nti -dia bet ic 
treat me nt i n pe diatric s u bjects wit h t y pe 2 dia betes 
mellit us;  
 T o assess t he effect of c olese vela m H Cl oral s us pe nsi o n 
o n  H b A 1c o ver 1 2 m o nt hs;  
 T o assess t he effect of c olese vela m H Cl oral s us pe nsi o n 
o n fasti n g plas ma gl u c os e ( F P G) o v er 1 2 m o nt hs ; 
 T o assess gl yce mic res p o nse t o c olese vel a m  H Cl  oral 
s us pe nsi o n t hera p y o ver ti me .  Res p o n se t o t hera p y will 
be a nal yz e d b y t he perce nt a ge of s u bjects wit h a 
decrease i n H b A 1c 0. 7 %  a n d ≥0. 5 %, fi nal H b A 1c 
7. 0 %  a n d < 6. 5 %, an d/ or a decrease i n 
F P G   3 0  m g/ d L; a n d  
 T o  assess t he effects of c olese vela m H Cl oral 
s us pe nsi o n o n c ha n ges i n plas ma li pi ds i ncl u di n g t otal 
c h olester ol ( T C), l o w -d e nsit y li p o pr ot ei n c h olester ol 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 of 6 4 
( L D L-C), hi g h -d e nsit y li p o pr otei n c h olester ol 
( H D L-C), n o n -hi g h -de nsit y li p o pr otei n c h olester ol  
( n o n-H D L -C ), tri gl yceri des ( T G), a p oli p o pr otei n A-1 
(a p o A-1), a n d a p oli p o pr otei n B (a p o B).  
 T o assess t he pr o p orti o n of s u bjects re q uiri n g resc ue 
a n d t he ti me fr o m ra n d o mizati o n t o i nitiati o n of resc ue 
me dicati o n.  
St u d y  Desi g n:  
T his is a m ulti -ce nter, ra n d o mize d, d o u ble -bli n d , 2-gr o u p 
st u d y i n pe diatric s u bjects wit h t y pe 2 dia bet es mellit us 
wit h s u b o pti mal gl yce mic c o ntr ol wit h or wit h o ut 
metf or mi n.  T he st u d y will c o nsist of : 
 A s cree ni n g visit,  
 A 2 -wee k  si n gle-bli n d lea d-i n/sta bilizati o n peri o d, 
 A  1 2 -m o nt h d o u ble -bli n d  treat me nt peri o d, a n d 
 A  f oll o w-u p visit a p pr o xi matel y 2 wee ks after t he e n d 
of treat me nt.  
S u bjects ma y eit her be o n  metf or mi n m o n ot hera p y or b e 
c urre ntl y u ntreate d wit h a ntidia betic a ge nts. “ U ntreate d” 
i ncl u des s u bjects w h o ha ve eit her  
 ne ver recei ve d a nti dia betic t hera p y (n aï ve ) or  
 recei v e d a nti dia betic me dicati o ns  f or less t ha n 1 4 da ys 
wit hi n 3 m o nt hs pri or t o scree ni n g  b ut n o i ns uli n 
t hera p y wit hi n 1 4 da ys of scree ni n g .   
T he pri or t y pe 2 dia betes melli t us treat me nt stat us will be 
use d as a stratificati o n fact or at ra n d o mizati o n.  
All s u bjects will e nter a 2 -wee k, si n gle -bli n d 
lea d-i n/sta bilizati o n peri o d after bei n g c o nfir me d as eli gi ble 
t o partici pate i n t his st u d y.  S u bjects o n metf or mi n 
m o n ot hera p y wi ll re mai n o n t he sa me d ose as at scree ni n g 
t hr o u g h o ut t he sta bilizati o n peri o d. A bli n de d o nce -dail y 
me dicati o n (l o w -d ose c olese vela m H Cl) will be pr o vi de d t o 
all s u bjects.  
A p pr o xi matel y 2 2 0  s u bj ects will be ra n d o mize d i n a 3:2 
rati o of hi g h -d ose c ol ese vel a m H Cl oral s us pe nsi o n ( 3. 7 5 
g) o nce dail y t o l o w -d ose c olese vela m H Cl oral s us pe nsi o n 
( 0. 6 2 5 g)  o nce d ail y  f or t he treat me nt peri o d.     
After ra n d o mizati o n, s u bjects m ust c o nti n ue o n t he sa me 
d ose of metf or mi n as d uri n g lea d -i n/sta bilizati o n, u nless 
a n d u ntil t he s u bject meets t he criteria f or gl yce mi c resc u e.  
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 of 6 4 
I n t he e ve nt t hat t he s u bj ect’s H b A 1 c le vel ca n n ot be 
c o ntr olle d bel o w 8. 5 % after 3 m o nt hs or bel o w 7. 5 % 
(c o nfir me d persiste nt h y per gl yce mia) after 6 m o nt hs of 
st u d y me dicati o n, as m eas ure d b y t he ce ntral la b orat or y, 
gl yce mic res c ue m ust be starte d wit h metf or mi n  ( b y 
i nitiati n g or o pti mizi n g d oses t o a ma xi mall y t olerate d d ose 
u p t o  2  g / d), a n d if t his is n ot a de q uate, wit h o nce -dail y 
i ns uli n s uc h as i ns uli n glar gi ne. 
T h ose l o w -d ose s u bjects w h o c o m plete M o nt h 6 a n d are 
s witc he d t o t he hi g h d os e pri or t o t he a p pr o val of pr ot oc ol 
versi o n 2. 0 a n d its I nf or me d C o nse nt will c o nti n ue o n t he 
hi g h -d ose t o t he e n d of t he st u d y, acc or di n g t o t h e ori gi n al 
pr ot oc ol.  
Gl uc o meters will be pr o vi de d f or self-m o nit or i n g of bl o o d 
gl uc ose l e vels, w hic h will be rec or de d d uri n g t he l ea d -i n 
peri o d a n d t hr o u g h o ut t h e t w o 6 -m o nt h treat me nt peri o ds.  
St u d y D urati o n:  
T he st u d y  will c o nsist  of a scree ni n g visit, a 2 -wee k , 
si n gle-bli n d  lea d-i n/sta bilizati o n peri o d, a d o u ble -bli n d  1 2 -
m o nt h  treat me nt peri o d, a n d a f oll o w-u p visit 2 wee ks aft er 
t he e n d of treat me nt.  T h e t otal d urati o n of partici pati o n f or 
a n i n di vi d ual s u bject will be a p pr o xi matel y 5 8 wee ks.  
St u d y Sites a n d L o cati o n:   
A p pr o xi matel y 2 0 t o 3 0 sites i n t he U nite d States will 
partici pate.  
Pla n ne d Sa m ple Size:   
A p pr o xi matel y 2 2 0 s u bj ects will be ra n d o mize d i n t his 
st u d y: a p pr o xi matel y 1 3 2  t o t he hi g h-d ose c olese v ela m 
H Cl gr o u p a n d 8 8  t o t he l o w-d ose c olese vela m H Cl gr o u p.  
S u bject Eli gi bilit y Criteri a:  
I n di vi d uals w h o are eli gi ble f or t his st u d y are mal es a n d 
fe males, 1 0 t o 1 7 years of a ge  at ra n d o mizati o n , wit h a 
dia g n osis of t y pe 2 dia betes mellit us, as defi ne d b y t he 
A merica n Di a betes Ass o ciati o n.  At scree ni n g, s u bjects 
m ust ha ve a n H b A 1 c bet wee n 7. 0 % a n d 1 0. 0 %, i ncl u si ve, 
a n d a fasti n g C -pe pti de 0. 6 n g/ m L.  S u bjects m ust be o n 
metf or mi n m o n ot hera p y, or c urre ntl y u ntreate d wit h 
a nti dia betic p har mac ot hera p y as defi ne d a b o v e . 
I n di vi d uals are t o be e x cl u de d fr o m partici pati o n i n t he 
st u d y if, at scree ni n g, t he y ha v e a n FP G 2 7 0 m g/ d L , 
dia g n osis of t y pe 1 dia betes , or hist or y of m ore t h a n 
1  e pis o de of ket oaci d osis after t he i nitial dia g n osis of 
t y pe 2 dia betes mellit us.  S u bjects m ust n ot ha ve a 
creati ni ne cleara nce 7 0 m L/ m i n or a n al a ni ne 
tra nsa mi nase or as part ate a mi n otra nsferase el e vati o n 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 of 6 4 
2. 5   t he u p per li mit of n or mal at scree ni n g. 
D osa ge F or m, D ose a n d 
R o ute of A d mi nistrati o n:  
D uri n g t h e 2 -wee k, si n gle -bli n d lea d -i n/sta bilizati o n 
peri o d, all s u bjects will recei ve l o w -d ose c ol ese vela m H Cl 
oral s us pe nsi o n 0. 6 2 5 g t o be mi x e d i n 4 t o 8 o u nces of 
water , fr uit j uice or diet s oft dri n k f or oral a d mi nistrati o n 
o nce dail y wit h a di n ner meal . 
C olese vela m H Cl oral s us pe nsi o n will be pr o vi de d i n 
i de nticall y a p peari n g p ac kets of 3. 7 5 g ( hi g h d ose, 6 -ta blet 
e q ui vale nt) a n d p ac ke ts of 0. 6 2 5 g (l o w d ose, 1 -ta blet 
e q ui vale nt) t o be mi x e d i n 4 t o 8 o u nces of wat er , fr uit 
j uice or diet s oft dri n k f or oral a d mi nistrati o n o nce dail y 
wit h a di n ner meal .  
St u d y E n d p oi nts:   
T he pri mar y efficac y  en d p oi nt is t he c ha n ge i n H b A 1c 
fr o m baseli ne t o M o nt h 6 wit h last o bser vati o n carrie d 
f or war d ( L O C F). 
T he  sec o n d ar y e n d p oi nts i ncl u de t he f oll o wi n g: 
 T he c ha n ge i n H b A 1c fr o m baseli ne at eac h sc he d ule d 
visit u p t o M o nt h 1 2;  
 T he c ha n ge i n F P G fr o m baseli ne t o M o nt h 6 a n d 
M o nt h 1 2 ; 
 Perce nta ge of s u bjec ts ac hie vi n g a res p o nse t o t hera p y 
at M o nt h 6 a n d M o nt h 1 2, defi ne d as H b A 1c 7. 0 %  
a n d 6. 5 %, re d u cti o n i n H b A 1c 0. 7 %  a n d ≥0. 5 % fr o m 
baseli ne , a n d/ or re d ucti o n i n F P G 3 0  m g/ d L fr o m 
baseli ne ; a n d 
 T he c ha n ge s i n plas ma li pi ds (i ncl u di n g T C, L D L -C, 
H D L -C, n o n -H D L -C, T G , a p o A -1, a n d a p o B) at eac h 
ti me p oi nt w here meas ure d. 
 Pr o p orti o n of s u bjects re q uiri n g resc ue a n d ti me f r o m 
ra n d o mizati o n t o i nitiati o n of resc u e me dicati o n. 
Safet y v aria bl es f or ass ess me nt i ncl u de a d verse e v e nts, 
vital si g ns, a n d c h e mistr y a n d he mat ol o g y la b orat or y 
para meters.  
Statistical A nal yses:   
T he pri mar y efficac y a n al ysis is t o c o m pare hi g h -d ose 
( 3. 75 g/ d a y) t o l o w -d ose ( 0. 6 2 5 g/ d a y) c olese vela m H CI 
oral s us pe nsi o n f or c h a n ge i n H b A 1c fr o m baseli ne t o 
M o nt h 6 usi n g t he I nte nt -T o -Treat (I T T) p o p ul ati o n  wit h 
L O C F .  F or s u bjects w h o recei v e d res c ue t hera p y, t he last 
p ost -baseli ne H b A 1 c val ue o bser ve d pri or t o res c ue will be 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 7 of 6 4 
carri e d f or war d.  T h e treat me nt differe nce will be teste d at 
a 2-si de d si g nifica n ce le vel of 0. 0 5, usi n g 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 p  a n d 
pre vi o us T 2 D M treat me nt strat u m as fi x e d effects a n d 
baseli ne H b A 1c as a c o v ariate.  P -val u e o btai ne d fr o m 
bet wee n -treat me nt c o m p aris o n will be prese nt e d.  T he L S 
mea n, sta n dar d err or, a n d 9 5 % CI f or eac h treat me nt as 
well as f or t he differe nce bet wee n hi g h - a n d l o w-d ose 
c olese vela m H CI gr o u ps will be esti mate d.  
T he a n al yses of t he c o nti n u o us sec o n dar y effi cac y 
varia bles will be carrie d o ut usi n g t he sa me met h o d as f or 
t he pri mar y efficac y varia ble, u nless ot her wise state d.  T he 
bet wee n -treat me nt c o m p aris o n f or c h a n ge i n T G will be 
carri e d o ut usi n g a n o n -p ara metric A N C O V A.  T he 
gl yce mic c o ntr ol rates will be c o m pare d b et wee n 
treat me nts usi n g Fis her’s e x act test. 
Safet y assess me nts i ncl u de e val uati o ns of a d verse e ve nts, 
cli nical la b orat or y meas ure me nts ( he mat ol o g y, bl o o d 
c he mistr y, a n d uri nal ysis), vital si g ns, p h ysical 
e x a mi nati o ns, pri or a n d c o nc o mita nt me dicati o ns, a n d 
vita mi n D le vel.  
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 8 of 6 4 
T A B L E O F C O N T E N T S 
I N V E S TI G A T O R A G R E E M EN T  ................................................................................... 2 
P R O T O C O L S Y N O P SI S .................................................................................................. 3  
T A B L E O F C O N T E N T S .................................................................................................. 8  
L I S T O F I N- T E X T T A B L E S ......................................................................................... 1 3 
L I S T O F I N- T E X T FI G U R E S ....................................................................................... 1 4 
L I S T O F A B B R E VI A TI O N S ......................................................................................... 1 5 
1.  
I N T R O D U CTI O N A N D B A C K G R O U N D I N F O R M A TI O N .................. 1 6  
1. 1.  
Data S u m mar y  ................................................................................................ 1 6 
1. 1. 1.  
I nte n de d Use U n der I n vesti gati o n .................................................................. 1 6 
1. 1. 2.  
N o ncli nical St u dies ......................................................................................... 1 6  
1. 1. 3.  
Cli nical E x perie nce ......................................................................................... 1 6  
1. 2.  
St u d y R ati o nale ............................................................................................... 1 7  
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects ............................................................ 1 7  
1. 4.  
P o p ulati o n, R o ute, D osa ge, D osa ge Re gi me n, Treat me nt Peri o d .................. 1 8  
1. 5.  
C o m plia nce State me nt, Et hics, a n d Re g ul at or y C o m plia nce ......................... 1 8  
1. 5. 1.  
S u bject C o nfi de ntialit y ................................................................................... 1 8  
1. 5. 2.  
I nf or me d C o nse nt a n d Asse nt Pr oce d ure ....................................................... 1 9 
1. 5. 3.  
Re g ulat or y C o m plia nce .................................................................................. 2 0  
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S ........................................... 2 1  
2. 1.  
St u d y O bjecti ves ................................ ............................................................. 2 1 
2. 1. 1.  
Pri mar y O bj ecti ves ......................................................................................... 2 1  
2. 1. 2.  
Sec o n dar y O bj ecti ves ..................................................................................... 2 1  
2. 2.  
St u d y H y p ot hesis ............................................................................................ 2 1  
3.  
S T U D Y D E SI G N .......................................................................................... 2 2  
3. 1.  
O verall Pla n ................................ .................................................................... 2 2 
3. 1. 1.  
St u d y T y pe ................................ ...................................................................... 2 2 
3. 1. 2.  
Treat me nt Gr o u ps ........................................................................................... 2 3  
3. 1. 3.  
St u d y E n d p oi nts ................................ .............................................................. 2 3 
3. 1. 4.  
D urati o n of t he St u d y ...................................................................................... 2 3  
3. 1. 5.  
D urati o n of S u bject Parti ci pati o n ................................................................... 2 3  
3. 1. 6.  
Gl yce mic Resc u e ............................................................................................ 2 4  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 9 of 6 4 
3. 2.  
Selecti o n of D oses .......................................................................................... 2 4  
3. 2. 1.  
E x peri me ntal Treat me nts ................................................................................ 2 4  
3. 2. 2.  
C o ntr ol Treat me nts ......................................................................................... 2 4  
4.  
S T U D Y P O P U L A TI O N ............................................................................... 2 5  
4. 1.  
E nr oll me nt ................................ ...................................................................... 2 5 
4. 1. 1.  
I n cl usi o n Criteria ............................................................................................ 2 5 
4. 1. 2.  
E x cl usi o n Criteria ........................................................................................... 2 6  
4. 2.  
Re m o val of S u bjects Fr o m T hera p y ............................................................... 2 7  
4. 2. 1.  
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n ............................................. 2 7  
4. 2. 2.  
Wit h dra wal Pr oce d ures f or Earl y Ter mi nati o n ............................................... 2 8  
4. 2. 3.  
S u bject Re place me nt ...................................................................................... 2 8  
4. 2. 4.  
S u bject Re-scree ni n g Pr oce d ures ................................................................... 2 8  
5.  
T R E A T M E N T S A D MI NI S T E R E D ............................................................ 2 8  
5. 1.  
I n v esti gati o nal Pr o d ucts .................................................................................. 2 8 
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g ........................... 2 8  
5. 1. 1. 1.  
I d e ntificati o n N u m bers ................................................................................... 2 8 
5. 1. 1. 2.  
Dr u g Ra n d o mizati o n ....................................................................................... 2 9  
5. 1. 1. 3.  
Bli n di n g .......................................................................................................... 2 9  
5. 1. 2.  
Met h o d of Assessi n g Treat me nt C o m plia nce ................................................. 2 9  
5. 1. 3.  
La b eli n g a n d Pac k a gi n g .................................................................................. 3 0  
5. 1. 4.  
Pre parati o n ...................................................................................................... 3 0  
5. 1. 5.  
St ora ge ............................................................................................................ 3 0  
5. 1. 6.  
Dr u g Acc o u nta bilit y ....................................................................................... 3 0  
5. 1. 7.  
Rete nti o n Sa m ples .......................................................................................... 3 1  
5. 2.  
C o nc o mita nt Me dicati o ns ............................................................................... 3 1  
5. 3.  
Restricte d Me dicati o ns ................................................................................... 3 1  
6.  
S T U D Y P R O C E D U R E S .............................................................................. 3 2  
6. 1.  
Scree ni n g ( Visit 1) .......................................................................................... 3 2  
6. 2.  
Lea d-i n/ Sta bilizati o n Peri o d ( Wee k - 2; Visit 2) ............................................. 3 2  
6. 3.  
Treat me nt Peri o d ................................ ............................................................ 3 3 
6. 3. 1.  
Ra n d o mizati o n ( Da y 1; Visit 3) ...................................................................... 3 3  
6. 3. 2.  
M o nt h 1 ( Visit 4) ................................ ............................................................ 3 4 
6. 3. 3.  
M o nt h 3 ( Visit 5) ................................ ............................................................ 3 4 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 0 of 6 4 
6. 3. 4.  
M o nt h 6 ( Visit 6) ............................................................................................ 3 5  
6. 3. 5.  
M o nt h 9 ( Visit 7) ............................................................................................ 3 5  
6. 4.  
E n d of Treat me nt/ Earl y Ter mi nati o n Visit ..................................................... 3 6  
6. 5.  
F oll o w- u p ........................................................................................................ 3 6  
6. 6.  
Pr ot oc ol De viati o ns ........................................................................................ 3 8  
7.  
E F FI C A C Y A S S E S S M E N T S ...................................................................... 3 9  
7. 1.  
Pri mar y Efficac y Varia bl e .............................................................................. 3 9  
7. 2.  
Sec o n dar y Efficac y Varia bles ......................................................................... 3 9  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ............................................................................................ 4 0  
8. 1.  
P har mac o ki netic Varia bl es ............................................................................. 4 0  
8. 2.  
P har mac o d y na mic Varia bles .......................................................................... 4 0  
8. 3.  
Bi o mar ker a n d E x pl orat or y Varia bl es ............................................................ 4 0  
9.  
S A F E T Y A S S E S S M E N T S ........................................................................... 4 0  
9. 1.  
A d verse E v e nts ................................ ............................................................... 4 0 
9. 1. 1.  
Defi niti o ns ...................................................................................................... 4 1  
9. 1. 1. 1.  
A d verse E v e nt ................................................................................................. 4 1  
9. 1. 1. 2.  
Seri o us A d verse E v e nt .................................................................................... 4 1  
9. 1. 1. 3.  
A d verse E v e nt Se verit y .................................................................................. 4 1  
9. 1. 1. 4.  
Ca usalit y Assess me nt ..................................................................................... 4 2  
9. 1. 1. 5.  
Acti o n Ta ke n Re gar di n g t he St u d y Me dicati o n ............................................. 4 2  
9. 1. 1. 6.  
A d verse E v e nt O utc o me ................................................................................. 4 2  
9. 1. 1. 7.  
Ot her Acti o n Ta k e n f or E ve nt ........................................................................ 4 3  
9. 2.  
Seri o us A d verse E v e nt Re p orti n g – Pr oce d ure F or I n vesti gat ors .................... 4 3  
9. 2. 1.  
I nitial Re p orts ................................................................................................. 4 3 
9. 2. 2.  
F oll o w- u p Re p orts .......................................................................................... 4 3  
9. 2. 3.  
N otif yi n g I n v esti gat ors or I nstit uti o nal Re vie w B o ar d .................................. 4 4  
9. 3.  
E x p os ure I n Uter o D uri n g Cli nical St u dies .................................................... 4 4  
9. 4.  
Cli nical La b orat or y E val uati o ns ..................................................................... 4 4  
9. 5.  
Vital Si g ns ................................ ...................................................................... 4 4 
9. 5. 1.  
Seate d Bl o o d Press ure a n d Heart Rate M eas ure me nt ..................................... 4 5  
9. 5. 2.  
Hei g ht, Wei g ht, a n d B o d y Mass I n d e x ........................................................... 4 5  
9. 6.  
Electr ocar di o gra ms ......................................................................................... 4 5  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 1 of 6 4 
9. 7.  
P h ysical Fi n di n gs ............................................................................................ 4 5  
9. 8.  
Ot her Safet y Ass ess me nts ............................................................................... 4 5  
9. 8. 1.  
Me dical Hist or y a n d De m o gra p hi cs  ............................................................... 4 5 
9. 8. 2.  
H o me Gl uc ose M o nit ori n g ............................................................................. 4 6  
1 0.  
O T H E R A S S E S S M E N T S ............................................................................ 4 6  
1 1.  
S T A TI S TI C A L M E T H O D S ........................................................................ 4 6  
1 1. 1.  
A nal ysis Sets ................................ ................................................................... 4 6 
1 1. 1. 1.  
Ra n d o mize d P o p ulati o n .................................................................................. 4 6  
1 1. 1. 2.  
Efficac y P o p ulati o n ........................................................................................ 4 6  
1 1. 1. 3.  
Per- pr ot oc ol P o p ulati o n .................................................................................. 4 6  
1 1. 1. 3. 1.  
Safet y P o p ulati o n ............................................................................................ 4 7  
1 1. 2.  
Ge neral Statistical C o nsi derati o ns .................................................................. 4 7  
1 1. 3.  
St u d y P o p ulati o n Dat a .................................................................................... 4 7  
1 1. 4.  
Efficac y A nal yses ........................................................................................... 4 8  
1 1. 4. 1.  
Pri mar y Efficac y A nal ysis .............................................................................. 4 8  
1 1. 4. 2.  
Sec o n dar y Efficac y A nal ys es ......................................................................... 4 8  
1 1. 5.  
P har mac o ki netic/ P har mac o d y n a mic A nal yses ............................................... 4 9  
1 1. 5. 1.  
P har mac o ki netic A n al ys es .............................................................................. 4 9  
1 1. 5. 2.  
P har mac o d y na mic A nal yses ........................................................................... 4 9  
1 1. 5. 3.  
Bi o mar ker a n d E x pl orat or y A nal yses ............................................................. 4 9  
1 1. 6.  
Safet y A nal yses .............................................................................................. 4 9  
1 1. 6. 1.  
A d verse E v e nt A nal yses ................................................................................. 4 9  
1 1. 6. 2.  
Cli nical La b orat or y E val uati o n A nal ys es ....................................................... 4 9  
1 1. 6. 3.  
Vital Si g n A nal yses ........................................................................................ 5 0  
1 1. 6. 4.  
Electr ocar di o gra m A n al yses ........................................................................... 5 0  
1 1. 6. 5.  
P h ysical Fi n di n g A nal ys es .............................................................................. 5 0  
1 1. 6. 6.  
Ot her Safet y A nal yses .................................................................................... 5 0  
1 1. 7.  
Ot her A nal yses ................................ ................................................................ 5 0 
1 1. 8.  
I nteri m A nal yses ............................................................................................. 5 0 
1 1. 9.  
Data a n d Safet y M o nit ori n g B oar d ................................................................. 5 0  
1 1. 1 0.  
Sa m ple Size Deter mi nati o n ............................................................................ 5 0  
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E .............................. 5 1  
1 2. 1.  
M o nit ori n g a n d I ns p ecti o ns ............................................................................ 5 1  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 2 of 6 4 
1 2. 2.  
Data C ollecti o n ............................................................................................... 5 1  
1 2. 3.  
Data Ma na ge me nt ........................................................................................... 5 2  
1 2. 4.  
St u d y D oc u me ntati o n a n d St ora ge ................................................................. 5 2  
1 2. 5.  
Rec or d Kee pi n g .............................................................................................. 5 3  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  ............................................................... 5 3 
1 3. 1.  
Fi na nces .......................................................................................................... 5 3  
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura n ce .................................................... 5 3  
1 4.  
P U B LI C A TI O N P O LI C Y ............................................................................ 5 3  
1 5.  
S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N ....................................... 5 4  
1 5. 1.  
Pr ot oc ol A me n d me nts .................................................................................... 5 4  
1 5. 2.  
A d dress List .................................................................................................... 5 4  
1 5. 2. 1.  
S p o ns or ........................................................................................................... 5 4  
1 5. 2. 2.  
C R O  ................................................................................................................ 5 4 
1 5. 2. 3.  
Dr u g Safet y ..................................................................................................... 5 4  
1 5. 2. 3. 1.  
D S P D .............................................................................................................. 5 4  
1 5. 2. 4.  
Data Ma na ge me nt ........................................................................................... 5 5  
1 5. 2. 5.  
Bi ol o gical S peci me ns ..................................................................................... 5 5  
1 5. 2. 6.  
I nteracti ve V oice Res p o nse S yste m ................................................................ 5 5 
1 6.  
R E F E R E N C E S ................................ ............................................................. 5 6 
1 7.  
A P P E N DI C E S ............................................................................................... 5 7  
1 7. 1.  
I nstr u cti o ns f or S peci me n C ollecti o n, St ora ge, a n d S hi p me nt ....................... 5 8 
1 7. 2.  
Listi n g of La b orat or y Assa ys .......................................................................... 5 9  
1 7. 3.  
Ta n ner Sta gi n g ................................................................................................ 6 2  
1 7. 4.  
Sc he d ule of E ve nts ......................................................................................... 6 3  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 3 of 6 4 
LI S T O F I N- T E X T T A B L E S 
Ta ble 1 7. 1:  
La b orat or y Ass a ys b y Visit ........................................................................ 5 9  
Ta ble 1 7. 2:  
Sc he d ule of E ve nts ..................................................................................... 6 4  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 4 of 6 4 
LI S T O F I N- T E X T FI G U R E S 
Fi g ure 3. 1:  
St u d y Sc h e matic......................................................................................... 2 3  
F i g ure 1 7. 1: 
A nal yt es f or Safet y E val uati o n .................................................................. 6 1  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 5 of 6 4 
LI S T O F A B B R E VI A TI O N S 
A B B R E VI A TI O N  
D E FI NI TI O N  
A N C O V A   
A nal ysis of C o varia nce  
a p o A-1  
A p oli p o p r otei n A-1  
a p o B 
A p oli p o pr otei n B  
B MI  
B o d y mass i n de x  
CI  
C o nfi de nce i nter val  
C F R  
C o de of Fe d eral Re g ul ati o ns  
C R F  
Case Re p ort F or m  
C R L  
Ce ntral Refere nce La b orat or y  
C R O  
C o ntract Researc h Or ga nizati o n  
D S P D  
Daiic hi Sa n k y o P har ma De vel o p me nt  
E D C  
Electr o nic Data Ca pt ure  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F P G  
Fasti n g plas ma gl uc ose  
G C P  
G o o d Cli nical Practice  
H b A 1c  
He m o gl o bi n A 1c  
H C l 
H y dr oc hl ori de  
H D L -C  
Hi g h -d e nsit y li p o pr otei n c h olester ol  
H M G -C o A   
H y dr o x yl -met h yl -c oe nz y me A 
I A F 
I nf or me d Ass e nt F or m 
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 nfere nce o n Har m o nizati o n 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-t o-treat 
I V R S 
I nteracti ve v oice res p o ns e s yste m 
L D L -C  
L o w -de nsit y li p o pr otei n c h olester ol  
L O C F  
Last o bser vati o n carrie d f or war d  
L S  
Lea st-s q uares 
n o n -H D L -C   
N o n -hi g h -de nsit y li p o pr otei n c h olester ol  
O A D  
Oral a nti -dia betic  
S A E  
Seri o us A d verse E ve nt  
S A V E R  
Seri o us A d verse E ve nt Re p ort  
S O P  
Sta n dar d o perati n g p r oce d ure 
T C  
T otal c h olester ol  
T G  
Tri gl yceri des  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 6 of 6 4 
1.   
I N T R O D U CTI O N A N D B A C K G R O U N D I N F O R M A TI O N 
1. 1.   
D at a S u m m a r y 
S u p p orti n g details, data, a n d st u d y refere n ces f or t he f oll o wi n g s u m mar y i nf or mati o n ca n 
be  f o u n d i n t he Prescri bi n g I nf or mati o n f or Welc h ol®  (c olese v ela m H Cl).1   
T he na me of t h e i n vesti gati o nal pr o d uct is c olese v ela m h y dr oc hl ori de ( H Cl) oral 
s us pe nsi o n ( Welc h ol f or Oral S us pe nsi o n). 
C olese vela m is a bile aci d se q uestra nt i nitiall y mar kete d as a n a dj u nct t o di et a n d e x ercise 
t o red uce ele vate d l o w- d e nsit y li p o pr otei n c h olest er ol ( L D L- C) i n patie nts wit h pri mar y 
h y perli pi de mia as m o n ot hera p y or i n c o m bi nati o n wit h a h y dr o x yl- met h yl-c oe nz y me A 
( H M G- C o A) re d uctas e i n hi bit or.  T he i n dicati o n f or pe diatric us e i n li pi d re d ucti o n has 
be e n a p pr o ve d. 
Welc h ol has rece ntl y b ee n a p pr o ve d as a n a dj u nct t o diet a n d e x ercise t o i m pr o ve 
g l yce mic c o ntr ol i n a d ults wit h t y pe 2 dia bet es mellit us. T his i n dicati o n is base d o n 
res ults of 3 se parate d o u ble- bli n d, place b o-c o ntr olle d pi v otal cli nical st u dies i n w hic h 
colese vela m H Cl was use d i n c o m bi nati o n wit h metf or mi n, s ulf o n yl ureas, or i ns uli n f or 
t he treat me nt of t y pe 2 di a betes mellit us.  T hese st u dies e nr olle d a t otal of 1 0 1 8 s u bjects 
wit h base li ne he m o gl o bi n H b A 1 c le vels 7. 5 % t o 9. 5 %.  S u bjects were e nr olle d a n d 
mai ntai ne d o n t heir pre-e xisti n g, sta ble, bac k gr o u n d, a nti- dia betic re gi me n.  C olese vela m 
H Cl  a n d place b o were a d mi nistere d eit her as 3 ta blets t wice dail y wit h l u nc h a n d di n ner 
or  as 6 ta blets wit h di n ner al o ne. I n all 3 pi v otal a d d- o n t hera p y trials, treat me nt wit h 
W elc h ol res ulte d i n a statisticall y si g nifi ca nt re d u cti o n i n H b A 1c of 0. 5 % c o m pare d t o 
plac e b o.  
T he F o o d a n d Dr u g A d mi nistrati o n ( F D A) h as als o a p pr o ve d Welc h ol f or Oral 
S us pe nsi o n, pr o vi di n g a n alter nati ve t o t he c urre nt ta blet f or m ulati o n.   
T his pre se nt st u d y is bei n g c o n d u cte d t o e v al uate t he effect of c olese v ela m H Cl oral 
s us pe nsi o n as m o n ot hera p y or as a d d- o n t h era p y t o metf or mi n o n t he c ha n ge i n H b A 1c i n 
pe diatric s u bjects wit h t y pe 2 dia betes mellit us. 
1. 1. 1.   
I nte n de d Use U n der I n vesti g ati o n 
T his st u d y will pr o vi de s u p p ort f or t he use of c olese vela m H Cl oral s us pe nsi o n as 
m o n ot hera p y or as a d d- o n  t hera p y t o metf or mi n t o i m pr o ve gl yce mic c o ntr ol i n pe diatric 
s u bjects wit h t y pe 2 dia betes mellit us.  
1. 1. 2.   
N o ncli nic al St u dies 
N o ncli nical st u dies are s u m marize d i n t he pr o d uct la bel. 1  
1. 1. 3.   
Cli nic al E x perie nce 
Cli nical e x perie nce is s u m marize d i n t he pr o d uct la bel. 1 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 7 of 6 4 
1. 2.   
St u d y R ati o n ale 
T he pre v ale nce of t y pe 2 dia betes mellit us i n pe diatric s u bjects has bee n i ncreasi n g i n 
rece nt years, d u e i n part t o a ra pi d rise i n c hil d h o o d o besit y.  I n t he U nite d States, 
Welc h ol has bee n a p pr o ve d as a treat me nt f or L D L- C l o weri n g i n a d ults a n d c hil dre n 
wit h pri m ar y h y p erli pi de mia a n d f or gl uc ose l o w eri n g i n a d ults wit h t y p e 2 dia betes 
mellit us.  T he lar ge ta blet siz e a n d t he hi g h n u m ber of ta blets per da y ( 6) ca n prese nt 
challe n ges t o me dicati o n c o m plia nce i n s o me patie nts treate d wit h Welc h ol.  
C olese vela m H Cl  oral s us pe nsi o n was de vel o p e d as a n alter nati ve f or m ulati o n t hat is 
co n ve nie ntl y mi x e d wit h water, fr uit j uice or diet s oft dri n k a n d i n geste d.  T his oral 
s us pe nsi o n f or m ulati o n ca n be m ore acce pta ble t o pe diatric s u bjects w h o mi g ht ha ve 
diffic ult y s w all o wi n g s e v eral lar ge-size d ta blets.  T h us, t he c urre nt st u d y e val uates t he 
cli nical efficac y a n d safet y of c ol ese vel a m H Cl  oral s us pe nsi o n as a n a nti- dia bet ic a ge nt 
i n pe diatric s u bjects wit h t y pe 2 dia betes mellit us.  
1. 3.   
Ris ks a n d Be nefits f or St u d y S u bjects 
I n t his st u d y, s u bjects will recei ve c olese v ela m H Cl oral s us pe nsi o n, a n alter nati ve 
f orm ulati o n of Welc h ol, w hic h has bee n s h o w n t o be nefit a d ults wit h t y p e 2 dia betes 
t hr o u gh i m pr o ve m e nts i n gl yce mic c o ntr ol a n d re d ucti o n of L D L- C.  
I n dir ect be nefits f or all s u bjects i n t his st u d y i ncl u de cli nicall y rele va nt dia betes-s pecific 
ba seli ne e val u ati o ns wit h t he o p p ort u nit y t o disc uss a n d re vie w res ults wit h st u d y 
p h ysicia ns.  All st u d y partici pa nts will be pr o vi de d wit h h o me gl uc ose m o nit ori n g 
s u p plies a n d a p pr o priat e i nstr ucti o n.  I n a d diti o n, t he c or nerst o nes of dia b etes t hera p y, 
diet a n d e x ercise, will be re vie we d a n d rei nf orce d wit h fre q ue nt st u d y visits. 
T he ris k of pr ol o n ge d h y per gl yce mia ma y b e hi g h er f or s u bjects ra n d o mize d t o l o w- d ose 
colese vela m H Cl or al s us pe nsi o n, a pres u me d s u b-t hera pe utic d os e. T o mi ni mize a n d 
miti gate t his ris k, all s u bjects are m o nit ore d f or ele vate d bl o o d gl u c ose at h o me a n d at 
eac h st u d y visit. Gl yce mi c resc u e me dicati o ns will be pr o vi de d t o s u bjects if t he y m eet 
ele vate d H b A 1 c le vels after 3 m o nt hs o n st u d y t hera p y. Stricter gl yce mic resc ue criteria 
will  be use d after 6 m o nt hs o n st u d y t hera p y t o mi ni mize pr ol o n ge d ele vati o ns of H b A 1c  
a n d pr o vi de s u bjects wit h a de q uate m e dical care. 
T h ose s u bjects ra n d o mize d t o t he l o w- d ose gr o u p w h o c o m plete M o nt h 6 pri or t o t he 
a p pr o val of t his a me n d e d pr ot oc ol a n d its I nf or me d C o nse nt will c o m plete t he st u d y o n 
t he hi g h- d os e t o w hic h t h e y were s witc he d at M o nt h 6 acc or di n g t o t he ori gi nal pr ot oc ol. 
C olese vela m H Cl ca n i ncrease tri gl yceri de ( T G) le vels, partic ularl y w he n use d wit h 
s ulf o nyl ur eas.  Mar ke d h y p ertri gl yceri de mia ca n ca use ac ut e pa ncreatitis.  T he effect of 
h y pertri gl yceri d e mia o n t he ris k of c or o n ar y arter y disease is u ncertai n.  Li pi d le vels, 
i ncl u di n g T G, will be meas ure d d uri n g t he st u d y f or all s u bjects. 
Bile aci d s e q uestra nts, i n cl u di n g c ol ese vela m H Cl, ma y als o decrease a bs or pti o n of 
fat-s ol u ble vita mi ns; t heref ore, ca uti o n s h o ul d be use d i n s u bjects s usce pti ble t o 
fat-s ol u ble vita mi n defici e ncies.  C olese vel a m H Cl re d uces t he a bs or pti o n of s o me dr u gs.  
Dr u gs t hat ha ve a k n o w n i nteracti o n wit h c olese v ela m H Cl s h o ul d be a d mi nistere d at 
least 4 h o urs pri or t o c olese vela m H Cl.  If a dr u g or dr u g class has n ot b ee n teste d f or a n 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 8 of 6 4 
i nteracti o n wit h c olese v ela m H Cl, partic ularl y t h ose wit h a narr o w t hera pe utic i n de x, t he 
dr u g s h o ul d be gi v e n 4 h o urs pri or t o c olese v ela m H Cl.  
C olese vela m H Cl is n ot a bs or be d s yst e micall y fr o m t he gastr oi ntesti nal tract, s o 
c olese vela m H Cl is n ot e x pecte d t o be e x crete d i n h u ma n mil k.  Ne vert heless, t he safet y 
of c olese v e la m H Cl i n n ursi n g m ot hers a n d c hil dre n has n ot yet b ee n est a blis he d.  
Preca uti o ns are i m ple me nte d t o e ns ure t hat w o me n of c hil d beari n g p ote nti al are n ot 
pre g na nt w he n t he y e nr oll i n t he st u d y a n d d o n ot bec o me pre g na nt d uri n g or 
i m me diatel y after t he c o m pleti o n of t he st u d y.  Pre g n a nt or n ursi n g w o me n are n ot t o be 
e nr olle d.  If a s u bject bec o mes pre g na nt des pite a p pr o priate preca uti o ns, s h e is t o be 
disc o nti n ue d fr o m t he st u d y.  F oll o w- u p will be re q uire d as descri be d i n t his pr ot oc ol. 
T his st u d y is desi g n e d t o yi el d scie ntifi call y v ali d a n d cli nicall y usef ul i nf or mati o n.  T he 
ris ks ass ociate d wit h t he deferral of sta n dar d t hera p y are reas o na bl e a n d a p pr o priatel y 
pr o p orti o nal t o t he ma g nit u de of p ote ntial be nefit fr o m st u d y partici pati o n. 
1. 4.   
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d 
A p pr o xi matel y 2 2 0 p e diatric s u bjects, 1 0 t o 1 7 years of a ge at ra n d o mizati o n, wit h a 
dia g n osis of t y pe 2 dia betes mellit us will be ra n d o mize d.   
D uri n g t h e 2- wee k, si n gle- bli n d lea d-i n/sta bilizati o n peri o d, all s u bjects will recei ve 
l o w- d ose c oles e vela m H Cl oral s us pe nsi o n 0. 6 2 5 g t o be mi x e d i n 4 t o 8 o u nces of water, 
fr uit j uice or diet s oft dri n k f or oral a d mi nistrati o n o nce dail y wit h a di n ner meal. 
D ur i n g t h e 1 2- m o nt h bli n de d treat me nt peri o d, c olese vela m H Cl oral s us pe nsi o n will be 
pr o vi de d i n i de nticall y a p peari n g pac kets of 3. 7 5 g ( hi g h d ose, 6-ta blet e q ui vale nt) a n d 
pa c kets of 0. 6 2 5 g (l o w d ose, 1-ta blet e q ui val e nt) t o be mi x e d i n 4 t o 8 o u nces of water, 
fruit j uice or diet s oft dri n k f or oral a d mi nistrati o n o nce dail y wit h a di n ner meal.   
1. 5.   
C o m pli a nce St ate me nt, Et hics, a n d Re g ul at or y C o m pli a nce 
T his s t u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter n ati o nal C o nfere n ce o n 
Har m o nizati o n (I C H) c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( G C P) 
( C P M P/I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire me nt(s) i n cl u di n g F D A G C P 
Re g ulati o ns: C o de of Fe deral Re g ulati o ns ( C F R) Title 2 1, Parts 1 1, 5 0, 5 4, 5 6 a n d 3 1 2 as 
ap pr o priate. 
1. 5. 1.   
S u bject C o nfi de nti alit y 
T he I n vesti gat ors a n d t h e S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g 
part i n t he st u d y, i n acc or da nce wit h G C P a n d l ocal re g ul ati o ns. 
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he Case 
Re p ort F or ms ( C R Fs) or ot her d oc u me nts s u b mitte d t o Daiic hi Sa n k y o P har ma 
De vel o p me nt ( D S P D ) or its desi g nee, s u bjects s h o ul d be i de ntifie d b y a u ni q ue s u bject 
i de ntifier as desi g nat e d b y t he S p o ns or.  D o c u me nts t hat are n ot f or s u b missi o n t o D S P D 
or its desi g nee (e g, si g ne d I nf or me d C o nse nt F or ms [I C Fs]) s h o ul d be ke pt i n strict 
c o nfi de nce b y t he I n v esti gat or. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 1 9 of 6 4 
I n c o m plia nce wit h Fe deral re g ulati o ns/I C H G C P G ui deli nes, it is re q uire d t hat t he 
I n v esti gat or a n d i nstit uti o n per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he 
re g ulat or y a ge nc y(s), a n d t he I nstit uti o nal Re vie w B oar d (I R B) direct access t o re vie w 
t he s u bject’s ori gi nal me dical rec or ds f or v erificati o n of st u d y-relate d pr oce d ures a n d 
data.  T he I n v esti gat or is o bli gate d t o i nf or m t he s u bject t hat his/ her st u d y-relate d rec or ds 
will be re vie we d b y t h e a b o ve na me d re pres e ntati ves wit h o ut vi olati n g t he c o nfi de ntialit y 
of t he s u bject. 
1. 5. 2.   
I nf or me d C o nse nt a n d Asse nt Pr oce d ure 
B ef ore a mi n or s u bject’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o 
o btai n freel y gi ve n c o nse nt, i n writi n g, fr o m t he s u bject’s pare nt or le gal g uar dia n 
(co nse nt) a n d fr o m t he s u bject (asse nt) after a de q u ate e x pla nati o n of t he ai ms, met h o ds, 
antici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d b ef ore a n y pr ot oc ol-s pecific 
scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  A le gall y acce pta ble 
re pres e ntati ve is a n i n di vi d ual or ot her b o d y a ut h orize d u n der a p plica ble l a w t o c o nse nt, 
o n be half of a pr os pecti ve s u bject, t o t he s u bject’s partici pati o n i n t he cli nical st u d y 
( pr o of of stat us m ust be pr o vi de d).  T he writte n I nf or me d Asse nt F or m (I A F) a n d I C F 
s h o uld be pre pare d i n t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n.  T he 
f orms i ncl u de c o nse nts f or t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act. 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt a n d asse nt, t he I n vesti gat or s h o ul d 
co m pl y wit h t he a p plica ble re g ulat or y re q uire m e nts, a n d s h o ul d a d here t o G C P a n d t o t he 
et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he I C F, I A F, a n d 
an y re visi o n(s) s h o ul d be a p pr o ve d b y t he I R B pri or t o bei n g pr o vi de d t o p ote ntial 
s u bjects. 
T he le gall y acce pta bl e re prese ntati ve’s i nf or me d c o nse nt a n d t he s u bject’s writte n asse nt 
s h o uld be o btai ne d pri or t o t he s u bject’s partici pati o n i n t he st u d y a n d s h o ul d be 
d oc u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y 2 1 C F R Part 3 1 2. 6 2.  T he  
I C F s h o ul d be si g n e d a n d pers o nall y date d b y t he s u bject’s le gall y acce pta bl e 
repres e ntati ve a n d b y t he pers o n w h o c o n d u cte d t he i nf or me d c o ns e nt disc ussi o n ( n ot 
ne cessaril y t he I n vesti gat or), a n d t he I A F s h o ul d b e pers o nall y si g ne d a n d d ate d b y t he 
s u bject.  T he ori gi nal si g ne d I C F a n d I A F s h o ul d be retai ne d i n acc or da nce wit h 
i nstit uti o nal p olic y, a n d a c o p y of t he si g ne d I C F a n d I A F s h o ul d be pr o vi de d t o t he 
s u bject a n d le gal r e pres e ntati ve.  T he date a n d ti me (if a p plica ble) t hat i nf or me d c o nse nt 
wa s gi ve n s h o ul d be rec or de d o n t he C R F . 
If t he s u bject or l e gall y acce pta bl e re prese ntati ve ca n n ot rea d, t he n acc or di n g t o I C H 
G C P G ui deli ne, Secti o n 4. 8. 9, a n i m partial wit ness s h o ul d be prese nt d uri n g t he e ntire 
i nf or me d c o nse nt a n d/ or asse nt disc ussi o n.  T his wit ness s h o ul d si g n a n d date t he I C F 
a n d/ or I A F aft er t he s u bj ect or t he le gall y acce pta ble re prese ntati ve has orall y c o nse nte d 
t o t he s u bject’s partici pati o n a n d, if p ossi ble, si g ne d t he I C F.  B y si g ni n g t h e I C F, t he 
wit ness a ttests t hat t he i nf or mati o n i n t he I C F a n d a n y ot h er writte n i nf or mati o n was 
a de q uatel y e x plai ne d t o a n d a p pare ntl y u n derst o o d b y t he s u bject or t he le gall y 
acce pta ble re pres e ntati ve a n d t hat i nf or me d c o ns e nt was freel y gi v e n b y t he s u bject or t he 
le gall y acce pta ble re pres e ntati ve. 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 0 of 6 4 
S u g geste d te xt f or t he I C F a n d I A F will be pr o vi d e d f or t he I n v esti gat or t o pre pare site-
s pecific d oc u m e nts. U p dates t o a p plica ble f or ms will be c o m m u nicate d via letter fr o m 
t he Cli nical St u d y M a na ger. 
 
