Clinical trial NCT02682381
Conditions: Short Bowel Syndrome
Keywords: Teduglutide pediatric GLP-2 parenteral support Short Bowel Syndrome short gut syndrome short gut SBS parenteral nutrition
Sponsor: Shire
Start date: 2016-06-23; Completion date: 2017-08-18
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Teduglutide is approved for treatment of adults with short bowel syndrome (SBS). The purpose of this study is to evaluate the safety and efficacy of teduglutide in children up to the age of 17 with SBS who are dependent on parenteral support. Subjects may choose whether to receive the study drug or to participate in a standard-of-care arm. All participants who complete the study may be eligible to receive the study drug in a long-term extension study.

Detailed description:

Arms: arm 1: 0.025 milligrams per kilogram per day (mg/kg/day) of teduglutide for 24 weeks. arm 2: 0.05 mg/kg/day of teduglutide for 24 weeks. arm 3: Observational cohort for the 24-week treatment period and 4 week follow-up. The subjects in the standard of care group will follow the same visit schedule as the randomized subjects.
Interventions: intervention 1: Teduglutide 0.05mg/kg intervention 2: Teduglutide 0.025 mg/kg intervention 3: Standard of Care
Intervention descriptions: intervention 1: 0.05 mg/kg intervention 2: 0.025 mg/kg intervention 3: Observational cohort for the 24-week treatment period and 4 week follow-up.

Protocol documents:
SAP_004.pdf: 
D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 of 4 8
S T A TI S TI C A L A N A L Y SI S P L A N
T E D -C 1 4 -0 0 6
A 2 4 -wee k  D o u ble-bli n d, S afet y, Effic ac y, a n d P h ar m ac o d y n a mic St u d y 
I n vesti g ati n g T w o D oses of Te d u gl uti de i n Pe di atric S u bjects T hr o u g h 1 7
Ye ars of A ge wit h S h ort B o wel S y n dr o me w h o are De pe n de nt o n P are nter al 
S u p p ort
A U T H O R :
V E R SI O N N U M B E R A N D D A T E : FI N A L V 1. 0 1 4 J U L
P P D
2 0 1 7
P P D


Q QUINTILES. 
STATISTICAL ANALYSIS PLAN: PROTOCOL TED-C14-006 
Page 2 of 44 
Statistical Analysis Plan Signature Page 
Statistical Analysis Plan Final Vl.O (Dated 14Jul2017) for Protocol TED-C14-006 
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Upon review of this document, the undersigned approves this version of the Statistical Analysis 
Plan and shells, authorizing that the content is acceptable for the reporting of this study. 
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Biostatistics, 
 
QuintilesiMS 
 
 
Shire 
 
 
Shire 
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Document: 
\\qui nti les. net\ Enterprise \Ap ps \sasd a ta \SA Sa \sa s \Shire\ Ted u gl uti de\ B i ostatistlcs \Do cum e nta ti on \SAP\ TE 
D-C14-006_SAP _Finai_Vl.0_20170714 
Author: 
 
Template No: CS_TP _BS016- Revision 3 
Effective Date: 01May2012 
Copyright <C> 2012 Quintiles Transnational Corp. All rights reserved. 
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Final Vl.O 
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The contents of this document are confidential and proprietary to Quintiles Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
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D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 of 4 8
M O DI FI C A TI O N H I S T O R Y
U ni q ue 
I de ntifier f or 
t his Versi o n
Date of t he 
D oc u me nt
Versi o n
A ut h or
Si g nifica nt 
C ha n ges 
fr o m 
Pre vi o us A ut h orize d Versi o n
Draft 1. 0
1 2 Se p 2 0 1 6
N ot A p plica ble – First Versi o n
Draft 2. 0
3 1 Oct 2 0 1 6
U p date d per S hire re vie wers’ c o m me nts.
Draft 3. 0 
1 4 Dec 2 0 1 6
U p date d per S hire re vie wers’ fee d bac k.
Draft 4. 0
3 0Ja n 2 0 1 7
( 1) U p date d 
t he S hire 
Bi os 
lea d 
c o ntact i nf or mati o n d ue t o tea m 
me m ber tra nsiti o n;
( 2) Re m o ve d 
t he D M C 
a nal ys is 
fr o m t he S A P;
( 3) U p date d t he Me d D R A a n d W H O 
D D dicti o nar y  versi o n t o 1 9. 0 
a n d 0 1 Se p 2 0 1 6;
( 4) U p date d t he act ual P N/I V a n d 
E N v ol u me a n d cal oric i nta ke 
deri vati o n usi n g a vera ge dail y 
val ue 
n or malize d 
t o 
wei g ht 
base d o n t he dair y  data; 
( 5) U p date d 
t he me dicati o n 
data 
i m p utati o n al g orit h m;
( 6) U p date d t he mar ke dl y a b n or mal 
criteria f or la b data base d o n 
S hi re’s re q uire me nt.
Draft 5. 0
1 0 A pr 2 0 1 7
U p date d per S hire re vie wers’ re q uests.
Fi nal 1. 0
3 0J u n 2 0 1 7
U p date d per S hire re vie wers’ re q uests.
1 4J ul 2 0 1 7
A d de d P K c o nce ntrati o n s u m maries.
P P D
P P D
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 of 4 8
T A B L E O F C O N T E N T S
1.
LI S T O F A B B R E VI A TI O N S .........................................................................................................9
2.
I N T R O D U C TI O N ..........................................................................................................................1 0
3.
S T U D Y O B J E C TI V E S .................................................................................................................1 0
4.
S T U D Y D E SI G N ............................................................................................................................1 0
4. 1.
G e n er al D escri pti o n ...................................................................................................................................1 0
4. 2.
Sc h e d ul e of E v e nts .....................................................................................................................................1 2
4. 3.
C h a n g es t o A n al ysis fr o m Pr ot oc ol ............................................................................................................1 2
5.
P L A N N E D A N A L Y S E S ...............................................................................................................1 3
5. 1.
Fi n al A n al ysis .............................................................................................................................................1 3
6.
A N A L Y SI S S E T S ...........................................................................................................................1 3
6. 1.
All S u bj ects Scr e e n e d [ S R N] S et .................................................................................................................1 3
6. 2.
All S u bj ects E nr oll e d [ E N R] S et ..................................................................................................................1 3
6. 3.
I nt e nti o n-t o-Tr e at [I T T] S et ........................................................................................................................1 4
6. 4.
P er Pr ot oc ol [ P P] S et .................................................................................................................................1 4
6. 5.
S af et y [ S A F] A n al ysis S et ...........................................................................................................................1 4
6. 6.
P h ar m ac o ki n etic [ P K] S et ..........................................................................................................................1 4
7.
G E N E R A L C O N SI D E R A TI O N S ..............................................................................................1 5
P P D
7. 1.
R ef er e nc e St art D at e a n d St u d y D a y ..........................................................................................................1 5
7. 2.
B as eli n e .....................................................................................................................................................1 5


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 5 of 4 8
7. 3.
R et ests, U nsc h e d ul e d Visits a n d E arl y T er mi n ati o n D at a ...........................................................................1 5
7. 4.
Wi n d o wi n g C o n v e nti o ns ............................................................................................................................1 6
7. 5.
St atistic al T ests ..........................................................................................................................................1 6
7. 6.
C o m m o n C alc ul ati o ns ................................................................................................................................1 6
7. 7.
S oft w ar e V ersi o n .......................................................................................................................................1 7
8.
S T A TI S TI C A L C O N SI D E R A TI O N S .......................................................................................1 7
8. 1.
A dj ust m e nts f or C o v ari at es a n d F act ors t o b e I ncl u d e d i n A n al ys es ..........................................................1 7
8. 2.
M ultic e nt er St u di es ...................................................................................................................................1 7
8. 3.
Missi n g d at a ..............................................................................................................................................1 7
8. 4.
M ulti pl e C o m p aris o ns/ M ulti plicit y ...........................................................................................................1 7
8. 5.
E x a mi n ati o n of S u b gr o u ps .........................................................................................................................1 7
9.
O U T P U T P R E S E N T A TI O N S .....................................................................................................1 8
1 0.
DI S P O SI TI O N A N D WI T H D R A W A L S ..................................................................................1 8
1 1. D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S .............................1 9
1 1. 1.
D eri v ati o ns ............................................................................................................................................1 9
1 2. M E DI C A L HI S T O R Y ...................................................................................................................2 0
1 2. 1.
S h ort B o w el S y n dr o m e Hist or y ..............................................................................................................2 0
1 2. 2.
G astr oi nt esti n al S y m pt o ms Hist or y .......................................................................................................2 0
1 2. 3.
S ur gic al a n d M e dic al Hist or y ..................................................................................................................2 0
1 3. P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S
P P D
................................................................2 1


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 6 of  4 8
1 4. DI A G N O S TI C, S U R GI C A L , O R T H E R A P E U TI C P R OC E D U R E S D U RI N G T H E 
S T U D Y
........................................................................................................................... 2 2
1 5. S T U D Y D R U G C O M P LI A N C E .................................................................................................2 2
1 5. 1.
D eri v ati o ns ............................................................................................................................................2 2
1 6. P H A R M A C O KI N E TI C S .............................................................................................................2 2
1 7. E F FI C A C Y O U T C O M E S ............................................................................................................2 3
1 7. 1.
Pri m ar y Effic ac y .....................................................................................................................................2 4
1 7. 1. 1.
Pri m ar y Effic ac y V ari a bl e & D eri v ati o n .....................................................................................................2 4
1 7. 1. 2.
Pri m ar y A n al ysis of Pri m ar y Effic ac y V ari a bl e ..........................................................................................2 5
1 7. 1. 3.
S e nsiti vit y A n al ysis of Pri m ar y Effic ac y V ari a bl e .......................................................................................2 5
1 7. 2.
Ot h er Effic ac y ........................................................................................................................................2 5
1 7. 2. 1.
Ot h er Effic ac y V ari a bl es & D eri v ati o ns .....................................................................................................2 5
1 7. 2. 1. 1.
≥ 2 0 % R e d ucti o n i n P N/I V v ol u m e at e ac h st u d y visit ......................................................................2 5
1 7. 2. 1. 2.
C o m pl et e w e a ni n g off P N/I V s u p p ort at E O T ...................................................................................2 5
1 7. 2. 1. 3.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n P N/I V s u p p ort ..........................................................2 6
1 7. 2. 1. 4.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n citr ulli n e ...................................................................2 6
1 7. 2. 1. 5.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n e nt er al n utriti o n al s u p p ort ......................................2 6
1 7. 2. 1. 6.
C h a n g e a n d p erc e nt c h a n g e fr o m E O T i n P N/I V s u p p ort, citr ulli n e, E N s u p p ort at E O S ..................2 6
1 7. 2. 1. 7.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n h o urs p er d a y a n d d a ys p er w e e k of P N/I V s u p p ort 2 7
1 7. 2. 2.
A n al ysis of Ot h er Effic ac y V ari a bl es ..........................................................................................................2 7
1 7. 2. 2. 1.
A n al ysis of All Ot h er Effic ac y V ari a bl es .............................................................................................2 7
1 8. S T U D Y D R U G E X P O S U R E .......................................................................................................2 8
1 8. 1.
D eri v ati o ns ............................................................................................................................................2 8
1 9. S A F E T Y O U T C O M E S .................................................................................................................2 8
1 9. 1.
A d v ers e E v e nts ......................................................................................................................................2 8
P P D
1 9. 1. 1.
All T E A Es ...................................................................................................................................................2 9
1 9. 1. 1. 1.
S e v erit y .............................................................................................................................................2 9
1 9. 1. 1. 2.
R el ati o ns hi p t o St u d y Dr u g ...............................................................................................................2 9
1 9. 1. 2.
S eri o us A d v ers e E v e nts .............................................................................................................................3 0
1 9. 1. 3.
A Es L e a di n g t o Disc o nti n u ati o n of St u d y Dr u g .........................................................................................3 0
1 9. 1. 4.
A d v ers e E v e nts L e a di n g t o D e at h .............................................................................................................3 0


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 7 of 4 8
1 9. 2.
L a b or at or y E v al u ati o ns ..........................................................................................................................3 0
1 9. 2. 1.
L a b or at or y R ef er e nc e R a n g es a n d M ar k e dl y A b n or m al Crit eri a ..............................................................3 2
1 9. 3.
A nti b o di es t o T e d u gl uti d e .....................................................................................................................3 2
1 9. 4.
G astr oi nt esti n al -S p ecific T esti n g ............................................................................................................3 3
1 9. 5.
P h ysic al E x a mi n ati o n .............................................................................................................................3 3
1 9. 6.
Vit al Si g ns ..............................................................................................................................................3 3
1 9. 6. 1.
Vit al Si g ns S p ecific D eri v ati o ns .................................................................................................................3 4
1 9. 7.
E C G E v al u ati o ns .....................................................................................................................................3 4
1 9. 8.
F ec al a n d Uri n e O ut p ut ..........................................................................................................................3 5
2 0. D A T A N O T S U M M A RI Z E D O R P R E S E N T E D ...................................................................3 5
A P P E N DI X 1.
P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S .................................3 7
S hir e O ut p ut St a n d ar ds – T FLs 4 S hir e Fi n al V 6. 0 ......................................................................................................3 7

St atistics Pr es e nt ati o n ...................................................................................................................................3 7

Ali g n m e nt ......................................................................................................................................................3 7

D eci m al Pl ac es a n d R o u n di n g R ul es ..............................................................................................................3 8

Pr es e nt ati o n of Tr e at m e nt Gr o u ps ................................................................................................................3 8
A P P E N DI X 2.
P A R TI A L D A T E C O N V E N T I O N S ...................................................................3 9
I m p ut ati o n of P arti al A E D at es..............................................................................................................................3 9
I m p ut ati o n of P arti al M e dic ati o n D at a..................................................................................................................4 1
A P P E N DI X 3.
M A R K E D L Y A B N O R M A L L A B O R A T O R Y C RI T E RI A .........................4 6
A P P E N DI X 4.
T A B L E, FI G U R E A N D D A T A LI S TI N G S H E L L S ......................................4 8
P P D
T a bl e a n d Fi g ur e S h ells ..........................................................................................................................................4 8


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 8 of 4 8
D at a Listi n g S h ells .................................................................................................................................................4 8
LI S T O F T A B L E S
P P D
T a ble A
St u d y Di a gr a m ........................................................................................................................................1 2
T a ble B
L a b or at or y Tests .....................................................................................................................................3 1


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 9 of 4 8
1. L I S T O F A B B R E VI A TI O N S
A C S
A b n or m al, Cli nicall y Si g nifica nt 
A E
A d verse E ve nt
A L T
Ala ni ne A mi n otra nsferase 
A N C S
A b n or m al, N ot Cli nicall y Si g nifica nt 
A S T
As partate A mi n otra nsferase 
B L Q
B el o w  T he L o wer Li mit of Q ua ntificati o n 
B MI
B o d y  Mass I n de x 
C D C
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n 
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C T M S
Cli nical Trial Ma na ge me nt S yste m
D M C
Data M o nit ori n g C o m mittee 
E C G
Electr ocar di o gra m
e C R F
Electr o nic Case Re p ort F or m
E N
E nteral N utriti o n 
E N R
All S u bjects E nr olle d 
E O S
E n d of St u d y 
E O T
E n d of Treat me nt 
G F R
Gl o m er ular Filtrati o n Rate 
G G T
Ga m ma Gl uta m yl Tra nsferase
GI
Gastr oi ntesti nal
I N R
Pr ot hr o m bi n I ntl. N or malize d Rati o 
I T T
I nte nti o n-t o-Treat 
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
N A
N ot A p plica ble
P D
P har m a c o d yna mics 
P K
P har m ac o ki netic
P N/I V
Pare nteral N utriti o n/I ntra ve n o us Fl ui d 
P P
Per Pr ot oc ol
P T
Preferre d Ter m 
S A E
Seri o us A d verse E ve nt
S A F
Safet y 
S A P
Statistical A nal ysis Pla n 
S B S
S h ort B o w el S y n dr o me 
S O C
S y st e m Or ga n Class
S R N
All S u bjects Scree ne d 
T E A E
Treat me nt- E mer ge nt A d verse E ve nt
T E S A E
Treat me nt- E mer ge nt Seri o us A d verse E ve nt
U L Q
A b o ve t he U p per Li mit of Q ua ntificati o n 
W H O D D
W H O Dr u g Dicti o nar y 
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 0 of 4 8
2. IN T R O D U C TI O N
T his d oc u me nt descri bes t he r ules a n d c o n ve nti o ns t o be use d i n t he prese ntati o n a n d a nal ys is 
of efficac y an d safet y data f or Pr ot oc ol T E D -C 1 4 - 0 0 6. It descri bes t he data t o be s u m marize d 
a n d a nal yze d, i ncl u di n g s pecifics of t he statistical a nal ys es t o be p erf or me d. P har mac o ki netic 
( P K) c o nce ntrati o n will be s u m marize d b ut t he a nal ysis of P K para meters will be detaile d i n a 
se parate a nalys is pla n.
T his statistical a nal y sis pla n ( S A P) is base d o n pr ot oc ol a me n d me nt 4, date d 1 5 Marc h 2 0 1 6.
3. S T U D Y O B J E C TI V E S
T he
o bjecti ve of t his cli nical st u d y is t o e val uate t he safety, p har mac o ki netics, a n d 
efficac y/ p har mac o d yna mics ( P D) of te d u gl uti de i n pe diatric s u bjects t hr o u g h 1 7 ye ars of a ge 
wit h s h ort b o wel s y n dr o me ( S B S) a n d w h o are de pe n de nt o n pare nteral s u p p ort.
4. S T U D Y D E SI G N
4. 1.
G E N E R AL D E S C RI P TI O N
P P D
T his st u d y will i ncl u de 2 treat me nt ar ms: a te d u gl uti de treat me nt ar m a n d a sta n dar d of care 
treat me nt ar m. S u bjects i n b ot h ar ms will partici pate i n a 2- wee k mi ni m u m scree ni n g peri o d, a 
2 4- wee k treat me nt peri o d, a n d a 4- wee k f oll o w - u p peri o d. D uri n g t he scree ni n g peri o d, 
s u bjects will c h o ose i nt o w hic h ar m t o e nr oll. D uri n g t he 2 4 -wee k treat me nt peri o d, s u bjects i n 
t he sta n dar d of care treat me nt ar m will recei ve sta n dar d me dical t hera p y of S B S, w hile t h ose i n 
t he te d u gl uti de treat me nt ar m will recei ve dail y s u bc uta ne o us i njecti o ns of te d u gl uti de (st u d y 
dr u g) i n a d diti o n t o sta n dar d me dical t hera py. T he te d u gl uti de treat me nt ar m s u bjects will be 
ra n d o mize d 1: 1 i n a d o u ble - bli n de d ma n ner i nt o t w o parallel te d u gl uti de d ose gr o u ps: 0. 0 2 5 
m g/ k g/ da y  an d 0. 0 5 m g/ k g/ da y . Ra n d o mizati o n acr oss d ose gr o u ps will be stratifie d b y a ge: < 1 
ye ar, 1 t o < 1 2 years, 1 2 t o < 1 7 years, a n d 1 7 t o < 1 8 years. 
All s u bjects will be scree ne d f or a mi ni m u m of 2 wee ks pri or t o start of treat me nt t o verif y  th e
re q uire me nts f or n utriti o nal s u p p ort f or eac h s u bject a n d t o e ns ure a d here nce t o eli gi bilit y 
para meters. After scree ni n g, t he 2 4- wee k treat me nt peri o d will c o nsist of site visits at baseli ne, 
wee kl y f or t he first 2 wee ks ( wee k 1 a n d 2), a n d t he n e ver y ot her wee k t hr o u g h wee k 1 2 ( wee k 
4, 6, 8, 1 0, a n d 1 2). F or t he re mai n der of t he treat me nt peri o d, visits at t he sites will be 
c o n d ucte d e ver y 3 wee ks (at wee k 1 5, 1 8, 2 1, a n d 2 4). Tele p h o ne c o ntacts will be ma de o n all 
ot her wee ks d uri n g t he treat me nt peri o d. T he s u bjects i n b ot h ar ms will f oll o w t he sa me visit 
sc he d ule. At all site visits a n d tele p h o ne c o ntacts, safet y will be m o nit ore d a n d n utriti o nal 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 1 of 4 8
P P D
s u p p ort will be re vie we d a n d a dj uste d as nee de d. At t he e n d of t he treat me nt peri o d ( wee k 
2 4/ E O T), all s u bjects will e nter a 4- wee k f oll o w- u p peri o d u ntil t he e n d of st u d y (wee k 
2 8/ E O S) d uri n g w hic h ti me n o st u d y dr u g (ie, te d u gl uti de) will be a d mi nistere d. A fi nal visit 
will be sc he d ule d at wee k 2 8, 4 wee ks f oll o wi n g wee k 2 4 or t he e n d of treat me nt ( E O T). 
Tele p h o ne c o ntact will be ma de d uri n g t he i nteri m wee ks fr o m E O T t o e n d of st u d y (E O S) t o 
m o nit or safet y  a n d a n y c ha n ges i n n utriti o nal s u p p ort.
T o mai ntai n c o nsiste nc y  acr oss all ce nters, sites a n d s u bjects (ra n d o mize d a n d sta n dar d of care) 
s h o ul d be ma de t o foll o w t he n utriti o nal s u p p ort a dj ust me nt g ui deli nes ( de vel o pe d wit h S B S 
e x pert 
i n p ut a n d 
pr o vi de d 
i n t he pr ot oc ol) 
f or 
decisi o ns 
re gar di n g 
pare nteral 
n utriti o n/i ntra ve n o us fl ui d ( P N/IV) s u p p ort re d ucti o n a n d a d va nces i n e nteral fee ds base d o n 
wei g ht gai n, uri ne a n d st o ol o ut p ut, a n d cli nical sta bilit y . 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 2 of 4 8
T a ble A
St u d y Di a gr a m
4. 2.
S C H E D UL E O F E V E N T S
Sc he d ule of e ve nts ca n be f o u n d i n Secti o n 6 ( Ta ble 6- 2, Ta ble 6- 3, Ta ble 6- 4, a n d Ta ble 6- 5) 
of t he pr ot oc ol.
4. 3.
C H A N G E S T O A N AL Y SI S F R O M P R O T O C OL
T here is n o c ha n ge of a nal ysis fr o m pr ot oc ol. T he pr ot oc ol defi nes t he efficac y po p ulati o n as 
all e nr olle d s u bjects. T he a nal ysis pla n refers t o t he efficac y po p ulati o n as t he I nte nti o n-t o-
Treat (I T T) p o p ulati o n, w hic h is t he sa me as t he efficac y p o p ulati o n.
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 3 of 4 8
5. P L A N N E D A N A L Y S E S
T he f oll o wi n g a nal ys es will be perf or me d f or t his st u d y:

Fi nal A nal ys is 
5. 1.
F I N AL A N AL Y SI S 
All fi nal, pla n ne d a nal ys es i de ntifie d i n t his S A P will be perf or me d b y  Qui ntiles bi ostatistics 
f oll o wi n g s p o ns or a ut h orizati o n of t his statistical a nal ysis pla n, dat a base l oc k, s p o ns or 
a ut h orizati o n of a nal ys is sets a n d u n bli n di n g of treat me nt. 
P har mac o ki netic c o nce ntrati o n data will be s u m marize d b ut t he a nal ys es of P K para meters will 
be perf or me d b y a S hire desi g nate d ve n d or i n acc or da nce wit h t he P K S A P.
6. A N A L Y SI S S E T S
A nal y sis of efficac y an d safety e n d p oi nts will be perf or me d base d o n t he a nal ys is sets defi ne d 
i n t his secti o n a n d as s pecifie d f or eac h e n d p oi nt t hr o u g h o ut t his S A P. I ncl usi o n/e xcl usi o n of 
s u bjects fr o m eac h a nal ysis set will be c o nfir me d pri or t o t he u n bli n di n g of t he st u d y base d o n 
bli n de d data re vie w. 
6. 1.
A LL S U BJ E C T S S C R E E N E D [ S R N] S E T 
T he all s u bjects scree ne d ( S R N) set will c o ntai n all s u bjects w h o pr o vi de si g ne d i nf or me d 
c o nse nt f or t he st u d y.
Data f or s u bjects w h o fail t o pass t he scree ni n g peri o d will be i ncl u de d i n t he listi n gs b ut will 
n ot be i ncl u de d i n a n y a nal yses.
6. 2.
A LL S U BJ E C T S E N R OLL E D [ E N R] SE T 
P P D
T he all s u bjects e nr olle d ( E N R) set will c o ntai n all s u bjects w h o pr o vi de i nf or me d c o nse nt f or 
t his st u d y, satisf y all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria defi ne d i n t he 
pr ot oc ol a n d ma ke t he c h oice of treat me nt ar m (ie. te d u gl uti de or sta n dar d of care) at t he 
baseli ne visit.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 4 of 4 8
6. 3.
IN T E N TI O N -T O - TR E A T [I T T] S E T   
T he i nte nti o n-t o-treat (I T T) set will c o ntai n all s u bjects i n t he E N R set; s u bjects will be 
classifie d acc or di n g t o treat me nt ar m (te d u gl uti de or sta n dar d of care), a n d wit hi n t he 
te d u gl uti de treat me nt ar m, acc or di n g t o d ose gr o u p ( 0. 0 2 5 or 0. 0 5 m g/ k g). 
All efficac y  a nal yses will be c o n d ucte d o n t his p o p ulati o n, u nless ot her wise s pecifie d.
6. 4.
P E R P R O T O C OL [ P P] S E T 
T he per pr ot oc ol ( P P) set will c o ntai n all s u bjects i n t he I T T w h o c o m plete t he st u d y treat me nt 
peri o d wit h o ut pr ot oc ol de viati o ns or ot her sit uati o ns t hat c o ul d p ote ntiall y affect t he efficac y 
c o ncl usi o ns of t he st u d y.   
T he sit uati o ns t hat ma y  affect i ncl usi o n i n t he P P set i ncl u de: 

U ni nter preta ble P K data

N o n -c o m pliance t o st u d y dr u g f or t he treat me nt gr o u p as defi ne d i n Secti o n 1 5

Cli nicall y  si g nifica nt discre pa ncies bet wee n pla n ne d a n d act ual treat me nt

Missi n g baseli ne or wee k 2 4 efficac y  data
6. 5.
S A F E T Y [ S A F] A N AL Y SI S S E T 
T he safet y a nal ys is set will c o ntai n all s u bjects w h o meet t he f oll o wi n g criteria:

Te d u gl uti de treat me nt ar m: s u bjects w h o recei ve at least 1 d ose of te d u gl uti de a n d ha ve 
u n der g o ne at least 1 p ost -baseli ne safety assess me nt ; a nal yses will be perf or me d 
acc or di n g t o d ose gr o u p as a p pr o priate.   

Sta n dar d of care treat me nt ar m: s u bjects w h o ha ve u n der g o ne at least 1 p ost -baseli ne 
safety assess me nt
S u bjects will be classifie d acc or di n g t o treat me nt ar m a n d t he te d u gl uti de d ose t he y act uall y 
recei ve d. All safety a nal yses will be c o n d ucte d o n t his p o p ulati o n , u nless ot her wise s pecifie d. 
6. 6.
P H A R M A C O KI N E TI C [ P K] S E T 
P P D
T he p har mac o ki netic set will 
c o ntai n all e nr olle d s u bjects w h o 
recei ve at least o ne 
s u bc uta ne o us i njecti o n of te d u gl uti de a n d ha ve e val ua ble a n d i nter preta ble P K data. S u bjects 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 5 of 4 8
will be classifie d acc or di n g t o d ose gr o u p ( 0. 0 2 5 or 0. 0 5 m g/ k g)
i n t he te d u gl uti de treat me nt 
ar m. 
7. G E N E R A L C O N SI D E R A TI O N S
7. 1.
R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y
St u d y  Da y will be calc ulate d fr o m t he refere nce start date, a n d will be use d t o s h o w start/st o p 
da y  of assess me nts a nd e ve nts. 
Refere nce start date f or te d u gl uti de ar ms is defi ne d as t he d a y  of t he first d ose of st u d y dr u g 
( Da y 1), w hile f or sta n dar d of care treat me nt ar m it is defi ne d as t he da y  of t he baseli ne visit 
date. St u d y  da ys bef ore t he first d ose of st u d y dr u g ( or baseli ne) will be ne gati ve. 
If t he date of t he e ve nt is o n or after t he refere nce start date t he n: 
                St u d y  D a y = ( date of e ve nt – refere nce start date) + 1.
If t he date of t he e ve nt is pri or t o t he refere nce start date t he n: 
                St u d y  D a y = ( date of e ve nt – refere nce start date).
I n t he sit uati o n w here t he e ve nt date is partial or missi n g, t he date will a p pear partial or missi n g 
i n t he listi n gs, a n d St u d y D a y , a n d a n y c orres p o n di n g d urati o ns will be prese nte d base d o n t he 
i m p utati o ns s pecifie d i n A p pe n di x 2 , Partial Date C o n ve nti o ns.
7. 2.
B A S ELI N E
U nless ot her wise s pecifie d, baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt ta ke n pri or 
t o or o n t he refere nce start date (i ncl u di n g u nsc he d ule d assess me nts). F or a d verse e ve nts ( A E)
or c o nc o mita nt me dicati o ns t hat start o n t he refere nce start date , t he ti me of o nset will be 
c o m pare d t o t he ti me of t he first d ose of st u d y dr u g t o deter mi ne if t he A E or me dicati o n was 
pre -baseli ne or p ost -baseli ne. If t he ti mi n g relati ve t o t he first d ose of st u d y dr u g is u n k n o w n, 
A Es a n d me dicati o ns c o m me nci n g o n t he refere nce start date will be c o nsi dere d p ost -baseli ne . 
A ct ual P N/I V a n d E N a d mi nistrati o n o n t he d a y  of t he refere nce start will be c o nsi dere d p ost -
baseli ne.
7. 3.
R E T E S T S, UN S C H E D UL E D V I SI T S A N D E A RL Y T E R MI N A TI O N D A T A
P P D
I n ge neral, f or b y -visit s u m maries, data rec or de d at t he n o mi nal visit will be prese nte d. 
U nsc he d ule d meas ure me nts will n ot be i ncl u de d i n b y -vi sit s u m maries, b ut ca n c o ntri b ute t o 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 6 of 4 8
t he E O S/ E O T val ue, or best/ w orst case val ue w here a p plica ble. U nsc he d ule d P N/I V or E N 
prescri pti o n a dj ust me nts carr y f or war d u ntil t he net a dj ust me nt, a n d as s uc h, ma y  co ntri b ute t o 
data assi g ne d t o s u bse q ue nt visits.
Listi n gs will i ncl u de sc he d ule d, u nsc he d ule d, retest a n d earl y disc o nti n uati o n data.
7. 4.
W I N D O WI N G C O N V E N TI O N S 
N o mi nal visits will occ ur wit hi n t w o d a y s of t he sc he d ule d wee k 1 a n d wee k 2 visits, wit hi n 
t hree d a y s of t he sc he d ule d wee k 3 t o wee k 2 7 visits a n d wit hi n f o ur da y s of t he wee k 2 8 
( E O S) visit. T here will be n o wi n d o wi n g of sc he d ule d visits base d o n st u d y da y, a n d 
u nsc he d ule d visits will n ot be i ncl u de d i n b y -visit s u m maries. Earl y ter mi nati o n data will be 
ma p pe d t o a sc he d ule d visit if it falls i nt o the a p pr o priate visit wi n d o w as defi ne d i n t he 
pr ot oc ol a n d if t hat sc he d ule d visit di d n ot occ ur. 
A n E n d of Treat me nt ( E O T) ti me p oi nt, defi ne d as t he last deter mi nati o n of e n d p oi nt or last 
a vaila ble meas ure me nt after t he date of first d ose d uri n g t he 2 4- wee k treat me nt peri o d, will be 
a nal yz e d i n a d diti o n t o t he sc he d ule d visits.
7. 5.
S T A TI S TI C AL T E S T S
D ue t o t he li mite d size of t he st u d y po p ulati o n descri pti ve statistics will be use d wit h a g oal of 
s u m marizi n g t he sa m ple. As s uc h, n o clai ms of si g nifica nce will be ma de f or a ny of t he data. 
C o nti n u o us varia bles, i ncl u di n g t h ose assesse d o n a discrete scale, will be s u m marize d usi n g 
descri pti ve statistics i ncl u di n g n u m ber of s u bjects, mea n, 
me dia n, 
sta n dar d de viati o n, 
ma xi m u m, a n d mi ni m u m. F or cate g orical varia b les, statistical s u m maries will i ncl u de n u m ber 
of s u bjects a n d perce nta ges. 
7. 6.
C O M M O N C AL C UL A TI O N S
P P D
F or q ua ntitati ve meas ure me nts, c ha n ge fr o m baseli ne will be calc ulate d as:
Test Val ue at Visit X – Baseli ne Val ue
Perce nt c ha n ge fr o m baseli ne will be calc ula te d as:
(( Test Val ue at Visit X – Baseli ne Val ue) / Baseli ne Val ue ) * 1 0 0
C ha n ge ( or perce nt c ha n ge) fr o m baseli ne ta bles will be calc ulate d base d o n t he n u m ber of 
s u bjects i n t he treat me nt gr o u p wit h a n o n-missi n g val ue at baseli ne a n d at t he ti me p oi nt b ei n g 
a nal yz e d. 


D oc u m e nt: 
\\ q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\ S hir e\T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4 -0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 7 of 4 8
7. 7.
S O F T W A R E V E R SI O N
All a nal y ses will be c o n d ucte d usi n g S A S versi o n 9. 4 or hi g her. 
8. S T A TI S TI C A L C O N SI D E R A TI O N S
8. 1.
A DJ U S T M E N T S F O R C O V A RI A T E S A N D F A C T O R S T O B E IN CL U D E D I N A N AL Y S E S
N o a dj ust me nts f or c o variates are pla n ne d f or t he statistical a nal yses. 
8. 2.
M UL TI C E N T E R S T U DI E S
T his st u d y will be c o n d ucte d b y  multi ple i n vesti gat ors at m ulti ple ce nters i nter nati o nally.  
Ra n d o mizati o n t o treat me nt ar ms is n ot stratifie d b y  c o u ntr y/ ce nter.
8. 3.
M I S SI N G D A T A
Missi n g data will i n ge neral n ot be i m p ute d. H o we ver, partial dates will c o ntri b ute t o a nal ys es 
as descri be d i n A p pe n di x 2 . All a vaila ble data will be i ncl u de d i n t he safety a nal ys is.
Details f or t he i m p utati o n al g orit h m f or t he missi n g e n d p oi nt val ues f or P N/I V s u p p ort 
para meters ( v ol u me, cal ories a n d etc.) will be descri be d i n Secti o n 1 7. 1. 1 of t his a nal y sis pla n. 
8. 4.
M UL TI PL E C O M P A RI S O N S / M UL TI PLI CI T Y
Gi ve n t he s mall sa m ple size, n o h y p ot hesis testi n g will be c o n d ucte d. T heref ore, t here will be 
n o a dj ust me nt f or al p ha le vel. 
8. 5.
E X A MI N A TI O N O F S U B G R O U P S
S u b gr o u p a nal ys es will be c o n d ucte d as state d i n t he e x pl orat or y anal y sis secti o n. T he 
f oll o wi n g s u b gr o ups will be assesse d a n d descri be d wit hi n t he secti o n: 

A ge gr o u p ( years) at scree ni n g
< 1 
o
1 t o < 1 2 
P P D
o


D oc u m e nt: 
\\ q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\ S hir e\T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4 -0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 8 of 4 8
1 2 t o < 1 7
o
1 7 t o < 1 8
o

E nteral g l uta mi ne use ( Yes/ N o) at least o nce d uri n g t he 2 4-wee k treat me nt peri o d
9. O U T P U T P R E S E N T A TI O N S
A p pe n di x 1 s h o ws c o n ve nti o ns f or prese ntati o n of data i n o ut p uts. T he o ut p ut te m plates 
pr o vi de d t o get her wit h t his S A P descri be t he prese ntati o ns f or t he a nal ys es of t his st u d y base d 
o n S hire i nter nal sta n dar ds T F L s 4 S hire Fi nal V 6. 0. T he f or mat a n d c o nte nt of t he s u m m ar y 
ta bles, fi g ures a n d listi n gs ( T F Ls) will be pr o vi de d b y Q ui ntiles Bi ostatistics.
1 0.
D I S P O SI TI O N A N D W
I T H D R A W A L S
All s u bjects w h o pr o vi de i nf or me d c o nse nt will be acc o u nte d f or i n t his st u d y. 
Assess me nt of eli gi bilit y t o t he i ncl usi o n a n d e xcl usi o n criteria will be perf or me d at Scree ni n g 
a n d re -c o nfir me d at t he Baseli ne visit. 
Pr ot oc ol de via ti o ns (as defi ne d i n S ecti o n 6. 4 ) as o btai ne d fr o m a cli nical trial ma na ge me nt 
s yste m ( C T M S) will be assesse d t hr o u g h o ut t he st u d y. All i de ntifie d de viati o ns will be re p orte d 
i n t he C T M S. Pr ot oc ol de viati o ns fr o m t he C T M S will be c o de d t o cate g ories a n d pr o vi de d as 
part of t he C T M S tra nsfer t o Bi ostatistics. 
S u bjects w h o disc o nti n ue t he st u d y pri or t o c o m pl eti o n (t hr o u g h wee k 2 8 or E O S) will ha ve 
t heir reas o n f or disc o nti n uati o n d oc u me nte d i n t he e C R F. Re gar dless of t he reas o n f or earl y 
disc o nti n uati o n, all data a vaila ble f or t he s u bject at t he ti me of c o m pleti o n/ disc o nti n uati o n will 
be rec or de d o n t he e C R F a n d i ncl u de d i n t he a nal yses. 
T he prese ntati o n of pla n ne d listi n gs will i ncl u de t he f oll o wi n g:

S u bject Dis p ositi o n ( S R N set)

I ncl usi o n a n d e xcl usi o n criteria vi olati o ns ( S R N set)

Pr ot oc ol de viati o ns ( E N R set). 

S u bjects e xcl u de d fr o m Per Pr ot oc ol Set ( E N R set)

Assi g n me nt t o a nal ys is sets ( E N R set) 
T he f oll o wi n g s u m mar y  ta bles are pla n ne d f or prese ntati o n:

P P D
S u bject dis p ositi o n ( S R N set) b y  re gi o n a n d o verall


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 1 9 of 4 8

A nal y sis sets ( E N R set)

S u m mar y  of site visits ( E N R set)

Maj or pr ot oc ol de viati o ns ( E N R set)
1 1.
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S
De m o gra p hic data a n d ot her baseli ne c haracteristics will be prese nte d f or t he IT T a n d P P 
A nal y sis Sets.
T he f oll o wi n g de m o gra p hic a n d ot her baseli ne c haracteristics will be s u m marize d f or t his 
st u d y:

A ge ( years) - calc ulate d as a c o nti n u o us para meter relati ve t o date of scree ni n g. If 
partial date of birt h date is e ntere d wit h missi n g da y  an d/ or m o nt h d ue t o re g ulat or y 
c o nstrai nts, a ge i nf or mati o n will be o btai ne d fr o m I nteracti ve V oice Res p o nse S y ste m 
(I V R S); if it is n ot a vaila ble i n I V R S, birt h date will be i m p ute d as t he first d a y  of t he 
m o nt h if da y  is missi n g or first da y of t he ye ar if b ot h da y a n d m o nt h are missi n g.

A ge Gr o u p – A ge is cate g orize d i n pre -defi ne d gr o u ps: < 1, 1 t o < 1 2, 1 2 t o < 1 7, 1 7 t o 
< 1 8

S e x ( wit h re pr o d ucti ve stat us f or fe males)

Race 

Et h nicit y

Hei g ht Z -sc ore at Baseli ne 

Wei g ht Z -sc ore at Baseli ne 

Hea d Circ u mfere nce Z-sc ore at Baseli ne ( o nly f or s u bjects w h o are < = 3 6 m o nt hs of 
a ge)

B MI Z -sc ore at Baseli ne 
T he de m o gra p hic data c ollecte d i n t he e C R F will be liste d b y s u bject f or t he E N R set.
1 1. 1.
D E RI V A TI O N S

B MI ( k g/ m 2) = 1 0 0 0 0 * wei g ht ( k g)/ hei g ht (c m)2

Z- sc ore of wei g ht, hei g ht, B MI a n d hea d circ u mfere nce will be calc ulate d base d o n t he 
met h o d descri be d i n Secti o n 1 9. 6. 1
P P D
.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 0 of 4 8
1 2.
M E DI C A L H I S T O R Y
Me di cal hist or y will be prese nte d f or t he I T T A nal ysis Set.
1 2. 1.
S H O R T B O W EL S Y N D R O M E H I S T O R Y
T he f oll o wi n g S h ort B o wel S y n dr o me ( S B S) Hist or y  will be c ollecte d at scree ni n g a n d will be 
s u m marize d a n d liste d:

Pri mar y  reas o n f or t he dia g n osis of S B S 

Prese nce of st o ma; if Y, st o ma t y pe 

Prese nce a n y re mai ni n g c ol o n; if Y, esti mate d perce nt c ol o n re mai ni n g a n d w het her t he 
c ol o n is i n c o nti n uit y wit h t he s mall b o wel

Prese nce of distal/ter mi nal ile u m a n d ile ocecal val ve 
1 2. 2.
G A S T R OI N T E S TI N AL S Y M P T O M S H I S T O R Y
T he f oll o wi n g G astr oi ntesti nal S y m pt o ms Hist or y  collecte d at Baseli ne will be s u m marize d 
base d o n cate g ories of n ot prese nt, mil d, m o derate, a n d se vere, wit h cli nical si g nifica nce als o 
s u m marize d w here t he e ve nt is prese nt:

A b d o mi nal/ bell y  pai n

Na usea/feeli n g q ueas y

V o miti n g /t hr o w u p

Heart b ur n/refl u x/s pit u p

Gas/ bl oati n g

Diarr hea/l o ose st o ol 

C o nsti pati o n/ ver y  har d st o ol 
A listi n g will als o be prese nte d b y  treat me nt gr o u p a n d s u bject i de ntifier. 
1 2. 3.
S U R GI C AL A N D M E DI C AL H I S T O R Y
Me dical a n d S ur gical Hist or y will be c o de d usi n g Me dic al Dicti o n ary f or Re g ul at ory Activities 
( Me d D R A) versi o n 1 9. 1
P P D
. Me dical 
a n d S ur gical Hist or y  co n diti o ns are defi ne d as t h ose 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 1 of 4 8
c o n diti o ns w hic h be ga n pri or t o i nf or me d c o nse nt. Me dical a n d s ur gical hist or y i ncl u des all 
rele va nt past me dical dia g n os es a n d s ur geries ot her t ha n relate d t o t he ca use or dia g n osis of 
S B S. Data ca pt ure d o n t he Me dical a n d S ur gical Hist or y  pa ge of t he C R F will be prese nte d b y  
S y ste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T). S O C wi ll be s orte d al p ha betically a n d P T 
wit hi n S O C will be s orte d b y  desce n di n g i nci de nce i n t he T otal Te d u gl uti de treat me nt gr o u p. 
1 3.
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S
Me dicati o ns will be prese nte d f or t he S A F a nal y sis set.
' Pri or’ me dicati o ns are t h ose ta ke n b y t he s u bject wit hi n 1 4 da y s bef ore scree ni n g a n d 
disc o nti n ue d pri or t o t he first d ose of st u d y dr u g ( or t he baseli ne visit f or t he sta n dar d of care
treat me nt ar m). 
‘ C o nc o mita nt’ me dicati o ns are defi ne d as:

me dicati o ns wit h o nset dates o n or after t he first d ose of st u d y  dr u g ( or baseli ne visit f or 
sta n dar d of care treat me nt ar m); or

me dicati o ns wit h o nset dates pri or t o first d ose of st u d y dr u g ( or baseli ne visit f or 
sta n dar d of care treat me nt ar m) wit h o ut a st o p date or st o p date after t he first d ose of 
st u d y dr u g
T he s u bject’s usa ge of pri or me dicati o n will be assesse d at scree ni n g a n d baseli ne a n d t he 
s u bject’s usa ge of c o nc o mita nt me dicati o n will be assesse d at t he baseli ne visit a n d visit
t hereafter. T he c ha n ges i n me dicati o n or d osa ge of me dicati o ns will be rec or de d o n t he e C R F.  
C o nc o mita nt me dicati o ns i ncl u de I V me dicati o ns mi xe d i nt o t he P N/I V fl ui ds, li ke he pari n or 
H 2 bl oc kers. Me dicati o ns use d f or li ne mai nte na nce, s uc h as T P A, a n d et ha n ol a n d ta ur oli di ne 
l ocks, are als o i ncl u de d as c o nc o mita nt me dicati o ns. H o we ver, 
I V fl ui d a n d n utriti o nal 
c o m p o ne nts of pare nteral n utriti o n, i ncl u di n g electr ol yt es, vita mi ns a n d mi nerals, 
ot her 
micr o n utrie nts, a mi n o aci ds, gl uc ose, a n d li pi ds, are part of P N/I V will n ot be i ncl u de d as a 
pri or or c o nc o mita nt me dicati o ns.
Me dicati o ns 
will be c o de d t o preferre d na me usi n g W H O 
Dr u g Dicti o n ary ( W H O D D), 
0 1 S E P 2 0 1 6
P P D
. Pri or a n d c o nc o mita nt me dicati o n use will be s u m marize d b y  preferre d na me 
usi n g t he n u m ber a n d perce nta ge of s u bjects b y  treat me nt gr o u p. Me dicati o ns will be s orte d 
al p ha beticall y b y  preferre d na me. S u bjects wit h m ulti ple occ urre nces of a me dicati o n i n 
preferre d na me will o nl y be c o u nte d o nce wit hi n eac h preferre d na me. Me dicati o n s u m maries 
will be prese nte d b y treat me nt gr o u p f or t he S A F a nal ys is set.
A listi n g of all me dicati o ns, b ot h pri or a n d c o nc o mita nt will be prese nte d. T he listi n g will be 
s orte d b y  treat me nt gr o u p a n d s u bject i de ntifier a n d will i ncl u de re p orte d na me, d ose, r o ute of 
a d mi nistrati o n, d osi n g fre q ue nc y, start date, e n d date, i n dicati o n a n d peri o d of me dicati o n 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 2 of 4 8
( pri or o nl y , c o nc o mita nt o nl y , pri or a n d c o nc o mita nt).  In vesti gat or ver bati m as well as c o de d 
ter ms will be i ncl u de d i n t he listi n gs.
See A p pe n di x 2 f or ha n dli n g of partial dates f or me dicati o ns.
1 4.
D I A G N O S TI C, SU R GI C A L , O R T H E R A P E U TI C P R O C E D U R E S 
D U RI N G T H E S T U D Y
T he dia g n ostic, s ur gical, or t hera pe utic pr oce d ures d uri n g t he st u d y are rec or de d i n t he e C R F 
a n d will o nl y be prese nte d i n a listi n g.
1 5.
S T U D Y D R U G C O M P LI A N C E 
St u d y  dr u g a d mi nistrati o n diar y  data will be use d t o meas ure st u d y dr u g c o m plia nce. O nl y 
diar y  e ntries wit h
“ Yes” i n res p o nse t o t he q uesti o n “ Was t he st u d y dr u g a d mi nistere d per 
i nstr ucti o ns t o da y?” will be dee me d c o m plia nt.
S u bjects will be c o nsi dere d c o m plia nt o ve rall f or st u d y dr u g a d mi nistrati o n if t he calc ulate d 
c o m plia nce is > 8 0 %. O verall treat me nt c o m plia nce will be prese nte d f or perce nt c o m plia nce 
calc ulati o ns usi n g descri pti ve statistics a n d t he n u m ber a n d perce nta ge of s u bjects w h o are > 
8 0 % c o m plia nt b y  treat me nt gr o u p f or t he IT T a n d P P a n d S A F A nal ys is Sets. 
1 5. 1.
D E RI V A TI O N S
C o m plia nce wit h 
d o u ble -bli n d st u d y dr u g will 
be calc ulate d as t he n u m ber of d oses 
a d mi nistere d di vi de d b y  the pla n ne d n u m ber of d oses e x presse d as a perce nta ge . T his ca n be 
s u m marize d as:
O verall perce nt c o m plia nce = (T otal n u m ber of diar y  d a y s mar ke d “ Yes” f or st u d y dr u g 
a d mi nistrati o n / N u m ber of da ys o n treat me nt) * 1 0 0
w here n u m ber of d a y s o n treat me nt will be calc ulate d as ( Date of last st u d y dr u g – Date of first 
st u d y dr u g + 1) a n d d ose i nterr u pti o n da y s will n ot be e xcl u de d.
Dr u g a d mi nistrati o n diar y  data, first d ose date, a n d last d ose data are re p orte d i n t he e C R F.
1 6.
P H A R M A C O KI N E TI C S
P P D
T he p har mac o ki netic ( P K) c o nce ntrati o n data will be s u m marize d o n t he P K set f or t he s u bjects 
i n t he te d u gl uti de treat me nt ar m o nl y. T he descri pti ve statistics of P K c o nce ntrati o n will be 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 3 of 4 8
s u m marize d b y  treat me nt ar m a n d d ose gr o u p f or eac h ti me p oi nt. T he listi n gs f or P K 
c o nce ntrati o n data will als o be pr o vi de d. 
F or t he P K e val uati o n, bl o o d will be c ollecte d at t he cli nic o n d a y  0 whe n t he s u bject recei ves 
t he first d ose of te d u gl uti de. Bl o o d sa m pli n g will occ ur at t he f oll o wi n g ti me p oi nts: pre d ose 
a n d 1, 2, a n d 4 h o urs p ost d ose.

0- h o ur ( pre d ose) dra w: a n y ti me pri or t o t he dai l y dose, o n t he d a y  of d osi n g, b ut at 
least 1 4 h o urs after t he pre vi o us d ose (if t he P K bl o o d dra w d oes n ot occ ur at da y 0)

1 -h o ur p ost d ose dra w: ± 1 0 mi n utes

2- h o ur p ost d ose dra w: ± 1 0 mi n utes

4- h o ur p ost d ose dra w: ± 3 0 mi n utes
If a s u bject is u na ble t o pr o v i de bl o o d sa m ples at baseli ne ( da y 0) on t he first da y  of treat me nt,
t he n bl o o d ma y  be c ollecte d f or P K a nal ysis d uri n g a n y ot her f ut ure cli nic visit w hile t he 
s u bject is still recei vi n g treat me nt wit h te d u gl uti de.
T he act ual date a n d ti me of te d u gl uti de ad mi nistrati o n a n d bl o o d dra w will be d oc u me nte d o n
t he P K bl o o d sa m pli n g e C R F.
Descri pti ve statistics ( mea n, me dia n, sta n dar d de viat i o n, mi ni m u m a n d ma xi m u m val ues ) of 
P K c o nce ntrati o n will be calc ulate d t o s u m marize t he a bs ol ute val ues a n d c ha n ge fr o m pre d ose
at eac h ti me p oi nt. T he P K para meters will be deri ve d a n d esti mate d base d o n meas ure d 
te d u gl uti de plas ma c o nce ntrati o ns usi n g a p o p ulati o n P K m o deli n g a p pr oac h a n d will be 
descri be d wit h i n a se parate S A P. 
1 7.
E F FI C A C Y O U T C O M E S
P P D
Efficac y  anal y ses f or t he pr i mar y efficac y en d p oi nt , ≥2 0 % re d ucti o n i n wei g ht -n or malize d 
P N/I V v ol u me bet wee n t he baseli ne a n d wee k 2 4/ E O T visit, will be perf or me d usi n g b ot h diar y 
a n d prescri be d data o n t he I T T a n d P P a nal ysis sets. All ot her efficac y an al y ses will be 
perf or me d o n t he I T T a nal ysis set o nl y . A nal ys es base d o n d iar y data a n d prescri be d data will 
be prese nte d se parately. T he descri pti ve statistics of efficac y outc o mes will be s u m marize d b y  
treat me nt ar m a n d d ose gr o u p . T he listi n gs f or efficac y meas ures w hic h are c ollecte d o n t he 
C R F f or ms will be pr o vi de d. 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 4 of 4 8
1 7. 1.
P RI M A R Y E F FI C A C Y
1 7. 1. 1.
P RI M A R Y E F FI C A C Y V A RI A BL E & D E RI V A TI O N
T he pri mar y  efficac y varia ble is wei g ht -n or malize d re d ucti o n i n P N/I V v ol u me of at least 2 0 % 
at E O T c o m pare d t o baseli ne. T his will be a nal yz e d i n t w o w a y s: 1) base d o n t he s u bject diar y 
data (als o referre d t o as “act ual”), a n d 2) base d o n t he i n vesti gat or-prescri be d data (referre d t o 
as “ prescri be d”) . P N/I V s u p p ort will be re p orte d i n b ot h s u bject diar y data a n d t he i n vesti gat or-
prescri be d data i n t he e C R F. I n vesti gat or-prescri be d data are t he m ost 
rece nt P N/I V 
prescri pti o n (fr o m eit her baseli ne or prescri pti o n a dj ust me nts) pri or t o or o n t he date of visit, 
ca pt ure d i n t he P N/I V hist or y  a n d P N/I V a dj ust me nts e C R Fs. P N/I V diar y  data are c ollecte d 
o ver 2 4- h o ur peri o d s t hat start o n t he assi g ne d date. De pe n di n g o n t he ti me of da y at w hic h t he 
2 4 h o ur peri o d be gi ns, w hic h ca n v ar y  by s u bject, o ver ni g ht P N/I V i nf usi o n v ol u mes after 
mi d ni g ht ma y be ass ociate d wit h pri or t he date. Baseli ne act ual P N/I V para meters will be 
calc ulate d usi n g all t he diar y  data c ollecte d wit hi n 1 4 da y s pri or t o t he first d ose or baseli ne 
visit. Calc ulati o n of p ost -baseli ne act ual P N/I V para meters will be base d o n t he daily s u p p ort 
rec or de d i n s u bjects’ diaries wit hi n 7 da y s pri or t o t he date of eac h sc he d ule d p ost -baseli ne 
visit . Wee k 1 calc ulati o ns will e xcl u de a n y pre-baseli ne diar y  data. T he calc ulati o n of act ual 
P N/I V v ol u me n or malize d t o wei g ht will f oll o w t he f or m ula bel o w:
A vera ge dail y val ue = [(s u m of n o n- missi n g dail y  val ues i n t he diar y  / nu m ber of d a y s 
wit h n o n -missi n g val ues)] / last a vaila ble b o d y  wei g ht pri or t o t he visit
If m ore t ha n 2 d a y s’ val ues i n a wee k are missi n g, t he a vera ge dail y val ue will n ot be 
calc ulate d a n d will be assi g ne d as missi n g . T he sa me strate g y will be use d t o calc ulate all ot her 
a vera ge diar y  para meters, i ncl u di n g P N/I V cal ories, P N/I V h o urs per d a y , E N v ol u me, a n d E N 
cal ories. If m ore t ha n 5 d a y s’ val ues i n t w o wee ks bef ore baseli ne visit, t he baseli ne val ues are 
missi n g.
T he calc ulati o n of prescri be d P N/I V v ol u me n or malize d t o wei g ht will f oll o w t he f or m ula 
bel o w:
A vera ge dail y  val ue = ( prescri be d wee kl y P N/I V v ol u me / 7) / last a vaila ble wei g ht 
pri or t o or o n t he date of visit
A n a nal o g o us strate g y will be use d t o calc ulate ot her prescri be d para meters, i ncl u di n g P N/I V 
cal ories, P N/I V h o urs per da y, E N v ol u me, a n d E N cal ories. 
Perce nt re d ucti o n i n wei g ht -n or malize d act ual a n d prescri be d P N/I V v ol u me fr o m baseli ne at 
t he sc he d ule d visit will be calc ulate d usi n g t he f or m ula bel o w: 
% re d ucti o n i n P N/I V v ol u me at t he visit = [ (a vera ge dail y val ue at t he sc he d ule d visit -
P P D
a vera ge dail y val ue at baseli ne) / a vera ge dail y val ue at baseli ne ] * 1 0 0 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 5 of 4 8
Perce nt re d ucti o n calc ulati o n will be perf or me d o n b ot h act ual a n d prescri be d P N/I V v ol u me 
data.
1 7. 1. 2.
P RI M A R Y A N AL Y SI S O F P RI M A R Y E F FI C A C Y V A RI A BL E
Efficac y  a nalys es will be c o n d ucte d o n t he I T T a n d P P set. 
T he n u m ber a n d perce nta ge of s u bjects w h o ac hie ve at least a 2 0 % re d ucti o n i n wei g ht -
n or malize d a vera ge dail y  act ual a n d prescri be d P N/I V v ol u me at E O T will be s u m marize d b y  
treat me nt ar m a n d d ose gr o u p. T he de n o mi nat or will be t he n u m ber of s u bjects f or t he 
p o p ulati o n i n eac h treat me nt ar m a n d d ose gr o u p. 
1 7. 1. 3.
S E N SI TI VI T Y A N AL Y SI S O F P RI M A R Y E F FI C A C Y V A RI A BL E
T he sa me descri pti ve statistics will als o be s u m marize d o n i n vesti gat or prescri be d data. 
A se nsiti vit y a nalys is will als o be perf or me d usi n g t he P P a nal ysis set f or b ot h t he s u bject diar y 
data a n d t he i n ve sti gat or prescri be d data.
1 7. 2.
O T H E R E F FI C A C Y
1 7. 2. 1.
O T H E R E F FI C A C Y V A RI A BL E S & D E RI V A TI O N S
1 7. 2. 1. 1.
≥ 2 0 % R e d ucti o n i n P N/I V v ol u m e at e ac h st u d y visit
Si milar t o t he pri mar y  anal ys is, P N/I V v ol u me re d ucti o n at eac h st u d y visit c o m pare d t o 
baseli ne will be calc ulate d. T he n u m ber a n d perce nta ge of s u bjects w h o ac hie ve at least a 2 0 % 
re d ucti o n i n wei g ht -n or malize d P N/I V v ol u me at eac h visit d uri n g t he 2 4- wee k treat me nt 
pe ri o d will be s u m marize d b y treat me nt gr o u p. 
S u b gr o u p a nal ys is b y  age gr o u p a n d b y  oral gl uta mi ne use will be perf or me d o n s u bject diar y  
data as a n e x pl orat or y  a nal ysis f or t he I T T a nalys is set o nl y.
1 7. 2. 1. 2.
C o m pl et e w e a ni n g off P N/I V s u p p ort at E O T
P P D
A s u bject will be c o nsi dere d t o ha ve ac hie ve d i n de pe n de nce fr o m P N/I V s u p p ort (c o m pletely 
wea ne d off P N/I V) at E O T if t he i n vesti gat or prescri bes n o P N/I V at t hat visit a n d t here is n o 
use of P N/I V rec or de d i n t he s u bject diar y  d uri n g t he wee k pri or t o E O T.  


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 6 of 4 8
T he a nal ys is will s u m marize h o w ma n y  su bjects ac hie ve c o m plete wea ni n g of P N/I V s u p p ort 
at E O T. 
1 7. 2. 1. 3.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n P N/I V s u p p ort
C ha n ges i n a vera ge dail y  wei g ht -n or malize d act ual a n d prescri be d P N/I V v ol u me at all p ost -
baseli ne visits d uri n g t he 2 4- wee k treat me nt peri o d a n d 4 - wee k f oll o w-u p peri o d will be 
deri ve d usi n g t he sa me f or m ulas as f or pri mar y  efficac y calc ulati o ns. A nal o g o us calc ulati o ns 
will be use d t o calc ulate c ha n ges i n wei g ht -n or malize d act ual a n d prescri be d P N/I V cal ories. 
Mea n
± S E pl ots of perce nt c ha n ge i n P N/I V v ol u me ( m L/ k g/ da y) a n d cal oric i nta ke 
( kcal/ k g/ da y) will be ge nerate d.
1 7. 2. 1. 4.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n citr ulli n e
Plas ma citr ulli ne le vels are meas ure d, c ollecte d a n d tra nsferre d b y  Co va nce ce ntral la b wit h
ot her la b data. C ha n ge a n d perce nt c ha n ge fr o m baseli ne i n plas ma citr ulli ne at wee k 1 2, wee k 
2 4 a n d E O T will be prese nte d b y treat me nt ar m a n d d ose gr o u p usi n g descri pti ve statistics. 
1 7. 2. 1. 5.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n e nt er al n utriti o n al s u p p ort
T he c ha n ge a n d perce nt c ha n ge fr o m baseli ne i n a vera ge dail y  wei g ht -n or malize d act ual a n d 
prescri be d E N v ol u me a n d cal ories at eac h p ost -baseli ne visit d uri n g t he 2 4- wee k treat me nt 
peri o d a n d 4- wee k f oll o w- u p peri o d will be calc ulate d a n d s u m marized usi n g a nal o g o us
met h o ds as f or P N/I V para meters. H o we ver, perce nt c ha n ge will n ot be calc ulate d if s u bject di d 
n ot ta ke a n y E N at baseli ne.
1 7. 2. 1. 6.
C h a n g e a n d p erc e nt c h a n g e fr o m E O T i n P N/I V s u p p ort, citr ulli n e, E N s u p p ort at E O S
P P D
T he c ha n ge fr o m E O T i n eac h par a meter or meas ure me nt at E O S will be calc ulate d usi n g t he 
f or m ula bel o w: 
C ha n ge fr o m E O T i n para meter ( or meas ure me nt) at E O S = Val ue at E O S – Val ue at 
E O T
T he perce nt c ha n ge fr o m E O T i n eac h para meter or meas ure me nt at E O S will be calc ulate d 
usi n g t he f or m ula bel o w:
Perce nt c ha n ge fr o m E O T i n para meter ( or meas ure me nt) at E O S = [( Val ue at E O S –
Val ue at E O T) / Val ue at E O T] * 1 0 0
If t he E O S val ue is n ot a vaila ble, t he last n o n-missi n g assess me nt after t he E O T will be use d as 
E O S f or calc ulati o n. If s u bject has wea ne d -off P N/I V or E N at E O T, perce nt c ha n ge f or t h ose 
para meters will n ot be calc ulate d.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 7 of 4 8
1 7. 2. 1. 7.
C h a n g e a n d p erc e nt c h a n g e fr o m b as eli n e i n h o urs p er d a y a n d d a ys p er w e e k of 
P N/I V s u p p ort 
C ha n ge a n d perce nt c ha n ge of act ual a n d prescri be d P N/I V h o urs per da y  fr o m baseli ne t o eac h 
visit d uri n g 2 4- wee k treat me nt peri o d a n d t he 4- wee k f oll o w- u p peri o d will be s u m marize d. 
T hese s u m maries will be prese nte d b y  treat me nt ar m a n d d ose gr o u p usi n g descri pti ve 
statistics.
H o urs per d a y  of act ual P N/I V s u p port f or all visits e x ce pt t he baseli ne visit will be calc ulate d 
as f oll o ws: 
H o urs per da y  of act ual P N/IV s u p p ort = (s u m of h o urs per da y  for eac h da y t hat P N/I V 
i nta ke data is rec or de d wit hi n t he 7 da y s pri or t o t he visit / n u m ber of da ys t hat P N/I V 
h o ur s per da y data is rec or de d wit hi n t he 7 da ys pri or t o t he visit)
Prescri be d P N/I V h o urs per d a y  for eac h visit (i ncl u di n g baseli ne) will be ta ke n fr o m t he m ost 
rece nt prescri pti o n data pri or t o or at t hat visit.
D a y s per wee k of act ual P N/I V s u p p ort f or all visits e xce pt t he baseli ne visit w ill be calc ulate d 
as f oll o ws:
D a y s per wee k of act ual P N/I V s u p p ort = ( n u m ber of d a y s wit h n o n- zer o val ues f or 
P N/I V v ol u me wit hi n t he 7 da y s pri or t o t he visit / n u m ber of da ys f or w hic h a n y P N/I V 
i nta ke data is rec or de d wit hi n t he 7 da ys pri or t o t he visit) * 7 
F or t he wee k 1 visit, data pri or t o t he baseli ne visit will n ot be use d f or t he calc ulati o n. 
1 7. 2. 2.
A N AL Y SI S O F O T H E R E F FI C A C Y V A RI A BL E S
1 7. 2. 2. 1.
A n al ysis of All Ot h er Effic ac y V ari a bl es 
P P D
Act ual a n d prescri be d P N/I V a n d E N data will be a nal yz e d a n d s u m marize d se paratel y. 
H o we ver, visit -le vel listi n gs f or a vera ge dail y wei g ht -n or malize d P N/I V v ol u me , cal oric 
i nta ke, d a y s per wee k a n d h o urs per d a y  of P N/I V s u p p ort, will prese nt act ual a n d prescri be d 
data si de -b y -si de.
F or t he varia bles of pre -s pecifie d % re d ucti o n i n P N/I V v ol u me, t he n u m ber a n d perce nta ge of 
s u bjects will be prese nte d b y  visit a n d treat me nt ar m a n d d ose gr o u p. Baseli ne val ues, p ost -
baseli ne val ues, c ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m t he basel i ne i n P N/I V s u p p ort 
will be s u m marize d b y  visit a n d treat me nt ar m a n d d ose gr o u p usi n g descri pti ve statistics 
i ncl u di n g n u m ber of s u bjects, mea n, sta n dar d de viati o n, me dia n, mi ni m u m a n d ma xi m u m. 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 8 of 4 8
1 8.
S T U D Y D R U G E X P O S U R E
T he e xte nt of e x p os ure is defi ne d as t he n u m ber of da y s o n treat me nt. T he n u m ber a n d 
perce nta ges of s u bject will be ta b ulate d f or e xte nt of e x p os ure cate g orize d i nt o wee ks ( < 4, 4-
< 1 2, 1 2- < 2 4, > = 2 4). E x p os ure s u m maries will be prese nte d b y  te d u gl uti de d ose
gr o u p 
(e xcl u di n g t he sta n dar d of care treat me nt ar m) f or t he I TT, P P a n d S A F A nal y sis Sets. T he 
st u d y dr u g a d mi nistrati o n a n d st u d y dr u g acc o u nta bilit y data w hic h are c ollecte d o n t he C R F 
will be liste d.
C o m plia nce a n d d ose i nterr u pti o ns are n ot ta ke n i nt o acc o u nt f or t he e xte nt of e x p os ure. 
Inf or mati o n a b o ut i nterr u pti o ns of st u d y dr u g b y  in vesti gat or decisi o n (start date of 
i nterr u pti o n, date st u d y dr u g res u me d, a n d reas o n f or i nterr u pti o n) will be i ncl u de d i n data 
listi n gs. 
1 8. 1.
D E RI V A TI O N S
T he e xte nt of e x p os ure i n da y s will be calc ulate d as:
E xte nt of e x p os ure ( da ys) = ( date of last st u d y dr u g a d mi nistrati o n – date of first st u d y 
dr u g a d mi nistrati o n) + 1. 
T he date of first st u d y dr u g a d mi nistrati o n is c ollecte d o n t he e C R F “ First S C I njecti o n” f or m. 
T he date of last st u d y  dr u g is c ollecte d o n t he e C R F “ E n d of Treat me nt” f or m.
1 9.
S A F E T Y O U T C O M E S
All o ut p uts f or safet y o utc o mes will be base d o n t he Safet y A nal ys is Set. 
T here will be n o statistical c o m paris o ns bet wee n t he treat me nt gr o u ps f or safet y data. 
1 9. 1.
A D V E R S E E V E N T S
A d verse E ve nts ( A Es) will be c o de d usi n g Me dic al 
Dicti o n ary f or Re g ul at ory Activities 
( Me d D R A) ce ntr al c o di n g dicti o n ary, Versi o n 1 9. 1
P P D
. I nvesti gat or ver bati m as well as preferre d 
ter ms a n d sys te m or ga n classes will be i ncl u de d i n t he listi n gs. 
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as A Es t hat starte d or w orse ne d o n or 
after t he date of first d ose f or treat me nt ar ms a n d a d verse e ve nts t hat starte d or w orse ne d o n or 
after t he baseli ne visit f or sta n dar d of care gr o u p.  For e ve nts t hat start or w orse n o n t he date of


