Clinical trial NCT02865122
Conditions: Short Bowel Syndrome
Sponsor: Elgan Pharma Ltd.
Start date: 2017-03-20; Completion date: 2018-03-22
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study is to evaluate the efficacy and safety of NTRA-9620 compared with placebo in pediatric subjects (aged 28 weeks postmenstrual age to 52 weeks old) with SBS following surgical resection

Detailed description:

Arms: arm 1: NTRA-9620 Dose 1 To be dosed orally for 24 weeks, 4 times/day arm 2: NTRA-9620 Dose 2 To be dosed orally for 24 weeks, 4 times/day arm 3: Placebo To be dosed orally for 24 weeks, 4 times/day
Interventions: intervention 1: NTRA-9620 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral daily dose intervention 2: Oral daily dose

Protocol documents:
Prot_SAP_001.pdf: 
 
1 3 W a di El H a dj , N az ar et h, Isr a el  P h o n e + 9 7 2- 4- 6 0 9 8 6 0 0   F a x + 9 7 2 - 4-6 5 6 4 1 2 9  
 
 
P R O T O C O L N U M B E R GI F T -0 2  
 
 
 A M U L TI -C E N T E R, R A N D O MI Z E D D O U B L E -B LI N D, T H R E E -A R M, 
P A R A L L E L -G R O U P T RI A L T O A S S E S S T H E E F FI C A C Y A N D 
S A F E T Y O F N T R A -9 6 2 0 I N I N F A N T S WI T H S H O R T B O W E L 
S Y N D R O M E ( S B S) F O L L O WI N G S U R GI C A L R E S E C TI O N  
 
1 0 J A N U A R Y 2 0 1 7  
 
N C T 0 2 8 6 5 1 2 2  
 
 
 


 
 
I N V E S TI G A TI O N A L N E W D R U G P R O T O C O L 
N T R A - 9 6 2 0 
(I N S U LI N F O R O R A L A DMI NI S T R A TI O N)  
 
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A M U L TI -C E N T E R, R A N D O MI Z E D D O U B L E -B LI N D,  T H R E E-A R M, 
P A R A L L E L -G R O U P T RI A L  T O A S S E S S T H E E F F I C A C Y A N D S A F E T Y 
O F N T R A -9 6 2 0 I N I N F A N T S WI T H S H O R T B O W E L  S Y N D R O M E ( S B S) 
F O L L O WI N G S U R GI C A L R E S E C TI O N 
 
S P O N S O R:  
N U T RI NI A L T D.  
6 H A- K HI L A Z O N S T R E E T , 
R A M A T - G A N 5 2 5 2 2 7 0, IS R A E L  
 
C o nfi de ntialit y State me nt  
T his d oc u me nt is a c o nfi de ntial c o m m u nicati o n of N utri nia Lt d.  Acce pta n ce of t his d oc u me nt 
c o nstit utes a gr ee me nt b y t he reci pie nt t hat n o u n p u blis he d i nf or mati o n c o ntai ne d herei n will be 
p u blis he d or discl ose d wit h o ut pri or writte n a p pr o val, wit h t he e x ce pti o n of discl os ure t o t he 
a p pr o priate I nstit uti o nal Re vie w B o ar d/I n de p e n de nt Et hics C o m mittee a n d/ or Re g ul at or y 
A ut h orit y u n der t he c o n diti o n t hat c o nfi de ntialit y is mai ntai ne d.


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T his pr ot oc ol has bee n r e vie we d a n d a p pr o ve d b y N utri nia, Lt d.  B y m y si g nat ure, I 
a p pr o ve t his d oc u me nt. 
 
 
 
 
 
 
 
 
 
 
Date  
 
 
 
  
 
 
 
 
 
 
 
 
Date  
 
 
 
  
 
 
 
 
 
 
Me dical M o nit or  
Sari na Ta ni m ot o, M D, P h D, M B A 
 
Date  
 
 


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T A B L E O F C O N T E N T S  
S P O N S O R SI G N A T U R E P A G E  .................................................................................................... 2 
LI S T O F A B B R E VI A TI O N S .......................................................................................................... 8  
S T A T E M E N T O F C O M P LI A N C E  ............................................................................................... 1 0 
I N V E S TI G A T O R SI G N A T U R E P A G E ....................................................................................... 1 1 
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1.  
I N T R O D U C TI O N ...................................................................................................... 1 7 
1. 1.  
B A C K G R O U N D  ........................................................................................................ 1 7 
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P U R P O S E  ................................................................................................................... 1 9 
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S T U D Y D E SI G N  ....................................................................................................... 2 0 
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D E S C RI P TI O N O F S T U D Y  D E SI G N  ...................................................................... 2 0 
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D O S E R A TI O N A L E  .................................................................................................. 2 1 
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D O SI N G  ..................................................................................................................... 2 2 
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S T U D Y E N D P OI N T S  ................................................................................................ 2 2 
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C o - Pri mar y E n d p oi nts ................................................................................................ 2 2 
3. 4. 2.  
Sec o n dar y E n d p oi nts .................................................................................................. 2 3  
3. 4. 2. 1.  
Ke y Sec o n dar y E n d p oi nts ........................................................................................... 2 3  
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Sec o n dar y E n d p oi nts .................................................................................................. 2 3  
3. 4. 3.  
St u d y P o p ulati o n ......................................................................................................... 2 4  
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I n cl usi o n Criteria ........................................................................................................ 2 4 
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E x cl usi o n Criteria  ....................................................................................................... 2 4 
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S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T  ........................................................ 2 5 
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D E FI NI TI O N S O F S T U D Y P R O C E D U R E S  ............................................................ 2 5 
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I nf or me d C o nse nt ....................................................................................................... 2 5 
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Me dical Hist or y a n d D e m o gra p hi cs ........................................................................... 2 6  
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Mater nal D ata  ............................................................................................................. 2 7 
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P h ysical E x a mi nati o n  ................................................................................................. 2 7 
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Wei g ht a n d B o d y Le n gt h ............................................................................................ 2 7  


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Electr ocar di o gra m ( E K G)  ........................................................................................... 2 7 
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Cli nical La b or at or y Tests  ........................................................................................... 2 8 
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Ser u m C he mistr y  ........................................................................................................ 2 8 
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E pis o des of Si g nifica nt Fee di n g I nt olera nce .............................................................. 2 9  
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C o nc o mita nt Me dicati o n  ............................................................................................ 3 0 
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L o n g -T er m F oll o w- U p Visits  ..................................................................................... 3 0 
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A d verse E v e nts ( A Es)  ................................................................................................. 3 1 
4. 1. 1 4.  
E val uati o n of Res p o nse .............................................................................................. 3 1  
4. 1. 1 4. 1.  
Pare nter al N utriti o n ( P N) I nta k e  ................................................................................. 3 1 
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E nteral N utriti o n ( E N) I nta ke  ..................................................................................... 3 1 
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S T U D Y VI SI T S .......................................................................................................... 3 2 
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Scree ni n g Pr oce d ures  .................................................................................................. 3 2 
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Baseli ne  ....................................................................................................................... 3 2 
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Ra n d o mizati o n ............................................................................................................ 3 3  
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St u d y Treat me nt  .......................................................................................................... 3 4 
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S u bject Site Visits  ....................................................................................................... 3 4 
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Visit a n d Earl y Disc o nti n uati o n fr o m St u d y Me dicati o n Visit  .................................. 3 5 
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Ter mi nati o n Visit a n d Earl y Disc o nti n uati o n fr o m L o n g- T er m F oll o w - u p 
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U nsc he d ule d Visit ....................................................................................................... 3 5  
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S A F E T Y C O N SI D E R A TI O N S A N D G UI D A N C E F O R 
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P R E M A T U R E DI S C O N TI N U A TI O N F R O M S T U D Y M E DI C A TI O N  ................. 3 8 
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P R E M A T U R E DI S C O N TI N U A TI O N F R O M S T U D Y ............................................ 3 8 
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Defi niti o n of A d vers e E v e nts ..................................................................................... 4 3  
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S E RI O U S A D V E R S E E V E N T S  ................................................................................ 4 5 
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S T A TI S TI C A L C O N SI D E R A TI O N S  ....................................................................... 4 6 
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I nteri m C hec k of V aria n ce Ass u m pti o n ..................................................................... 4 7 
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Statistical Tests of C o - Pri mar y a n d Ke y Sec o n dar y E n d p oi nts ................................. 4 7 
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Treat me nt of S u bjects L ost t o F oll o w - u p ................................................................... 4 8 
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Ke y Sec o n dar y E n d p oi nt ............................................................................................ 5 0  
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Ot her Sec o n d ar y E n d p oi nts ........................................................................................ 5 0  
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S A M P L E SI Z E  ........................................................................................................... 5 1 
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S T A TI S TI C A L A N A L Y SI S  ...................................................................................... 5 1 
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O ver vie w  ..................................................................................................................... 5 1 
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D A T A C O L L E C TI O N, S T U D Y M O NI T O RI N G, A N D D A T A 
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D A T A C O L L E C TI O N A N D R E P O R TI N G  .............................................................. 5 3 
9. 2.  
S T U D Y M O NI T O RI N G  ............................................................................................ 5 4 
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C O N FI D E N TI A LI T Y, D A T A DI S C L O S U R E, A N D P U B LI C A TI O N  ................... 5 5 
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Ta ble 1:  A d vers e E ve nts O bser ve d i n Pre vi o us N utri nia Cli nical St u dies of Oral I ns uli n 
i n Pre mat ure I nf a nts .................................................................................................... 3 6 
Ta ble 2:  Se verit y Assess me nt Ter mi n ol o g y f or Re p orti n g A d vers e E ve nts ................................ 4 5  
 
LI S T O F A P P E N DI C E S  
A p pe n di x A:  Fee di n g Pr ot oc ol ..................................................................................................... 6 1  
A p pe n di x B:  Sc he d ule of St u d y Pr oce d ures ................................................................................. 6 3  
A p pe n di x C:  C o m m o n Ter mi n ol o g y Cr iteri a f or A d verse E v e nts ............................................... 6 6 
A p pe n di x D:  2 Y C orrect e d A ge N e ur o de v el o p me ntal Assess me nt ............................................. 6 7  
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A b bre vi ati o n  
E x pl a n ati o n  
A E  
A d verse E ve nt  
A L T  
Ala ni ne A mi n otra nsferase  
A S T  
As partate A mi n otra nsferase  
Ca  
Calci u m  
C F R  
C o de of Fe deral Re g ulati o ns  
c G C P 
C urre nt G o o d Cli nical Practice(s)  
c G M P 
C urre nt G o o d Ma n ufact uri n g Practices  
c m 
Ce nti meter  
C R F  
Case Re p ort F or m  
C S R  
Cli nical St u d y Re p ort  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
d L  
Deciliter  
D S M B  
Data Safet y M o nit ori n g B oar d  
e C R F 
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
E K G  
Electr ocar di o gra m  
E N  
E nteral N utriti o n  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
g  
Gra m  
G C P  
G o o d Cli nical Practice(s)  
G G T  
Ga m ma -gl uta m yl Tra ns pe pti dase  
GI  
Gastr oi ntesti nal  
I C F 
I nf or me d C o nse nt F or m 
I CH  
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I C H-G C P  
I nter nati o nal C o nfere nce o n Har m o nizati o n-G o o d Cli nical Practice(s)  
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I U 
I ns uli n U nit(s) 
I V 
I ntra ve n o us 
K  
P otassi u m  
k g  
Kil o gra m  
M A R  
Mi ssi n g at Ra n d o m 
M C H  
Mea n C or p usc ular He m o gl o bi n  
M C H C  
Mea n C or p usc ular He m o gl o bi n C o nce ntrati o n  
M C V  
Mea n C or p usc ular V ol u me  
M D  
Malt o de xtri n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  


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A b bre vi ati o n  
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mI T T  
M o difie d I nte nt -t o-Treat  
m L  
Milliliter  
Na  
S o di u m  
n p o  
N ot hi n g b y M o ut h  
O M M  
O w n M ot her’s Mil k  
% P N  
Perce nt Pare nteral N utriti o n  
P C _ P N  
Perce nt C ha n ge i n Perce nt Pare nteral N utriti o n  
P N  
Pare nteral N utriti o n  
P P  
Per -Pr ot oc ol  
R A  
Re g ulat or y A ut h orit y  
R B C  
Re d Bl o o d Cells  
S A E  
Seri o us A d verse E v e nt  
S A P  
Statistical A nal ysis Pla n  
S B S  
S h ort B o wel S y n dr o me  
S O C  
Sta n dar d of Care  
T P N  
T otal Pare nteral N utriti o n  
U  
U nits  
U S  
U nite d States ( of A merica)  
W B C  
W hite Bl o o d Cells  
Y  
Year  
 


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T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, I nter n ati o nal C o nfere n ce o n 
Har m o nizati o n G o o d Cli nical Practice G ui deli nes E 6 (I C H- G C P), a n d t he a p plica ble re g ulat or y 
re q uire me nts. 


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I N V E S TI G A T O R SI G N A T U R E P A G E 
I h a ve r ea d a n d u n derst o o d t he pr ot oc ol a n d a gree t o i m ple me nt the st u d y i n acc or d a nce wit h t he 
pr oce d ur es set f ort h i n t h e pr ot oc ol a n d i n acc or d a nce wit h t he S p o ns or's g ui deli nes, all 
a p plica ble g o ver n me nt re g ulati o ns, a n d t he I nter nati o nal C o nfere nce o n Har m o nizati o n G o o d 
Cli nical Practice G ui deli nes E 6 (I C H -G C P).  
I will pr o vi de a de q u ate pr ot oc ol trai ni n g t o m y ass ociates, c ollea g u es a n d e m pl o yees assisti n g i n 
t he c o n d uct of t he st u d y.  
I will o btai n I nstit uti o nal Re vie w B o ar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C) a p pr o v al of 
t he pr ot oc ol a n d t he s u bj ect I nf or m e d C o nse nt F or m (I C F) pri or t o e nr oll m e nt of s u bjects i n t he 
st u d y.  I u n dersta n d t hat a n y m o dificati o ns t o t he pr ot oc ol ma de d uri n g t he c o urse of t he st u d y 
m ust first be a p pr o ve d b y t he I R B/I E C e x ce pt w he n s uc h m o dificati o n is ma de t o re m o ve a n 
i m me diate hazar d t o a s u bject.  
I will e ns ure t hat a f ull y e x ec ute d s u bject I C F is o btai ne d o n be half of eac h s u bject pri or t o 
i nitiati o n of a n y st u d y pr oce d ures.  
I will pr o m ptl y re p ort a n y Seri o us A d v erse E v e nt ( S A E) ( wit hi n 2 4 h o urs f or relate d S A Es a n d 
wit hi n 4 8 h o urs f or u nrel ate d S A Es) t hat occ urs d uri n g t he c o urse of t he st u d y i n acc or d a nce 
wit h t he pr oce d ur es descri be d i n Secti o n 7  of t he pr ot oc ol.  
I will all o w t he S p o ns or, N utri nia Lt d. a n d its a ge nts, as well as t he U nite d States ( U S) F o o d a n d 
Dr u g A d mi nistrati o n ( F D A) a n d ot her re g ulat or y a ge n cies, t o i ns pect st u d y facilities a n d 
perti ne nt rec or ds at r eas o na ble ti mes a n d i n a reas o na ble ma n ner, e ns uri n g s u bjects 
c o nfi de ntialit y.  If I a m n otifie d t hat t his st u d y is t o be i ns pecte d  b y a re g ul at or y a ge n c y, I will 
n otif y t he S p o ns or as s o o n as p ossi ble t hereafter ( wit hi n o ne wee k of recei pt of n otificati o n).  
 
 
 
 
  
I n v esti gat or’s N a me 
 
I n v esti gat or’s Si g n at ure 
 Date  
 
Site Na me : 
 
 
Site 
A d dress : 
 
 
 
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 2  of 7 1  
P R O T O C O L S Y N O P SI S  
Pr ot oc ol 
N u m ber  
GI F T -0 2  
St u d y title  
A M ulti -Ce nter, Ra n d o mize d, D o u ble -Bli n d, T hree -Ar m, P arallel -Gr o u p Trial t o Assess t he 
Efficac y a n d Safet y of N T R A -9 6 2 0 i n I nfa nts wit h S h ort B o wel S y n dr o me ( S B S) F oll o wi n g 
S ur gical Resecti o n  
Sites  
A p pr o xi matel y 4 0 w orl d wi de  
I n dic ati o n 
N T R A -9 6 2 0 ( 8 i ns uli n u nits (I U)/ k g/ da y or 4 I U/ k g/ da y) is i nte n de d t o treat i nfa nts wit h S B S t o 
i m pr o ve i ntesti nal a bs or pti o n of n utrie nts a n d fl ui ds. 
Pri m ar y 
O bjecti ve  
T he pri mar y o bj ecti ve is t o e val uate t he efficac y a n d safet y of N T R A -9 6 2 0 c o m p are d wit h 
place b o w he n a d de d t o sta n dar d of care ( S O C) i n pe diatric s u bj ects (a ge d 2 8 wee ks p ost -
me nstr ual a ge t o 5 2 wee ks c hr o n ol o gical a ge) wit h S B S wit hi n 4 m o nt hs fr o m s ur gical 
resecti o n w h o are o n pare nteral n utriti o n ( P N) s u p p ort. 
St u d y Desi g n  
T his m ulti -ce nter, ra n d o mize d, d o u ble -bli n d, t hree -ar m, parallel-gr o u p trial is desi g ne d t o 
assess t he efficac y a n d safet y of t w o d oses ( 8 I U/ k g/ da y a n d 4 I U/ k g/ da y) of N T R A -9 6 2 0 or 
matc hi n g place b o at t w o ti me p oi nts ( 1 2 a n d 2 4 wee ks p ost ra n d o mizati o n) a d mi ni stere d t o 
i nfa nts less t ha n 5 2 wee ks c hr o n ol o gical a ge wit h S B S (f oll o wi n g s ur gical resecti o n).  T he 
st u d y will be c o n d ucte d i n a p pr o xi matel y 4 0 cli nical trial sites w orl d wi de.  S u bj ects will 
c o nti n ue o n S O C n utriti o n aft er t he 2 4 wee k i nter ve nti o n peri o d.   A fi nal st u d y visit will be 
c o n d ucte d at W ee k 2 8, 4 wee ks after t he e n d of d osi n g.  All s u bj ects will be f urt her f oll o we d 
f or l o n g-ter m safet y t hr o u g h W ee k 1 0 4; t hese safet y data will be re p orte d as a n a d de n d u m t o 
t he fi nal cli nical st u d y re p ort. 
D os a ge  & 
Re gi me n  
All t hree gr o u ps will recei ve N T R A -9 6 2 0 or matc hi n g place b o f o ur ti mes per da y f or 2 4 wee ks.  
Gr o u p 1:  N T R A -9 6 2 0 2  I U/ k g f or eac h d ose ( 8 I U/ k g per da y). 
Gr o u p 2:  N T R A -9 6 2 0 1  I U/ k g f or eac h d ose ( 4 I U/ k g per da y). 
Gr o u p 3:  Matc hi n g place b o f or  eac h d ose. 
S a m ple Size  
A p pr o xi matel y 5 0 s u bj ects per treat me nt ar m ( 1 5 0 s u bj ects).  
St u d y 
P o p ul ati o n  
S u bj ects w h o are at least 2 8 wee ks p ost -me nstr ual a ge 1 a n d u p t o 5 2 wee ks c hr o n ol o gical a ge 
a n d, after t heir maj or s ur gical resecti o n, ha ve less t ha n or e q ual t o 7 0 % of t heir e x pecte d b o wel 
le n gt h re mai ni n g a n d re q uire at least 7 0 % pare nteral s u p p ort ( P N/I V) at st u d y e ntr y. 
I ncl usi o n 
Criteri a  
S u bj ects m ust meet all  of t he f oll o wi n g criteria t o be i ncl u de d:  
1)  S u bj ect m ust be at least 2 8 we e ks p ost -me nstr ual a ge a n d u p t o 5 2 wee ks c hr o n ol o gical a ge 
at e nr oll me nt.  
2)  S u bj ect wei g ht m ust be at least 5 0 0  gra ms ( 1 7. 6  o u nces) at ti me of e nr oll me nt.  
3)  Cli nicall y dia g n ose d wit h S B S re q uiri n g P N/I V sec o n dar y t o s ur gical resecti o n of t he 
i ntesti ne. 
4)  After maj or s ur gical resecti o n lea di n g t o S B S, t he s u bj ect has ma xi mall y 7 0 % of e x pecte d 
b o wel le n gt h preser ve d  or a n ost o m y i n place s uc h t hat ≤ 7 0 % of t he s mall b o wel is 
a vaila ble f or a bs or pti o n 2. 
                                                 
1 P ost me nstr u al a ge is defi ne d as gestati o nal pl us c hr o n ol o gical a ge  
2 % b o wel left is calc ulate d as t he a m o u nt of s mall b o wel r e mai ni n g of t he t otal e x pecte d b o wel.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 3  of 7 1  
5)  S u bj ect ca n t olerate at least 1 0  m L/ k g/ da y of e nteral n utriti o n ( E N) f or at least 7 da ys at 
ti me of e nr oll me nt.  
6)  At ti me of e nr oll me nt s u bj ect is o n at least 7 0 % of prescri be d P N/I V a n d n o m ore t ha n 
3 0 % of E N base d o n t otal cal oric i nta ke  f or at least 7 da ys pri or t o st u d y e ntr y.  
7)  S u bj ect is ra n d o mize d i nt o t he trial wit hi n 4 m o nt hs fr o m t he s ur gical resecti o n t hat has le d 
t o t he dia g n osis of S B S. 
8)  S u bj ect’s pare nt(s) or le gal g uar dia n(s) pr o vi de writte n i nf or me d c o nse nt. 
9)  S u bj ect’s pare nt(s) or le gal g uar dia n(s) u n dersta n d a n d are willi n g t o c o m pl y wit h all st u d y 
pr oce d ures a n d re q uire me nts.  
E xcl usi o n 
Criteri a  
S u bj ects meeti n g a ny  of t he f oll o wi n g criteria at st u d y e ntr y will be e xcl u de d:  
1)  S u bj ect has u n der g o ne a n y b o wel le n gt he ni n g pr oce d ure.  
2)  S u bj ect has a mala bs or pti o n dis or der s uc h as:  
•  
C o n ge nital eti ol o g y  (s uc h as micr o villi i ncl usi o n disease, t ufti n g e nter o pat h y) 
•  
U ntreate d Hirc hs pr u n g’s disease  
3)  Si g nifica nt m otilit y dis o r der s uc h as: 
•  
Pse u d o o bstr ucti o n  
•  
Se vere gastr osc hisis defi ne d as:  pri mar y reas o n f or P N s u p p ort is d ue t o persiste nt 
fee di n g i nt olera nce of less t ha n 2 0 ml/ k g/ da y E N i nta ke or si g ns a n d s y m pt o ms (i.e., 
a b d o mi nal diste nti o n, v o miti n g) re q uiri n g pr o ki netic a ge nts.  
4)  A n y k n o w n i n herite d a b n or malit y (e. g., Fa nc o ni s y n dr o me,) t hat is n ot relate d t o S B S.  
5)  Pri or b o wel resecti o n d ue t o is olate d s p o nta ne o us i ntesti nal perf orati o n.  
6)  < 1 0 c m of re mai ni n g s mall b o wel left wit h n o c ol o n.  
7)  U nc o ntr olle d s yste mic i nfecti o n, ac ute gastr oe nteritis, p ne u m o nia, car di o vasc ular or ot her 
a b n or malit y i ncl u di n g E K G fi n di n gs t hat i n t he o pi ni o n of t he i n vesti gat or ma kes t he i nfa nt 
u nsta ble a n d at si g nifica nt ris k of n ot c o m pleti n g t he first 1 2 wee ks of t he st u d y.  
8)  S u bj ects wit h k n o w n h y pe ri ns uli ne mia 3. 
9)  S u bj ects wit h u ne x plai ne d or rec urre nt h y p o gl yce mia wit h bl o o d gl uc ose ≤ 5 0  m g/ d L 
wit hi n 4 8 h o urs of treat me nt i nitiati o n.  
1 0)  S u bj ects wit h se vere a ne mia of He m o gl o bi n less t ha n 6 0 g/ L a n d re q uiri n g tra nsf usi o n 
wit hi n 4 8 h o urs of treat me nt i nit iati o n t o a v oi d a life t hreate ni n g e ve nt. 
1 1)  S u bj ects w h o re q uire pa ncreatic e nz y me re place me nt t hera p y.  
1 2)  S u bj ect is c urre ntl y recei vi n g oral or i nj ecta ble i ns uli n f or a n y reas o n.  
1 3)  P artici pati o n i n a n ot her i nter ve nti o nal cli nical st u d y wit hi n t he past 3 0 da ys t hat ma y 
i nterfere wit h t he res ults of t his st u d y. 
1 4)  Hist or y or c urre nt use of gr o wt h fact ors or gl uta mi ne.  
1 5)  I n t he o pi ni o n of t he i n vesti gat or, t he s u bj ect has a n y ot her me dical c o n diti o n t hat w o ul d 
ma ke partici pati o n i n t his st u d y eit her u nsafe or w o ul d c o m pr o mise t he p ote ntial be nefit of 
i ns uli n treat me nt. 
                                                 
3  F ull d efi niti o n of h y peri ns uli ne mia is pr o vi de d bel o w ( S ecti o n 3. 4. 5 ).  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 4  of 7 1  
St u d y Visit 
Sc he d ule  
( See A p pe n di x 
B :  Sc he d ule 
of St u d y 
Pr oce d ures )  
S u bj ects dia g n ose d wit h S B S res ulti n g fr o m s ur gical resecti o n ma y be e val uate d f or 
q ualific ati o n t o t his st u d y after t heir pare nt(s) or le gal g uar dia n(s) ha ve gi ve n writte n i nf or me d 
c o nse nt.  Scree ni n g assess me nts will i ncl u de me dical hist or y a n d de m o gra p hics, i ncl usi o n a n d 
e xcl usi o n criteria, mater nal data, wei g ht a n d b o d y le n gt h, he a d circ u mfere nce, vital si g ns, 
electr ocar di o gra m ( E K G) i n tri plicate, p h ysical e xa mi nati o n, uri nal ysis, he mat ol o g y, bl o o d 
c he mistr y, P N i nta ke, E N i nta ke a n d c o nc o mita nt me dicati o ns.  
D uri n g t he 2 4 -wee k treat me nt peri o d, s u bjects are e x pecte d t o be o n P N/I V f or all or  m ost of 
t he treat me nt peri o d a n d t h us are e x pecte d t o be h os pitalize d f or a p pr o xi matel y 1 2 wee ks, b ut 
t he y ma y be release d s o o ner acc or di n g t o l ocal i nstit uti o n’s S O C.  Eac h s u bj ect will recei ve t he 
st u d y treat me nt 4 ti mes dail y c o nc o mita ntl y wit h e nteral  fee di n gs.  Treat me nt will c o nti n ue f or 
t he f ull 2 4 wee ks re gar dless of t he % P N (i.e., treat me nt s h o ul d be c o nti n ue d e ve n if s u bj ect is 
wea ne d off P N).  E N i ncl u des S O C i nfa nt f or m ula, d o n or breast mil k, or o w n m ot her's mil k (as 
detaile d i n  A p pe n di x A ).  
O nce t he s u bj ect is release d f or h o me care, t he care gi vers, i ncl u di n g a n y at -h o me me dical 
pr ofessi o nals, will be trai ne d o n t he pr o per pr oce d ures f or d osi n g N T R A -9 6 2 0 or matc hi n g 
place b o a n d h o w t o rec or d st u d y i nf o r mati o n i n t he dail y diar y.  D ose i nterr u pti o ns o ver t he 2 4 
wee k st u d y treat me nt peri o d will o nl y be all o we d at i n vesti gat or discreti o n (i.e., N P O  f or 
pr oce d ure.)  N o d ose i nterr u pti o n s h o ul d last m ore t ha n 7 c o nsec uti ve da ys.  D uri n g t he first 1 2 
wee ks w h ere t he s u bj ect is li kel y t o be h os pitalize d, t here s h o ul d be n o m ore t ha n 1 0 da ys of 
d ose i nterr u pti o n.  D uri n g wee ks 1 2 t o 2 4, w here t he s u bj ect ma y be at h o me or at a sec o n dar y 
facilit y, t here s h o ul d be n o m ore t ha n 1 5 da ys of d ose i nterr u pti o n.  
D uri n g  t he st u d y, t he i n vesti gat or will f oll o w a rec o m me n d e d P N/I V a n d E N fee di n g pr ot oc ol 
(A p pe n di x A ). 
B ot h t he v ol u me a n d t he cal oric val ue of P N/I V a n d E N c o ns u me d will be rec or de d at eac h 
st u d y visit (as descri be d in,  A p pe n di x B ).  Vital si g ns, b o d y wei g ht, b o d y le n gt h, hea d 
circ u mfere nce, a n d gastric resi d uals (t hr o u g h W ee k 1 2 o nl y if it is d o ne as part of t he S O C), 
a d verse e ve nts, a n d c o nc o mita nt me dicati o ns will be c ollecte d b y wee kl y assess me nts 
t hr o u g h o ut W ee k 1 2 a n d at least o nce e ver y t w o wee ks bet wee n W ee k 1 2 a n d W ee k 2 4.  I n 
a d diti o n, at W ee k 1 2, assess me nts will i ncl u de f ull p h ysical e xa mi nati o n, he mat ol o g y, 
c he mistr y, uri nal ysis, a nti -i ns uli n a nti b o dies, a n d plas ma citr ulli ne.  T he n o n-r o uti ne use of oral 
a nti bi otics a n d pr o bi otics are all o we d if it is part of t he S O C.  Rec or di n g of pare nteral a n d 
e nteral n utriti o nal i nta ke will be c o nti n ue d u ntil t he e n d of t he 2 4 -wee k treat me nt peri o d.  
O nce release d f or h o me care, t he s u bj ect will ret ur n t o t he cli nic as nee de d acc or di n g t o 
sta n dar d me dical practice or at least e ver y t w o wee ks bet wee n W ee k 1 2 a n d W ee k 2 4 f or 
assess me nts, re ple nis h me nt of st u d y me dicati o ns, a n d a dj ust me nt of t he P N/I V a n d E N 
pr ot oc ols.  
At t he e n d of  t he treat me nt peri o d ( W ee k 2 4) s u bj ects will disc o nti n ue a d mi nistrati o n of st u d y 
me dicati o n.  At t his ti me, s u bj ects will be gi ve n a f ull p h ysic al e xa mi nati o n.  Assess me nts will 
i ncl u de b o d y wei g ht, b o d y le n gt h, hea d circ u mfere nce, vital si g ns, he mat ol o g y, c he mistr y, 
uri nal ysis, plas ma citr ulli ne, c o nc o mita nt me dicati o ns, P N, E N a n d A Es.  
T he pri mar y p orti o n of t he st u d y will be c o nsi dere d c o m plet e w he n t he last ra n d o mize d s u bj ect 
fi nis hes t he 2 4 wee k treat me nt peri o d a n d a 4 wee k i nitial safet y f oll o w-u p p eri o d ( W ee k 2 8).  
At W ee k 2 8, t he sa me assess me nts as i n W ee k 2 4 visit will ta ke place, e xce pt f or plas ma 
citr ulli ne.  I n a d diti o n, a nti -i ns uli n a nti b o dies will be assesse d.  
A d diti o nal l o n g -ter m safet y a n d f oll o w-u p e val uati o ns will be c o n d ucte d at 5 2 a n d  1 0 4 wee ks 
after i nitiati o n of treat me nt.  E ac h visit d uri n g t he f oll o w -u p peri o d will i ncl u de b o d y wei g ht, 
b o d y le n gt h, hea d circ u mfere nce, pare nteral n utriti o n i nta ke, e nteral n utriti o n i nta ke, re -
h os pitalizati o ns a n d a d verse e ve nts.  I n a d diti o n, gr o wt h  para meters a n d n utriti o nal s u p p ort 
i nf or mati o n fr o m r o uti ne care visits at t he pri mar y site will b e rec or de d i n t he e C R F.  T hese 
data will i ncl u de B a yle y's ne ur o de vel o p me ntal c o g niti ve, la n g ua ge a n d m ot or d o mai ns at 2 Y 
c orrecte d a ge.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 5  of 7 1  
St u d y 
D ur ati o n  
Eac h  s u bj ect is e x pecte d t o be treate d i n t he st u d y f or 2 4 wee ks, a n d t o partici pate f or u p t o 
1 0 4  wee ks i ncl u di n g t he l o n g -ter m safet y f oll o w-u p peri o d:  
T he pri mar y p orti o n of t he st u d y is 2 8 wee ks:  2 4 wee ks of treat me nt pl us a 4 wee k i nitial 
safet y f oll o w- up.  T he t otal le n gt h of t he st u d y is 1 0 4 wee ks:  2 8 wee ks of t he pri mar y p orti o n 
pl us 7 6 wee ks of l o n g -ter m safet y a n d f oll o w-u p e val uati o ns.  
Pri m ar y 
Effic ac y 
E n d p oi nt s 
T his trial has  t w o c o-pri mar y e n d p oi nts.  
T he first c o-pri mar y e n d p oi nt s are t he perce nt c ha n ges i n % P N ( P C _ P N 0-t) fr o m baseli ne base d 
o n cal oric i nta ke t o 1 2 wee ks a n d a gai n t o 2 4 wee ks.  Eac h e n d p oi nt is calc ulate d as:  
P C _P N 0 −t = 1 0 0 × % P N
B a s eli n e −% P N
t
% P N
B a s eli n e
 
w here:  
t = 1 2 or 2 4 wee ks.  
% P N = % P are nteral N utriti o n (fee di n g) ca lc ulate d as pare nt eral cal ories di vi de d b y 
calc ulate d t otal cal oric re q uire me nts (t he Sc h ofiel d e q uati o n (1 )). 
•  
Eac h P C _P N 0 −t  o bser vati o n will be c o m p ute d as a n a vera ge o ver a si n gle wee k.  
•  
T h us, f or e xa m ple, P C _ P N at 1 2 wee ks will be t he a vera ge of P C _ P N o ver da ys 
7 8 t o 8 4. 
P C _ P N at 2 4 wee ks will be t he a vera ge of P C _ P N o ver da ys 1 6 2 t o 1 6 8. 
T he st u d y will ha ve s h o w n be nefit if eit her P C _ P N 0- 1 2 or P C _ P N 0- 2 4 i n t he treate d gr o u p is 
statisticall y si g nifica ntl y s u peri or t o place b o.  
 