1. 5. 3.   
Re g ul at or y C o m pli a nce 
T he st u d y pr ot oc ol, s u bject i nf or mati o n a n d I C F/I A F, t he I n v esti gat or br oc h ure, a n y 
s u bject diar y car d or writte n i nstr ucti o ns t o be gi v e n t o t he s u bject, a vaila bl e safet y 
i nf or mati o n, s u bject recr uit me nt pr oce d ures (e g, a d vertise me nts), i nf or mati o n a b o ut 
pa y m e nts a n d c o m pe ns ati o n a vaila ble t o t he s u bjects, a n d d oc u me ntati o n e vi de nci n g t h e 
In v esti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o t he I R B f or et hical re vi e w a n d 
ap pr o val acc or di n g t o l ocal re g ulati o ns, pri or t o t h e st u d y start.  T he writte n a p pr o val 
s h o ul d i de ntif y all d oc u me nts re vie we d b y n a me a n d versi o n. 
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he St atistical A nal ysis Pla n. 
T he I n vesti gat or m ust s u b mit a n d, w here necess ar y, o btai n a p pr o val fr o m t he I R B f or all 
s u bse q uent pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o ns e nt a n d asse nt 
d oc u me nts or c ha n ges i n t he i n vesti gati o nal site, facilities, pers o n nel, pr o m oti o nal 
i nf ormati o n, or s u bject m aterials.  T he I n vesti gat or s h o ul d n otif y t he I R B  of de viati o ns 
fro m t he pr ot oc ol or seri o us a d verse e ve nts ( S A Es) occ urri n g at t he site a n d ot her a d verse 
e ve nt re p orts recei ve d fr o m D S P D or its desi g nee, i n acc or d a nce wit h l ocal pr oce d ures. 
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p will i ns ure 
all le gal as pects are c o vere d, a n d a p pr o val of t he a p pr o priate re g ulat or y b o dies o btai ne d, 
pri or t o st u d y i nitiati o n, a n d t hat i m ple me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d 
ot her rele va nt st u d y d o c u me nts ha p pe n o nl y after t he a p pr o priate n otificati o n of or 
a p pr o val b y t he rele va nt re g ulat or y b o dies. 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 1 of 6 4 
2.   
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S 
2. 1.   
St u d y O bjecti ves 
2. 1. 1.   
Pri m ar y O bjecti ves 
T he pri mar y o bjecti ve of t he st u d y is t o de m o nstrate t he effects of c olese vel a m H Cl oral 
s us pe nsi o n as m o n ot hera p y or as a n a d d- o n t hera p y t o metf or mi n o n c h a n ge i n H b A 1c 
fr o m baseli ne o ver t he first 6- m o nt h treat me nt peri o d i n pe diatric s u bjects wit h t y p e 2 
dia be tes mellit us. 
2. 1. 2.   
Sec o n d ar y O bjecti ves 
T he sec o n d ar y o bjecti ves of t he st u d y are: 
 T o de m o nstrate t he safet y a n d t olera bilit y of c olese vela m H Cl oral s us pe nsi o n 
as a n a nti- dia bet ic treat m e nt i n pe diatric s u bjects wit h t y pe 2 dia betes 
melli t us; 
 T o a ssess t he effect of c olese vela m H Cl oral s us pe nsi o n o n H b A 1c o ver 1 2 
m o nt hs i n pe diatric s u bjects wit h t y pe 2 dia betes mellit us; 
 T o assess t he effect of c olese vela m H Cl oral s us pe nsi o n o n fasti n g plas ma 
gl uc ose ( F P G) o ver 1 2 m o nt hs; 
 T o a ssess gl yce mic res p o nse t o c olese vel a m H Cl oral s us pe nsi o n t hera p y o v er 
ti me.  Res p onse will be a nal yze d b y t he p erce nta ge of s u bjects wit h a decrease 
i n H b A 1c 0. 7 % or ≥0. 5 %, fi nal H b A 1c 7. 0 % a n d < 6. 5 %, a n d/ or a decrease 
i n FP G 3 0  m g/ d L; a n d 
 T o a ssess t he effects of c olese vela m H Cl oral s us pe nsi o n o n c ha n ges i n 
plas ma li pi ds i ncl u di n g t otal c h olester ol ( T C), L D L- C, hi g h- d e nsit y 
lip o pr otei n c h olester ol ( H D L- C), n o n- hi g h- d e nsit y li p o pr otei n c h olest er ol 
(n o n- H D L- C), T G, a p oli p o pr otei n A- 1 (a p o A- 1), a n d a p oli p o pr otei n B 
(ap o B). 
 T o assess t he pr o p orti o n of s u bjects re q uiri n g resc ue a n d t he ti me fr o m 
ra n d o mizati o n t o i nitiati o n of resc u e me dicati o n. 
2. 2.   
St u d y H y p ot hesis 
C olese vela m H Cl oral s us pe nsi o n f or pe diatric s u bjects wit h t y pe 2 dia betes mellit us is 
safe, well t olerate d, a n d de m o nstrates gl yce mic efficac y (as e vi de n ce d b y a statisticall y 
si g nifica nt c ha n ge i n H b A 1c fr o m bas eli ne at 6 m o nt hs). 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 2 of 6 4 
3.   
S T U D Y D E SI G N 
3. 1.   
O ver all Pl a n 
3. 1. 1.   
St u d y T y pe 
T his is a m ulti-ce nter, ra n d o mize d, d o u ble- bli n d, 2- gr o u p st u d y i n p e diatric s u bjects wit h 
ty pe 2 dia betes mellit us wit h s u b o pti mal gl yce mic c o ntr ol wit h or wit h o ut metf or mi n.  
T he  st u d y will c o nsist of a scree ni n g visit, a 2- wee k si n gle- bli n d lea d-i n/sta bilizati o n 
pe ri o d, a 1 2- m o nt h d o u bl e- bli n d treat me nt peri o d, a n d a f oll o w- u p visit a p pr o xi matel y 2 
wee ks afte r t he e n d of treat me nt. 
S u bjects ma y eit her be o n metf or mi n m o n ot hera p y or c urre ntl y u ntreate d wit h 
anti dia betic a ge nts. “ U ntreate d” is defi ne d as eit h er ne ver ha vi n g recei v e d a nti dia betic 
t hera p y or recei ve d a nti dia betic me dicati o ns f or l ess t ha n 1 4 da ys wit hi n 3 m o nt hs pri or 
t o scree ni n g b ut n o i ns uli n t hera p y wit hi n 1 4 da ys of scree ni n g 
All s u bjects will e nter a 2- wee k, si n gle- bli n d lea d- i n/sta bilizati o n peri o d after bei n g 
co nfir me d as eli gi ble t o p artici pate i n t his st u d y.  A bli n de d o nce- d ail y me dicati o n 
(l o w- d ose c ol ese vela m H Cl) will be pr o vi de d t o all s u bjects. 
F or t he 1 2- m o nt h treat me nt peri o d, a p pr o xi matel y 2 2 0 s u bjects will be ra n d o mize d i n a 
3: 2 ra ti o t o hi g h- d ose c olese vela m H Cl oral s us pe nsi o n ( 3. 7 5 g) o nce d ail y or t o l o w- d ose 
colese vela m H Cl oral s us pe nsi o n ( 0. 6 2 5 g) o nce d ail y wit h a di n ner meal.     
S u bjects o n metf o r mi n m o n ot hera p y will re mai n o n t he sa me d ose as at t he ti me of 
scree ni n g, u nless a n d u ntil t he s u bject meets t he criteria f or gl yce mic res c ue.  T he 
i n vestigat or will be bli n d t o H b A 1c val ues t hr o u g h t he st u d y. La b orat or y re p orts will 
alert t he i n vesti gat or t o a b n or mal val ues. I n t he e v e nt t hat a s u bject’s H b A 1 c le vel ca n n ot 
be  c o ntr olle d bel o w 8. 5 % after 3 m o nt hs or b el o w 7. 5 % after 6 m o nt hs (c o nfir me d 
persiste nt h y p er gl yce mia) of st u d y m e dicati o n, as meas ure d b y t he ce ntral la b orat or y, 
(see Secti o n 3. 1. 6), o p e n-la bel gl yce mic resc ue wit h metf or mi n m ust be i nitiate d or 
o pti mize d, a n d if t his is n ot a de q uate, wit h a o n ce- dail y i ns uli n pre parati o n s uc h as 
i ns uli n glar gi ne. 
T h ose l o w- d ose s u bjects w h o c o m plete M o nt h 6 a n d are s witc he d t o t he hi g h d ose pri or 
t o t he a p pr o val of pr ot o c ol versi o n 2. 0 a n d its I nf or me d C o nse nt will c o nti n ue o n t he 
hi g h- d ose t o t he e n d of t he st u d y, acc or di n g t o t h e ori gi n al pr ot oc ol. 
Gl uc o meters will be pr o vi de d f or self- m o nit ori n g of bl o o d gl uc ose le vels, w hic h will be 
rec or d e d d uri n g t he lea d-i n peri o d a n d t hr o u g h o ut t he t w o 6- m o nt h treat me nt peri o ds. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 3 of 6 4 
3. 1. 2.   
Tre at me nt Gr o u ps 
T he st u d y d esi g n is ill ustrate d i n Fi g ure 3. 1 . 
F i g ure 3. 1:  
St u d y Sc he m atic 
 