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 2 9 of 4 8
first d ose, a n y a vaila ble start ti me will be c o m pare d t o t he ti me of first d ose f or t he treat me nt 
ar ms.
See A p pe n di x 2 f or ha n dli n g of partial dates f or A Es. I n t he case w here it is n ot p ossi ble t o 
defi ne a n A E as treat me nt-e mer ge nt or n ot, t he A E will be classifie d b y  the w orst case; i.e. 
treat me nt-e mer ge nt. 
A n o verall s u m mar y of n u m ber of s u bjects wit hi n eac h of t he cate g ories descri be d bel o w will 
be pr o vi de d as s pecifie d i n t he te m plates. A d verse e ve nts will be s u m marize d usi n g descri pti ve 
statistics (e. g., n u m ber a n d perce nta ge of s u bjects) f or eac h treat me nt ar m a n d d ose gr o u p. T he 
n u m ber of e ve nts will als o be prese nte d e xce pt f or s u m maries b y  hi ghest cate g or y. T he 
s u m mar y 
will i ncl u de a n y T E A E, se verity of T E A Es ( hi g hest categ or y) , i n vesti gat or 
assess me nt of relati o ns hi p of T E A Es t o st u d y dr u g, treat me nt-e mer ge nt seri o us A Es ( T E S A Es), 
i n vesti gat or assess me nt of relati o ns hi p of T E S A Es t o st u d y dr u g, T E A Es lea di n g t o 
disc o nti n uati o n a n d T E A Es lea di n g t o deat h.
Listi n gs will i nclu de b ot h T E A Es a n d N o n -T E A Es ( u nless s pecifie d ot her wise) a n d will be 
pr o vi de d f or seri o us a d verse e ve nts, a d verse e ve nts lea di n g t o deat h, a n d a d verse e ve nts 
lea di n g t o disc o nti n uati o n of st u d y dr u g. Listi n gs will i n dicate w het her a n A E is treat me nt 
e mer ge nt or n ot.
1 9. 1. 1.
A LL T E A E S 
I nci de nce of T E A Es will be prese nte d b y  Sys te m Or ga n Class a n d Preferre d Ter m a n d als o 
a nal yz e d b y  relati o ns hi p t o st u d y dr u g, seri o us ness, se verit y, a n d ma xi m u m 
se verit y. 
S u m maries b y  S O C a n d P T will prese nt S O C i n al p ha betical or de r a n d P T wit hi n t he S O C i n 
desce n di n g or der of i nci de nce i n t he t otal te d u gl uti de treat me nt ar m .
1 9. 1. 1. 1.
S e v erit y
Se verit y  is classifie d as mil d/ m o derate/se vere. T E A Es wit h a missi n g se verit y will be classifie d 
as se vere. If a s u bject re p orts a T E A E m ore t ha n o nce wit hi n t hat S O C / P T, s u m maries b y  
se verity will o nl y pr o vi de t he hi g hest se verit y classificati o n of t he s u bject f or t he c orres p o n di n g 
i nci de nce s u m maries b y S O C / P T.
T he e ve nts t hat are gra de d acc or di n g t o C T C A E criteria will be i n dicate d i n t he listi n g s.
1 9. 1. 1. 2.
R el ati o ns hi p t o St u d y Dr u g
Relati o ns hi p, as i n dicate d b y  the I n vesti gat or, is classe d as “ n ot rel ate d ” or “rel ate d ” . A 
“rel ate d ” T E A E is defi ne d as a T E A E wit h a relati o ns hi p of “relate d” t o st u d y dr u g. T E A Es 
wit h a missi n g relati o ns hi p t o st u d y dr u g will be re gar de d as “rel ate d ”
P P D
t o st u d y dr u g. A E 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 0 of 4 8
su m maries b y  relati o ns hi p will e xcl u de t he sta n dar d of care treat me nt ar m. 
1 9. 1. 2.
S E RI O U S A D V E R S E E V E N T S
Seri o us a d verse e ve nts ( S A Es) are t h ose e ve nts rec or de d as “ Seri o us” o n t he A d verse E ve nts 
F or m of t he e C R F. A n y S A E t hat occ urs fr o m t he ti me of t he si g ni n g of t he I CF t hr o u g h last 
st u d y visit ( wee k 2 8 or E O S) will be ca pt ure d. A s u m mar y of T E S A Es b y  S O C a n d P T will be 
pre pare d, as well as s u m maries b y  eve nt a n d ca usal relati o ns hi p t o st u d y dr u gs. A listi n g of 
S A Es will be prese nte d.
1 9. 1. 3.
A E S L E A DI N G T O D I S C O N TI N U A TI O N O F S T U D Y D R U G
A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y dr u g will be i de ntifie d b y  the “ St u d y dr u g 
disc o nti n ue d” res p o nse f or acti o n ta ke n wit h st u d y  treat me nt i n t he A d verse E ve nts F or m of t he 
e C R F. 
Se parate listi n gs will be pr o vi de d f or A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y  dr u g.
1 9. 1. 4.
A D V E R S E E V E N T S L E A DI N G T O D E A T H
A Es lea di n g t o Deat h are t h ose e ve nts w hic h are rec or de d as “ Fatal” o n t he A d verse E ve nts 
F or m of t he e C R F. A listi n g of A Es lea di n g t o deat h will be prese nte d.
1 9. 2.
L A B O R A T O R Y E V AL U A TI O N S
La b orat or y  eval uati o ns t hat are d o ne at st u d y site visits will be c ollecte d a n d pr ocesse d via a 
ce ntral la b orat or y (C o va nce ), i ncl u di n g pa nels 
f or He mat ol o g y , Cli nical 
C he mistr y , 
C oa g ulati o n a n d Uri nal y sis. T he ce ntral la b orat or y data will be tra nsferre d t o Q ui ntiles f or 
a nal ys es. La b orat or y  eval uati o ns t hat are re q uire d at i nter vals t hat d o n ot c oi nci de wit h st u d y 
site visits ma y  be o btai ne d b y  a local la b orat or y. T he l ocal la b orat or y data will be c ollecte d o n 
t he l ocal la b orat or y tests f or m of e C R F. La b orat or y  eval uati o ns t o be i ncl u de d i n t he ta bles or 
listi n gs are prese nte d i n t he la b test ta ble ( Ta ble B
P P D
) bel o w.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 1 of 4 8
T a ble B
L a b or at or y Tests
H e m at ol o g y
C he mistr y
C o a g ul ati o n
Uri n al ysis
H e m o gl o bi n
Al b u mi n
Pr ot hr o m bi n Ti me 
Ur Bl o o d *
H e m at ocrit
Al kali ne P h os p hatase
Pr ot hr o m bi n I ntl. 
N or malize d Rati o (I N R)
Ur Gl uc ose *
Platelets
Ala ni ne A mi n otra nsferase 
( A L T)
Ur Micr osc o pic *
Er yt hr oc ytes
As partate 
A mi n otra nsferase ( A S T)
Ur P H
R B C M or p h ol o g y *
A m ylase
Ur Os m olalit y
Le u k oc ytes
Li pase
Ur Pr otei n
Ne utr o p hils
Bicar b o nate
Ur S o di u m
L y m p h oc ytes
Bilir u bi n
Ur S pecific Gra vit y
M o n oc ytes
Direct Bilir u bi n
E osi n o p hils
I n direct Bilir u bi n
Bas o p hils
Bl o o d Urea Nitr o ge n
Ne utr o p hils/ Le u k oc ytes
Calci u m
L y m p h oc ytes/ Le u k oc ytes
C hl ori de
M o n oc ytes/ Le u k oc ytes
C h olester ol
E osi n o p hils/ Le u k oc ytes
Creati ni ne
Bas o p hils/ Le u k oc ytes
C Reacti ve Pr otei n
Gl o m er ular Filtrati o n Rate 
( G F R)
Gl uc ose
Ga m ma Gl uta m yl 
Tra nsferase ( G G T)
Li pase
Ma g nesi u m
P h os p h or us
P otassi u m
S o di u m
Tri gl yceri des
Uric Aci d
P P D
N ote: * la b tests wit h cate g orical res ults.
L a b data will be prese nte d i n SI u nits. T he s u m maries will be base d o n ce ntral la b res ults o nly.
Q ua ntitati ve la b orat or y meas ure me nts 
re p orte d as “ < X”, i.e. bel o w t he l o wer li mit of 
q ua ntificati o n ( B L Q), or “ > X”, i.e. a b o v e t he u p per li mit of q ua ntificati o n ( U LQ), will be 
c o n verte d t o X f or t he p ur p ose of q ua ntitati ve s u m maries, b ut will be prese nte d as rec or de d, i.e. 
as “ < X” or “ > X” i n t he listi n gs.
T he f oll o wi n g s u m maries will be pr o vi de d f or he mat ol o g y , cli nical c he mistr y an d selecte d 
uri nal y sis la b orat or y data wit h q ua ntitati ve res ults:


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 2 of 4 8

Act ual a n d c ha n ge fr o m baseli ne b y sc he d ule d site visit 

S hift fr o m baseli ne acc or di n g t o n or mal ra n ge criteria at eac h sc he d ule d p ost -baseli ne 
site visit

I nci de nce of mar ke dl y a b n or mal val ues acc or di n g t o criteria defi ne d i n secti o n 
A p pe n di x 3

Listi n g of s u bjects meeti n g mar ke dl y a b n or mal criteria
1 9. 2. 1.
L A B O R A T O R Y R E F E R E N C E R A N G E S A N D M A R K E DL Y A B N O R M AL C RI T E RI A
Q ua ntitati ve la b orat or y meas ure me nts will be c o m pare d wit h t he rele va nt la b orat or y refere nce 
ra n ges i n SI u nits a n d cate g orize d as:

L o w: Bel o w t he l o wer li mit of t he la b orat or y  refere nce ra n ge. 

N or mal: Wit hi n t he la b orat or y  refere nce ra n ge ( u p per a n d l o wer li mit i ncl usi ve).

Hi g h: A b o ve t he u p per li mit of t he la b orat or y  refere nce ra n ge.
I n a d diti o n t o t he hi g h a n d l o w q ua ntitati ve la b orat or y assi g n me nts (as i de ntifie d b y  mea ns of 
t he la b orat or y refere nce ra n ges), mar ke dl y a b n or mal q ua ntitati ve safety (a n d ot her) la b orat or y 
assess me nts will als o be i de ntifie d i n acc or da nce wit h t he pre defi ne d mar ke dl y a b n or mal 
criteria as prese nte d i n A p pe n di x 3 . 
T he n u m ber a n d perce nta ge of s u bjects w h ose p ost -baseli ne res ults q ualif y i n g as mar ke dl y 
a b n or mal will be s u m marize d b y  treat me nt gr o u p a n d t he para meter. A listi n g will pr ese nt all 
val ues f or a s u bject a n d la b orat or y para meter if at least o ne p ost -baseli ne val ue f or t hat s u bject 
a n d para meter is mar ke dl y a b n or mal.
La b orat or y  res ults will als o be i ncl u de d i n a p pe n di x data listi n gs f or eac h la b pa nel (c he mistr y, 
he mat ol o g y , c oa g ulati o n a n d uri nal ys is) b y  treat me nt, s u bject, visit a n d para meter. Val ues 
o utsi de t he n or mal ra n ge will be fla g ge d. L ocal la b test res ults wi ll o nl y  be prese nte d i n 
a p pe n di x data listi n gs. Cate g orical test res ults, c oa g ulati o n a n d pre g na nc y  res ults ( B-h C G, 
Q ualitati ve a n d B -h C G, Q ua ntitati ve) als o will o nl y  be i ncl u de d i n data listi n gs. 
1 9. 3.
A N TI B O DI E S T O T E D U GL U TI D E
P P D
T he n u m ber a n d perce nt of s u bjects wit h a n a nti b o d y fi n di n g ( A nti b o dies t o Te d u gl uti de 
Ne gati ve/ P ositi ve, Ne utralizi n g A nti b o dies Prese nt/ N o Ne utralizi n g A nti b o dies Prese nt) will 
be s u m marize d at baseli ne, E O T a n d E O S. N o n -s pecific a nti b o dies will be cate g orize d as 
Ne gati ve.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 3 of 4 8
T he f oll o w-u p a nti b o d y  assess me nts after st u d y co m pleti o n will n ot be tra nsferre d fr o m t he la b 
ve n d or f or a n y statistical a nal ys is. 
1 9. 4.
G A S T R OI N T E S TI N AL - SP E CI FI C T E S TI N G
GI -s pecific testi n g will be re p orte d f or t he te d u gl uti de treat me nt ar m o nl y . T he cli nicall y 
si g nifica nt a b n or mal res ults will 
be prese nte d i n a data listi n g. T he res ults of u p per 
gastr oi ntesti nal ( GI) series wit h s mall b o wel f oll o w t hr o u g h, a b d o mi nal ultras o u n d, a n d 
c ol o n osc o p y or si g m oi d osc o p y will be re p orte d as ‘ N or mal’, ‘ A b n or mal, n ot cli nicall y 
si gnifica nt’, or ‘ A b n or mal, cli nicall y si gnifica nt’ . Fecal occ ult bl o o d testi n g will be re p orte d as 
‘ Ne gati ve’, ‘ P ositi ve, n ot cli nicall y si g nifica nt’, ‘ P ositi ve, cli nicall y si g nifica nt’.
1 9. 5.
P H Y SI C AL E X A MI N A TI O N 
P h y sical e xa mi nati o n dates a n d reas o n t hat a n e xami nati o n was n ot d o ne will be prese nte d i n 
data listi n gs.  An y  cli nicall y si gnifica nt fi n di n gs f or p h y sical e xa mi nati o n are rec or de d as 
a d verse e ve nts. 
1 9. 6.
V I T AL S I G N S
T he f oll o wi n g vital si g ns meas ure me nts will be re p orte d f or t his st u d y :

S y st olic Bl o o d Press ure ( m m H g)

Diast olic Bl o o d Press ure ( m m H g)

P ulse Rate ( b p m)

Te m perat ure (° C)

Wei g ht ( k g)

Hei g ht or le n gt h (c m) 

Hea d circ u mfere nce (c m) f or s u bjects ≤ 3 6 m o nt hs of a ge
T he f oll o wi n g vital si g ns para meters will be deri ve d f or t his st u d y :

B MI ( k g/ m 2)

Hei g ht Z- sc ore

Wei g ht Z -sc ore

P P D
B MI Z -sc ore


D oc u m e nt: 
\\ q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\ S hir e\T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4 -0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 4 of 4 8

Hea d circ u mfere nce Z -sc ore f or s u bjects ≤ 3 6 m o nt hs of a ge
Descri pti ve statistics will be use d t o s u m marize vital si g ns meas ure me nts 
a n d deri ve d 
para meters i n act ual val ue a n d c ha n ge fr o m baseli ne f or eac h treat me nt gr o u p b y  age gr o u p 
(a ge stratificati o n use d f or ra n d o mizati o n: < 1 year, 1 -< 1 2 ye ars, 1 2 -< 1 7 ye ars a n d 1 7 -< 1 8 ye ars 
a n d o verall) at st u d y site visits (i ncl u di n g E O T) w here  ass ociate d para meters are c ollecte d. Z -
sc ores of vital si g ns by site visits will be pres e nte d i n b o x pl ots. A listi n g will als o be pr o vi de d.
1 9. 6. 1.
V I T AL S I G N S S P E CI FI C D E RI V A TI O N S 

B MI
B MI = 1 0 0 0 0 * B o d y wei g ht ( k g)/ b o dy hei g ht (c m) 2, w here b ot h b o d y  wei g ht a n d b o d y  
hei g ht data are a vaila ble at t he sa me sc he d ule d visit 

Hei g ht, Wei g ht, Hea d Circ u mfere nce a n d B MI Z -sc ores
Official a n d vali date d S A S pr o gra ms create d b y  Ce nters f or Disease C o ntr ol a n d 
Pre ve nti o n ( C D C) will be use d t o calc ulate t he Z- sc ores (sta n dar d de viati o ns) f or a 
c hil d’s se x a n d a ge ( u p t o 2 0 years of a ge) f or B MI, wei g ht, h ei g ht, a n d hea d 
circ u mfere nce base d o n t he C D C gr o wt h c harts f or c hil dre n a ge 2 ye ars a n d ol der a n d 
t he W H O gr o wt h c harts f or i nfa nts a n d c hil dre n < 2 years of a ge. F or m ore i nf or mati o n 
o n 
t he 
C D C 
S A S 
pr o gra ms, 
see 
htt p:// w w w.c dc. g o v/ gr o wt hc harts/c o m p uter _ pr o gra ms. ht m .
Z- sc ores are calc ulate d as t he f or m ula bel o w:
Z- sc ore = [(( o bser ve d val ue / M) ^ L) – 1] / ( S * L)
I n w hic h ‘ o bser ve d val ue’ is t he c hil d’s hei g ht, wei g ht, hea d circ u mfere nce or deri ve d 
B MI. T he L, M, a n d S val ues var y  acc or di n g t o t he c hil d ’s se x a n d a ge. F or m ore 
i nf or mati o n 
o n 
t he 
L M S 
met h o d, 
see htt p:// w w w. nc bi. nl m. ni h. g o v/ p mc/articles/ P M C 2 7 3 6 5/ .
1 9. 7.
E C G E V AL U A TI O N S
Electr ocar di o gra m ( E C G) res ults wit h descri pti o n of a n y  fi n di n gs will be rec or de d i n t he e C R F. 
T he f oll o wi n g E C G para meters will be re p orte d f or t his st u d y :

O verall assess me nt of E C G (I n vesti gat or’s j u d g me nt):
N or mal
o
A b n or mal, N ot Cli nicall y Si g nifica nt ( A N C S)
P P D
o


D oc u m e nt: 
\\ q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\ S hir e\T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4 -0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 5 of 4 8
A b n or mal, Cli nicall y  Si g nifica nt ( A C S)
o
T he f oll o wi n g s u m maries will be pr o vi de d f or E C G data b y  treat me nt gr o u p at baseli ne , wee k 
1 2, wee k 2 4 a n d E O T:

I nci de nce of N or mal, A N C S a n d A C S

Listi n g of all E C G descri pti o ns f or s u bjects meeti n g A C S criteria
1 9. 8.
F E C AL A N D U RI N E O U T P U T
Uri ne a n d st o ol o ut p ut data is rec or de d o ver a 4 8 h o ur peri o d of P N/I V a n d E N sta bilit y b ef ore 
e ver y sc he d ule d site visit a n d wit hi n 1 wee k of i m ple me nti n g a n y P N/I V prescri pti o n 
a dj ust me nt. 
T he a vera ge dail y uri ne o ut p ut ( m L/ k g/ da y) at t he sc he d ule d site visit will be calc ulate d as 
f oll o ws:
( T otal uri ne o ut p ut o ver 4 8 h o urs / 2) / b o d y wei g ht ( k g) at t he sche d ule d visit
w here t otal uri ne o ut p ut is calc ulate d as t he s u m of t he uri ne o ut p ut i n m L  an d t he uri ne -o nl y 
dia per wei g hts i n g ( 1 g = 1 m L) f or t he s u bject c ollecte d o n t he o ut p ut diar y  for m of e C R F. 
Val ues will n ot be calc ulate d if t he uri ne o ut p ut is n ot a vaila ble at t he visit. If t he b o d y  wei g ht 
at t he sc he d ule d visit is missi n g, t he last a vaila ble wei g ht assess me nt will be use d. 
T he a vera ge dail y fecal o ut p ut will be s u m marize d se parately b y  the a vera ge n u m ber of st o ols 
per d a y , t he a vera ge t ypical st o ol f or m sc ore usi n g Brist ol St o ol F or m Scale, t he a vera ge t otal 
dail y  st o ol/ mi xe d st o ol dia per wei g ht ( g/ k g/ da y) a n d t he a vera ge ost o m y  out p ut per da y 
( m L/ k g/ da y) f or eac h visit . T he a vera ge n u m ber of st o ols per da y  an d t he a vera ge t ypical st o ol
f or m sc ore will be calc ulate d as (s u m of t he dail y  data i n a 4 8 -h o ur peri o d / 2). T he b o d y 
wei g ht will be use d t o calc ulate t he dail y  st o ol/ mi xe d st o ol dia per wei g ht ( g/ k g/ da y) a n d t he 
t otal ost o m y  out p ut per da y  (m L / k g/ da y) usi n g t he sa me f or m ula as we u se f or calc ulate t he 
a vera ge dail y uri ne o ut p ut.
T he c ha n ge a n d t he perce nt c ha n ge i n a vera ge dail y  out p ut f or st o ol a n d uri ne fr o m baseli ne t o 
eac h sc he d ule d visit, as well as at E O T, will be prese nte d b y  treat me nt gr o u p usi n g descri pti ve 
statistics. T he c ha n ge a n d t he perce nt c ha n ge i n a vera ge dail y o ut p ut f or fecal a n d uri ne o ut p ut 
fr o m baseli ne t o eac h sc he d ule d visit, as well as at E O T, will be prese nte d b y  treat me nt gr o u p 
usi n g descri pti ve statistics. A listi n g will als o be pr o vi de d.
2 0.
D A T A N O T S U M M A RI Z E D O R P R E S E N T E D
P P D
Ot her t ha n select fiel ds t hat ca pt ure reas o n a n assess me nt is n ot d o ne, all c o m me nts a n d 


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 6 of 4 8
P P D
s pecifie d te xt fiel ds ca pt ure d i n t he e C R F will be dis pla y e d i n a p pe n di x listi n gs o nl y . T hese 
varia bles will n ot be s u m marize d or prese nte d, b ut will b e a vaila ble i n t he cli nical st u d y 
data base, S D T M a n d/ or A Da M datasets.
Ot her data c ollecte d i n e C R F, I V R S s yste m or a n y ot her cli nical trial data c ollecti o n s yste m 
w hic h is n ot descri be d a b o ve will be prese nte d i n t he a p pe n di x listi n gs, s uc h as ra n d o mizati o n 
i nf or mati o n, I E criteria n ot met a n d pr oce d ures.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 7 of 4 8
A P P E N DI X 1.
P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S
S HI R E O U T P U T S T A N D A R D S – T FL S4 S HI R E F I N ALV 6. 0
O ut p uts will be prese nte d acc or di n g t o S hire o ut p ut sta n dar ds d oc u me nt T F Ls 4 S hire Fi nal V 6. 0. 
Ge neral c o nsi derat i o ns w hic h are a p plica ble t o t he st u d y are s u m marize d as f oll o wi n g:

S T A TI S TI C S P R E S E N T A TI O N
F or t he b y -ti me-p oi nt ta bles, t he n u m ber of s u bjects at eac h ti me p oi nt ( n) re prese nts t he 
n u m ber t hat ha d a vali d res ult f or a gi ve n para meter at t hat ti me p oi nt.
T h e defa ult s u m mar y statistics prese nte d i n t he T F Ls 4 S hire ta ble s hells f or c o nti n u o us 
varia bles i ncl u de n, mea n, 
sta n dar d de viati o n, me dia n, 
mi ni m u m, 
a n d ma xi m u m. 
F or 
cate g orical varia bles, t he c o u nt ( n) a n d perce nt ( %) are t he defa ult statistics; u nless ot her wise 
state d or t he ass ociate d n u m ber of s u bjects f or t he c orres p o n di n g ti me p oi nt is pr o vi de d, t he 
de n o mi nat or f or perce nta ges is N (t he n u m ber of s u bjects i n t he treat me nt gr o u p/a nal ys is set).  
N ote t hat f or a n y s u m mar y by s u b gr o u ps (e. g., b y  se x), t he de n o mi nat or is t he n u m ber of 
s u bjects i n t hat s u b gr o u p/treat me nt gr o u p/a nal ys is set.  For m ost safety ta bles t he st u d y tea ms 
s h o ul d use t he defa ult statistics; t he st u d y tea m s h o ul d caref ull y c o nsi der a n d gi ve s ufficie nt 
j ustificati o n pri or t o re q uesti n g t he use of ot her s u m mar y statistics.  Perce nta ges will be 
re p orte d t o 1 deci mal place, e xce pt w he n t he perce nta ge e q uals e xactl y 10 0 w here it will be 
dis pla y e d as a n i nte ger ( 1 0 0).  F or zer o, o nl y c o u nt a n d n o perce nta ge will be dis pla y e d.