T he sec o n d  c o -pri mar y e n d p oi nt s are res p o n der e n d p oi nts . T he o utc o me varia ble f or eac h 
s u bj ect will be t he sa me o utc o me as f or t he first pri mar y, b ut t he statistical test will be 
calc ulate d as c o nti n u o us res p o n der c o m paris o n at 1 2  wee ks a n d a gai n at 2 4 wee ks .  
Sec o n d ar y 
Effic ac y 
E n d p oi nts  
Ke y Sec o n d ar y E n d p oi nt  
Ti me t o re d ucti o n of P N t o less t ha n 1 0 % of t he t otal cal oric i nta ke o n 1 4 c o nsec uti ve da ys .  
Ot her Sec o n d ar y E n d p oi nts  
a) Ti me  t o wea n off 4pare nteral n utriti o n  
b)  N u m ber of patie nts reac hi n g r ea di ness t o wea n 5 off at 1 2 a n d 2 4 wee ks fr o m baseli ne.  
c) Ti me t o 5 0 % P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n t otal cal ories.  
d)  Ti me t o 5 0 % P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n v ol u me.   
e) N u m ber of patie nts reac hi n g  5 0 % P N/I V re d ucti o n fr o m bas eli ne i n % P N base d o n 
t otal cal ories at 1 2 a n d  2 4  wee ks . 
f) 
N u m ber of patie nts reac hi n g 5 0 % P N/I V re d ucti o n fr o m bas eli ne i n % P N base d o n 
v ol u me  at 1 2 a n d  2 4 wee k s. 
g)  P erce nt c ha n ge fr o m baseli ne i n % P N /I V base d o n t otal cal ories.  
h)  P erce nt c ha n ge fr o m baseli ne i n % P N /I V base d o n v ol u me.  
i) 
P erce nt c ha n ge fr o m bas eli ne i n P N/I V fl ui d v ol u me d uri n g treat me nt peri o d.  
j) 
C ha n ge i n Z -sc ores ( Fe nt o n) fr o m baseli ne d uri n g t he treat me nt peri o d 
k)  P erce nt c ha n ge fr o m baseli ne i n % E N base d o n t otal cal ories.  
l) 
P erce nt c ha n ge fr o m baseli ne i n % E N base d o n t otal v ol u me.  
m)  C ha n ge fr o m b aseli ne i n li ver e nz y mes ( A L T, G G T, a n d t otal a n d direct bilir u bi n).  
n)  C ha n ge fr o m baseli ne i n plas ma citr ulli ne le vels.  
                                                 
4 Wea n off d efi n e d as c o m plete cessati o n of pare nteral n utriti o n a n d ac hie vi n g f ull e nteral a ut o n o m y f or t w o wee ks.
 
5 Re d ucti o n t o P N of less t ha n 1 0 % of t he t otal cal oric i nta ke f or 1 4 c o nsec uti ve da ys is defi ne d as rea di ness t o wea n off.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 6  of 7 1  
o)  C ha n ge fr o m baseli ne i n b o d y wei g ht d uri n g t he treat me nt p eri o d.  
p)  W ee kl y a vera ge of h o urs o n prescri be d P N/I V d uri n g t he last m o nt h of tr eat me nt.  
q)  Ge neral safet y varia bles i ncl u di n g e pis o des of si g nifica nt fe e di n g i nt olera nce  
c o m pare d t o place b o. 
St atistic al 
A n al ysis of 
E n d p oi nts  
First C o -Pri m ar y E n d p oi nt s 
T he pri mar y e n d p oi nts ( meas ure d at 1 2 wee ks a n d 2 4 wee ks) will eac h be a nal yze d usi n g a n 
a nal ysis of c o varia nce m o del wit h P C _ P N 0- 1 2 a n d P C _ P N 0- 2 4 ser vi n g as t he de pe n de nt vari a ble 
f or eac h res pecti ve a nal ysis.  Treat me nt gr o u p a n d t he ra n d o misati o n stratificati o n varia bl es 
will ser ve as fact ors a n d t he baseli ne % P N val ue will ser ve as a c o variate i n eac h a nal ysis.  I n 
eac h a nal ysis, t he hi g her d ose gr o u p will be c o m pare d t o place b o gr o u p first.  T he hi g h -d ose 
c o m paris o n will be teste d at t he 0. 0 2 5 t w o -si de d si g nifica nce le vel at eac h ti me p oi nt.  If t he 
hi g h -d ose c o m paris o n at a partic ular  ti me p oi nt is si g nifica nt at p < 0. 0 2 5, t he n t he l o w -d os e 
c o m paris o n wit h place b o (at t he sa me ti me p oi nt) will be teste d at t he 0. 0 2 5 le vel.  
Sec o n d C o -Pri m ar y E n d p oi nt s 
T he res ults will be dis pla ye d o n a gra p h w here t he x -a xis dis pla ys t he perce nt re d ucti o n i n % P N  
a n d the y -a xis s h o ws t he pr o p orti o n of i nfa nts w h o meet eac h res p o nse t hres h ol d (fr o m 0 t o 
1 0 0 %).  T he c o nti n u o us res p o n der c ur ves f or eac h d ose vs. place b o will be c o m pare d usi n g t he 
Ma n n W hit ne y U test base d o n t he 1 2 wee k data a n d a n ot her gra p h  a n d a nal ysis will  ma ke t he 
si milar c o m paris o n at 2 4 wee ks.  A p ositi ve o utc o me f or t he c o nti n u o us res p o n der a nal yses will 
be a o ne -si de d p-val ue less t ha n 0. 1 0.  
T he trial will ha ve s h o w n be nefit if a n y gr o u p c o m paris o n state d a b o ve is s h o w n t o be s u peri or  
t o place b o o n b ot h of t he c o -pri mar y e n d p oi nts  at t he sa me ti me ( 1 2 or 2 4 wee ks, or b ot h) , eac h 
at t he state d si g nifica nce le vel . 
Ke y Sec o n d ar y E n d p oi nt  
T he ke y sec o n dar y e n d p oi nt will be a nal yze d usi n g a stratifie d l o g -ra n k test wit h fact ors f or 
treat me nt gr o u p a n d t he ra n d o mizati o n stratificati o n varia bles.  Se parate a nal yses will be 
carrie d o ut f or eac h d ose gr o u p.   Ti me t o t he e n d p oi nt will b e ta ke n as t he 1 4 t h da y of 
c o nsec uti ve less t ha n 1 0 % P N.  
S a m ple Size  
T he sa m ple size is base d o n testi n g t he s u peri orit y of t he hi g h d ose of N T R A -9 6 2 0 c o m pare d 
t o place b o o n t he pri mar y e n d p oi nts of perce nt c ha n ge i n % P N fr o m baseli ne t o ti me “t” 
( P C _ P N 0-t) w here “t” = 1 2 a n d 2 4 wee ks.  O n t he basis of hist orical data, t he ass u me d 
re d ucti o n i n P C _ P N 0-t is 3 0 % a n d 4 2 % i n place b o a n d N T R A-9 6 2 0, res pecti vel y, at b ot h 1 2 
a n d 2 4 wee ks.  A c o m m o n wit hi n -gr o u p sta n dar d de viati o n of 2 0 % has bee n ass u me d f or b ot h 
ar ms.  
Gi ve n t he a b o ve s pecificati o ns, a n d base d o n t he use of a t w o -si de d, t w o-sa m ple c o m paris o n of 
mea ns at t he al p ha = 0. 0 2 5 le vel of si g nifica nce, a sa m ple of 4 5 s u bj ects per gr o u p w o ul d 
pr o vi de a p pr o xi matel y 8 0 % p o wer t o de m o nstrate s u peri orit y.  Si nce s o me s u bj ects ma y n ot 
c o m plete t he e ntire trial, a n a d diti o nal 1 0 % of s u bj ects will b e e nr olle d per ar m ( 5 0 s u bj ects per 
ar m) t o acc o u nt f or t his p ote ntial l oss.  T h us, t he pr o p ose d sa m ple size is 1 5 0 s u bj ects.   ( N ote 
t hat t he pr ot oc ol pr o vi des f or a sa m ple size recalc ulati o n; t he pr oce d ure descri be d i n t he 
pr ot oc ol will be f oll o we d).  
S afet y 
A n al ysis  
T he safet y a nal yses will be descri pti ve a n d narrati ve i n nat ur e, wit h S A Es a n d A Es c o de d usi n g 
Me d D R A a n d ta b ulate d b y b o d y s yste m, preferre d ter m, treat me nt gr o u p, se verit y a n d relati o n 
t o pr oce d ure.  Descri pti ve statistics will be pr o vi de d b y treat me nt gr o u p as a p pr opriate.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 7  of 7 1  
1.  
I N T R O D U C TI O N 
1. 1.  
B A C K G R O U N D  
T he maj orit y of t he tar get p o p ulati o n c o nsists of preter m a n d t er m i nfa nts s ufferi n g fr o m 
c o n diti o ns s o o n after birt h t hat res ult i n t he l oss of or da ma ge t o t he s mall b o wel.  Gi ve n t hat t he 
nat ural de vel o p me nt a n d mat urat i o n of t he i ntesti ne occ urs d uri n g t he t hir d tri mester a n d first 
year of lif e, t he a d diti o nal i ns ult of b o wel l oss at t his critical peri o d of ti me ma kes t his gr o u p a 
hi g h ris k p o p ulati o n f or pr ol o n ge d i ntesti nal fail ure re q uiri n g p ote ntiall y lifel o n g p are n teral 
n utriti o n ( P N).  All i nfa nts i n t his gr o u p of patie nts re q uire P N p ost- o perati vel y.  E arl y e nteral 
( E N) f ee di n g s h o ul d be pr o m ote d as s o o n as p ossi ble t o e n ha nce gastr oi ntesti nal ( GI) mat urati o n, 
gr o wt h a n d f u ncti o nal d e vel o p me nt. I nfa nts s h o ul d be w ea n e d off P N as e nteral t olera n ce t o 
fee di n g is e n ha n ce d (2 ). 
I ntesti nal f ail ure i n t he c o nte xt of S h ort B o wel S y n dr o me ( S B S) is ass oci ate d wit h de pe n de n c y 
o n P N f or a pr ol o n ge d p eri o d of ti me.  E vi de nce s u g gests t hat t he s ur vi v al rate after massi ve 
s mall b o wel resecti o n de pe n ds o n t he a bilit y of t h e resi d ual b o w el t o a da pt w hile decreasi n g t he 
pr o ba bilit y of P N ass o ciate d c o- m or bi dities.  M ore o ver, s uccessf ul a d a ptati o n all o ws patie nts 
wit h S B S t o gr o w a n d re mai n healt h y w hile recei vi n g oral n utriti o n  or E N.  As i n dicate d, t he 
m ost i m p orta nt t hera p y f or c hil dre n wit h S B S is t he earl y i ntr o d u cti o n of E N. 
I ns uli n, w hic h pla ys a r ol e i n i ntesti nal gr o wt h, cell mat urati o n, a n d differe ntiati o n, has bee n 
s h o w n t o e n ha nce i ntesti nal a da ptati o n.  N utri nia is de vel o pi n g a n i ns uli n f or m ulati o n, 
N T R A - 9 6 2 0, t o e n ha n ce E N i nta ke i n i nfa nts wit h S B S f oll o wi n g s ur gical resecti o n.  
N T R A -9 6 2 0 is a n oral i ns uli n f or m ulati o n f or l ocal GI t hera p y ai me d at accelerati n g t he n at ural 
c o urse of i ntesti nal a d a pti o n a n d mat urati o n. 
N T R A - 9 6 2 0 is a n oral f or m ulati o n of i ns uli n f or l ocal GI t hera p y wit h o ut s yste mic i ns uli n 
e x p os ure ai me d at i ncreasi n g i ntesti nal a da pti o n.   
E vi de nce s u p p orts t he f act t hat i ntesti nal a da ptati o n is e n ha nce d a n d s ustai ne d w he n gr o wt h 
fact ors are pr o vi d ed i m me diatel y f oll o wi n g i ntesti nal l oss (3 ).  T his a da ptati o n is li kel y t o be 
f urt her a u g m e nte d w he n gr o wt h fact ors are a d mi nistere d d uri n g earl y de vel o p me nt, t he m ost 
critical peri o d of g ut gr o wt h.  T he d ual effects of N T R A- 9 6 2 0 t o e n ha n ce b ot h a da ptati o n a n d 
e nteral t olera nce at t his vital ti me are maj or stre n gt hs of t he pr o d uct c o nce pt.  
Be nefits of accelerati n g a da ptati o n o ver place b o ca n be tra nslat e d t o bei n g  eli gi ble f or a n a v era ge 
of 2 - 3 fe wer h o urs a da y “attac h e d” t o P N, w hic h is ass ociate d wit h t he f oll o wi n g: 
1.  I ns uli n’s r ece pt or-me diat e d str uct ural effects o n t he GI tract s uc h as i ncreas e d rate of 
e nter oc yte pr olifer ati o n, vill o us hei g ht, a n d cr y pt de pt h t hat lea ds t o better g ut a d a ptati o n 
(4 ). 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 8  of 7 1  
2.  A de q uate e n teral n utri e nts a bs or pti o n f or s u p p orti n g t he i nfa nt's gr o wt h a n d 
de vel o p me nt, a n d, i n t he l o n g- ter m, i m pr o ve d n utriti o n earl y i n life t hat lea ds t o better 
gr o wt h a n d de v el o p me nt has bee n li n ke d t o o verall i m pr o ve d healt h o utc o mes i n t his 
p o p ulati o n (2 ). 
3.  Mi ni mizi n g e x p os ure t o t o xic c o nstit ue nts s uc h as li pi ds a n d de xtr ose w hic h ma y res ult 
i n less meta b olic stress o n t he gr o wi n g i nfa nt (5 ). 
4.  Re d ucti o n of P N- ass ociat e d c o -m or bi dities s uc h as pare nteral n utriti o n -ass o ciate d li ver 
disease ( P N A L D), bacterial o ver gr o wt h, cat heter -ass ociate d bl o o dstrea m i nfecti o ns, 
c h olestatic li ver diseas e, a n d deat h (6 , 7 ). 
5.  As P N/I V re q uire m e nts decrease, t his ca n p ot e ntiall y be tra nsl ate d t o a n o p p ort u nit y t o 
a d va nce c ycli n g of P N/I V.   T his is a n i m p orta nt o p p ort u nit y t o i ntr o d uce oral 
re ha bilitati o n strate gies d uri n g t he d a yti me a wa k e h o urs a n d t he n pr o vi de t h e re mai ni n g 
P N/I V s u p p ort o v er ni g ht f or e x a m ple.   
6.  Less o p p ort u nities of necessit y t o ha n dle fra gile ce ntral li ne access t hat ma y pre dis p ose t o 
i nfecti o n or malf u ncti o n (8 ). 
7.  I n crease d or al sti m ulati o n t o fee d, E G F secreti o n lea di n g t o g ut de v el o p me nt a n d re d uce d 
mal n utriti o n,  t h us e n ha nce d gr o wt h a n d ass ociate d de vel o p me nt 
8.  I n crease d h o urs of n or mal de vel o p me nt be ha vi or as a c hil d gr o ws wit h o ut bei n g 
“attac h e d” or c o n nect e d t o a li ne (9 , 1 0 ). 
9.  Less  h o urs of necessar y s pecialize d s u per visi o n, w hic h re d uce t he c osts a n d pr o vi des 
s u p p ort i n pare nts.  
T heref ore, acceler ati o n i n t he re d ucti o n i n t he perce nt P N a n d e n h a nce m e nt of E N i nta ke d uri n g 
t his peri o d of g ut a d a ptati o n is h y p ot hesize d t o be t he m ost a p pr o priate met h o d t o assess 
pr o gress t o war ds f ull e nt eral a ut o n o m y, e v e n if t h e latter ta kes years t o ac hie ve.  
1. 2.  
N O N C LI NI C A L A S S E S S M E N T S A N D C LI NI C A L S T U DI E S IN 
I N F A N T S 
N utri nia’s n o ncli nical pr o gr a m was desi g n e d t o assess w het her oral a d mi nistrati o n of h u ma n 
rec o m bi na nt i ns uli n i n ne w b or n a ni mals affects ser u m gl uc os e le vels, as w ell as t o assess ot her 
safet y meas ure me nts.  N utri nia has c o n d ucte d s e v eral pre-cli nical safet y st u dies i n la m bs, cal ves, 
pi glets, a n d p o ultr y.  T he ne w b or n a ni mals w ere e x p ose d t o vari o us le vels of i ns uli n i n t heir 
n utriti o n, u p t o t w o or ders of ma g nit u de hi g h er t ha n t he i ns uli n le vels i n e x presse d mil k.  T he 
res ults c o nsiste ntl y de m o nstrate d t hat oral i ns uli n a d mi nistrati o n at a n earl y sta ge of life di d n ot 
affect bl o o d gl u c ose, i ns uli n le vels, or hist ol o gical, bi oc he mistr y, a n d h e m at ol o g y para meters.  
N utri nia perf or me d i n vi v o st u dies i n ne w b or n a ni mals wit h N T R A- 2 1 1 2, a c o m p o u n d si milar t o 
N T R A - 9 6 2 0.  T he a ni mals were d ose d wit h hi g her le vels of i ns uli n a n d f or a l o n ger d urati o n 
t ha n will be use d i n t he pr o p ose d st u d y.  T h ese st u dies di d n ot res ult i n h y p o gl yce mic e ve nts or 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 1 9  of 7 1  
c ha n ges i n bl o o d c he mistr y or he mat ol o g y.  I n a d diti o n t o t he a vaila ble n o ncli nical data, 
N utri nia’s cli nical e x peri e nce wit h a 2 6 - 3 3 wee k pre-ter m i nfa nt p op ulati o n treate d f or 2 4 t o 
2 8 da ys wit h oral i ns uli n di d n ot res ult i n h y p o gl yce mic e v e nts or c ha n ges i n bl o o d c he mistr y or 
he mat ol o g y. 
St u dies wit h orall y a d mi nistere d i ns uli n i n ne o natal mi ni -pi gs at 8  I U/ da y (4 ) a d ult rats at 
2 6 I U/ da y (1 1 , 1 2 ) a n d h u ma n i nfa nts at 4 I U/ da y s h o we d n o l ocal a d v erse effects.  I n fact, t he 
data s h o we d e vi de nce t h at t he l ocal effects w ere be neficial s u c h as a n i ncrease i n m uc osal 
s urface ar ea a n d vill o us hei g ht a n d cr y pt de pt h.  D ail y d osi n g f or mi ni- pi gs, rats, a n d h u ma n 
i nfa nts were 4 da ys, 4 t o 1 2 da ys, a n d 2 4 t o 2 8 da ys, res pecti vel y.  T h ese st u dies s u g gest t hat 
re peat e d dail y d oses of oral i ns uli n prese nt n o ris k of l ocal a d verse effects. 
Rec o m bi na nt h u ma n i ns uli n is a p pr o ve d f or c hr o nic, dail y, p are nt eral a d mi nistrati o n t o pe diatric 
patie nts as y o u n g as t w o years ol d w h o ha v e T y pe I dia b etes.  N utri nia’s patie nt p o p ulati o n is 
y o u n ger t ha n t he patie nt p o p ulati o n f or t he a p pr o v e d pr o d uct; h o we v er, n o n cli nical a n d cli nical 
data s u p p ort t hat t his differe nce is n ot li kel y t o res ult i n a n y ne w s yste mic a d verse effects, f or 
t w o reas o ns:  s yste mic a bs or pti o n of i ns uli n is ver y u nli kel y, a n d t he s yste mic effects of i ns uli n 
are w ell u n derst o o d a n d, alt h o u g h u nli kel y t o ha p pe n, ca n b e rea dil y d etect e d a n d ma na ge d. 
T he dail y i ns uli n d ose le vels i n t he pr o p ose d cli nical trial ( 4 I U/ k g/ da y a n d 8 I U/ k g/ d a y) were 
safe a n d free of l ocal or s yste mic a d v erse effects i n ne o natal mi ni- pi gs ( 1 8 I U/ k g), a d ult rats 
( 2 6 I U/ k g), a n d h u m a n i nfa nts ( 4 I U/ k g).  T h e res ults o btai ne d t o date s u p p ort t he i nitiati o n of 
t his cli nical trial.  T he d ose le vels ar e s u p p orte d b y a l o n g-t er m G L P l ocal GI t o xicit y st u d y i n 
ne o natal mi ni pi gs N T R A - 9 6 2 0 wit h t w o d ose le vels ( 4 I U/ k g/ d a y a n d 4 0 I U/ k g/ da y).  
T he I n vesti gat or's Br oc h ure descri bes t he met h o ds a n d res ults fr o m t hese s a fet y st u dies. 
2.  
P U R P O S E A N D S T U D Y O B J E C TI V E S 
2. 1.  
P U R P O S E  
T his P hase II b cli nical st u d y is a m ulti ple d ose safet y a n d efficac y st u d y i nt e n de d t o assess 
w het her N T R A - 9 6 2 0 ( 4 I U/ k g/ da y or 8 I U/ k g/ da y) is be neficial i n i nfa nts wit h S B S if 
a d mi nistere d f oll o wi n g s ur gical res ecti o n t o i m pr o ve i ntesti nal a bs or pti o n of n utrie nts a n d fl ui ds. 
2. 2.  
S T U D Y O B J E C TI V E S  
T he o bjecti ves of t his cli nical st u d y are t o e v al uat e t he efficac y a n d safet y of N T R A - 9 6 2 0 
c o m pare d wit h place b o w he n a d de d t o sta n d ar d of care ( S O C) i n pe diatri c s u b jects (a ge d 2 8 
wee ks p ost- me nstr u al a ge t o 5 2 wee ks c hr o n ol o gical a ge) wit h S B S wit hi n 4 m o nt hs fr o m 
resecti o n w h o are o n p ar e nteral n utriti o n s u p p ort. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 0  of 7 1  
3.  
S T U D Y D E SI G N  
3. 1.  
D E S C RI P TI O N O F S T U D Y D E SI G N  
T his m ulti -ce nter, ra n d o mize d, d o u ble- bli n d, t hree-ar m, p arallel- gr o u p trial is desi g ne d t o assess 
t he efficac y a n d saf et y of t w o d oses ( 4 I U/ k g/ da y a n d 8 I U/ k g/ da y) of N T R A- 9 6 2 0 c o m pare d t o 
matc hi n g place b o at t w o ti me p oi nts ( 1 2 a n d 2 4 wee ks p ost ra n d o mizati o n) a d mi nistere d t o 
i nfa nts less t ha n 5 2 wee ks c hr o n ol o gi cal a ge wit h S B S (f oll o wi n g s ur gi cal resecti o n).  T h e st u d y 
will be c o n d ucte d at u p t o 4 0 cli nical trial sites i n N ort h A merica, E ur o pe a n d Israel.  All 
s u bjects will be e nr olle d after t heir p are nt(s) or le gall y a ut h orize d g uar dia n(s) si g n a n I R B/I E C 
a p pr o ve d i nf or me d c o nse nt f or m (I C F).  S u bjects e nteri n g t he st u d y will be dia g n ose d wit h S B S; 
t he y will ha v e at m ost 7 0 % of t heir e x pecte d b o w el le n gt h pres er ve d or f u n cti o ni n g, re q uiri n g 
P N b y i ntra v e n o us (I V) i nf usi o n; t he y will ha ve a t otal b o d y wei g ht of at least 5 0 0 gra ms 
( 1 7. 6 o u nces) a n d be at least 2 8 wee ks of gestati o n i n a ge at t he ti me of e ntr y i nt o t he st u d y.  At 
ti me of st u d y e ntr y, s u bjects s h o ul d be a ble t o t olerate at least 1 0 m L/ k g/ da y of E N b ut n ot less 
t ha n 7 0 % of P N base d o n cal oric i nta ke f or at least 7 da ys.  
Eac h s u bject, after p are nt(s) or le gal g u ar dia n(s) c o nse nt t o t he st u d y, will c o m plete scree ni n g 
assess me nts.  Scree ni n g e val uati o ns will i ncl u de assess me nt of e ntr y criteria, me dical hist or y, as 
well as a c o m plete p h ysi cal e x a mi nati o n, b l o o d c he mistr y, he m at ol o g y a n d uri nal ysis 
e val uati o ns, E K G a n d c o nc o mita nt me diati o ns. 
After meeti n g all scree ni n g a n d b aseli ne criteria, s u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 
eit her 8 I U/ k g/ da y N T R A- 9 6 2 0, 4 I U/ k g/ da y N T R A- 9 6 2 0, or matc hi n g place b o.  
Ra n d o mizati o n, w hic h will be perf or me d ce ntrall y, will be stratifie d b y  esti mate d perce nt le n gt h 
of t he re mai ni n g s mall i ntesti ne ( L  < 5 0 % or 5 0 % ≤ L ≤ 7 0 %; w h ere L is re mai ni n g le n gt h of 
s mall i ntesti ne relati ve t o t he e x pecte d le n gt h f or gestati o nal a ge (1 3 )) a n d prese nce or a bs e nce 
of a n ile ocecal val v e.  Ra n d o mizati o n will ta ke place as cl os e as p ossi ble t o treat me nt i nitiati o n 
a n d n ot m ore t ha n 2 4 h o urs bef or e t he first d ose of st u d y me dicati o n.  
D uri n g t h e 2 4- wee k treat me nt peri o d, s u bjects are e x pecte d t o be o n P N/I V f or all or m ost of t he 
treat me nt peri o d a n d t h us are e x pecte d t o b e h os pitalize d f or a p pr o xi matel y 1 2 wee ks, b ut t he y 
ma y b e release d s o o ne r acc or di n g t o l ocal i nstit uti o n’s S O C. 
All s u bjects will recei ve S O C P N/I V a n d e nt eral fee di n gs c o ntai ni n g N T R A - 9 6 2 0 or matc hi n g 
place b o.  N T R A- 9 6 2 0 or matc hi n g place b o will b e d ose d t o tar get a n i ns uli n d ose of 1 I U/ k g or 
2 I U/ k g a d mi nistere d f o ur ti mes a da y, s pace d as e q uall y o ver 2 4 h o urs as p ossi ble (i deall y at 
e ver y si x h o urs, b ut n o less t ha n 3 h o urs bet wee n a n y t w o d os es).  T he st u d y me dicati o ns ca n be 
rec o nstit ute d i n n or mal ( 0. 9 %) or half n or mal ( 0. 4 5 %) sali ne ( N a Cl) a n d a d mi nistere d 
c o nc o mita ntl y wit h S O C i nfa nt f or m ula, d o n or breast mil k, or o w n m ot her’s mil k ( O M M) use d 
f or e nter al fee ds.  D uri n g t he h os pitalizati o n peri o d, d osi n g will be perf or m e d as a b ol us 
a d mi nistrati o n f o ur ti mes a da y.  I n h o me care, s u bjects will recei ve N T R A - 9 6 2 0 or matchi n g 
place b o f o ur ti mes a da y as well.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 1  of 7 1  
S u bjects will c o nti n ue treat me nt f or t he f ull 2 4 wee ks of d osi n g re gar dless of t he % P N use (i.e., 
e ve n if s u bject is wea ne d off P N).  D ose i nterr u pti o ns o ver t he 2 4 wee k st u d y treat me nt peri o d 
will o nl y b e all o we d at i n vesti gat or discreti o n (i.e., n ot hi n g b y m o ut h ( n p o) f or pr oce d ure.)  N o 
d ose i nterr u pti o n s h o ul d last m ore t ha n 7 c o nsec uti ve da ys.  D uri n g t he first 1 2 wee ks w h e n t he 
s u bject is li kel y t o be h os pitalize d, t he s u bject s h o ul d e x perie nce n o m ore t ha n 1 0 da ys of d ose 
i nterr u pti o n.  D uri n g wee ks 1 2 t o 2 4, w he n t he s u bject ma y be at h o me or at a sec o n dar y facilit y, 
t he s u bject s h o ul d e x perie nce n o m or e t ha n 1 5 da ys of d os e i nterr u pti o n.  T he dail y P N a n d E N 
i nta ke f or eac h s u bject will be rec or d e d i n a st u d y diar y.  S u bjects will be assesse d wee kl y or 
o nce e v er y t w o w ee ks as descri be d o n t he Sc h e d ul e of St u d y Pr oce d ures ( A p pe n di x B ) f or t he 
treat me nt peri o d.  M ost s u bjects will re mai n h os pitalize d f or at least 1 2 wee ks t o c ollect acc urat e 
P N a m o u nts, b ut s o me ma y b e rel ease d fr o m t he i nstit uti o n per l ocal S O C.  S u bjects will 
c o nti n ue treat me nt f or t he f ull 2 4 wee ks of d osi n g re gar dl ess of t he % P N use (i.e., e v e n if s u bject 
is wea ne d off P N).  E nter al  n utriti o n i ncl u des S O C i nfa nt f or m ula, d o n or breast mil k, or o w n 
m ot her's mil k (as d etaile d i n  A p pe n di x A ).  S u bjects will c o nti n ue o n S O C fee di n gs aft er t he 2 4 
wee k i nter v e nti o n peri o d.  A fi nal st u d y statistical a nal ysis of efficac y  a n d safet y will be 
c o n d ucte d at Wee k 2 8, 4 wee ks after t he e n d of d osi n g.  All s u bjects will be f urt her f oll o w e d f or 
l o n g-ter m safet y t hr o u g h Wee k 1 0 4; t hese safet y d ata will be re p orte d as a n a d de n d u m t o t he 
fi nal cli nical st u d y re p ort. 
3. 2.  
D O S E R A TI O N A L E  
T h is is a place b o–c o ntr olle d, t w o d ose le vel st u d y.  T he c h oice of t he pr o p ose d d osi n g re gi me n 
of 1  I U/ k g or 2 U/ k g 4 ti mes a da y ( 4 I U/ k g/ da y a n d 8 I U/ k g/ d a y res p ecti vel y) is b ase d o n a 
series of st u dies i n S B S a ni mal m o dels a n d o n t w o i n de pe n de nt cli nical st u dies.  M ore o ver, 
N utri nia c o n d ucte d a re p eate d - d os e, l ocal GI t o xic ol o g y st u d y wit h N T R A- 9 6 2 0 ( 4 I U/ k g/ da y 
a n d 4 0 I U/ k g/ da y) t o s u p p ort t he pr o p ose d cli nical d oses ( 4 I U/ k g/ da y a n d 8 I U/ k g/ d a y). 
I n t he first cli nical st u d y, pre-ter m i nf a nts ( 2 6- 2 9 wee ks  of gestati o nal a ge) were d os e d 
4 I U/ k g/ d a y f or 2 8 d a ys i n or der t o assess w h et her e nteral a d mi nistrati o n of i ns uli n t o preter m 
i nfa nts w o ul d e n ha nce GI a da ptati o n a n d re d uce e nteral fee di n g i nt olera nce wit h o ut a d verse 
effects (1 4 ).  N o dr u g-r elate d a d verse effect, s uc h as h y p o gl yce mia, was o bser ve d after 
a d mi nistrati o n of i ns uli n.  T he i nfa nts w h o recei v e d i ns uli n ha d hi g her lactase acti vit y a n d less 
fee di n g i nt olera n ce t ha n t he c o ntr ols ( 3 0 % s h ort er ti me t o f ull e nteral fee ds; fe wer gastric 
resi d uals per i nf a nt).  T h us, t he pr o p ose d d osi n g re gi me n was effecti ve a n d di d n ot s u g gest a n y 
safet y c o n cer ns. 
A sec o n d cli nical st u d y was perf or me d wit h t he s a me d osi n g re gi me n i n i nfa nts a n d y o u n g 
c hil dre n wit h S B S (1 5 ).  I nfa nts i n t he trial ha d 8- 4 0 c m re mai ni n g b o wel a n d were n ot e x pecte d 
t o wea n off T otal Pare nteral N utriti o n ( T PN).  O n a vera ge, e nteral i nta ke i n creas e d fr o m 
4 5. 6 % ± 3 0. 6 ( Mea n ± S D) t o 5 8. 9 % ± 2 8. 2, a n d A L T bl o o d le v els decrease d fr o m 
1 9 4 ± 1 2 8 U/ L t o 1 3 6 ± 7 9 U/ L.  T w o ( 2/ 1 0) i nfa nts were w ea ne d off P N a n d sta ye d off P N.  
N o ne of t he c hil dre n de v el o pe d i ns uli n a nti b o dies.  I n t hat st u d y, oral i ns uli n s u p ple me ntati o n i n 
pe diatric S B S was n ot ass ociate d wit h si de effects.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 2  of 7 1  
T he c h oice of t he pr o p os e d d osi n g r e gi me n of 4 or 8 I U/ k g/ da y is base d o n a series of st u dies i n 
S B S a ni mal m o dels a n d pre d o mi na ntl y o n 2 cli nical st u dies as descri be d a b o ve.  N o d ose use d 
pre vi o usl y raise d a n y s af et y c o ncer ns.  T he d ose l e vels are s u p p orte d b y a G L P l ocal GI t o xicit y 
st u d y assess e d i n ne o natal mi ni pi gs ( 2 6-wee k G L P re peat -d ose t o xicit y st u d y i n mi ni pi gs).   
T he l o wer d os e of 4 I U/ k g/ da y h as bee n pre vi o usl y use d i n S B S c hil dre n (1 5 ) a n d i n preter m 
i nfa nts (1 4 ), s h o wi n g pr o misi n g efficac y res ults.  T he s u g geste d sec o n d d ose le vel is d o u ble t he 
cli nicall y teste d d os e, re mai ni n g bel o w t he d os e le vel use d i n t he 2 6- w ee k G L P re peat -d ose 
t o xicit y st u d y i n mi ni pi gs. 
T he decisi o n t o di vi de t he d ose i nt o 4 dail y a d mi nistrati o ns is base d o n pre vi o us cli nical 
e x perie nce.  T h e rati o nal e is t o pr ol o n g t he l ocal i ntesti nal e x p os ure t o i ns uli n.  Eac h d ose will be 
c o m pare d a gai nst place b o i n eac h pri mar y a n d sec o n dar y a n al ysis.  
3. 3.  
D O SI N G  
All t hree gr o u ps will recei ve N T R A - 9 6 2 0 or matc hi n g place b o f o ur ti mes per da y. 
Gr o u p 1:  N T R A- 9 6 2 0 2 I U/ k g f or eac h d ose ( 8 I U/ k g per da y) 
Gr o u p 2:  N T R A- 9 6 2 0 1 I U/ k g f or eac h d ose ( 4 I U/ k g per da y) 
Gr o u p 3:  Matc hi n g place b o 
3. 4.  
S T U D Y E N D P OI N T S  
3. 4. 1.  
C o -Pri m ar y E n d p oi nts  
T h is trial has t w o c o-pri m ar y e n d p oi nts . 
T he first c o- pri mar y e n d p oi nts is t he perce nt c ha n ge i n % P N ( P C _ P N 0-t) fr o m baseli ne6 base d o n 
cal oric i nta ke t o 1 2 wee ks  a n d a gai n t o 2 4 wee ks.  T he 1 2 a n d 2 4 w ee k e n d p oi nts are cal c ulate d 
as: 
P C _P N 0 −t =  1 0 0 ∗ % P N B a s eli n e  − %P N t
% P N
B a s eli n e
 