F/ U = f oll o w- u p; met = metf or mi n; R’ = ra n d o mizati o n; T 2 D M = t y pe 2 dia betes mellit us.  
3. 1. 3.   
St u d y E n d p oi nts 
T he pri mar y efficac y e n d p oi nt is t he c ha n ge i n H b A 1c fr o m bas eli ne t o M o nt h 6 wit h last 
o bser vati o n carrie d f or war d ( L O C F). 
T he sec o n d ar y e n d p oi nts i ncl u de t he f oll o wi n g: 
 T he  c ha n ge i n H b A 1c fr o m baseli ne t o M o nt h 1 2 at eac h sc he d ule d visit 
w here meas ure d; 
 T he  c ha n ge i n F P G fr o m baseli ne t o M o nt h 1 2 at eac h sc he d ul e d visit w here 
meas ure d; 
 P erce nta ge of s u bjects ac hie vi n g a res p o nse t o t hera p y at M o nt h 6 a n d 
M o nt h 1 2, defi ne d as H b A 1c 7. 0 %  or < 6. 5 %, re d ucti o n i n H b A 1c 0. 7 %  or 
≥0. 5 %  fr o m baseli ne, a n d/ or re d ucti o n i n F P G 3 0  m g/ d L fr o m bas eli ne;  
 T he  c ha n ge a n d perce nt c ha n ge i n plas ma li pi ds at eac h sc he d ule d visit w here 
meas ure d, s pecificall y T C, L D L- C, H D L- C, n o n- H D L- C, T G, a p o A- 1, a n d 
ap o B. ; an d 
 P r o p orti o n of s u bjects re q uiri n g resc ue a n d ti me fr o m ra n d o mizati o n t o 
i nitiati o n of resc ue me dicati o n  
S afet y v aria bl es f or ass ess me nt i ncl u de a d verse e v e nts, vital si g ns, a n d c h e mistr y a n d 
he mat ol o g y la b orat or y p ara meters. 
3. 1. 4.   
D ur ati o n of t he St u d y 
It is e x pecte d t hat t he first s u bject will be e nr olle d i nt o t he st u d y i n N o v e m b er 2 0 1 0 a n d 
t hat t he last s u bject will c o m plete f oll o w- u p bef ore Ma y 2 0 1 5. 
3. 1. 5.   
D ur ati o n of S u bject P a rtici p ati o n 
T he t otal d urati o n of partici pati o n f or a n i n di vi d ual s u bject will be a p pr o xi matel y 
5 8 wee ks. 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 4 of 6 4 
3. 1. 6.   
Gl yce mi c Res c ue 
I n t he e ve nt t hat a s u bj ect’s H b A 1c le vel ca n n ot b e c o ntr olle d bel o w 8. 5 % after 3 m o nt hs 
or  bel o w 7. 5 % (c o nfir me d persiste nt h y p er gl yce mia) after 6 m o nt hs of st u d y me dicati o n 
treat me nt, as meas ure d b y t he ce ntral la b orat or y, o pe n-la bel gl yce mic res c ue m ust be 
i nitiate d.   
Gl yce mi c  Res c ue first wit h metf or mi n:  W he n gl yce mic res c ue is nee d e d, all s u bjects 
w h o a re n ot o n t he ma xi mall y t olerat e d d ose of metf or mi n m ust first ha ve t heir 
metf o r mi n m o n ot hera p y u p-titrate d t o 2 g/ d or t h e ma xi mall y t olerat e d d ose, i ncl u di n g 
i nitiati o n a n d d ose titrati o n t o t he ma xi mall y t olerate d d ose u p t o 2 g/ d f or t h ose s u bjects 
n ot o n m etf or mi n t hera p y at t he ti me of s cree ni n g. 
Gl yce mi c Res c ue wit h i ns uli n:   If a s u bject has b ee n o n 2 g or t he ma xi mall y t olerate d 
d oses of  metf or mi n m o n ot hera p y a n d re q uires res c ue, a o n ce- d ail y i ns uli n pre parati o n 
s uc h as i ns uli n glar gi n e ( La nt us ® ) will be a d de d.  S u bjects a n d cli nicia ns will re mai n 
bli n de d t o t he st u d y treat me nt assi g n me nt, b ut will be u n bli n de d t o H b A 1c le vels.  T he 
rec o m me n de d i nitial i ns uli n glar gi ne treat me nt is 0. 2 U/ k g t o 0. 4 U/ k g eac h e ve ni n g, 
w hic h ca n b e i ncrease d t o 1. 0 U/ k g/ d ( ma xi m u m 1 0 0 U). 
S u bjects ma y re q uire te m p orar y use of ac ute i ns uli n ( n o n- basal) d u e t o h os pitalizati o n, 
i nterc urre nt ill ness, or c o n diti o ns lea di n g t o meta b olic dec o m pe nsati o n.  I n t hese 
circ u msta nces, a n y t y pe or d ose of i ns uli n ca n be use d at t he discreti o n of t he treat me nt 
tea m.  H o we v er, i na bilit y t o disc o nti n ue ac ute i ns uli n wit hi n 8 wee ks wit h o ut 
dec o m pe nsati o n ( ket o n uria a n d s y m pt o matic h y p er gl yce mia) is t o be c o nsi dere d as 
pri mar y treat me nt fail ure, a n d t he s u bject will be disc o nti n ue d fr o m t he st u d y. 
3. 2.   
Selecti o n of D oses 
3. 2. 1.   
E x peri me nt al Tre at me nts 
T his st u d y will e val uate t he cli nical efficac y a n d s afet y of c olese vel a m H Cl oral 
s us pe nsi o n 3. 7 5 g ( hi g h d ose, 6-ta blet e q ui val e nt) o nce dail y wit h a di n ner meal, as a n 
anti- dia bet ic a ge nt i n pe diatric s u bjects wit h t y p e 2 dia betes mellit us.  T his is t he 
curre ntl y a p pr o ve d d ose i n a d ults. 
3. 2. 2.   
C o ntr ol Tre at me nts 
A place b o oral s us pe nsi o n ( p o w der) pr o d uct wit h matc hi n g c haracteristics t o t he acti ve 
c olese vela m H Cl oral s us pe nsi o n pr o d uct ( 3. 7 5 g) is n ot a vaila ble.  T heref ore, t he 
l o w- d ose c oles e vela m H Cl oral s us pe nsi o n ( 0. 6 2 5 g) is use d i nstea d of a pl ace b o as t he 
refere nce c o m paris o n treat me nt f or t his st u d y. 
 
