Effect of Adiposity on Hepatic and Peripheral Insulin Resistance in Type 1 Diabetes
Phase: NA
Conditions: Type1 Diabetes Mellitus, Adiposity
Sponsor: Yale University

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
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H R P- 5 0 3 B – BI O M E DI C AL R E S E A R C H P R O T O C OL 
( 2 0 1 7- 1)
Pr ot oc ol Titl e: 
H R P- 5 0 3 B – BI O M E DI C AL R E S E A R C H P R O T O C OL 
( 2 0 1 7- 1)
Pr ot oc ol Titl e: Effect  of A di p osit y o n He patic a n d Peri p heral I ns uli n Resista nce i n T y pe 1 Dia betes
Pri nci p al I nv esti g at or: Mic h ell e V a n N a m e, M D
V ersi o n 4 D at e: 8- 3 1- 1 8
Pri nci p al I nv esti g at or: Mic h ell e V a n N a m e, M D
V ersi o n 4 D at e: 8- 3 1- 1 8
(If a p plic a bl e) Cli nic altri als. g ov R e gistr ati o n #:
) Cli nic altri als. g ov R e gistr ati o n #:  N C T 2 0 0 0 0 2 3 1 4 9
I N S T R U C TI O N S
I N S T R U C TI O N S
T his t e m pl at e is i nt e n d e d t o h el p i nv esti g at ors pr e p ar e a pr ot oc ol t h at i ncl u d es all of t h e n ec ess ary i nf or m ati o n 
n e e d e d by t h e I R B t o d et er mi n e w h et h er a st u dy m e ets a p pr ov al crit eri a. R e a d t h e f oll o wi n g i nstr ucti o ns 
R e a d t h e f oll o wi n g i nstr ucti o ns 
b ef or e pr oc e e di n g:
b ef or e pr oc e e di n g:
1.
Us e t his pr ot oc ol t e m pl at e f or a PI i niti at e d st u dy t h at i ncl u d es dir ect i nt er acti o ns wit h r es e arc h 
s u bj ects. A d diti o n al t e m pl at es f or ot h er ty p es of r es e arc h pr ot oc ols ar e av ail a bl e i n t h e syst e m Li br ary.
2.
If a s ecti o n or q u esti o n d o es n ot a p ply t o y o ur r es e arc h st u dy, ty p e “ N ot A p plic a bl e” u n d er n e at h.
3.
O nc e c o m pl et e d, u pl o a d y o ur pr ot oc ol i n t h e “ B asic I nf or m ati o n” scr e e n i n I R E S I R B syst e m. 
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
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w hi c h will l e a d t o i m pr o v e d gl y c e mi c c o ntr ol  a n d hi g h er i n s uli n d o s e s t h at f u el f urt h er i n cr e a s e s i n 
s e v erit y a n d r at e s of o b e sit y i n y o ut h wit h T 1 D. 
W hil e n e w dr u g s h a v e b e c o m e a v ail a bl e t h at h ol d pr o mi s e a s a dj u n cti v e a g e nt s t o i m pr o v e gl y c e mi c 
c o ntr ol, l o w er i n s uli n d o s e s, a n d pr o m ot e w ei g ht l o s s, t h eir i m p a ct o n gl u c o s e a n d f at m et a b oli s m i n 
m u s cl e a n d a di p o s e ti s s u e i n a d ol e s c e nt s i n t h e s etti n g of o b e sit y a n d T 1 D i s u n k n o w n. I d e ntif yi n g t h e 
ar e a s of si g nifi c a nt i n s uli n r e si st a n c e i n o b e s e y o ut h wit h T 1 D m u st b e el u ci d at e d pri or t o i d e ntif yi n g 
a n d t e sti n g t h er a pi e s t o i m pr o v e gl y c e mi c c o ntr ol a n d w ei g ht.  
   D e cr e a si n g t h e ri s k of mi cr o v a s c ul ar a n d m a cr o v a s c ul ar c o m pli c ati o n s h a s b e e n a m ai n 
dri vi n g f a ct or i n i m pr o vi n g m a n a g e m e nt of T 1 D i n y o ut h, wit h t h e eff e ct s of i nt e n si v e m a n a g e m e nt 
pr o vi di n g pr ot e cti o n fr o m pr o gr e s si o n t o at h er o s cl er o si s a n d c ar di o v a s c ul ar di s e a s e. H o w e v er, r e c e nt 
e vi d e n c e i n di c at e s t h at t h e i n s uli n r e si st a n c e r e s ulti n g fr o m t h e w ei g ht g ai n t h at a c c o m p a ni e s i nt e n si v e 
m a n a g e m e nt m a y c o u nt er s o m e of t h e b e n efit s g ai n e d fr o m i m pr o v e d gl y c e mi c c o ntr ol o n C V D ri s k 
( 9, 1 0). N e v ert h el e s s, a s n ot e d pr e vi o u sl y, t h e eff e ct s of o b e sit y o n m et a b oli c c o ntr ol a n d i n s uli n 
s e n siti vit y i n y o ut h wit h T 1 D h a v e y et t o b e ri g or o u sl y st u di e d. 
H e p ati c a n d p eri p h er al i n s uli n s e n siti vit y i n y o ut h wit h T 1 D
T h e h y p eri n s uli n e mi c- e u gl y c e mi c cl a m p t e c h ni q u e ( 1 7) w a s fir st a d a pt e d f or u s e i n c hil dr e n a n d 
a d ol e s c e nt s b y Dr. T a m b orl a n e ( m y pri m ar y m e nt or) a n d hi s c oll e a g u e s i n a st u d y t h at d e m o n str at e d 
t h at t h e h or m o n al c h a n g e s of p u b ert y i n d u c e d a p h y si ol o gi c st at e of i n s uli n r e si st a n c e i n h e alt h y l e a n 
a d ol e s c e nt s c o m p ar e d t o h e alt h y l e a n pr e a d ol e s c e nt s a n d y o u n g a d ult s ( 2). I n f oll o w- u p st u di e s, t h e s e 
i n v e sti g at or s u s e d t h e st e p p e d h y p eri n s uli n e mi c- e u gl y c e mi c cl a m p i n c o m bi n ati o n wit h st a bl e i s ot o p e 
i nf u si o n s t o d e m o n str at e t h at t h e i n s uli n r e si st a n c e of n or m al p u b ert y w a s r el at e d t o i m p air m e nt s i n 
i n s uli n’ s a bilit y t o sti m ul at e p eri p h er al gl u c o s e u pt a k e; w h er e a s, i n s uli n’ s a bilit y t o s u p pr e s s h e p ati c 
gl u c o s e pr o d u cti o n di d n ot a p p e ar t o b e a d v er s el y aff e ct e d ( 1 1). Dr. C a pri o ( m y s e c o n d ar y m e nt or) h a s 
u s e d si mil ar t e c h ni q u e s t o d e s cri b e, i n d e pt h, t h e m et a b oli c c o n s e q u e n c e s of o b e sit y i n n o n- di a b eti c 
c hil dr e n o v er t h e p a st 2 0 y e ar s ( 1 2- 2 0), i n cl u di n g i n dir e ct c al ori m etr y t o m e a s ur e r at e s of gl u c o s e a n d 
f at o xi d ati o n. N e v ert h el e s s, t h e eff e ct of o b e sit y o n h e p ati c a n d p eri p h er al i n s uli n s e n siti vit y i n 
a d ol e s c e nt s wit h T 1 D d uri n g p u b ert y h a s n ot b e e n e st a bli s h e d; t hi s i s t h e g a p i n k n o wl e d g e t h at AI M 1 
of t hi s st u d y i s i nt e n d e d t o fill. T hi s Ai m i s p arti c ul arl y si g nifi c a nt, a s a d ol e s c e nt s wit h T 1 D h a v e t h e 
p o or e st gl y c e mi c c o ntr ol a n d m a y g ai n t h e m o st b e n efit fr o m p h ar m a c ol o gi c i nt er v e nti o n t o i m pr o v e 
i n s uli n s e n siti vit y, pr o m ot e w ei g ht l o s s, a n d r e d u c e c ar di o v a s c ul ar c o m pli c ati o n s.
 B a s e d o n r e c e nt w or k e st a bli s hi n g br a n c h e d c h ai n a mi n o a ci d s ( B C A A s) a n d - h y dr o x y b ut yr at e a s 
m ar k er s of  p eri p h er al a n d h e p ati c i n s uli n r e si st a n c e i n o b e s e y o ut h wit h o ut T 1 D ( 2 1, 2 2), I will w or k  
 