W here  
•  t = 1 2 or 2 4 wee ks   
•  % P N = % Par e nteral N utriti o n (fee di n g) will be calc ulate d as pare nteral cal ories di vi de d b y  
calc ulate d t otal cal oric re q uire me nts (t he Sc h ofiel d e q uati o n (1 )). 
•  P C _ P N 0- t o bser vati o ns will be c o m p ute d as a n o ver a si n gl e wee k.  
T h us, P C _ P N at 1 2 wee ks will be t he a vera ge of P C _ P N o ver Da ys 7 8 t o 8 4. 
P C _ P N at 2 4 wee ks will be t he a vera ge of P C _ P N o ver da ys 1 6 2 t o 1 6 8. 
                                                 
6 B aseli ne: pri or t o treat me nt. B aseli ne  meas ure me nt  peri o d s h o ul d be at least 7 da ys . 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 3  of 7 1  
T he sec o n d c o - pri mar y e n d p oi nts are res p o n d er e n d p oi nts. T he o utc o me varia ble f or eac h 
s u bject will be t he sa me o utc o me as f or t he first pri mar y, b ut t he statistical test will be calc ulate d 
as c o nti n u o us res p o n der c o m paris o ns at 1 2 wee ks a n d a gai n at 2 4 w ee ks. 
3. 4. 2.  
Sec o n d ar y E n d p oi nts  
3. 4. 2. 1.  
Ke y Sec o n d ar y E n d p oi nts  
Ti me t o r e d ucti o n of P N t o less t ha n 1 0 % of t he t otal cal oric i nta ke o n 1 4 c o nsec uti ve da ys.  
3. 4. 2. 2.  
Sec o n d ar y E n d p oi nts  
Ot her Sec o n d ar y E n d p oi nts  
a)  Ti me t o wea n off 7 pare nt eral n utriti o n 
b)  N u m ber of patie nts ac hie vi n g rea di ness t o wea n off  8 at 1 2 a n d 2 4 wee ks fr o m baseli ne   
c)  Ti me t o 5 0 % P N/I V re d u cti o n fr o m baseli ne i n % P N base d o n t otal cal ories.  
d)  Ti me t o 5 0 % P N/I V re d u cti o n fr o m baseli ne i n % P N base d o n v ol u me. 
e)  N u m ber of patie nts r eac hi n g 5 0% P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n t otal 
cal ories at 1 2 a n d 2 4 wee ks  
f) N u m ber of patie nts r eac hi n g 5 0 % P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n 
v ol u me at 1 2 a n d 2 4 wee ks. 
g)  Perce nt c h a n ge fr o m bas eli ne i n % P N/I V base d o n t otal cal ories.   
h)  Perce nt c h a n ge fr o m bas eli ne i n % P N/I V base d o n v ol u me.  
i) Perce nt c h a n ge fr o m bas eli ne i n P N/I V fl ui d v ol u me d uri n g treat me nt peri o d. 
j) C ha n ge i n Z-sc or es ( Fe nt o n) fr o m baseli ne d uri n g t he treat me nt peri o d. 
k)  Perce nt c h a n ge fr o m bas eli ne i n % E N base d o n t otal cal ories.  
l) Perce nt c h a n ge fr o m bas eli ne i n % E N base d o n t otal v ol u me.  
m)  C ha n ge fr o m bas eli ne i n li ver e nz y mes ( A L T, G G T, a n d t otal a n d direct bilir u bi n).  
n)  C ha n ge fr o m bas eli ne i n plas ma citr ulli ne le vels.  
o)  C ha n ge fr o m bas eli ne i n b o d y w ei g ht d uri n g t he treat me nt peri o d. 
p)  Wee kl y a v era ge of h o urs o n prescri be d P N/I V d uri n g t he last m o nt h of treat me nt. 
q)  Ge ner al safet y v aria bles i ncl u di n g e pis o des of si g nifica nt fee di n g i nt olera nce c o m pare d 
t o place b o 
                                                 
7 W ea n off defi ne d as c o m plete cessati o n of pare nteral n utriti o n a n d ac hie vi n g f ull e nteral a ut o n o m y f or t w o wee ks.  
8 R e d ucti o n t o P N of  less t ha n 1 0 % of t he t otal cal oric i nta ke  f or 14 c o nsec uti ve da ys.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 4  of 7 1  
3. 4. 3.  
St u d y P o p ul ati o n  
S u bjects i n t his trial are bet wee n 2 8 w ee ks p ost- m e nstr ual a ge 9a n d 5 2 wee ks c hr o n ol o gi cal a ge 
a n d, after t heir maj or s ur gical resecti o n, ha ve less t ha n or e q ual t o 7 0 % of t heir e x pecte d b o wel 
le n gt h r e mai ni n g a n d r e q uire at least 7 0 % p are nt eral s u p p ort ( P N/I V) at st u d y e n d. 
3. 4. 4.  
I ncl usi o n Criteri a 
S u bjects m ust meet all  of t he f oll o wi n g criteria t o be i ncl u de d: 
1)  S u bject m ust be at least 2 8 wee ks p ost- me nstr u al a ge a n d u p t o 5 2 wee ks c hr o n ol o gical 
a ge at e nr oll me nt. 
2)  S u bject wei g ht m ust be at least 5 0 0  gra ms ( 1 7. 6 o u nces) at ti me of e nr oll me nt.  
3)  Cli nicall y di a g n ose d wit h S B S re q uiri n g P N/I V s ec o n dar y t o s ur gical resecti o n of t he 
i ntesti ne. 
4)  After maj or s ur gical r esecti o n lea di n g t o S B S, t he s u bject has ma xi m all y 7 0 % of 
e x pecte d b o wel le n gt h pr eser ve d  or a n ost o m y i n place s uc h t hat ≤ 7 0 % of t he s mall 
b o wel is a vaila ble f or a bs or pti o n 1 0. 
5)  S u bject ca n t olerat e at least 1 0  m L/ k g/ da y of E N f or at least 7 da ys at ti me of e nr oll me nt.  
6)  At ti me of e nr oll me nt s u bject is o n at least 7 0 % of prescri be d P N/I V a n d n o m ore t ha n 
3 0 % of e nter al n utriti o n base d o n t otal cal ori c i nta ke f or at least 7 da ys pri or t o st u d y 
e ntr y. 
7)  S u bject is ra n d o mize d i nt o t he trial wit hi n 4 m o nt hs fr o m t he s ur gical resecti o n t hat has 
le d t o t he dia g n osis of S B S 
8)  S u bject’s pare nt(s) or le gal g u ar dia n(s) pr o vi de writte n i nf or me d c o nse nt. 
9)  S u bject’s pare nt(s) or le gal g u ar dia n(s) u n dersta n d a n d are willi n g t o c o m pl y wit h all 
st u d y pr oce d ur es a n d r e q uire me nts. 
3. 4. 5.  
E xcl usi o n Criteri a  
S u bjects meeti n g a ny  of t he f oll o wi n g criteria at st u d y e ntr y will be e x cl u de d:  
1)  S u bject has u n der g o ne a n y b o w el le n gt he ni n g pr oce d ure. 1 1 
2)  S u bject has a mala bs or pti o n dis or der s uc h as: 
•  C o n ge nital eti ol o g y  (s uc h as micr o villi i ncl usi o n disease, t ufti n g e nter o p at h y) 
•  U ntreate d Hirc hs pr u n g’s disease 
3)  Si g nifica nt m otilit y dis or der s uc h as:  
•  Pse u d o o bstr ucti o n 
                                                 
9 P ost me nstr ual a ge is defi ne d as gestati o nal pl us c hr o n ol o gi cal a ge  
1 0  % b o wel left is calc ulate d as t he a m o u nt of s mall b o wel re mai ni n g of t he t otal e x pecte d b o wel.  
1 1 T his criteria w o ul d be rele va nt t hr o u g h o ut t he i nter ve nti o n d urati o n.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 5  of 7 1  
•  Se vere gastr os c hisis defi ne d as:  pri mar y reas o n f or P N s u p p ort is d ue t o 
persiste nt fee di n g i nt olera nce of l ess t ha n 2 0  ml/ k g/ da y E N i nta ke or si g ns a n d 
s y m pt o ms ( i.e., a b d o mi n al diste nti o n, v o miti n g) re q uiri n g pr o ki netic a ge nts. 
4)  A n y k n o w n i n h erite d a b n or malit y (e. g., Fa nc o ni s y n dr o me,) t hat is n ot relate d t o S B S. 
5)  Pri or b o wel resecti o n d ue t o is olate d s p o nta ne o us i ntesti nal perf orati o n. 
6)  < 1 0 c m of r e mai ni n g s m all b o wel left wit h n o c ol o n.  
7)  U nc o ntr olle d s yste mic i nfecti o n, ac ut e gastr oe nt eritis, p ne u m o nia, car di o vasc ular or 
ot her a b n or malit y i ncl u di n g E K G fi n di n gs t h at i n t he o pi ni o n of t he i n vesti gat or ma kes 
t he i nfa nt u nsta ble a n d at si g nifica nt ris k of n ot c o m pleti n g t he first 1 2 wee ks of t he 
st u d y. 
8)  S u bjects wit h k n o w n h y p eri ns uli ne mia (1 6 )1 2.  
9)  S u bjects wit h u ne x plai ne d or rec urre nt h y p o gl yce mia wit h bl o o d gl uc ose ≤ 5 0 m g/ d L 
wit hi n 4 8 h o urs of treat m e nt i nitiati o n. 
1 0)  S u bjects wit h se vere a n e mia  ( he m o gl o bi n less t ha n 6 0 g/ L ) a n d re q uiri n g tra nsf usi o n 
wit hi n 4 8 h o urs of treat m e nt i nitiati o n. 
1 1)  S u bjects  w h o re q uire p a n creatic e nz y me re place m e nt t hera p y.  
1 2)  S u bject is c urre ntl y recei vi n g oral or i njecta ble i ns uli n f or a n y reas o n. 
1 3)  Partici pati o n i n a n ot her i nter ve nti o nal cli nical st u d y wit hi n t he past 3 0 da ys t hat ma y 
i nterfer e wit h t he res ults of t his st u d y. 
1 4)  Hist or y or c urr e nt use of gr o wt h fact ors or gl uta mi ne.  
1 5)  I n t he o pi ni o n of t h e i n vesti gat or, t he s u bject has a n y ot her m e dical c o n diti o n t hat w o ul d 
ma ke partici pati o n i n t his st u d y eit her u ns afe or w o ul d c o m pr o mise t he p ote ntial be nefit 
of i ns uli n treat me nt . 
4.  
S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T  
See A p pe n di x B:  Sc he d ule of St u d y Pr oce d ures  f or ti mi n g of t he ass ess me nts.  
4. 1.  
D E FI NI TI O N S O F S T U D Y P R O C E D U R E S  
4. 1. 1.  
I nf or me d C o nse nt 
Pri or t o i nitiati o n of a n y st u d y pr oce d ure, eac h s u bj ect’s pare nt(s) or le gal g uar dia n(s) will 
u n der g o a n I nf or me d C o nse nt pr ocess i n w hic h t h e y v ol u ntaril y c o nfir m t h eir willi n g ness t o 
i ncl u de t heir c hil d i n t he trial, after h a vi n g b ee n i nf or me d of all as p ects of t he trial rele v a nt t o 
t heir decisi o n a b o ut t heir c hil d’s partici pati o n.  T h e i n vesti gat or, or a p ers o n desi g nat e d b y t he 
i n vesti gat or, will f ull y i nf or m t he s u bject’s pare nt(s) or le gal g u ar dia n(s) of all perti ne nt as pects 
of t he trial.  I n a d diti o n, t he i n vesti gat or or desi g n ee will i nf or m t he s u bj ect’s pare nt(s) or le gal 
                                                 