A LI G N M E N T
P P D
O ut p ut s h o ul d be ali g ne d s o t hat i n t he b o d y  of t he ta ble, w here a p plica ble, te xt is left-j ustifie d 
wit hi n a cell, stats o ut p ut is ali g ne d ce ntrall y wit hi n a cell a n d li ne d u p b y deci mal p oi nt.
Ha n dli n g of missi n g val ues:  I n listi n gs, missi n g val ues f or n u merical data will be re p orte d as a 
peri o d “.” a n d missi n g val ues f or c haracter data as a bla n k “ ”.  In t he s u m mar y ta bles f or 
cate g orical data, “ Missi n g” will al wa ys be dis pla y e d as a cate g or y to re prese nt missi n g data, 
w here a p plica ble.  The defa ult de n o mi nat or will be all s u bjects i n t he a nal ysis set u nless 
ot her wise s pecifie d i n t he S A P.  For b ot h ta bles a n d listi n gs w here t here are n o o bser vati o ns 
(a n d he nce t here w o ul d be n o o ut p ut), t he ta ble/listi n g s h o ul d be pr o d uce d wit h all titles a n d 
f o ot n otes as per its s hell, b ut wit h t he te xt s h o wi n g n o o bser vati o ns i n t he b o d y of t he o ut p ut.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 8 of 4 8

D E CI M AL P L A C E S A N D R O U N DI N G R UL E S
o
F or meas ures of me dia n a n d mea n, use 1 deci mal place b e y o n d t h ose use d f or t he 
meas ure me nt.
o
F or meas ures of sta n dar d de viati o n a n d sta n dar d err or, use 2 deci mal places b e y o n d 
t h ose use d f or t he meas ure me nt.
o
F or meas ures of mi ni m u m a n d ma xi m u m val ues, use t he sa me n u m ber of deci mal 
places as t h ose use d f or t he meas ure me nt.
o
≥5 is r o u n de d u p a wa y fr o m zer o, w hereas < 5 is r o u n de d d o w n t o war d zer o t o acc o u nt 
f or r o u n di n g of ne gati ve n u m bers.
o
B MI s h o ul d be r o u n de d t o 1 deci mal place f or re p orti n g.
o
Deri ve d 
q uesti o n naire sc ores, a n d ot her si milar efficac y para meters rec or de d as 
i nte gers, s h o ul d be r o u n de d t o 1 deci mal place f or re p orti n g.
o
A vera ge d la b res ults e. g. Diast olic/ S y st olic Bl o o d Press ure a n d P ulse ( w he n ta ke n i n 
tri plicate) s h o ul d be r o u n de d t o 1 deci mal place f or re p orti n g.

P R E S E N T A TI O N O F T R E A T M E N T G R O U P S
P P D
Ta bles will be or ga nize d b y  asce n di n g or der of S hire dr u g treat me nt d ose le vels, f oll o we d b y  
all d oses of S hire dr u g, t he n f oll o we d b y  the sta n dar d of care at t he e n d e. g., 0. 0 2 5 m g/ k g/ da y 
Te d u gl uti de, 0. 0 5 m g/ k g/ da y  Te d u gl uti de, T otal Te d u gl uti de, Sta n dar d of Care. If t he n u m ber 
of treat me nt gr o u ps dictates t hat n ot all ca n fit o n 1 pa ge, the n, u nless s pecifie d i n t he 
c orres p o n di n g “ Ge neral c o nsi derati o ns”, it will be left t o t he discreti o n of t he s hell a ut h or, 
f oll o wi n g disc ussi o ns wit h st u d y tea m, as t o h o w t hese will be prese nte d.  For e xa m ple, s o me 
of t he treat me nt gr o u ps ma y  be prese nte d i n a se parate ta ble.  If t he st u d y is t o be s u m marize d 
b y  dose gr o u p rat her t ha n treat me nt gr o u p, t he n t he n o me nclat ure “ Act ual D ose” will be use d 
i n place of “ Treat me nt Gr o u p” t hr o u g h o ut. If prese nti n g s u b gr o u ps, T F L 4 S hire rec o m me n ds 
t hat s u b-hea ders ar e a d de d s o t hat a ta b ulati o n is re peate d b y s u b gr o u p (rat her t ha n a d di n g e xtra 
c ol u m ns i n t he ta ble t o s h o w t he s u b gr o u ps). T hese s h o ul d be or dere d per t he C R F dec o de e. g. 
1 = Male, 2 = Fe male. 
W he n re q uire d, a c ol u m n f or c o m bi ne d acti ve a n d c o m parat or statistics will be i ncl u de d a n d it 
will be la bele d “ T otal”.  By defa ult, t his c ol u m n has o nl y bee n i ncl u de d i n t he dis p ositi o n, 
de m o gra p hics, a n d i m p orta nt pr ot oc ol de viati o ns T F L s hells.  Use i n a n y ot her d o mai ns s h o ul d 
be caref ull y disc usse d wit h t he st u d y tea m.


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 3 9 of 4 8
A P P E N DI X 2.
P A R TI A L D A T E C O N V E N TI O N S
I m p ute d dates will N O T be prese nte d i n t he listi n gs. T he first d ose date f or te d u gl uti de gr o u ps 
a n d t he date of baseli ne visit f or sta n dar d of care treat me nt gr o u p will be treate d as t he 
refere nce start date, a n d t he last d osi n g date or t he date of last visit f or sta n dar d of care gr o u p 
d uri n g t he 2 4 - wee k treat me nt peri o d will be treate d as t he refere nce e n d date. 
IM P U T A TI O N O F P A R TI AL A E D A T E S
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
K n o w n
Partial
If A E start year a n d m o nt h are k n o w n, i m p ute st o p date as 
latest p ossi ble date (t hat is t he last d a y  of t he m o nt h if da y 
is u n k n o w n or 3 1 st Dece m ber 
if d a y  an d m o nt h 
are 
u n k n o w n).
Missi n g
If A E st o p date is u n k n o w n lea ve as missi n g.
Partial
K n o w n
If A E start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date if A E st o p date > t he refere nce start 
date;
Else if A E start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d year of t he i nf or me d c o nse nt: I m p ute start date 
as t he i nf or me d c o nse nt date if A E start year a n d m o nt h < 
t he year a n d m o nt h of t he refere nce start date;
Else if A E start year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d 
c o nse nt: Im p ute start date as t he first da y  of t he m o nt h;
Else if o nl y  AE start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: I m p ute start date as t he refere nce start 
date if A E st o p date > t he refe re nce start date;
Else if o nl y  AE start year is k n o w n a n d is after year of t he 
refere nce start date: I m p ute start date as t he first da y  of t he 
ye ar ( 1 st Ja n uar y).
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 0 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
Partial
If A E start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date if A E st o p ye ar a n d m o nt h are k n o w n 
a n d > = t he ye ar a n d m o nt h of t he refere nce start date Or If 
o nl y  AE st o p ye ar is k n o w n a n d > = ye ar of t he refere nce 
start date;
Else if A E start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d year of t he i nf or me d c o nse nt: I m p ute start date 
as t he i nf or me d c o nse nt date if A E start year a n d m o nt h < 
t he year a n d m o nt h of t he refere nce start date;
Else if A E start year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d 
c o nse nt: Im p ute start date as t he first da y  of t he m o nt h;
Else if o nl y  AE start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: I m p ute start date as t he refere nce start 
date if A E st o p year a n d m o nt h are k n o w n a n d > = t he year 
a n d m o nt h of t he refere nce start date Or If o nl y A E st o p 
ye ar is k n o w n a n d > = year of t he refere nce start date;
Else if o nl y  AE start year is k n o w n a n d is after year of t he 
refere nce start date: I m p ute start date as t he first da y  of t he 
ye ar ( 1 st Ja n uar y).
I m p ute st o p date as latest p ossi ble date (t hat is t he last da y 
of t he m o nt h if d a y  is u n k n o w n or 3 1 st Dece m ber if da y 
a n d m o nt h are u n k n o w n).
Missi n g
If A E start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date;
Else if A E start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d year of t he i nf or me d c o nse nt: I m p ute start date 
as t he i nf or me d c o nse nt date if A E start year a n d m o nt h < 
t he year a n d m ont h of t he refere nce start date;
Else if A E start year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d 
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 1 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
c o nse nt: Im p ute start date as t he first da y  of t he m o nt h;
Else if o nl y  AE start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: I m p ute start date as t he refere nce start 
date;
Else if o nl y  AE start year is k n o w n a n d is after year of t he 
refere nce start date: I m p ute start date as t he first da y  of t he 
ye ar ( 1 st Ja n uar y).
If A E st o p date is u n k n o w n lea ve as missi n g.
Missi n g
K n o w n
If A E start date is u n k n o w n lea ve as missi n g; e ve nt will be 
c o nsi dere d 
treat me nt-e mer ge nt if st o p date 
> = 
t he 
refere nce start date.
Partial
If A E start date is u n k n o w n lea ve as missi n g; e ve nt will be 
c o nsi dere d treat me nt-e mer ge nt if st o p date partial st o p date 
> = sa me partial p orti o ns of t he refere nce start date
Missi n g
If A E start or st o p date is u n k n o w n lea ve as missi n g; e ve nt 
will be c o nsi dere d treat me nt-e mer ge nt.
IM P U T A TI O N O F P A R TI AL M E DI C A TI O N D A T A
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 2 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
K n o w n
Partial
If me dicati o n st o p year a n d m o nt h are k n o w n a n d t he refere nce e n d 
date d uri n g t hat m o nt h a n d ye ar: I m p ute st o p date as t he refere nce 
e n d date if me dicati o n start date < = t he refere nce e n d date;
Else if me dicati o n st o p year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d year of t he refere nce start date: I m p ute st o p date as t he 
last da y of t he m o nt h;
Else if o nl y me dicati o n st o p ye ar is k n o w n a n d is t he ye ar of t he 
refere nce e n d date: I m p ute st o p date as t he refere nce e n d date if 
me dicati o n start date < = t he refere nce e n d date;
Else if o nl y  me dicati o n st o p ye ar is k n o w n a n d is pri or t o t he ye ar 
of t he refere nce e n d date: I mp ute st o p date as t he last da y  of t he 
ye ar ( 3 1 st Dece m ber).
Missi n g
If me dicati o n st o p date is u n k n ow n lea ve as missi n g.
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 3 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
Partial
K n o w n
If me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date if me dicati o n st o p date > t he refere nce start 
date;
Else if me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d ye ar of t he i nf or me d c o nse nt: I mp ute start date as t he 
i nf or me d c o nse nt date if me dicati o n start year a n d m o nt h < t he 
ye ar a n d m o nt h of t he refere nce start date;
Else if me dicati o n start yea r a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d c o nse nt: 
I m p ute start date as t he first da y of t he m o nt h;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: I m p ute start dat e as t he refere nce start date if 
me dicati o n st o p date > t he refere nce start date;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is t he year of t he 
i nf or me d c o nse nt date: I m p ute start date as t he i nf or me d c o nse nt 
date if me dicati o n start year < t he year o f t he refere nce start date;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is after ye ar of t he 
refere nce start date: I m p ute start date as t he first da y of t he year ( 1 st
Ja n uar y).
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 4 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
Partial
If me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date if me dicati o n st o p ye ar a n d m o nt h are k n o w n 
a n d > = t he year a n d m o nt h of t he refere nce start date Or If o nly A E 
st o p year is k n o w n a n d > = year of t he refere nce start date;
Else if me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d ye ar of t he i nf or me d c o nse nt: I mp ute start date as t he 
i nf or me d c o nse nt date if me dicati o n start year a n d m o nt h < t he 
ye ar a n d m o nt h of t he refere nce start date;
Else if me dicati o n start year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d c o nse nt: 
I m p ute start date as t he first da y of t he m o nt h;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: I m p ute start date as t he refere nce start date if 
me dicati o n st o p ye ar a n d m o nt h are k n o w n a n d > = t he ye ar a n d 
m o nt h of refere nce start date Or If o nl y A E st o p y ear is k n o w n a n d 
> = ye ar of refere nce start date;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is after ye ar of t he 
refere nce start date: I m p ute start date as t he first da y  of t he ye ar 
( 1st Ja n uar y).
If me dicati o n st o p year a n d m o nt h are k n o w n a n d st u d y dr u g 
st o p pe d d uri n g t hat m o nt h a n d year: I m p ute st o p date as t he st o p 
date of st u d y  dr u g if me dicati o n start date < = t he st o p date of st u d y 
dr u g;
Else if me dicati o n st o p year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d year of t he refere nce start date: I m p ute st o p date as t he 
last da y of t he m o nt h;
Else if o nl y me dicati o n st o p ye ar is k n o w n a n d is t he ye ar of t he 
refere nce e n d date: I m p ute st o p date as t he refere nce e n d date if 
me dicati o n start date < = t he refere nce e n d date;
Else if o nl y  me dicati o n st o p ye ar is k n o w n a n d is pri or t o t he ye ar 
of t he refere nce e n d date: I mp ute st o p date as t he last da y  of t he 
ye ar ( 3 1st Dece m ber).
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 5 of 4 8
S T A R T
D A T E
S T O P 
D A T E
A C TI O N
Missi n g
If me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he m o nt h 
a n d ye ar of t he refere nce start date: I m p ute start date as t he 
refere nce start date;
Else if me dicati o n start ye ar a n d m o nt h are k n o w n a n d it is t he 
m o nt h a n d ye ar of t he i nf or me d c o nse nt: I mp ute start date as t he 
i nf or me d c o nse nt date if me dicati o n start year a n d m o nt h < t he 
ye ar a n d m o nt h of t he refere nce start date;
Else if me dicati o n start year a n d m o nt h are k n o w n a n d are n ot t he 
m o nt h a n d ye ar of t he refere nce start date or i nf or me d c o nse nt: 
I m p ute start date as t he first da y of t he m o nt h;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is t he year of t he 
refere nce start date: Im p ute start date as t he refere nce start date;
Else if o nl y  me dicati o n start ye ar is k n o w n a n d is after ye ar of t he 
refere nce start date: I m p ute start date as t he first da y of t he year ( 1 st
Ja n uar y).
If me dicati o n st o p date is u n k n o w n lea ve as missi n g.
Missi n g
K n o w n
If me dicati o n st o p date is u n k n o w n lea ve as missi n g.
Partial
If me dicati o n st o p date is u n k n o w n lea ve as missi n g.
Missi n g
If me dicati o n st o p date is u n k n o w n lea ve as missi n g.
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 6 of 4 8
A P P E N DI X 3.
M A R K E D L Y A B N O R M A L L A B O R A T O R Y C RI T E RI A  
L a b P ar a meter
U nit
L o wer 
Li mit 
Criteri a
U p per 
Li mit 
Criteri a
C he mistr y
Al b u mi n 
g/ L
< 2 0
> 6 8
Al kali ne P h os p hatase 
U/ L
> 5 x U L N
Ala ni ne A mi n otra nsferase 
( A L T)
U/ L
> 8 x U L N
As partate 
A mi n otra nsferase ( A S T)
U/ L
> 8 x U L N
A m y lase
U/ L
> 3 x U L N
Li pase
U/ L
> 3 x U L N
Bilir u bi n T otal
u m ol/ L
> 3 x U L N
Direct Bilir u bi n
u m ol/ L
> 3 4. 2 0 8
Bl o o d Urea Nitr o ge n 
m m ol/ L
> 1 2. 4 9 5
Calci u m 
m m ol/ L
< 1. 5
> 3
Creati ni ne
u m ol/ L
> 1 3 2. 6 if a ge < 1 0 
y;
> 1 5 0. 2 8
if a ge 1 0-
< 1 3 y ;
> 1 7 6. 8 if a ge 1 3 -
< 1 6 y ;
> 2 2 1 if a ge 1 6 +
C Reacti ve Pr otei n 
m g/ L
> = 1 0 0
Gl uc ose
m m ol/ L
< 2. 2 2
> 1 3. 8 7 5
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 7 of 4 8
Ma g nesi u m 
m m ol/ L
< 0. 4 1 1 4
> 1. 2 3 4 2
P h os p h or us 
m m ol/ L
< 0. 6 4 4
> 2. 2 5 4
P otassi u m 
m m ol/ L
< 2. 5
> 6. 5
S o di u m 
m m ol/ L
< 1 2 0
> 1 6 0
Tri gl yc eri des 
m m ol/ L
> 5. 6 5
He m at ol o g y
He m o gl o bi n 
g/ L
< 7 0
> 2 0 0
He mat ocrit 
fracti o n of 1
< 0. 2 1
> 0. 6 0
Platelets 
1 0 ^ 9/ L
< 7 5
> 7 0 0
Le u k oc y tes 
1 0 ^ 9/ L
< 2
> 3 0
Ne utr o p hils, a bs ol ute
1 0 ^ 9/ L
< 0. 5
P P D


D oc u m e nt:
\\q ui ntil es. n et \E nt er pris e \A p ps \s as d at a\S A S a \s as\S hir e \T e d u gl uti d e \Bi ost atistics \D oc u m e nt ati o n \S A P \T E
D- C 1 4- 0 0 6 _ S A P _ Fi n al _ V 1. 0 _ 2 0 1 7 0 7 1 4
A ut h or:
V ersi o n N u m b er:
Fi n al V 1. 0
V ersi o n D at e:
1 4J ul 2 0 1 7
T e m pl at e N o: C S _ T P _ B S 0 1 6 – R e visi o n 3
R ef er e nc e: C S _ WI _ B S 0 0 5
Eff ecti v e D at e: 0 1 M a y 2 0 1 2
C o p yri g ht © 2 0 1 2 Q ui ntil e s Tr a n s n ati o n al C or p. All ri g ht s r e s er v e d.
T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y t o Q ui ntil e s Tr a n s n ati o n al C or p. U n a ut h ori z e d u s e, di s cl o s ur e or 
r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S T A TI S TI C AL A N AL Y SI S PL A N: P R O T O C OL T E D -C 1 4 -0 0 6
P a g e 4 8 of 4 8
A P P E N DI X 4.
T A B L E , FI G U R E A N D D A T A L I S TI N G S H E L L S
T A BL E A N D F I G U R E S H ELL S
See se parate file.
D A T A L I S TI N G S H ELL S
P P D
See se parate file.