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 5 of 6 4 
4.   
S T U D Y P O P U L A TI O N 
A p pr o xi matel y 2 2 0 p e diatric s u bjects, 1 0 t o 1 7 years of a ge at ra n d o mizati o n, wit h a 
dia g n osis of t y pe 2 dia betes mellit us will be ra n d o mize d.   
4. 1.   
E n r oll me nt 
I n v esti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects (i nitials, a ge, s e x) a n d date a n d o utc o me 
of  scree ni n g pr ocess (e g, e nr oll i n t he st u d y, reas o n f or i neli gi bilit y, ref use d t o 
partici pate). 
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n 
t he st u d y i n dicati n g t heir assi g ne d st u d y n u m ber. 
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his 
c o nfi de ntial list of na mes of all s u bjects all ocate d t o st u d y n u m bers o n e nr olli n g i n t he 
st u d y all o ws t he I n v esti gat or t o re veal t he i de ntit y of a n y s u bject w h e n necessar y. 
A s u bjec t is c o nsi dere d t o be partici pati n g i n t he st u d y u p o n t he I n v esti gat or’s ( or 
In v esti gat or’s desi g nee) o btai ni n g writte n i nf or m e d c o nse nt fr o m t he s u bj ect’s le gall y 
acce pta ble re pres e ntati ve a n d asse nt fr o m t he s u bj ect.  Bef ore t he s u bject is scree n e d t o 
be  i n t he st u d y, t he I A F a n d t he I C F pr o vi de d b y t he site m ust be pers o nall y si g ne d a n d 
date d b y t he s u bject a n d t he s u bject’s le gall y acce pta ble re prese ntati ve a n d b y t he p ers o n 
w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o ns ( n ot necessaril y t h e I n vesti gat or).  F or 
m ore  i nf or mati o n o n i nf or me d c o nse nt a n d asse nt, refer t o Secti o n 1. 5. 2 . 
4. 1. 1.   
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteri a at scree ni n g t o be i ncl u d e d i n t he st u d y: 
1.  Dia g n osis of t y p e 2 dia betes mellit us, as defi ne d b y t he A m erica n Dia betes 
Ass ociati o n 2; 
2.  U n dersta n d st u d y pr oce d ures a n d a gree t o p artici pate b y gi vi n g writte n asse nt a n d 
o btai ni n g writte n c o ns e nt fr o m a pare nt or le gal g u ar dia n at scree ni n g ( Wee k ≤ -
4) ; 
3.  Male s a n d fe m ales a ge d 1 0 t o 1 7 years, i ncl usi ve, at ra n d o mizati o n 
(ra n d o mizati o n m ust occ ur bef ore 1 8 t h birt h da y); 
4.  H b A 1c at scree ni n g b et w ee n 7. 0 % a n d 1 0. 0 %, i ncl usi ve; 
5.  F asti n g C- pe pti de > 0. 6 n g/ m L; a n d 
6.  A nti - dia betic treat me nt at scree ni n g: 
 O n me tf or mi n m o n ot hera p y:  Metf or mi n m o n ot hera p y h as bee n i nitiate d pri or 
t o scree ni n g; or  
 O n n o a nti dia betic treat me nt (c urre ntl y u ntreate d), defi ne d as: 
o  Naï ve, ne v er recei v e d a nti dia betic t hera p y or  
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 6 of 6 4 
o  U ntre ate d, recei ve d a nti- dia betic me dicati o ns f or l ess t ha n 1 4 da ys 
wit hi n 3 m o nt hs pri or t o scree ni n g b ut n o i ns uli n t hera p y wit hi n 1 4 
da ys of scree ni n g. 
4. 1. 2.   
E xcl usi o n Criteri a 
S u bjects w h o meet a n y of t he f oll o wi n g criteri a at scree ni n g are n ot eli gi bl e t o e nter t he 
st u d y: 
1.  F asti n g plas ma gl uc ose 2 7 0 m g/ d L; 
2.  Dia g n osis of t y p e 1 dia betes; 
3.  Hist or y of m ore t ha n o ne e pis o de of ket oaci d osis after t he i nitial dia g n osis of 
t y pe 2 dia betes mellit us; 
4.  P ositi ve a ut oi m m u ne mar kers i ncl u di n g a nti-islet cell a nti ge n 5 1 2 (a nti-I C A 5 1 2) 
or  a nti- gl uta mic aci d decar b o x yl ase (a nti- G A D);  
5.  C reati ni ne cleara n ce < 7 0 m L/ mi n; 
6.  A la ni ne tra nsa mi nase or as partate a mi n otra nsferas e ele vati o n > 2. 5  t he u p per 
li mit of n or mal; 
7.  Use  of i n hale d gl uc oc orti c oi ds at d ose > 1 m g of dail y fl uticas o n e e q ui vale nt or 
a n y oral gl uc oc ortic oi ds wit hi n t he last 6 0 d a ys or 2 0 da ys d uri n g t he past year; 
8.  Use  of t he f oll o wi n g me dicati o n: 
 Ins uli n f or ≥1 4 d a ys i n t he prece di n g 3 m o nt hs or i ns uli n wit hi n 1 4 da ys of 
scree ni n g; 
 M e dicati o n(s) ( ot her t ha n metf or mi n) k n o w n t o affect i ns uli n se nsiti vit y or 
secreti o n wit hi n t he last 3 0 da ys ( oral c o ntrace pti ve pill e xce pte d); 
 M e dicati o ns(s) k n o w n t o ca use wei g ht gai n or ta ke n f or wei g ht l oss wit hi n t he 
last 3 0 da ys; 
 Gr o wt h h or m o nes/s o mat otr o pi n; or 
 A na b olic ster oi ds wit hi n t he last 6 0 da ys; 
9.  P artici pati o n i n a f or mal wei g ht-l oss pr o gra m (c urre nt or pla n ne d); 
1 0.  P artici pati o n i n a n ot her i nter ve nti o nal res earc h st u d y pr ot oc ol i n t he p ast 6 0 da ys; 
1 1.  A b n or mal retic ul oc yt e c o u nt or H b A 1c c hr o mat o gra m i n dicati n g a b n or mal 
he m o gl o bi n vari a nts ot her t ha n heter oz y g osit y f or S a n d C; 
1 2.  Ge netic s y n dr o me or dis or der k n o w n t o affect gl uc ose; 
1 3.  F e male s u bjects w h o are lactati n g, pre g na nt, or pla n t o bec o me pre g na nt wit hi n 
1 year of s cree ni n g; 
1 4.  F e male s u bjects w h o are se x uall y acti ve a n d u n willi n g t o use a p pr o priate 
c o ntrace pti o n f or t he d urati o n of t he st u d y.  St u d y-acce pta ble met h o ds of birt h 
c o ntr ol are at least si n gle- barrier met h o ds, w hic h i ncl u de a n y of t he f oll o wi n g: 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 7 of 6 4 
s yste mic h or m o nal re gi m e ns, dia p hra g m, c o n d o m, c o p per i ntra ut eri ne de vi ce, 
s p o n ge, or s per mici de; 
1 5.  Hist or y of b o wel o bstr ucti o n; 
1 6.  Ot he r si g nifica nt or ga n s yste m ill ness or c o n diti o n (i ncl u di n g ps yc hi atric or 
de vel o p me ntal dis or der) t hat, i n t he o pi ni o n of t he I n v esti gat or, w o ul d pre v e nt 
f ull partici pati o n; 
1 7.  S yst olic bl o o d press ure 1 5 0 m m H g or diast olic bl o o d press ure 9 5 m m H g, 
des pite a p pr o priat e me di cal t hera p y; 
1 8.  Tr i gl yceri des > 5 0 0 m g/ d L; or 
1 9.  He mat ocrit < 3 0 % or he m o gl o bi n < 1 0 g m/ d L, des pite a p pr o priate me dical 
t hera p y. 
4. 2.   
Re m o v al of S u bjects Fr o m T her a p y 
4. 2. 1.   
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n 
Data fr o m all ra n d o mize d s u bjects t o t he st u d y are i m p orta nt t o t he o bjecti ves of t his 
cli nical i n vesti gati o n.  E v er y st u d y s u bj ect is e nc o ura ge d t o a d h ere t o pr ot o c ol 
i nstr ucti o ns a n d visit sc he d ules.  H o we v er, t he s u bject is free t o wit h dra w fr o m t he st u d y 
f or a n y reas o n a n d at a n y ti me wit h o ut gi vi n g reas o n f or d oi n g s o a n d wit h o ut pe nalt y or 
prej u dice.  T h e I n vesti gat or is als o free t o ter mi nat e a s u bject’s i n v ol ve me nt i n t he st u d y 
at a n y ti me if t he s u bject’s cli nical c o n diti o n warra nts it.  It is als o p ossi ble f or t he 
S p o ns or or t he re g ulat or y a ut h orities t o re q uest ter mi nati o n of t he st u d y if t here are 
c o ncer ns a b o ut c o n d uct or safet y. 
F or a n y of t he f oll o wi n g reas o ns, st u d y me dicati o n a n d st u d y p artici pati o n s h o ul d be 
disc o nti n ue d f or a s u bject:  
 P ersiste nt He m o gl o bi n A 1c 1 1. 0 %; 
 In a bilit y t o disc o nti n ue ac ute i ns uli n t hera p y wit hi n 8 wee ks wit h o ut 
dec o m pe nsati o n; 
 Oc c urre nce of a m e dical c o n diti o n or circ u msta nce t hat e x p oses t he s u bject t o 
s u bsta ntial ris k; 
 A n y S A E, cli nicall y si g nifica nt a d verse e v e nt, or se vere l a b orat or y 
a b n or malit y w hi c h i n t he o pi ni o n of t he I n v esti gat or i n dicates t hat c o nti n ue d 
pa rtici pati o n i n t he st u d y is n ot i n t he best i nterest of t he s u bject; or 
 P re g n a nc y. 
If a s u bject wit h dra ws fr o m t he st u d y, t he I n v esti gat or will c o m plete a n d re p ort all 
o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he d ate of wit h dra wal i ncl u di n g t he date of 
last treat me nt a n d t he reas o n f or wit h dra wal. 
If t he s u bject is wit h dra w n d ue t o a n a d verse e v e nt, t he I n v esti gat or will f oll o w t he 
s u bject u ntil t he a d verse e ve nt has res ol ve d or sta bilize d. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 8 of 6 4 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol-s p ecifie d 
wit h dra wal pr o ce d ures ( Secti o n 4. 2. 2 ). 
4. 2. 2.   
Wit h dr a w al Pr oce d ures f or E arl y Ter mi n ati o n 
S u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o Visit 8 ( M o nt h 1 2) s h o ul d ha ve all 
p ossi ble E n d of Treat me nt visit pr oce d ures perf or me d ( See Secti o n 6. 5 ).  
All s u bjects, if p ossi ble, s h o ul d be sc he d ule d t o ret ur n f or a f oll o w- u p visit 2 wee ks after 
st o p pi n g treat me nt wit h st u d y me dicati o n ( See Secti o n 6. 6 f or a descri pti o n of pr oce d ures 
pe rf or me d at t he f oll o w- u p visit).  
4. 2. 3.   
S u bject Re pl ace me nt 
S u bjects wit h dra w n fr o m t he st u d y will n ot be re pl ace d.  
4. 2. 4.   
S u bject Re-scree ni n g Pr oce d ures 
S u bjects will n ot be re-scree n e d f or t his st u d y, u nl ess a la b orat or y err or is s us pecte d. 
5.   
T R E A T M E N T S A D MI NI S T E R E D 
5. 1.   
I n vesti g ati o n al Pr o d ucts 
T he I n vesti gat or m ust e ns ure t hat t he i n vesti gati o nal pr o d uct will be use d o nl y i n 
acc or d a nce wit h t he pr ot oc ol. 
Acc or di n g t o I C H G C P G ui deli ne, Secti o n 1. 3 3, a n i n vesti gati o nal pr o d uct is a 
p ha r mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d or use d as a refere nce 
i n a cli nical st u d y.  T his i ncl u des pr o d ucts wit h mar keti n g a ut h orizati o ns w he n use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a p pr o ve d f or m or w he n 
use d f or a n u n a p pr o ve d i n dicati o n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut a n 
a p pr o ve d use. 
T he i n vesti gati o nal pr o d uct t hat will be use d f or t his st u d y is c olese vel a m H Cl oral 
s us pe nsi o n.  C olese vela m H Cl oral s us pe nsi o n is a citr us-fla v ore d, w hite t o pale yell o w 
p o w de r c o ntai ni n g yell o w gra n ules pac ka ge d i n si n gle- d os e pac k ets of eit her 0. 6 2 5 g or 
3. 7 5 g  c ol ese vela m H Cl.  I n a d diti o n, eac h p ac ket c o ntai ns t he f oll o wi n g i n acti ve 
i n gre di e nts: le m o n fla v or, ora n ge fl a v or, pr o p yle ne gl yc ol al gi nate, si met hic o ne, 
as parta me, citric aci d, me di u m c hai n tri gl yceri des, a n d ma g nesi u m trisilicate.  
5. 1. 1.   
Met h o d of Assi g ni n g S u bjects t o Tre at me nts a n d Bli n di n g 
5. 1. 1. 1.  
I de ntific ati o n N u m bers 
At scree ni n g, eac h s u bject will be assi g ne d a u ni q ue i de ntificati o n n u m ber b y t he site ( vi a 
t he i nteracti ve v oice res p o nse s yste m [I V R S]), i n se q ue ntial or der acc or di n g t o t he 
f oll o wi n g f or m ula: s u bject i de ntificati o n n u m ber will c o nsist of 8 di gits; t he first 4 di gits 
will  reflect t he site n u m b er assi g ne d t o t he i n vesti gat or, a n d t he last 4 di gits will reflect 
t he s u bject n u m ber.  T he s u bject n u m ber will be use d t o i de ntif y t he s u bject t hr o u g h o ut 
t he st u dy a n d will be e ntere d o n all d oc u m e ntati o n. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 2 9 of 6 4 
T he u ni q ue s u bject i de ntificati o n n u m ber will be e ntere d i nt o t he I V R S i n or der t o o btai n 
t he kit n u mber t o dis pe nse at t he e nr oll me nt, ra n d o mizati o n, a n d all ot her dis pe nsi n g 
visits. 
5. 1. 1. 2.  
Dr u g R a n d o miz ati o n 
A p pr o xi matel y 2 2 0 s u bj ects will be ra n d o ml y assi g ne d i n a 3: 2 rati o t o recei ve eit her 
hi g h- d ose c olese v ela m H Cl oral s us pe nsi o n 3. 7 5 g t o be ta ke n o nce dail y wit h a di n ner 
meal or l o w- d ose c olese v ela m H Cl oral s us pe nsi o n 0. 6 2 5 g t o be ta k e n o nce dail y wit h a 
di n ner  meal.  
Ra n d o mizati o n will be stratifie d base d o n pri or t y pe 2 dia betes mellit us treat me nt stat us 
( naï ve or metf or mi n m o n ot hera p y). 
T h ose l o w- d ose s u bjects w h o c o m plete M o nt h 6 a n d are s witc he d t o t he hi g h d ose pri or 
t o t he a p pr o val of pr ot o c ol versi o n 2. 0 a n d its I nf or me d C o nse nt will c o nti n ue o n t he 
hi g h- d ose t o t he e n d of t he st u d y, acc or di n g t o t h e ori gi n al pr ot oc ol. 
5. 1. 1. 3.  
Bli n di n g 
B ot h hi g h- d ose a n d l o w- d ose c olese v ela m H Cl oral s us pe nsi o n will be pr o vi de d i n 
i de nticall y a p peari n g p ac kets.   
T he st u d y bli n d ma y be br o ke n f or i n di vi d ual s u bj ects i n t he e ve nt of a S A E or ot her 
safet y c o n cer n w h e n k n o wle d ge of t he st u d y me di cati o n ma y pr o vi de i m p orta nt cli nical 
i nf or mati o n. E mer ge n c y u n bli n di n g will ta ke place usi n g t he I V R S.  I n cas e of a n 
e mer ge n c y, t he I n v esti gat or m ust ma ke e ver y eff ort t o c o ntact a n d c o ns ult wit h t he 
Me dical M o nit or or D S P D pri or t o brea ki n g t he bli n d.  If t he bli n d is br o ke n wit h o ut 
co ns ulti n g t he Me dical M o nit or, a f ull e x pla nati o n f or t his e ve nt m ust be pr o vi de d wit hi n 
2 4 h o urs.  C o ntact i nf or mati o n is liste d i n Secti o n 1 5. 2. 
D uri n g t h e si n gle- bli n d place b o lea d- i n peri o d, o nl y t he st u d y s u bject will b e bli n de d t o 
t he treat me nt assi g n me nt.  D uri n g t h e 1 2- m o nt h treat me nt peri o d, D S P D, t he C o ntract 
R esearc h Or ga nizati o n ( C R O ), t he I n v esti gat or, a n d t he st u d y s u bject will be bli n de d t o 
t he treat me nt assi g n me nt. T he st u d y bli n d will be br o ke n at t he e n d of t he st u d y o nce t he 
st u dy data base has b ee n l oc ke d. 
O nce t he decisi o n f or u n bli n di n g is reac he d, t he st u d y tea m will pre p are a n u n bli n di n g 
me m o wit h si g nat ures fr o m at least t he st u d y direct or a n d S p o ns or bi ostatisticia n. 
5. 1. 2.   
Met h o d of Assessi n g Tre at me nt C o m pli a nce 
St u d y m e dicati o n ( hi g h- d ose a n d l o w- d ose c olese v ela m H Cl oral s us pe nsi o n) will be 
dis pe nse d i n a m o u nts e xcee di n g t he mi ni m u m a m o u nt re q uire d f or t he peri o d of ti me 
u ntil t he ne xt cli nic visit.  S u bjects will be i nstr ucte d t o ret ur n all u n use d st u d y 
me dicati o n a n d use d e m pt y pac kets at t he ne xt cli nic visit.  C o m plia nce t o t he st u d y 
me dic ati o n will be e val u ate d b y t he n u m ber of st u d y me dicati o n pac k ets use d.  
D ur i n g t h e acti ve tr eat me nt peri o d, if c o m plia nce is n ot bet wee n 8 0 % a n d 1 2 0 %, 
i ncl usi ve, t he s u bject will be c o u nsele d a b o ut t he i m p orta nce of a d here nce t o t he 
ma n date d re gi me n. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 0 of 6 4 
5. 1. 3.   
L a beli n g a n d P ac k a gi n g 
St u d y m e dicati o n will be pac ka ge d i n b o x es f or distri b uti o n la bele d wit h t he f oll o wi n g 
i nf ormati o n, at a mi ni m u m: st u d y n u m ber, s u bject n u m ber, kit n u m ber, c o nte nts a n d 
q ua ntit y, directi o ns, st ora ge stat e me nt, a n d S p o ns or i nf or mati o n al o n g wit h C A U TI O N 
an d W A R NI N G state me nts. T he pac ket la b els will n ot ha ve s u bject n u m ber, kit n u m ber 
or  q ua ntit y i nf or m ati o n, b ut will ha ve all ot her la bel ele me nts. 
5. 1. 4.   
Pre p ar ati o n 
T o pre pare c oles e vela m H Cl oral s us pe nsi o n, e m pt y t he e ntire c o nte nts of 1 pac ket i nt o a 
glass or c u p.  A d d ½ t o 1 c u p ( 4 t o 8 o u nces) of water, fr uit j uice or diet s oft dri n k.  Stir 
we ll a n d dri n k ( ha v e t he s u bject dri n k).  C olese vel a m H Cl oral s us pe nsi o n s h o ul d n ot be 
ta ken i n its dr y f or m.   
I n t his st u d y, c olese v ela m H Cl oral s us pe nsi o n s h o ul d be ta ke n wit h a di n ner meal.   
5. 1. 5.   
St or a ge 
Dr u g s u p plies m ust be st ore d at 2 5° C ( 7 7° F)  a n d pr otecte d fr o m m oist ure; e x c ursi o ns are 
pe r mitte d t o 1 5° – 3 0°C (5 9 °– 8 6 °F ). 
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n der t he 
rec o m me n de d st ora ge c o n diti o ns.  T he  ke y t o t he st ora ge area is t o be k e pt b y t he 
In v esti gat or or a n ot h er pers o n res p o nsi ble f or t he me dicati o n.  T he st ora ge area will be 
accessi ble o nl y t o t h ose p ers o ns a ut h ori ze d b y t he I n v esti gat or t o dis pe nse i n vesti gati o nal 
pr o d uct.  T he I n v esti gat or wi ll be res p o nsi ble f or t he dis pe nsi n g of me dicati o n acc or di n g 
t o t he d osa ge sc he m e. 
5. 1. 6.   
Dr u g Acc o u nt a bilit y 
W he n a dr u g s hi p me nt is recei v e d, t he I n v esti gat or or desi g nee will c hec k t he a m o u nt 
a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l o cal la n g ua ge i n t he la bel a n d dr u g 
ex pirati o n date, a n d si g n t he Recei pt of S hi p me nt F or m pr o vi de d.  T he Recei pt of 
S hi p me nt F or m s h o ul d be fa x e d as i nstr ucte d o n t he f or m.  T he ori gi n al will be retai ne d 
at t he site.  I n a d diti o n, t he I n vesti gat or or d esi g n ee s hall c o ntact D S P D as s o o n as 
p ossi ble if t here is a pr o ble m wit h t he s hi p me nt. 
A Dr u g Acc o u nta bilit y R ec or d will be pr o vi d e d f or t he i n vesti gati o nal pr o d uct.  T he 
rec or d m ust be ke pt c urre nt a n d s h o ul d c o ntai n t he dates a n d q ua ntities of dr u g recei ve d, 
s u bject’s i de ntificati o n n u m ber a n d/ or i nitials or s u p pl y n u m ber as a p plica ble f or w h o m 
t he i n vesti gati o nal pr o d u ct was dis pe nse d, t he date a n d q ua ntit y of i n vesti gati o nal 
pr o d uct dis pe nse d a n d re mai ni n g, if fr o m i n di vi d u al s u bject dr u g u nits,  as well as t he 
i nitials of t he dis pe nser. 
At t he e n d of t he st u d y, or as direct e d, all i n vesti gati o nal pr o d ucts, i ncl u di n g u n use d, 
pa rtiall y us e d, or e m pt y c o ntai ners, will be ret ur ne d t o a desi g n ee as i nstr ucte d b y D S P D.  
I n v esti gati o nal pr o d uct will be ret ur ne d o nl y after t he st u d y m o nit or has c o m plete d a 
fi nal i n ve nt or y t o verif y t he q ua ntit y t o be ret ur ne d.  T he ret ur n of i n vesti gati o nal pr o d uct 
m ust  be d oc u me nte d a n d t he d oc u me ntati o n i ncl u de d i n t he s hi p me nt.  At t he e n d of t he 
st u d y, a fi n al i n vesti gati o nal pr o d uct rec o nciliati o n state me nt m ust be c o m plete d b y t h e 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 1 of 6 4 
I n v esti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.  U n use d dr u g s u p pli es ma y b e 
destr o ye d b y t he I n v esti gat or w he n a p pr o ve d i n writi n g b y D S P D a n d D S P D has recei ve d 
c o pies of t he site’s dr u g ha n dli n g a n d dis p ositi o n sta n dar d o perati n g pr oce d ures ( S O Ps). 
All i n vesti gati o nal pr o d u ct i n ve nt or y f or ms m ust be ma de a v aila ble f or i ns pecti o n b y a 
S p o ns or-a ut h orize d re prese ntati ve or desi g nee a n d re g ulat or y a ge nc y i ns pect ors.  T he 
I n v esti gat or is res p o nsi ble f or t he acc o u nt a bilit y of all use d a n d u n use d st u d y s u p plies at 
t he site. 
5. 1. 7.   
Rete nti o n S a m ples 
N ot a p plica ble. 
5. 2.   
C o nc o mit a nt Me dic ati o ns 
S u bjects m ust n ot ha ve ta ke n a n y p har mac ol o gic t hera p y f or dia betes wit hi n 3 m o nt hs of 
t he scree ni n g visit, wit h t he e x ce pti o n of metf or mi n, w hic h ma y ha ve b ee n i nitiate d as 
m o n ot hera p y pri or t o scree ni n g.  A d mi nistrati o n of all c o nc o mita nt me dicati o ns, 
i ncl u di n g t he na m e of eac h me dicati o n, t he d osa ge, a n d date a n d ti me of a d mi nistrati o n is 
t o be d oc u me nte d o n t he C o nc o mita nt Me dicati o n pa ge of t he C R F.  Per mitte d 
c o nc o mita nt me dicati o ns s h o ul d re mai n at a sta ble d ose t hr o u g h o ut t he st u d y. 
If me dicati o ns are iss ue d or altere d d u e t o a n a d v erse e ve nt, t he c h a n ge i n t h era p y or 
d osa ge m ust be rec or de d o n t he C R F.  If a c ha n ge i n d ose is me dicall y i n dicate d, t he 
cha n ge m ust be rec or d e d o n t he C R F.   
I n t he e ve nt t hat a s u bj ect’s H b A 1c le vel ca n n ot b e c o ntr olle d bel o w 8. 5 % after 3 m o nt hs 
or  bel o w 7. 5 % after 6 m o nt hs of st u d y me dicati o n treat me nt, o pe n-la bel gl yce mic res c ue 
m ust be i nitiate d.  See Secti o n 3. 1. 6. 
S u bjects ma y re q uire te m p orar y use of ac ut e i ns uli n ( n o n- basal) d u e t o h os pitalizati o n, 
i nterc urre nt ill ness, or c o n diti o ns lea di n g t o meta b olic dec o m pe nsati o n.  I n t hese 
circ u msta nces, a n y t y pe or d ose of i ns uli n ca n be use d at t he discreti o n of t he treat me nt 
team.  H o we v er, i na bilit y t o disc o nti n ue ac ute i ns uli n wit hi n 8 wee ks wit h o ut 
dec o m pe nsati o n ( ket o n uria a n d s y m pt o matic h y p er gl yce mia) is t o be c o nsi dere d as 
pri mar y treat me nt fail ure, a n d t he s u bject will be disc o nti n ue d fr o m t he st u d y. 
5. 3.   
Restricte d Me dic ati o ns 
T he use of a n y ot her i n vesti gati o nal dr u g is pr o hi bite d.  T he f oll o wi n g m e dicati o ns are 
s peciall y e x cl u de d fr o m t his st u d y: 
 In h ale d gl uc oc ortic oi ds at d ose > 1 m g of dail y fl uticas o ne e q ui val e nt or a n y 
oral gl u c oc ortic oi ds wit hi n 6 0 da ys; 
 Me dic ati o n(s) k n o w n t o affect i ns uli n se nsiti vit y or secreti o n ( oral 
co ntrace pti ve pill e xce pte d); 
 Me dic ati o ns(s) k n o w n t o ca use wei g ht gai n or ta ke n f or wei g ht l oss ; a n d 
 A na b olic ster oi ds. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 2 of 6 4 
6.   
S T U D Y P R O C E D U R E S 
A st u d y visit sc he d ule i n ta b ular f or mat is pr o vi de d i n Ta ble 1 7 .2 .  
6. 1.   
Scree ni n g ( Visit 1) 
T he s u bject s h o ul d arri v e i n a f aste d st ate f or t his visit. T he f oll o wi n g acti vities a n d/ or 
assess me nts will be p erf or me d at/ d uri n g scree ni n g ( Visit 1, 1 m o nt h pri or t o baseli ne): 
 A pa re nt or l e gal g uar dia n m ust si g n a n I R B-a p pr o ve d I C F. T he s u bject m ust 
asse nt t o t he st u d y as p er t he I R B re g ulati o ns. T he ori gi nal si g ne d I C F a n d 
IA F will be k e pt o n file i n t he I n v esti gat or’s office a n d a c o p y will be gi ve n t o 
the s u bject. 
 Asse ss s u bject eli gi bilit y will be assesse d usi n g t he st u d y’s 
i ncl usi o n/e xcl usi o n criteria. 
 R ec or d de m o gra p hic dat a (i ncl u di n g a ge, s e x, a n d race) a n d ot her baseli ne 
c haracteristics. 
 Rec or d  me dical an d s ur gical hist or y.   
 R ec or d pri or a n d c o nc o mita nt me dicati o ns ( i ncl u di n g a ntidia betic, 
a nti h y perte nsi ve, a n d re n al me dicati o ns ta ke n o ver t he past 3  m o nt hs) . 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect faste d b l o o d sa m ples f or e val u ati o n of efficac y p ara met ers, i ncl u di n g 
F P G, H b A 1c, T C, H D L -C, L D L -C, n o n -H D L -C, T G, a p o A -1, a n d a p o B.  
 C ollect faste d b l o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d la b orat or y 
safet y tests (c h e mistr y, h e mat ol o g y, a n d uri nal ysis).   Cli nical safet y an d 
dia g n ostic ass ess me nts will i ncl u de vita mi n D , C -pe pti de , A nti-G A D  a n d 
A nti -I C A 5 1 2. 
 P erf or m  a uri n e pre g n a nc y test o n  all fe male s u bjects (ser u m test als o d o ne). 
 P erf or m a p h ysic al e xa mi nati o n. 
 Assess de vel o p me nt wit h Ta n ner Sta gi n g. 
 C o ntact I V R S/I W R S t o re gister t he s u bject. 
 Pr o vi de c o u nseli n g o n di et a n d e x ercise.  
6. 2.   
Le a d-i n/ St a biliz ati o n Peri o d ( Wee k - 2; Visit 2) 
T he re is n o fasti n g re q uir e me nt f or t his visit.  All s u bjects will c o m plete a full 2 - wee k, 
si n gle- bli n d lea d-i n peri o d after bei n g c o nfir me d as eli gi ble t o partici pat e i n t his st u d y.  
All s u bjects will recei ve si n gle- bli n d l o w- d ose c ol ese vela m H Cl oral s us pe nsi o n t o be 
ta ken o nce d ail y wit h a di n ner meal.  Gl uc o met ers will be pr o vi de d f or dail y self-
m o ni t ori n g of bl o o d gl uc ose le vels, w hic h will be rec or d e d d uri n g t his peri o d.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 3 of 6 4 
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at t he lea d-i n visit ( Visit 2, 
2 we e ks pri or t o b aseli ne): 
 Asse ss s u bject eli gi bilit y usi n g t he st u d y’s i ncl usi o n/e xcl usi o n criteria. 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 De ter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 P erf or m a p h ysic al e xa mi nati o n. 
 If t he Scree ni n g Vita mi n D assess me nt ( 2 5- O H D) is l o w ( < 3 0 n g/ ml           
[ 7 5 n m ol/ L]), c h olecalcifer ol ( D 3) s u p ple m e ntati o n is rec o m me n de d a n d 
s h o uld be c o nti n ue d t hr o u g h t he st u d y.  
 U p da te I V R S/I W R S i nf or mati o n a n d o btai n st u d y me dicati o n kit n u m ber. 
 Dis pe nse st u d y m e dicati o n kit a n d i nstr uct s u bject o n pr o per d osi n g. 
 Dis pe nse gl uc o meters a n d relate d s u p plies a n d i nstr uct s u bject o n use. 
 P r o vi de c o u nseli n g o n di et a n d e x ercise.  
6. 3.   
Tre at me nt Peri o d  
Sites will mai ntai n fre q ue nt c o m m u nicati o n wit h s u bjects bet wee n visits f or m oti vati o n 
an d i nf or mati o n a b o ut t h e st u d y. Visit dates are calc ulate d fr o m Ra n d o mizati o n. 
6. 3. 1.   
R a n d o miz ati o n ( D a y 1; Visit 3) 
T he  s u bject s h o ul d arri v e i n a f aste d st ate f or t his visit. All s u bjects s h o ul d ha ve 
co m plete d a f ull t w o wee k lea d-i n pri or t o ra n d o mizati o n. If fr o m t hat lea d-i n a 
s u bject re p orts  ≥ 2 h o me gl uc o meter re a di n gs of fasti n g bl o o d gl uc ose ( F B G) > 2 4 0 
m g / d L ( or 1 v al ue > 2 4 0 m g/ d L a n d w orse ni n g s y m pt o ms of h y per gl yce mia) a cli nic 
visi t s h o ul d be sc he d ule d f or a f oll o w u p la b orat or y e v al uati o n of fasti n g gl uc ose. If 
co nfir me d, disc o nti n ue t he s u bject; d o n ot ra n d o mize. If a s u bject is disc o nti n ue d base d 
o n a  l ocal meas ure me nt, a sa m ple s h o ul d still be se nt t o t he ce ntral la b orat or y. T he 
f oll o wi n g acti vities a n d/ or assess me nts will be per f or me d at t he ra n d o mizati o n visit ( Da y 
1, Visi t 3): 
 Asse ss s u bject eli gi bilit y usi n g t he st u d y’s i ncl usi o n/e xcl usi o n criteria. 
 Rec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect faste d bl o o d sa m ples f or e val u ati o n of efficac y p ara met ers, i ncl u di n g 
F P G, H b A 1c, T C, H D L- C, L D L- C, n o n- H D L- C, T G, a p o A- 1, a n d a p o B. 
 C ollect faste d b l o o d a n d uri ne f or e v al uati o n of st a n dar d l a borat or y safet y 
tests (c he mistr y, h e mat ol o g y, a n d uri nal ysis).    
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 Deter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 4 of 6 4 
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
c o m paris o n; dis pe nse a d diti o nal s u p plies as nee de d. 
 P erf or m a p h ysic al e xa mi nati o n. 
 C ollect st u d y me dicati o n a n d re vie w c o m plia nce (at least 8 0 %, n o m ore t ha n 
1 2 0 %). 
 U p da te I V R S/I W R S a n d o btai n ne w st u d y me di cati o n kit n u m ber. 
 Dis pe nse o ne st u d y me di cati o n kit a n d re vie w d osi n g i nstr ucti o ns.  
 P r o vi de c o u nseli n g o n di et a n d e x ercise.      
6. 3. 2.   
M o nt h 1 ( Visit 4) 
T here is n o fasti n g re q uir e me nt f or t his visit. T he f oll o wi n g acti vities a n d/ or assess me nts 
will be perf or me d at M o nt h 1: 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect b l o o d sa m ple f or e val uati o n of sta n dar d la b orat or y safet y tests 
(c he mistr y a n d he m at ol o g y).  
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 De ter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
c o m paris o n ; dis pe nse a d diti o nal s u p plies as nee de d. 
 C ollect st u d y me dicati o n a n d re vie w c o m plia nce. 
 U p da te I V R S/I W R S a n d o btai n ne w st u d y me di cati o n kit n u m bers. 
 Dis pe nse t w o st u d y m e dicati o n kits a n d re vie w d osi n g i nstr ucti o ns. 
 P r o vi de c o u nseli n g o n di et a n d e x ercise.  
6. 3. 3.   
M o nt h 3 ( Visit 5) 
T here is n o fasti n g re q uir e me nt f or t his visit.  T he f oll o wi n g acti vities a n d/ or assess me nts 
will  be perf or me d at M o nt h 3: 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect bl o o d sa m ples f or e val uati o n of sta n dar d safet y tests (c h e mistr y a n d 
he mat ol o g y) a n d efficac y para meters, i ncl u di n g H b A 1c, T C, H D L- C, L D L- C, 
n o n- H D L- C, T G, a p o A- 1, a n d a p o B. 
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 Deter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns.  
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
c o m paris o n ; dis pe nse a d diti o nal s u p plies as nee de d. 
 P erf or m a p h ysic al e xa mi nati o n. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 5 of 6 4 
 C ollect st u d y me dicati o n a n d re vie w m e dicati o n c o m plia nce.  
 U p da te I V R S/I W R S a n d o btai n ne w st u d y me di cati o n kit n u m bers. 
 Dis pe nse t hree st u d y me dicati o n kits a n d re vie w d osi n g i nstr ucti o ns.  
 P r o vi de c o u nseli n g o n di et a n d e x ercise. 
6. 3. 4.   
M o nt h 6 ( Visit 6) 
T he s u bject s h o ul d arri v e i n a f aste d st ate f or t his visit.  T he f oll o wi n g acti vities a n d/ or 
assess me nts will be perf or me d at M o nt h 6: 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect faste d bl o o d sa m ples f or e val u ati o n of efficac y p ara met ers, i ncl u di n g 
F P G, H b A 1c, T C, H D L- C, L D L- C, n o n- H D L- C, T G, a p o A- 1, a n d a p o B. 
 C ollect faste d b l o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d la b orat or y 
safet y tests (c h e mistr y, h e mat ol o g y, a n d uri nal ysis).   
 P erf or m a uri n e pre g n a nc y tes t o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 De ter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 P erf or m a p h ysic al e xa mi nati o n. 
 A ssess Ta n ner Sta gi n g of p u bertal de vel o p me nt. 
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
c o m paris o n ; dis pe nse a d diti o nal s u p plies as nee de d. 
 C ollect st u d y me dicati o n a n d re vie w m e dicati o n c o m plia nce. 
 U p da te I V R S/I W R S a n d o btai n ne w st u d y me di cati o n n u m bers. 
 Dis pe nse t hree st u d y me dicati o n kits a n d re vie w d osi n g i nstr ucti o n. 
 P r o vi de c o u nseli n g o n di et a n d e x ercise. 
6. 3. 5.   
M o nt h 9 ( Visit 7) 
T here is n o fasti n g re q uir e me nt f or t his visit.  T he f oll o wi n g acti vities a n d/ or assess me nts 
will  be perf or me d at M o nt h 9: 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 A p h ysic al e xa mi nati o n will be perf or me d. 
 C ollect bl o o d sa m ples f or e val uati o n of H b A 1c a n d  sta n dar d la b orat or y safet y 
tests (che mistr y  a n d he m at ol o g y).  
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 Deter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 Re vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
c o m paris o n ; dis pe nse a d diti o nal s u p plies as nee de d. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 6 of 6 4 
 C ollect st u d y me dicati o n a n d re vie w m e dicati o n c o m plia nce. 
 U p da te I V R S/I W R S a n d o btai n ne w st u d y me di cati o n kit n u m bers. T h ose 
l o w- d ose s u bjects w h o c o m plete M o nt h 6 a n d are s witc he d t o t he hi g h d os e 
pr i or t o t he a p pr o val of pr ot oc ol versi o n 2. 0 a n d its I nf or me d C o nse nt will 
c o nti n ue o n t he hi g h- d os e t o t he e n d of t he st u d y, acc or di n g t o t he ori gi n al 
pr ot oc ol. 
 Dis pe nse t hree st u d y me dicati o n kits a n d re vie w d osi n g i nstr ucti o n. 
 P r o vi de c o u nseli n g o n di et a n d e x ercise. 
6. 4.   
E n d of Tre at me nt/ E arl y Ter mi n ati o n * Visit  
T he  s u bject s h o ul d arri v e i n a f aste d st ate f or t his visit.  T he f oll o wi n g acti vities a n d/ or 
assess me nts will be perf or me d at t he E n d of Treat me nt visit ( M o nt h 1 2, Visit 8 or Earl y 
T er mi nati o n):      * Earl y Ter mi nati o n pr oce d ures t o be d o ne, e v e n if fasti n g is n ot p ossi ble 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect faste d bl o o d sa m ples f or e val u ati o n of efficac y p ara met ers, i ncl u di n g 
F P G, H b A 1c, T C, H D L- C, L D L- C, n o n- H D L- C, T G, a p o A- 1, a n d a p o B. 
 C ollect faste d b l o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d la b orat or y 
safet y tests (c h e mistr y, h e mat ol o g y, a n d uri nal ysis).  Cli nical safet y 
assess me nts will i ncl u de vita mi n D. 
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve 
(ser u m test als o d o ne). 
 De ter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 A p h ysic al e xa mi nati o n will be perf or me d. 
 Asse ss de vel o p me nt wit h Ta n ner Sta gi n g. 
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
co m paris o n. 
 C ollect st u d y me dicati o n a n d re vie w m e dicati o n c o m plia nce. 
 U p da te I V R S/I W R S wit h s u bject stat us (treat me nt c o m plete or ter mi nate d). 
6. 5.   
Resc ue Visit 
S u bj ects w h ose H b A 1c l e vel ca n n ot b e c o ntr olle d bel o w 8. 5 % after 3 m o nt h s or  bel o w 
7. 5 % (c o nfir m e d persiste nt h y per gl yce mia) after 6 m o nt hs, as meas ure d b y t he ce ntral 
la b orat or y, of st u d y me di cati o n treat me nt will u n d er g o o pe n-l a bel gl yce mic resc ue. A 
p ha r mac y car d will be pr o vi de d f or filli n g metf or mi n or i ns uli n prescri pti o ns, as 
necessar y (see Secti o n 3. 1. 6).  If at all p ossi ble, t h e resc u e visit s h o ul d be sc he d ule d t o 
all o w t he patie nt t o arri v e i n a f aste d st ate. T he f oll o wi n g acti vities or ass ess me nts will 
be  perf or me d f or t h e Res c ue Visit, e ve n t h o u g h s u bject will c o nti n ue i n t he st u d y a n d 
eve n if fasti n g is n ot p ossi ble: 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 7 of 6 4 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 C ollect faste d bl o o d sa m ples f or e val u ati o n of efficac y p ara met ers, i ncl u di n g 
F P G, H b A 1c, T C, H D L - C, L D L- C, n o n- H D L- C, T G, a p o A- 1, a n d a p o B. 
 C ollect faste d b l o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d la b orat or y 
safet y tests (c h e mistr y, h e mat ol o g y, a n d uri nal ysis).   
 P erf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 R e vie w h o me gl uc ose rec or d a n d perf or m o nsite fi n gerstic k gl u c ose c h ec k f or 
co m paris o n; dis pe nse a d diti o nal s u p plies as necessar y. 
 P erf or m a p h ysic al e xa mi nati o n. 
 Asse ss de vel o p me nt wit h Ta n ner Sta gi n g. 
 De ter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 C ollect st u d y me dicati o n a n d re vie w m e dicati o n c o m plia nce. 
 U p da te I V R S/I W R S wit h s u bject stat us R E S C U E D. If at a re g ularl y 
sche d ule d visit, o btai n ne w st u d y me dicati o n kit n u m bers. 
 P rescri be metf or mi n as n ee de d, i n acc or d a nce wit h m etf or mi n la bel. 
 Instr u ct s u bject t o ta ke m etf or mi n as pres cri be d a n d t o c o nti n ue ta ki n g st u d y 
me dicati o n as i nstr ucte d per pr ot oc ol. 
 If t he s u bject’s d os e of metf or mi n has bee n u p-titrate d t o 2 g ms/ da y or t he 
s u bjects ma xi mall y t olerate d d ose, prescri be i ns uli n as nee de d, i n acc or da n ce 
wit h i ns uli n la bel. 
 Instr u ct s u bject t o ta ke i ns uli n as prescri be d a n d t o c o nti n ue ta ki n g st u d y 
me dicati o n as i nstr ucte d per pr ot oc ol. 
 S u bject will c o nti n ue wit h n or mall y sc he d ule d st u d y visits. 
 If res c ue has o cc urre d at a sc he d ule d visit, dis pe nse ne w st u d y me dicati o n kits 
as prescri be d f or t h at visit a n d re vie w d osi n g. 
 P r o vi de c o u nseli n g o n di et a n d e x ercise. 
6. 6.   
F oll o w- u p  
T here is n o fasti n g re q uir e me nt f or t his visit. T he f oll o wi n g acti vities a n d/ or assess me nts 
will be perf or me d at t he 2- wee k f oll o w- u p visit ( Visit 9): 
 R ec or d vital si g ns, h ei g ht, a n d wei g ht. 
 Deter mi ne a n d rec or d a d verse e v e nts a n d pri or a n d c o nc o mita nt me dicati o ns. 
 Perf or m a uri n e pre g n a nc y test o n all fe male s u bjects a n d c o nfir m ne gati ve. 
 U p date I V R S/I W R S wit h s u bject stat us c o m plete. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 8 of 6 4 
6. 7.   
Pr ot oc ol D e vi ati o ns 
T he I n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y 
D S P D a n d, if re q uire d, b y t he re g ulat or y a ut h orit y(ies), a n d w hi c h was gi ve n 
a p pr o val/fa v ora ble o pi ni o n b y t he I R B. 
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y stat e d criteria will n ot be all o we d 
i n this st u d y e x ce pt w h ere necessar y t o eli mi nate i m me diate hazar d(s) t o t h e s u bject.  
D S P D m ust be n otifie d of all i nte n de d or u ni nte n d e d de viati o ns t o t he pr ot oc ol 
(e g, i ncl usi o n/e xcl usi o n criteria, d osi n g, misse d st u d y visits) o n a n e x pe dite d basis. 
T he  I n vesti gat or, or p ers o n desi g n ate d b y t he I n v esti gat or, s h o ul d d oc u m e nt a n d e x plai n 
a n y d e viati o n fr o m t he a p pr o ve d pr ot oc ol. 
A n y d ata rec or d e d o n t he st u d y C R F  will be c ollecte d a n d i ncl u de d i n t he d ata base 
acc or di n g t o Cli nical Dat a I nterc ha n ge Sta n dar ds C o ns orti u m sta n dar ds a n d s u bjecte d t o 
t he sa me pr oce d ures as ot her data.  If a s u bject was i neli gi ble or recei v e d t he i nc orrect 
d ose or i n vesti gati o nal treat me nt, a n d ha d at least o ne a d mi nistrati o n of i n vesti gati o nal 
pr o d uct, data s h o ul d be c ollecte d f or safet y p ur p os es. 
T he I n vesti gat or s h o ul d n otif y t he I R B of de vi ati o ns fr o m t he pr ot oc ol i n acc or d a nce 
wit h l ocal pr oce d ures. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 3 9 of 6 4 
7.   
E F FI C A C Y A S S E S S M E N T S 
La b orat or y e val uati o ns of H b A 1c, F P G, a n d ot her sec o n dar y effi cac y p ara meters will be 
perf or me d b y a certifie d cli nical pat h ol o g y la b orat or y.  La b orat or y certificati o n 
(i ncl u di n g e x pirati o n dat e) a n d n or m al refere n ce ra n ges f or all la b orat or y p ara meters 
use d d uri n g t h e st u d y will be o n file at D S P D pri or t o st u d y i nitiati o n.   
T he  I n vesti gat or m ust re vie w, si g n, a n d date all la b orat or y test re p orts.   
D ur i n g t h e treat me nt p eri o d, t he I n vesti gat or will be n otifie d i n t he e ve nt of la b orat or y 
va l ues o utsi de t he n or mal ra n ge a n d f or alert val u es.  I n t his case, t he I n vesti gat or will be 
re q uire d t o c o n d uct cli nicall y a p pr o priate f oll o w- u p pr oce d ures.  Gl yce mic-rel ate d 
pa ra meters, H b A 1 c a n d F P G, will be bli n de d t o t he I n vesti gat or.  O nl y al ert val ue stat us 
will  be c o n ve ye d. T h e I n vesti gat or m a y be gi ve n u n bli n de d val ues as nee d e d t o e val uate 
a p ote ntial a d verse e x perie nce, or i n a n y sit uati o n w here s afet y m o nit ori n g of a n 
i n divi d ual s u bject mi g ht re q uire access t o act ual l a b orat or y v al ues.  All s uc h 
circ u msta nces m ust be re vie we d wit h t he Me dical M o nit or.  At t he scree ni n g, M o nt h 6 
an d M o nt h 1 2 cli nic visits, bl o o d s peci me ns m ust be o btai ne d u n der fasti n g c o n diti o ns 
(ie, after t he s u bject has faste d o ver ni g ht f or at least 8 h o urs).  If a s u bject h as n ot faste d, 
t he I n v esti gat or will resc he d ule t he s u bject wit hi n 3 da ys.  
7. 1.   
Pri m ar y Effic ac y V ari a ble 
T he pri mar y efficac y varia ble is H b A 1c at M o nt h 6.  F or s u bjects w h o disc o nti n ue 
treat me nt or recei v e res c ue t hera p y pri or t o M o nt h 6, t he last p ost- M o nt h 1 visit val ue 
o bser ve d pri or t o disc o nt i n uati o n or resc ue will be carri e d f or war d ( L O C F). 
7. 2.   
Sec o n d ar y Effic ac y V ari a bles 
T he sec o n d ar y efficac y v aria bles are ass esse d b y cli nical la b orat or y e v al uati o ns. 
T he  sec o n d ar y efficac y v aria bles f or t he st u d y i n cl u de: 
 C ha n ge i n F P G fr o m b aseli ne t o M o nt hs 6 a n d 1 2; 
 C ha n ge i n H b A 1c fr o m baseli ne t o M o nt hs 3,  6  a n d 1 2; 
 Perce nta ge of s u bjects ac hie vi n g H b A 1 c tar gets of 7. 0 %  a n d < 6. 5 % at 
M o nt h 6; 
 P erce nta ge of s u bjects at M o nt hs 6 a n d 1 2 ac hie vi n g a c ha n ges i n H b A 1c 
fr o m baseli ne 0. 7 % a n d 0. 5 %; 
 P erce nta ge of s u bjects ac hie vi n g a re d ucti o n i n F P G 3 0 m g/ d L at M o nt h 6;  
 C ha n ges a n d perce nt c ha n ges i n T C, L D L- C, H D L- C, n o n- H D L- C, T G, 
a p o A- 1, a n d a p o B fr o m baseli ne t o M o nt hs 3, 6 a n d 1 2; a n d 
 P r o p orti o n of s u bjects re q uiri n g resc ue a n d ti me fr o m ra n d o mizati o n t o 
i nitiati o n of resc ue me dicati o n. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 0 of 6 4 
 