1 2 I n or d er t o d efi ne h y peri ns uli ne mia all criteria m ust be met: 
a. 
Gl u c ose re q uire me nts >  6- 8 m g/k g/ mi n t o m ai nt ai n bl o o d gl uc ose a b ove 2. 6 - 3 m m ol/litre  
b.  
L a b or at ory bl o o d gl uc ose <  2. 6  m m ol/litre ( m g/liter)  
c. 
Detect a ble i ns uli n at t he p oi nt of hy p o glyc ae mi a wit h r aise d C pe pti de  
d.  
I n a p pr o pri ately l o w bl o o d free f atty aci d a n d ket o ne b o dy c o nce ntr ati o ns at t he ti me of hy p o glyc ae mi a 
e. 
Glyc a e mic res p o nse after t he a d mi nistr ati o n of gl uc a g o n w he n hy p o glyc ae mic  
f. 
A bse n ce of ket o n uri a  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 6  of 7 1  
g uar dia n(s) t h at t he y ar e free t o r ef use t o e nter t heir c hil d i n t he st u d y or t o wit h dra w t he c hil d 
fr o m t he st u d y at a n y ti me, f or a n y reas o n.  T he s u bject’s pare nt(s) or le gal g uar dia n(s) s h o ul d 
als o be i nf or me d t hat f or mal trai n i n g f or h o me care a n d d osi n g of t he st u d y me dicati o n t o t he 
i nfa nt will be re q uire d. 
T he I C F a p pr o ve d b y t he I R B/I E C will c o ntai n a descri pti o n of t he st u d y’s p ur p ose, pr oce d ures, 
i nc o n ve nie nces, a n d p ote ntial ris ks, a n d a ntici pate d be nefits. 
Pri or t o a s u bject’s partici pati o n i n t he trial, a n I C F will be si g n e d a n d pers o nall y dat e d b y t he 
s u bject’s par e nt(s) or le gal g u ar dia n(s) a n d b y t he pers o n w h o c o n d u cte d t h e I nf or me d C o ns e nt 
disc ussi o n.  
If a s u bject’s par e nt(s) or le gal g u ar dia n(s) is u na ble t o rea d, t he I nf or me d C o nse nt ma y be rea d 
t o t he s u bject’s par e nt(s) or le gal g uar di a n(s), pr o vi de d t hat a n i m partial wit ness is prese nt d uri n g 
t he e ntire I nf or me d C o ns e nt disc ussi o n.  After t he writte n I C F is rea d a n d e x plai ne d t o t he 
s u bject’s par e nt(s) or le gal g u ar dia n(s) a n d after t he y h a ve orall y c o nse nte d t o i ncl u de t heir c hil d 
i n t he trial a n d, if ca p a ble of d oi n g s o, ha v e si g ne d a n d pers o nall y dat e d t he I C F, t he wit ness 
s h o ul d als o si g n a n d pers o nall y dat e t he I C F.  B y si g ni n g t he I C F, t he wit ness attests t hat t he 
i nf or mati o n i n t he I C F w as acc uratel y e x plai ne d t o, a n d a p pare ntl y u n d erst o o d b y, t he s u bject’s 
pare nt(s) or le gal g uar dia n(s) a n d t hat I nf or me d C o nse nt was freel y gi ve n b y t he s u bject’s 
pare nt(s) or le gal g uar dia n(s).  
Pri or t o partici pati o n i n t he trial, t he s u bject’s p are nt(s) or le gal g u ar dia n(s) will recei v e a c o p y 
of t he si g n e d a n d dat e d writte n I C F.  D uri n g p artici pati o n i n t he trial, t he s u bject’s pare nt(s) or 
le gal g u ar dia n(s) will recei ve a c o p y of a n y si g ne d a n d date d re vise d c o nse nt f orms, a n d a c o p y 
of a n y a me n d me nts t o t h e writte n i nf or mati o n pr o vi de d t o s u bject’s pare nt(s) or le gal 
g uar dia n(s).  
T he I C F ma y b e si g n e d b y t he s u bject’s pare nt(s) or le gal g uar di a n(s) pri or t o t he b o wel 
resecti o n a n d u p t o 3 0 d a ys pri or t o i nitiati o n of dosi n g i n t he trial.  
T he i n vesti gat or s h o ul d d oc u me nt i n t he s o urce d ata t hat t he I nf or me d C o ns e nt F or m w as si g n e d 
pri or t o s u bject’s partici p ati o n i n t he st u d y a n d acc or di n g t o t he I nt er nati o nal C o nfere nce o n 
Har m o nizati o n (I C H) g ui deli nes, as descri be d a b o ve. 
4. 1. 2.  
Me dic al Hist or y a n d De m o g r a p hics  
T he s u bject ’s me dical hist or y will  be f ull y d oc u m e nte d at scree ni n g t o e ns ure c o m plia nce wit h 
st u d y eli gi bilit y criteria.  Me dical hist or y i nf or mati o n m ust i ncl u de, b ut n ot be li mite d t o, past 
a n d prese nt me di cal c o n d iti o ns, c o nc o mita nt n o n-dr u g treat me nts a n d h y p erse nsiti vit y t o dr u gs.   
A n y e ve nt t hat occ urs bef ore st u d y dr u g d osi n g will be rec or d e d as me dical hist or y. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 7  of 7 1  
4. 1. 3.  
M ater n al D at a  
At scree ni n g, d ata o n t he i nfa nt’s m ot her will be c ollecte d i ncl u di n g a ge, m e dical his t or y of a n y 
c o n ge nital a b n or malities a n d c o m plicati o ns d uri n g gestati o n or d eli ver y. 
4. 1. 4.  
P h ysic al E x a mi n ati o n 
T he i n vesti gat or will c o n d uct a c o m plete p h ysical e x a mi nati o n at scree ni n g a n d o n Da y 8 4 
( Wee k 1 2), Da y 1 6 8 ( Wee k 2 4), a n d D a y 1 9 6 ( Wee k 2 8).  A li mite d pr o ble m-orie nte d p h ysical 
e x a mi nati o n will be perf or me d o n eac h visit bet wee n Wee k 1 2 ( D a y 8 4) a n d Wee k 2 4 ( Da y 
1 6 8):  Da ys  9 8, 1 1 2, 1 2 6, 1 4 0, a n d 1 5 4, if nee d e d.   
4. 1. 5.  
Wei g ht a n d B o d y Le n gt h 
S u bjects’ wei g ht a n d b o d y le n gt h will be meas ure d at scree ni n g, b aseli ne, a n d ra n d o mizati o n.  
Wei g ht a n d b o d y le n gt h will be meas ure d w ee kl y at eac h st u d y e v al uati o n (at t he i n -patie nt 
i nstit uti o n) or visit if t he s u bject has bee n disc h ar ge d fr o m t he site fr o m s cree ni n g t hr o u g h 
Da y  1 9 6 ( Wee k 2 8).  L o n g-ter m saf et y e val uati o ns p ost pri mar y st u d y c o m pleti o n will als o 
i ncl u de meas ur e me nt of s u bjects’ wei g ht a n d b o d y le n gt h o n D a y 3 6 4 ( Wee k 5 2) a n d D a y  7 2 8 
( Wee k 1 0 4). 
4. 1. 6.  
He a d Circ u mf ere nce  
T he s u bject’s hea d cir c u mfere n ce will be meas ure d at scree ni n g, ra n d o mi zati o n a n d at eac h  
wee kl y st u d y e val uati o n (at t he i nstit uti o n) or visit, if disc har ge d, t hr o u g h Da y 1 9 6 ( Wee k 2 8).  
L o n g -t er m saf et y e val uati o ns will als o be c o n d ucte d after st u d y c o m pleti o n o n Da y 3 6 4 
( Wee k 5 2) a n d D a y 7 2 8 ( Wee k 1 0 4). 
4. 1. 7.  
Vit al Si g ns  
T he s u bject’s vital si g ns  will be meas ure d at scree ni n g , bas eli ne, a n d ra n d o mizati o n i n or der t o 
e ns ure c o m plia n ce wit h st u d y i ncl usi o n criteri a.  Vital si g ns will als o be meas ure d at eac h st u d y 
e val uati o n (at i nstit uti o n), or visit if disc har ge d, fr o m scree ni n g t o Da y 1 9 6 ( Wee k 2 8).  
Vital si g n meas ur e me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y 
rate, a n d b o d y te m p erat ure. 
4. 1. 8.  
Electr oc a r di o gr a m ( E K G)  
T he s u bject’s E K G will be perf or me d at scree ni n g i n or der t o e ns ure c o m plia nce wit h st u d y 
i ncl usi o n criteria.  T he E K G is t o be perf or me d o n at least a tri plicate of h eart beats f or all 
meas ure me nts a n d will be rec or de d at a s pee d of 2 5  m m/sec a n d a n a m plit u de of 1 0 m m/ m V.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 8  of 7 1  
C o m p uterize d E K G a nal ysis will i ncl u de:  heart rate, R - R i nter val, si n us r h yt h m, P R i nter val, 
Q R S a xis, a n d Q R S d urati o n.  Q T i nter val a n d Q T c F will be calc ulate d ma n uall y acc or di n g t o 
t he Fri dericia f or m ula.   
4. 1. 9.  
Cli nic al L a b or at or y Tests 
Cli nical la b orat or y tests will be c o n d ucte d at scree ni n g i n or d er t o e ns ure c o m plia nce wit h st u d y 
i nclusi o n criteria.  A d diti o nal tests will be c o n d uct e d o n differe nt st u d y visits acc or di n g t o t he 
sc he d ule as writte n i n t he secti o ns bel o w.  T he ma xi m u m v ol u me of c ollecte d bl o o d w o ul d n ot 
e x cee d 3 m L/ K g o v er 2 4 h o urs a n d u p t o 5 0 m L t otal v ol u me o ver 8 wee k s. All la b orat or y test 
res ults re q uire d b y t his pr ot oc ol will be rec or d e d i n t he E D C f or e v al uati o n of a n y c ha n ge o ver 
ti me d uri n g treat me nt.  T he i n vesti gat ors will assess e ver y o ut - of-ra n ge la b orat or y val ue a n d 
dee m eac h as eit her cli nicall y si g nifica nt or n ot cli nicall y si g nifica nt.  V al ues t hat re prese nt a 
c ha n ge fr o m baseli ne i n s u bject’s me dical stat us acc or di n g t o t he la b orat or y n or mal ra n ges a n d 
c o nsi dere d as cli nicall y si g nifica nt will be a de q uat el y d o c u me nte d as a n a d verse e v e nt ( A E) as 
descri be d i n Secti o n 7. 1. 1 . 
4. 1. 9. 1.  
Bl o o d C o u nt 
He mat ol o g y t ests will be c o n d ucte d at scree ni n g i n or der t o e ns ure c o m plia n ce wit h st u d y 
i ncl usi o n criteria.  A d diti o nal he mat ol o g y t esti n g will be c o n d ucte d o n st u d y visit Wee k 1 2 
( Da y 8 4) a n d Wee k 2 4 ( Da y 1 6 8)/ Earl y T er mi nati o n.  Re peat testi n g at f oll o w- u p visit Wee k 2 8 
( Da y 1 9 6) will be p erf or me d o nl y if a b n or mal cli nicall y si g nifica nt val ues are o btai ne d at t he 
Wee k  2 4 ( Da y 1 6 8) visit. 
He mat ol o g y t ests will i ncl u de:  w hite bl o o d cells ( W B C), re d bl o o d cells ( R B C), he m o gl o bi n, 
he mat ocrit, mea n c or p us c ular v ol u me ( M C V), mea n c or p usc ul ar he m o gl o bi n ( M C H), mea n 
c or p usc ular h e m o gl o bi n c o nce ntr ati o n ( M C H C), r e d cell distri b uti o n wi dt h  ( R D W), platelets, 
a n d mea n platelet v ol u m e ( M P V).  
Testi n g i ncl u des R B C m or p h ol o g y a n d retic ul oc yte c o u nt. 
4. 1. 9. 2.  
Ser u m C he mistr y  
Testi n g of bl o o d c h e mistr y v al ues will be c o n d u cte d at scree ni n g i n or der t o e ns ure c o m plia n ce 
wit h st u d y i ncl usi o n criteria.  A d diti o nal ser u m c h e mistr y testi n g will be w ee kl y w he n p atie nts 
are i n the h os pital a n d at st u d y visits  w he n patie nts are i n a h o me care setti n g. Re peat testi n g at 
f oll o w- u p visit Wee k 2 8 ( Da y 1 9 6) will o nl y be p erf or me d if a b n or mal cli nicall y si g nifica nt 
val ues ar e o btai ne d at W ee k 2 4 ( D a y  1 6 8) visit. Ser u m c he mistr y will i nc l u de ser u m al kali ne 
p h os p hatase, tri gl yceri de, A L T, A S T, G G T, gl uc ose, calci u m, p h os p h or us, c hl ori de, s o di u m, 
p otassi u m, B U N, cr eati ni ne, t otal a n d direct bilir u bi n, al b u mi n, t otal pr otei n, a m ylas e, 
bicar b o nate/ car b o n di o xi de ( C O 2), uric aci d, a n d l actate d e h y dr o ge n ase ( L D H).  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 2 9  of 7 1  
4. 1. 9. 3.  
Uri n al ysis  
Uri nal ysis will be c o n d u cte d at scr ee ni n g.  A d diti o nal testi n g will be c o n d ucte d o n st u d y visit 
Wee k 1 2 ( Da y 8 4) a n d Wee k 2 4 ( Da y 1 6 8)/ E arl y Ter mi nati o n.  Re peat testi n g at f oll o w - u p visit 
Wee k 2 8 ( Da y 1 9 6) will o nl y be p erf or m e d if a b n or mal cli nicall y si g nifica nt val ues are o bt ai ne d 
at t he Wee k  2 4 ( Da y 1 6 8) visit. 
Uri nal ysis will i ncl u de:  nitrite, Na, K, Ca, P, Pr otei n, R B C, W B C, bl o o d, gl uc ose, ket o ne 
b o dies, bilir u bi n (c o nj u gate d), ur o bili n o ge n, uri ne s pecific gra vit y, os m olarit y, a n d p H. 
4. 1. 9. 4.  
Pl as m a Cit r ulli ne  
Testi n g of plas m a citr ulli ne val ue will be c o n d u cte d at baseli ne i n or der t o esta blis h a baseli ne 
le vel.  A d diti o nal testi n g will be c o n d ucte d o n st u d y visit Wee k 1 2 ( Da y 8 4) a n d Wee k 2 4 
( Da y 1 6 8)/ Earl y Ter mi nati o n.   
4. 1. 9. 5.  
Bl o o d Gl uc ose Le vels  
Bl o o d gl uc ose m o nit ori n g will be perf or me d pre- d ose at ra n d o mizati o n ( D a y 0) a n d o n D a ys 1, 
2, a n d 3, a n d t wice a wee k f or t he rest of t he treat me nt peri o d  w hile h os pitalize d . If s u bjects are 
disc har ge d h o me t h e test w o ul d be d o ne o n e ac h visit o nce a wee k. I n a d diti o n, a n y a b n or malit y 
i n bl o o d gl uc ose le v els t hat w o ul d be ca pt ure d o utsi de of t hese tests, w o ul d als o be re p ort e d. 
T his is a part of sta n dar d m o nit ori n g c o n d ucte d o n t his p o p ulati o n. 
4. 1. 9. 6.  
A nti -I ns uli n A nti b o dies 
Bl o o d will be dra w n t o test f or t he pres e nce of a nti-i ns uli n a nti b o dies at baseli ne .  A d diti o nal 
a nti-i ns uli n a nti b o d y testi n g will be c o n d u cte d o n st u d y visit Wee k 1 2 ( Da y 8 4) a n d Wee k 2 8 
( Da y 1 9 6).  
4. 1. 1 0.  
E pis o des of Si g nific a nt Fee di n g I nt oler a nce  
E pis o des of si g nifica nt fee di n g i nt oler a nce will be c ollecte d t hr o u g h o ut t he st u d y peri o d at 
baseli ne, ra n d o mizati o n, i nitial treat me nt peri o d ( Da ys 1, 2 a n d 3), at eac h wee kl y st u d y 
e val uati o n (at t he i nstit uti o n) or visit, if disc har ge d, t hr o u g h Wee k 1 2, a n d Wee k 2 4. 
Si g nifica nt f e e di n g i nt olera nce is d efi ne d as:  
•  T he nee d t o h ol d e nteral fee ds f or 2 4 h o urs. 
Reas o ns or re q uir e me nts t o h ol d fee di n gs m a y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  I n crease d st o ol o ut p ut (c o m pare d t o t he pre vi o us 2 4 h o urs or lea di n g t o peria nal 
e x coriati o n)  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 0  of 7 1  
•  I n crease d v o miti n g (ass o ciate d wit h resi d uals of pre vi o us fee ds, bili o us v o miti n g, 
i ncreas e of v ol u me of r e g ur gitati o n or n u m ber of e ve nts of e mesis c o m pare d t o t he 
pre vi o us 2 4 h o urs). 
•  A b d o mi nal diste nti o n (lea di n g t o a b d o mi nal p ai n wit h res pira t or y c o m pr o mise)  
4. 1. 1 1.  
C o nc o mit a nt Me dic ati o n  
All c o nc o mita nt me dicati o n gi ve n wit hi n 3 0 da ys pri or t o st u d y e ntr y will be d oc u me nte d.  
Dietar y s u p ple me nts, pr escri pti o n dr u g, a n d n o n- prescri pti o n dr u gs will be liste d at scree ni n g, at 
baseli ne, ra n d o mizati o n, a n d at eac h visit t hr o u g h t he Wee k 2 8 ( Da y 1 9 6) assess me nt.  After 
wee k 2 8, o nl y cli nicall y si g nifica nt me di cati o ns t hat are us e d t o treat p ote ntial a d verse effects of 
N T R A - 9 6 2 0 will be rec or de d at 5 2 a n d 1 0 4 wee ks.  T he i n vesti gat or will assess t he cli nical 
si g nifica n ce of t h e me dicati o n use.  Eac h e ntr y will i ncl u de t he treat me nt’s start date, 
me dicati o n/treat me nt na me ( ge neric), i n dicati o n f or use, d osi n g re gi me n ( d ose a n d fre q ue nc y of 
use), r o ute of a d mi nistrati o n, a n d st o p date (if a p plica ble) or o n g oi n g.  St u d y s u bjects will be 
r o uti nel y ass esse d f or c h a n ges i n t he a d mi nistrati o n of c o nc o mita nt me dicati o n d uri n g t he tri al. 
S u bjects ma y n ot r ecei v e t he f oll o wi n g me dicati o ns w hile o n st u d y:  
•  S yste mic i ns uli n a d mi nistrati o n u nless a n ac ute life -t hreate ni n g e ve nt occ urs.   
•  Ot her i n vesti gati o nal dr u gs or gr o wt h fact ors a n d gl uta mi ne. 
•  Pa ncreatic e nz y mes (re pl ace me nt t hera p y).  
C h olest yra mi ne, if gi v e n, s h o ul d be a d mi nistere d 2 h o urs a part fr o m st u d y me dicati o n beca us e of 
its p ote ntial t o a bs or b i ns uli n. 
A n y c o n c o mita nt me dicati o n a n d its p ote ntial t o i nterfere wit h t he st u d y me dicati o n will be 
disc usse d wit h t he i n vesti gat or. 
4. 1. 1 2.  
L o n g- Ter m F oll o w -U p Visits  
F oll o w- u p e v al uati o ns will be c o n d ucte d at 5 2 a n d 1 0 4 wee ks after i nitiati o n of treat me nt.  Eac h 
f oll o w- u p visit d uri n g t h e safet y f oll o w- u p peri o d will i ncl u de b o d y w ei g ht, b o d y le n gt h, hea d 
circ u mfere nce, pare nter a l n utriti o n i nta ke, e nteral n utriti o n i nta ke, re- h os pitalizati o ns a n d 
a d verse e ve nts . 
I n t his patie nt p o p ulati o n, S O C  visits are r o uti ne a n d ma y o cc ur b ef ore t he sc he d ule d st u d y visits 
o n wee ks 5 2 a n d 1 0 4.  T h us, a n y a vaila ble cli nical data o n b o d y wei g ht, b o d y le n gt h, hea d 
circ u mfere nce,  pare nter al n utriti o n i nta ke, e nteral n utriti o n i nta ke, re- h os pitalizati o ns a n d 
a d verse e ve nts  will be d o c u me nte d a n d e ntere d i n t he U nsc he d ule d Visit f or m a n d e ntere d i nt o 
t he e C R F.  T hese d ata will i ncl u de ne ur o de vel o p m e ntal Ba yl e y's sc ore c o g niti ve, la n g ua ge a n d 
m ot or d o mai ns at 2 Y c orrecte d a ge ( d etails of ne ur o de vel o p me nt assess me nt are i ncl u de d i n 
A p pe n di x D ).  If s uc h a r o uti ne Sta n dar d of Care visit is n ot c o n d ucte d or c o m plete data is n ot 
c ollecte d as p art of t hes e visits, t hese will n ot be c o nsi dere d missi n g dat a.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 1  of 7 1  
I n t he i nteri m, sc he d ule d tele p h o ne calls will be ma de t o t he patie nt a n d t he fa mil y e v er y t hree 
m o nt hs after wee k 2 8.  
4. 1. 1 3.  
A d verse E ve nts ( A Es)  
T he i nf or mati o n o btai ne d d uri n g st u d y visits, p h ysical e x a mi nati o ns, vital si g ns meas ure me nts, 
bl o o d testi n g, a n d b y a n y ot her mea ns will be e v al uate d i n li g ht of bas eli ne m e dical data a n d t h us 
pr o vi de t he basis f or i de ntificati o n a n d gra di n g of A Es. 
T he A Es re p orte d d uri n g t he trial will be gra de d (s ee Secti o n  7. 1 ), d oc u m e nte d, a n d assesse d i n 
li g ht of t heir cli nical si g nifica nce a n d relati o n t o i n vesti gati o nal pr o d u ct.  I n a d diti o n, t he 
f oll o wi n g i nf or mati o n r e gar di n g t h e A E m ust be o btai ne d a n d rec or d e d i n s u bject’s s o urce 
d oc u me nt a n d Case Re p ort F or m ( C R F):  A E descri pti o n, start date, e n d dat e (if a p plica ble) or 
o n g oi n g, se v erit y, s eri o us ness, i n vesti gat or’s assess me nt of t he relati o ns hi p of t he A E t o st u d y 
dr u g, o ut c o me (i.e., r es ol ve d, res ol ve d wit h se q u elae, o n g oi n g, deat h d u e t o t his A E, deat h d ue t o 
ot her e ve nts, u n k n o w n) a n d acti o n ta ke n (e. g., c o n c o mita nt me dicati o n).  I nf or mati o n re gar di n g 
occ urr e nce of A E m o nit ori n g will be ca pt ure d t hr o u g h o ut t he st u d y, fr o m D a y 7 (i nitiati o n of 
d osi n g) 2 8 da ys after t he fi nal pri mar y st u d y visit at Wee k 2 8 ( Da y 1 9 6).  A Es c o nsi dere d 
treat me nt relat e d b y t he I n vesti gat or will be d oc u me nte d after t he pri mar y st u d y c o m pleti o n o n 
Wee k  5 2 ( Da y 3 6 4) a n d Wee k 1 0 4 ( Da y 7 2 8) t o assess a n y p ot e ntiall y relate d a d vers e o utc o mes 
of treat me nt a n d re - h ospitalizati o ns.  Pre -treat me nt e mer ge nt e v e nts will n ot be c o nsi dere d as 
A Es , b ut will be rec or d e d as me dical hist o r y. 
Pri or t o t his c urre nt trial, f o ur cli nical trials i ncl u di n g t hree i n pret er m i nfa nts a n d o ne i n S B S 
i nfa nt s u bjects ha ve b ee n perf or me d wit h oral a d mi nistrati o n of i ns uli n.  N o treat me nt-relate d 
a d verse e ve nts ha v e bee n re p orte d a n d n o s yst e mic a bs or pti o n of i ns uli n has bee n detecte d. 
4. 1. 1 4.  
E v al u ati o n of Res p o nse 
4. 1. 1 4. 1.  P are nter al N utriti o n ( P N) I nt a ke  
P N i nta ke will be o btai ne d at scree ni n g, b aseli ne, ra n d o mizati o n, a n d at eac h st u d y visit (as 
descri be d i n A p p e n di x B ).  I n cas e of a n ac ute m e dical e ve nt d uri n g t he st u d y peri o d t he patie nt 
will be cli nicall y sta ble b ef ore st u d y visit occ urs.  T he t otal v ol u me a n d t he cal oric val u e of 
pare nteral n utriti o n a d mi nistere d will be rec or de d i n eac h st u d y visit.  T he dail y t otal a m o u nt of 
P N/I V, a n d n u m ber of h o urs per da y o n P N/I V will be e ntere d i nt o t he C R F.  F or patie nts 
disc har ge d h o me a diar y will be pr o vi de d t o c o nfir m prescri be d P N a n d E N i nta ke. 
4. 1. 1 4. 2.  E nter al N utriti o n ( E N) I nt a ke  
E N i nta ke will be o btai ne d at scree ni n g, b aseli ne, ra n d o mizati o n, a n d at eac h st u d y visit (as 
descri be d i n A p p e n di x B ).  I n cas e of a n ac ute m e dical e ve nt d uri n g t he st u d y peri o d t he patie nt 
will be cli nicall y sta ble b ef ore st u d y visit occ urs.  T he t otal v ol u me a n d  t he cal oric val u e of 
e nteral n utriti o n a d mi nistere d will be r ec or d e d i n eac h st u d y visit.  T he dail y  t otal a m o u nt of E N 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 2  of 7 1  
a n d cal oric c o nte nt will be e nter e d i nt o t he C R F .  F or patie nts disc har ge d h o me a diar y will be 
pr o vi de d t o c o nfir m pr escri be d E N a n d P N i nta ke. 
S oli ds i nta ke i nf or mati o n will be c ollecte d at t he site le vel a n d re p orte d b y t he i n vesti gat or as 
part of e nteral i nta ke i n t he C R F. 
Ne gli gi ble a m o u nts of br east mil k/f or m ula /s oli ds i nta ke t hat are o nl y pr o vi de d f or sti m ulati o n of 
s uc k a n d s wall o w c o or di nati o n a n d n ot use d as part of t he cal c ulati o ns f or pr o vi di n g a d e q uate 
cal oric nee ds f or gr o wt h will n ot be calc ulate d as part f or dail y e nt eral i nta ke.  
4. 2.  
S T U D Y VI SI T S  
4. 2. 1.  
Scree ni n g Pr oce d ures  
All i nf or mati o n c ollecte d a n d d oc u me nte d d uri n g scree ni n g pr o ce d ures will be re vie w e d t o 
e ns ure t hat t he s u bject satisfies eli gi bilit y re q uire me nts as descri be d b y t h e st u d y i ncl usi o n a n d 
e x cl usi o n criteria.  T his i nf or mati o n will be f ull y d oc u me nte d i n t he s u bject’s file.  
T he Scree ni n g Visit will be perf or me d at a  mi ni m u m 7 da ys pri or t o t he Baseli ne Visit.  St u d y 
scree ni n g pr o ce d ures will i ncl u de t he f oll o wi n g:  
•  I nf or me d C o nse nt - Secti o n 4. 1. 1  
•  Me dical Hist or y a n d D e m o gra p hi cs - Secti o n  4. 1. 2  
•  Mater nal D ata - Secti o n  4. 1. 3  
•  P h ysical E x a mi nati o n - Secti o n  4. 1. 4  
•  Wei g ht a n d B o d y Le n gt h - Secti o n  4. 1. 5  
•  Hea d Circ u mf ere n ce - Secti o n 4. 1. 6  
•  Vital Si g ns - Secti o n  4. 1. 7  
•  E K G - Secti o n  4. 1. 8  
•  Cli nical La b or at or y Tests - Secti o n  4. 1. 9  (as a p plica ble wit hi n Secti o n 4. 1. 9 ) 
•  C o nc o mita nt Me dicati o n Listi n g - Secti o n  4. 1. 1 1  
•  P N/I V a n d E N I nta k e - S ecti o ns  4. 1. 1 4. 1  a n d 4. 1. 1 4. 2  
4. 2. 2.  
B aseli ne  
All i nf or mati o n c ollecte d a n d d oc u me nte d d uri n g baseli ne pr oce d ures will be re vie w e d t o e ns ure 
eli gi bilit y i n refer e nce t o st u d y i ncl usi o n a n d e x cl usi o n criteria, a n d f ull y d o c u me nte d i n t he 
s u bject’s file. 
T he i nter val bet w ee n t he si g ni n g of t he c o ns e nt ( Scree ni n g Visit) a n d t h e Baseli ne Visit is 
c o nsi dere d t he b aseli ne p eri o d.  It is defi ne d as a mi ni m u m of 1 4 da ys pri or t o t he 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 3  of 7 1  
Ra n d o mizati o n Visit.  D uri n g t his peri o d, dat a will be c ollecte d o n P N/I V a n d E N use t hat will 
be use d f or calc ulati n g t h e baseli ne % P N a n d t o c o nfir m eli gi bilit y.  All assess me nts will be 
perf or me d a n d r ec or d e d f o r eac h d a y of b aseli ne, e x ce pt f or plas ma citr ulli ne a n d a nti-i ns uli n 
a nti b o dies t hat will be c o n d ucte d a n d rec or d e d o n t he last da y of baseli ne, 0- 1 da y pri or t o t he 
ra n d o mizati o n visit.  Baseli ne pr oce d ures will i ncl u de t he f oll o wi n g:  
•  Wei g ht a n d B o d y Le n gt h - Secti o n  4. 1. 5 4. 1. 5  
•  Vital Si g ns - Secti o n  4. 1. 7  
•  Plas ma Citr ulli ne - Secti o n  4. 1. 9. 4  
•  A nti -i ns uli n A nti b o dies - Secti o n  4. 1. 9. 6  
•  E pis o des of si g nifica nt fee di n g i nt olera nce - Secti o n  4. 1. 1 0  
•  C o nc o mita nt Me dicati o n Listi n g - Secti o n  4. 1. 1 1  
•  P N/I V a n d E N I nta k e - S ecti o ns  4. 1. 1 4. 1  a n d 4. 1. 1 4. 2  
4. 2. 3.  
R a n d o miz ati o n 
O nce q ualifie d f or t he st u d y, s u bjects will be ra n d o mize d i n a 1: 1: 1 rati o t o 2 I U/ k g of 
N T R A - 9 6 2 0 or t o 1 I U/ k g of N T R A- 9 6 2 0 or mat c hi n g place b o.  Ra n d o mizati o n s h o ul d ta ke 
place as cl ose as p ossi ble t o treat me nt i nitiati o n a n d n ot m ore t ha n 2 4 h o urs bef ore t h e first d ose 
of st u d y dr u g.  Ra n d o mizati o n, w hic h will be d o ne ce ntrall y , will be stratifi e d b y l e n gt h of s mall 
i ntesti ne ( L < 5 0 % or 5 0 % ≤ L ≤ 7 0 %, L is t he le n gt h re m ai ni n g c o m pare d t o e x pecte d le n gt h f or 
gestati o nal a ge (1 3 )) a n d prese nce or a bs e nce of a n ile ocecal val ve. 
T he st u d y h as recr uit me nt g oals ai me d at ra n d o mi zi n g at least 3 0 s u bjects wit h <  5 0 % re mai ni n g 
le n gt h of s mall i ntesti ne f or gestati o nal a ge a n d at least 3 0 s u bjects b or n pre mat urel y.  D uri n g t he 
c o urse of t he st u d y, N utri nia or its desi g nees will m o nit or recr uit me nt of s u bjects wit h <  5 0 % 
re mai ni n g b o wel a n d of pre mat ure i nf a nts.  If t he g oal of 3 0 s u bjects wit h < 5 0 % re m ai ni n g 
b o wel is u nli kel y t o be ac hie ve d, N utri nia will c o ns ult a p pr o priate Re g ulat or y A ut h orities a n d 
ma y i ncreas e t he sa m ple size of t he trial t o e ns ure e nr olli n g at least 3 0 s u bjects wit h <  5 0 % 
b o wel re mai ni n g. 
T he ra n d o mizati o n a n d b aseli ne visits are e x pecte d t o occ ur at  t he s a me visit .  H o we ver, i n s o me 
i nsta nces t he l o gistical c o m plicati o ns at t he i n vesti gati ve site ma y re q uire t hese visits t o be u p t o 
2 4 h o urs a part.  All i nf or mati o n c ollecte d a n d d oc u me nte d d uri n g t h e ra n d o mizati o n visit will be 
re vie we d pri or t o ra n d o mizi n g t he s u bjects t o e ns ure t he s u bject meets st u d y i ncl usi o n a n d 
e x cl usi o n criteria.  T he i nf or mati o n will be f ull y d oc u me nte d i n t he s u bject’s file. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 4  of 7 1  
T he f oll o wi n g d ata will b e c ollecte d at t he ra n d o mizati o n visit:  
•  Wei g ht a n d b o d y le n gt h - Secti o n  4. 1. 5  
•  Hea d cir c u mfere nce - Secti o n 4. 1. 6  
•  Vital si g ns - Secti o n  4. 1. 7  
•  Bl o o d gl uc ose le v el - Secti o n 4. 1. 9. 5  
•  E pis o des of si g nifica nt fee di n g i nt olera nce - Secti o n  4. 1. 1 0  
•  C o nc o mita nt me dicati o n Listi n g - Secti o n  4. 1. 1 1  
•  P N/I V a n d E N i nta ke - Secti o ns  4. 1. 1 4. 1  a n d 4. 1. 1 4. 2  
4. 2. 4.  
St u d y Tre at me nt  
N T R A - 9 6 2 0 is a n i ns uli n- base d dr u g pr o d uct i nte n de d t o e n ha nce b o wel a da ptati o n, pr o m ote 
E N, a n d re d u ce d e pe n de nce o n P N/I V.  N T R A- 9 6 2 0 c o nsists of malt o de xtri n ( M D) a n d 
rec o m bi na nt h u ma n i ns uli n i n p o w der f or m f or rec o nstit uti o n. 
S u bjects will recei ve S O C P N/I V a n d e nteral fee di n gs c o ntai ni n g eit her d ose of N T R A - 9 6 2 0 or 
ma tc hi n g place b o.  N T R A- 9 6 2 0 will be d ose d t o tar get a n i ns uli n d ose of 4 I U/ k g/ da y or 
8 I U/ k g/ d a y f or 2 4 w ee ks.  N T R A - 9 6 2 0 a n d matc hi n g place b o ca n be rec o nstit ute d i n n or mal 
( 0. 9 %) or h alf n or mal ( 0. 4 5 %) sali ne ( N a Cl) a n d ca n be a d mi nistere d c o nc o mita ntl y wit h S O C 
i nfa nt f or m ula, d o n or br east mil k, or m ot her’s mil k use d f or e nt eral fee ds.  D uri n g 
h os pitalizati o n, N T R A- 9 6 2 0 or matc hi n g pl ace b o will be d ose d 4 ti mes a da y as b ol us 
a d mi nistrati o n s pace d as e q uall y o v er 2 4 h o urs as p ossi ble (i deall y at e ver y si x h o urs, b ut n o less 
t ha n 3 h o urs bet wee n a n y t w o d oses).  I n h o me care setti n g, s u bjects will recei ve N T R A- 9 6 2 0 or 
matc hi n g place b o f o ur ti mes a da y (i deall y at e ver y si x h o urs, b ut n o less t ha n 3 h o urs bet wee n 
a n y t w o d os es).   
4. 2. 5.  
S u bject Site Visits  
S u bjec t site visits will be perf or me d as f oll o ws:  
•  F or st u d y Da ys 1 t o 8 4, t he st u d y d a y wi n d o w will be ± 2 da y. 
•  F or st u d y Da ys 9 8 t o 1 6 8, t he st u d y da y wi n d o w will be ± 7 da ys. 
•  F or st u d y da ys after D a y 1 9 6, t he st u d y da y wi n d o w will be ± 1 4 da ys.  
•  S u bject site visits will i ncl u de pr oce d ures as descri be d i n A p pe n di x B:  Sc he d ule of 
St u d y Pr o ce d ur es . 
•  F or site visit t hat res ults i n st u d y disc o nti n uati o n, see ter mi nati o n visit i n 
Secti o n  4. 2. 6 . 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 5  of 7 1  
4. 2. 6.  
Vi sit a n d E arl y Disc o nti n u ati o n fr o m St u d y Me dic ati o n Visit 
If a s u bject pre mat ur el y disc o nti n ues st u d y me dicati o n, all reas o na bl e meas ures will be ta ke n t o 
perf or m a n Earl y Disc o nti n uati o n fr o m St u d y Me dicati o n Visit ( Wee k 2 8 visit).  T his visit 
s h o ul d i ncl u de all pr oce d ures liste d i n t he sc he d ul e of e ve nts F oll o w U p ( Fi nal Pri mar y St u d y 
Visit) f or Wee k 2 8 ( D a y 1 9 6).  T hese pr o ce d ures are necessar y t o c o m plet e s u bjects’ rec or ds:  
p h ysical e x a mi nati o n, wei g ht, b o d y le n gt h, hea d circ u mfere nce, vital si g ns, cli nical la b orat or y 
test ( o nl y if cli nicall y si g nifica nt val ues w ere o btai ne d at t he Da y 1 9 6, or if ter mi nate d earlier), 
a nti-i ns uli n a nti b o dies, plas ma citr ulli ne ( o nl y if ter mi nate d bef ore Da y 1 6 8), pare nt eral n utriti o n 
i nta ke, e nter al n utriti o n i nta ke, c o nc o mita nt me di cati o n, a d vers e e v e nt, a n d u p dati n g of s u bject 
c o ntact i nf or mati o n.   
All reas o na ble eff orts will be ma de t o perf or m a ter mi nati o n visit ( Wee k 2 8) i n patie nts w h o 
disc o nti n ue earl y. 
4. 2. 7.  
Ter mi n ati o n Visit a n d E arl y Disc o nti n u ati o n fr o m L o n g- Ter m F o ll o w-u p Visits  
If a s u bject pre mat ur el y disc o nti n ues fr o m t he l o n g-ter m f oll o w- u p p orti o n of t he st u d y, all 
reas o na bl e meas ur es will be ta ke n t o perf or m a n E arl y Disc o nti n uati o n Visit.  T his visit s h o ul d 
i ncl u de all pr oce d ures liste d i n t he F oll o w U p a n d u p dati n g of s u bject c o ntact i nf or mati o n. 
4. 2. 8.  
U nsc he d ule d Visit  
U nsc he d ule d visits will be perf or me d u p o n t he i n v esti gat or’s discreti o n, u p o n S p o ns or re q uest t o 
re d o tests wit h u n us ual res ults, or t o c o m plete missi n g res ults.  T hes e visits ma y als o occ ur u p o n 
s ubject’s par e nt or g uar di a n re q uest.  U ns c he d ule d visits will i ncl u de a n y st u d y pr o ce d ure 
dee me d necessar y.  
D uri n g t h e l o n g ter m f oll o w - u p peri o d after t he i nt er ve nti o n peri o d a n d Wee k 2 8 visit, t his 
patie nt p o p ulati o n is e x pecte d t o c o nti n ue r o uti ne Sta n dar d of Care visits t hat ma y b e c o n d u cte d 
at a p pr o xi matel y t hree m o nt h i nter vals.  If t hese r o uti ne Sta n dar d of Care visits are c o n d ucte d t he 
f oll o wi n g data will be c ollecte d:  b o d y wei g ht, b o d y le n gt h, hea d circ u mfere nce, p are nteral 
n utriti o n i nta ke, e ntera l n utriti o n i nta ke, re- h os pitalizati o ns a n d a d verse e ve nts.  T hese data will 
be e nter e d i nt o t he e C R F as U nsc he d ule d Visits.  If a r o uti ne Sta n dar d of Care visit is n ot 
c o n d ucte d or c o m plete d ata ar e n ot c ollecte d as p art of t hese visits, t hese will n ot be  c o nsi dere d 
missi n g data.  T hes e data will i ncl u de ne ur o de vel o p me ntal Ba yle y's s c ore c o g niti ve, la n g ua ge 
a n d m ot or d o mai ns at 2 Y c orrecte d a ge. 
5.  
S A F E T Y C O N SI D E R A TI O N S A N D G UI D A N C E F O R 
I N V E S TI G A T O R S 
A d here n ce t o pr ot oc ol m o nit ori n g pr oce d ures al o n g wit h t he f oll o wi n g safet y g ui da n ce will ai d 
a n d pr o m ote s u bject safet y. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 6  of 7 1  
5. 1.  
S A F E T Y M E A S U R E M E N T S  
N utri nia has perf or me d f o ur trials, t hree i n preter m i nfa nts a n d o ne i n S B S i nfa nts, wit h oral 
a d mi nistrati o n of i ns uli n.  I n t hes e trials n o treat me nt -relat e d a d verse e v e nt has bee n re p orte d 
a n d n o s yste mic a bs or pti o n of i ns uli n was detecte d.  T he N T R A- 9 6 2 0 f or m ulati o n has bee n 
e xte nsi vel y st u die d i n t w o cli nical st u dies wit h pre -ter m i nfa nts ( 2 6- 3 3 wee k gestati o nal a ge) a n d 
i n o ne cli nical st u d y wit h ter m i nfa nts ( 3 4- 4 2 w eek gestati o nal a ge).  T a ble 1  s u m marizes t he 
n o n- dr u g relat e d A Es a n d S A Es o bser ve d i n t he pre vi o us cli nical trials. 
T a ble 1 :  A d verse E ve nts O bser ve d i n Pre vi o us N utri ni a Cli nic al St u dies of Or al I ns uli n i n  
Pre m at ure I nf a nts  
Acc or di n g t o t he st u d y i n vesti gat or, n o n e of t he rec or de d a d v erse e ve nts w as relate d t o t he 
i n vesti gati o nal pr o d u ct or trial. 
P h ase I E ffic ac y T ri al ( n  = 8) 
A d verse E ve nts  
N o. of s u bjects wit h a n e ve nt ( n = 8)  
Gree n gastric resi d ue + re si d ue of 2 0- 5 0 % of t he pri or 
meal, 3 meals i n a r o w  
1  
Bra d ycar dia  
1  
H y perte nsi o n 
1  
A p nea 
1  
 