Prot_003.pdf: 
A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic 
Study Investigating Two Doses of Teduglutide in Pediatric Subjects 
Through 17 Years of Age with Short Bowel Syndrome who are 
Dependent on Parenteral Support
Clinical Study Protocol TED-C14-006
Version 5.0
Phase 3
US IND# 058213 
US NDA# 203441
EuDRACT #2015-002252-27
NPS Pharmaceuticals, Inc.*
300 Shire Way Lexington, MA 02421 USA
(*NPS Pharmaceuticals was acquired by Shire, Inc on 21 February 2015)
ISSUED:
Amendment 4, version 5.0
15 March 2016
Amendment 3, version 4.0
25 February 2016
Amendment 2, version 3.0
06 October 2015
Amendment 1, version 2.0:
22 June 2015
Original Protocol version 1.0:
12 March 2015
SPONSOR
NPS Pharmaceuticals, Inc.*
300 Shire Way Lexington, MA 02421 USA
(*NPS Pharmaceuticals was acquired by Shire, Inc on 21 February 2015)


S hire
C o nfi de nti al
P a ge 2
Pe di atric St u d y T E D -C 1 4 -0 0 6 – A m e n d me nt 4
Versi o n 5. 0 / 1 5 M ar 2 0 1 6
K E Y S P O N S O R C O N T A C T S

Q ui ntiles Me dic al S u p p ort
, M D –
P H :
 ( me dical emer ge ncies – U S & Ca na da)
P H :
 (me dical e mer ge ncies – gl o bal)

S hire Me dic al M o nit or
, M D, P h D –
P H :
( M-F, 9 a m t o 5 p m E S T)
Fa x:
T O R E P O R T A S E RI O U S A D V E R S E E V E N T :
Gl o b al P h ar m ac o vi gil a nce a n d Ris k M a n a ge me nt
P P D
Sca n a n d e -mail:
Fa x:
 ( Gl o bal)
Fa x:
 ( N ort h A merica)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire
C o nfi de nti al
P a ge 3
Pe di atric St u d y T E D -C 1 4 -0 0 6 – A m e n d me nt 4
Versi o n 5. 0 / 1 5 M ar 2 0 1 6
P R O D U C T Q U A LI T Y C O M P L AI N T S
I n vesti gat ors are re q uire d t o re p ort i n vesti gati o nal pr o d uct q ualit y c o m plai nts t o S hire wit hi n 
2 4 h o urs. T his i ncl u des a n y  i nsta nces w herei n t he q ualit y or perf or ma nce of a S hire pr o d uct 
( mar kete d or i n vesti gati o nal) d oes n ot meet e x pectati o ns (e g, i na de quate or fa ult y  cl os ure, 
pr o d uct c o nta mi nati o n) or t hat t he pr o d uct di d n ot meet t he s pecificati o ns defi ne d i n t he 
a p plicati o n f or t he pr o d uct (e g, wr o n g pr o d uct s uc h t hat t he la bel a n d c o nte nts are differe nt 
pr o d ucts).  F or i nstr ucti o ns o n re p orti n g A Es re late d t o pr o d uct c o m plai nts, see Secti o n 6. 3.
Please use t he i nf or mati o n bel o w as a p plica ble t o re p ort t he Pr o d uct Q ualit y C o m plai nt:
Ori gi n of Pr o d uct Q ualit y C o m plai nt
E- mail A d dress
U nite d States
Rest of W orl d
P P D
Tele p h o ne n u m bers ( pr o vi de d f or refere nce):   
 S hire ( U S A)
P P D
P P D


Shire
Confidential
Page 4
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
SYNOPSIS
Protocol TED-C14-006
Title of Study: A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Protocol No: TED-C14-006
Development phase: 3
Objective: The objective of this clinical study is to evaluate the safety, tolerability,
pharmacokinetics, and efficacy/pharmacodynamics of teduglutide in pediatric subjects through
17 years of age with short bowel syndrome (SBS) and who are dependent on parenteral support.
Methodology: This study will include 2 treatment arms:  a teduglutide treatment arm and a 
standard of care treatment arm.  Subjects in both arms will participate in a 2-week minimum 
screening period, a 24-week treatment period, and a 4-week follow-up period.  During the 
screening period, subjects will choose into which arm to enroll.  During the 24-week treatment 
period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; while 
those in the teduglutide treatment arm will receive daily subcutaneous (SC) injections of 
teduglutide (study drug) in addition to standard medical therapy.  These subjects will be 
randomized 1:1 in a double-blinded manner into two parallel teduglutide dose groups:  
0.025 mg/kg/day and 0.05 mg/kg/day.  Randomization across dose groups will be stratified by 
age:  <1 year, 1 to <12 years, 12 to <17 years, and 17 to <18 years.
Each subject will be screened minimally for 2 weeks before the baseline visit (day 0) to allow for 
adequate time verifying enrollment eligibility.  Subjects in both arms will follow the same visit 
schedule. After the screening period, subjects will visit the site at baseline (day 0), weekly for 
the first 2 weeks (ie, weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 
10, and 12). For the remainder of the treatment period, subjects will visit the sites once every 
3 weeks (ie, weeks 15, 18, 21, and 24). For all other study weeks, subjects will be contacted by 
telephone. At all site visits and telephone contacts, safety will be monitored and nutritional 
support will be reviewed and adjusted as needed. At the end of the treatment period (week 
24/EOT), all subjects will enter a 4-week follow-up period until the end of study (week 28/EOS) 
during which time no study drug (ie, teduglutide) will be administered.  A final visit will occur at 
week 28, 4 weeks after EOT. Telephone contact will be made during the weeks from EOT to 
EOS to monitor safety and any changes in nutritional support.
All subjects who complete the study, including those in the SOC treatment arm, may participate 
in a long-term extension study in which eligible subjects could receive teduglutide.
To maintain consistency across centers, all attempts should be made to follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) 
for decisions regarding PN/IV support reduction and advances in enteral feeds based on weight 
gain, urine and stool output, and clinical stability.  Any departure from the guidelines will not
constitute a protocol deviation.
If a blood sample is positive for antibodies to teduglutide at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.


Shire
Confidential
Page 5
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) that 
will convene approximately every 3 months during the treatment period.  The treatment period 
for the study is defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT. The DMC committee members will include all cumulative 
safety data from study assessments through the end of each review period.
Number of Subjects:  Approximately 26 subjects who are teduglutide-naïve (a minimum of 
10 subjects per teduglutide dose arm) will be enrolled into the teduglutide treatment arm and at 
least 8 subjects who are teduglutide-naïve will be enrolled into the SOC treatment arm.  
Enrollment will proceed at approximately 28 investigational sites globally.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
Duration of Study:  For each subject, the study duration will be a minimum of 30 weeks:

2-week minimum screening period

24-week treatment period

4-week follow-up period
A subject will be considered enrolled in the study at the baseline visit (day 0) when the choice of 
treatment arm (ie, teduglutide or SOC) has been made.
Criteria for inclusion/exclusion:  Male and female children and adolescents through 17 years of 
age, who satisfy all of the following inclusion criteria and none of the following exclusion 
criteria will be eligible to be enrolled in this study.
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures 
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
6. Sexually active female subjects of child-bearing potential (in the teduglutide treatment arm
only) must use medically acceptable methods of birth control during and 4 weeks after the 
treatment period
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening


Shire
Confidential
Page 6
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done 
within 6 months prior to screening
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to the screening visit (insertion of feeding tube, anastomotic ulcer repair, minor intestinal 
resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the teduglutide treatment arm only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
a.
Total bilirubin (TBL) ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN


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For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are 
provided in Table 4-1.
Test Product, Dose, and Mode of Administration
Subjects who elect to receive teduglutide treatment will be randomized 1:1 in a double-blinded 
manner into two dose groups:  0.025 mg/kg/day and 0.05 mg/kg/day.  The dose calculation will 
be based on subject body weight measured at the baseline visit (visit 2) and adjusted, as needed, 
based on measurements made at week 12 (visit 14).  Subjects in both dose groups of the 
teduglutide treatment arm will receive 0.005 mL/kg of reconstituted study drug at a blinded 
concentration.  No other adjustments to the dose will be made during the treatment period, unless 
discussed with the Shire medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.
Reference Therapy, Dose, and Mode of Administration:  Not applicable
Criteria for Evaluation
Pharmacokinetics:  Subjects in the teduglutide treatment arm only
For the PK evaluation, blood will be collected at the clinic on day 0 when the subject receives 
the first dose of teduglutide.  Blood sampling will occur at the following timepoints:  predose 
and 1, 2, and 4 hours postdose.  In smaller children for whom blood sampling may impose 
unacceptable phlebotomy volume, the number of PK samples may be reduced.
If a subject is unable to provide blood samples at baseline (day 0) on the first day of treatment, 
then blood may be collected for PK analysis during any other future clinic visit while the subject 
is still receiving treatment with teduglutide.
Safety and tolerability
Safety and tolerability will be assessed by evaluating the following:

Assessment of adverse events including those pertaining to GI symptoms

Physical examinations

Vital signs, including temperature, heart rate, blood pressure

Body weight, height (or length), head circumference (up to 36 months of age), body mass 
index (BMI); z-scores will be calculated for height (or length), weight, head 
circumference, and BMI


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Pediatric Study TED-C14-006 – Amendment 4
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
Electrocardiograms

Laboratory safety data (ie, clinical chemistry, hematology, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide (teduglutide treatment arm only)

GI-specific testing (teduglutide treatment arm only) including colonoscopy or
sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, upper GI series with 
small bowel follow through
Efficacy/pharmacodynamics
The primary efficacy/PD endpoint is a reduction in PN/IV volume of at least 20% at week 24 
(or EOT) compared to baseline.
Additional PD endpoints include:

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or 
EOT) compared to baseline

Changes (absolute and percent change) from baseline in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, at 
each clinic visit

Changes (absolute and percent change) from week 24 (or EOT) in PN/IV support
(volume and calories), citrulline, and enteral nutritional support (volume and calories), 
separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support

≥20% reduction in PN/IV volume at each clinic visit
Statistical methods
Because of the small size of the study population only descriptive statistics will be used to 
summarize data.  Accordingly, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum.  For categorical variables, statistical summaries will include number of subjects 
and percentages.
Demographics and baseline
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate.
Pharmacokinetics
The PK parameters will be estimated based on measured teduglutide plasma concentrations using 
a population PK modeling approach.


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Safety
Safety data will include clinical laboratory test results; physical examinations; measurements of
weight, height or length, and head circumference (if applicable); vital signs; concomitant 
medications; and electrocardiogram monitoring. Adverse events will be collected and 
summarized. Descriptive statistics will be calculated for quantitative safety data as well as for 
the difference from baseline, if applicable.  Frequency counts will be compiled for classification 
of qualitative safety data.
Efficacy/Pharmacodynamics
Efficacy/pharmacodynamics data will include changes in PN/IV support, enteral nutritional 
support, citrulline, and hours per day or days per week of PN/IV support and will be summarized 
by visit and time point.


S hi r e 
P e di at ri c St u d y T E D- CI 4- 0 0 6- A m e n d m e nt 4 
C o nfi d e nti al 
P a g e 1 0 
V e rsi o n 5. 0 I 1 5 M a r 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p p r o v e d: 
 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h ar m a c o vi gil a n c e 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h D 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h a r m D 
 
S hire I nt er n ati o n al G m b H 
Zli hl er w e g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
, M D, P h D 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g nat ure 
D at e 
( D D M M M Y Y Y Y) 
Si g nat ure 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g nat ure 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hir e 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 4 
C o nfi d e nti al 
P a g e 1 0 
V ersi o n 5. 0 I 1 5 M ar 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o v e d: 
 
 
S hir e, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 M D 
Gl o b al P h ar m a c o vi gil a n c e 
S hir e, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Z a hl er w e g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
 M D, P h D 
 
S hir e, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hir e 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 4 
C o nfi d e nti al 
P a g e 1 0 
V ersi o n 5. 0 I 1 5 M ar 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o v e d: 
 
 
S hir e, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h ar m a c o vi gil a u c e 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Z a hl er w e g I 0 
6 3 0 0 Z u g 
S wit z erl a n d 
 M D, P h D 
 
S hir e, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hi r e 
P e di at ri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 4 
C o nfi d e nti al 
P a g e 1 0 
V e rsi o n 5. 0 I 1 5 M a r 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p p r o v e d: 
 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
M D 
Gl o bal P h ar m a c o vi gil a n c e 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h D 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
P h a r m D 
 
S hire I nt er n ati o n al G m b H 
Zii hler we g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
M D, P h D 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hir e 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 4 
C o nfi d e nti al 
P a g e 1 0 
V ersi o n 5. 0 I 1 5 M ar 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o v e d: 
 
 
S hire, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h a n n a c o vi gil a n c e 
S hire, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h D 
 
S hire, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h ar m D 
 
S hire I nt er n ati o n al G m b H 
Z a hl er w e g I 0 
6 3 0 0 Z u g 
S wit z erl a n d 
M D, P h D 
 
S hire, I nc. 
3 0 0 S hire W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL TED-C14-006
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics Committee 
(IEC) for the study protocol and any amendments thereof, written informed consent or updates 
thereof, subject recruitment procedures (eg, advertisements), and any other written information 
to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from 
the sponsor and review and documented approval from the IRB/IEC, except to eliminate an 
immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 10 years or 
until instructed in writing by the sponsor that records may be destroyed or forwarded to the 
sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................4
SIGNATURES FOR PROTOCOL TED-C14-006........................................................................10
PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL TED-C14-006....................11
TABLE OF CONTENTS...............................................................................................................12
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................15
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................16
1
INTRODUCTION .................................................................................................................18
1.1 Background........................................................................................................................18
1.2 Rationale for the Clinical Study.........................................................................................20
1.3 Rationale for Study Design................................................................................................21
2
OBJECTIVES........................................................................................................................24
2.1 Primary Objective..............................................................................................................24
3
STUDY DESIGN...................................................................................................................25
3.1 Overall Design and Control Methods ................................................................................25
3.2 Study Duration...................................................................................................................28
4
SUBJECT SELECTION AND PARTICIPATION...............................................................29
4.1 Number of Subjects............................................................................................................29
4.2 Criteria for Inclusion/Exclusion.........................................................................................29
4.2.1
Inclusion Criteria ...............................................................................................29
4.2.2
Exclusion Criteria ..............................................................................................29
4.3 Subject Withdrawal Criteria ..............................................................................................31
4.4 Data Monitoring Committee..............................................................................................32
5
TREATMENTS AND TREATMENT PLAN.......................................................................33
5.1 Treatment Administered ....................................................................................................33
5.1.1
Identification of Investigational Product ...........................................................33
5.1.2
Packaging and Labeling.....................................................................................33
5.1.3
Storage, Accountability, and Stability...............................................................33
5.2 Methods of Assigning Subjects to Study Treatment Arms................................................34
5.3 Dose Regimens ..................................................................................................................35
5.3.1
Selection of Doses in Study...............................................................................35
5.3.2
Selection and Timing of Dose for Each Subject in the Teduglutide 
Treatment Arm...................................................................................................35
5.3.3
Compliance with Dosing Regimens ..................................................................36
5.3.4
Prior and Concomitant Treatments....................................................................36
6
STUDY EVALUATIONS AND PROCEDURES ................................................................37
6.1 Pharmacokinetics...............................................................................................................37
6.2 GI-specific Symptoms History ..........................................................................................37


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6.3 Diaries................................................................................................................................37
6.4 Nutritional Support ............................................................................................................38
6.5 Gastrointestinal-specific Testing .......................................................................................38
6.5.1
Upper Gastrointestinal Series with Contrast......................................................39
6.5.2
Abdominal Ultrasound.......................................................................................39
6.5.3
Fecal Occult Blood Testing ...............................................................................39
6.5.4
Colonoscopy/Sigmoidoscopy ............................................................................39
6.6 Laboratory Evaluations......................................................................................................39
6.6.1
Laboratory Tests ................................................................................................40
6.6.1.1
Plasma Citrulline......................................................................................40
6.6.1.2
Antibodies to Teduglutide........................................................................40
6.7 Physical Examinations.......................................................................................................41
6.8 Body and Weight Measurements.......................................................................................41
6.9 Vital Signs..........................................................................................................................41
6.10
Electrocardiograms ......................................................................................................41
6.11
Adverse Events ............................................................................................................41
6.11.1
Adverse Event Definition ..................................................................................42
6.11.2
Procedures for Reporting Adverse Events.........................................................42
6.11.3
Relationship to study drug (not related, related)................................................43
6.11.4
Abuse, Misuse, Overdose, and Medication Error..............................................44
6.12
Serious Adverse Events ...............................................................................................44
6.12.1
Serious Adverse Event Definition .....................................................................45
6.12.2
Procedures for Reporting Serious Adverse Events............................................45
6.13
Adverse Events of Special Interest ..............................................................................47
6.14
Dose Interruption of Individual Subjects in the Teduglutide Treatment Arm.............47
6.14.1
Dose Interruption Criteria Based on Known Risks of Teduglutide...................47
6.14.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ......................49
6.15
Early Termination of the Clinical Study......................................................................49
6.16
Prior and Concomitant Treatments..............................................................................50
6.17
Female Subjects of Child-bearing Potential ................................................................50
6.18
Unblinding ...................................................................................................................51
7
DATA MANAGEMENT.......................................................................................................60
7.1 Data Collection ..................................................................................................................60
7.2 Rescreening........................................................................................................................61
7.3 Record Retention ...............................................................................................................61
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE ..................................................62
8.1 Demographic and Baseline Variables................................................................................62
8.2 Safety and Tolerability Variables ......................................................................................63


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8.3 Pharmacokinetic Variables ................................................................................................63
8.4 Efficacy/Pharmacodynamic Variables...............................................................................64
8.5 Other Variables ..................................................................................................................64
8.6 Analysis Populations, Data Sets, and Time Points ............................................................65
8.6.1
Analysis Populations..........................................................................................65
8.7 Statistical/Analytical Issues ...............................................................................................65
8.7.1
Adjustments for Covariates ...............................................................................65
8.7.2
Handling of Dropouts or Missing Data..............................................................65
8.7.3
Interim Analyses and Data Monitoring .............................................................65
8.7.4
Multiple Comparisons/Multiplicity ...................................................................66
8.7.5
Use of an Efficacy Subset of Subjects...............................................................66
8.7.6
Examination of Subgroups.................................................................................66
8.8 Determination of Sample Size ...........................................................................................66
8.9 Changes to Planned Statistical Analyses ...........................................................................66
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS..................................................67
9.1 Declaration of Helsinki and Ethical Review......................................................................67
9.2 Subject Information, Informed Consent and Assent..........................................................67
9.3 Subject Data Protection......................................................................................................67
9.4 Financial Disclosure...........................................................................................................68
9.5 Changes to the Protocol .....................................................................................................69
9.6 Investigator Obligations.....................................................................................................69
9.7 Confidentiality/Publication of the Study ...........................................................................69
9.8 Selection of a Primary Principal Investigator....................................................................70
9.9 Study Termination .............................................................................................................70
10
REFERENCES ......................................................................................................................71


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LIST OF IN-TEXT TABLES AND FIGURES
In-Text Tables
Table 4-1
Excluded Diseases and Illnesses............................................................................31
Table 6-1
Adverse Events that May Lead to Dose Interruption.............................................48
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm –
Screening to Week 12 ............................................................................................52
Table 6-3
Schedule of Events in the Teduglutide Treatment Arm –
Weeks 13 to 28 (EOT)...........................................................................................55
Table 6-4
Schedule of Events in the Standard of Care Treatment Arm –
Screening to Week 12 ............................................................................................57
Table 6-5
Schedule of Events in the Standard of Care Arm – Weeks 13 to 28 (EOT)..........59
In-Text Figures
Figure 3-1
Study Diagram ......................................................................................................27


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-inf
AUC from zero to infinity
AUClast
AUC from zero to the last measurable concentration
AUC
AUC at steady state
CL/F
apparent clearance
Cmax
maximum plasma concentration
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
FDA
Food and Drug Administration
FOCBP
female (subjects) of child-bearing potential
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IB
Investigator’s brochure
IBD
inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous fluids
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
Short bowel syndrome


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Abbreviation
Definition
SC
subcutaneous
SOC
standard of care
SUSAR
suspected, unexpected, serious, adverse reaction
t1/2
terminal-phase half-life
TEAEs
treatment-emergent adverse events
Tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow through
ULN
upper limit of normal
Vλz/F
apparent volume of distribution


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1
INTRODUCTION
1.1
Background
Compound
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide-
2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase-IV and therefore 
maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Thymann et 
al. 2014; Tappenden et al. 2013).  The European Commission granted a centralized marketing 
authorization valid throughout the European Union for teduglutide (Revestive™) on 30 August 
2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by the US 
Food and Drug Administration (FDA) on 21 December 2012 for the treatment of adult patients 
with Short Bowel Syndrome (SBS) who are dependent on parenteral support.
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes to 
the label which provide for long-term use of Gattex in adults.
Preclinical Studies
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated rats. 
Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those observed 
in studies conducted using adult animals (rodents and primates). No treatment-related malignant 
tumors were noted in a 2-year carcinogenicity study in rats; treatment-related changes included 
benign tumors of the bile duct epithelium and adenomas of the jejunal mucosa in males treated at 
35 mg/kg/day. The results from a second 2-year carcinogenicity study in Crl:CD1(ICR) mice 
were provided to the FDA in a NDA Supplement which received agency approval on 26 June 
2014. Subcutaneous doses of 1, 3.5, and 12.5 mg/kg/day (about 20, 70, and 250 times the 
recommended daily human dose of 0.05 mg/kg, respectively) were studied and adenocarcinoma 
in the jejunum was observed in males given a dose of 12.5 mg/kg/day.


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Clinical Studies
Two completed adult studies (CL0600-004 and CL0600-005) evaluated safety and tolerability of 
daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on parenteral 
nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, placebo-controlled 
study in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed the effects of 
teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was a statistically 
significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) by using a 
graded response at the end of the study.  At week 24, the weekly reduction of PN/IV volume was 
similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, assessed the long-
term safety of teduglutide and the proportion of responders in the CL0600-004 study that 
maintained their response at the end of a further 28 weeks of treatment. The extension study also 
assessed the effects of teduglutide at 28 weeks on those subjects previously receiving placebo in 
Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial phase 3 study, which included significant reductions in PN/IV.  
Seventy-five percent of the subjects who previously responded to teduglutide treatment in Study 
CL0600-004 maintained this response or experienced further improved benefit from teduglutide 
treatment.  More than 60% of the subjects’ previously receiving placebo in Study CL0600-004 
achieved a clinical response after switching to teduglutide treatment for 6 months. Most of the 
adverse events (AEs) reflected the underlying disease and were not treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus
13/43 subjects [30.2%], respectively). This difference was clinically and statistically significant 
in both the intention-to-treat (ITT) (p = 0.002) and per protocol (p < 0.001) populations. 
Generally, the incidence of treatment-emergent AEs (TEAEs) was distributed similarly across all 
treatment groups. The TEAEs with a higher incidence in the teduglutide group were mainly of 
GI origin. A long-term, open-label extension study (CL0600-021) assessed safety and efficacy 
for up to 24 additional months (ie, up to 30 months of exposure for subjects who received 
teduglutide in Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in 
Study CL0600-020 and entered Study CL0600-021 completed a total of 30 months of treatment 
with teduglutide. Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral 
support resulting in a PN/IV volume reduction of 7.55 L/week, corresponding to a mean 
reduction of 65.6% relative to baseline prior to exposure to teduglutide at the beginning of 
Study CL0600-021. PN/IV frequency was reduced by at least 1 day per week in 21 of 30 subjects 
(70%) who completed 30 months of treatment. Of the 39 subjects who entered 
Study CL0600-021 after receiving placebo in Study CL0600-020, 29 completed 24 months of 
treatment with teduglutide. The mean reduction in PN/IV volume was 3.11 L/week from baseline 
at the start of Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support. Of the 12 subjects entering 


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Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support.
One phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and UK. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose.  In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts.  
There were no deaths during the study and no TESAEs related to teduglutide were reported.  No 
discontinuations from study were due to adverse events.
1.2
Rationale for the Clinical Study
Short bowel syndrome is a rare disorder. At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, market 
research performed in 2012 indicates that the true addressable adult patient population is 
between 3000 to 5000 patients qualifying SBS as an ultra-orphan condition. In addition to adult 
SBS patients, it is estimated that, at most, there are a few hundred children 1 year and older with 
SBS (Wales et al. 2004). As a result of congenital abnormalities or severe intestinal disease in 
children and adolescents, major surgical resections of the intestine can become necessary, 
resulting in SBS. Common causes of SBS in children include necrotizing enterocolitis (NEC) in 
infants, midgut volvulus, intestinal atresia, and gastroschisis (Duro et al. 2008; Squires et al. 
2012). New onset SBS in older children may stem from the same etiologies as in adults (ie, 
Crohn’s disease, trauma, cancer) but is far less common. As the characteristics are similar to the 
adult disease, pediatric SBS is defined as a disease where there is diminished absorptive capacity 
for fluids and/or nutrients, sometimes requiring a dependence on PN/IV support to maintain 
energy and clinical status.
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able to 
adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al. 1999; Jeppesen 
and Mortensen 2000), other patients with intestinal failure depend on PN/IV for nutritional 
support (Fleming et al. 1980; O'Keefe et al. 2006; Buchman et al. 2003).  Although PN/IV can 
provide this nutritional support for patients with compromised fluid and nutritional status, it is 
also associated with serious complications, such as infections and liver damage.  The risk for 
these effects increases over time with longer duration of PN/IV support.