8.   
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S 
8. 1.   
P h ar m a c o ki netic V ari a bles 
N ot a p plica ble. 
8. 2.   
P h ar m a c o d y n a mi c V ari a bles 
N ot a p plica ble. 
8. 3.   
Bi o m ar ker a n d E x pl or at or y V ari a bles 
N ot a p plica ble. 
9.   
S A F E T Y A S S E S S M E N T S 
9. 1.   
A d verse E ve nts 
All cli nical a d verse e ve nts occ urri n g after t he s u bj ect si g ns t he I C F a n d u p t o t he e n d of 
t he st u dy ass ess me nt a n d f oll o w- u p peri o d, w het her o bser ve d b y t he I n v esti gat or or 
re p orte d b y t he s u bject, p are nt or le gal g uar dia n, will be rec or d e d o n t he A d verse E ve nt 
C R F pa ge.  A n y fi n di n gs n ote d d uri n g b aseli ne assess me nt will be rec or d e d as part of 
me dical hist or y.  All S A Es are t o be re p orte d acc or di n g t o t he pr oce d ures i n Secti o n 9. 2 
S A E Re p orti n g- Pr oce d ure f or I n v esti gat ors.  I n a d diti o n, a n y u nt o war d e ve nt t hat ma y 
occ ur s u bse q ue nt t o t he re p orti n g p eri o d t hat t he I n vesti gat or assesses as relate d t o st u d y 
dr u g s h o ul d als o b e re p orte d a n d ma na ge d as a n a d verse e v e nt.  Pre- pla n ne d ( pri or t o 
si g ni n g t he I C F) pr oce d ure/ h os pitalizati o n f or pre- e xisti n g c o n diti o ns w hic h d o n ot 
w orse n i n se verit y s h o ul d n ot be re p orte d as S A Es (see Secti o n 9. 1. 1 f or Defi niti o ns). 
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y a d v erse e ve nts h a ve occ urre d 
b y e v al uati n g t he s u bject.  A d verse e ve nts ma y be directl y o bs er ve d, re p orte d 
s p o nta ne o usl y b y t he s u bject, pare nt, or le gal g uar dia n, or b y q uesti o ni n g t he s u bject, 
pa re nt or le gal g uar dia n at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a ge neral 
wa y, wit h o ut as ki n g a b o ut t he occ urre nce of a n y s pecific s y m pt o ms.  All la b or at or y 
val ues m ust be a p prais e d b y t he I n vesti gat or as t o cli nical si g nifica nce.  All p ost- baseli ne 
a b n or mal la b orat or y val u es c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or m ust be 
rec or d e d i n t he a d v erse e ve nt pa ge of t he C R F. 
I n v esti gat or s h o ul d f oll o w s u bjects wit h a d verse e ve nts u ntil t he e ve nt has res ol ve d or t he 
c o n diti o n has sta bilize d.  I n case of u nres ol v e d a d v erse e v e nts i ncl u di n g si g nifica nt 
a b n or mal la b orat or y val u es at t he e n d of st u d y ass ess me nt, t hese e ve nts will be f oll o we d 
u p u ntil res ol uti o n or u ntil t he y bec o me cli nicall y n ot rele va nt. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 1 of 6 4 
9. 1. 1.   
Defi niti o ns 
9. 1. 1. 1.  
A d verse E ve nt  
A n y u nt o w ar d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necess aril y h a ve t o ha ve a 
ca usal relati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n ( e g, a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w het her or n ot c o nsi dere d 
relate d t o t he me dici n al pr o d uct (I C H E 2 A G ui deli ne.  Cli nical Safet y Data Ma na ge me nt: 
De fi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4). 
It is t he res p o nsi bilit y of I n v esti gat ors, base d o n t h eir k n o wle d ge a n d e x perie nce, t o 
deter mi ne t h ose cir c u msta nces or a b n or mal la b orat or y fi n di n gs w hic h s h o ul d be 
co nsi dere d a d verse e ve nts. 
9. 1. 1. 2.  
Seri o us A d verse E ve nt  
A n S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat at a n y d os e: 
 R es ults i n deat h, 
 Is life-t hreate ni n g, 
 R e 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, 
 R es ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y, 
 Is a c o n ge nital a n o mal y/ birt h defect, or 
 Is a n i m p orta nt me dical e ve nt. 
N ote: T he ter m “lif e-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 s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere (I C H E 2 A G ui deli ne.  
Cli nical Safet y Data Ma n a ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, 
Oct 1 9 9 4). 
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 priat e 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 hreate 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 s u bject or ma y re q uir e i nter ve nti o n 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.  E x a m ples i ncl u de aller gic br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d 
d yscrasias or d e vel o p me nt of dr u g d e pe n d e nc y or dr u g a b use. 
N o te: A pr oce d ure is n ot a n a d verse e v e nt or S A E, b ut t he reas o n f or t he pr oce d ure m a y 
be  a n a d v erse e ve nt.  Pre- pla n ne d ( pri or t o si g ni n g t he I C F) s ur geries or h os pitalizati o ns 
f or pre-existi n g c o n diti o ns w hic h d o n ot w orse n i n se verit y are n ot S A Es. 
9. 1. 1. 3.  
A d verse E ve nt Se verit y 
T he  f oll o wi n g d efi niti o ns s h o ul d be use d t o assess i nte nsit y of a d v erse e ve nts: 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 2 of 6 4 
 Mi l d: A ware ness of si g n or s y m pt o m, b ut easil y t olerate d (i e, d oes n ot 
i nterfere wit h s u bject’s us ual f u ncti o n). 
 M o der ate: Disc o mf ort e n o u g h t o ca use i nterfere nce wit h us ual acti vit y. 
 S e vere: I n ca pacitati n g wit h i na bilit y t o w or k or d o us ual acti vit y (i e, i nterferes 
si g nifica ntl y wit h s u bject’s us ual f u ncti o n). 
9. 1. 1. 4.  
C a us alit y Assess me nt 
T he relati o ns hi p bet wee n a n a d verse e v e nt a n d t he st u d y me dicati o n will be deter mi ne d 
b y t he I n vesti gat or o n t he basis or his/ her cli nical j u d g me nt a n d t h e f oll o wi n g defi niti o ns: 
 1 =  Relate d: 
 T he a d verse e v e nt f oll o ws a reas o n a ble te m p oral se q ue nce fr o m st u d y 
dr u g a d mi nistrati o n, a n d ca n n ot be reas o na bl y e x plai ne d b y t h e s u bject’s 
cli nical state or ot her fact ors (e g, diseas e u n der st u d y, c o n c urre nt diseases, 
a n d c o nc o mita nt me dicati o ns). 
 T he a d verse e v e nt f oll o ws a reas o n a ble te m p oral se q ue nce fr o m st u d y 
dr u g a d mi nistrati o n, a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its 
c he mical gr o u p, or is pre dicte d b y k n o w n p har mac ol o g y. 
 2 = N ot relate d: 
 T he  a d verse e v e nt d oes n ot f oll o w a reas o n a ble se q ue nce fr o m st u d y 
pr o d uct a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s 
cli nical state or ot her fact ors (e g, diseas e u n der st u d y, c o n c urre nt diseases, 
a n d c o nc o mita nt me dicati o ns). 
9. 1. 1. 5.  
Acti o n T a ke n Re g ar di n g t he St u d y Me dic ati o n 
Acti o ns ta ke n re gar di n g st u d y me dicati o n ma y i n cl u de t he f oll o wi n g: 
 1 = N o ne: N o c h a n ge i n st u d y me dicati o n d osa ge was ma de. 
 2 =  Disc o nti n ue d per m a n e ntl y: T he st u d y me dicati o n was per ma ne ntl y 
st o p pe d. 
 3 =  I nterr u pte d: T he st u d y me dicati o n was te m p oraril y st o p pe d. 
9. 1. 1. 6.  
A d verse E ve nt O utc o me 
T he a d verse e v e nt o utc o me will be classifie d as 1 of t he f oll o wi n g: 
 1 =  Rec o vere d/res ol v e d 
 T he s u bject f ull y rec o vere d fr o m t he a d v erse e ve nt wit h n o resi d ual effect 
o bser ve d. 
 2 =  Rec o vere d/res ol v e d wit h se q uelae 
 T he resi d ual effects of t h e a d verse e v e nt are still prese nt a n d o bser va ble. 
 I d e ntif y se q uelae/resi d ual effects. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 4 of 6 4 
 Me d p ace will re vie w a n d f or war d t he f oll o w- u p S A V E R f or m a n d s u p p orti n g 
d oc u me nts t o Daiic hi Sa n k y o Cli nical Safet y a n d P har mac o vi gila nce ( C S P V-
Cli nical @ dsi.c o m ). 
 P lace t he f oll o w- u p S A V E R f or m a n d all s u p p orti n g d oc u m e ntati o n i n t he 
s u bject’s file. 
9. 2. 3.   
N otif yi n g I n vesti g at ors or I nstit uti o n al Re vie w B o ar d 
Daiic hi Sa n k y o a n d/ or M e d pace will i nf or m I n vesti gat ors of a n y seri o us, u ne x pecte d ( n ot 
liste d i n t he I n vesti gat or’s Br oc h ure) a n d rel ate d a d verse e v e nts occ urri n g i n ot her st u d y 
ce nters or ot h er Daiic hi Sa n k y o st u dies of t he i n vesti gati o nal pr o d uct, as a p pr o priate. 
Daiic hi Sa n k y o or Me d pace will i nf or m a n y ce ntral I R B, w hile t he I n vesti gat or will 
i nf or m t he l ocal I R B of seri o us u ne x pecte d a n d relate d a d verse e v e nts re p orte d wit h 
Da iic hi Sa n k y o’s i n vesti gati o nal pr o d uct. 
9. 3.   
E x p os ure I n Uter o D uri n g Cli nic al St u dies 
Daiic hi Sa n k y o m ust be n otifie d of a n y s u bject w h o bec o mes pre g na nt w hile recei vi n g 
t he st u d y me dicati o n or wit hi n 2 wee ks of disc o nti n ui n g t he i n vesti gati o nal pr o d uct.  
Alt h o u g h pre g na nc y is n ot tec h nicall y a n a d v erse e ve nt, all pre g n a ncies m ust be f oll o we d 
t o c o ncl usi o n t o deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g 
safet y a n d p u blic h ealt h c o ncer ns.  It is t he res p o nsi bilit y of t he I n vesti gat or, or desi g n ee, 
t o re p ort a n y pre g na nc y i n a s u bject usi n g t h e E x p os ure I n Uter o Re p orti n g f or m.  
In v esti gat ors, or t heir d esi g nees, s h o ul d c o ntact t h eir st u d y m o nit or t o recei ve t he 
E x p os ure I n Uter o Re p orti n g F or m u p o n lear ni n g of a pre g n a nc y.  T he I n v esti gat or 
s h o ul d ma ke e very eff ort t o f oll o w t he s u bject u ntil c o m pleti o n of t he pre g na nc y.  If t he 
o utc o me  of t he pre g na nc y meets t he criteri a f or i m me diate classificati o n as a S A E (ie, 
p ost- part u m c o m plicati o ns, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, or c o n ge nital 
a n o mal y, i n cl u di n g t hat i n a n a b orte d fet us), t he I n vesti gat or s h o ul d f oll o w t he 
pr oce d ures f or re p orti n g S A Es. 
9. 4.   
Cli nic al L a b or at or y E v al u ati o ns 
All sta n dar d bl o o d a n d uri ne tests t o assess safet y varia bles will be perf or m e d as 
s pecifie d i n Secti o n 7 ( Efficac y Ass ess me nts).  Cli nical safet y assess me nts will i ncl u de 
C - pe pti de at scree ni n g as well as vita mi n D at scree ni n g a n d E n d of Treat m e nt 
( M o nt h 1 2).  S u bjects wit h a vita mi n D le vel less t ha n t he la b orat or y c ut off are 
rec o m me n ded t o b e s u p ple me nte d wit h c h olecalcifer ol.  
A s u m mar y of la b orat or y tests b y visit is prese nte d i n Fi g ure 1 7. 1 f or refere nce.  N or mal 
ra n ges will be d oc u m e nte d i n t he la b orat or y m a n ual.  
9. 5.   
Vit al Si g ns 
At all visits, te m perat ure, bl o o d press ure, a n d h eart rate are t o be meas ure d. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 5 of 6 4 
9. 5. 1.   
Se ate d Bl o o d Press ure a n d He art R ate Me as ure me nt 
Bl o o d press ur e s h o ul d be meas ure d usi n g t he f oll o wi n g sta n dar dize d pr ocess: 
 R ec or d t he ar m use d f or t he meas ure me nt.  Use t h e sa me bl o o d press ure 
meas uri n g de vice a n d ar m t hr o u g h o ut t he st u d y. 
 Meas ure a n d rec or d t he seate d heart rate. 
At t he scree ni n g visit o nl y, a bl o o d press ure rea di n g s h o ul d be ta ke n i n b ot h ar ms ( u nless 
t here is a me dical reas o n n ot t o use a partic ular ar m).  T he ar m wit h t he hi g her s yst olic 
rea di n g s h o ul d t he n be us e d t hr o u g h o ut t he rest of t he st u d y.   
Bl o o d press ur e s h o ul d be rec or d e d t o t he nearest 2 m m H g mar k o n t he m a n o meter or t o 
t he nearest w h ole n u m ber o n a n a ut o matic de vi ce. 
9. 5. 2.   
Hei g ht, Wei g ht, a n d B o d y M ass I n de x 
Meas ure me nt of hei g ht s h o ul d be perf or me d at e ver y visit, wit h t he s u bject i n a sta n di n g 
p osi ti o n a n d wit h s h oes re m o ve d.  T he s u bject’s k nees s h o ul d be strai g hte ne d, hea d h el d 
erect, wit h e yes f or war d. 
Meas ure me nt of wei g ht s h o ul d be perf or me d at e ver y visit wit h t he s u bject dresse d i n 
i n d o or cl ot hi n g wit h s h o es re m o ve d.  S u bjects s h o ul d be wei g he d o n t he sa me scale at all 
visi ts. 
B o d y mass i n de x ( B MI) will be calc ulate d at eac h visit as wei g ht ( k g) di vi de d b y h ei g ht 
( m) s q uare d.  A B MI ta bl e will be pr o vi de d t o eac h site. 
9. 6.   
Electr oc a r di o gr a ms 
N ot a p plica ble. 
9. 7.   
P h ysic al Fi n di n gs 
F ull p h ysic al e xa mi nati o ns m ust mi ni mall y i ncl u d e vital si g ns a n d cli nical e val uati o ns of 
t he hea d, nec k, t h yr oi d, e yes, ears, n ose, t hr oat, heart, l u n gs, l y m p h n o des, a b d o me n, 
s ki n, e xtre mities, a n d m usc ul os keletal a n d ne ur ol o gical s yste ms. 
F or t he descri pti o n of Ta n ner Sta gi n g, s ee A p pe n di x 1 7. 3. 
9. 8.   
Ot her S afet y Assess me nts 
9. 8. 1.   
Me dic al Hist or y a n d De m o g r a p hics 
De m o gra p hic i nf or mati o n i ncl u di n g m o nt h a n d year of birt h, race, a n d ge n der will be 
c ollecte d o n all s u bjects at scree ni n g.  M e dical hist or y, i ncl u di n g details r e gar di n g all 
ill nesses a n d aller gies, date(s) of o nset, w h et her c o n diti o n c urre ntl y p ersist(s) will be 
c ollecte d o n all s u bjects.  A d diti o nal i nf or mati o n t o be c ollecte d i ncl u d es p ast s ur gical 
a n d me dical pr o ce d ures as well as me dicati o ns. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 6 of 6 4 
9. 8. 2.   
H o me Gl uc ose M o nit ori n g 
All s u bjects e nr olle d will be pr o vi de d wit h h o me gl uc ose m o nit ori n g s yste ms wit h 
me m or y t o meas ure gl uc ose le vels t hr o u g h o ut t he st u d y.  S u bjects will be i nstr ucte d t o 
o btai n gl uc ose l e vels e v er y m or ni n g b ef ore ha vi n g brea kfast. S u bjects will be i nstr ucte d 
t o call t he cli nic i m me diatel y if t he m o nit ori n g de vice i n dicates a fasti n g gl uc ose le vel 
< 5 0 m g/ d L or 2 4 0 m g/ d L.  S u bjects will recei ve a p pr o priate m e dical a d vi ce base d o n 
t heir gl uc os e le vel a n d, if dee me d necessar y b y t he I n v esti gat or, a cli nic visit will be 
sc he d ule d wit hi n 3 da ys f or a f oll o w- u p la b orat or y e val uati o n of fasti n g gl u c ose. S u bjects 
will  als o be i nstr ucte d t o m o nit or a ra n d o m, n o n-fasti n g gl uc ose l e vel o nce a da y. 
 