P h ase I S af et y T ri al ( n  = 1 1) 
A d verse E ve nts  
N o. of s u bjects wit h a n e ve nt ( n = 1 1)  
Se b orr hea der matitis  
1  
R hi nitis  
3  
R osse olla i nfa nt u m  
1  
U p per res pirat or y  tract i nfecti o n 
1  
C o u g h 
1  
S oft st o ol  
1  
C o nj u ncti vitis  
1  
Viral i nfecti o n  
2  
Mil d stri d or 
1  
Otitis me dia mil d  
1  
Fi ne mac ular ras h o n face a n d a b d o me n  
1  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 7  of 7 1  
A d verse E ve nts  
N o. of s u bjects wit h a n e ve nt ( n = 1 1)  
Fe ver  
1  
Viral ras h  
1  
 
P h ase II E ffic ac y T ri al ( n  = 3 3) 
A d verse E ve nts  
N o. of S u bjects affecte d  
N u m ber of A E defi ne d as 
Seri o us A d verse E ve nts 
( S A E) 
C offee gr o u n d 
1 
0 
S u pra ve ntric ular tac h ycar dia  
1 
0 
Gastr o e nteritis  
2 
1 
Her nia I n g ui nal 
4 
0 
L o w he m o gl o bi n 
1 
0 
Se psis d ue t o sta p h yl oc occ us e pi der mi dis  1 
0 
Se psis gra m p ositi ve c olli  
1 
0 
Se psis  
4 
2 
Ac ute otitis me dia  
1 
0 
U p per res pirat or y tract i nfecti o n  
2 
0 
Res pirat or y distress  
1 
0 
Rt. U p per L o be p ne u m o nia 
1 
1 
Ne utr o pe nia  
1 
0 
H y p ot h yr oi dis m 
2 
1 
Gastr oes o p ha geal refl u x  
1 
1 
Dia per der matitis  
1 
0 
S ki n irritati o n  
1 
0 
Ulcerati o n of stra w berr y  he ma n gi o ma  
1 
0 
A p nea 
2 
1 
Fe ver  
1 
1 
Mil d c o nj u ncti vitis  
1 
0 
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 8  of 7 1  
5. 2.  
P R E M A T U R E DI S C O N TI N U A TI O N F R O M S T U D Y 
M E DI C A TI O N  
S u bjects will  be disc o nti n u e d fr o m t he st u d y me dicati o n after e val uati o n b y t he i n vesti gat or a n d 
s p o ns or's me dical m o nit or i n a n y of t he f oll o wi n g cases:  
•  A n y C T C A E Gra de 3 or 4 a d verse e ve nt (s ee Secti o n  7 ) t hat t he i n vesti gat or 
c o nsi ders rel ate d t o st u d y me dicati o n a n d n ot attri b uta ble t o t he u n derl yi n g disease 
or c o nsi dere d c o m m o n e ve nts liste d i n A p pe n di x C .  
•  S yste mic h y pers e nsiti vit y reacti o n relate d t o st u d y me dicati o n.  
•  N o n -c o m plia nce of t he s u bject’s pare nt(s) or le gal g uar di a n(s) wit h st u d y pr oce d ures  
•  Ot her reas o ns re gar de d as warra nti n g s u bject's dis c o nti n uati o n fr o m st u d y 
me dicati o n.  
•  Pre mat ure st u d y ter mi nati o n as descri be d i n Secti o n  5. 3 .   
Pare nt(s) or le gal g uar di a n(s) w h o v ol u ntaril y ha v e t heir c hil d disc o nti n ue t he st u d y me dicati o n 
will be q uesti o ne d t o deter mi ne w het her a n A E c o ntri b ute d t o t he decisi o n t o disc o nti n ue st u d y 
me dicati o n.  
S u bjects w h o are wit h dr a w n fr o m treat me nt b eca use of a n a d v erse e ve nt will be f oll o we d a n d 
treate d b y t he i n vesti gat or u ntil t he a b n or mal para meter/c o n diti o n or s y m pt o m has res ol ve d or 
sta bilize d or t he i n vesti gat or dee ms f urt her o bser vati o ns or e x a mi nati o ns n o l o n ger re q uire d as 
me dicall y i n dicate d.  
T he i n vesti gat or will ma ke reas o n a ble atte m pts t o pr o vi de a reas o n f or a s u bject ’s bei n g 
wit h dra w n fr o m st u d y m e dicati o n.  T he reas o n f or t he s u bject’s wit h dra wal fr o m st u d y 
me dicati o n will be descri be d i n t he s u bject’s s o urce d oc u me nts a n d C R F 
S u bjects w h o pre mat urel y disc o nti n ue will ha ve a n Earl y Disc o nti n uati o n f or St u d y Me dicati o n 
Visit as descri be d i n Secti o n  4. 2. 6  .  S u bjects w h o disc o nti n ue st u d y me di cati o n earl y s h o ul d 
ret ur n f o ur ( 4) w ee ks after st u d y me dicati o n disc o nti n uati o n t o recei ve f oll o w- u p visits. 
5. 3.  
P R E M A T U R E DI S C O N TI N U A TI O N F R O M S T U D Y  
Partici pati o n i n t he st u d y is str ictl y v ol u ntar y.  I n acc or d a nce wit h t he c urre nt re visi o n of t he 
Declar ati o n of Helsi n ki, pare nt(s) or le gal g uar dia n(s) of s u bjects ha v e t he ri g ht t o wit h dra w t h eir 
c hil d fr o m t he st u d y at a n y ti me, f or a n y reas o n, s pecifie d or u ns p ecifie d, a n d wit h o ut pr ej u dice 
t o a n y f ut ure me dical car e b y t h e p h ysicia n or t he i nstit uti o n.  If t he p are nt(s) or le gal g uar dia n(s) 
of s u bjects c h o ose t o wit h dra w t heir c hil d, t he i n vesti gat or a n d t he S p o ns or m ust be i nf or me d 
i m me diatel y. 
T he s u bject will be wit h dra w n fr o m t he  st u d y if t h e pare nt(s) or le gal g u ar dia n (s) wit h dra ws 
c o nse nt.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 3 9  of 7 1  
T he i n vesti gat or will ma ke reas o n a ble atte m pts t o pr o vi de a reas o n f or wit h dra wal of s u bj ects 
fr o m t he st u d y.  T h e reas o n f or t he s u bject’s wit h dra wal fr o m t he st u d y will be s pecifie d i n t he 
s u bject’s s o urce d oc u me nts a n d C R F.  W he n a pare nt or g uar di a n as ks t o wit h dra w c o nse nt, t he 
i n vesti gat or s h o ul d c o nfir m t hat t he pare nt/ g uar dia n u n dersta n ds t he differe nce b et wee n 
wit h dra wal of st u d y me dicati o n a n d wit h dra w al fr o m t he st u d y.  If t he p are nt/ g uar dia n is willi n g 
t o wit h dra w t he s u bject fr o m st u d y me dicati o n b ut re mai n i n t he st u d y, t he n t he i n vesti gat or 
s h o ul d f oll o w pr oce d ur es i n Secti o n 4. 2. 6 . 
5. 4.  
P R E M A T U R E S T U D Y T E R MI N A TI O N  
T he st u d y s u bjects are e x pecte d t o  e x perie nce ma n y a d v erse e ve nts , i ncl u di n g se v ere a d vers e 
e ve nts relat e d t o pre mat ure birt h, i n vasi ve s ur ger y, t heir me dical/s ur gical c o m plicati o ns or ot her 
u n derl yi n g c o n diti o ns i ncl u di n g b ut n ot li mite d t o t he s h ort b o wel c o n diti o n.  T heref ore, all 
safet y c o n cer ns p ote ntiall y lea di n g t o st u d y ter mi n ati o n will be refer re d t o t he Data Safet y 
M o nit ori n g B o ar d ( D S M B), w hic h is r es p o nsi ble f or a f or mal assess me nt of t he safet y of t he 
st u d y.  T his B o ar d will pr o p ose t he a p pr o priate c o urse of acti o n t o t he S p o ns or. 
I ndi vi d u al E ve nts:  
A n y of t he f oll o wi n g i n di vi d ual e ve nts w o ul d be referre d b y  t he st u d y Me dical M o nit or t o t he 
D S M B c hair m a n f or r e vi e w, w h o ma y deci de t hat t he e ve nts warra nt a f ull D S M B re vie w.  T he 
D S M B will re vie w t hes e e ve nts u n bli n d e d t o f ull y e val uate t he p ote ntial ris k t o s u bjects i n t his 
trial.  Gi ve n t his is a bli n de d trial, t he D S M B re vi e w is re q uire d t o c o nsi der if t he e ve nts, b ot h 
seri o us a n d rel ate d n o n-s eri o us e ve nts, are occ urri n g m ore fre q u e ntl y i n t he acti ve ar ms a n d t o 
j u d ge w h et her t here is a mea ni n gf ul li keli h o o d t hat t hese e ve nts are dr u g-relate d.  T he D S M B 
ma y r ec o m me n d t o t he S p o ns or t o st o p t he st u d y, or a n y p orti o n of it, at a n y ti me f or s afet y 
reas o ns o n t he b asis of t heir re vie w.  I n di vi d ual e v e nts t hat ma y tri g ger a D S M B re vie w b ase d o n 
i n di vi d ual cases: 
•  T w o or m ore cases of Gr a de 3 or greater aller gic reacti o ns or a n a p h yla xis, t hat t he 
i n vesti gat or d ee ms as p ossi bl y relate d t o st u d y me dicati o n;  
•  A n y case of a ut oi m m u ne disease ass oci ate d wit h ne utralizi n g a nti b o dies t o i ns uli n a n d 
w here ot her rel ate d ca uses, s uc h as T y pe I di a betes, are r ul e d o ut; 
•  T w o or m ore cases of p ersiste nt Gra de 3 or greater h y p o gl yce mia  t hat is n o n-res p o nsi ve 
t o treat me nt wit hi n 7 2- h o ur s a n d re o cc urs after t e m p orar y disc o nti n uati o n of st u d y 
me dicati o n a n d re-challe n ge d . 
•  T w o or m ore s u bjects w h o  de vel o p li ver e nz y m e i ncreas es of greater t ha n 1 0 ti mes t he 
U L N  t hat is attri b ute d t o st u d y me dicati o n a n d t h e i n vesti gat or d o es n ot c o nsi der relate d 
t o t he u n derl yi n g disease pr ocess or a d mi nistrati o n of pare nt eral n utriti o n. 
F urt her, t h e Me dical M o nit or will be res p o nsi ble f or re vie w of all re p orte d S A Es i n a n o n g oi n g 
ma n ner.  A n y S A E t hat is dee me d p ote ntiall y relate d t o st u d y me dicati o n, or of partic ular 
c o ncer n b y t h e Me dical M o nit or, will als o be se nt t o t he D S M B C h air ma n f or re vie w wit hi n 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 0  of 7 1  
1 5 da ys.  T h e D S M B C h air me n ma y deci de t o bri n g a n y i n di vi d ual S A E e ve nt t hat ma y b e 
relate d a n d of c o n cer n t o t he f ull D S M B f or re vie w. 
C ollecti ve E ve nts:  
T he Me dical M o nit or a n d D S M B will re vie w a g gre gate s afet y dat a i n a n o n g oi n g ma n ner , at 
D S M B meeti n gs w hic h will be hel d a p pr o xi matel y eac h 4 m o nt hs t hr o u g h o ut t he trial.  T he 
Me dical M o nit or will re mai n bli n de d t o treat me nt assi g n me nt f or c u m ulati ve data at all ti mes, 
b ut ma y r efer a n y safet y c o ncer ns b ase d o n re vie w of safet y d ata t o t he D S M B f or f urt h er 
e val uati o n.  T he D S M B will recei ve u n bli n de d s afet y d ata s u m maries fr o m a n i n de pe n de nt 
statisticia n t hat is assi g ne d t o pre par e t he u n ble n de d st u d y re p orts f or all s u bjects at eac h D S M B 
meeti n g.  Re vie ws of c u m ulati ve safet y dat a will be c o n d ucte d e ver y f o ur (4) m o nt hs d uri n g t he 
trial c o n d uct d uri n g sc he d ule d D S M B meeti n gs.  T he D S M B statisticia n will c o m pare t he e v e nt 
rates f or A Es bet wee n t h e gr o u ps a n d t he pr o ba bilit y t hat t he gr o u ps differ i n t he fre q ue n c y of 
e ve nts.  If t here are diff er e nces i n Gr a de 3 or hi g h er a d verse e v e nts t hat differ materiall y b et wee n 
acti ve a n d c o ntr ol a n d t h at ma y b e attri b uta ble t o st u d y me dicati o n bas e d o n t he mec ha nis m of 
acti o n of t he dr u g, t he D S M B has t he o pti o n t o rec o m me n d t hat t he S p o ns or st o p t he st u d y, or 
m o dif y t he pr ot o c ol f or s afet y r eas o ns.   
T he st u d y ma y als o be pr e mat urel y ter mi nate d f or a d mi nistrati ve reas o ns, et hical c o nsi derati o ns, 
at t he re q uest of l o cal r e g ulat or y a ge nci es, or f or a n y ot her reas o n t he S p o ns or dee ms 
a p pr o priate.  
5. 5.  
D E VI A TI O N F R O M S T U D Y P R O T O C O L  
T he i n vesti gat or s hall n ot de viate fr o m t he st u d y pr ot oc ol wit h o ut first o btai ni n g writte n 
a p pr o val fr o m t he S p o ns or, or its official desi g nee, a n d fr o m t he l o cal I R B/I E C acc or di n g t o 
l ocal re g ulati o ns.  
I n t he e ve nt of m e dical e mer ge ncies, t h e i n vesti gat or s hall use a p pr o priat e me dical j u d g m e nt a n d 
will re m o ve t he s u bject fr o m a n y i m me diat e hazar d.  T he n , wit hi n 2 4 h o urs f or relat e d S A Es a n d 
wit hi n 4 8 h o urs f or u nrel ate d S A Es, t he i n vesti gat or s hall n otif y t he S p o ns or or its official 
desi g nee a n d, if a p plica bl e, t he l ocal I R B/I E C of t he t y p e of e mer ge n c y a n d c o urse of acti o n 
ta ke n. 
A n y ot her c ha n ges t o or de viati o ns fr o m t he pr ot o c ol will be ma de as a n a me n d me nt t o t he 
pr ot oc ol a n d m ust be a p pr o ve d b y t he S p o ns or or its offici al desi g nee a n d t he l ocal I R B/I E C 
bef ore t h e y ca n b e i m ple me nte d.  Acc or di n gl y, t h e S p o ns or will n ot ass u me res p o nsi bilit y or 
lia bilit y f or a n y u n a ut h orize d de viati o n fr o m or c h a n ge t o t he pr ot oc ol. 
6.  
I N V E S TI G A TI O N A L P R O D U C T S P E CI FI C A TI O N S 
N T R A - 9 6 2 0 dr u g pr o d u ct is ma n ufact ure d i n acc or da nce wit h c urre nt G o o d Ma n ufact uri n g 
Practices ( c G M Ps).   


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 1  of 7 1  
6. 1.  
F O R M U L A TI O N, P A C K A GI N G, A N D L A B E LI N G O F 
N T R A -9 6 2 0  
N T R A - 9 6 2 0 ( 4 I U/ g, 8 I U/ g), w hic h c o ntai ns rec o m bi na nt h u ma n i ns uli n as t he acti ve 
i n gre di e nt, is i nte n de d f or oral a dmi nistrati o n t o i nfa nts wit h S B S.  
N T R A - 9 6 2 0 c o nsists of malt o de xtri n, 0. 4 5 % s o di u m c hl ori de, a n d h u ma n i ns uli n (r D N A ori gi n).   
T o mai ntai n d o u ble bli n di n g, f or t h e l o wer d os e ( 4 I U/ k g/ da y) stic k pac ks will ha ve p o w der 
c o nce ntr ati o n of 4 I U/ g w hile f or t he hi g h d ose ( 8 I U/ k g/ d a y) stic k pac ks will ha ve p o w der 
c o nce ntr ati o n of 8 I U/ g. 
N T R A - 9 6 2 0 a n d matc hi n g place b o will be s u p plie d i n 1 gra m stic k p ac ks as a p o w der f or 
rec o nstit uti o n f or oral a d mi nistrati o n.  T he stic k pac ks will be pr o vi de d i n b o x cart o ns.  
N T R A -9 6 2 0 or Place b o will be la bele d wit h at least t he mi ni m u m i nf or mati o n liste d bel o w:  
N T R A - 9 6 2 0 or Place b o 
E q ui vale nt t o 4 I U I ns uli n or 8 I U I ns uli n or Place b o i n 1 stic k pac k f or oral s ol uti o n 
D ose acc or di n g t o st u d y pr ot oc ol i nstr ucti o ns 
St ore at r o o m te m perat ur e ( 1 5- 2 5º C/ 5 9- 7 7º F) 
Ca uti o n:  Ne w Dr u g – Li mite d f or Cli nical Trial Use O nl y  
6. 2.  
S T O R A G E A N D S T A BI LI T Y O F N T R A -9 6 2 0  
T he N T R A - 9 6 2 0 pac kets will be st ore d at r o o m te m perat ure ( 1 5- 2 5° C ± 2° C/ 5 9- 7 7° F ± 4° F).  
St ora ge s p ace will be se p arate, d esi g n ate d, a n d a d e q uatel y la bele d as c o ntai ni n g i n vesti gati o nal 
pr o d uct.  
A sta bilit y pr o gra m of N T R A - 9 6 2 0 is o n g oi n g.  T he S p o ns or will ma na ge site i n ve nt or y 
acc or di n g t o acc u m ulati n g sta bilit y d ata a n d t hr o u g h t he I V R S s yste m.   
6. 2. 1.  
D os a ge 
N T R A - 9 6 2 0 ( or al i ns uli n) a n d matc hi n g place b o will be pr o vi de d i n stic k pac ks of o ne gra m f or 
rec o nstit uti o n. 
6. 2. 2.  
A d mi nistr ati o n a n d I nstr ucti o ns f or Use  
Eac h i n di vi d ual stic k pac k m ust be ke pt a n d ha n dl e d at r o o m te m perat ure pri or t o rec o nstit uti o n.  
S u bjects will recei ve S O C pare nter al n utriti o n a n d e nteral fee di n gs c o ntai ni n g eit her d os e of 
N T R A - 9 6 2 0 or matc hi n g place b o.  N T R A- 9 6 2 0 or matc hi n g pl ace b o will be d ose d t o tar get a n 
i ns uli n d ose of 8 I U/ k g/ d a y or 4 I U/ k g/ da y f or 2 4 wee ks.  N T R A- 9 6 2 0 a n d matc hi n g place b o ca n 
be rec o nstit ute d i n n or mal ( 0. 9 %) or half n or mal ( 0. 4 5 %) sali ne ( N a Cl) a n d ca n be a d mi nistere d 
c o nc o mita ntl y wit h S O C i nfa nt f or m ula, d o n or breast mil k or o w n m ot her’s mil k use d f or e nteral 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 2  of 7 1  
fee ds.  D uri n g h os pitalizati o n, assi g ne d treat me nt will be d ose d 4 ti mes a da y as b ol us 
a d mi nistrati o n s pace d as e q uall y o v er 2 4 h o urs as p ossi ble (i deall y at e ver y si x ( 6) h o urs, b ut n o 
less t ha n t hree ( 3) h o urs bet wee n a n y t w o d oses).  I n h o me care, s u bjects will recei ve assi g ne d 
treat me nt f o ur ti mes a d a y (i deall y at e ver y si x ( 6) h o urs, b ut n o less t ha n t hree ( 3) h o urs 
bet wee n a n y t w o d oses).  A d diti o nal i nstr ucti o ns will be pr o vi de d i n t he I nstr ucti o n f or Use 
d oc u me nt.   
T he S O C wit h N T R A - 9 6 2 0 or matc hi n g pl ace b o will be ma n uall y s ha k e n bef ore c o ns u m pti o n.  
•  Gr o u p 1: 
N T R A - 9 6 2 0 will be a d mi nistere d 4 ti mes a da y eac h at a d ose of 2  I U/ k g 
( 8 I U/ k g/ da y) 
•  Gr o u p 2: 
N T R A - 9 6 2 0 will be a d mi nistere d 4 ti mes a da y eac h at a d ose of 1 I U/ k g 
( 4 I U/ k g/ da y) 
•  Gr o u p 3: 
Matc hi n g place b o will be a d mi nistere d 4 ti mes a d a y  
6. 3.  
A C C O U N T A BI LI T Y O F N T R A -9 6 2 0  
N T R A - 9 6 2 0 will be s u p plie d i n stic k pac ks, i n q ua ntities as nee de d t o c o m pl y wit h t he treat me nt 
of site s u bjects acc or di n g t o t he st u d y pr ot oc ol. 
T he i nitial st u d y dr u g s u p pl y will be s hi p pe d after site acti vati o n (i.e., aft er t he S p o ns or has 
recei v e d all re q uir e d re g ulat or y d o c u me ntati o n a n d a c o ntract has bee n e x ec ute d).  T he i nitial 
st u d y dr u g s hi p me nt will i ncl u de a s pecifie d n u m b er ( bas eli ne q ua ntit y) of st u d y dr u g kits f or 
eac h tr eat me nt ar m.  H o we ver, si nce b ot h d oses of N T R A- 9 6 2 0 a n d t he matc hi n g place b o are 
pac ka ge d a n d la b ele d i n a bli n de d ma n ner, t he st u d y sites will n ot be a ble t o disti n g uis h a m o n g 
t he t hree ( 3) differe nt st u d y dr u g t y p es a n d will treat all st u d y dr u g kits i n t he sa me ma n ner.   
S u bse q ue nt st u d y dr u g s hi p me nts will be ma de w he n t he i n ve nt or y le vel f or a n y st u d y dr u g t y pe 
( N T R A- 9 6 2 0 l o w d ose, N T R A- 9 6 2 0 hi g h d os e, or matc hi n g pl ace b o) reac hes its alert q ua ntit y.  
I n t his case, t he el ectr o ni c ra n d o mizati o n a n d dr u g s u p pl y s yste m ge nerates a s hi p me nt re q uest i n 
or der t o bri n g t he site’s i n ve nt or y of all st u d y dr u g t y pes t o t heir b aseli ne q ua ntit y. 
S hi p me nt, st ora ge, a n d i n ve nt or y d oc u me ntati o n will be u p date d re g ularl y a n d ke pt i n t he 
i n vesti gati o n files at t he site t o all o w i ns pecti o n a n d trace of t he s u p plie d pr o d uct.  
Use d i nvesti g ati o n al pr o d uct:   Use d/ o pe n e d stic k pac ks will be destr o ye d.  
All u n use d stic k pac ks m ust be ret ur ne d t o t he S p o ns or after acc o u nta bilit y rec or ds h a ve bee n 
c o nfir me d b y t he st u d y m o nit or.  Acc o u nta bilit y of t he st u d y me di cati o n m ust i ncl u de 
rec o nciliati o n of a n y u n use d stic k pac ks n ot ret ur n e d. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 3  of 7 1  
7.  
S A F E T Y M O NI T O RI N G A N D A D V E R S E E V E N T S  
7. 1.  
A D V E R S E E V E N T S  
Data re gar di n g treat me nt -e mer ge nt A Es will be c ollecte d.  Treat me nt -e mer ge nt A Es are e ve nts 
t hat are n ot pr ese nt at bas eli ne or, if pres e nt at bas eli ne, ha ve w orse ne d i n s e verit y or fre q ue n c y. 
If a p plica bl e t o t his st u d y p o p ulati o n, t he descri pti o ns a n d gra di n g scales f o u n d i n t he C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E) v 4. 0 3 will be use d f or A E re p orti n g.  F or 
e ve nts w here t he s pecific defi niti o ns f or gra di n g i n C T C A E d oes n ot a p pl y t o t his st u d y 
p o p ulati o n, ge n eral gr a di n g criteria d escri be d i n C T C A E will be use d a n d i n vesti gat or j u d g me nt 
o n se verit y will deter mi n e t he gra d e of t he e ve nt.  See A p pe n di x C  f or li n k t o a c o p y of C T C A E 
v 4. 0 3. 
7. 1. 1.  
Defi niti o n of A d verse E ve nts  
A d verse E ve nt ( A E)  
A n a d vers e e ve nt ( A E) is a n y u nt o w ar d me dical o cc urre nce i n a cli nical i n vesti gati o n of a 
s u bject a d mi nistere d a p h ar mace utical pr o d uct (eit her test pr o d uct or c o ntr ol pr o d uct); a n A E 
d oes n ot necess aril y h a ve a ca usal relati o ns hi p wit h t he treat me nt.  A n A E is t heref ore a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n, s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a n 
i n vesti gati o nal ( me dici n al) pr o d uct or ot her pr ot oc ol-i m p ose d i nter ve nti o n, re gar dl ess of 
attri b uti o n, i.e., w het her or n ot relate d t o t hat i n vesti gati o nal ( me dici nal) pr o d uct.  A n A E ma y 
i ncl u de i nterc urre nt ill nesses or i nj uries t hat re prese nt a n e x acer b ati o n (i ncrease i n fre q u e nc y, 
se verit y, or s pecificit y) of pre-e xistin g c o n diti o ns (e. g., w ors e ni n g of ast h m a).  A la b orat or y 
a b n or malit y will be re p orte d o n t he “ A d verse E ve nt” case re p ort f or m o nl y if t he i n vesti gat ors 
c o nsi dere d it cli nicall y si g nifica nt, or if it is ass oci ate d wit h cli nical se q uel ae or re q uires 
t hera pe utic i nter v e nti o n.   
A d verse D r u g Re acti o n ( A D R)  
A n y A E f or w hi c h t here is a reas o n a ble p ossi bilit y t hat t he st u d y dr u g ca use d t he a d vers e e ve nt, 
mea ns t here is e vi d e nce t o s u g gest a ca us al relati o ns hi p bet wee n t he st u d y dr u g a n d t he a d v erse 
e ve nt, or t hat a ca usal r el ati o ns hi p bet wee n a st u d y dr u g a n d a n a d vers e e v e nt is at least a 
reas o na bl e p ossi bilit y, i. e., t he relati o ns hi p ca n n ot be r ule d o ut.  T he relati o ns hi p ma y be r ule d as 
u nli kel y, p ossi bl y or pr o ba bl y r elate d t o st u d y dr u g – see defi niti o ns bel o w.  
U ne x pecte d A E  
A n u ne x pecte d A E is o ne of a t y p e n ot i de ntifie d i n nat ure, se v erit y, or fre q ue nc y i n t he c urre nt 
I n v esti gat or’s Br oc h ure or of greater se v erit y or fre q ue nc y t ha n e x pecte d b ase d o n t he 
i nf or mati o n i n t he I n v esti gat or’s Br oc h ure. 
A pre -tr eatme nt e mer ge nt e ve nt will n ot be c o nsi dere d a n A E, b ut will be rec or de d as me dical 
hist or y. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 4  of 7 1  
W he ne ver p ossi ble, it is prefera ble t o r ec or d a dia g n osis as t he A E t er m rat her t ha n a s eries of 
s y m pt o ms relati n g t o a di a g n osis.  A Es will be gra de d acc or di n g t o t he C T C A E v 4. 0 3 
(A p pe n di x C ).  F or e ve nts w here t he s p ecific d efi niti o ns f or gra di n g i n C T C A E d oes n ot a p pl y t o 
t his st u d y p o p ulati o n, ge neral gr a di n g criteria d es cri be d i n C T C A E will be use d a n d i n vesti gat or 
j u d g me nt o n se verit y will deter mi ne t he gra de of t he e ve nt. 
A Es m o nit ori n g will be ca pt ure d t hr o u g h o ut t he st u d y, fr o m Da y 0 (i nitiati o n of d osi n g) u ntil 
fi nal pri mar y st u d y visit at Wee k 2 8 ( Da y 1 9 6).  L o n g-t er m safet y e val uati o ns will als o be 
c o n d ucte d p ost pri mar y st u d y c o m pleti o n o n Wee k 5 2 ( Da ys 3 6 4) a n d Wee k 1 0 4 ( Da y 7 2 8) t o 
assess a n y p ote ntiall y rel ate d a d verse o utc o mes of treat me nt.  
If a n u nr elate d A E re mai ns u nres ol ve d aft er Wee k 2 8, at t he I n vesti gat or’s discreti o n, t he s u bject 
ma y b e f oll o we d u ntil Wee k  1 0 4, or u ntil res ol uti o n of t he e ve nt.  T h e i n vesti gat ors m ust f oll o w 
a relate d A E a n d a n y u nr elate d/relat e d S A E u ntil res ol uti o n e ve n if t he ti me e xte n ds be y o n d t he 
st u d y-r e p orti n g peri o d.  Res ol uti o n is defi ne d as t he ret ur n t o bas eli ne stat us or sta bilizati o n of 
t he c o n diti o n wit h t he e x pectati o n t hat it will re mai n c hr o nic; it is n ot a disc har ge d ate fr o m t he 
h os pital. 
T he i n vesti gat or will assess A Es f or se v erit y, f or relati o ns hi p t o t he st u d y dr u g, a n d as t o w het h er 
t he e ve nt meets o ne or m ore of t he d efi niti o ns of a n S A E. 
T he i n vesti gat or will deter mi ne t he r elati o ns hi p of a n A E t o t he st u d y dr u g a n d will rec or d it o n 
t he s o urce d o c u me nts a n d A E C R F, usi n g t he cate g ories d efi ne d b el o w. 
C a us alit y 
C ate g or y 
Descri pti o n  
U nli kel y  
A cli nical e ve nt, i n cl u di n g la b orat or y test a b n or malit y, wit h a te m p oral relati o ns hi p t o 
dr u g a d mi nistrati o n w hic h ma kes a ca usal relati o ns hi p i m pr o ba ble, a n d i n w hic h ot her 
dr u gs, c he micals or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns.  F or t he p ur p ose 
of t his pr ot oc ol, t he ter m u nli kel y will be c o nsi dere d n ot relate d t o st u d y me dicati o n a n d 
a n “ A d verse E ve nt”. 
P ossi ble 
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble ti me se q ue nce 
t o a d mi nistrati o n of t he dr u g, b ut w hic h c o ul d als o be e x plai ne d b y c o nc urre nt disease or 
ot her dr u gs or c he micals.  I nf or mati o n o n dr u g wit h dra wal ma y be lac ki n g or u nclear.  
F or t he p ur p ose of t his pr ot oc ol, a n e ve nt t hat has p ossi ble relati o ns hi p t o st u d y 
me dicati o n will be defi ne d as a “ S us pecte d A d verse Dr u g Reacti o n”.   
Pr o ba ble 
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble ti me se q ue nce 
t o a d mi nistrati o n of t he dr u g, u nli kel y t o be attri b ute d t o c o nc urre nt disease or ot her 
dr u gs or c he micals, a n d w hic h f oll o ws a cli nicall y reas o n a ble res p o nse o n wit h dra wal.  
F or t he p ur p ose of t his pr ot oc ol, a n e ve nt t hat has pr o ba ble relati o ns hi p t o st u d y 
me dicati o n will be defi ne d as a n “ A d verse Dr u g Reacti o n”.  
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 5  of 7 1  
I n or der t o cl assif y a d verse e ve nts a n d diseases, t h e s p o ns or or its desi g n ee will assi g n preferre d 
ter ms t o t he ori gi nal ter ms e ntere d o n t he C R F, usi n g t he M e dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A).  
A Es will be gra de d o n a 5- p oi nt scale ( mil d, m o derate, s e vere, life-t hreate ni n g, a n d d eat h) a n d 
re p orte d as i n dicate d o n t he C R F.  I nte nsit y of a d v erse e v e nt is defi ne d as f oll o ws: 
T a ble 2 :  Se verit y Assess me nt Ter mi n ol o g y f or Re p orti n g A d verse E ve nts  
C T C A E 
Gr a de  
C o m m o n 
Ter m  
Descri pti o n  
1 
Mil d  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d  
2 
M o derate 
M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge -a p pr o priate i nstr u me ntal Acti vities of Dail y Li vi n g ( A D L)  
3 
Se vere  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y li fe-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care A D L 
4 
Life -
t hreate ni n g 
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d 
5 
Deat h  
O utc o me of A E was deat h  
 