 t o u s e t ar g et e d n u cl e ar m a g n eti c r e s o n a n c e ( N M R) s p e ctr o s c o p y t o a s s e s s t h e s e 
r el ati o n s hi p s i n l e a n a n d o b e s e a d ol e s c e nt s wit h T 1 D. V ali d ati o n of t h e s e r e c e ntl y i d e ntifi e d bi o m ar k er s 
r efl e cti n g p eri p h er al or h e p ati c i n s uli n r e si st a n c e i n a d ol e s c e nt s i n o ur st u d y c o h ort s will h el p i d e ntif y 
p ati e nt s w h o m a y p arti c ul arl y b e n efit fr o m t ar g et e d e arl y i nt er v e nti o n s.
F att y li v er di s e a s e i n o b e s e a d ol e s c e nt s wit h  T 1 D 
A n e m er gi n g b o d y of e vi d e n c e i n di c at e s t h at f att y li v er di s e a s e, a s a s s e s s e d b y a b d o mi n al M a g n eti c 
R e s o n a n c e I m a gi n g ( M RI), h a s a d v er s e eff e ct s o n gl u c o s e m et a b oli s m, e s p e ci all y i n a d ult s wit h T 2 D 
( 2 3). S o m e b ut n ot all st u di e s h a v e r e p ort e d t h at n o n- al c o h oli c f att y li v er di s e a s e i s c o m m o n i n a d ult s 
wit h T 1 D ( 2 4- 2 6) a n d pr e s e n c e of t hi s c o- m or bi dit y i s a s s o ci at e d wit h di st al n e ur o p at h y ( 2 7) 
c ar di o v a s c ul ar di s e a s e ( 2 4) a n d dr a sti c all y i n cr e a s e s t h e ri s k of c ar di o v a s c ul ar e v e nt s ( h a z ar d r ati o 
8. 1 6) ( 2 5). It i s p arti c ul arl y n ot e w ort h y t h at h e p ati c f at c o nt e nt i n c hil dr e n a n d a d ol e s c e nt s wit h T 1 D h a s 
o nl y b e e n st u di e d u si n g g ol d st a n d ar d M RI t e c h ni q u e s b y R e g n ell a n d c oll e a g u e s ( 2 8). I n t h at st u d y, 
h e p ati c f at c o nt e nt w a s sli g htl y l o w er i n 2 2 T 1 D s u bj e ct s ( 1. 3 %) t h a n i n 3 2 c o ntr ol s wit h o ut di a b et e s 
( 1. 8 %), h o w e v er, t h at st u d y di d n ot e v al u at e t h e eff e ct s of o b e sit y o n h e p ati c f at.
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
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I n c o ntr a st t o t h e i n cr e a s e d r at e s of li p ol y si s a s s o ci at e d wit h l o s s of i n s uli n s e n siti vit y, p h y si ol o gi c 
m e c h a ni s m s h a v e b e e n pr o p o s e d t o pr o m ot e h e p ati c li pi d a c c u m ul ati o n i n T 1 D. A b n or m al li p o pr ot ei n 
f u n cti o n or r ati o m a y li mit tri gl y c eri d e tr a n s p ort o ut of t h e li v er vi a V L D L ( 2 9). F urt h er m or e, tr a n s cri pti o n 
f a ct or s of h e p ati c li p o g e n e si s ( C h R E B P a n d S R E B P- 1 c) ar e sti m ul at e d u n d er h y p er gl y c e mi c c o n diti o n s 
( 2 9). 
Dr. C a pri o h a s e xt e n si v e e x p eri e n c e i n t h e u s e of M RI t o a s s e s s h e p ati c f at c o nt e nt i n o b e s e y o ut h 
wit h o ut di a b et e s ( 1 2, 3 0, 3 1). H er pri or w or k i n a d ol e s c e nt s wit h o b e sit y h a s s h o w n t h at hi g h li v er f at 
c o nt e nt i s a s s o ci at e d wit h si g nifi c a nt i n cr e a s e s i n i n s uli n r e si st a n c e. M or e s p e cifi c all y, hi g h h e p ati c f at 
fr a cti o n i s a s s o ci at e d wit h a n i m p air e d a cti o n of i n s uli n i n b ot h t h e li v er a n d m u s cl e, a n d m a y al s o li mit 
gl y c er ol t ur n o v er ( 1 2).  I will u s e t hi s t e c h n ol o g y t o e x a mi n e t h e p ut ati v e r ol e of f att y li v er di s e a s e ( Ai m 
2) o n t h e d e v el o p m e nt of h e p ati c i n s uli n r e si st a n c e of o b e sit y i n a d ol e s c e nt s wit h T 1 D st u di e d i n AI M 1.
I n n o v ati o n
A m aj or f o c u s of t hi s pr o gr a m of r e s e ar c h will b e dir e ct e d at a d v a n ci n g t h e u n d er st a n di n g of t h e m et a b oli c 
c o n s e q u e n c e s of o b e sit y a n d p u b ert y i n a d ol e s c e nt s wit h T 1 D. F or m a n y y e ar s, o ur c e nt er h a s b e e n at 
t h e f or efr o nt of st u di e s t h at c o m bi n e d e u gl y c e mi c- h y p eri n s uli n e mi c cl a m p s wit h n o n-r a di o a cti v e st a bl e 
i s ot o p e i nf u si o n s t o d e s cri b e t h e i n s uli n r e si st a n c e of p u b ert y i n y o ut h wit h a n d wit h o ut T 1 D a n d t h e 
i n s uli n r e si st a n c e of o b e sit y i n n o n- di a b eti c c hil dr e n 1- 5 . T h u s, a n i n n o v ati v e a s p e ct of Ai m 1 i s t h at it will 
b e t h e fir st t o u s e t h e s e s o p hi sti c at e d m et a b oli c t e c h ni q u e s t o e x a mi n e t h e eff e ct s of o b e sit y a n d h e p ati c 
st e at o si s o n i n s uli n s e n siti vit y i n p u b ert al a d ol e s c e nt s wit h T 1 D; n a m el y, t h e 2- st e p h y p eri n s uli n e mi c 
e u gl y c e mi c cl a m p wit h tr a c er e n h a n c e m e nt, w hi c h will all o w f or d efi niti o n of h e p ati c a n d p eri p h er al i n s uli n 
r e si st a n c e, gl y c er ol t ur n o v er, a n d gl u c o s e a n d f at o xi d ati o n ( Ai m 1). A s e c o n d n o v el a s p e ct i s t h at t hi s 
will b e t h e fir st st u d y t o utili z e g ol d st a n d ar d M RI m et h o d s t o q u a ntif y a n d c o m p ar e i ntr a h e p ati c f at c o nt e nt 
i n l e a n a n d o b e s e a d ol e s c e nt s wit h T 1 D ( Ai m 2). T hi s will all o w a gl o b al a n d m or e d et ail e d u n d er st a n di n g 
of t h e p ot e nti al alt er ati o n s of i n s uli n’ s eff e ct s o n k e y i n s uli n s e n siti v e ti s s u e s i n y o ut h t h at ar e i m p a ct e d 
b y b ot h T 1 D a n d o b e sit y. F urt h er m or e, e v al u ati o n of bi o m ar k er s f or i n s uli n r e si st a n c e a n d f att y li v er 
di s e a s e i n t hi s p o p ul ati o n will b e p erf or m e d f or t h e fir st ti m e.
U n d er st a n di n g t h e m et a b oli c p h e n ot y p e  a n d t h e pr e v al e n c e of n o n al c o h oli c h e p ati c st e at o si s i n 
o v er w ei g ht/ o b e s e a d ol e s c e nt s wit h T 1 D ar e t h e criti c al fir st st e p s t o w ar d s d e si g ni n g t h er a p e uti c 
i nt er v e nti o n s t o i m pr o v e m et a b oli c c o ntr ol i n t h e s e y o ut h a n d t o i m pr o v e t h eir l o n g t er m c ar di o v a s c ul ar 
o ut c o m e s. T h e k n o wl e d g e g ai n e d fr o m t hi s pr o gr a m of r e s e ar c h will i nf or m s el e cti o n of a dj u n cti v e 
p h ar m a c ol o gi c a g e nt s t o t ar g et i n s uli n r e si st a n c e i n s p e cifi c ti s s u e s. F or e x a m pl e, a d ol e s c e nt s wit h 
si g nifi c a nt h e p ati c st e at o si s a n d h e p ati c i n s uli n r e si st a n c e m a y b e n efit fr o m tr e at m e nt wit h S G L T 2i 
t h er a p y gi v e n it s p ot e nti al t o i n d e p e n d e ntl y i m pr o v e h e p ati c st e at o si s, b e y o n d t h e w ei g ht l o s s eff e ct s. M y 
f ut ur e w or k will f o c u s o n t h e a bilit y of a dj u n cti v e p h ar m a c ol o gi c a g e nt s t o i m p a ct t ur n o v er of li pi d a n d 
gl u c o s e, a s w ell a s r e d u c e h e p ati c a n d p eri p h er al i n s uli n r e si st a n c e a n d h e p ati c f at, w hi c h ar e c urr e ntl y 
u n e x pl or e d i n a d ol e s c e nt s wit h T 1 D, a s i niti al st u di e s i n t hi s ar e a f o c u s e d o n s af et y a n d gl y c e mi c 
o ut c o m e s. 
I a nti ci p at e t h at t h e r e s ult s of t hi s pr o p o s al will h el p t o i nf or m f ut ur e st u di e s of S G L T 2 i n hi bit or s i n 
p e di atri c p ati e nt s wit h T 1 D. M or e o v er, i d e ntifi c ati o n of m ar k er s a s s o ci at e d wit h i n s uli n r e si st a n c e a n d 
pr o gr e s si o n of f att y li v er di s e a s e 6  will f a cilit at e i d e ntifi c ati o n of p arti ci p a nt s w h o st a n d t o b e n efit fr o m 
tr e at m e nt i n f ut ur e st u di e s. 
 