1 0.   
O T H E R A S S E S S M E N T S 
N ot a p plica ble. 
1 1.   
S T A TI S TI C A L M E T H O D S 
1 1. 1.   
A n al ysis Sets 
1 1. 1. 1.   
R a n d o mize d P o p ul ati o n 
T he Ra n d o mize d P o p ulati o n i ncl u des all s u bjects w h o gi ve asse nt a n d o btai n c o nse nt 
fr o m a pare nt or a l e gal g uar dia n, a n d are assi g n e d a ra n d o mizati o n n u m ber.  Baseli ne 
a n d de m o gra p hic c haract eristics will be s u m marize d f or t his p o p ulati o n. 
1 1. 1. 2.   
I nte nt-t o- Tre at P o p ul ati o n 
T he I nte nt- t o-treat (I T T) P o p ulati o n i ncl u des all ra n d o mize d s u bjects w h o ha ve ta ke n at 
least 1 d ose of ra n d o mize d st u d y me dicati o n, ha v e a baseli ne H b A 1c meas ure me nt, a n d 
ha ve at least 1 p ost- baseli ne H b A 1c meas ure me nt pri or t o a n y res c ue t hera p y.  T he I T T 
P o p ulati o n is t he pri mar y a nal ysis p o p ulati o n.   
1 1. 1. 3.   
Per- pr ot o c ol P o p ul ati o n 
T he per- pr ot oc ol set will be t h ose s u bjects w h o meet t he I T T defi niti o n as well as all 
of  t he f oll o wi n g a d diti o nal criteria: 
 O ve rall st u d y me dicati o n c o m plia nce bet w ee n 80 %  a n d 1 2 0 %; 
 N o ma j or pr ot oc ol vi olati o ns; a n d 
 C o m pleti o n of first 6- m o nt h treat me nt wit h o ut nee d of res c ue. 
All criteria f or maj or pr ot oc ol vi olati o ns a n d s u bject e val ua bilit y will be esta blis he d 
b y t he st u d y tea m pri or t o u n bli n di n g of t he data base a n d will be d oc u m e nte d i n a 
me m o b y st u d y tea m. 
If less t ha n 9 0 % of t h e I T T set meet t he per- pr ot oc ol defi niti o n, a per- pr ot o c ol a nal ysis 
o n t he pri mar y efficac y v aria ble, c h a n ge i n H b A 1c fr o m baseli ne t o M o nt h 6, will be 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 7 of 6 4 
perf or me d usi n g t he s a me met h o d descri be d f or t h e pri mar y efficac y varia ble t o pr o vi de 
s u p p orti ve anal ysis res ults.  
1 1. 1. 4.   
S afet y P o p ul ati o n 
T he Safet y P o p ulati o n is defi ne d as all ra n d o mize d s u bjects w h o ha ve ta ke n at least 
o ne d ose of ra n d o mize d st u d y me dicati o n. 
1 1. 2.   
Ge ner al St atistic al C o nsi der ati o ns 
S u m mar y statistics will be prese nt e d b y tr eat me nt gr o u p.  F or c o nti n u o us varia bles, t he 
n u m ber of a v aila ble o bser vati o ns ( n), mea n, sta n d ar d de viati o n, me dia n, mi ni m u m, a n d 
ma xi m u m will be pr o vi de d.  F or cate g orical varia bles, t he fre q u e nc y a n d p erce nt a ge i n 
eac h cate g or y will be dis pla ye d.     
Sa fet y a nal yses will be descri pti ve a n d will be prese nte d i n ta b ular f or mat wit h t he 
a p pr o priate s u m mar y statistics. 
F or t he pri mar y efficac y data a nal ysis at M o nt h 6, t he last o bser ve d p ost- M o nt h 1 H b A 1c 
val ue bef ore a n y resc u e t hera p y will be carri e d f or war d f or i m p uti n g t he missi n g or 
dr o p o ut data.  P ost- M o nt h 1 val ue was c h ose n beca use c ha n ges i n H b A 1c at 1 m o nt h of 
t hera p y are e x pecte d t o b e ne gli gi ble, a n d it t y picall y ta kes 2 t o 3 m o nt hs t o ac hie ve a 
sta ble H b A 1c le vel f oll o wi n g a n y n e w t hera p y. 
T h ose s u bjects ra n d o mize d t o t he l o w- d ose gr o u p w h o c o m plete M o nt h 6 pri or t o t he 
a p pr o val of t his a me n d e d pr ot oc ol a n d its I nf or me d C o nse nt will c o m plete t he st u d y o n 
t he hi g h- d os e t o w hic h t h e y were s witc he d at M o nt h 6 acc or di n g t o t he ori gi nal pr ot oc ol. 
A detaile d Statistical A nal ysis Pla n ( S A P) descri bi n g t he met h o d ol o g y t o b e use d i n t he 
fi nal a nal ysis will be pre pare d a n d fi nalize d pri or t o data base l oc k.  Statistical met h o ds 
descri be d wit hi n ma y be c ha n ge d b ase d o n a d v a nces i n researc h.  A n y c ha n ge will 
req uire a pr ot oc ol a me n d me nt o nl y if it c ha n ges pri nci pal feat ures of t he pr ot oc ol.  A n y 
de viati o ns fr o m t he pla n ne d statistical a nal yses i n t he pr ot oc ol will be f ull y descri be d i n 
t he S A P a n d i n t he cli nical st u d y re p ort. 
1 1. 2. 1  St u d y Me dic ati o n C o m pli a nce 
A calc ulati o n of st u d y m e dicati o n c o m plia nce is r e q uire d t o i de ntif y s u bjects f or t he 
per- pr ot oc ol a nal ysis set. C o m plia nce t o t he st u d y me dicati o n re gi me n will be 
e val uate d b y c o u nti n g u n use d ta blets a n d ca ps ules: 
% c o m plia nce =   
( # of pac k ets dis pe nse d − # of pac k ets ret ur ne d)   
X  1 0 0  
 