A Es t hat are n ot des cri be d o n t he C T C A E v 4. 0 3 will be gra de d acc or di n g t o t he scale defi ne d i n 
Ta ble 2 . 
7. 2.  
S E RI O U S A D V E R S E E V E N T S  
Acc or di n g t o t he I C H G ui deli nes f or G o o d Cli nical Practice ( G C P) ( E 6), a n S A E is a n y 
u nt o war d me dical o cc urr e nce d uri n g t he c o urse of a cli nical i n vesti gati o n t hat is c haracterize d b y 
o ne or m ore of t he f oll o wi n g: 
•  Res ults i n deat h  
•  Is life-t hreate ni n g 
•  Re q uires i n -s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y  
•  I m p ort a nt me dical e v e nts 
7. 2. 1.  
S A E Re p orti n g  
All S A Es m ust be pr o m ptl y re p orte d t o t he S p o ns or b y t he I n vesti gat or, st u d y c o or di nat or, ot her 
desi g nat e d st u d y p ers o n n el, or cli nical res earc h ass ociate wit hi n 2 4 h o urs of n otificati o n of t he 
S A E f or relat e d S A Es a n d wit hi n 4 8 h o urs f or u nrelate d S A Es.  T o re p ort s uc h e ve nts, t he 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 6  of 7 1  
I n v esti gat or m ust c o m plete a n S A E f or m a n d s e nd it  wit hi n 2 4 h o urs b y e m ail or fa x wit h 
rele va nt i nf or m ati o n.   
Wit hi n t he 4 8 h o urs f oll o wi n g t he i nitial re p ort, t he I n vesti gat or m ust pr o vi de f urt her i nf or mati o n 
o n t he S A E.  T his s h o ul d i ncl u de a c o p y of t h e c o m plete d S A E f or m, a n d a n y ot her i nf or mati o n 
t hat will assist t he u n dersta n di n g of t he e ve nt.  Si g nifica nt ne w i nf or m ati o n o n o n g oi n g S A Es 
will be pr o vi de d pr o m ptl y as a f oll o w- u p. 
T he I n vesti gat or als o m ust re p ort all S A Es pr o m ptl y t o t he a p pr o priate I R B/I E C as re q uire d b y 
t he I R B/I E C.  
C o ntact I nf or mati o n f or S A E Re p orti n g 
S A E Re p orti n g will be se nt t o:  
P R E MI E R R ese a rc h P h ar m a c o vi gil a nce ( P R E MI E R P V):  
U S/ C a n a d a C ases:  fa x + 2 1 5- 9 7 2- 8 7 6 5 O R e-mail “ Gl o b al P V- U S @ pre mier -rese a rc h.c o m ” 
E U/ R O W C ases:  fa x + 4 2 1 2 6 8 2 0 3 7 1 3 O R e-mail “ P V D S -R O W @ pre mi er -rese a rc h.c o m  
 
Me dic al M o nit or C o nt a ct: Sari na Ta ni m ot o, M D, P h D  
Office/ Cell ular  
+ 1 - 8 5 8- 2 2 7- 3 0 0 8/ + 1- 8 5 8- 7 7 4- 8 7 1 6 
E mail  
Sari na @ pacificli n kc o ns ulti n g.c o m   
 
7. 2. 2.  
Rec or di n g of Seri o us A d verse E ve nts  
All S A E i nf or mati o n m ust be rec or d e d o n t he S A E f or m pr o vi de d b y t he S p o ns or.  A d diti o nal 
f oll o w- u p i nf or mati o n (e. g., test r es ults, a ut o ps y re p ort, disc har ge s u m mar y, a n d C R F pa ges f or 
A Es, c o nc o mita nt me dicati o ns, st u d y dr u g a d mi nistrati o n, a n d me dical hist or y) m ust be o btai ne d 
t o s u p ple me nt t he S A E re p ort f or m.  A c o p y of all i nitial a n d f oll o w- u p re p orts m ust be file d 
wit h t he s u bject’s C R F.  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1.  
O V E R VI E W  
T he ai m of t his st u d y is t o e val uate t he s afet y a n d efficac y of N T R A - 9 6 2 0 relati ve t o matc hi n g 
place b o o n i ntesti nal fa il ure d ue t o S B S.  Safet y will be assesse d b y A Es w hile pri mar y efficac y 
will be assesse d b y c h a n ge i n p are nteral fee di n g.  
T his secti o n briefl y descri bes t he a nal yses pla n n e d f or t he trial.  A f ull statistical a nal ysis pla n 
( S A P), t o be writte n w hile t he st u d y is still bli n d, will descri be t he met h o ds i n detail.  S h o ul d t he 
S A P a n d t his pr ot oc ol n ot be i n c o m plete a gree me nt, t he met h o d ol o g y i n t he S A P will pre vail. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 7  of 7 1  
8. 1. 1.  
I nteri m C hec k of V ari a nce Ass u m pti o n 
T his m ultice nter trial will all o w i ncl usi o n of a lar ge p o p ul ati o n of i nfa nts fr o m preter m t o o ne 
year, S B S of v ar yi n g eti ol o gies, b o w el le n gt h of v ar yi n g sizes, prese nce or a bse nce of ile ocecal 
val ve, a n d var yi n g fee di n g r e gi mes (e. g., f or m ula o nl y, f ull or partial o w n m ot her’s mil k).  We 
k n o w of n o si milar st u d y t hat has bee n c o n d u cte d i n s uc h a wi de -ra n gi n g p o p ulati o n - a 
p o p ulati o n t hat is e x pecte d t o ha ve es p eciall y hi g h variati o n wit h res pect t o pr o g n osis a n d 
t heref or e t o st u d y o ut c o me.  O ur best esti mate of wit hi n- gr o u p v ariati o n, w hic h is critical f or 
acc ur atel y c o m p uti n g st u d y p o w er, is base d o n a s mall pil ot st u d y i n a relat e d, b ut n ot i de ntical, 
i n dicati o n.  C o nse q ue ntl y, w e will assess t he ass u m pti o ns use d f or calc ulati n g p o wer b y 
c o m p uti n g t he c o m m o n p o ole d sta n dar d de vi ati o n of perce nt c ha n ge i n % P N w he n 7 5 s u bjects 
ha ve c o m plete d 1 2 wee ks i n t he st u d y.  S h o ul d t he calc ul ate d sta n dar d d e viati o n be at least 2 2 % 
(i.e., 1 0 % greater t h a n t he 2 0 % ass u me d i n t he pr ot oc ol), sa m ple size ma y be a dj uste d u p war d 
acc or di n gl y.  A statisticia n bli n de d t o gr o u p assi g n me nt will c o m p ute t his i nteri m sta n dar d 
de viati o n.  T hat statisticia n will n ot be i n v ol ve d i n a n y ot h er as p ect of t he trial.  T he s p o ns or will 
deci de w h et her t o i ncr eas e t he sa m ple size d uri n g t he trial; t he decisi o n will be base d o n t he 
esti mate d varia n ce b ut wit h o ut a n y k n o wle d ge of t he i nteri m effect size. 
8. 1. 2.  
St atistic al Tests of C o -Pri m a r y a n d Ke y Sec o n d ar y E n d p oi nts  
C o -Pri m ar y E n d p oi nt  ( me a ns) 
T he t w o e n d p oi nts ( 1 2 w ee ks a n d 2 4 w ee ks) will eac h b e a nal yze d usi n g a n a nal ysis of 
c o varia n ce m o del wit h P C _ P N 0- 1 2 a n d P C _ P N0- 2 4 ser vi n g as t he de p e n de nt varia ble f or eac h 
res pecti ve a nal ysis.  Treat me nt gr o u p a n d t h e ra n d o mizati o n stratificati o n varia bles will ser v e as 
fact ors a n d t h e baseli ne % P N val ue will ser ve as a c o vari ate i n eac h a n al ysis.  I n eac h a nal ysis, 
t he hi g her d ose gr o u p will be c o m pare d t o place b o gr o u p first.  T he hi g h- d ose c o m paris o n will 
be teste d at t he 0. 0 2 5 t w o- si de d si g nifica nce le vel at eac h ti me p oi nt.  If t he hi g h- d ose 
c o m paris o n at a p artic ular ti me p oi nt is si g nifica nt at p  < 0. 0 2 5, t he n t he l o w- d ose c o m paris o n 
wit h place b o (at t he s a me ti me p oi nt) will be teste d at t he 0. 0 2 5 le vel.  
F or t his e n d p oi nt, t he T y pe I err or r ate will be c o ntr olle d at 0. 0 5 b y usi n g a B o nferr o ni c orrecti o n 
f or t he t w o ti me p oi nts a n d a ste p- d o w n pr o ce d ure t o c o m pare eac h d os e gr o u p ( hi g h d ose first, 
t he n l o w d ose) wit h place b o.  
C o -Pri m ar y E n d p oi nt  (res p o n ders) 
T he c o nti n u o us res p o n der a nal ysis will be dis pla ye d gra p hicall y w h ere t he x-a xis dis pla ys t he 
perce nt re d ucti o n i n % P N a n d t he y- a xis s h o ws t he pr o p orti o n of i nfa nts w h o meet eac h res p o ns e 
t hres h ol d (fr o m 0 t o 1 0 0 %).  T he c o nti n u o us res p o n der c ur v es f or eac h d ose vs. place b o will be 
c o m pare d usi n g t he Ma n n W hit ne y U test base d o n t he 1 2 wee k d ata a n d a n ot her gra p h a n d 
a nal ysis will ma ke t h e si milar c o m paris o n at 2 4 w ee ks.  Eac h test will be carrie d o ut at t he 1 -
si de d p < 0. 1 0 si g nifica nce le vel. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 8  of 7 1  
T he trial will ha ve s h o w n be nefit if a n y gr o u p c o m paris o n state d a b o ve is s h o w n t o be s u peri or 
t o place b o o n b ot h of t he c o-pri mar y e n d p oi nts  at t he sa me ti me ( 1 2 or 2 4  w ee ks, or b ot h), eac h 
at t he state d si g nifi ca nce le vel .  
Ke y Sec o n d ar y E n d p oi nt  
T he ke y sec o n dar y e n d p oi nt will be a nal yze d usi n g a stratifie d l o g-ra n k test wit h fact ors f or 
treat me nt gr o u p a n d t h e r a n d o mizati o n stratificati o n varia bles.  Se parate a nal ys es will be carrie d 
o ut f or eac h d ose gr o u p. 
T he Statistical A nal ysis Pla n will descri be i n detail t he met h o ds t o be use d f or t he pri mar y a n d 
ke y s ec o n dar y e n d p oi nts.  T he met h o ds will be desi g ne d t o e ns ure pr otecti o n of t he T y pe I err or 
rate acr oss t he primar y a n d ke y s ec o n d ar y e n d p oi nts. 
8. 1. 3.  
Tre at me nt of S u bjects L ost t o F oll o w- u p  
Se veral s u bjects i n t his trial ma y u n d er g o si g nifica nt i nter ve nti o ns d uri n g t h e trial a n d s o me ma y 
die.  S pecificall y, a b o ut 1 0 % of s u bjects are n ot e x pecte d t o reac h t he 1 2- w ee k ti m e p oi nt f or 
reas o ns s uc h as deat h, ris k of or act u al necr otizi n g e nter oc olitis ( N E C), or ot her c o m plicati o ns.  
A n a d diti o nal 1 0 % of s u bjects are n ot e x pecte d t o reac h t h e 2 4 wee k ti me p oi nt f or si milar 
reas o ns.  Partial dat a c oll ecte d fr o m s uc h i nfa nts are i nf or mati ve f or c o m pari n g t he treat me nt 
ar ms.  F or s u bjects w h o d o n ot pr o vi de a n y data d uri n g t he 1 0- da y peri o d f or t he wee k 1 2 or 
wee k 2 4 ti me p oi nt, t he e n d p oi nt will be i m p ute d usi n g m ulti ple i m p utati o n, re placi n g eac h 
missi n g val ue wit h a set of pla u si ble val ues t hat re prese nt t he u n cert ai nt y a b o ut t he c orrect val ue 
t o i m p ute.  T he m ulti ple  i m p ute d datasets will t he n be a nal yz e d b y sta n dar d statistical pr oce d ures 
f or c o m plete d ata a n d c o m bi ni n g t he res ults fr o m t hese a nal yses.  M ulti ple i m p utati o n d oes n ot 
atte m pt t o esti mate eac h missi n g val ue t hr o u g h si m ulate d val ues, b ut rat her t o prese nt a ra n d o m 
sa m ple of t he missi n g val ues.   
M ulti ple i m p utati o n i n v ol ves t hree ste ps:  
1.  t he missi n g val ues are fille d i n m  ti mes t o ge nerat e m  c o m plete d ata sets,  
2.  t he m  c o m plete dat asets are a nal yze d usi n g sta n dar d statistical pr oce d ures,  
3.  t he res ults fr o m t he m  a n al yses are c o m bi ne d ( usi n g a r oll -u p esti mat or) f or statistical 
i nfere n ce. 
T he S A P will prese nt f ull details of t he met h o d ol o g y.  
8. 2.  
A N A L Y SI S S E T S  
8. 2. 1.  
S af et y A n al ysis Set  
T he safet y a nal ysis set will c o nsist of all s u bjects f or w h o m t he st u d y treat me nt, w het her place b o 
or N T R A - 9 6 2 0, was i niti ate d. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 4 9  of 7 1  
8. 2. 2.  
F ull A n al ysis Set  
T he F ull A nal ysis Set ( F A S) will c o nsist of all ra n d o mize d s u bjects.  S u bjects will be a nal yz e d 
b y r a n d o mi ze d treat me nt.  
Bli n d re vie w will be use d t o assess w hic h i nter ve nti o ns u n der g o n e d uri n g t he trial are li kel y t o 
affect o utc o me. As n ote d i n t he prece di n g s ecti o n, maj or i nter ve nti o ns are e x pecte d t o be 
i n de pe n de nt of tr eat me nt. 
8. 2. 3.  
M o difie d I nte nt -t o-Tre at Se t 
T he M o difie d I nte nt- t o-Treat ( mI T T) set will c o nsist of all ra n d o mize d s u bjects w h o recei ve d at 
least o ne d ose of N T R A- 9 6 2 0 or place b o, a n d w h o ha ve baseli ne a n d at least o ne p ost-baseli ne 
meas ure me nt o n t he pri mar y e n d p oi nt (f or pri mar y e n d p oi nt testi n g) or t he ke y s ec o n dar y 
e n d p oi nts (f or ke y s ec o n dar y e n d p oi nt testi n g).  S u bjects will be a nal yz e d b y ra n d o mize d 
treat me nt. 
Bli n d re vie w will be use d t o assess w hic h i nter ve nti o ns u n der g o n e d uri n g t he trial are li kel y t o 
affect o utc o me. As n ote d i n t he prece di n g s ecti o n, maj or i nter ve nti o ns are e x pecte d t o be 
i n de pe n de nt of tr eat me nt. 
8. 2. 4.  
Per - Pr ot oc ol A n al ysis Set 
T he per - pr ot oc ol ( P P) a n al ysis set will be t he s u bs et of F A S s u bjects wit h n o maj or pr ot oc ol 
vi olati o n li kel y t o affect o utc o me pri or t o t he ti me p oi n t at w hic h a c o nfir m at or y e n d p oi nt is 
teste d.  Bli n d re vie w will be use d t o assess w hic h i nter ve nti o ns u n der g o ne d uri n g t he tri al are 
li kel y t o affect o utc o me.  S u bjects wit h t hese maj or i nter ve nti o ns will be i ncl u de d i n t he P P u p t o 
t he p oi nt of i nter ve nti o n. 
A nal ysis of P P sets nee d t o be perf or m e d i n a wa y t hat a dj usts f or t he selecti o n bias i n here nt i n 
P P sets.  T he S A P will descri be t hes e a nal ys es.  
8. 3.  
S T U D Y E N D P OI N T S  
T his secti o n prese nts t he safet y a n d efficac y e n d p oi nts i n t his trial.  T he pri mar y e n d p oi nts are 
c o m p ute d as per ce nt c h a n ge fr o m baseli ne t o 1 2 wee ks a n d t o 2 4 w ee ks , w here t he c ha n ge is 
base d o n t he a v era ge of t he dail y v al ues o btai ne d d uri n g t he s p ecifie d w ee k.  T he differe nce 
bet wee n t he rele v a nt wee k a n d baseli ne is calc ulat e d s uc h t hat t he e x pecte d o utc o mes are 
p ositi ve (i.e., si nce greater % P N at baseli ne is e x pecte d, t he pri mar y e n d p oi nt is c o m p ute d b y 
s u btracti n g t h e 1 2-wee k or 2 4 wee k m eas ure me nt fr o m baseli ne).  
8. 3. 1.  
S af et y E n d p oi nts  
Safet y e n d p oi nts are S A Es a n d A Es occ urri n g at a n y ti me  d uri n g t he trial or f oll o w- u p. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 0  of 7 1  
8. 3. 2.  
C o - Pri m ar y Effic ac y E n d p oi nts 
T he first c o-pri mar y e n d p oi nts i n t his trial is  perce nt c ha n ge i n % P N ( P C _ P N 0-t) fr o m baseli ne1 3 
base d o n cal oric i nta ke t o 1 2 wee ks a n d a gai n t o 2 4 wee ks.  T he 1 2 a n d 2 4 w ee k e n d p oi nts are 
calc ulate d as: 
P C _P N 0 −t =  1 0 0 ∗ % P N B a s eli n e  − %P N t
% P N B a s eli n e
 
W here  
•  𝑡𝑡 = 1 2 or 2 4 wee ks   
•  % P N = % Par e nteral N utriti o n (fee di n g) will be calc ulate d as pare nteral cal ories di vi de d b y 
t otal cal oric re q uire me nts (t he Sc h ofiel d e q u ati o n (1 )). 
•  P C _ P N 0- t o bser vati o ns will be c o m p ute d as a n a v era ge o ver a si n gle w ee k.  
T h us, P C _ P N at 1 2 wee ks will be t he a vera ge of P C _ P N o ver Da ys 7 8 t o 8 4. 
P C _ P N at 2 4 wee ks will be t he a vera ge of P C _ P N o ver da ys 1 6 2 t o 1 6 8. 
T he use of t he Sc h ofiel d e q uati o n w o ul d be s olel y i n t he a nal ysis of t h e st u d y a n d w o ul d n ot be 
use d at be dsi de d uri n g t h e act ual trial.  
T he sec o n d c o - pri mar y e n d p oi nts are res p o n d er e n d p oi nts, calc ulate d as c o nti n u o us res p o n der 
c o m paris o ns at 1 2 wee ks a n d a gai n at 2 4 w ee ks .  Eac h test will be carrie d o ut at t he 1 -si de d 
p < 0. 1 0 si g nifica nce le vel. 
8. 3. 3.  
Ke y Sec o n d ar y E n d p oi nt  
T he trial has t he f oll o wi n g ke y s ec o n dar y e n d p oi nt: 
Ti me t o re d ucti o n of P N t o less t ha n 1 0 % of t he t otal cal oric i nta ke o n eac h of 1 4 c o nsec uti ve 
da ys . 
8. 3. 4.  
Ot her Sec o n d ar y E n d p oi nts  
T he st u d y h as t he f oll o wi n g a d diti o nal sec o n dar y e n d p oi nts: 
a)  Ti me t o wea n off 1 4 pare nt eral n utriti o n 
b)  N u m ber of patie nts ac hie vi n g rea di ness t o wea n off  1 5 at 1 2 a n d 2 4 wee ks fr o m baseli ne   
c)  Ti me t o 5 0 % P N/I V re d u cti o n fr o m baseli ne i n % P N base d o n t otal cal ories.  
d)  Ti me t o 5 0 % P N/I V re d u cti o n fr o m baseli ne i n % P N base d o n v ol u me. 
                                                 