F ut ur e pr oj e ct s t o u n d er st a n d a n d t h e s ci e ntifi c pr e mi s e, r ati o n al e, a n d m e c h a ni s m s of a dj u n cti v e 
t h er a pi e s i n T 1 D
I n br o a d t er m s, tr e at m e nt of T 1 D h a s n ot c h a n g e d i n al m o st 1 0 0 y e ar s; si m pl y m or e a n d b ett er t y p e s of 
i n s uli n d eli v er e d i n diff er e nt w a y s. T h u s f ar, t h e o nl y a dj u n cti v e a g e nt st u di e d i n y o ut h wit h T 1 D i s 
m etf or mi n, b ut t h e b e n efit s of tr e at m e nt wit h t hi s a g e nt w er e di s a p p oi nti n g. Y al e w a s o n e of t h e c e nt er s 
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 7  of 2 6
v ari a bl e 2 0 % d e xtr o s e i nf u si o n 5 . Pl a s m a gl u c o s e will b e m o nit or e d e v er y 5 mi n ut e s d uri n g b ot h i n s uli n 
i nf u si o n p eri o d s b y t h e Y SI 2 3 0 0 gl u c o s e a n al y z er t o a dj u st d e xtr o s e i nf u si o n r at e s t o m ai nt ai n pl a s m a 
gl u c o s e 9 0- 9 5 m g/ d L.
 M et a b olit e C oll e cti o n:  S a m pl e s f or m e a s ur e m e nt s of gl u c o s e a n d gl y c er ol e nri c h m e nt, a s w ell 
a s h or m o n e s a n d s u b str at e s, will b e o bt ai n e d e v er y 5- 1 0 mi n ut e s d uri n g t h e fi n al 3 0 mi n ut e s of t h e 
b a s eli n e e q uili br ati o n p h a s e, a s w ell a s d uri n g t h e fi n al 3 0 mi n ut e s of t h e l o w a n d hi g h d o s e i n s uli n 
i nf u si o n p h a s e s. 
 M e a s ur e s of O xi d ati o n: I n dir e ct c al ori m etr y will b e utili z e d at b a s eli n e a n d t h e e n d of e a c h st e p 
of t h e cl a m p t o e v al u at e r at e s of gl u c o s e a n d f at o xi d ati o n.   
D E X A s c a n ( H ol o gi c, B o st o n, M A, U S A): T ot al b o d y f at a n d l e a n b o d y m a s s will b e a s s e s s e d b y d u al 
e n er g y x-r a y a b s or pti o m etr y ( D E X A).
Vi sit 2: A d ol e s c e nt p arti ci p a nt s ( a g e 1 2- 1 6). Y o u n g a d ult s will n ot p arti ci p at e i n t hi s vi sit. P arti ci p a nt s 
wit h tr a n s a mi n a s e s > 2. 5 t h e u p p er li mit of n or m al will u n d er g o cli ni c al e v al u ati o n t o e x cl u d e li v er 
di s e a s e ( ot h er t h a n n o n- al c o h oli c st e at o si s) pri or t o pr o c e e di n g wit h M RI. 
P arti ci p a nt s will pr e s e nt t o t h e M a g n eti c R e s o n a n c e R e s e ar c h C e nt er ( M R R C) f or a b d o mi n al M RI. U si n g 
a 3 T e sl a M a g n et ( Si e m e n s), w e will a s s e s s i ntr a- a b d o mi n al f at d e p o siti o n a n d a n al y z e t h e s u b c ut a n e o u s 
a n d vi s c er al u si n g m et h o d s o ur gr o u p h a s e m pl o y e d i n t h e p a st 8 . 
W e will q u a ntit at e t h e li v er f at a c c u m ul ati o n u si n g t h e  m a g nit u d e- b a s e d M RI of t h e li v er t o d et er mi n e 
M RI- e sti m at e d Pr ot o n d e n sit y f at fr a cti o n ( P D F F) 9 . T h e P D F F str o n gl y c orr el at e s wit h h e p ati c st e at o si s 
a s a s s e s s e d b y hi st o p at h ol o g y of li v er bi o p s y. T h e 3 T m a g n et will b e u s e d t o s c a n p arti ci p a nt s a n d t h e 
gr a di e nt-r e c all e d- e c h o t e c h ni q u e will e sti m at e li v er P D F F 9 . 
5.
G e n etic T esti n g    
N/ A 
5.
G e n etic T esti n g    
N/ A ☒
A.
D escri b e
i.
t h e ty p es of f ut ur e r es e arc h t o b e c o n d uct e d usi n g t h e m at eri als, s p ecifyi n g if i m m ort aliz ati o n of 
c ell li n es, w h ol e ex o m e or g e n o m e s e q u e nci n g, g e n o m e wi d e ass oci ati o n st u di es, or a ni m al 
st u di es ar e pl a n n e d Writ e h er e
ii.
t h e pl a n f or t h e c oll ecti o n of m at eri al or t h e c o n diti o ns u n d er w hic h m at eri al will b e r ec eiv e d 
Writ e h er e
iii. t h e ty p es of i nf or m ati o n a b o ut t h e d o n or/i n divi d u al c o ntri b ut ors t h at will b e e nt er e d i nt o a 
d at a b as e Writ e h er e
i v. t h e m et h o ds t o u p h ol d c o nfi d e nti ality Writ e h er e
B.
W h at ar e t h e c o n diti o ns or pr oc e d ur es f or s h ari n g of m at eri als a n d/ or distri b uti n g f or f ut ur e r es e arc h 
pr oj ects ? Writ e h er e
C.
Is wi d es pr e a d s h ari n g of m at eri als pl a n n e d ? Writ e h er e
D.
W h e n a n d u n d er w h at c o n diti o ns will m at eri als b e stri p p e d of all i d e ntifi ers ? Writ e h er e
E.
C a n d o n or-s u bj ects wit h dr a w t h eir m at eri als at a ny ti m e, a n d/ or wit h dr a w t h e i d e ntifi ers t h at c o n n ect 
t h e m t o t h eir m at eri als ?  Writ e  h er e
i.
H o w will r e q u ests t o wit h dr a w m at eri als b e h a n dl e d ( e. g., m at eri al n o l o n g er i d e ntifi e d: t h at is, 
a n o ny miz e d) or m at eri al d estr oy e d) ? Writ e h er e
F.
D escri b e t h e pr ovisi o ns f or pr ot ecti o n of p artici p a nt priv acy Writ e h er e
G.
D escri b e t h e m et h o ds f or  t h e s ec urity of st or a g e a n d s h ari n g of m at eri als  Writ e h er e
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 8  of 2 6
6.
S u bj ect P o p ul ati o n: 
S u bj ect P o p ul ati o n: Pr ovi d e a d et ail e d  d escri pti o n of t h e ty p es of h u m a n s u bj ects w h o will b e r ecr uit e d i nt o 
t his st u dy.
T hi s st u d y ai m s t o e nr oll 3 6 o b e s e/ o v er w ei g ht a d ol e s c e nt s a n d 3 6 l e a n a d ol e s c e nt s wit h T 1 D. A 
c o m p ari s o n c o ntr ol gr o u p of 3 6 l e a n y o u n g a d ult s wit h T 1 D m at c h e d f or g e n d er a n d H b A 1 c will al s o 
b e e nr oll e d, si n c e t h e y will b e u n aff e ct e d b y t h e a d v er s e m et a b oli c eff e ct s of p u b ert y or o b e sit y.
7. S u bj ect cl assific ati o n: 
S u bj ect cl assific ati o n: C h eck off all cl assific ati o ns of s u bj ects t h at will b e s p ecific ally r ecr uit e d f or e nr oll m e nt i n 
t h e r es e arc h pr oj ect. Will s u bj ects  w h o m ay r e q uir e a d diti o n al s af e g u ar ds or ot h er c o nsi d er ati o ns b e e nr oll e d 
i n t h e st u dy ? If s o, i d e ntify t h e p o p ul ati o n of s u bj ects r e q uiri n g s p eci al s af e g u ar ds a n d pr ovi d e a j ustific ati o n 
f or t h eir i nv olv e m e nt.
☒C hil dr e n
☐ H e alt hy 
☐F et al m at eri al, pl ac e nt a, or d e a d f et us
☐N o n- E n glis h S p e aki n g
☐ Pris o n ers
☐Ec o n o mic ally dis a dv a nt a g e d p ers o ns
☐D ecisi o n ally I m p air e d
☐ E m pl oy e es
☐Pr e g n a nt w o m e n a n d/ or f et us es
☐Y al e St u d e nts 
☒ F e m al es of c hil d b e ari n g p ot e nti al
N O T E: Is t his r es e arc h pr o p os al d esi g n e d t o e nr oll c hil dr e n w h o ar e w ar ds of t h e st at e as p ot e nti al s u bj ects ?
Y es 
Y es ☐  N o 
  N o ☒ 
T o u n d er st a n d t h e eff e ct s of a di p o sit y i n p u b ert y o n m et a b oli s m i n t y p e 1 di a b et e s, w e m u st st u d y 
a d ol e s c e nt s d uri n g p u b ert y, a n d t hi s m u st al s o o c c ur i n a p e di atri c p o p ul ati o n a s a d ol e s c e nt s u s u all y 
c o m pl et e p u b ert y b y a g e 1 8. F urt h er m or e, t hi s a g e gr o u p c o nt ai n s f e m al e s of c hil d b e ari n g p ot e nti al 
a n d e x cl u si o n of f e m al e s w o ul d li mit t h e fi n di n g s o nl y t o m al e s. O ur gr o u p i s e x p eri e n c e d i n c o n d u cti n g 
e u gl y c e mi c h y p eri n s uli n e mi c cl a m p s a n d a b d o mi n al M RI i n c hil dr e n. Pri or p u bli s h e d w or k i s e vi d e n c e 
of o ur s ci e ntifi c all y ri g or o u s pr o c e s s w hil e m ai nt ai ni n g s af et y f or st u d y p arti ci p a nt s. 
8. I ncl usi o n/ Excl usi o n Crit eri a:
I ncl usi o n/ Excl usi o n Crit eri a: W h at ar e t h e crit eri a us e d t o d et er mi n e s u bj ect i ncl usi o n or excl usi o n ?
• I n cl u si o n crit eri a: 
All P arti ci p a nt s:
1.
Cli ni c al di a g n o si s of T 1 D
2.
H b A 1 c ≤9 %
3.
Di a b et e s d ur ati o n of at l e a st 1 2 m o nt h s
A d ol e s c e nt s wit h T 1 D : 
1. A g e 1 2- 1 6 y e ar s
2. B MI < 7 5t h f or l e a n p e di atri c s u bj e ct s, > 8 5t h p er c e ntil e f or o v er w ei g ht/ o b e s e p e di atri c s u bj e ct s;
3. T a n n er st a g e 2- 5
4. P ar e nt a bl e t o  pr o vi d e writt e n c o n s e nt a n d p arti ci p a nt a bl e t o pr o vi d e a s s e nt
L e a n, y o u n g a d ult s wit h  T 1 D: 
1. A g e 1 8- 2 4 y e ar s
2. B MI 1 8. 5- 2 4. 9 k g/ m 2
3. A bl e t o pr o vi d e writt e n c o n s e nt.  
• E x cl u si o n crit eri a: 
1.
U s e of a dj u n cti v e  di a b et e s m e di c ati o n s or ot h er m e di c ati o n s k n o w n t o i m p a ct i n s uli n s e n siti vit y
2.
W ei g ht l o s s m e di c ati o n s wit hi n t h e p a st si x m o nt h s
3.
C urr e nt p s y c hi atri c di s or d er s, i n cl u di n g e ati n g di s or d er s ( D S M- V crit eri a)
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 9  of 2 6
4. K n o w n li v er di s e a s e ot h er t h a n n o n al c o h oli c h e p ati c st e at o si s
5. F e m al e s w h o ar e pr e g n a nt or l a ct ati n g
6. A n e mi a or a n ot h er m e di c al c o n diti o n t h at pr e cl u d e s p arti ci p ati o n i n t h e st u d y 
7.
N ot m e eti n g M RI s af et y crit eri a
8.
Cl a u str o p h o bi a t h at will  pr e v e nt p arti ci p ati o n i n t h e M RI
9. H o w will eli gi bility
eli gi bility  b e d et er mi n e d, a n d by w h o m ? Writ e h er e
PI or c o-i n v e sti g at or s will d et er mi n e eli gi bilit y aft er r e vi e w of m e di c al hi st or y, s cr e e ni n g t e st s a n d 
i n cl u si o n/ e x cl u si o n crit eri a t hr o u g h t h e r e g ul ar cli ni c al e n c o u nt er s a n d t hr o u g h r e vi e w of t h e E M R 
r e c or d of p ati e nt s u n d er t h eir cli ni c al c ar e
1 0. Risks:
Risks:  D escri b e t h e r e as o n a bly f or es e e a bl e risks, i ncl u di n g risks t o s u bj ect priv acy, disc o mf orts, or 
i nc o nv e ni e nc es ass oci at e d wit h s u bj ects p artici p ati n g i n t h e r es e arc h. 
T h e ri s k of di s cl o s ur e of pr ot e ct e d h e alt h i nf or m ati o n i s s m all. Eff ort s ar e t a k e n a n d pr o c e d ur e s ar e i n 
pl a c e t o a s s ur e t h at t hi s d o e s n ot o c c ur, i n c o m pli a n c e wit h HI P A A/ HI T E C H/f ut ur e pri v a c y r e g ul ati o n s. 
i.  Ri s k s r el at e d t o t h e h y p eri n s uli n e mi c e u gl y c e mi c cl a m p:
( a) T h e bl o o d dr a w s a n d I V pl a c e m e nt c o ul d r e s ult i n di s c o mf ort or br ui si n g, or r ar el y a n d i nf e cti o n or 
bl o o d cl ot
( b) H y p o gl y c e mi a/ H y p er gl y c e mi a:. D uri n g t h e s e cl a m p s i n s uli n i s i nf u s e d, w hi c h c a n c a u s e 
h y p o gl y c e mi a. F or t hi s r e a s o n, bl o o d gl u c o s e i s m e a s ur e d fr e q u e ntl y t hr o u g h o ut t h e st u d y b y a r eli a bl e 
d e vi c e ( Y SI 2 3 0 0) s o t h at t h e r at e of d e xtr o s e i nf u si o n c a n b e a dj u st e d r e g ul arl y t o m ai nt ai n t h e bl o o d 
gl u c o s e at t ar g et a n d pr e v e nt h y p o gl y c e mi a. T h e st u d y pr o c e d ur e s m a y r e s ult i n el e v at e d or l o w 
gl u c o s e v al u e s. At t h e e n d of e a c h vi sit, t h e p arti ci p a nt will r e c ei v e g ui d a n c e f or gl u c o s e m o nit ori n g, 
f o o d i nt a k e, a n d i n s uli n d o si n g a s n e e d e d. 
F urt h er m or e, o ur gr o u p i s v er y e x p eri e n ce d i n c o n d ucti n g t hese st u dies . A d diti o n all y, w h e n w e b e g a n 
d oi n g t h e s e st u di e s, t h er e w a s c o n c er n of a d v er s e p s y c h ol o gi c al eff e ct s o n c hil dr e n w hi c h w e c ar ef ull y 
a s s e s s e d i n e arl y st u di e s. Dr. C a pri o f o u n d n o a d v er s e i m p a ct of cl a m p st u di e s o n c hil dr e n.
( c) St a bl e i s ot o p e s: D e s pit e t h e t h e or eti c al ri s k of i nf e cti o n wit h i nf u si o n of st a bl e i s ot o p e s, o ur t e a m 
h a s b e e n u si n g i s ot o p e s d uri n g cl a m p st u di e s f or 1 5 y e ar s i n c hil dr e n a n d a d ol e s c e nt s a n d h a v e n ot 
e x p eri e n c e d a n y a d v er s e e v e nt s. 
( d) Ri s k of i n d w elli n g c at h et er: T h er e ar e p ot e nti al c o m pli c ati o n s a s s o ci at e d wit h i n d w elli n g c at h et er s, 
i n cl u di n g h e m at o m a s, di s c o mf ort, a n d r ar el y i nf e cti o n, t hr o m b o p hl e biti s, or bl e e di n g at t h e c at h et er 
i n s erti o n sit e. 
( e) A n e mi a:  T h e ri s k of a n e mi a e xi st s i n st u di e s wit h fr e q u e nt bl o o d dr a w s. I n o ur m a n y y e ar s of 
p erf or mi n g cl a m p st u di e s w e h a v e n ot k n o w n a n y p arti ci p a nt s t o e x p eri e n c e t hi s c o m pli c ati o n. 
ii.  Ri s k s r el at e d t o i m a gi n g a s s e s s m e nt s:
( a) D E X A S c a n: T h er e i s r a di ati o n e x p o s ur e d uri n g t h e D E X A S c a n, w hi c h i s e sti m at e d t o b e l e s s t h a n 
1/ 1 0 t h e r a di ati o n i n di vi d u al s r e c ei v e d uri n g a c h e st X-r a y. It i s b el o w t h e F D A li mit s f or r a di ati o n 
e x p o s ur e i n r e s e ar c h s u bj e ct s. W e h a v e r o uti n el y u s e d D E X A t o m o nit or b o d y c o m p o siti o n i n c hil dr e n.  
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 1 0  of 2 6
( b) A b d o mi n al M RI: M RI u s e s m a g n eti s m a n d r a di o w a v e s t o cr e at e i m a g e s of v ari o u s b o d y p art s. M RI 
d o e s n ot u s e x-r a y s t o cr e at e i m a g e s. A n y m et al i n t h e s c a n n er r o o m i s d a n g er o u s d u e t o t h e str o n g 
m a g n et s i n t h e s c a n n er, w hi c h c a n attr a ct m et al. T h e s c a n s h o ul d t a k e n o m or e t h a n 4 5 mi n ut e s. 
1 1. Mi ni mizi n g Risks:
Mi ni mizi n g Risks:  D escri b e t h e m a n n er i n w hic h t h e a b ov e- m e nti o n e d risks will b e mi ni miz e d.
I n or d er t o pr ot e ct t h e c o nfi d e nti alit y of e a c h p arti ci p a nt, t h e y will b e a s si g n e d a c o d e d i d e ntifi er t h at will 
b e u s e d i n st e a d of t h eir n a m e. 
i. Pr ot e cti o n a g ai n st ri s k s r el at e d t o t h e h y p eri n s uli n e mi c e u gl y c e mi c cl a m p:
(a) I V i n s erti o n will b e p erf or m e d b y tr ai n e d r e s e ar c h n ur s e s o n t h e H R U. N u m bi n g cr e a m c a n b e u s e d 
t o r e d u c e t h e p ai n. 
( b) H y p o gl y c e mi a/ H y p er gl y c e mi a d uri n g cl a m p st u di e s: Fr e q u e nt bl o o d gl u c o s e c h e c k s u si n g a b e d si d e 
a n al y z er will all o w f or c ar ef ul m o nit ori n g s o t h at t h e st u d y d o ct or s a n d n ur s e s c a n i d e ntif y tr e n d s t h at 
m a y l e a d t o h y p o or h y p er gl y c e mi a. I nf u si o n of b ot h i n s uli n a n d gl u c o s e all o w f or r a pi d c orr e cti o n of 
eit h er sit u ati o n. T h e st u d y will b e p erf or m e d u n d er t h e c o ntr ol of a p h y si ci a n. 
( c) St a bl e i s ot o p e s: I s ot o p e s will b e c ar ef ull y m o nit or e d a n d a d mi ni st er e d, a n d will b e pr e p ar e d i n t h e 
i n v e sti g ati o n al p h ar m a c y t o e n s ur e pr o p er t e c h ni q u e.
( d) Ri s k of i n d w elli n g c at h et er: Tr ai n e d n ur s e s will u s e a s e pti c t e c h ni q u e t o i n s ert t h e I V c at h et er s. W e 
will mi ni mi z e t h e ri s k of p ai n b y off eri n g a n o pti o n of t o pi c al a n e st h eti c t o t h e p ati e nt pri or t o I V 
i n s erti o n. P arti ci p a nt s will b e a d vi s e d t o c o nt a ct t h e st u d y t e a m i m m e di at el y if t h e y b e c o m e a w ar e of a 
l at e a d v er s e eff e ct.
( e) A n e mi a: P arti ci p a nt s will b e s cr e e n e d wit h a h e m at o crit l e v el pri or t o i niti ati o n of st u d y pr o c e d ur e s. 
S a m pl e s will b e o bt ai n e d wit h t h e mi ni m u m n e c e s s ar y bl o o d v ol u m e. T h e p oi nt of c ar e Y SI gl u c o s e 
d et er mi n ati o n s r e q uir e o nl y 0. 3 ml of bl o o d. W e will e n s ur e t h at bl o o d v ol u m e o bt ai n e d d o e s n ot e x c e e d 
a m a xi m u m of 5 c c/ k g i n p e di atri c p arti ci p a nt s a n d 5 5 0 ml i n a d ult p arti ci p a nt s.  
ii. Pr ot e cti o n a g ai n st ri s k s r el at e d t o i m a gi n g a s s e s s m e nt s: 
( a) D E X A S c a n: S u bj e ct s r e c ei v e mi ni m al r a di ati o n fr o m a D E X A s c a n ( 0. 0 1- 0. 0 4 millir e m p er 
m e a s ur e m e nt), w hi c h i s e sti m at e d t o b e l e s s t h a n 1/ 1 0 t h e r a di ati o n t h at i s r e c ei v e d d uri n g a c h e st X-
r a y. T h e s e ar e b el o w t h e F D A r a di ati o n e x p o s ur e li mit s f or r e s e ar c h s u bj e ct s. W e c ar ef ull y f oll o w t h e 
U nit e d St at e s F o o d a n d Dr u g A d mi ni str ati o n g ui d eli n e s f or m a g n et str e n gt h a n d r a di o w a v e e x p o s ur e. 
S u bj e ct s will b e a s k e d a b o ut pri or r a di ati o n e x p o s ur e t o e n s ur e t h at c u m ul ati v e a n n u al e x p o s ur e 
d o e s n’t e x c e e d F D A li mit s. All s c a n s will b e u n d er m e di c al s u p er vi si o n wit h tr ai n e d n ur si n g st aff. 
( b) M RI S c a n ni n g: W e o b s er v e t h e F D A g ui d eli n e s r e g ar di n g m a g n et str e n gt h a n d r a di o w a v e 
e x p o s ur e. P arti ci p a nt s will b e s cr e e n e d f or m a g n eti c r e s o n a n c e ( M R) s af et y u si n g t h e M R S af et y 
Q u e sti o n n air e, a n d w e will e n c o ur a g e t h e m t o pr o vi d e a n y i nf or m ati o n t h e y t hi n k mi g ht b e i m p ort a nt. 
P arti ci p a nt s a n d st u d y st aff i n v ol v e d i n t h e s c a n will e nt er a d et e ct or d e si g n e d t o d et e ct m et al o bj e ct s t o 
mi ni mi z e t h e p o s si bilit y of m et al e nt eri n g t h e M R r o o m. N o m et al c a n b e br o u g ht i n t h e M R r o o m at a n y 
ti m e. T h e d o or will b e cl o s e d s o t h at n o i n di vi d u al s fr o m o ut si d e a c ci d e nt all y e nt er t h e m a g n eti c s p a c e. 
N o p er s o n s h o ul d h a v e a n M RI ( M a g n eti c R e s o n a n c e I m a gi n g) t e st f or a n y r e a s o n w hil e eit h er u si n g a 
c o nti n u o u s gl u c o s e m o nit or ( C G M) d e vi c e n or m all y or if t h er e i s p o s si bl y a br o k e n s e n s or u n d er t h e 
c hil d' s s ki n. I n s uli n p u m p s m u st b e r e m o v e d pri or t o M RI.
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