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Treatment of both pediatric and adult patients is focused on achieving adequate intestinal 
absorption to allow for minimization or discontinuation of PN/IV support. Because children are 
at higher risk for intestinal failure-associated liver disease, reducing PN support is far more 
urgent in this population. About 30% of infants who develop SBS during the neonatal period 
become independent of PN/IV requirements by 12 months of age, and an additional 10% wean 
off PN/IV support by 24 months of age. After this time, intestinal adaptation and growth occurs 
much more slowly, and many children remain terminally dependent on PN/IV support. Due to 
the risks of intestinal failure-associated liver disease, catheter-related blood stream infections, 
central line-associated venous thrombosis and dwindling central venous access, achieving 
autonomy from parenteral support remains an urgent goal for all affected children (Khan et al. 
2015; Squires et al. 2012).
This study proposes to investigate the safe and appropriate use of teduglutide in the pediatric 
population for up to 24 weeks of administration for the purpose of providing longer-term data in 
regard to safety and the potential to explore further efficacy including PN reduction and ability to 
completely wean off parenteral support.  This protocol was developed with input from expert 
advisors from intestinal rehabilitation centers who offered advice on the most appropriate use of 
teduglutide in pediatric patients.  The aim of teduglutide treatment is to increase absorptive 
capacity in order to yield decreases in parenteral support requirements.  The experts anticipated 
that there would be several direct benefits from decreased parenteral support, including less 
exposure to PN/IV constituents, less central line manipulation with lower risk of infection, and 
more time to focus on oral rehabilitation strategies.
1.3
Rationale for Study Design
Dose
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily in adult SBS subjects requiring PN. The recommended daily clinical 
dosage for the adult SBS patient population is 0.05 mg/kg. The completed 12 week pediatric 
study (TED-C13-003) included doses of 0.0125, 0.025, and 0.05 mg/kg/day. It demonstrated that 
teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk 
profile. In addition, population pharmacokinetic (PK) modeling and simulations were conducted 
to determine the effective dose to be used in pediatric subjects using data from 8 adult clinical 
studies including adult phase 1 studies and phase 2 and 3 studies as well as the pediatric phase 3 
study, TED-C13-003. The analysis suggested that pediatric patients aged 1 to 17 years were 
likely to require the same dose as that used in adults, namely 0.05 mg/kg/day. To further explore 
additional safety and efficacy of 0.025 and 0.05 mg/kg/day doses, a 24-week study is currently 
proposed.
Treatment Duration/Design
Safety, tolerability, pharmacokinetics, and efficacy/PD measures will be the main outcomes of
the current study. The main efficacy/PD effect of teduglutide to be measured in children is a 
decrease in the volume of PN/IV support. Measurement of a decrease in PN/IV volume was the 
primary endpoint in the adult SBS clinical studies and can be used in children with SBS who are 
dependent on PN/IV support.


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A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of treatment was used as the primary endpoint in the adult clinical development program 
during pivotal phase 3 studies and the previous pediatric study and will be the same endpoint 
used in the current pediatric study.  A 20% decrease in PN/IV volume over 24 weeks is 
considered clinically meaningful to these PN/IV-dependent children who have plateaued in their 
ability to wean PN/IV requirements and advance their oral/enteral feeds.  A decrease of this 
magnitude may allow a child several hours a day for more age-appropriate activities or an 
opportunity to introduce an extra oral/enteral feed to encourage oral rehabilitation.
This study will include 2 treatment arms:  a teduglutide treatment arm and a standard of care 
treatment arm.  Subjects in both arms will participate in a 24-week treatment period and a 4-
week follow-up period.  The teduglutide treatment arm will have a double-blind, parallel group 
design in which subjects are randomized 1:1 to teduglutide at either 0.025 mg/kg/day or 0.05 
mg/kg/day subcutaneous injection for 24 weeks.  The 24-week teduglutide treatment period will 
provide additional pharmacokinetic, safety, tolerability, and efficacy data beyond that which was 
collected in the previous 12-week pediatric study (TED-C13-003).
Thus, this study is designed to provide further information on the safety, PK, and efficacy/PD 
profile of teduglutide in pediatric subjects treated for up to 24 weeks.
Subject Population
The current significant unmet medical need is for children who remain dependent on parenteral 
support. Patients who reach a plateau in their ability to advance oral/enteral feeds or decrease 
PN/IV support are not expected to achieve spontaneous adaptation. The subjects in the study will 
be children who have not reached full enteral autonomy and whose PN/IV requirements had been 
stable without any clinically meaningful or substantial reduction in parenteral support for the 
3 months prior to, and during, screening.
This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000).
Gastrointestinal Screening Measures
Pediatric patients with SBS who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for small bowel obstruction due to history of intestinal surgery. 
Teduglutide has been found to have a targeted intenstinotrophic effect on the GI tract and areas 
of special interest in regards to safety have been identified throughout the development program. 
Taking into account the patient population and the pharmacologic effect of teduglutide, 
GI-specific screening tests that are usually part of the routine care of these subjects will be 
performed on subjects in the treatment arms only to ensure safety. These include: abdominal 
ultrasound, upper GI series with small bowel follow through (UGI/SBFT), fecal occult blood 
testing, and colonoscopy/sigmoidoscopy.
General Guidance for Nutritional Support Adjustment
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status and will include measures of weight, hydration status, and stool output.  
Because the primary efficacy/PD endpoint for this study is a reduction in PN/IV volume of at 
least 20% at week 24 (or EOT) compared to baseline, guidelines for nutritional support 
adjustment, including a weaning algorithm, are provided in Appendix 1.  These guidelines were 


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developed with input from SBS experts.  All attempts should be made to follow these guidelines 
to ensure uniform care across study sites and participants; however, a departure from the 
guidelines will not constitute a protocol deviation. 


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2
OBJECTIVES
2.1
Primary Objective
The objective of this clinical study is to evaluate the safety, pharmacokinetics, and efficacy/PD 
of teduglutide in pediatric subjects through 17 years of age with short bowel syndrome (SBS) 
and who are dependent on parenteral support.
Details of study assessments are provided in Sections 8.2 and 8.4.


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3
STUDY DESIGN
3.1
Overall Design and Control Methods
This study will include 2 treatment arms:  a teduglutide treatment arm and a standard of care 
treatment arm.  Subjects in both arms will participate in a 2-week minimum screening period, a 
24-week treatment period, and a 4-week follow-up period.  During the screening period, subjects 
will choose into which arm to enroll.  During the 24-week treatment period, subjects in the 
SOC treatment arm will receive standard medical therapy for SBS; while those in the teduglutide 
treatment arm will receive daily subcutaneous injections of teduglutide (study drug) in addition 
to standard medical therapy.  These subjects will be randomized 1:1 in a double-blinded manner 
into two parallel teduglutide dose groups:  0.025 mg/kg/day and 0.05 mg/kg/day.  Randomization 
across dose groups will be stratified by age:  <1 year, 1 to <12 years, 12 to <17 years, and 17 to 
<18 years.
Each subject will be screened minimally for 2 weeks before the baseline visit (day 0) to allow for 
adequate time verifying enrollment eligibility.  Subjects in both arms will follow the same visit 
schedule. After the screening period, subjects will visit the site at baseline (day 0), weekly for 
the first 2 weeks (ie, weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 
10, and 12).  For the remainder of the treatment period, subjects will visit the sites once every 
3 weeks (ie, weeks 15, 18, 21, and 24).  For all other study weeks, subjects will be contacted by 
telephone.  At all site visits and telephone contacts, safety will be monitored and nutritional 
support will be reviewed and adjusted as needed.  At the end of the treatment period (week 
24/EOT), all subjects will enter a 4-week follow-up period until the end of study (week 28/EOS) 
during which time no study drug (ie, teduglutide) will be administered.  A final visit will occur at 
week 28, 4 weeks after EOT.  Telephone contact will be made during the weeks from EOT to 
EOS to monitor safety and any changes in nutritional support.
All subjects who complete the study, including those in the SOC treatment arm, may participate 
in a long-term extension study in which eligible subjects could receive teduglutide.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) 
for decisions regarding PN/IV support reduction and advances in enteral feeds based on weight 
gain, urine and stool output, and clinical stability.  Any departure from the guidelines will not 
constitute a protocol deviation.
If a blood sample is positive for antibodies to teduglutide at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) that 
will convene approximately every 3 months during the treatment period.  The treatment period 
for the study is defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT.  The DMC’s data review will include all cumulative safety data 
from study assessments through the end of each review period.
A schematic of the study design is displayed in Figure 3-1.


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Timing of study visits and evaluations can be found in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).


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Figure 3-1
Study Diagram
Note:  Subjects in both treatment arms (SOC and teduglutide) will follow the same visit schedule.


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3.2
Study Duration
A 2-week minimum screening period will be followed by 24 weeks of teduglutide treatment for 
all subjects.  At EOT, all subjects will enter the follow-up period, during which time subjects 
will have a final site visit at week 28 (EOS), 4 weeks after EOT (ie, week 24).
A subject will be considered enrolled in the study at the baseline visit (day 0) when the choice of 
treatment arm (ie, teduglutide or SOC) has been made.


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4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects
Approximately 26 subjects who are teduglutide-naïve (a minimum of 10 subjects per teduglutide 
dose group) will be enrolled into the teduglutide treatment arm and at least 8 subjects who are 
teduglutide-naïve will be enrolled into the SOC treatment arm.  Enrollment will proceed at 
approximately 28 investigational sites globally.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
4.2
Criteria for Inclusion/Exclusion
Male and female children and adolescents through 17 years of age, who satisfy all of the 
following inclusion criteria and none of the following exclusion criteria are eligible to be 
enrolled in this study.
4.2.1
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures 
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
6. Sexually active female subjects of child-bearing potential (in the teduglutide treatment arm 
only) must use medically acceptable methods of birth control during and 4 weeks after the 
treatment period
4.2.2
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.


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6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done 
within 6 months prior to screening
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to the screening visit (insertion of feeding tube, anastomotic ulcer repair, minor intestinal 
resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the teduglutide treatment arm only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
e.
Total bilirubin (TBL) ≥2x upper limit of normal (ULN)
f.
Aspartate aminotransferase (AST) ≥7x ULN
g. Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease:
h. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease


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24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are listed 
in Table 4-1.
Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in GI tract 
identified by upper GI series, biopsy or polypectomy

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease; SBS=short bowel syndrome
4.3
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
Shire’s medical monitor prior to the patient discontinuing/withdrawing.  A subject may (but not 
automatically) be withdrawn from the study under any of the following circumstances:


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
Withdrawal of informed consent and/or assent when applicable

If, in the opinion of the investigator, IRB or the sponsor, it is no longer in the subject’s 
best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any of the exclusionary criterion

Lack of compliance with study procedures or study drug administration, as determined by 
the investigator

Occurrence of a serious adverse event (SAE) determined by the investigator to be related 
to study drug and not alleviated with treatment of symptoms

AEs resulting in dose interruption (Section 6.14)

Hypersensitivity determined by the investigator to be related to study drug

Administrative reasons
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.3.
As far as possible, all examinations scheduled for the EOT evaluations must be performed on all 
subjects who participate even if they do not complete the study according to the protocol (ie, 
early terminate [ET]). Any subject who discontinues treatment prematurely will be asked to 
return 4 weeks later for the EOS visit and will be contacted weekly for wellness checks during 
the interim period between EOT and EOS.
4.4
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
charter agreed to by members of the committee and the sponsor. Committee members may not 
be study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying, or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
The DMC members will review the data approximately every 3 months during the study’s
treatment period (defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT).  DMC’s data review will include all cumulative safety data from 
study assessments through the end of each review period.


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5
TREATMENTS AND TREATMENT PLAN
5.1
Treatment Administered
Subjects who elect to receive teduglutide treatment will be randomized 1:1 in a double-blinded 
manner into one of two dose groups:  0.025 mg/kg/day or 0.05 mg/kg/day.  The dose calculation 
will be based on subject body weight measured at the baseline visit (day 0/visit 2) and adjusted, 
as needed, based on measurements made at week 12 (visit 14).  Subjects in both dose groups of 
the teduglutide treatment arm will receive 0.005 mL/kg of reconstituted study drug at a blinded 
concentration.  No other adjustments to the dose will be made during the treatment period, unless 
discussed with the Shire medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.
5.1.1
Identification of Investigational Product
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.  
The 5-mg vial is a 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is a 5 mg/mL
solution upon reconstitution.
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients.
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength.
5.1.2
Packaging and Labeling
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements.  Sterile water for injection syringes will also 
be provided separately and will be labeled in accordance with the applicable regulatory 
requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures.  Study drug will be shipped once the first subject at a 
site is screened. Upon receipt, the study site’s pharmacist or delegate is responsible for ensuring 
that all study drug received at the site is inventoried and accounted for throughout the study.  A 
copy of the shipping documents must be maintained for the investigator’s records.
Study drug must be kept in a locked area with access restricted to specific study personnel.  
Study drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated or 


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up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F).  
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature.  If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated.
Study drug kits will be dispensed at each of the study visits at which the subject is required to be 
at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough kits 
will be supplied to cover the period to the next planned study visit.  Additional study kits will be 
provided as necessary.
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies.  This record will be made available to the sponsor’s site monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded and will 
include an explanation.  All supplies sent to the investigator must be accounted for and in no case 
will clinical supplies be used in any unauthorized situation.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian and 
will be retained at the site. All original containers, whether empty or containing study drug will 
be returned to the pharmacy. Returned study drugs will NOT be relabeled or reassigned for use 
by other subjects. Contents of the study drug containers will not be combined. All used and
unused vials must be returned to the distribution center according to the sponsor’s instruction. 
No vial/kit may be destroyed on site without approval by the sponsor.
Please see the Pharmacy Manual for additional information.
5.2
Methods of Assigning Subjects to Study Treatment Arms
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of the 
study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These 
numbers will be used to identify the subjects in the teduglutide treatment arm and those in the
SOC treatment arm.  Subjects may be rescreened only once and with prior sponsor approval.  See 
Section 7.2 for rescreening instructions.
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the teduglutide treatment arm or 
the SOC treatment arm.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all inclusion criteria and none of the exclusion criteria.
If the subject or subject’s parent/guardian/caretaker decides to participate in the study and 
receive study drug (defined as treatment with teduglutide), then the investigator or designee will 
request that the subject be randomized to a teduglutide dose group using an interactive web 
response system (IWRS) centrally administered as described in the IWRS Manual of Procedures.  
Subjects in teduglutide treatment arm will be double-blinded and randomized at the baseline visit 
(day 0) 1:1 into parallel dose groups of either 0.025 mg/kg/day or 0.05 mg/kg/day.  To ensure 
balance across dose groups, randomization will be stratified by the following age subgroups:  
<1 year, 1 to <12 years, 12 to <17 years, and 17 to <18 years.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.


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Study drug kits will be assigned through IWRS to each subject at each site visit through 
completion of the treatment period. The IWRS will automatically assign the correct number of 
kits for each visit based on the randomization date.  If additional kits are needed (eg, subject is 
going on holiday), then the IWRS and the sponsor must be notified to assign additional kits.  
Subjects will be randomized across centers rather than within a center.
5.3
Dose Regimens
Study drug will be supplied in 2 powder strengths:

5.0 mg/vial for subjects randomized to 0.05 mg/kg/day teduglutide

2.5 mg/vial for subjects randomized to 0.025 mg/kg/day teduglutide
Subjects in the teduglutide dose groups will be administered study drug for 24 weeks by SC 
injection.  See Section 5.3.2 for more detail.  The dose calculation will be based on subject
weight measured at the baseline visit (day 0/visit 2), and adjusted as needed, based on weight 
measured at week 12 (visit 14).  No other adjustments will be made during the treatment period 
unless discussed with the Shire medical monitor.
5.3.1
Selection of Doses in Study
A recently completed 12-week pediatric study (TED-C13-003) that included doses of 0.0125, 
0.025, and 0.05 mg/kg/day demonstrated a favorable risk/benefit profile at the 2 higher doses as 
evident by reduction in PN/IV volume and advance in feeds. Furthermore, results from
modeling and simulation data of previously completed studies indicate that pediatric patients are 
likely to require the same dose as adults (ie, 0.05 mg/kg daily).
This study will evaluate teduglutide doses of 0.05 mg/kg and 0.025 mg/kg administered daily for 
24 weeks.
5.3.2
Selection and Timing of Dose for Each Subject in the Teduglutide Treatment Arm
Teduglutide will be administered after reconstitution by SC injection into 1 of the 4 quadrants of 
the abdomen (in subjects without a stoma) or into either the thigh or arm.  For subjects with a 
stoma, the quadrant of the abdomen containing the stoma should not be used. The first SC 
injection should be administered under the supervision of the investigator or designee and the 
subject observed for hypersensitivity reactions for at least 4 hours after teduglutide 
administration during their initial dosing visit.  The site of administration (arm, thigh, abdomen) 
of the first teduglutide dose must be specified and recorded in the eCRF.  Detailed instructions 
for reconstitution and injection of teduglutide can be found in the Dosing Instructions.  Each day, 
the injection site should be rotated.
The subject should be dosed at approximately the same time each day.  If a dose is forgotten, that 
day’s dose should be administered as soon as possible, even if this is later in the day or evening.  
Consecutive doses should be separated by at least 12 hours.
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily teduglutide dosing regimen.  Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, a lapse in teduglutide delivery, etc.


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5.3.3
Compliance with Dosing Regimens
Subject compliance with teduglutide dosing will be monitored by the sponsor/designee by 
counting and examining used and unused vials.  In addition, compliance will be checked by site 
personnel at every visit by reviewing the subject diaries and asking the subject or the subject’s 
parent or guardian if they have administered teduglutide according to instructions.  If any doses 
have been missed, the reason for missed dose should be documented in the subject’s source 
documentation including, as applicable, the eCRF.
5.3.4
Prior and Concomitant Treatments
All non-study treatments, including medications, herbal treatments, vitamins, invasive and 
diagnostic procedures, received within 14 days before screening through week 28 (EOS) or final 
study contact must be recorded on the appropriate section of the eCRF.
Prior treatment includes all treatments (medications, herbal treatments, vitamins, invasive and 
diagnostic procedures) received within the 14 days before screening.
Concomitant treatments will be assessed at each site visit and will include all non-study 
treatments (medications, herbal treatments, vitamins, invasive and diagnostic procedures) 
received between the first teduglutide dose (teduglutide treatment arm) or day 0 (SOC treatment 
arm) though week 28 (EOS), or the end of the follow-up period. Details of medication changes 
and/or dosages will be recorded on the eCRF.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin).  Accordingly, due consideration should be given to 
modifying concomitant medication regimens.  Down-titration of concomitant medications should 
be considered when drugs, especially those with a narrow therapeutic range, are prescribed at 
dosages that are higher than usual.


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6
STUDY EVALUATIONS AND PROCEDURES
6.1
Pharmacokinetics
Blood samples for PK analysis should be collected at baseline (day 0).  If a subject is unable to 
provide blood samples for PK at the baseline visit (day 0), then PK samples may be collected 
during any other future site visit while the subject is still receiving treatment with teduglutide.
Pharmacokinetic variables are listed in Section 8.3.  Instructions for sample collection and 
handling are included in the Laboratory Manual.
Blood will be drawn predose and 1, 2, and 4 hours postdose.  In smaller children for whom blood 
sampling may impose unacceptable phlebotomy volume, the number of PK samples may be 
reduced.  For example, the sampling timepoints postdose may be reduced from 3 to 2.  The 
decision to reduce blood sampling postdose timepoints will be made by the investigator and the 
Shire medical monitor.
The time points indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these time points may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 
14 hours after the previous dose (if the PK blood draw does not occur at day 0)

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes
The actual date and time of teduglutide administration and blood draw must be documented on 
the PK blood sampling eCRF.
If a subject is unable to provide blood samples for PK at the baseline visit (day 0), then PK 
samples may be collected during any other future site visit while the subject is still receiving
treatment with teduglutide.
6.2
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/guardian in a 
GI-Specific Symptoms History diary on a daily basis.  At the baseline visit, the investigator or 
sub-investigator will review the GI-symptoms diary and summarize the findings.
6.3
Diaries
Intake diaries will be used to collect and evaluate each subject’s nutritional support.
The subject/parent/guardian will complete the appropriate fields of the PN/IV and enteral 
nutrition (formula) sections of the Intake diary.
Intake diary:  The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:


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
PN/IV volume and infusion duration

EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
Output diary:  Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every clinic visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects WHO DO NOT WEAR DIAPERS
Measure and record all urine output in mL or cc.  The subject or parent will perform 
dipstick specific gravity tests on the first urine produced after the daily infusions of 
PN/IV support.