1 3 B aseli ne: pri or t o treat me nt. B ase li ne meas ure me nt  peri o d s h o ul d be at least 7 da ys . 
1 4 W ea n off defi ne d as c o m plete cessati o n of pare nteral n utriti o n a n d ac hie vi n g f ull e nteral a ut o n o m y f or t w o wee ks.  
1 5 R e d ucti o n t o P N of  less t ha n 1 0 % of t he t otal cal oric i nta ke  f or t w o wee ks. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 1  of 7 1  
e)  N u m ber of patie nts r eac hi n g 5 0 % P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n t otal 
cal ories at 1 2 a n d 2 4 wee ks  
f) N u m ber of patie nts r eac hi n g 5 0 % P N/I V re d ucti o n fr o m baseli ne i n % P N base d o n 
v ol u me at 1 2 a n d 2 4 wee ks. 
g)  Perce nt c h a n ge fr o m bas eli ne i n % P N/I V base d o n t otal cal ories.   
h)  Perce nt c h a n ge fr o m bas eli ne i n % P N/I V base d o n v ol u me.  
i) Perce nt c h a n ge fr o m bas eli ne i n P N/I V fl ui d v ol u me d uri n g treat me nt peri o d. 
j) C ha n ge i n Z-sc or es ( Fe nt o n) fr o m baseli ne d uri n g t he treat me nt peri o d. 
k)  Perce nt c h a n ge fr o m bas eli ne i n % E N base d o n t otal cal ories.  
l) Perce nt c h a n ge fr o m bas eli ne i n % E N base d o n t otal v ol u me.  
m)  C ha n ge fr o m bas eli ne i n li ver e nz y mes ( A L T, G G T, a n d t otal a n d direct bilir u bi n). 
n)  C ha n ge fr o m bas eli ne i n plas ma citr ulli ne le vels.  
o)  C ha n ge fr o m bas eli ne i n b o d y w ei g ht d uri n g t he treat me nt peri o d. 
p)  Wee kl y a v era ge of h o urs o n prescri be d P N/I V d uri n g t he last m o nt h of treat me nt. 
q)  Ge ner al safet y v aria bles i ncl u di n g e pis o des of si g nifica nt fee di n g i nt olera nce c o m pare d 
t o place b o  
8. 4.  
S A M P L E SI Z E  
T he sa m ple size is base d o n testi n g t he s u peri orit y of t he hi g h d os e of N T R A- 9 6 2 0 c o m pare d t o 
place b o o n t he pri mar y e n d p oi nts of perce nt c h a n ge i n % P N fr o m baseli ne t o ti me “t” ( P C _ P N 0-
t) w here “t” = 1 2 a n d 2 4 wee ks.  O n t he b asis of hist orical data, t he ass u me d re d ucti o n i n 
P C _ P N 0 -t is 3 0 % a n d 4 2 % i n place b o a n d N T R A- 9 6 2 0, res pecti vel y, at b ot h 1 2 a n d 2 4 wee ks.  
A c o m m o n wit hi n - gr o u p sta n dar d de viati o n of 2 0 % has bee n ass u me d f or b ot h ar ms.  
Gi ve n t he a b o ve s p ecificati o ns, a n d base d o n t he use of a t w o-si de d, t w o-s a m ple c o m paris o n of 
mea ns at t he al p ha  = 0. 0 2 5 le vel of si g nifi ca nce, a sa m ple of 4 5 s u bjects per gr o u p w o ul d 
pr o vi de a p pr o xi matel y 8 0 % p o wer t o de m o nstrate s u peri orit y.  Si nce s o m e s u bjects ma y n ot 
c o m plete t he e ntire tri al,  a n a d diti o nal 1 0 % of s u bjects will be e nr olle d per ar m ( 5 0 s u bjects per 
ar m) t o acc o u nt f or t his p ote ntial l oss.  T h us, t he pr o p ose d sa m ple size is 1 5 0 s u bjects. 
8. 5.  
S T A TI S TI C A L A N A L Y SI S  
8. 5. 1.  
O ver vie w  
Safet y a n d F ull A nal ysis Set ( F A S) will be c o n d u cte d o n t he saf et y a nal ysis set.  Pri mar y a n d 
ke y s ec o n dar y efficac y testi n g will be d o ne usi n g t he F A S a n d t he mI T T sets.  Efficac y testi n g, 
i ncl u di n g pri mar y a n d ke y sec o n dar y e n d p oi nts, ma y als o be perf or me d o n t he P P set. 
T he data will be s u m mari ze d b y gr o u p a n d o verall.  F or c o nti n u o us data, t a bles will prese nt 
mea ns, sta n dar d d e viati o ns, me dia ns, mi ni ma, ma xi ma, a p pr o priate perce ntiles, a n d n u m ber of 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 2  of 7 1  
s u bjects.  F or cate g ori cal data, ta bles will s h o w c o u nts a n d perce nta ges.  “ Ti me-t o-e ve nt” d ata 
will be s u m marize d us i n g t he K a pla n-M eier met h o d.  Data listi n gs b y s u bj ect will be pr o vi de d.  
Statistical a nal yses will ge nerall y be p erf or me d usi n g t he S A S ® s yste m.  T he effects of 
n o nc o m plia nce, dr o p o uts, a n d p ossi ble c o variat es s uc h as gestati o nal a ge, birt h wei g ht a n d 
ge n d er will be ass esse d as se nsiti vit y a n al yses.  
8. 5. 2.  
S u bject Dis p ositi o n  
S u bject dis p ositi o n will be ta b ulate d; t he n u m ber of s u bjects e nr olle d, e x p ose d, pre mat urel y 
ter mi nate d fr o m st u d y dr u g, pr e mat urel y ter mi nate d fr o m st u d y, a n d c o m plete d will be 
s u m marize d b y treat me nt gr o u p a n d o verall.  A list of dr o p o uts will be pre p are d i ncl u di n g reas o n 
f or, a n d ti me of, disc o nti n uati o n.  
8. 5. 3.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
S u bjects i n eac h treat me nt ar m will be c haracterize d usi n g ta bles, fi g ures, a n d descri pti ve 
statistics f or de m o gra p hi c a n d baseli ne cli nical varia bles.  Treat me nt gr o u ps will be c o m pare d t o 
e val uate t he b ala nce ac hi e ve d b y ra n d o mizati o n.  O bser ve d differe nces b et wee n t he gr o u ps, 
s h o ul d t here be a n y, will be i nter pret e d f or t heir cli nical si g nifica nce a n d t heir p ote ntial use as 
c o variates i n se nsiti vit y a nal yses of t he a n al ysis of efficac y e n d p oi nts.  
8. 5. 4.  
S af et y A n al ysis 
T he safet y a nal yses will be descri pti ve a n d narrati ve i n nat ure, wit h S A Es a n d A Es c o de d usi n g 
Me d D R A a n d ta b ulate d b y b o d y s yste m, preferre d ter m, treat me nt gr o u p, se verit y a n d relati o n t o 
pr oce d ur e.  Des cri pti ve statistics will be pr o vi de d b y treat me nt gr o u p as a p pr o priate. 
8. 5. 5.  
Pri m ar y Effic ac y A n al ysis 
8. 5. 5. 1.  
C o -Pri m ar y E n d p oi nt s  
T he first t w o pri mar y e n d p oi nts ( 1 2 wee ks a n d 2 4 wee ks) will eac h be  a nal yz e d usi n g a n 
a nal ysis of c o varia nce m o del wit h P C _ P N 0- 1 2 a n d P C _ P N 0- 2 4 ser vi n g as t he de pe n de nt varia ble 
f or eac h res p ecti ve a nal ysis.  Treat me nt gr o u p a n d t he ra n d o misati o n stratificati o n varia bles  will  
ser ve as fact ors  a n d t he b aseli ne % P N val ue wi ll ser ve as a c o v ariate i n eac h a nal ysis.  I n eac h 
a nal ysis, t he hi g h er d ose gr o u p will be c o m pare d t o place b o gr o u p first.  T he hi g h- d os e 
c o m paris o n will be teste d at t he 0. 0 2 5 t w o-si de d si g nifica n ce le v el at eac h ti me p oi nt .  If t he 
hi g h - d ose c o m paris o n at a partic ular ti me p oi nt is si g nifica nt at p < 0. 0 2 5, t h e n t he l o w- d ose 
c o m paris o n wit h place b o (at t he sa me ti me p oi nt) will be teste d at t he 0. 0 2 5 le vel.  
T he sec o n d c o - pri mar y e n d p oi nts are res p o n d er e n d p oi nts, calc ulate d as c o nti n u o us res p o n der 
c o m paris o ns at  1 2 wee ks a n d a gai n at 2 4 w ee ks.  Eac h test will be carrie d o ut at t he 1 -si de d 
p < 0. 1 0 si g nifica nce le vel. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 3  of 7 1  
T he trial will ha ve s h o w n be nefit if a n y gr o u p c o m paris o n state d a b o ve is s h o w n t o be s u peri or 
t o place b o, at t he sa m e ti me ( 1 2 or 2 4 wee ks, or b ot h), eac h at t he st ate d si g nifica nce l e vel . 
8. 5. 5. 2.  
Ke y Sec o n d ar y E n d p oi nt  
T he ke y sec o n dar y e n d p oi nt will be a nal yze d usi n g a stratifie d l o g-ra n k test wit h fact ors f or 
treat me nt gr o u p a n d t h e r a n d o mizati o n stratificati o n varia bles.   
8. 5. 5. 3.  
Ot her Sec o n d ar y E n d p oi nts  
T h e S A P will descri be t he a nal yses pla n n e d f or t h e ot her sec o n dar y e n d p oi nts. 
8. 5. 6.  
Se nsiti vit y A n al yses 
T he S A P will descri be t he se nsiti vit y a nal yses pl a n ne d f or t he pri mar y a n d ke y s ec o n dar y 
e n d p oi nts. 
8. 5. 7.  
Tre at me nt of Missi n g V al ues  
T he S A P will descri be t he pla n n e d a p pr oac h es f or missi n g pri mar y a n d k e y sec o n dar y e n d p oi nts. 
8. 5. 8.  
A n al yses of F oll o w- u p D at a  
I n t his 2 4-w ee k st u d y, pri mar y efficac y is meas ure d at 1 2 a n d 2 4 w ee ks.  Data l oc k will occ ur 
after all s u bjects ha ve c o m plete d 2 4 wee ks i n t he trial, bef ore w hic h t he S A P will ha ve bee n 
fi nalize d a n d si g ne d.  T h e fi nal statistical re p ort will i ncl u de o utc o mes u p t o a n d i ncl u di n g 2 4 
wee ks.  
8. 5. 9.  
I nteri m A n al ysis 
As descri be d i n Secti o n 8. 1. 1 , a bli n d re vie w of t h e data will be perf or me d d uri n g t he st u d y i n 
or der t o esti mate t he v ari a nce.   
A Data Saf et y M o nit ori n g B oar d  ( Secti o n 1 0. 3 ) will re vie w t he o n g oi n g d ata t o e ns ure safet y of 
t he s u bjects. 
N o f or mal i nteri m a nal ysis of efficac y will be perf or me d.  
9.  
D A T A C O L L E C TI O N, S T U D Y M O NI T O RI N G,  A N D D A T A 
DI S C L O S U R E  
9. 1.  
D A T A C O L L E C TI O N A N D R E P O R TI N G  
T he I n vesti gat or will mai ntai n a de q uate a n d acc urate s o urce d oc u me nts desi g ne d t o rec or d all 
o bser vati o ns a n d ot her p erti ne nt data f or eac h s u bject treate d wit h t he st u d y dr u g. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 4  of 7 1  
St u d y p e rs o n nel at eac h site will e nter data fr o m s o urce d oc u m e nts c orres p o n di n g t o a s u bject’s 
visit i nt o t he pr ot oc ol- s pecific el ectr o nic Cas e Re p ort F or m (i.e., El ectr o ni c Data Ca pt ure ( E D C) 
s yste m) w h e n t he i nf or m ati o n c orres p o n di n g t o t h at visit is a vaila ble.  S u bjects will n ot be 
i de ntifie d b y n a me i n t he st u d y data b ase or o n a n y st u d y d oc u me nts t o be c ollecte d b y t he 
S p o ns or ( or desi g nee), b ut will be i de ntifie d b y a site n u m ber, s u bject n u m ber a n d i nitials.  A n 
electr o nic C R F will be c o m plete d f or eac h s u bject w h o is assi g ne d a st u d y n u m ber a n d f or w h o m 
a st u d y- a p pr o v e d I C F is si g ne d a n d date d.  F or all e ntries i nt o t he E D C t hat are n ot s o urce 
electr o nic d ata, t he dat a e ntries m ust be s u p p orte d b y ori gi nal s o urce d oc u m e ntati o n 
(e. g., la b or at or y re p orts, me dical rec or ds) mai ntai ne d at t he i n vesti gati o nal site.  If a c orrecti o n is 
re q uire d f or a n E D C, t he ti me a n d date sta m ps trac k t he pers o n e nteri n g or u p dati n g E D C dat a 
a n d create a n electr o ni c a u dit trail.  
T he I n vesti gat or will ma ke safet y assess me nts ( A Es,  vital si g ns, res ults fr o m p h ysical 
e x a mi nati o ns, a n d la b orat or y tests) o n a n o n g oi n g basis.  T he I n vesti gat or is res p o nsi ble f or all 
i nf or mati o n c ollecte d o n s u bjects e nr olle d i n t his st u d y.  All data c ollecte d d uri n g t he c o urse of 
t his st u d y m ust be r e vie w e d a n d verifie d f or c o m plete ness a n d acc urac y b y t he I n vesti gat or.   
If a s u bject is l ost t o f oll o w- u p, (i.e., f ails t o ret ur n f or sc he d ule d visits) e ver y reas o n a ble eff ort 
m ust be ma de t o c o ntact t he s u bject’s pare nt or g u ar dia n i n or der t o deter mi ne w h y t he s u bject 
faile d t o ret ur n.  All acti o ns ta ke n i n t his re gar d will be d oc u me nte d a n d d ate d i n t he C R F.  
T he i n vesti gat or is re q uir e d t o electr o nicall y si g n t he E D C at a p pr o priate ti mes.  T he 
i n vesti gat or’s si g nat ure o n t he C R F ser ves t o certif y t hat t he d ata c ollecte d f or eac h s u bject is 
acc ur ate, c o m plet e a n d le gi ble.  A c o p y of t he C R F will re mai n at t he st u d y site at t he 
c o m pleti o n of t he st u d y. 
All pr oce d ures f or t he h a n dli n g a n d a n al ysis of d ata will be c o n d ucte d usi n g g o o d c o m p uti n g 
practices m eet i n g F D A g ui deli nes f or t he ha n dli n g a n d a nal ysis of data f or cli nical trials. 
9. 2.  
S T U D Y M O NI T O RI N G  
T he S p o ns or’s desi g nees will m o nit or all as pects of t he st u d y caref ull y wit h res pect t o c G C Ps 
a n d S O Ps f or c o m plia nce wit h a p plica ble g o ver n m e nt re g ulati o ns.  T h e i n vesti gat or is 
res p o nsi ble f or pr o vi di n g all st u d y rec or ds, i ncl u di n g e C R Fs, s o urce d o c u m e nts, me dical hist or y, 
etc., f or r e vie w a n d i ns pecti o n b y t he cli nical m o nit or. 
E D C ( C R Fs) will be peri o dicall y m o nit ore d a n d s o urce verifie d a gai nst c orres p o n di n g s o urce 
d oc u me ntati o n (e. g., office a n d cli nical la b orat or y rec or ds) f or eac h s u bj ect.  Cli nical m o nit ors 
will e val uate peri o dicall y t he pr o gress of t h e st u d y, i ncl u di n g t he verificati o n of a p pr o priat e 
c o nse nt f or m pr o ce d ur es, re vie w of dr u g acc o u nta bilit y a n d st u d y dr u g pre parati o n pr oce d ures, 
a d here n ce t o d osi n g pr oce d ures, t he i n vesti gat or’s a d here n ce t o t he pr ot oc ol, mai nte na nce of 
rec or ds a n d re p orts, re vie w of s o urce d oc u me nts f or acc urac y, c o m plete ness, a n d le gi bilit y, a n d 
re vie w of st u d y r e g ulat or y d oc u m e nts, i ncl u di n g, b ut n ot li mite d t o: st u d y a gree m e nt, st u d y 
i ns ura nce, st u d y a p pr o val letters b y t he I R B/I E C a n d t he Re g ulat or y A ut h orit y, site staff C V a n d 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 5  of 7 1  
fi na ncial state me nts, st u d y f or ms, pr ot oc ol si g n at ure pa ge, etc.  I n a d diti o n, t he m o nit or s hall 
re vie w c o m plet e d electr o nic case re p ort f or m (e C R F) a n d st u d y d oc u me nt ati o n f or acc urac y a n d 
c o m plete ness, a n d pr ot o c ol c o m plia nce.  T he m o nit or s h o ul d ass ure t hat data ca pt ure d i n t he 
e C R F is f ull y s u p p orte d b y t he s o ur ce d o c u me nts.  Cli nical m o nit ors w ill als o e ns ure t hat all 
pr ot oc ol re q uire m e nts, a p plica ble F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns ( C F R Title 
2 1 Parts 5 0, 5 6, a n d 3 1 2 a n d I C H G ui deli nes f or G C P - E 6), ot her re q uire me nts, a n d 
I n v esti gat or’s o bli gati o ns are bei n g f ulfille d. 
B y si g ni n g t his pr ot oc ol, t he I n v esti gat or gra nts per missi o n t o t he S p o ns or ( or desi g n ee), a n d 
a p pr o priate re g ulat or y a ut h orities t o c o n d uct o n-site m o nit ori n g a n d/ or a u diti n g of all a p pr o priate 
st u d y d oc u me ntati o n. 
A part fr o m ass u mi n g r es p o nsi bilit y f or t h e c o m m u nicati o n bet wee n t h e i n vesti gat or a n d t he 
S p o ns or, t he cli nical m o nit or d uties i ncl u de: 
•  O n -site visits; a n d  
•  Re vie w of st u d y d oc u me nts a n d res ults. 
O n -site m o nit ori n g visits i ncl u de pre-st u d y/ q ualifi cati o n visits, i nitiati o n visits, i nteri m 
m o nit ori n g visits a n d, a cl ose- o ut visit at t he e n d of t he st u d y.  At t he cl ose of t he st u d y, t he 
m o nit or will be re q uire d t o ma ke a fi nal o n- site visit t o ass ure t hat all st u d y data has bee n 
pr o perl y c o m plete d.  
Re p orts of o n- site visits s hall be ma de b y t he m o nit or a n d s h o ul d i ncl u de, as a p plica ble, 
res ol uti o n of c o ncer ns a n d q ueries, c o m pleti o n of a p pr o priate f oll o w- u p acti vities, c o m pleti o n of 
assi g ne d t as ks, a n d c orrecti ve acti o ns.  M o nit ori n g visits F oll o w- u p letters will be se nt t o t he site 
f or fili n g a n d a d here n ce.  
All data ge ner ate d i n t he c urre nt cli nical i n vesti gati o n will be ma na ge d acc or di n g t o rele va nt 
g ui deli nes ( e. g., G C P, 2 1 C F R Part 1 1). 
9. 3.  
C O N FI D E N TI A LI T Y, D A T A DI S C L O S U R E, A N D 
P U B LI C A TI O N  
S u bject me dical i nf or mati o n o btai ne d as a res ult of t his st u d y is c o nsi dere d c o nfi de ntial.  
Discl os ure t o t hir d parties ot her t ha n t h ose n ote d bel o w is pr o hi bite d.  All re p orts a n d 
c o m m u nicati o ns relati n g t o s u bjects a n d t heir pare nt(s) or g uar di a ns(s) i n t his st u d y will i de ntif y 
all pers o ns o nl y b y t heir i nitials a n d n u m b er.  Me dical i nf or mati o n res ulti n g fr o m a s u bject’s 
partici pati o n i n t his st u d y ma y b e gi ve n t o t he s u bject’s pers o n al p h ysicia n or t o t he a p pr o priat e 
me dical pers o n n el res p o nsi ble f or t he s u bject’s w elfare.  D ata ge n erat e d as a res ult of t his st u d y 
are t o be a vaila ble f or i ns pecti o n o n re q uest b y F D A or ot her g o ver n me nt re g ulat or y a ge nc y 
a u dit ors, t he S p o ns or, t he S p o ns or-assi g n e d cli nical m o nit or ( or desi g n ee), a n d t he I R B/I E C. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 6  of 7 1  
All la b orat or y s peci me ns, e val uati o n f or ms, re p orts, a n d ot her rec or ds t hat l e a ve t he site will be 
i de ntifie d b y a c o de d n u m ber t o mai ntai n s u bject c o nfi de ntialit y.  All rec or ds will be mai ntai ne d 
i n l oc ka ble file ca bi nets.  All c o m p uter e ntr y a n d net w or ki n g pr o gra ms will be i de ntifia ble o nl y 
b y c o d e d n u m bers.  Cli nical i nf or mati o n will n ot be release d wit h o ut writte n per missi o n fr o m t he 
s u bject’s par e nt or g uar di a n, e x ce pt as necessar y f or m o nit ori n g b y t he I R B, t he F D A, or 
re pres e ntati ves of t he st u d y S p o ns or.  
A n y i nf or mati o n, i n ve nti o ns, or disc o veries ( w het her pate nta bl e or n ot), i n n o vati o ns, 
s u g gesti o ns, i deas, a n d re p orts, ma de or de v el o pe d b y a n i n v esti gat or as a res ult of c o n d ucti n g 
t his st u d y s h all be pr o m ptl y discl ose d t o t he S p o ns or a n d s hall be t he s ole pr o pert y of t he 
S p o ns or.  T he I n vesti gat or a grees, u p o n t he S p o ns or’s re q u est a n d at t he S p o ns or's e x pe nse, t o 
e x ec ute s uc h d oc u me nts a n d t o ta ke s uc h ot her acti o ns, as t he S p o ns or dee ms necessar y or 
a p pr o priate, t o o btai n p ate nts i n t he S p o ns or’s na me c o veri n g a n y of t he f ore g oi n g. 
T he res ults of t his st u d y will be p u blis h e d u n der t he directi o n of t he S p o ns or.  Res ults will n ot be 
p u blis he d wit h o ut pri or re vie w a n d a p pr o val b y t h e S p o ns or. 
1 0.  
P R O T E C TI O N O F H U M A N S U B J E C T S 
1 0. 1.  
D E C L A R A TI O N O F H E L SI N KI  
B ot h t he I n vesti gat or a n d t he S p o ns or will e ns ure t hat t he st u d y is c o n d u cte d i n a g ree me nt wit h 
t he Declarati o n of H elsi n ki, I C H- G C P, a n d t he l ocal la ws a n d re g ulati o n. 
T o mai ntai n c o nfi de ntialit y, all la b or at or y s peci me ns, e val uati o n f or ms, re p orts a n d ot her rec or ds 
will be i de ntifie d b y a c o de d n u m ber a n d i nitials o nl y.  All st u d y rec o r ds will be ke pt i n a l oc ke d 
file ca bi net a n d c o de s h eets li n ki n g a s u bject’s n a me t o a s u bject i de ntificati o n n u m ber will be 
st ore d se par atel y i n a n ot her l oc ke d file ca bi net.  T he I n vesti gat or m ust als o c o m pl y wit h all 
a p plica ble pri vac y re g ulati o ns (e. g., H ealt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 
1 9 9 6). 
1 0. 2.  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S 
C O M MI T T E E 
T he I n vesti gat or a grees t o pr o vi de t he I R B/I E C wit h all a p pr o priate material, i ncl u di n g a c o p y of 
t he I C F.  T he st u d y will n ot be i nitiate d u ntil t he I n vesti gat or o bt ai ns writte n a p pr o val of t he 
researc h pla n a n d t he I C F fr o m t he a p pr o priat e I R B/I E C a n d c o pies of t h ese d oc u me nts are 
recei v e d b y t he S p o ns or.  A p pr o priate re p orts o n t he pr o gress of t his st u d y will be ma de b y t he 
I n v esti gat or t o t he I R B/I E C a n d S p o ns or i n acc or da nce wit h a p plica ble g o ver n me nt re g ul ati o ns 
a n d i n a gree me nt wit h t he p olicies esta blis he d b y t he S p o ns or.  T he S p o ns or e ns ures t hat t he 
I R B/I E C c o m plies wit h t he re q uir e me nts set f ort h i n 2 1 C o de of Fe d eral Re g ulati o ns ( C F R) 
Part  5 6. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 7  of 7 1  
Pr ot oc ol a n d/ or i nf or me d c o nse nt m o dificati o ns or c ha n ges ma y n ot be i niti ate d wit h o ut pri or 
writte n I R B/I E C a p pr o val e x ce pt w he n necessar y t o eli mi nate i m me diate hazar ds t o t he s u bject 
or w he n t he c ha n ge i n v ol ves o nl y l o gistical or a d mi nis trati ve as pects of t h e st u d y.  S uc h 
m o dificati o ns will be s u b mitte d t o t he I R B/I E C a n d writte n verificati o n t hat t he m o dificati o n 
was s u b mitte d a n d s u bse q ue ntl y a p pr o ve d will  be o btai ne d.   
T he I R B/I E C m ust be i nf or me d of re visi o ns t o ot her d oc u me nts ori gi nall y s u b mitte d f or re vie w; 
seri o us a n d/ or u ne x pecte d a d verse e ve nts occ urri n g d uri n g t he st u d y i n acc or da nce wit h t he 
sta n dar d o per ati n g pr oce d ures a n d p olicies of t h e I R B/I E C; ne w i nf or m ati o n t hat ma y affect 
a d versel y t he s afet y of t h e s u bjects of t he c o n d u ct of t he st u d y; a n a n n ual u p date a n d/ or re q uest 
f or re-a p pr o v al; a n d w he n t he st u d y has b ee n c o m plete d. 
1 0. 3.  
D A T A S A F E T Y M O NI T O RI N G B O A R D ( D S M B)  
A D S M B will be c o n ve n e d f or t his pr ot oc ol t o e ns ure t he safet y of s u bjects e nr olle d.  T he det ails 
of t he D S M B ac ti vities, i ncl u di n g r e vie w of t h e safet y d ata, will be o utli ne d i n a s pecific c harter 
a p pr o ve d b y t he D S M B me m bers, Me dical M o nit or, a n d S p o ns or.   
1 0. 4.  
I N F O R M E D C O N S E N T 
See Secti o n  4. 1. 1 . 
1 0. 5.  
I N V E S TI G A T O R’ S R E S P O N SI BI LI TI E S 
B y si g ni n g t he I n vesti gat or A gree me nt, t he i n vesti gat or a grees t o t he f oll o wi n g: 
See k I R B/I E C a n d Re g ul at or y A ut h orit y ( R A) a p pr o val ( w he n n ee d e d) f or t he st u d y pr ot o c ol, 
I nf or me d C o nse nt F or m (I C F), a n y ot her writte n i nf or mati o n pr o vi de d t o s u bjects a n d 
a d vertisi n g m aterial a n y f oll o w a n y re q u est ma de b y t he I R B/I E C or R A.  Writte n a p pr o val of 
t he pr ot oc ol a n d I C F a n d a n y a d vertisi n g materi al m ust be o btai ne d fr o m t he I R B/I E C a n d if 
a p plica ble t he c orres p o n di n g R A pri or t o a n y s u bject e nr oll me nt. 
C o n d uct t he st u d y i n acc or da nce wit h t he pr ot oc ol a n d o nl y ma k e c ha n ges after n otif yi n g t he 
S p o ns or ( or desi g nee), e x ce pt w he n t o pr otect t he safet y, ri g hts or w elfare of s u bjects.  
Pers o nall y c o n d uct or s u per vise t he st u d y ( or i n vesti gati o n). 
E ns ure t hat t he r e q uire m e nts rel ati n g t o o btai ni n g i nf or me d c o nse nt a n d I R B/I E C re vie w a n d 
a p pr o val meet fe deral g ui deli nes, as state d i n 2 1 C F R, Parts 5 0 a n d 5 6. 
Re p ort t o t he S p o ns or or desi g nee a n y A Es t hat occ ur i n t he c o urs e of t he st u d y, i n acc or d a nce 
wit h 2 1 C F R Part 3 1 2. 6 4. 
E ns ur e t hat all ass ociat es, c ollea g ues a n d e m pl o ye es assisti n g i n t he c o n d u ct of t he st u d y are 
i nf or me d a b o ut t heir o bli gati o ns i n meeti n g t he a b o ve c o m mit me nts. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 8  of 7 1  
Mai ntai n a de q uate a n d acc urat e rec or ds i n acc or d a nce wit h 2 1 C F R Part 3 1 2. 6 2 a n d t o ma ke 
t h ose rec or ds a vaila ble f or i ns pecti o n wit h t he S p o ns or ( or desi g nee). 
E ns ure t hat a n I R B/I E C t hat c o m plies wit h t he re q uire me nts of 2 1 C F R Part 5 6 will be 
res p o nsi ble f or i nitial a n d c o nti n ui n g re vi e w a n d a p pr o val of t he cli nical st u d y. 
Pr o m ptl y re p ort t o t he I R B/I E C a n d t he S p o ns or ( or desi g n ee) all c ha n ges i n t he researc h acti vit y 
a n d all 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 (t o i ncl u de a me n d me nts a n d 
I N D saf et y re p orts). 
See k I R B/I E C a p pr o val bef ore a n y c h a n ges are m a de i n t he res earc h st u d y, e x ce pt w he n 
necessar y t o eli mi nate hazar ds t o t he s u bjects.  
C o m pl y wit h all ot her re q uire me nts re gar di n g t he o bli gati o ns of cli nical i n vesti gat ors a n d all 
ot her perti ne nt r e q uire me nts liste d i n 2 1 C F R Part 3 1 2, G o o d Cli nical Practice (I C H- G C P E 6) 
a n d t he et hical pri n ci ples t hat ha ve t heir ori gi n i n t he Decl arati o n of H elsi n ki. 
1 0. 6.  
LI A BI LI T Y A N D I N S U R A N C E C O N DI TI O N S  
N utri nia Lt d . h ol ds a cli nical trial lia bilit y i ns ura n ce p olic y.  A c o p y of  t he p olic y s u m mar y will 
be fil e d i n t he i n vesti gat or's site file.  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 5 9  of 7 1  
1 1.  
R E F E R E N C E S  
1.  
Se nt o n g o T A, T ers ha k o v ec A M, Mas care n has M R, Wats o n M H, Stalli n gs V A. Resti n g 
e ner g y e x pe n dit ure a n d pre dicti o n e q uati o ns i n y o u n g c hil dre n wit h fail ure t o t hri ve. T he J o ur nal 
of pe diatrics. 2 0 0 0; 1 3 6( 3): 3 4 5- 5 0. 
2. 
Se nterre T. Pr actice of e nteral n utriti o n i n ver y l o w birt h wei g ht a n d e xtre mel y l o w birt h 
wei g ht i nf a nts. W orl d Re v N utr Diet. 2 0 1 4; 1 1 0: 2 0 1- 1 4. 
3.  
Garris o n A P, De k a ne y C M, v o n All me n D C, L u n d P K, He n ni n g SJ, Hel mrat h M A. Earl y 
b ut n ot late a d mi nistrati o n of gl uca g o n- li ke p e pti de-2 f oll o wi n g ile o -cecal resecti o n a u g me nts 
p utati ve i ntesti nal ste m cell e x pa nsi o n. A m J P h ysi ol Gastr oi ntest Li ver P h ysi ol. 
2 0 0 9; 2 9 6( 3): G 6 4 3- 5 0. 
4. 
S h ul ma n RJ. Oral i ns uli n i ncreas es s mall i ntesti nal mass a n d disacc hari das e acti vit y i n 
t he ne w b or n mi niat ure pi g. Pe diatric researc h. 1 9 9 0; 2 8( 2): 1 7 1- 5. 
5.  
C ole C R, Fre m J C, Sc h m otzer B, Ge wirtz A T, Me d di n gs J B, G ol d B D, et al. T he rate of 
bl o o dstrea m i nfecti o n is hi g h i n i nfa nts wit h s h ort b o wel s y n dr o me: relati o ns hi p wit h s mall 
b o wel bacterial o ver gr o wt h, e nteral f ee di n g, a n d i nfla m mat or y a n d i m m u ne res p o nses. T he 
J o ur nal of pe diatrics. 2 0 1 0; 1 5 6( 6): 9 4 1- 7, 7 e 1. 
6.  
Sc h wartz M Z. N o v el t her a pies f or t he ma n a ge me nt of s h ort b o wel s y n dr o m e i n c hil dre n. 
Pe diatric s ur ger y i nter nati o nal. 2 0 1 3; 2 9( 1 0): 9 6 7- 7 4. 
7.  
G utierrez I M, Ka n g K H, J a ksic T. Ne o natal s h ort b o wel s y n dr o me. Se mi nars i n fetal & 
ne o natal me dici ne. 2 0 1 1; 1 6( 3): 1 5 7- 6 3. 
8.  
Fl y n n P M. Dia g n osis a n d ma na ge me nt of ce ntral v e n o us cat heter- relate d bl o o dstrea m 
i nfecti o ns i n pe diatric patie nts. Pe diatr I nfect Dis J. 2 0 0 9; 2 8( 1 1): 1 0 1 6- 7. 
9. 
Ba xter J P, Fa yers P M, Mc Ki nla y A W. A re vie w of t he q ualit y of life of a d ult patie nts 
treate d wit h l o n g-ter m p are nter al n utriti o n. Cli n N utr. 2 0 0 6; 2 5( 4): 5 4 3- 5 3. 
1 0.  
J e p pese n P B, La n g h olz E, M orte nse n P B. Q u alit y of life i n patie nts recei vi n g h o me 
pare nteral n utriti o n. G ut. 1 9 9 9; 4 4( 6): 8 4 4- 5 2. 
1 1.  
S u k h ot ni k I, S he ha de h N, S ha mir R, Bejar J, Ber ns hte y n A, M o gil ner J G. Oral i ns uli n 
e n ha nces i ntesti nal re gr o wt h f oll o wi n g massi ve s mall b o wel resecti o n i n rat. Di gesti ve disease s 
a n d scie nces. 2 0 0 5; 5 0( 1 2): 2 3 7 9- 8 5. 
1 2.  
Be n L ul u S, C ora n A G, M o gil ner J G, S ha o ul R, S ha mir R, S he ha de h N, et al. Oral 
i ns uli n sti m ulates i ntesti nal e pit helial cell t ur n o ver i n c orrelati o n wit h i ns uli n-rece pt or e x pressi o n 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 0  of 7 1  
al o n g t he vill us-cr y pt a xis i n a rat m o del of s h ort b o wel s y n dr o me. Pe diatric s ur ger y 
i nter nati o nal. 2 0 1 0; 2 6( 1): 3 7- 4 4. 
1 3. 
Str uijs M C, Dia m o n d I R, de Sil va N, Wales P W. Esta blis hi n g n or ms f or i ntesti nal le n gt h 
i n c hil dre n. J o ur nal of pe diatric s ur ger y. 2 0 0 9; 4 4( 5): 9 3 3- 8. 
1 4.  
S h ul ma n RJ. Effect of e nteral a d mi nistrati o n of i ns uli n o n i ntesti nal de vel o p me nt a n d 
fee di n g t oler a nce i n pr eter m i nfa nts: a pil ot st u d y. Arc hi ves of disease i n c hil d h o o d Fetal a n d 
ne o natal e diti o n. 2 0 0 2; 8 6( 2): F 1 3 1- 3. 
1 5.  
S ha mir R, K olace k S, K oletz k o S, Ta v ori I, Ba de r D, Lit ma n o vitz I, et al. Oral i ns uli n 
s u p ple me ntati o n i n pae diatric s h ort b o wel disease: a pil ot o bser vati o nal st u d y. J o ur nal of 
pe diatric gastr o e nter ol o g y a n d n utriti o n. 2 0 0 9; 4 9( 1): 1 0 8- 1 1. 
1 6.  
A b del ha di A A. Re vie w Article: Ma na ge met of N e o natal H y p o gl yc ae mia. S u da nese 
J o ur nal of Pae diatrics. 2 0 0 7; 8: 9- 2 6. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 1  of 7 1  
A p pe n di x A :  Fee di n g Pr ot oc ol  
Ge ner al  
St u d y e ntr y t hres h ol d: S u bject ca n t olerate at least 1 0  m L/ k g/ da y of e nteral n utriti o n a n d n ot less 
t ha n 7 0 % of pare nter al n utriti o n f or at least 7 da ys at ti me of e nr oll me nt.  
E nteral n utriti o n:   I nfa nt F or m ula (s o y- b ase d n ot rec o m me n de d p er S O C c o nse ns us), d o n or 
breast mil k, a n d o w n m ot her’s mil k will be all o we d i n t he st u d y.  
Pr ot oc ol  
1.  Fee ds of at least 1 0  m L/ k g/ da y after e vi de nce of b o wel f u ncti o n are c o nfir me d 
2.  Base d o n cli nical stat us a d va nce e nteral fee ds as t olerate d a n d c o nsi der P N/I V re d ucti o n  
S u g geste d criteria f or ass ess me nt:  
a. 
Gr o wt h at least mai ntai n e d t hr o u g h Z sc ore sta ble o n a wee kl y b asis ( Fe nt o n).  
b.  
E nter ost o m y or fecal l osses ≤ 5 0 m L/ k g/ da y a n d w ei g ht gai n.  
c. 
T olerati n g fee ds  ( n o h ol d of fee ds lasti n g 2 4 h o urs).  
d.  
If criteria a-c are met, patie nt ma y a d va nce e nteral fee ds  b y:  
1.  I n- patie nts - dail y  
2.  O ut -patie nts - wee kl y  
3.  E nteral a d v a nce me nt w o ul d be 5 - 1 0 ml/ k g/ da y 
e. 
If i ncrease i n f ee ds is t olerate d a n d patie nt is cli nicall y rea d y, p atie nt s h o ul d 
u n der g o P N re d u cti o n  b y 5 - 1 5 % of P N/I V 
f. 
If a d va n ce i n f ee ds n ot t olerate d reassess e nteral fee di n g a n d P N re gi me n  
St o p P N/I V pr ot oc ol 
S u bjects wit h <  1 0 % cal oric i nta ke fr o m P N/I V  f or t w o weeks will be c o nsi dere d cli nicall y f or 
c o m plete wea ni n g off as t he y are n ot r ecei vi n g a n y mea ni n gf ul cal ori es f or mai ntai ni n g gr o wt h 
fr o m P N, base d o n r ec o m me n de d cal oric g o als p er a ge 
15 F1 6.  
I V fl ui ds t hat are n ot pr o vi di n g mea ni n gf ul cal ori es a n d are use d f or mai ntai ni n g ce ntral li ne 
pate nc y are still per mitte d e ve n w he n wea n e d off P N/I V.  
Rei niti ati n g P N/I V pr ot oc ol 
                                                 