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P arti ci p a nt s will b e cl o s el y m o nit or e d  w hil e i n t h e s c a n n er, a n d if t h e y f e el a n xi o u s or u n c o mf ort a bl e 
t h e y will h a v e t h e o pti o n t o st o p t h e st u d y a n d c o m e o ut of t h e M R s c a n n er. R ar el y, i n di vi d u al s i n a M R 
s c a n n er m a y e x p eri e n c e di z zi n e s s, st o m a c h u p s et, m et alli c t a st e i n t h e m o ut h, ti n gli n g s e n s ati o n s or 
m u s cl e t wit c hi n g, a n d t h e s e e x p eri e n c e s u s u all y r e s ol v e q ui c kl y. P arti ci p a nt s will b e a s k e d t o l et t h e 
r e s e ar c h t e a m k n o w if t h e y e x p eri e n c e t h e s e s e n s ati o n s. 
T h e i m a g e s o bt ai n e d ar e f or r e s e ar c h p ur p o s e s a n d n ot f or cli ni c al di a g n o s e s. If a c o n c er n ari s e s 
b a s e d o n a s c a n, w e will a s k a r a di ol o gi st or ot h er a p pr o pri at e p h y si ci a n t o r e vi e w t h e fi n di n g. B a s e d o n 
t hi s r e c o m m e n d ati o n, if a d diti o n al e v al u ati o n i s n e e d e d, t h e PI will c o nt a ct t h e p ati e nt or f a mil y t o 
r e c o m m e n d t h e y s e e k m e di c al e v al u ati o n a s a pr e c a uti o n ar y m e a s ur e. T h e i m a g e s o bt ai n e d a s p art of 
t hi s st u d y ar e n ot f or di a g n o sti c p ur p o s e s. 
1 2. D at a a n d S af ety M o nit ori n g Pl a n:
D at a a n d S af ety M o nit ori n g Pl a n:  I ncl u d e a n a p pr o pri at e D at a a n d S af ety M o nit ori n g Pl a n ( D S M P) b as e d o n 
t h e i nv esti g at or’s risk ass ess m e nt st at e d b el o w. ( N ot e: t h e HI C will m ak e t h e fi n al d et er mi n ati o n of t h e risk t o 
s u bj ects.)
a.  
W h at is t h e i nv esti g at or’s ass ess m e nt of t h e ov er all risk l ev el f or s u bj ects p artici p ati n g i n t his 
st u dy ? Gr e at er t h a n mi ni m al risk
b. 
If c hil dr e n ar e i nv olv e d, w h at is t h e i nv esti g at or’s ass ess m e nt of t h e ov er all risk l ev el f or t h e 
c hil dr e n p artici p ati n g i n t his st u dy ? Gr e at er t h a n mi ni m al risk
c. 
I ncl u d e a n a p pr o pri at e D at a a n d S af ety M o nit ori n g Pl a n. 
Gre ater T h a n Mi ni m al Ris k D S M P
T his st u d y is dee me d gre ater t h a n mi ni m al ris k wit h n o pr os pect of direct be nefit t o t he i n di vi d u al
s u bjects i n v ol ve d i n t he rese arc h, b ut li kel y t o yiel d ge ner alize d k n o wle d ge a b o ut t he s u bject's 
dis or der or c o n diti o n
1. Pers o n nel res p o nsi ble f or t he s afet y re vie w a n d its fre q ue nc y:
T he pri nci pal i n vesti gat or will  be res p o nsi ble f or m o nit ori n g t he data, ass uri n g pr ot oc ol c o m plia nce, a n d 
c o n d ucti n g t he safet y re vie ws at t he s pecifie d fre q ue nc y, w hic h m ust be c o n d ucte d at a mi ni m u m of 
e ver y 6 m o nt hs (i ncl u di n g w he n rea p pr o val of t he pr ot oc ol is s o u g ht).  D uri n g t he re vie w pr ocess, t he 
pri nci pal i n vesti gat or ( m o nit or) will e val uate w het her t he st u d y s h o ul d c o nti n ue u nc ha n ge d, re q uire 
m o dificati o n/a me n d me nt, or cl ose t o e nr oll me nt. Eit her t he pri nci pal i n vesti gat or or t he I R B  ha ve t he 
a ut h orit y t o st o p or s us pe n d t he st u d y or re q uire m o dificati o ns.
2. T he ris ks ass oci ate d wit h t he c urre nt st u d y are dee me d gre ater t h a n mi ni m al f or t he f oll o wi n g 
re as o ns: (c h o ose t h ose t hat a p pl y)
1.
We d o n ot vie w t he ris ks ass ociate d wit h t he e u gl yce mic h y peri ns uli ne mic cla m p as mi ni mal 
ris ks.
2.
Gi ve n t he n o w esta blis he d safet y a n d vali dit y of t he c urre nt cla m p a n d M RI  pr oce d ures i n o ur 
pri or w or k, we d o n ot vie w t he pr o p ose d st u dies as hi g h ris k.
Alt h o u g h we ha ve assesse d t he pr o p ose d st u d y  as o ne of greater t ha n mi ni mal ris k, t he p ote ntial e xists 
f or a ntici pate d a n d/ or u na ntici pate d a d verse e ve nts, seri o us or ot her wise, t o occ ur si nce it is n ot p ossi ble 
t o pre dict wit h certai nt y t he a bs ol ute ris k i n a n y gi ve n i n di vi d ual or i n a d va nce of first- ha n d e x perie nce 
wit h t he pr o p ose d st u d y met h o ds. T heref ore, we pr o vi de a pla n f or m o nit ori n g t he data a n d safet y of t he 
pr o p ose d st u d y as f oll o ws:
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3. Attri b uti o n of A d verse E ve nts:
A d verse e ve nts will be m o nit ore d f or eac h s u bject partici pati n g i n t he st u d y a n d attri b ute d t o t he st u d y 
pr oce d ures / desi g n b y t he pri nci pal i n vesti gat or Mic helle Va n Na me acc or di n g  t o t he f oll o wi n g 
cate g ories:
a.) Defi nite: A d verse e ve nt is clearl y relate d t o i n vesti gati o nal pr oce d ures(s)/a ge nt(s).
b.) Pr o ba ble: A d verse e ve nt is li kel y relate d t o i n vesti gati o nal pr oce d ures(s)/a ge nt(s).
c.) P ossi ble: A d verse e ve nt ma y be relate d t o i n vesti gati o nal pr oce d ures(s)/a ge nt(s).
d.) U nli kel y:  A d verse e ve nt is li kel y n ot t o be relate d t o t he i n vesti gati o nal pr oce d ures(s)/a ge nt(s).
e.) U nrelate d:  A d verse e ve nt is clearl y n ot relate d t o i n vesti gati o nal pr oce d ures(s)/a ge nt(s).
4. Pl a n f or Gr a di n g A d verse  E ve nts:
T he f oll o wi n g scale will be use d i n gra di n g t he se verit y of a d verse e ve nts n ote d d uri n g t he st u d y:
1.
Mil d a d verse e ve nt
2.
M o derate a d verse e ve nt
3.
Se vere 
5. Pl a n  f or Deter mi ni n g Seri o us ness of A d verse E ve nts:
Seri o us A d verse  E ve nts:
I n a d diti o n t o gra di n g t he a d verse e ve nt, t he PI will deter mi ne w het her t he a d verse e ve nt meets t he 
criteria f or a Seri o us A d verse E ve nt ( S A E).  A n a d verse e ve nt is c o nsi dere d seri o us if it res ults i n a n y of 
t he f oll o wi n g o utc o mes:
1.
Deat h;
2.
A life-t hreate ni n g e x perie nce 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; 
3.
A persiste nt or si g nifica nt disa bilit y or i nca pacit y; 
4.
A c o n ge nital  a n o mal y or birt h defect; O R
5.
A n y ot her a d verse e ve nt t hat, base d u p o n a p pr o priate me dical j u d g me nt, ma y je o par dize t he 
s u bject’s healt h a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d  i n t his defi niti o n. 
A n a d verse e ve nt ma y be gra de d as se vere b ut still n ot meet t he criteria f or a Seri o us A d verse E ve nt.  
Si milarl y, a n a d verse e ve nt ma y be gra de d  as m o derate b ut still meet t he criteria f or a n S A E.  It is 
i m p orta nt f or t he PI t o c o nsi der t he gra de of t he e ve nt as well as its “seri o us ness” w he n deter mi ni n g 
w het her re p orti n g t o t he I R B is necessar y.
6. Pl a n f or re p orti n g U PI R S Os (i ncl u di n g A d verse E ve nts) t o t he I R B
T he pri nci pal i n vesti gat or will re p ort t he f oll o wi n g t y pes of e ve nts t o t he I R B: 
A n y i nci de nt, e x perie nce or o utc o me t hat meets  A L L 3 of t he f oll o wi n g criteria:
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1. Is u ne x pecte d (i n ter ms of nat ure, s pecificit y, se verit y, or fre q ue nc y) gi ve n (a) t he researc h 
pr oce d ures descri be d i n t he pr ot oc ol-relate d d oc u me nts, s uc h as t he I R B-a p pr o ve d pr ot oc ol  
a n d i nf or me d c o nse nt d oc u me nt a n d ( b) t he c haracteristics of t he s u bject p o p ulati o n bei n g 
st u die d; A N D 
2. Is relate d or p ossi bl y relate d t o partici pati o n i n t he researc h ( p ossi bly rel ate d  mea ns t here is a 
reas o na ble p ossi bilit y t hat t he i nci de nt, e x perie nce, or o utc o me ma y ha ve bee n ca use d b y t he 
pr oce d ures i n v ol ve d i n t he researc h); A N D
3.
S u g gests t hat t he researc h places s u bjects or ot hers at greater ris k of har m (i ncl u di n g 
p h ysical, ps yc h ol o gical, ec o n o mic, le gal, or s ocial har m) t ha n was pre vi o usl y k n o w n  or 
rec o g nize d.
U na ntici pate d Pr o ble ms I n v ol vi n g Ris ks t o S u bjects or Ot hers ( U PI R S Os) ma y be me dical or n o n-
me dical i n nat ure, a n d i ncl u de – b ut are n ot li mite d t o – seri o us, u nex pecte d, a n d rel ate d a dverse 
eve nts a n d u n a ntici p ate d a dverse device effects .  Ple ase n ote  t hat a d verse e ve nts are re p orta ble t o t he 
I R B as U PI R S Os o nl y  if t he y meet all 3 criteria liste d a b o ve.
T hese U PI R S Os/ S A Es will be re p orte d t o t he I R B i n acc or da nce wit h I R B P olic y 7 1 0, usi n g t he 
a p pr o priate f or ms f o u n d o n t he we bsite.  All relate d e ve nts i n v ol vi n g ris k b ut n ot meeti n g t he pr o m pt 
re p orti n g re q uire me nts descri be d i n I R B P olic y 7 1 0 s h o ul d be re p orte d t o t he I R B i n s u m mar y f or m at 
t he ti me of c o nti n ui n g re vie w. If a p pr o priate, s uc h s u m mar y ma y be a si m ple brief state me nt t hat e ve nts 
ha ve occ urre d at t he e x pecte d fre q ue nc y a n d le vel of se verit y as pre vi o usl y d oc u me nte d .  I n lie u of a 
s u m mar y of e xter nal e ve nts, a c urre nt D S M B re p ort ca n be s u b mitte d f or researc h st u dies t hat are 
s u bject t o o versi g ht b y a D S M B ( or ot her m o nit ori n g e ntit y t hat is m o nit ori n g t he st u d y o n be half of a n 
i n d ustr y s p o ns or).
7. Pl a n f or re p orti n g a d verse e ve nts t o c o-i n vesti g at ors o n t he st u d y, as a p pr o pri ate t he pr ot oc ol’s 
rese arc h m o nit or(s), e. g., i n d ustri al s p o ns or, Y ale C a ncer Ce nter D at a a n d S afet y M o nit ori n g 
C o m mittee ( D S M C), Pr ot oc ol Re vie w C o m mittee ( P R C), D S M Bs, st u d y s p o ns ors, f u n di n g a n d 
re g ul at or y a ge ncies, a n d re g ul at or y a n d decisi o n- m a ki n g b o dies.
F or t he c urre nt st u d y,  t he f oll o wi n g i n di vi d uals, f u n di n g, a n d/ or re g ulat or y a ge ncies will be n otifie d 
(c h o ose t h ose t hat a p pl y):
X All C o-I n vesti gat ors liste d o n t he pr ot oc ol.
□ Yale Ca ncer Ce nter Data a n d Safet y M o nit ori n g C o m mittee ( D S M C)
X Nati o nal I nstit utes of  Healt h
□ F o o d a n d Dr u g A d mi nistrati o n ( P h ysicia n- S p o ns ore d I N D # _ _ _ _ _ _ _)
□ Me dical Researc h F o u n dati o n ( Gra nt _ _ _ _ _ _)
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□ St u d y S p o ns or
□ Ot her Data Safet y M o nit ori n g B oar d ( D S M B) or C o m mittee ( D S M C)
T he pri nci pal i n vesti gat or Mic helle Va n Na me will c o n d uct a  re vie w of all a d verse e ve nts u p o n 
c o m pleti o n of e ver y st u d y s u bject. T he pri nci pal i n vesti gat or will e val uate t he fre q ue nc y a n d se verit y  of 
t he a d verse e ve nts a n d deter mi ne if m o dificati o ns t o t he pr ot oc ol or c o nse nt f or m are re q uire d.
Please n ote: F or a n y st u d y t hat ma y be c o nsi dere d hi g h ris k, t he I R B will be m ore  f oc use d o n t he safet y 