( # da ys si nce t he last visit) 
 
1 1. 3.   
St u d y P o p ul ati o n D at a 
F or all efficac y varia bles e x ce pt li pi ds, baseli ne is defi ne d as t he l ast meas ure me nt pri or 
t o t he first d ose of ra n d o mize d st u d y me dicati o n.  Baseli ne li pi d vari a bles will be t he 
a vera ge of scree ni n g a n d Da y 1 val ues.  Fasti n g plas ma gl u c ose a n d li pi d m eas ure m e nts 
fr o m a bl o o d sa m ple will be i ncl u de d i n efficac y a nal yses o nl y w h e n t he sa m ple is dra w n 
wit hi n 3 da ys of t he l ast d ose of st u d y m e dicati o n d uri n g t he bli n de d treat me nt peri o d a n d 
w he n t he s u bject has b ee n fasti n g f or 8 h o urs or m ore pri or t o t he bl o o d dra w. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 8 of 6 4 
De m o gra p hic a n d baseli n e c haracteristics will be s u m marize d usi n g t he n u m ber of 
a vaila ble o bser vati o ns ( n), mea ns, sta n dar d de viati o ns, me dia ns, mi ni m u m a n d ma xi m u m 
val ues f or c o nti n u o us varia bles, a n d fre q ue nci es a n d perce nt a ges f or cat e g orical 
varia bles. 
De m o gra p hic a n d baseli n e c haracteristics will be dis pla ye d i n b ot h a g gre gat e a n d b y 
treat me nt gr o u p f or t he all ra n d o mize d set as well as f or t he I T T P o p ulati o n. 
1 1. 4.   
Effic ac y A n al yses 
1 1. 4. 1.   
Pri m ar y Effic ac y A n al ysis 
T he pri mar y efficac y a n al ysis is t o c o m pare hi g h- d ose ( 3. 7 5 g/ da y) t o l o w- d ose ( 0. 6 2 5 
g/ da y) c olese v ela m H Cl oral s us pe nsi o n f or c h a n ge i n H b A 1c fr o m baseli ne t o M o nt h 6 
wit h L O C F usi n g t he I nte nt- T o - Treat (I T T) p o p ul ati o n.  F or s u bjects w h o recei ve d resc u e 
t hera p y, t he last p ost- M o nt h 1 H b A 1c val ue o bser ve d pri or t o res c ue will b e carrie d 
f or war d.  T he treat me nt differe n ce will be teste d at a 2-si de d si g nifica n ce l e vel of 0. 0 5, 
usi n g a n 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 p a n d pre vi o us 
O A D treat me nt strat u m as fi x e d effects a n d baseli ne H b A 1c as a c o v ariate.  P- val ue 
o btai ne d fr o m bet wee n-tr eat me nt c o m paris o n will be prese nt e d.  T he L S mea n, sta n dar d 
err or, a n d 9 5 % CI f or eac h treat me nt as well as f or t he differe nce b et wee n hi g h- a n d l o w-
d ose c olese v ela m H Cl gr o u ps will be esti mate d. 
T he treat me nt- b y - pre vi o us O A D strat u m i nteracti o n will be e val uate d f or t he pri mar y 
efficac y varia ble at a si g nifica n ce l e vel of 0. 1.  If a si g nifica nt i nteracti o n is s u g geste d b y 
t he data, f urt h er a n al ys es will be i m ple me nte d t o assess t he q ualitati ve or q ua ntitati ve 
nat ure of t he i nteracti o n. 
1 1. 4. 2.   
Se nsiti vit y A n al yses f or Pri m ar y Effic ac y A n al yses 
S e nsiti vit y a n al ys es will be perf or me d f or s u bj ects ra n d o mize d b ut wit h n o M o nt h 6 
meas ure me nt b y usi n g a n  i m p utati o n met h o d f or t he missi n g val ues of c ha n ge i n H b A1c 
fro m baseli ne. T his met h o d is t o i m p ute missi n g c ha n ge val ues b y m ulti ple i m p utati o n, 
w hic h is i m ple me nte d wit h t w o S A S pr oce d ures: P R O C MI a n d P R O C MI A N A L Y Z E. 
I nste a d of filli n g i n a si n gle val ue f or eac h missi n g val u e, m ulti ple i m p utati o n re places 
eac h missi n g v al ue wit h a set of pla usi ble val ues b y usi n g P R O C MI. T he missi n g data 
will be fille d i n m ulti ple ti mes t o ge nerate m ulti ple c o m plete data sets. T he 
M I A N A L Y Z E pr oce d ure will t he n be use d t o c o m bi ne t he res ults of a n al ys es o btai ne d 
fro m t he m ulti ple c o m plete data sets a n d deri ve vali d statistical i nfere nces. 
1 1. 4. 3.   
Sec o n d ar y Effic ac y A n al yses 
 T he a nal yses of t he c o nti n u o us sec o n dar y efficac y varia bles, i ncl u di n g H b A 1c, F P G, 
T C, L D L- C, H D L- C, n o n H D L- C, a p o A- 1, a n d a p o B, will be carrie d o ut usi n g t he sa me 
met h o d as f or t he pri mar y efficac y varia ble, u nless ot her wise state d.  T he b et wee n-
treat me nt c o m paris o n f or c ha n ge i n T G will be carrie d o ut usi n g a n o n- para metric 
A N C O V A. .  Perce nta ges of s u bjects wit h decreas es i n H b A 1c 0. 7 %  a n d ≥0. 5 %, fi nal 
H b A 1c 7. 0 % a n d < 6. 5 %, a n d/ or a d ecrease i n F P G 3 0 m g/ d L will be s u m marize d at 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 4 9 of 6 4 
ti me p oi nts w here assesse d.  T he gl yce mic c o ntr ol rates will be c o m pare d b et wee n 
treat me nts usi n g Fis her’s e x act test. 
T he pr o p orti o n of s u bjects re q uiri n g res c ue a n d t h e ti me fr o m ra n d o mizati o n t o i nitiati o n 
of resc u e me dicati o n will be s u m marize d usi n g Ka pla n- Meier met h o ds at M o nt h 6 a n d 
M o nt h 1 2.  
1 1. 5.   
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses 
N ot a p plica ble. 
1 1. 5. 1.   
P h ar m a c o ki netic A n al yses 
N ot a p plica ble. 
1 1. 5. 2.   
P h ar m a c o d y n a mi c A n al yses 
N ot a p plica ble. 
1 1. 5. 3.   
Bi o m ar ker a n d E x pl or at or y A n al yses 
N ot a p plica ble. 
1 1. 6.   
S afet y A n al yses 
Safet y assess me nts i ncl u de e val uati o ns of a d verse e ve nts, cli nical la b orat or y 
mea s ure me nts ( he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis), vital si g ns, p h ysical 
ex a mi nati o ns, pri or a n d c o nc o mita nt me dicati o ns, a n d vita mi n D le vel. T he Safet y 
P o p ulati o n will be use d f or all safet y a n al yses. 
T he n u m ber a n d p erce nta ge of s u bjects disc o nti n u e d or re q uiri n g resc u e me dicati o n as 
well as ti me t o disc o nti n uati o n or resc u e will be ta b ulate d. 
1 1. 6. 1.   
A d verse E ve nt A n al yses 
A d verse e ve nts, as defi ne d i n Secti o n 9. 1. 1, will be gr o u pe d b y s yste m or ga n class a n d b y 
preferre d t er m wit hi n s yste m or ga n class acc or di n g t o t he Me dical Dicti o nar y f or 
R e g ulat or y Acti vities ( Me d D R A).  Ta bl es s u m marizi n g s u bject i nci de nce of all a d verse 
eve nts, S A Es, se vere a d v erse e v e nts, st u d y dr u g-relate d a d v erse e ve nts, st u d y dr u g-
relate d S A Es, st u d y dr u g-relate d s e vere a d v erse e ve nts, a n d a d verse e v e nts lea di n g t o 
earl y wit h dra wal fr o m st u d y a n d/ or deat h will be pr o vi de d. 
O nl y a d v erse e ve nts oc c urri n g o n or after t he first d ose of ra n d o mize d st u d y me dicati o n 
(ie, treat me nt-e mer ge nt a d verse e v e nts) will be i ncl u de d i n t he a b o ve s u m maries.  
Treat me nt-e mer ge nt a d v erse e v e nts are defi ne d as a d verse e ve nts t hat first occ urre d or 
w orse ne d i n se v erit y after t he first d ose of ra n d o mize d st u d y me di cati o n.  A n y a d verse 
eve nt data c ollecte d fr o m t he si n gle- bli n d lea d-i n will be prese nte d se p aratel y. 
1 1. 6. 2.   
Cl i nic al L a b or at or y E v al u ati o n A n al yses 
Ta bles s u m marizi n g baseli ne, p ost- baseli ne, a n d c ha n ge fr o m baseli ne f or eac h sc he d ul e d 
c ollecti o n ti me p oi nt will be pr o vi de d f or c he mistr y, he m at ol o g y, a n d uri nal ysis 
para meters a n d vita mi n D le vel. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 0 of 6 4 
T he n u m ber a n d p erce nta ge of s u bjects wit h “ mar ke dl y a b n or mal” la b orat or y v al ues will 
be ta b ulate d.  T he cli nical la b orat or y data will be liste d, a n d val ues o utsi de t he n or mal 
ra n ges will be fla g ge d. 
1 1. 6. 3.   
Vit al Si g n A n al yses 
Vital si g ns at eac h treat me nt visit a n d c ha n ge fr o m b aseli ne at eac h pla n ne d p ost- baseli ne 
assess me nt will be s u m marize d b y treat me nt.   
1 1. 6. 4.   
Electr oc a r di o gr a m A n al yses 
N ot a p plica ble. 
1 1. 6. 5.   
P h ysic al Fi n di n g A n al yses 
Ta bles of s hifts fr o m bas eli ne t o E n d of Treat me nt ma y be pr o vi de d f or p h ysical 
ex a mi nati o n fi n di n gs.  
1 1. 6. 6.   
Ot her S afet y A n al yses 
Pri or a n d c o nc o mita nt m e dicati o n 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 a n d will be s u m marize d f or eac h treat me nt gr o u p.  
1 1. 7.   
Ot her A n al yses 
N ot a p plica ble. 
1 1. 8.   
I nteri m A n al yses 
N o  i nteri m a nal ysis has b ee n pla n ne d. 
1 1. 9.   
D at a a n d S afet y M o nit ori n g B o ar d 
A Steeri n g C o m mittee will be esta blis he d a n d will c o m prise 5 t o 7 e xter nal e x perts i n 
pe diatric t y pe 2 dia betes mellit us t o pr o vi de aca de mic lea ders hi p t o t he cli nical st u d y. 
A Data M o nit ori n g C o m mittee will be esta blis he d t o e ns ure b ot h safet y of t he st u d y 
partici pa nts a n d t he sci e ntific vali dit y of t he st u d y. 
1 1. 1 0.   
S a m ple Size Deter mi n ati o n 
A t otal of 2 2 0- 2 3 0 s u bjects will be ra n d o mize d i n a 3: 2 rati o t o recei ve eit h er hi g h- d ose 
or l o w- d ose c ol ese vela m H Cl oral s us pe nsi o n.  It is ass u me d t hat t he detect a ble 
differe n c e b et wee n hi g h- d ose a n d l o w- d ose c olese vela m H Cl f or t he c h a n ge fr o m 
ba seli ne i n H b A 1c is 0. 4 %, wit h a c o m m o n sta n d ar d de viati o n of 1. 0 %.  Usi n g a 2-si d e d 
si g nifica n ce le vel of 0. 0 5, a mi ni m u m sa m ple size of 2 0 8 e val ua ble s u bj ects ( 1 2 5 f or t he 
hi g h- d ose gr o u p a n d 8 3 f or t he l o w- d ose gr o u p) will pr o vi de 8 0 % p o wer t o detect t he 
differe n ce.  Wit h a n esti mate of 6- 1 0 % of s u bjects p ote ntiall y n ot ha vi n g e val ua ble 
baseli ne or p ost- M o nt h 1 H b A 1c data, t h e re q uire d sa m ple siz e f or t his st u d y will be 
a p pr o xi matel y 2 2 0- 2 3 0 s u bjects. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 1 of 6 4 
1 2.   
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E 
T he I n vesti gat or/i n vesti gati o nal site will per mit st u d y-relate d m o nit ori n g, a u dits, I R B 
re vie w a n d re g ulat or y i ns pecti o ns b y pr o vi di n g direct access t o s o urce data/ d oc u me nts.  
Dire ct access i ncl u d es per missi o n t o e x a mi ne, a nal yz e, verif y, a n d re pr o d uce a n y rec or ds 
a n d re p orts t hat are i m p orta nt t o t he e val uati o n of a cli nical st u d y. 
1 2. 1.   
M o nit ori n g a n d I ns pecti o ns 
T he C R O  m o nit or a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g a n d 
visi ti n g t he I n vesti gat or f or t he p ur p ose of i ns p ecti n g t he facilities a n d, u p o n re q uest, 
i ns pecti n g t he vari o us rec or ds of t he st u d y (e g, C R Fs, s o urce d ata, a n d ot h er perti ne nt 
d oc u me nts). 
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals of 4 t o 1 2 wee ks, 
de pe n di n g o n t he e nr oll me nt n u m bers, t hr o u g h o ut t he st u d y t o verif y a d h ere nce t o t he 
pr ot oc ol; c o m plete ness, acc urac y, a n d c o nsiste nc y of t he data; a n d a d here nce t o 
I C H G C P a n d l ocal re g ul ati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is 
res p o nsi ble f or i ns pe cti n g t he eC R F s a n d e ns uri n g c o m plet e ness of t he st u d y ess e ntial 
d oc u me nts.  T he m o nit or s h o ul d ha ve access t o s u bject me dical rec or ds a n d ot her 
st u d y-relate d rec or ds n ee de d t o verif y t he e ntries o n t he e C R Fs. 
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, G C P, a n d a p plica ble 
reg ulati o ns t o t he I n vesti gat or a n d will e ns ure t h at a p pr o priate acti o n desi g ne d t o c orrect 
a n d pre ve nt rec urre n ce of t he detect e d de viati o ns is ta ke n a n d d oc u me nte d. 
T he I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms 
detecte d i n t he c o urse of t hese m o nit ori n g visits are a d dress e d a n d d o c u me nte d. 
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be s el ecte d 
f or a u dit b y re prese ntati v es fr o m D S P D.  I ns pecti o n of site facilities (e g, p har mac y, dr u g 
st ora ge areas, la b orat ories, etc) a n d re vie w of st u d y relate d rec or ds will occ ur i n or der t o 
eval uate t he st u d y c o n d u ct a n d c o m plia nce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble 
re g ulat or y re q uire me nts. 
1 2. 2.   
D at a C ollecti o n 
All rele va nt o bser vati o ns a n d data relate d t o t he st u d y, as p er t he st u d y pr ot oc ol, will be 
rec or d e d o n electr o nic C R F pa ges. Daiic hi Sa n k y o P har ma De v el o p me nt or t heir 
desi g nee will s u p pl y i nstr ucti o n b o o ks f or t he c o m pleti o n of t he e C R F. A de q uate a n d 
acc urate case rec or ds s hall be mai ntai ne d, i ncl u di n g t he e val uati o n of i ncl usi o n a n d 
e x cl usi o n criteria, me dical hist or y, p h ysical e x a mi nati o n, cli nical assess me nts, a rec or d of 
cli nical safet y la b orat or y sa m ple c ollecti o n, p har mac o ki netic a n d p h ar mac o d y na mic 
sa m ple c ollecti o n if a vail a ble, dr u g a d mi nistrati o n, a d verse e ve nts a n d fi nal e val uati o n.  
T he e C R Fs m ust be c o m plete d f or eac h s u bject w h o si g ns t he i nf or me d ass e nt or c o nse nt 
f or m a n d u n der g oes scree ni n g pr oce d ures. T he e C R F data e ntr y s hall be c o m plete d o n 
t he day of cli nical visit c o m pleti o n. T he I n v esti gat or m ust electr o nicall y si g n a n d d ate t he 
e C R F.  T he si g nat ure s h all i n dicate t hat t he I n vesti gat or has re vi e we d t he data a n d data 
q ueries rec or d e d o n e C R Fs a n d t he site n otificati o ns, a n d a grees wit h t he c o nte nt.  After 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 2 of 6 4 
t he c o m pleti o n of t he st u d y, e C R Fs i n cl u di n g a u dit trail will be ret ur ne d t o D S P D a n d 
st ored i n t he arc hi v es. 
1 2. 3.   
D at a M a n a ge me nt 
T o e ns ure t he q ualit y of cli nical data acr oss all s u bjects a n d sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecifi cati o ns gi ve n 
t o t he C R O.  Data will be vette d b ot h electr o nicall y a n d m a n uall y.  F or electr o nic C R Fs, 
t he data will be electr o ni call y v ette d b y pr o gra m me d data r ules wit hi n t he a p plicati o n.  
Q ueries ge n erat e d b y r ul es a n d raise d b y re vie wers will be ge n erat e d wit hi n t he 
Electr o nic Data Ca pt ure ( E D C ) a p plicati o n.  D uri n g t his re vie w, s u bject data will be 
chec k e d f or c o nsiste nc y, o missi o ns, a n d a n y a p p are nt discre pa n cies.  I n a d diti o n, t he data 
will be re vie we d f or a d h ere nce t o t he pr ot oc ol a n d G C P.  Q ueries fr o m e C R Fs will be 
raise d a n d res ol ve d wit hi n t he E D C a p plicati o n. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la bs will be rec o n cile d t o t he cli nical 
data base. 
Seri o us a d verse e ve nts i n t he cli nical data bas e will be rec o n cile d wit h t he safet y d ata bas e. 
All a d verse e ve nts will be c o de d usi n g Me d D R A. 
1 2. 4.   
St u d y D oc u me nt ati o n a n d St or a ge 
T he I n vesti gat or will mai ntai n a Si g nat ure List of a p pr o priat el y q u alifie d p ers o ns t o 
w h o m he/s he has dele gat e d st u d y d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or 
c orrecti o ns o n case re p ort f or ms will be i ncl u de d o n t he Si g nat ure List. 
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s 
C R F  data are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o h os pital rec or ds, cli nical a n d 
of fice c harts, la b orat or y a n d p har mac y rec or ds, di aries, micr ofi c hes, X-ra ys, w or ks heets, 
a n d c orres p o n de n ce. 
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m ( Trial Master File) of all st u d y-relate d (esse ntial) 
d oc u me ntati o n, s uita ble f or i ns pecti o n at a n y ti me b y re pres e ntati ves fr o m D S P D a n d/ or 
a p plica ble re g ulat or y a ut h orities.  Esse ntial d oc u me nts i ncl u de: 
 S u bject files c o ntai ni n g c o m plete d case re p ort f or ms, i nf or me d asse nts a n d 
c o nse nts, a n d s u p p orti n g c o pies of s o urce d oc u me ntati o n (if ke pt). 
 S t u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I n v esti gat or’s 
Br oc h ure, c o pi es of rele v a nt esse ntial d oc u me nts r e q uire d pri or t o 
c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d fr o m t he I R B a n d 
D S P D. 
 Rec or ds rel ate d t o t he i n vesti gati o nal pr o d uct(s) i ncl u di n g ac k n o wle d g me nt of 
recei pt at site, acc o u nta bilit y rec or ds a n d fi nal rec o nciliati o n a n d a p plica bl e 
c orres p o n d e nce. 
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he electr o nic case re p ort 
f or ms m ust be mai ntai ne d a n d be rea dil y a vaila bl e. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 3 of 6 4 
All esse ntial d oc u me ntati o n will be retai ne d b y t he i nstit uti o n f or at least 5 years after 
c o m pleti o n of t he st u d y or f or a l o n ger peri o d, w here s o re q uire d b y ot her a p plica ble 
re g ulati o ns or re q uir e me nts.   
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt b et wee n D S P D 
a n d t he I n vesti gat or.  S h o ul d t he I n v esti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her 
part y or m o ve t he m t o a n ot her l ocati o n, he/s he m ust n otif y D S P D i n writi n g of t he n e w 
res p o nsi ble pers o n a n d/ or t he ne w l ocati o n. 
1 2. 5.   
Rec or d Kee pi n g 
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, data c orrecti o n f or ms, 
C R Fs, i n ve nt or y of st u d y pr o d uct, re g ulat or y d o c u me nts (e g, pr ot oc ol a n d a me n d me nts, 
I R B c orres p o n de n ce a n d a p pr o vals, a p pr o ve d a n d si g ne d i nf or me d asse nt a n d c o nse nt 
f orms, I n vesti gat or’s A gree me nt, cli nical s u p plies recei pts, distri b uti o n a n d ret ur n 
rec or ds), a n d ot her S p o ns or c orres p o n de nce pertai ni n g t o t he st u d y m ust be ke pt i n 
a p pr o priate st u d y files at t he site.  S o urce d oc u me nts i ncl u de all rec or di n gs a n d 
o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p orts a n d rec or ds n ecessar y f or 
t he eval uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hes e rec or ds will be retai ne d i n a 
sec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or site p olic y.  Pri or t o tra nsfer or 
destr ucti o n of t hese rec or ds D S P D m ust be n otifie d i n writi n g a n d be gi v e n t he 
o p p ort u nit y t o f urt her st ore s uc h rec or ds. 
1 3.   
FI N A N CI N G A N D I N S U R A N C E  
1 3. 1.   
Fi n a nces 
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical 
st u d y a gree me nt wit h t he C R O.  T his a gree me nt will i ncl u de t he fi na ncial i nf or mati o n 
a gree d u p o n b y t h e parties. 
1 3. 2.   
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce 
Rei m b urse me nt, i n de m nit y a n d i ns ura nce s h all be a d dresse d i n a se parate a gree me nt o n 
ter ms a gree d u p o n b y t he parties. 
1 4.   
P U B LI C A TI O N P O LI C Y 
 