1 6 E S P E N a n d  A A P E ner g y Nee ds g ui deli nes  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Ora l a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 2  of 7 1  
E val uate t he cli nical stat us i ncl u di n g wei g ht after 1 - 2 wee ks t o det er mi ne if P N/I V s h o ul d be re-
starte d. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 3  of 7 1  
A p pe n di x B :  Sc he d ule of S t u d y P r oce d ures  
St u d y Pr o ce d ure  
Scree ni n g  B aseli ne  R a n d o miz ati o n  
I niti al 
Tre at me nt 
Peri o d  
I niti al 
Tre at me nt 
Peri o d  
Wee k 1 2 
Assess me nt  
C o nti n ue d 
Tre at me nt 
Peri o d  
Wee k 2 4 
Assess me nt  
Wee k 2 8 
F oll o w -
U p 
( Fi n al 
Pri m ar y 
St u d y 
Visit) a, b 
F oll o w -u p  
( R o uti ne 
S O C) c 
Wee k 5 2 
S afet y 
F oll o w -U p  
F oll o w -u p  
( R o uti ne 
S O C)  c 
Wee k 1 0 4 
S afet y 
F oll o w -U p 
( Fi n al Visit 
of L o n g -
Ter m 
F oll o w -U p 
Peri o d) a 
F oll o w -u p  
( R o uti ne 
S O C)  c 
St u d y D a y  
D a y  -1 4 
t o - 1 
D a y  - 7 
t o 0 
D a y 0  
 D a ys 
1, 2, 3  
D a ys 7, 
1 4, 2 1, 2 8, 
3 5, 4 2, 4 9, 
5 6, 6 3, 7 0, 
7 7  
D a y 8 4  
D a ys 9 8, 
1 1 2, 1 2 6, 
1 4 0, 1 5 4  
D a y 1 6 8  
D a y 1 9 6  
 
D a y 3 6 4  
 
D a y 7 2 8  
 
Visit Wi n d o w  
 
 
 
± 2 d a ys  
± 2 d a ys  
± 2 d a ys  
± 7 d a ys  
± 7 d a ys  
± 7 d a ys  
 
± 1 4 d a ys  
 
± 2 8 d a ys  
 
Si g n e d i nf or me d 
c o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y
d 
a n d De m o gra p hics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl usi o n/ E xcl usi o n 
Criteria  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Mater n al Data
e 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m  
X  
 
 
 
 
X  
X f 
X  
X  
 
 
 
 
 
Wei g ht, B o d y 
Le n gt h  
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Hea d 
Circ u mfere n ce  
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Vital si g ns g  
X  
X  
X  
 
X  
X  
X  
X  
X  
 
 
 
 
 
E K G h  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
He mat ol o g y i, 
c h e mistr y j, 
uri n al ysis k 
X 
 
 
 
 
X 
 
X  
X l 
 
 
 
 
 
Plas ma Citr ulli n e  
 
X  
 
 
 
X  
 
X  
X m  
 
 
 
 
 
Bl o o d Gl u c ose 
le v elsn 
 
 
X  
X 
X 
X 
 
 
 
 
 
 
 
 
A nti -I ns uli n 
A nti b o dies  
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
C o n c o mita nt 
me dicati o n 
assess me nt 
X --------------------------------------------------------------------------------------------------------------------------  
 
X o 
 
X o 
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 4  of 7 1  
St u d y Pr o ce d ure  
Scree ni n g  B aseli ne  R a n d o miz ati o n  
I niti al 
Tre at me nt 
Peri o d  
I niti al 
Tre at me nt 
Peri o d  
Wee k 1 2 
Assess me nt  
C o nti n ue d 
Tre at me nt 
Peri o d  
Wee k 2 4 
Assess me nt  
Wee k 2 8 
F oll o w -
U p 
( Fi n al 
Pri m ar y 
St u d y 
Visit) a, b 
F oll o w -u p  
( R o uti ne 
S O C) c 
Wee k 5 2 
S afet y 
F oll o w -U p  
F oll o w -u p  
( R o uti ne 
S O C)  c 
Wee k 1 0 4 
S afet y 
F oll o w -U p 
( Fi n al Visit 
of L o n g -
Ter m 
F oll o w -U p 
Peri o d) a 
F oll o w -u p  
( R o uti ne 
S O C)  c 
St u d y D a y  
D a y  -1 4 
t o - 1 
D a y  - 7 
t o 0 
D a y 0  
 D a ys 
1, 2, 3  
D a ys 7, 
1 4, 2 1, 2 8, 
3 5, 4 2, 4 9, 
5 6, 6 3, 7 0, 
7 7  
D a y 8 4  
D a ys 9 8, 
1 1 2, 1 2 6, 
1 4 0, 1 5 4  
D a y 1 6 8  
D a y 1 9 6  
 
D a y 3 6 4  
 
D a y 7 2 8  
 
Visit Wi n d o w  
 
 
 
± 2 d a ys  
± 2 d a ys  
± 2 d a ys  
± 7 d a ys  
± 7 d a ys  
± 7 d a ys  
 
± 1 4 d a ys  
 
± 2 8 d a ys  
 
A d verse e ve nt 
assess me nt  p 
 
 
 
 
X -------------------------------------------------------------------------------------------- 
 
 
R a n d o miz ati o n  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
P a re nter al 
N utriti o n I nt a ke  q  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
E nter al N utriti o n 
I nt a ke  r 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
E pis o des of 
si g nific a nt f ee di n g 
i nt oler a nce 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
I n vesti g ati o n al 
Pr o d uct D osi n g  
 
 
X -------------------------------------------------------------------------------------- 
 
 
 
 
 
 
a. 
T h e fi n al st u d y d a y f or p ur p oses of t he trial statistical a nal ysis a n d Cli nical St u d y Re p ort ( C S R) is Da y 1 9 6.  S u bjects will  be f urt her f oll o we d l o n g -ter m f or safet y t o e val uate gr o wt h a n d n utriti o nal i nta ke as well as 
p ote ntial relate d a d verse e ve nts t hr o u g h Da y 7 2 8.   
b.  If a s u bject pre mat urel y disc o nti n ues st u d y me dicati o n, all reas o na ble meas ures will  be ta ke n t o perf or m a n Earl y Disc o nti n uati o n fr o m St u d y Me dicati o n Visit ( Wee k 2 8 visit).  T his visit s h o ul d i ncl u de all pr oce d ures 
liste d i n t h e sc h e d ule of e ve nts F oll o w U p ( Fi nal Pri mar y St u d y Visit) f or Wee k 2 8 ( Da y 1 9 6).  T hese pr oce d ures are n ecessar y t o c o m plete s u bjects’ rec or ds:  p h ysical e xa mi nati o n, wei g ht, b o d y le n gt h, hea d 
circ u mfere n ce, vital si g ns, cli nical la b orat or y test ( o nl y if cli nicall y si g nifica nt val ues wer e o btai ne d at t he Da y 1 9 6, or if ter mi nate d earlier), a nti -i ns uli n a nti b o dies, plas ma citr ulli ne ( o nl y if ter mi nate d bef ore Da y 1 6 8), 
gastric resi d u als ( o nl y if ter mi nate d bef or e Da y  8 4 a n d if part of S O C), pare nteral n utriti o n i nta ke, e nteral n utriti o n i nta ke, c o nc o mita nt me dicati o n, a d vers e e ve nt, a n d u p d ati n g of s u bject c o ntact i nf or mati o n . 
c. 
If r o uti n e Sta n d ar d of Care Visits are c o n d ucte d t his data, if c ollecte d will be e ntere d as a n u nsc he d ule d visit. T he data t o be i ncl u de d, if c ollecte d, is b o d y wei g ht, b o d y le n gt h, hea d circ u mfere nce, pare nteral n utr iti o n 
i nta k e, e nteral n utriti o n i nta ke, re-h os pitalizati o ns a n d a d verse e ve nts, If t hese r o uti ne S O C visits are n ot c o n d ucte d wit h t hese pr oce d ures, t hese will n ot be c o nsi dere d missi n g visits.  T hese data will i ncl u de 
n e ur o d e vel o p me ntal Ba yle y 's sc ore c o g niti ve, la n g ua ge a n d m ot or d o mai ns at 2 Y c orrecte d a ge.  After Wee k 2 8 ( Da y 1 9 6), a f oll o w u p p h o ne call e ver y 3  m o nt hs as part of l o n g-ter m f oll o w u p. 
d.  A c o m plete p h ysical e xa mi nati o n at scree ni n g a n d o n Da y 8 4 ( Wee k 1 2), Da y 1 6 8 ( Wee k 2 4), a n d Da y 1 9 6 ( Wee k 2 8).  A li mite d pr o b le m-orie nte d p h ysical e xa mi nati o n will be perf or m e d o n eac h visit bet wee n Wee k 1 2 
( Da y 8 4) a n d Wee k 2 4 ( Da y 1 6 8): Da ys 9 8, 1 1 2, 1 2 6, 1 4 0, a n d 1 5 4, if nee de d.  
e. 
A n y e v e nt t h at occ ur s b ef ore st u d y dr u g d osi n g will be rec or de d as me dical hist or y, i ncl u di n g b ut n ot li mite d t o prese nt me dical c o n diti o ns, c o nc o mita nt n o n -dr u g treat me nts a n d h y perse nsiti vit y t o dr u gs.  
f. 
I nfa nt’s m ot h er will b e c ollecte d i ncl u di n g a ge, me dical hist or y of a n y c o n ge nital a b n or malities a n d c o m plicati o ns d uri n g gestati o n or deli ver y. 
g.  M eas ure me nts will i n cl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d b o d y te m perat u re. 
h.  E K G is t o b e p erf or me d o n at least a tri plicate of heart beats f or all meas ure me nts a n d will be rec or de d at a s pee d of 2 5 m m/s ec a n d a n a m plit u de of 1 0 m m/ m V.  C o m p uterize d E K G a nal ysis will i ncl u de:  heart rate, R -R 
i nter val, si n us r h yt h m, P R i nter val, Q R S a xis, a n d Q R S d urati o n.  Q T i nter val a n d Q Tc F will be calc ulate d ma n uall y acc or di n g t o t he Fri dericia f or m ula . 
i. 
He mat ol o g y tests will i n cl u de: w hite bl o o d cells ( W B C), re d bl o o d cells ( R B C), he m o gl o bi n, he mat ocrit, mea n c or p usc ular v ol u m e ( M C V), mea n c or p usc ular he m o gl o bi n ( M C H), mea n c or p usc ular he m o gl o bi n 
c o n ce ntrati o n ( M C H C), re d cell distri b uti o n wi dt h ( R D W), platelets, a n d mea n platelet v ol u me ( M P V).   Testi n g i ncl u des R B C m o r p h ol o g y a n d retic ul oc yte c o u nt. 
j. 
Ser u m c h e mistr y will i n cl u de ser u m al kali ne p h os p hatase, tri gl yceri de, A L T, A S T, G G T, gl uc ose, calci u m, p h os p h or us, c hl ori de, s o di u m, p otassi u m, B U N, creati ni ne, t ota l a n d direct bilir u bi n, al b u mi n, t otal pr otei n, 
a m ylase, bicar b o n ate/car b o n di o xi de ( C O 2), uric aci d, a n d lactate de h y dr o ge nase ( L D H) .  A d diti o nal ser u m c he mistr y testi n g will be wee kl y w he n patie nts are i n t he h os pital a n d at st u d y visits w he n patie nts are i n a 
h o me care setti n g.   Re p eat testi n g at f oll o w -u p visit Wee k 2 8 ( Da y  1 9 6) will o nl y be perf or me d if a b n or mal cli nicall y si g nif ica nt val ues are o btai ne d at Wee k 2 4 ( Da y 1 6 8) visit . 
k.  Uri n al ysis will i n cl u d e: nitrite, Na, K, Ca, P, Pr otei n, R B C, W B C, bl o o d, gl uc ose, ket o ne b o dies, bilir u bi n (c o nj u gate d), ur o bili n o ge n, uri ne s pecific gra vit y, os m olarit y, a n d  p H  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 5  of 7 1  
l. 
Safet y la b orat or y e val u ati o ns ( he mat ol o g y, c he mistr y, uri nal ysis, c oa g ulati o n pr ofile) will be re peate d at t he f oll o w -u p visit o nl y  if a b n or mal cli nicall y si g nifica nt val ues wer e o btai ne d at t he Wee k 2 4 ( Da y  1 6 8) visit.   
m.  Sa m ple will o nl y b e ta k e n if ter mi nate d pri or t o Da y 1 6 8.  
n.  Bl o o d gl u c ose m o nit ori n g will be perf or me d pre -d ose o n Da y 0 a n d o n Da ys 1, 2 a n d 3 , a n d t wice a wee k f or t he rest of t he treat me nt peri o d w hile h os pitalize d. If s u bjects are disc har ge d h o me t he test w o ul d be d o ne o n 
eac h visit o n ce a wee k. I n a d diti o n, a n y a b n or malit y i n bl o o d gl u c ose le vels t hat w o ul d be ca pt ure d o utsi de of t hese tests, w o ul d als o be re p orte d. T his is a part of sta n dar d m o nit ori n g c o n d ucte d o n t his p o p ulati o n .   
o.  All c o n c o mita nt me dicati o n gi ve n wit hi n 3 0 da ys pri or t o t he ti me of c o nse nt  t hr o u g h t he Wee k 2 8 assess me nt.  After wee k 2 8, o nl y cli nicall y si g nifica nt me dicati o ns t hat are use d t o treat p ote ntial a d verse eff ects of 
N T R A -9 6 2 0 will b e rec or de d.  
p.  A E m o nit ori n g will b e c o n d ucte d t hr o u g h o ut t he st u d y fr o m Da y 0 (i nitiati o n of d osi n g)  u ntil 2 8 da ys after t he fi nal pri mar y st u d y visit at Wee k 2 8 ( Da y 1 9 6).  A Es c o nsi dere d t o be treat me nt relate d b y t he I n vesti gat or 
will b e d oc u me nte d at t h e p ost pri mar y st u d y c o m pleti o n o n Wee k 5 2 ( Da ys 3 6 4) a n d Wee k 1 0 4 ( Da y 7 2 8) t o assess a n y p ote ntia ll y r elate d a d verse o utc o mes of treat me nt. Pre -treat me nt e mer ge nt e ve nts will be rec or de d 
o n t h e me dical hist or y.    
q.  T h e t otal a m o u nt of pare nteral n utriti o n a d mi nistere d f or eac h fee di n g will be rec or de d i n eac h st u d y visit.  T he v ol u me a n d cal ori c val ue of par e nteral fee di n g will be e ntere d i nt o eac h st u d y visit.  
r. 
T h e t otal a m o u nt of e nteral n utriti o n a d mi nistere d f or eac h fee di n g d uri n g t he da y will be rec or de d.  T he v ol u me a n d cal ori c val ue of e nteral fee di n g will be e ntere d i nt o eac h st u d y visit. 
 
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 6  of 7 1  
A p p e n di x C :  C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts 
 
Versi o n 4. 0 3 
P u blic ati o n D ate: 1 4 J u ne 2 0 1 0 
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df  
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 7  of 7 1  
A p pe n di x D :  2 Y C orrecte d A ge Ne ur o de vel o p me nt al Assess me nt  
 
1.  Maj or m or bi dities a n d e v al uati o n of me dical hist or y  
•  Cere bral p als y  
•  Reti n o pat h y of pr e mat urit y ( R O P) t hat re q uires i nt er ve nti o n  
•  Deaf n ess  
•  Use of heari n g ai d  
•  Use of glasses  
•  Bli n d ness 
2.  Ba yle y Scale of I nfa nt a n d T o d dler De v el o p me nt, t hir d e diti o n: 
•  C o g niti ve d o mai n c o m p osite sc ore   
•  La n g u a ge d o mai n c o m p osite sc ore 
•  M ot or d o mai n c o m p osite sc ore 
•  S ocial -e m oti o nal d o mai n c o m p osite sc ore  
•  A da pti ve be ha vi or d o m ai n c o m p osite sc ore  
3.  Ne ur o de v el o p me nt Disa bilit y C o m p osite 
•  C o m p osite sc ore of less t ha n 7 0 or < 8 5 o n a n y of t he c o g niti ve, la n g ua ge or m ot or 
d o mai ns of Ba yle y s cale of i nfa nt a n d t o d dler d e v el o p me nt, t hir d e diti o n 
4.  C hil d Be ha vi or C hec klist t otal pr o ble m sc ore 
 
 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 8  of 7 1  
A p pe n di x E :  E x pecte d c o n diti o ns see n i n ne o n at al S B S  
S h ort b o wel s y n dr o m e ( S B S) is defi ne d as t he s pectr u m of mala bs or pti o n t hat occ urs after 
resecti o n of a maj or p orti o n of t he s mall i ntesti ne f or c o n ge nital or ac q uire d lesi o ns . It is als o 
defi ne d as t he n ee d f or pr ol o n ge d p are nteral n utriti o n sec o n dar y t o i ntesti nal f ail ure aft er b o w el 
resecti o n. T hes e patie nts s uffer a m ultit u de of c o m plicati o ns sec o n dar y t o l o n g-ter m 
h os pitalizati o n a n d pr ol o n ge d p are nt eral n utriti o n ( Wales, 2 0 0 5).  
T hese c o m plicati o ns ca n be br o ke n d o w n t o t he cate g ori es bel o w; GI relate d c o m plicati o ns, p ost-
s ur gical c o m plicati o ns, cat heter-relate d c o m plicati o ns, i nfecti o ns, e x pecte d la b orat or y 
a b n or malities,  ki d ne y c o m plicati o ns a n d T P N relate d iss ues.   
All t he c o m plicati o ns bel o w ca n be c o nsi dere d e x pecte d a n d c o m m o n i n ne o natal S B S.  
 
GI -r elate d c o m plicati o ns  
•  
St o ma  
o  Pr ola pse  
o  Blee di n g  
o  O bstr ucti o n / strict ure  
o  Retracti o n  
o  P ol y ps  
•  
G-t u be 
o  site i nfecti o ns 
o  mal f u ncti o n 
o  brea ka ge 
o  bl oc ka ge  
•  
Li ver disease  
o  I ntesti nal Fail ure Ass ociate d Li ver Diseas e 
o  P N Ass ociate d Li ver Dis ease  
o  Pre mat urit y Ass o ciate d Li ver Disease  
o  C oa g ul o pat h y  
o  C h olestasis  
•  
N utriti o nal deficie ncies  
o  Micr o n utrie nts a n d vita mi n deficie ncies  
•  
Gall bla d der 
o  C olelit hiasis   
o  Biliar y sl u d ge  
•  
Diarr hea  
•  
A b d o mi nal diste nti o n  
•  
Na usea  
•  
V o miti n g  
•  
Re g ur gitati o n / refl u x  
•  
C o nsti pati o n  
•  
De h y drati o n  


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 6 9  of 7 1  
P ost- s ur gical c o m plicati o ns 
•  
B o wel o bstr u cti o n  
•  
A d hesi o n a n d strict ure  
•  
Blee di n g  
•  
A nast o m otic ulcer  
•  
B o wel perf or ati o n  
•  
I ntr a-a b d o mi nal a bscess   
Cat heter rel ate d c o m plicati o ns  
•  
Ce ntral li ne a n d cat heter -relate d iss ues 
o  site i nfecti o ns   
o  malf u ncti o n  
o  brea ka ge 
o  bl oc ka ge   
I nfecti o ns  
•  
ce ntral li ne i nfecti o ns  
•  
sites i nfecti o ns 
•  
u p per-r es pirat or y i nf ecti o ns 
•  
GI i nfecti o ns  
•  
Fe ver  
•  
Se psis  
•  
Bact erial o ver gr o wt h  
E x pecte d la b orat or y a b n or malities  
•  
H y p o gl yce mia rel ate d t o se psis, T P N wea ni n g, a d va nce d li ver dis ease, pre mat urit y   
•  
H y p er gl ycae mia r elate d t o se psis, T P N  
•  
A ne mia sec o n d ar y t o pre mat urit y, n utriti o n, bl o o d dra ws  
•  
Bl o o d electr ol yt e a b n or m alities i.e Calci u m, Ma g n esi u m, P h os p h or us  
•  
Bl o o d n utriti o n a b n or malities i.e l o w al b u mi n, l o w pr otei n 
Ki d ne y c o m plicati o ns  
•  
Re nal i ns ufficie nc y  
•  
Ne p hr ocalci n osis    
•  
Ki d ne y st o n es / ne p hr olit hiasis  
T P N -relate d iss ues 
•  
Fl ui d o verl oa d  
•  
H y p o gl yce mia rel ate d t o T P N wea ni n g  
•  
H y p er gl ycae mia r elate d t o T P N, gl uc ose  
•  
Li ver disease  
•  
Ele vate d a m ylase a n d li pase sec o n d ar y t o li pi ds  
•  
Li ne i nf ecti o ns  
Pre m at urit y c o m plic ati o ns  
I n a d diti o n, ma n y S B S i nfa nts are pre mat ure i nfa nts, w h o s uffer fr o m a d diti o nal c o m plicati o ns 
t hat are c o m m o n a n d e x pecte d i n t he p o p ulati o n. T hese i ncl u de: 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 7 0  of 7 1  
 
 
•  
C ar di ac c o m plic ati o ns . T he m ost c o m m o n heart pr o ble ms pre mat ure ba bi es e x perie nce are pate nt 
d uct us  arteri os us  ( P D A)  a n d  l o w  bl o o d  press ure  ( h y p ote nsi o n).  P D A  is  a  persiste nt  o pe ni n g 
bet we e n t w o maj or bl o o d vessels lea di n g fr o m t he heart.  W hile t his h eart d efect ofte n cl oses o n its 
o w n, left u ntr eate d it ca n ca use t o o m uc h bl o o d t o fl o w t hr o u g h t h e heart a n d ca use heart fail ure 
as well as ot her c o m plicati o ns. L o w bl o o d press ure ma y re q uire a dj ust me nts i n i ntra ve n o us fl ui ds, 
me dici nes a n d s o meti mes bl o o d tra nsf usi o ns. 
•  
Ne ur o  pr o ble ms.  T h e earlier a ba b y is b or n, t he greater t he ris k of bl ee di n g i n t h e brai n, k n o w n 
as a n i ntra ve ntric ul ar h e m orr ha ge. M ost he m orr h a ges are mil d a n d res ol v e wit h li ttle s h ort-ter m 
i m pact. B ut s o me ba bies ma y h a ve lar ger brai n blee di n g w hi c h ca us es per m a ne nt brai n i nj ur y. 
•  
Te m per at ure c o nt r ol pr o ble ms.  Pre mat ure ba bies ca n l ose b o d y heat ra pi dl y; t he y d o n't ha ve t he 
st ore d b o d y f at of a f ull-ter m i nfa nt a n d t he y ca n't ge nerate e n o u g h h eat t o c o u nteract w hat's l ost 
t hr o u g h  t he  s urf ace  of  t heir  b o dies.  If  b o d y  te m perat ure  di ps  t o o  l o w,  h y p ot her mia  ca n  res ult. 
H y p ot her mia i n a pree mi e ca n l ea d t o breat hi n g pr o ble ms a n d l o w bl o o d s u gar le vels. I n a d diti o n, 
a pree mie ma y us e  u p all of t he e n er g y gai ne d fr o m fee di n gs j ust t o sta y w ar m, n ot t o gr o w bi g ger. 
T hat's w h y s maller pree mies re q uire a d diti o nal h eat fr o m a w ar mer or a n i nc u bat or u ntil t he y're 
lar ger a n d a ble t o mai ntai n b o d y te m perat ure wit h o ut assista nce. 
•  
Met a b olis m  pr o ble ms.  Pre mat ure  ba bies  ofte n  ha ve  pr o ble ms  wit h  t heir  meta b olis m.  S o me 
pree mies ma y d e vel o p a n a b n or mall y l o w le vel of bl o o d s u gar ( h y p o gl yce mia). T his ca n ha p pe n 
beca use  pr ee mies  t y picall y  h a ve  s maller  st ores  of  gl yc o ge n  (st ore d  gl uc ose)  t ha n  d o  f ull -ter m 
ba bies  a n d  beca use  pree mies'  i m mat ure  li vers  ha ve  tr o u bl e  c o n v erti n g  st ore d  gl yc o ge n  i nt o 
gl uc ose.  
•  
I m m u ne s yst e m pr o ble ms. A n u n der d e vel o pe d i m m u ne s yste m, c o m m o n i n pre mat ure b a bies, 
ca n lea d t o i nfecti o n. I nfecti o n i n a pre mat ure ba b y ca n q uic kl y s prea d t o t he bl o o dstrea m ca usi n g 
se psis, a life-t hreate ni n g c o m plicati o n. 
 
L o n g ter m c o m plic ati o ns  
•  
Cere br al  p als y.  Cer e br al pals y is  a dis or der of  m o ve me nt, m uscle  t o ne  or p ost ure t hat  ca n b e 
ca use d b y i nfecti o n, i na d e q uate bl o o d fl o w or i nj ur y t o a pree mie's  de v el o pi n g brai n eit her d uri n g 
pre g na nc y or w hile t he b a b y is still y o u n g a n d i m mat ure.  
•  
I m p aire d  c o g niti ve  s kills. Pre mat ure  ba bies  are  m ore  li kel y  t o  la g  be hi n d  t heir  f ull -ter m 
c o u nter parts  o n  vari o us  de vel o p me ntal  milest o nes.  U p o n  sc h o ol  a ge,  a  c hil d  w h o  was  b or n 
pre mat urel y mi g ht be m ore li kel y t o h a ve lear ni n g disa bilities.  
•  
Visi o n pr o ble ms.  Pre m at ure i nf a nts ma y d e vel o p reti n o pat h y of pre mat urit y, a disease t h at occ urs 
w he n bl o o d vess els s well a n d o ver gr o w i n t he li g ht -se nsiti ve la yer of ner ves at t he bac k of t he e ye 
(reti na). S o meti mes t he a b n or mal reti nal vessels gra d uall y scar t he reti na, p ulli n g it o ut of p ositi o n. 
W he n t he reti na is p ulle d a wa y fr o m t he b ac k of t h e e ye, it's calle d reti nal d etac h me nt, a c o n diti o n 
t hat, if u n detecte d, ca n i m pair visi o n a n d ca use bli n d ness. 


N utri nia Lt d.  
Pr ot oc ol GI F T -0 2  
N T R A -9 6 2 0 (I ns uli n  f or Oral  a d mi nistrati o n) 
Versi o n:  1. 6  
 
1 0 J a n uar y 2 0 1 7  
C O N FI D E N TI A L  
P a ge 7 1  of 7 1  
•  
He ari n g  pr o ble ms.  Pre mat ure  ba bies  are  at  i ncrease d  ris k  of  s o me  de gree  of  heari n g  l oss.  All 
ba bies will ha ve t heir h eari n g c h ec k e d bef ore g oi n g h o me.  
•  
De nt al pr o ble ms.  Pr ee mies w h o h a ve bee n criticall y ill are at i ncreas e d ris k of d e vel o pi n g d e ntal 
pr o ble ms, s uc h as dela ye d t o ot h er u pti o n, t o ot h disc ol orati o n a n d i m pr o pe rl y ali g ne d teet h. 
•  
Be h a vi or al  a n d  ps yc h ol o gic al  pr o ble ms.  C hil dre n  w h o  e x perie nce d  pre mat ure  birt h  ma y  be 
m ore li kel y t h a n f ull -ter m i nfa nts t o ha ve certai n be ha vi oral or ps yc h ol o gical pr o ble ms, s uc h as 
atte nti o n-deficit/ h y p er acti vit y dis or d er ( A D H D). H o we ver, m ore rece nt researc h s u g gests t hat — 
at least f or late preter m ba bies — t he ris k of A D H D ma y b e t he sa m e as it is f or c hil dre n w h o were 
b or n at f ull ter m.  
•  
C hr o nic he alt h iss ues.  Pre mat ure ba bies are m ore li kel y t o h a ve c hr o nic h ealt h iss ues — s o me of 
w hic h  ma y  re q uire  h os pital  care — 
t ha n  are  f ull-ter m  i nfa nts.  I nfecti o ns,  ast h ma  a n d  fee di n g 
pr o ble ms  ar e  m ore  li kel y  t o  d e vel o p  or  persist.  Pre mat ure  i nfa nts  are  als o  at  i ncrease d  ris k  of 
s u d de n i nfa nt deat h s y n dr o me ( SI D S).