re q uire me nts f or t he st u d y a n d a D S M B will li kel y be re q uire d. 
d. F or m ulti-sit e st u di es f or w hic h  t h e Y al e PI s erv es as t h e l e a d i nv esti g at or: N/ A
i.
H o w will a dv ers e ev e nts a n d u n a ntici p at e d pr o bl e ms i nv olvi n g risks t o s u bj ects or ot h ers b e 
r e p ort e d, r evi e w e d a n d m a n a g e d ? Writ e h er e
ii.
W h at pr ovisi o ns ar e i n pl ac e f or m a n a g e m e nt of i nt eri m r es ults ? Writ e h er e
iii.
W h at will t h e m ulti-sit e pr oc ess b e f or pr ot oc ol m o dific ati o ns ? Writ e h er e
1 3. St atistic al C o nsi d er ati o ns:
St atistic al C o nsi d er ati o ns:  D escri b e t h e st atistic al a n alys es t h at s u p p ort t h e st u dy d esi g n. 
Visit 1 E u gl yc e mic H y p eri ns uli n e mic Cl a m p:  S a m pl e Siz e:  Pri or w or k ev al u ati n g i ns uli n s e nsitivit y i n 
y o ut h wit h T 1 D is li mit e d i n c o nsist e nc y i n r e p orti n g i ns uli n- m e di at e d gl uc os e dis p os al. T h us, f or 
s a m pl e siz e c alc ul ati o n, gl uc os e i nf usi o n r at e will b e utiliz e d as t his c alc ul ati o n is m or e c o nsist e nt 
acr oss st u di es a n d c a n pr o vi d e a g o o d esti m at e of gl uc os e dis p os al. A cli nic all y m e a ni n gf ul diff er e nc e 
w o ul d b e at l e ast 2 0 % r e d ucti o n i n m e a n gl uc os e dis p os al r at e fr o m l e a n t o o b es e. I n a d diti o n, w e 
ex p ect T 1 D l e a n y o u n g a d ults t o h a v e t h e hi g h est m e a n gl uc os e i nf usi o n r at e, r efl ecti n g t h e a ntici p at e d 
r es p o ns e i n T 1 D c hil dr e n n ot aff ect e d b y h or m o n al c h a n g es of p u b ert y ( 2). T h er ef or e, w e pr o p os e t o 
c o m p ar e t h e t hr e e m e a ns i n a s e q u e nti al m a n n er: o b es e vs. l e a n a d ol esc e nts wit h T 1 D, a n d l e a n 
a d ol esc e nts wit h T 1 D vs. l e a n y o u n g a d ults wit h T 1 D, t h us r e d uci n g t h e al p h a l ev el of 0. 0 5 b y ½.  
Usi n g p u blis h e d lit er at ur e ( 4 3, 4 4), w e will  n e e d 3 6 l e a n a n d 3 6 o b es e/ ov er w ei g ht p u b ert al a d ol esc e nts 
wit h T 1 D, t o h a v e 8 0 % at al p h a of 0. 0 2 5, t o d et ect a diff er e nc e b et w e e n gr o u p m e a ns of 1 3. 6 ( S D = 3) 
a n d 1 1. 5 m g/ k g l e a n b o d y m ass/ mi n ( S D = 3); a n d 3 6 l e a n y o u n g a d ults t o d et ect a mi ni m u m p erc e nt 
i ncr e as e i n gl uc os e i nf usi o n r at e i n t h e r a n g e of 1 5- 1 8 % fr o m t h at of l e a n p u b ert al a d ol esc e nts wit h 
T 1 D -  f or t h e r es p ecti v e s e q u e nti al gr o u p c o m p aris o ns. Of n ot e, t h e lit er at ur e s u g g ests t h at t h e act u al 
i ncr e as e f or t h e l att er is ar o u n d 3 0 % 2, t h er ef or e, w e s h o ul d b e s uffici e ntl y p o w er e d.
A n i nt eri m a n al ysis will b e c o n d uct e d w h e n w e r ecr uit 1 5 s u bj ects i n e ac h gr o u p. If si g nific a nt 
diff er e nc es will b e o bs er v e d at t h at ti m e, w e will r ec o nsi d er t h e s a m pl e siz e.
D at a A n al ysis A p pr o ac h:  T h e d e p art m e nt al bi ost atistici a n Dr. S h a b a n ov a, will g ui d e Dr. V a n N a m e i n 
a n al ysis.
• M e as ur es of I ns uli n S e nsiti vit y: C alc ul ati o ns will b e c o n d uct e d usi n g m et h o ds us e d b y Drs. C a pri o a n d 
T a m b orl a n e i n pr e vi o us w or k ( 4 1). E n d o g e n o us gl uc os e pr o d ucti o n a n d f asti n g i ns uli n l ev els will b e 
us e d t o c alc ul at e h e p atic i ns uli n r esist a nc e. Gl yc er ol t ur n ov er will b e utiliz e d t o ass ess a di p os e s p ecific 
i ns uli n s e nsiti vit y.   
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• St atistic al A n al ysis: D escri pti v e st atistics, s uc h as m e a n, st a n d ar d d evi ati o n, c o u nt, a n d p erc e nt, will 
b e us e d t o c h ar act eriz e t h e gr o u ps. C o nti n u o us v ari a bl es will b e c o m p ar e d a m o n g t h e t hr e e gr o u ps 
usi n g t h e Kr us k al- W allis t est or A n al ysis of V ari a nc e ( A N O V A) f or n ot N or m al a n d G a ussi a n distri b uti o ns 
r es p ecti v el y, f oll o w e d b y p air- wis e gr o u p c o m p aris o ns wit h eit h er t h e St u d e nt’s t-t est or t h e M a n n-
W hit n e y U t est, d e p e n di n g u p o n t h e n or m alit y i n t h e distri b uti o n al ass u m pti o ns of t h e v ari a bl es. 
C at e g oric al v ari a bl es will b e c o m p ar e d wit h t h e C hi-s q u ar e t est of t h e Fis h er’s Ex act t est.  S p e ar m a n 
C orr el ati o n will ex pl or e ass oci ati o ns of t h e f oll o wi n g ass ess m e nts wit h m e as ur es of i ns uli n s u p pr essi o n 
of h e p atic gl uc os e pr o d ucti o n a n d sti m ul ati o n of p eri p h er al gl uc os e u pt a k e.
• Gl yc e mic c o ntr ol ( H b A 1c, f asti n g gl uc os e)
• A d diti o n al m e as ur es of i ns uli n s e nsiti vit y ( e n d o g e n o us gl uc os e pr o d ucti o n, gl yc er ol t ur n ov er, gl uc os e 
oxi d ati o n, f at oxi d ati o n).
Ass oci ati o ns of t h es e ass ess m e nts wit h m e as ur es of i ns uli n s e nsitivit y will b e ex pl or e d f or all gr o u ps. 
U n a dj ust e d diff er e nc es i n t h e gr o u p m e a ns of pri m ar y a n d s ec o n d ar y o utc o m es of i nt er est b et w e e n 
l e a n a n d o b es e a d ol esc e nt s u bj ects, as w ell as b et w e e n l e a n y o u n g a d ults a n d l e a n a d ol esc e nt 
s u bj ects, will b e ex a mi n e d usi n g t h e St u d e nt’s t-t est or t h e M a n n- W hit n e y U t est f or v ari a bl es wit h 
G a ussi a n a n d n ot n or m al distri b uti o ns r es p ectiv el y. T h e i m p act of gr o u p, g e n d er, s ex h or m o n es, 
p u b ert al st a g e, a n d gr o wt h f act ors o n t h e o utc o m e m e as ur es will als o b e ex pl or e d usi n g m ultiv ari a bl e 
li n e ar r e gr essi o n m o d eli n g. F or t h e pri m ar y a dj ust e d a n al ysis, w e will tr e at gr o u p as a c at e g oric al 
v ari a bl e, a n d c o n d uct t w o p ost- h oc p air- wis e c o m p aris o ns of m e a ns at al p h a of 0. 0 2 5. F or t h e 
s ec o n d ar y a dj ust e d a n al ysis, w e will als o tr e at o ur t hr e e gr o u ps of s u bj ects as a n or di n al v ari a bl e, 
w h er e b y t h e l o w est l e v el will b e gi v e n t o t h e o b es e a d ol esc e nts, f oll o w e d b y t h e l e a n a d ol esc e nts, a n d 
t h e n l e a n y o u n g a d ults. T h e l att er a p pr o ac h will all o w us t o o bt ai n a li n e ar i ncr e as e i n t h e m e a n 
gl uc os e dis p os al r at e acr oss t h e t hr e e gr o u ps, t h us all o wi n g us t o us e a n al p h a l ev el of 0. 0 5. T h e 
o utc o m e v ari a bl e will b e n or m aliz e d, if n e e d e d, usi n g t h e n at ur al l o g f u ncti o n.
Vi sit 2: A b d o mi n al M RI:  S a m pl e Si z e: B a s e d o n m e a n h e p ati c li pi d c o nt e nt i n h e alt h y o v er w ei g ht/ o b e s e 
a n d l e a n c hil dr e n 1 0 , gr o u p s si z e s of 3 6 l e a n a n d 3 6 o b e s e a d ol e s c e nt s will a c hi e v e > 9 9 % p o w er at al p h a 
of 0. 0 5 t o d et e ct a diff er e n c e b et w e e n gr o u p m e a n s of 3. 5 % ( S D = 2) a n d 1. 5 % ( S D = 0. 5). E v e n if a f e w 
s u bj e ct s d e cli n e p arti ci p ati o n i n t hi s Ai m, w e will still h a v e 9 0 % p o w er at al p h a of 0. 0 5 t o d et e ct t h e 
pr oj e ct e d eff e ct si z e u si n g wit h a mi ni m u m of 1 2 s u bj e ct s p er gr o u p. 
D at a A n al y si s A p pr o a c h: 
T h e Pr ot o n D e n sit y F at Fr a cti o n ( P D F F) , a bi o m ar k er f or h e p ati c st e at o si s, will b e c al c ul at e d fr o m 
t h e li v er i m a g e s o bt ai n e d li v er P D F F p ar a m etri c m a p s 9 . A P D F F v al u e a b o v e 5. 5 % i s i n di c ati v e of f att y 
li v er 1 1 . 
 St ati sti c al A n al y si s: D e s cri pti v e st ati sti c s ( m e a n, st a n d ar d d e vi ati o n, c o u nt, a n d p er c e nt) will b e 
u s e d t o c h ar a ct eri z e t h e gr o u p s. C o nti n u o u s v ari a bl e s will b e c o m p ar e d b et w e e n t h e l e a n a n d o b e s e 
a d ol e s c e nt s u si n g eit h er t h e St u d e nt’ s t-t e st or t h e M a n n- W hit n e y U t e st. C at e g ori c al v ari a bl e s will b e 
c o m p ar e d wit h t h e C hi- s q u ar e t e st or t h e Fi s h er’ s E x a ct t e st.  A s s o ci ati o n s of t h e f oll o wi n g a s s e s s m e nt s 
wit h h e p ati c f at fr a cti o n will b e e x pl or e d t hr o u g h S p e ar m a n C orr el ati o n.
 B o d y c o m p o siti o n (f at %, f at m a s s, l e a n m a s s)
 A b d o mi n al f at di stri b uti o n ( vi s c er al a n d s u b c ut a n e o u s)
A dj u st e d a s s o ci ati o n s of t h e s e a s s e s s m e nt s wit h m e a s ur e s of i n s uli n s e n siti vit y i n di c e s o bt ai n e d i n Ai m 
1 will b e e x pl or e d f or b ot h gr o u p s, a s d e s cri b e d i n t h e a n al y si s pl a n f or Ai m 1.
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 1 6  of 2 6
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 1 8  of 2 6
3. 
S o urc e:
S o urc e:   I d e ntify t h e s o urc e of t he dr u g or bi ol o gic t o be  use d. T here is n o st u d y dr u g (treat me nt) f or t his 
pr ot oc ol. H o we ver, is ot o pes will be o btai ne d fr o m Ca m bri d ge Is ot o pes, Ca m bri d ge, M A), w hic h is r o uti nel y 
a u dite d i nter nall y b y its Q A de part me nt a n d e xter nall y b y c ust o mers, n otifie d b o dies, a n d re g ulat or y 
a ge ncies (e. g. F D A).  Is ot o pes will be st ore d i n t he I n vesti gati o nal P har mac y a n d will be pre pare d bef ore 
t he s u bjects u n der g o tests.
a) 
Is t h e dr u g pr ovi d e d fr e e of c h ar g e t o s u bj ects ? ☒Y E S 
Y E S 
☐N O
N O  
If y es, by w h o m ? St u dy f u n di n g
4.
St or a g e,
St or a g e,  Pr e p ar ati o n a n d Us e:
Pr e p ar ati o n a n d Us e:  D escri b e t h e m et h o d of st or a g e, pr e p ar ati o n, st a bility i nf or m ati o n, a n d f or 
p ar e nt er al pr o d ucts, m et h o d of st eriliz ati o n a n d m et h o d of t esti n g st erility a n d pyr o g e nicity.
 T he gl ycer ol a n d gl uc ose is ot o pes will be ke pt wit h Yale- Ne w Ha ve n H os pital I n vesti gati o nal Dr u g 
Ser vice, w hic h will kee p all d oc u me ntati o n. T he I D S will pre pare pre parati o ns of is ot o pes bef ore  
eac h st u d y a n d st ore it i n t he me d r o o m i n t he Y C CI. P yr o ge n a n d sterilit y are teste d a n d 
d oc u me nte d b y Ca m bri d ge Is ot o pes bef ore s hi p pi n g t o us.
C h eck a p plic a bl e I nv esti g ati o n al Dr u g S ervic e  utiliz e d:
C h eck a p plic a bl e I nv esti g ati o n al Dr u g S ervic e  utiliz e d:
    ☒  Y N H H I D S                                                        
  Y N H H I D S                                                        ☐  C M H C P h ar m acy                                           
  C M H C P h ar m acy                                           ☐ W est H av e n V A
 W est H av e n V A
    