 
 
 
 
 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 5 of 6 4 
1 5. 2. 4.   
D at a M a n a ge me nt 
Me d pace, I nc. 
5 3 7 5 Me d pace Wa y 
Ci nci n nati, O hi o  4 5 2 2 7  
1 5. 2. 5.   
Bi ol o gic al S peci me ns 
Me d pace R efere nce La b orat ories 
4 6 2 0 Wesle y A ve n ue 
Ci nci n nati, O hi o  4 5 2 1 2 
1 5. 2. 6.   
I nter acti ve V oice Res p o nse S yste m  
Me d pace, I nc 
5 3 7 5 Me d pace Wa y 
Ci nci n nati, O hi o  4 5 2 2 7 
          
 
         
 
P P D
P P D
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 6 of 6 4 
1 6.   
R E F E R E N C E S 
 
1 . Pac ka ge I ns ert f or Welc h ol®  (c olese vela m H Cl), Iss ue d: J ul y 2 0 1 1. See at 
htt p:// w w w. welc h ol.c o m  f or t he m ost c urre nt versi o n.  
2 .  A merica n Di a betes Ass o ciati o n. Sta n dar ds of me dical care i n dia betes. Di a betes C are  
2 0 1 0; ( Dia betes Care; J a n uar y 2 0 1 0; 3 3(s u p pl. 1): S 6 2 -S 6 9 . 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 7 of 6 4 
1 7.   
A P P E N DI C E S 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 8 of 6 4 
1 7. 1.   
I nstr ucti o ns f or S peci me n C ollecti o n, St or a ge, a n d S hi p me nt 
S a m ples will be s hi p pe d t o: Me d pace Refere nce La b orat ories, 4 6 2 0 Wesle y A ve n ue 
C i nci n nati, O hi o  4 5 2 1 2 
S pecific c ollecti o n, st ora ge a n d s hi p me nt i nstr ucti o ns will be i nc or p orate d i nt o t he 
la b orat or y ma n ual f or eac h site. 
Pri or-s hi p me nt n otificati o n fr o m t he ce ntral refere nce la b orat or y ( C R L), 
ac k n o wle d ge me nt of i ntact sa m ple arri v al at t he C R L, a n d s a m ple i n ve nt or y vs. sa m ple 
la beli n g rec o n ciliati o n at t he C R L s h o ul d be c o n d u cte d, a n d discre pa n cies s h o ul d be 
re p orte d a n d res ol ve d pr o m ptl y. 
S a m ple A n al ysis 
A nal ysis will be perf or m e d b y M e d pace Refere n ce La b orat ories . 
Resi d u al S a m ples 
All resi d ual sa m ples will be retai ne d b y M e d pace Refere n ce La b orat ories . 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 5 9 of 6 4 
1 7. 2.   
Listi n g of L a b or at or y Ass a ys 
Ta ble 1 7. 1 pr o vi des a list of la b orat or y assa ys f or t he st u d y. 
T a ble 1 7. 1:  
L a b or at or y Ass a ys b y Visit 
Bl o o d S a m ples  
Uri ne S a m ples  
Scree ni n g ( M o nt h -1 ; Visit 1) N B: F asti n g Re q uire d  
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
F P G  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Vita mi n D   
A nti -G A D, A nti -I C A 5 1 2 
C -pe pti de  
β -H C G f or all fe males 
Uri ne di pstic k pre g na nc y test f or all fe males.  
Uri nal ysis  
Le a d -i n (Visit  2)  
N o ne  
Uri ne di pstic k pre g na nc y test f or all fe males.  
B aseli ne/ R a n d o miz ati o n ( D a y 1 ; Visit 3) N B: F asti n g Re q uire d  
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
F P G  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Uri ne di pstic k pre g na nc y test f or all fe males.  
Uri nal ysis  
 
M o nt h 1 ( Visit 4)  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
 
Uri ne di pstic k pre g na nc y test f or all fe males.  
M o nt h 3 ( Visit 5)  
H b A 1 c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Uri ne di pstic k pre g na nc y test f or all fe males.  
M o nt h 6 ( Visit 6)  N B: F asti n g Re q uire d  
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
F P G  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Uri ne di pstic k pre g na nc y test f or all fe males.  
Uri nal ysis  
M o nt h 9 ( Visit 7)  
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
Uri ne di pstic k pre g na nc y test f or all fe males.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 0 of 6 4 
 
E n d of Tre at me nt Visit ( M o nt h 1 2, Visit 8 , or E arl y Ter mi n ati o n) N B: F asti n g Re q uire d  
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
F P G  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Vita mi n D  
β -H C G f or all fe males 
Uri ne di pstic k pre g na nc y test f or all fe males.  
Uri nal ysis  
F oll o w -u p ( Visit 9)  
N o ne  
Uri ne di pstic k pre g na nc y test f or all fe males.  
 
 
Resc ue Visit  ( N B: F asti n g Re q uire d if p ossi ble) 
H b A 1c  
C o m plete Ser u m C he mistr y  
He mat ol o g y  
F P G  
Li pi ds ( T C, H D L -C, L D L -C, n o n -H D L -C, T G, 
a p o  A -1, a n d a p o B)  
Uri ne di pstic k pre g na nc y test f or all fe males.  
Uri nal ysis  
ap o A -1 = a p oli p o pr otei n A -1; a p o B = a p oli p o pr otei n B; β -H C G = beta -h u ma n c h ori o nic g o na d otr o p hi n; 
F P G = fasti n g plas ma gl uc ose; H b A 1c  =  he m o gl o bi n A 1c; H D L -C = hi g h -de nsit y li p o pr otei n c h olester ol; 
L D L -C = l o w -de nsit y li p o pr otei n c h olester ol; n o n -H D L -C  =  n o n -hi g h -de nsit y li p o pr otei n c h olester ol; 
T C  = t otal c h olester ol; T G  = tri gl yceri des.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 1 of 6 4 
Fi g ure 1 7. 1: 
A n al ytes f or S afet y E v al u ati o n 
He m at ol o g y 
He m o gl o bi n  
W hite bl o o d cell c o u nt wit h differe ntial  
He mat ocrit  
Bas o p hils  
Re d bl o o d cell c o u nt ( wit h i n dices)  
Platelets  
Mea n c or p usc ular v ol u me  
Ne utr o p hils  
Mea n c or p usc ular he m o gl o bi n  
Ba n ds  
Mea n c or p usc ular he m o gl o bi n  
c o nce ntrati o n  
L y m p h oc ytes  
Re d bl o o d cell m or p h ol o g y  
M o n oc ytes  
Retic ul oc yte c o u nt  
E osi n o p hils  
C he mistr y 
T otal a n d direct bilir u bi n  
Al b u mi n  
Al kali ne p h os p hatase  
S o di u m  
Ala ni ne tra nsa mi nase ( S G P T) 
P otassi u m  
As partate a mi n otra nsferase ( S G O T) 
Bicar b o nate  
Bl o o d urea nitr o ge n  
C hl ori de  
Creati ni ne (a n d calc ulate d Cr cleara nce)  
Calci u m  
Uric aci d  
Creati ne p h os p h o ki nase  
I n or ga nic p h os p h or us 
Gl uc ose  
T otal pr otei n  
Vita mi n D  
Uri n al ysis 
C he mical a n d micr osc o pi c assess me nts 
Effic ac y P ar a meters 
H b A 1c, F P G, a n d li pi ds ( T C, T G, L D L- C, H D L- C, n o n- H D L- C, a p o A- 1, a n d a p o B) 
S afet y P ar a meters 
See he mat ol o g y a n d c h e mistr y a b o ve. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 2 of 6 4 
1 7. 3.   
T a n ner St a gi n g 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 3 of 6 4 
1 7. 4.   
Sc he d ule of E ve nts 
Ta ble 1 7. 2 pr o vi des a s c he d ule of e v e nts f or t he st u d y. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


Pr ot oc ol W E L- A- U 3 0 7 
Versi o n 2. 0, 3 0 A u g ust 2 0 1 1 
P a ge 6 4 of 6 4 
T a ble 1 7. 2:  
Sc he d ule of E ve nts 
St u d y Peri o d   
Scree ni n g  Le a d -i n1  
B aseli ne/  
R a n d o miz ati o n  
O n -Tr e at me nt Visits  
E n d of 
Tre at me nt 2 
F oll o w -u p  
  
 
Resc ue Visit  
Visit  
1   
2  
3   
4   
5   
6   
7   
8  
9   
  
 
Ti me ( m o nt h, u nless n ote d)  
 -1  
-2 w ks   
D a y 1   
1   
3   
6   
9   
1 2   
+ 2 w ks  
  
 
Visit Wi n d o w ( d a ys)  
 
 
♦1 
± 7   
± 7   
± 7   
± 7   
± 7   
± 7  
  
 
Fasti n g state re q uir e d 
● 
 
● 
  
 
● 
 
● 
 
 
● 
St u d y c o nse nt a n d asse nt  
X   
 
  
  
  
  
  
 
 
  
 
I ncl usi o n/e xcl usi o n criteria  
X   
X  
X   
  
  
  
  
 
 
  
 
De m o gra p hic i nf or mati o n  
X   
 
  
  
  
  
  
 
 
  
 
Me dical/s ur gical hist or y  
X   
 
  
  
  
  
  
 
 
  
 
Pri or a n d c o nc o mita nt me dicati o n   
X   
X  
X   
X   
X   
X   
X   
X   
X  
  
X  
P h ysical e xa mi n ati o n  
X   
X  
X   
  
X   
X   
X   
X  
 
 
X  
  
Ta n ner S ta ge 
X   
 
  
  
  
X   
  
X  
 
 
X  
Vital si g ns, hei g ht, a n d wei g ht  
X   
X  
X   
X   
X   
X   
X   
X   
X  
 
X  
Efficac y para met ers  
  
 
  
  
  
  
  
 
 
 
 
  
Fasti n g plas ma gl u c ose  
X   
 
X   
  
  
X   
  
X  
 
 
X  
  
He m o gl o bi n A 1c  
X   
 
X   
  
X   
X   
X   
X  
 
 
X  
  
Li pi d s3 
X   
 
X   
  
X   
X   
  
X  
 
 
X  
Cli nical safet y la b orat or y tests  
X 4  
 
X 4  
X   
X   
X 4  
X   
X 4 
 
 
X 4 
C -pe pti de  
X   
 
  
  
  
  
  
 
 
  
 
A nti -G A D, A nti -I C A 5 1 2 
X   
 
  
  
  
  
  
 
 
  
 
Vita mi n D  
X   
 
  
  
  
  
  
X  
 
  
 
Pre g na nc y test5 
X   
X  
X   
X   
X   
X   
X   
X   
X  
 
X  
A d verse e ve nt r e p orti n g 
  
X  
X   
X   
X   
X   
X   
X   
X  
 
X  
St u d y dr u g dis pe nsi n g  
 
X  
X   
X   
X   
X   
X   
 
 
 
X  
St u d y dr u g c o m plia nce  
 
 
X   
X   
X   
X   
X   
X  
 
 
X  
I V R S c o ntact  
X  
X  
X   
X   
X   
X   
X   
X   
X  
 
X  
Self -m o nit ori n g of bl o o d gl u c ose  
 
X 6  
X 7  
X 7  
X 7  
X 7  
X 7  
X 7 
 
 
X 7 
Diet a n d e xercise i nstr ucti o n  
X   
X  
X  
X   
X   
X   
X  
 
 
  
X  
1.    
All st u d y s u bjects m ust c o m plete a 2 wee k ( 1 4 da y) lea d-i n bef ore ra n d o mizati o n; 
u p t o 7 da ys l o n ger will be all o we d.  
2.   I ncl u di n g Earl y Ter mi nati o n Visit. 
3.   
Li pi ds: T otal c h olester ol, l o w- de nsit y li p o pr otei n c h olester ol, hi g h- de nsit y 
li p o pr otei n c h olester ol, n o n- hi g h- de nsit y li p o pr otei n c h olester ol, tri gl yceri des, 
a p oli p o pr otei n A-I, a n d a p oli p o pr otei n B. 
4.   I ncl u des uri nal ysis at scree ni n g, baseli ne ( Visit 3), M o nt h 6 ( Visit 6), a n d M o nt h 1 2 
( E n d of Treat me nt or Earl y Ter mi nati o n; Visit 8). 
5.  
A ser u m pre g na nc y will be perf or me d f or all fe male s u bjects at scree ni n g a n d 
M o nt h 1 2 ( E n d of Treat me nt or Earl y Ter mi nati o n; Visit 8).  A uri ne pre g na nc y test 
will be perf or me d f or all f e male s u bjects at all visits. 
6.   I nstr ucti o ns o n gl uc o meter. 
7.    
Re vie w of gl uc ose meter res ults a n d dis pe nsi n g of s u p plies as nee d 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a