    ☐  P E T C e nt er                                                      
  P E T C e nt er                                                      ☐    N o n e      
    
    N o n e      
    ☐  Ot h er: 
  Ot h er: 
N ot e:
N ot e:  If t h e Y N H H I DS ( or c o m p ar a bl e s ervic e at C M H C or W H V A) will n ot b e utiliz e d, ex pl ai n i n d et ail h o w t h e PI 
will ov ers e e t h es e as p ects of dr u g acc o u nt a bility, st or a g e, a n d pr e p ar ati o n .  
5.
Us e of Pl ac e b o: 
5.
Us e of Pl ac e b o: 
☒N ot a p plic a bl e t o t his r es e arc h pr oj ect
N ot a p plic a bl e t o t his r es e arc h pr oj ect
6.
C o nti n u ati o n of Dr u g T h er a py Aft er St u dy Cl os ur e   
C o nti n u ati o n of Dr u g T h er a py Aft er St u dy Cl os ur e   ☒N ot a p plic a bl e t o t his pr oj ect
 B.  D E VI C E S 
 
N ot a p plic a bl e t o t his pr oj ect
 B.  D E VI C E S 
 ☒N/ A
N/ A
S E C TI O N
E C TI O N  III: R
 III: RE C R UI T M E N T
E C R UI T M E N T /C O N S E N T A N D A S S E N T P R O C E D U R E S 
C O N S E N T A N D A S S E N T P R O C E D U R E S 
1. T ar g et e d E nr oll m e nt: Giv e t h e n u m b er of s u bj ects:  1 0 8
1. T ar g et e d E nr oll m e nt: Giv e t h e n u m b er of s u bj ects:  1 0 8
a.
T ar g et e d f or e nr oll m e nt at Y al e f or t his pr ot oc ol: 1 0 8
b.
If t his is a m ulti-sit e st u dy, giv e t h e t ot al n u m b er of s u bj ects t ar g et e d acr oss all sit es: N/ A
2.
I n dic at e r ecr uit m e nt m et h o ds b el o w.
2.
I n dic at e r ecr uit m e nt m et h o ds b el o w.   Att ac h c o pi es of a ny r ecr uit m e nt m at eri als t h at will b e us e d.
☐
Fly ers
☐ I nt er n et/ w e b p osti n gs
☐ R a di o
☐ P ost ers
☐ M ass e m ail s olicit ati o n
☐ T el e p h o n e
☐ L ett er
☐ D e p art m e nt al/ C e nt er w e bsit e
☐ T el evisi o n
☐ M e dic al r ec or d r evi e w * 
☐ D e p art m e nt al/ C e nt er r es e arc h b o ar ds
☐ N e ws p a p er
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 2 0  of 2 6
ii. If r e q u esti n g a w aiv er of si g n e d
si g n e d a ut h oriz ati o n, d escri b e w hy it w o ul d b e i m pr actic a bl e t o o bt ai n t h e 
s u bj ect’s si g n e d a ut h oriz ati o n f or us e/ discl os ur e of t his d at a: S o m e p ot e nti al s u bj e ct s m a y c all or 
e m ail aft er l e ar ni n g a b o ut t h e tri al fr o m Cli ni c altri al s. g o v, or s u p p ort gr o u p s. W e c a n a s k 
s o m e b a si c s cr e e ni n g q u e sti o n s a b o ut a g e, d at e of di a g n o si s et c. b ef or e s c h e d uli n g a n 
e nr oll m e nt vi sit t o d o f urt h er s cr e e ni n g t o d et er mi n e st u d y eli gi bilit y.
T h e i nv esti g at or ass ur es t h at t h e  pr ot ect e d h e alt h i nf or m ati o n f or w hic h a W aiv er of A ut h oriz ati o n h as b e e n 
r e q u est e d will n ot b e r e us e d or discl os e d t o a ny p ers o n or e ntity ot h er t h a n t h os e list e d i n t his a p plic ati o n, exc e pt 
T h e i nv esti g at or ass ur es t h at t h e  pr ot ect e d h e alt h i nf or m ati o n f or w hic h a W aiv er of A ut h oriz ati o n h as b e e n 
r e q u est e d will n ot b e r e us e d or discl os e d t o a ny p ers o n or e ntity ot h er t h a n t h os e list e d i n t his a p plic ati o n, exc e pt 
as r e q uir e d by l a w, f or a ut h oriz e d ov ersi g ht of t his r es e arc h st u dy, or as s p ecific ally a p pr ov e d f or us e i n a n ot h er 
st u dy by a n I R B.
as r e q uir e d by l a w, f or a ut h oriz e d ov ersi g ht of t his r es e arc h st u dy, or as s p ecific ally a p pr ov e d f or us e i n a n ot h er 
st u dy by a n I R B.
R es e arc h ers ar e r e mi n d e d t h at u n a ut h oriz e d discl os ur es of P HI t o i n divi d u als o utsi d e of t h e Y al e HI P A A- C ov er e d 
e ntity m ust b e acc o u nt e d f or i n t h e “ acc o u nti n g f or discl os ur es l o g”, by s u bj ect n a m e, p ur p os e, d at e, r eci pi e nts, 
a n d a d escri pti o n of i nf or m ati o n pr ovi d e d.  L o gs ar e t o b e f or w ar d e d t o t h e D e p uty HI P A A Priv acy Offic er.
6.
Pr oc ess of C o ns e nt/ Ass e nt:
6.
Pr oc ess of C o ns e nt/ Ass e nt:  D escri b e t h e s etti n g a n d c o n diti o ns u n d er w hic h c o ns e nt/ ass e nt will b e o bt ai n e d, 
i ncl u di n g p ar e nt al p er missi o n or s urr o g at e p er missi o n a n d t h e st e ps t ak e n t o e ns ur e s u bj ects’ i n d e p e n d e nt 
d ecisi o n- m aki n g. 
P ot e nti al p arti ci p a nt s w h o e x pr e s s i nt er e st  i n t h e st u d y will b e gi v e n a c o p y of t h e C o n s e nt 
F or m/ P ar e nt P er mi s si o n/ A s s e nt F or m, a s k e d t o r e vi e w, a n d t h e n gi v e n t h e o p p ort u nit y t o di s c u s s 
t h e st u d y wit h t h e i n v e sti g at or s i n d et ail. T h e i n v e sti g at or will c o m pl y wit h all a p pli c a bl e r e g ul at or y 
a n d l e g al r e q uir e m e nt s, I C H G C P g ui d eli n e s a n d t h e D e cl ar ati o n of H el si n ki i n o bt ai ni n g a n d 
d o c u m e nti n g t h e i nf or m e d c o n s e nt. It will of c o ur s e b e str e s s e d t h at p arti ci p ati o n i s v ol u nt ar y, a n d 
n o n- p arti ci p ati o n will n ot aff e ct c o nti n ui n g c ar e at t h e Y al e C hil dr e n’ s Di a b et e s Pr o gr a m. T h e 
p arti ci p a nt will h a v e t h e ri g ht t o r ef u s e t o p arti ci p at e or t o wit h dr a w at a n y ti m e .
7.
Ev al u ati o n of S u bj ect(s) C a p acity t o Pr ovi d e I nf or m e d C o ns e nt/ Ass e nt:
7.
Ev al u ati o n of S u bj ect(s) C a p acity t o Pr ovi d e I nf or m e d C o ns e nt/ Ass e nt: I n dic at e h o w t h e p ers o n n el o bt ai ni n g 
c o ns e nt will ass ess t h e p ot e nti al s u bj ect’s a bility a n d c a p acity t o c o ns e nt t o t h e r es e arc h b ei n g pr o p os e d. 
S u bj e ct s will h a v e a f a c e-t o-f a c e m e eti n g wit h a n I n v e sti g at or a n d/ or St u d y P er s o n n el t o a d dr e s s 
q u e sti o n s a b o ut t h e st u d y r ati o n al e, pr o c e d ur e s, ri s k s a n d b e n efit s. I n or d er t o i d e ntif y a n d cl arif y 
a n y mi s c o n c e pti o n s, s u bj e ct s will b e e n c o ur a g e d t o d e s cri b e t h e r e s e ar c h pr o c e d ur e s a n d t h eir 
a s s o ci at e d ri s k s i n t h eir o w n w or d s, f oll o w e d b y c orr e cti o n of a n y err or s b y a n I n v e sti g at or or St u d y 
P er s o n n el.
8.
N o n- E n glis h S p e aki n g S u bj ects:
8.
N o n- E n glis h S p e aki n g S u bj ects:  Ex pl ai n pr ovisi o ns i n pl ac e t o e ns ur e c o m pr e h e nsi o n f or r es e arc h i nv olvi n g 
n o n- E n glis h s p e aki n g s u bj ects. If e nr oll m e nt of t h es e s u bj ects is a ntici p at e d, tr a nsl at e d c o pi es of all c o ns e nt 
m at eri als m ust b e s u b mitt e d f or a p pr ov al pri or t o us e. 
N/ A
As a li mit e d alt er n ativ e t o t h e a b ov e r e q uir e m e nt, will y o u us e t h e s h ort f or m * f or c o ns e nti n g pr oc ess if y o u 
u n ex p ect e dly e nc o u nt er a n o n- E n glis h s p e aki n g i n divi d u al i nt er est e d i n st u dy p artici p ati o n a n d t h e tr a nsl ati o n of 
t h e l o n g f or m is n ot p ossi bl e pri or t o i nt e n d e d e nr oll m e nt ?  Y E S ☐  N O ☒
N ot e *
N ot e *  If m or e t h a n 2 st u dy p artici p a nts ar e e nr oll e d usi n g a s h ort f or m tr a nsl at e d i nt o t h e s a m e l a n g u a g e, t h e n 
t h e f ull c o ns e nt f or m s h o ul d b e tr a nsl at e d i nt o t h at l a n g u a g e f or us e t h e n ext ti m e a s u bj ect s p e aki n g t h at 
l a n g u a g e is t o b e e nr oll e d.
S ev er al tr a nsl at e d s h ort f or m t e m pl at es  ar e av ail a bl e o n t h e H R P P w e bsit e (y al e. e d u/ hr p p) a n d tr a nsl at e d HI P A A 
R es e arc h A ut h oriz ati o n F or ms ar e av ail a bl e o n t h e HI P A A w e bsit e ( hi p a a.y al e. e d u). If t h e tr a nsl ati o n of t h e s h ort 
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 2 1  of 2 6
f or m is n ot av ail a bl e o n o ur w e bsit e, t h e n t h e tr a nsl at e d s h ort f or m n e e ds t o b e s u b mitt e d t o t h e I R B offic e f or 
a p pr ov al vi a m o dific ati o n pri or t o e nr olli n g t h e s u bj ect.   Pl e as e r evi e w t h e g ui d a nc e a n d pr es e nt ati o n o n us e of 
t h e s h ort f or m av ail a bl e o n t h e H R P P w e bsit e.
Pl e as e r evi e w t h e g ui d a nc e a n d pr es e nt ati o n o n us e of 
t h e s h ort f or m av ail a bl e o n t h e H R P P w e bsit e.
If usi n g a s h ort f or m wit h o ut a tr a nsl at e d HI P A A R es e arc h A ut h oriz ati o n F or m, pl e as e r e q u est a HI P A A w aiv er i n 
t h e s ecti o n a b ov e. 
If usi n g a s h ort f or m wit h o ut a tr a nsl at e d HI P A A R es e arc h A ut h oriz ati o n F or m, pl e as e r e q u est a HI P A A w aiv er i n 
t h e s ecti o n a b ov e. 
9. 
C o ns e nt W aiv er: I n c ert ai n circ u mst a nc es, t h e HI C m ay gr a nt a w aiv er of si g n e d c o ns e nt, or a f ull w aiv er 
of c o ns e nt, d e p e n di n g o n t h e st u dy. 
9. 
C o ns e nt W aiv er: I n c ert ai n circ u mst a nc es, t h e HI C m ay gr a nt a w aiv er of si g n e d c o ns e nt, or a f ull w aiv er 
of c o ns e nt, d e p e n di n g o n t h e st u dy. If y o u will r e q u est eit h er a w aiv er of c o ns e nt, or a w aiv er of si g n e d c o ns e nt 
f or t his st u dy, c o m pl et e t h e a p pr o pri at e s ecti o n b el o w.  
☐N ot R e q u esti n g a ny c o ns e nt w aiv ers 
N ot R e q u esti n g a ny c o ns e nt w aiv ers 
☐R e q u esti n g  a w aiv er of si g n e d c o ns e nt:
R e q u esti n g  a w aiv er of si g n e d c o ns e nt:
☐ R ecr uit m e nt/ Scr e e ni n g o nly 
 R ecr uit m e nt/ Scr e e ni n g o nly (if f or r ecr uit m e nt, t h e q u esti o ns i n t h e b ox b el o w will a p ply t o 
r ecr uit m e nt activiti es o nly)
☐ E ntir e St u dy (
 E ntir e St u dy (N ot e t h at a n i nf or m ati o n  s h e et m ay b e r e q uir e d.)
 F or a w aiv er of si g n e d c o ns e nt, a d dr ess t h e f oll o wi n g:
 F or a w aiv er of si g n e d c o ns e nt, a d dr ess t h e f oll o wi n g:
W o ul d t h e si g n e d c o ns e nt f or m b e t h e o nly r ec or d li nki n g t h e s u bj ect a n d t h e r es e arc h ?  Y E S 
 Y E S ☐  N O 
  N O ☐ 
D o es a br e ac h of c o nfi d e nti ality c o nstit ut e t h e pri nci p al risk t o s u bj ects ? Y E S 
Y E S ☐  N O 
  N O ☐
 
O R
O R
D o es t h e r es e arc h p os e gr e at er t h a n mi ni m al risk ? Y E S 
Y E S ☐    N O
    N O☐ 
D o es t h e r es e arc h i ncl u d e a ny activiti es t h at w o ul d r e q uir e si g n e d c o ns e nt i n a n o n-r es e arc h c o nt ext ? Y E S 
Y E S ☐   
N O 
   
N O ☐
 ☒ R e q u esti n g a w aiv er of c o ns e nt:
 R e q u esti n g a w aiv er of c o ns e nt:
☒ R ecr uit m e nt/ Scr e e ni n g o nly 
 R ecr uit m e nt/ Scr e e ni n g o nly (if f or r ecr uit m e nt, t h e q u esti o ns i n t h e b ox b el o w will a p ply t o 
r ecr uit m e nt activiti es o nly)
☐ E ntir e St u dy 
 E ntir e St u dy 
 
F or a f ull w aiv er of c o ns e nt, pl e as e a d dr ess all of t h e f oll o wi n g:
F or a f ull w aiv er of c o ns e nt, pl e as e a d dr ess all of t h e f oll o wi n g:

D o es t h e r es e arc h p os e  gr e at er t h a n mi ni m al risk t o s u bj ects ?  
☐ Y es
 Y es If y o u a ns w er e d y es, st o p. A w aiv er c a n n ot b e gr a nt e d.
If y o u a ns w er e d y es, st o p. A w aiv er c a n n ot b e gr a nt e d.  
☒ N o
 N o

Will t h e w aiv er a dv ers ely aff ect s u bj ects’ ri g hts a n d w elf ar e ? Y E S 
Y E S ☐    N O
    N O☒

W hy w o ul d t h e r es e arc h b e i m pr actic a bl e t o c o n d uct wit h o ut t h e w aiv er ? M e di c al r e c or d r e vi e w m u st 
b e c o n d u ct e d t o d et er mi n e w h o i s eli gi bl e f or p ot e nti al p arti ci p ati o n

W h er e a p pr o pri at e, h o w will p erti n e nt i nf or m ati o n b e r et ur n e d t o, or s h ar e d wit h s u bj ects at a l at er d at e ? 
Writ e h er e
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
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S E C TI O N
E C TI O N  I V: P
 I V: PR O T E C TI O N O F 
R O T E C TI O N O F R E S E A R C H 
E S E A R C H S U BJ E C T S
U BJ E C T S
    C o nfi d e nti ality & S ec urity of D at a:
C o nfi d e nti ality & S ec urity of D at a:
1.
W h at pr ot ect e d h e alt h i nf or m ati o n ( m e dic al i nf or m ati o n al o n g wit h t h e HI P A A i d e ntifi ers) a b o ut s u bj ects will 
b e c oll ect e d a n d us e d  f or t h e r es e arc h ?   Pr otecte d healt h i nf or mati o n t hat will be c ollecte d a n d use d f or t he 
researc h will i ncl u de t he researc h st u d y rec or ds, me dical rec or ds, bl o o d s u gars, res ults of meta b olic testi n g, 
ser vices pr o vi de d i n c o n necti o n wit h t his st u d y, t he e ntire researc h rec or d a n d a n y me dical rec or ds hel d b y Yale 
Ne w Ha ve n H os pital a n d t he Yale Sc h o ol of Me dici ne, me dical hist or y of dia betes a n d ot her c o n diti o ns t hat 
ma y affect eli gi bilit y f or st u d y partici pati o n.
H o w will t h e r es e arc h d at a b e c oll ect e d, r ec or d e d a n d st or e d ? S u bj e ct s will b e a s si g n e d a n i d e ntifi er t h at will 
b e u s e d i n st e a d of t h eir n a m e.
Cli ni c al r e s e ar c h f or m s will b e cr e at e d t o all o w f or c oll e cti o n of d at a fr o m s c h o ol s a n d f or st u d y vi sit s. O ur 
st u d y t e a m i s v er y e x p eri e n c e d i n c oll e cti n g d at a a n d m ai nt ai ni n g st u d y d at a b a s e s, a s w e r e g ul arl y 
c o n d u ct cli ni c al tri al s. St u d y r e c or d s will b e m ai nt ai n e d i n Mi cr o s oft E x c el d at a b a s e s, o n u ni v er sit y 
c o m p ut er s w hi c h ar e e n cr y pt e d a n d s er v e d b y a r e g ul ar b a c k u p s er vi c e. All st u d y st aff, offi c e, a n d 
c o m p ut er s ar e HI P P A c o m pli a nt.
2.
H o w will t h e di git al d at a b e st or e d ? ☐C D  ☐D V D  ☐Fl as h Driv e  ☐P ort a bl e H ar d  Driv e   ☒S ec ur e d S erv er  
☐L a pt o p C o m p ut er  ☐D eskt o p C o m p ut er  ☐Ot h er
3.
W h at m et h o ds a n d pr oc e d ur es will b e us e d t o s af e g u ar d t h e c o nfi d e nti ality a n d s ec urity of  t h e i d e ntifi a bl e 
st u dy d at a a n d t h e st or a g e m e di a i n dic at e d a b ov e d uri n g a n d aft er t h e s u bj ect’s p artici p ati o n i n t h e st u dy ? T h e 
li st of n a m e s of t h e st u d y s u bj e ct s a n d t h eir a s si g n e d c o d e n u m b er s will b e k e pt i n a l o c k e d fil e 
c a bi n et or p a s s w or d- pr ot e ct e d c o m p ut er fil e b y st u d y t e a m m e m b er s.
I n di vi d u al p ati e nt m e di c al i nf or m ati o n o bt ai n e d a s a r e s ult of t hi s st u d y i s c o n si d er e d c o nfi d e nti al a n d 
di s cl o s ur e t o t hir d p arti e s ot h er t h a n t h o s e n ot e d b el o w i s pr o hi bit e d.  S u c h m e di c al i nf or m ati o n m a y 
b e gi v e n t o t h e p ati e nt’ s p er s o n al p h y si ci a n or t o ot h er a p pr o pri at e m e di c al p er s o n n el r e s p o n si bl e f or 
t h e p ati e nt’ s w elf ar e. 
All i n di vi d u al s i n v ol v e d i n t h e c o n d u ct of t hi s st u d y will b e tr ai n e d o n HI P A A pri v a c y r e g ul ati o n s a n d 
will r e c ei v e h u m a n s u bj e ct pr ot e cti o n tr ai ni n g. T h e pri n ci p al i n v e sti g at or will p eri o di c all y m o nit or t h e 
m et h o d s a n d pr o c e d ur e s d e s cri b e d h er ei n t o e n s ur e pr o p er u s e a n d t h at c o nti n u e d pr ot e cti o n s ar e 
i n pl a c e a n d b ei n g f oll o w e d.
All p ort a bl e d evic es m ust c o nt ai n e ncry pti o n s oft w ar e, p er U niv ersity P olicy 5 1 0 0.  If t h er e is a t ec h nic al r e as o n a 
d evic e c a n n ot b e e ncry pt e d pl e as e s u b mit a n exc e pti o n r e q u est t o t h e I nf or m ati o n S ec urity, P olicy a n d C o m pli a nc e 
Offic e by clicki n g o n url htt p://its.y al e. e d u/ e grc or e m ail it.c o m pli a nc e @y al e. e d u
4.
W h at will b e d o n e wit h t h e d at a w h e n t h e r es e arc h is c o m pl et e d ? Ar e t h er e pl a ns t o d estr oy t h e i d e ntifi a bl e 
d at a ? If y es, d escri b e h o w, by w h o m a n d w h e n i d e ntifi ers will b e d estr oy e d. If n o, d escri b e h o w t h e d at a a n d/ or 
i d e ntifi ers will b e s ec ur e d. . It i s li k el y t h at d at a fr o m t hi s st u d y will b e p u bli s h e d i n s ci e ntifi c a n d m e di c al 
j o ur n al s a n d pr e s e nt e d at s ci e ntifi c a n d m e di c al c o nf er e n c e s. I n all s u c h c a s e s, pr oj e ct d at a will b e 
pr e s e nt e d i n s u c h a w a y t h at n o p arti ci p a nt c o ul d p o s si bl y b e i d e ntifi e d. D at a will b e d e-i d e ntifi e d at 
e n d of st u d y pri or t o st u d y t er mi n ati o n.
5.
If a p pr o pri at e, h as a C ertific at e of C o nfi d e nti ality b e e n o bt ai n e d ? N/ A
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
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S E C TI O N
E C TI O N  V: P
 V: PO T E N TI AL B E N E FI T S
O T E N TI AL B E N E FI T S
P ot e nti al B e n efits:
P ot e nti al B e n efits:  I d e ntify a ny b e n efits t h at m ay b e r e as o n a bly ex p ect e d t o r es ult fr o m t h e r es e arc h, eit h er t o 
t h e s u bj ect(s) or t o s oci ety at l ar g e. ( P ay m e nt of s u bj ects is n ot c o nsi d er e d a b e n efit i n t his c o nt ext of t h e risk 
b e n efit ass ess m e nt.) 
Ai m s 1 a n d 2 f o c u s o n c h ar a ct eri z ati o n of eff e ct s of o b e sit y a n d p u b ert y o n m et a b oli s m i n y o ut h wit h 
T 1 D a n d d o n ot  h a v e dir e ct s h ort-t er m b e n efit s t o t h e p arti ci p a nt s. 
L o n g-t er m b e n efit s of t hi s r e s e ar c h ar e a g e n er ali z a bl e u n d er st a n di n g of t h e c h a n g e s of i n s uli n 
r e si st a n c e r el at e d t o o b e sit y a n d p u b ert y i n y o ut h wit h T 1 D, w hi c h will h el p t o i nf or m f ut ur e tr e at m e nt 
str at e gi e s. 
         S
         SE C TI O N
E C TI O N  VI: R
 VI: RE S E A R C H 
E S E A R C H A L T E R N A TI V E S A N D 
L T E R N A TI V E S A N D E C O N O MI C 
C O N O MI C C O N SI D E R A TI O N S
O N SI D E R A TI O N S
1.
Alt er n ativ es:
Alt er n ativ es:  W h at ot h er alt er n ativ es ar e av ail a bl e t o t h e st u dy s u bj ects o utsi d e of t h e r es e arc h ? 
T h e alt er n ati v e t o p arti ci p ati n g i n t hi s st u d y i s n o n- p arti ci p ati o n. S u bj e ct s w h o c h o o s e n ot t o 
p arti ci p at e m a y c o nti n u e t h eir n or m al c ar e i n t h e Y al e P e di atri c Di a b et e s Pr o gr a m. T h er e ar e n o 
ri s k s of n o n- p arti ci p ati o n.
2.
P ay m e nts f or P artici p ati o n ( Ec o n o mic C o nsi d er ati o ns):
P ay m e nts f or P artici p ati o n ( Ec o n o mic C o nsi d er ati o ns):  D escri b e a ny p ay m e nts t h at will b e m a d e t o s u bj ects, 
t h e a m o u nt a n d sc h e d ul e of p ay m e nts, a n d t h e c o n diti o ns f or r ec eivi n g t his c o m p e ns ati o n.
P arti ci p a nt s will r e c ei v e $ 2 0 0 f or a n o v er ni g ht h o s pit al st a y a n d c o m pl eti o n of a n i n s uli n cl a m p a n d 
D E X A s c a n, $ 7 5 f or c o m pl eti o n of M RI. C o m p e n s ati o n will b e di stri b ut e d vi a a r el o a d a bl e B a n k of 
A m eri c a c ar d p er u ni v er sit y p oli c y.
3.
C osts f or P artici p ati o n ( Ec o n o mic C o nsi d er ati o ns):
C osts f or P artici p ati o n ( Ec o n o mic C o nsi d er ati o ns):  Cl e arly d escri b e t h e s u bj ect’s c osts ass oci at e d wit h 
p artici p ati o n i n t h e r es e arc h, a n d t h e i nt erv e nti o ns or pr oc e d ur es of t h e st u dy t h at will b e pr ovi d e d at n o c ost 
t o s u bj ects. 
T h e st u d y will b e p a yi n g f or all of t h e c o st s r el at e d t o t h e st u d y vi sit s.  
4.
I n C as e of I nj ury:
I n C as e of I nj ury: T his s ecti o n is r e q uir e d f or a ny r es e arc h i nv olvi n g m or e t h a n mi ni m al risk, a n d f or mi ni m al 
risk r es e arc h t h at pr es e nts t h e p ot e nti al f or p hysic al h ar m ( e. g., r es e arc h i nv olvi n g bl o o d dr a ws).
a.
Will m e dic al tr e at m e nt b e av ail a bl e if r es e arc h-r el at e d i nj ury occ urs ? Y es
b.
W h er e a n d fr o m w h o m m ay tr e at m e nt b e o bt ai n e d ? Fr o m t h e r e s e ar c h st aff or Y N H H if 
n e c e s s ar y
c.
Ar e t h er e a ny li mits t o t h e tr e at m e nt b ei n g pr ovi d e d ? I nj uri e s c a u s e d dir e ctl y b y p arti ci p ati o n 
i n t h e st u d y. T h er e will b e n o p a y m e nt f or l o st w a g e s a n d/ or dir e ct or i n dir e ct l o s s e s.
a.
W h o will p ay f or t his tr e at m e nt ? S u bj e ct s will b e r e s p o n si bl e f or t h e c o st s of s u c h m e di c al 
c ar e t h at i s n ot c o v er e d b y t h eir o w n h e alt h i n s ur a n c e.
d.
H o w will t h e m e dic al tr e at m e nt b e acc ess e d by s u bj ects ? B y n otif yi n g R e s e ar c h T e a m  
m e m b er s
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
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I M P O R T A N T
I M P O R T A N T R E MI N D E R S
R E MI N D E R S
Will t his st u dy h av e a bill a bl e s ervic e ?  Y es 
Y es ☐  
 N o
  
 N o☒
A bill a bl e s ervic e is d efi n e d as a ny s ervic e r e n d er e d t o a st u dy s u bj ect t h at, if h e/s h e w as n ot o n a st u dy, w o ul d 
n or m ally g e n er at e a bill  fr o m eit h er Y al e- N e w H av e n H os pit al or Y al e M e dic al Gr o u p t o t h e p ati e nt or t h e p ati e nt’s 
i ns ur er. T h e s ervic e m ay or m ay n ot b e p erf or m e d by t h e r es e arc h st aff o n y o ur st u dy, b ut m ay b e pr ovi d e d by 
pr of essi o n als wit hi n eit h er Y al e- N e w H av e n H os pit al or Y al e M e dic al Gr o u p ( ex a m pl es i ncl u d e x-r ays, M RIs, C T 
sc a ns, s p eci m e ns s e nt t o c e ntr al l a bs, or s p eci m e ns s e nt t o p at h ol o gy). N ot es: 1. T h er e is n o disti ncti o n m a d e 
w h et h er t h e s ervic e is p ai d f or by t h e s u bj ect or t h eir i ns ur a nc e (St a n d ar d of C ar e) or by t h e st u dy’s f u n di n g 
m ec h a nis m ( R es e arc h S p o ns or e d). 2. T his g e n er ally i ncl u d es n e w s ervic es or or d ers pl ac e d i n E PI C f or r es e arc h 
s u bj ects. 
If a ns w er e d, “y es”, t his st u dy will n e e d t o b e s et u p i n O n C or e, Y al e’s cli nic al r es e arc h m a n a g e m e nt syst e m, f or 
E pic t o a p pr o pri at ely r o ut e r es e arc h r el at e d c h ar g es. Pl e as e c o nt act 
If a ns w er e d, “y es”, t his st u dy will n e e d t o b e s et u p i n O n C or e, Y al e’s cli nic al r es e arc h m a n a g e m e nt syst e m, f or 
E pic t o a p pr o pri at ely r o ut e r es e arc h r el at e d c h ar g es. Pl e as e c o nt act o nc or e.s u p p ort @y al e. e d u
o nc or e.s u p p ort @y al e. e d u
Ar e t h er e a ny pr oc e d ur es i nv olv e d i n t his pr ot oc ol t h at will b e p erf or m e d at Y N H H or o n e of its affili at e d e ntiti es ?  
Y es 
Y es ☒  N o 
  N o ☐ 
If Y es, pl e as e a ns w er q u esti o ns a t hr o u g h c a n d n ot e i nstr ucti o ns b el o w.  
If Y es, pl e as e a ns w er q u esti o ns a t hr o u g h c a n d n ot e i nstr ucti o ns b el o w.  
a. D o es y o ur Y N H H privil e g e d eli n e ati o n c urr e ntly i ncl u d e t h e s p ecific pr oc e d ur e
s p ecific pr oc e d ur e t h at y o u will p erf or m ? Y es 
Y es ☒  N o 
  N o 
☐
b. Will y o u b e usi n g a ny n e w e q ui p m e nt or e q ui p m e nt t h at y o u h av e n ot us e d i n t h e p ast f or t his pr oc e d ur e ? Y es 
Y es 
☐  N o 
  N o ☒
c. Will a n ov el a p pr o ac h usi n g existi n g e q ui p m e nt b e a p pli e d ? Y es 
Y es ☐  N o 
  N o ☒
 
If y o u a ns w er e d “ n o” t o q u esti o n 4 a, or "y es" t o q u esti o n 4 b or c, pl e as e c o nt act t h e Y N H H D e p art m e nt of 
P hysici a n S ervic es ( 6 8 8- 2 6 1 5) f or pri or a p pr ov al b ef or e c o m m e nci n g wit h y o ur r es e arc h pr ot oc ol.
I M P O R T A N T R E MI N D E R A B O U T R E S E A R C H A T Y N H H 
I M P O R T A N T R E MI N D E R A B O U T R E S E A R C H A T Y N H H 
Pl e as e n ot e t h at if t his pr ot oc ol i ncl u d es Y al e- N e w H av e n H os pit al p ati e nts, i ncl u di n g p ati e nts at t h e H R U, t h e 
Pri nci p al I nv esti g at or a n d a ny c o-i nv esti g at ors w h o ar e p hysici a ns or mi d-l ev el pr actiti o n ers (i ncl u d es P As, A P R Ns, 
psyc h ol o gists a n d s p e ec h p at h ol o gists) w h o m ay h av e dir ect p ati e nt c o nt act wit h p ati e nts o n Y N H H pr e mis es 
m ust h av e m e dic al st aff a p p oi nt m e nt a n d a p pr o pri at e cli nic al privil e g es at Y N H H. If y o u ar e u nc ert ai n w h et h er 
t h e st u dy p ers o n n el m e et t h e crit eri a, pl e as e t el e p h o n e t h e P hysici a n S ervic es D e p art m e nt at 2 0 3- 6 8 8- 2 6 1 5. By 
s u b mitti n g t his pr ot oc ol as a PI, y o u att est t h at y o u a n d a ny c o-i nv esti g at or w h o m ay h av e p ati e nt c o nt act h as a 
m e dic al st aff a p p oi nt m e nt a n d a p pr o pri at e cli nic al privil e g es at Y N H H.
 By 
s u b mitti n g t his pr ot oc ol as a PI, y o u att est t h at y o u a n d a ny c o-i nv esti g at or w h o m ay h av e p ati e nt c o nt act h as a 
m e dic al st aff a p p oi nt m e nt a n d a p pr o pri at e cli nic al privil e g es at Y N H H.
Refere nces
1.  
A miel S A, Ca pri o S, S her wi n R S, Ple we G, Ha y m o n d M W, Ta m b orla ne W V. I ns uli n resista nce 
of p u bert y: a defect restricte d t o peri p heral gl uc ose meta b olis m. T he J o ur n al of cli nic al 
e n d ocri n ol o gy a n d met a b olis m. 1 9 9 1; 7 2( 2): 2 7 7- 2 8 2.
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 9/ 1 4/ 2 0 1 8 V A LI D T H R O U G H 8/ 2 1/ 2 0 1 9
HI C # 2 0 0 0 0 2 3 1 4 9
Pa ge 2 6  of 2 6
2.  
A miel S A, S her wi n R S, Si m o ns o n D C, La urita n o A A, Ta m b orla ne W V. I m paire d i ns uli n acti o n 
i n p u bert y. A c o ntri b uti n g fact or t o p o or gl yce mic c o ntr ol i n a d olesce nts wit h dia betes. T he Ne w  
E n gl a n d j o ur n al of me dici ne. 1 9 8 6; 3 1 5( 4): 2 1 5- 2 1 9.
3.  
D' A da m o E, Cali A M, Weiss R, et al. Ce ntral r ole of fatt y li ver i n t he pat h o ge nesis of i ns uli n 
resista nce i n o bese a d olesce nts. Di a betes C are. 2 0 1 0; 3 3( 8): 1 8 1 7- 1 8 2 2.
4.  
Gia n ni ni C, Weiss R, Cali A, et al. E vi de nce f or earl y defects i n i ns uli n se nsiti vit y a n d secreti o n 
bef ore t he o nset of  gl uc ose d ysre g ulati o n i n o bese y o ut hs: a l o n git u di nal st u d y. Di a betes. 
2 0 1 2; 6 1( 3): 6 0 6- 6 1 4.
5.  
Weiss R, D uf o ur S, Ta ksali S E, et al. Pre dia betes i n o bese y o ut h: a s y n dr o me of i m paire d 
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