Nontoilet-trained subjects WHO WEAR DIAPERS
Measure and record the weight of all urine-only diapers.  Urine volume will be 
calculated using the following formula:  1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first void after the 
daily PN/IV infusion to measure specific gravity.
Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects WHO DO NOT WEAR DIAPERS
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see Output diary)

Nontoilet-trained subjects WHO WEAR DIAPERS
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form Scale 
(see Output diary).  Stool volume will be calculated using the formula:
1 g (scale weight = 1 mL or 1 cc)
All ostomy output volume should be recorded.  Ostomy output will not be scored using the 
Bristol scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
6.4
Nutritional Support
Nutritional support includes PN/IV and EN.  Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status, 
and safety laboratory results.  Guidelines for nutrition support adjustment, including a weaning 
algorithm, are provided in Appendix 1.
Intake diaries will be used to collect each subject’s nutritional support.
6.5
Gastrointestinal-specific Testing
Only subjects in the teduglutide treatment arm will undergo GI-specific testing.  GI-specific 
testing includes upper GI with small bowel follow through, abdominal ultrasound, FOBT, and 


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colonoscopy/sigmoidoscopy.  These procedures will be performed during or before screening 
(visit 1).
Follow-up testing will be performed as necessary according to the guidelines provided. See 
Table 6-2 and Table 6-3 for details and scheduling.
6.5.1
Upper Gastrointestinal Series with Contrast
An upper GI with small bowel follow through will be performed following the ingestion of 
barium contrast material.  Results from procedures performed within 6 months prior to visit 1 are 
acceptable also.
6.5.2
Abdominal Ultrasound
An abdominal ultrasound will be performed.  Results from procedures performed within the 
6 months before screening (visit 1) are also acceptable.
6.5.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, week 12, and week 24 (EOT). Subjects 
with positive FOBT results at screening or at week 24 for whom a readily detectable cause 
cannot be not identified (eg, anal fissure) will undergo a colonoscopy/sigmoidoscopy.  Subjects 
with positive FOBT results at week 12 for which a cause is not identified by a physical exam will 
be discussed with the Shire medical monitor.  If clinically indicated, an 
esophagogastroduodenoscopy (EGD) may also be performed.
Subjects with negative endoscopy findings at screening may enroll in the study.
Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with Shire’s medical monitor, the subject is considered 
appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with Shire’s medical monitor, the subject is 
considered inappropriate to be enrolled in the study.
6.5.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children younger than 12 years will undergo the procedure if they test positive for fecal occult 
blood at screening and if the source is not identified by physical exam (see Section 6.5.3).
If the FOBT is negative at screening and the procedure was performed within 1 year before the 
screening visit (visit 1), then those prior results are acceptable for the screening assessment.
6.6
Laboratory Evaluations
The following laboratory evaluations will be performed according to the Schedules of Events
(Table 6-2 and Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the 
SOC treatment arm).  A result outside of the normal range may be repeated for confirmation.
Laboratory collections that are required at intervals that do not coincide with clinic visits (ie, for 
lab assessments done following PN/IV adjustments) may be obtained by a Home Health Agency 
at subjects’ homes.


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6.6.1
Laboratory Tests
Hematology
Hemoglobin
Hematocrit
Platelets
Red blood cell (RBC) count
RBC morphology, if necessary
White blood cell (WBC) count with differential
Coagulation
PT/INR will be measured in subjects in the teduglutide treatment arm at screening and 
subsequently if DILI is suspected (Section 6.14.2)
Clinical Chemistry
Albumin
ALP
ALT
Amylase
AST
Bicarbonate
Bilirubin (total and direct)
Blood urea nitrogen
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma) (Section 6.6.1.1)
Creatinine
C-reactive protein
eGFR (Schwartz formula)
Glucose
Gamma glutamyl transferase
HCG for FOCBP in the teduglutide treatment 
arm (serum at screening only; Section 6.17)
Lipase
Magnesium
Phosphorous
Potassium
Sodium
Triglycerides
Uric acid
Urinalysis
Blood
Glucose
HCG for FOCBP in the teduglutide 
treatment arm (Section 6.17)
Leukocytes
Microscopic analysis
pH and osmolality
Protein
Sodium
Specific gravity
For children in diapers, urine specimen collection should be attempted as part of the safety 
labs, but lack of urinalysis will not constitute a protocol deviation.
6.6.1.1
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass.  Blood will be 
collected from all subjects 2 to 4 hours postprandial, whenever possible, timepoints specified in 
the Schedule of Events (Table 6-2 and Table 6-3 for the teduglutide treatment arm and Table 6-4
and Table 6-5 for the SOC treatment arm).  Samples may be drawn from a central line or from 
peripheral access and processed according to instructions in the Laboratory Manual. 
6.6.1.2
Antibodies to Teduglutide
Blood will be sampled from subjects in the teduglutide treatment arm to test for antibodies to 
teduglutide.  Samples will be taken before teduglutide administration at the baseline visit (day 0) 
and ≥14 hours after the previous dose at the EOT visit (week 24 or ET); samples may be drawn 


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from a central line or from peripheral access.  One additional sample will be collected at the final 
visit, 4 weeks after the EOT (ie, week 28/EOS).
If a blood sample is positive for anti-teduglutide antibodies at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.
6.7
Physical Examinations
Complete and comprehensive physical examinations will be performed by a medically qualified 
professional during the study to assess the subject’s physical status.  Timing of physical 
examinations is presented in the Schedules of Events (Table 6-2 and Table 6-3 for the 
teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment arm).
6.8
Body and Weight Measurements
Body measurements will be recorded on the appropriate section of the eCRF.  Subjects should be 
weighed in kilograms on the same scale at each site visit.  Height and body length and head 
circumference (subjects ≤36 months old) will be measured at selected visits.
BMI and z-scores for height/length, weight, and head circumference will be calculated by the 
sponsor.
Timing of body measurements and weight is provided in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).
6.9
Vital Signs
Examinations will be made at the timepoints specified in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).
Measurements will include systolic and diastolic blood pressure (mmHg), pulse (beats per 
minute), and body temperature (°C/°F).
6.10
Electrocardiograms
Examinations will be made at the timepoints specified in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).  The ECG tracing will be read by a local experienced physician.  Results (normal, 
abnormal not clinically significant, and abnormal clinically significant with description of the 
finding) will be recorded on the eCRF.
6.11
Adverse Events
Timing of all safety/tolerability evaluations is presented in the Schedule of Events (Table 6-2 and 
Table 6-3 for the treatment arms and Table 6-4 and Table 6-5 for the SOC treatment arm).
During the study, the investigator is responsible for the detection and documentation of any and 
all AEs or SAEs as defined and instructed in this protocol.


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6.11.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product.  An AE does not necessarily have a causal relationship 
with study drug treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality, vital sign abnormality, and 
clinically significant electrocardiogram (ECG) abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study evaluations have begun (after signing of the ICF)

Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease 
or disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen
6.11.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs and 
SAEs will be recorded from the time of the signing of the informed consent form (ICF) and, if 
applicable, the informed assent form, through the last study visit (visit 28 or EOS).  SAEs will be 
monitored with a telephone call by the investigator, as necessary, for approximately 4 weeks 
after the last dose of study drug or until resolution or until the SAE is judged by the investigator 
to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  The following features are recorded also:

Onset and stop date and time

Frequency (intermittent, continuous)

Severity (mild, moderate, severe)

Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities

Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs 
usual activities

Severe:  requires vigorous therapeutic intervention and interrupts usual activities; 
hospitalization may or may not be required.


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
Note that the severity of adverse events that constitute dose interruption criteria 
will also be evaluated using the NCI CTCAE grading criteria (Section 6.14)
6.11.3
Relationship to study drug (not related, related)
A physician/investigator must make the assessment of relationship to investigational product for 
each AE.  The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product.  If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”.  Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”.  The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the investigational product 
is compelling and/or follows a known or suspected response pattern to that product, and the event 
cannot be explained by the subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic relationship 
exists between the investigational product and the event.

Whether the AE is serious (ie, an SAE).  An event identified as an SAE should be 
reported on the form entitled “Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol” (Section 6.12)

Actions taken with regards to study drug:  none; study drug dose changed, interrupted, or 
permanently discontinued/withdrawn

Other action taken

Outcome:  fatal; not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; recovering/resolving; unknown
Adverse events that are related to study drug that are not resolved at EOT will be followed until 
the event resolves or stabilizes, as judged by the investigator.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if:

The investigator considers the finding to be a clinically significant change from the 
baseline visit (day 0)

The finding fulfills SAE criteria, and/or

The finding results in subject discontinuation


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6.11.4
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE.  Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.
Abuse – Persistent or sporadic intentional intake of investigational product when used for a non-
medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society
Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed at 
the dose prescribed by the protocol)
Overdose – Administration of a dose greater than the allocated dose of study drug or at a 
frequency greater than the dosing interval specified by the protocol
Medication Error – An error made in prescribing, dispensing, administration, and/or use of an 
investigational product.  For studies, medication errors are reportable to the sponsor only as 
defined below.

Cases of subjects missing doses of the investigational product are not considered 
reportable as medication errors.

Medication errors should be collected and reported for all products under investigation.

The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.

The administration and/or use of an expired investigational product should be considered 
as a reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
6.12
Serious Adverse Events
An SAE must be reported as described in Section 6.12.2 and recorded on the sponsor’s form
entitled “Shire Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-
serious AEs as Required by Protocol”.  An SAE requires expeditious handling to comply with 
regulatory requirements.  Any SAE that occurs from the time of the signing of the ICF through 
last study visit (visit 28 or EOS) will be captured and must be reported within 24 hours after the 
investigator or the investigator’s site personnel is made aware of the event.
Note:  The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless they result in an SAE.


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6.12.1
Serious Adverse Event Definition
An SAE is an AE that has any of the following outcomes:

Death

Is life-threatening: a life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred.  It 
does not include a reaction that, had it occurred in a more serious form, might have 
caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal 
life functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study

Are for elective treatment of a condition unrelated to the studied indication or its 
treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling 
the previous criteria)

Are part of the normal treatment or monitoring of the studied indication and not
associated with any deterioration in condition
Any laboratory test result that meets the criteria for an SAE must also be recorded on the 
sponsor’s form entitled “Shire Clinical Study Adverse Event Form for Serious Adverse Events 
(SAEs) and Non-serious AEs as Required by Protocol” so that the sponsor/designee can collect 
additional information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome.
6.12.2
Procedures for Reporting Serious Adverse Events
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor within 
24 hours of the first awareness of the event.  Note: The 24-hour reporting requirement for SAEs 
does not apply to reports of abuse, misuse, overdose, or medication errors unless the event results 
in an SAE.
The investigator must complete, sign, and date the form entitled “Shire Clinical Study Serious 
Adverse Event and Non-serious AEs Required by Protocol” and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 


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Pharmacovigilance and Risk Management Department. A copy of the sponsor’s form (and any 
applicable follow-up reports) must also be sent to the Shire medical monitor using the details 
specified in the key sponsor contact information provided at the beginning of the protocol.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator and/or the investigator’s site personnel at any interval after the study has completed 
must be reported to Shire’s Pharmacovigilance and Risk Management Department within 
24 hours of the first awareness of the event.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline
or

Becomes stable to a clinically acceptable level that is safe for the subject
The investigator is required to assess the causal relationship of each reported SAE to the study 
drug (see below).  A causality assessment should always be included on the “Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” form.  The investigator should make the causality assessment based on 
the information available at the time of the event.  The causality can be updated at a future date if 
additional information is received.
Relationship of an AE to investigational product is to be determined by the 
physician/investigator based on the definitions of “related” and “not related” provided in 
Section 6.11.2.
Contact information for SAE reporting and emergency contact details can be found in the key 
sponsor contact information provided at the beginning of the protocol and in the Investigator Site 
File.
As required by International Council of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Lack of causality does not 
negate SAE reporting requirements to the sponsor.  An AE, whether serious or not serious, is 
designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator’s brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 
expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.
The investigator should also comply with the IEC/IRB procedures for reporting any other safety 
information.


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The sponsor/designee will be responsible for submitting SUSAR reports to the appropriate health 
authorities.  These reports will be submitted within the expedited timeframe.  All fatal and life-
threatening SUSAR reports will be submitted by the sponsor or designee within 7 days of receipt 
(day 0) of the initial report.  All other SUSAR reports will be submitted by day 15 following the 
event.
6.13
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the sponsor’s product or program and for which ongoing monitoring 
and immediate notification by the investigator to the sponsor is required.
The AESIs that require expedited reporting for this study include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the gastrointestinal tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AESIs, the sponsor will be informed within 24 hours as per the SAE notification instructions 
described in Section 6.12.2 even if the event does not fulfill the serious criterion.
6.14
Dose Interruption of Individual Subjects in the Teduglutide Treatment Arm
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted.  Attempts should be make to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but 
are not limited to hospitalization, incidents of certain AEs, SAEs considered to be related to the 
study drug, a lapse in investigational product delivery, etc.
Study drug (teduglutide) must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include anti-teduglutide antibodies, mild injection site 
reactions or mild symptoms that according to the investigator do not pose a significant 
risk to the subject.

An AE listed in Table 6-1 that is of NCI CTCAE severity Grade 3 or 4 and considered to 
be related to study drug administration

Confirmed drug-induced liver injury (DILI) related to teduglutide (See Section 6.14.2).
6.14.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The study drug may be discontinued if the subject has an adverse event listed in Table 6-1 that is 
of severity ≥Grade 3 per the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (NCI CTCAE).  All such AEs should be discussed with Shire’s medical monitor 
as soon as possible. Teduglutide administration must be discontinued if the AE is considered 
related to study drug. The length of discontinuation, whether it is temporary or permanent, 
depends on the clinical situation.


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Investigators and the DMC members should be guided by the descriptions of Grade 3 and 4 
events presented in Table 6-1.
Table 6-1
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal disorders
Colorectal polyps
Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of existing 
hospitalization indicated; disabling; limiting self-care 
activities of daily living
Life-threatening consequences;
urgent intervention indicated
Intestinal 
Obstruction
Hospitalization indicated; elective operative intervention 
indicated; limiting self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct diseases
Cholecystitis
Severe symptoms; radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Gallbladder 
perforation
Not Applicable
Life-threatening consequences;
urgent intervention indicated
Gallbladder 
obstruction
Symptomatic and severely altered gastrointestinal 
function; tube feeding, total parenteral nutrition or
hospitalization indicated; nonemergent operative 
intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Gallbladder 
infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative intervention 
indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline 
Phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin 
increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; radiologic, 
endoscopic, or elective operative intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Pancreatic diseases
Pancreatitis
Severe pain; vomiting; medical intervention indicated 
(eg, analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Pancreatic duct 
stenosis
Severely altered gastrointestinal function; tube feeding 
or hospitalization indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or antiviral 
intervention indicated; radiologic or operative
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase 
increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Cardiovascular diseases
Heart failure
Severe with symptoms at rest or with minimal 
activity or exertion; intervention indicated
Life-threatening consequences;
urgent intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)


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Table 6-1
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
ULN=upper limit of normal
a
In the setting of clinically acute and symptomatic pancreatitis 
Source:  Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
6.14.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (TBL >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (TBL >2x ULN or INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification labs and an inquiry should be made 
as to the presence of clinical symptoms consistent with new liver injury.  The subject should be 
followed closely to determine the trajectory of the laboratory abnormalities and to evaluate the 
cause of liver injury. This evaluation may include, as clinically indicated, consideration of 
sepsis, acute viral hepatitis (eg, HepA IgM, HepB sAg, HepC Ab, CMV IgM, EBV antibody 
panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (antinuclear, anti-smooth 
muscle, anti-actin, or anti-liver/kidney mucosal antibodies), intestinal failure associated liver 
disease, cardiovascular causes such as ischemic hepatitis, and concomitant hepatotoxic 
treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with Shire medical monitor.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
study drug.
6.15
Early Termination of the Clinical Study
The DMC members may recommend stopping the study if:

≥2 subjects being administered study drug develop the same event listed in Table 6-1 of 
severity CTCAE Grade 3


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or

1 subject develops an event listed in Table 6-1 of severity CTCAE Grade 4 that is 
attributable to teduglutide or is not reasonably related to the underlying disease process
6.16
Prior and Concomitant Treatments
All non-study treatments, including invasive and diagnostic procedures, herbal treatment, and 
vitamins received within 14 days before screening through week 28 or final study contact must 
be recorded on the appropriate section of the eCRF.  The following information should be 
included, as appropriate:

Medication name, route, dose, indication, dates used

Procedure type, reason, dates
Changes in any medication and/or dosage will be recorded on the eCRF.  See also Sections 5.3.4
and 8.1.
6.17
Female Subjects of Child-bearing Potential
Any female subject in the teduglutide treatment arm who has reached menarche must have a 
negative serum pregnancy test to enroll or continue in the study. Pregnancy tests will be 
performed at screening (serum HCG) and at all subsequent clinic visits (urine HCG).  Female 
subjects in the standard of care treatment arm will not be required to undergo pregnancy testing.  
Sexually active females of child-bearing potential (FOCBP) must use medically acceptable 
methods of birth control during and for 4 weeks after the treatment period (eg, true abstinence1, 
oral contraceptive pills, barrier methods with spermicide) in a manner such that the risk of failure 
is minimized.  The investigator will discuss these methods as well as their side effects with the 
subject.  If a pregnant subject also reports an SAE, then the SAE form will be completed and 
submitted within 24 hours.
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
discontinued immediately, unless clearly needed, and a Pregnancy Report Form should be 
completed to capture potential drug exposure during pregnancy.  The pregnancy should be 
reported within 24 hours of becoming aware of the condition.  The subject should be followed 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
(miscarriage), voluntary abortion, or therapeutic abortion).
                                                
1 True abstinence:  Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception).


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6.18
Unblinding
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the dose of the investigational product is required for further 
treatment of the subject.  If warranted, the principal investigator or designee will place an 
unblinding call to the IWRS to receive treatment assignment information. The investigator 
should contact the Shire medical monitor as soon as possible after the investigator has been 
unblinded.  Greater detail is provided in the Investigator Site File.
In the event that the treatment assignment is broken, the date, the name of the person who broke 
the code and the reason for breaking the code are recorded in the IWRS and the source 
documents.  Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes.


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
Informed consent/assenta
X
Eligibility
X
X
Demographics
X
Medical/Surgical history
X
Electrocardiogram
X
X
Short bowel syndrome history
X
Upper GI with small bowel follow through and 
abdominal ultrasoundb
X
Fecal occult blood testc 
X
X
Colonoscopy/Sigmoidoscopyc
(X)
(X)
Provide GI-specific symptoms history diary
X
Review GI-specific symptoms history diary
X
Randomizationd
X
Dispense druge
X
X
X
X
X
X
X
X
Pharmacokinetic samplingf
Xf
Safety laboratory testingg
Xh
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testh
X
X
X
X
X
X
X
X
X
Citrulline testi
X
X
Antibodies to teduglutidej
X
Provide intake and output diaries
X
X
X
X
X
X
X
X
X
Review diaries and nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
PE/Vitals/Weight
X
X
X
X
X
X
X
X
X
Height (or length) and head circumferencem
X
X
X
X
X
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; BL=baseline; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; S=site; 
SRN=screening; T=telephone; W=week
Note:  Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate subject visits to the site.
a
Informed consent/assent must be obtained before performing any study-related procedure.
b
If the subject has undergone an upper GI with small bowel follow through and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable 
for the screening assessments.  If the subject has not had these procedures within the 6 months before visit 1 (screening), then the procedure(s) will be performed any time after providing 
informed consent with the results available and reviewed before the baseline visit (day 0).
c
All subjects enrolled in a treatment arm will have an FOBT after providing consent/assent.  Subjects with positive FOBT at screening for whom a readily detectable cause cannot be not identified 
(eg, anal fissure) will undergo a colonoscopy/sigmoidoscopy.  Colonoscopy/sigmoidoscopy will be conducted at screening on all subjects 12 years of age and older; however if the screening 
FOBT is negative and the subject has undergone the procedure within 1 year before visit 1 (screening), then that result will be acceptable for the screening assessment (See Section 6.5.4).  
Subjects with positive FOBT results at week 12 for which a cause is not identified by a physical exam will be discussed with the Shire medical monitor (See Section 6.5.3).
d
Treatment arm assignment and randomization and will be completed before dispensing teduglutide.
e
The first subcutaneous injection of teduglutide will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at 
least 4 hours. The site of administration (arm, thigh, abdomen) must be specified and recorded in the eCRF.  Teduglutide dose may be adjusted based on weight at week 12.
f
See Section 6.1 for PK blood draw timepoints.  If a subject is unable to provide blood samples for PK at the baseline visit (day 0), then PK samples may be collected during any other future site 
visit while the subject is still receiving treatment with teduglutide.
g
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits may be collected 
by a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should 
be attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed approximately within 5-7 days of any adjustment to the PN/IV 
prescription.  For all subjects in the teduglutide treatment arm, PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine thereafter.
i
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
j
For antibody testing, blood will be obtained from subjects in the teduglutide treatment arm at the site before receiving the first dose of teduglutide. Blood samples may be drawn from a central 
line or from peripheral access (See Section 6.6.1.2).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
m
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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Table 6-3
Schedule of Events in the Teduglutide Treatment Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense drug
X
X
X
Provide intake and output diaries
X
X
X
X
Review diaries and nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testingd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Pregnancy teste
X
X
X
X
X
Citrulline testf
X
X
PE/vitals/weight/height (or length)/head 
circumferenceg
X
X
X
X
X
Fecal occult blood testh
X
Colonoscopy/Sigmoidoscopy
(X)
Electrocardiogram
X 
X
Antibodies to teduglutidei
X
X
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; S=site visit; 
T=telephone contact; W=week
a
Any subject who discontinues from the study before week 24 (EOT) (ie, early terminates) will undergo EOT procedures at the time of discontinuation and will complete a follow-up visit 4 weeks 
later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.


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Table 6-3
Schedule of Events in the Teduglutide Treatment Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
d
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected by 
a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the PN/IV 
prescription.  For all subjects in the teduglutide treatment arm, PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine thereafter.
f
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
g
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).
h
Subjects with positive FOBT at week 24 (EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory colonoscopy/sigmoidoscopy.  See 
Section 6.5.3.
i
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, ≥14 hours after the previous dose of teduglutide. If a blood sample is positive for antibodies at week 28 or EOS, 
then the subject will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 6 months after EOT.


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Table 6-4
Schedule of Events in the Standard of Care Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
Informed consent/assenta
X
Eligibility
X
X
Demographics
X
Medical/Surgical history
X
Electrocardiogram
X
X
Short bowel syndrome history
X
Provide GI-specific symptoms history diary
X
Review GI-specific symptoms history diary
X
Safety laboratory testingb
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Citrulline testc
X
X
Provide intake and output diaries
X
X
X
X
X
X
X
X
X
Review diaries and nutritional supportd
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportg
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
PE/Vitals/Weight
X
X
X
X
X
X
X
X
X
Height (or length) and head circumferenceh
X
X
X
X
X
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; AE=adverse event; BL=baseline; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PE=physical examination; PN/IV=parenteral nutrition/intravenous 
fluid; S=site; SRN=screening; T=telephone; W=week
Note:  Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate subject visits to the site.
a
Informed consent/assent must be obtained before performing any study-related procedure.
b
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected 
by a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should 
be attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the 
PN/IV prescription.
c
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
d
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 


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Table 6-4
Schedule of Events in the Standard of Care Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
e
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.
f
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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Table 6-5
Schedule of Events in the Standard of Care Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Provide Intake and Output diaries
X
X
X
X
Diary and nutritional support reviewb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testingd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Citrulline teste
X
X
PE/vitals/weight/height (or length)/head 
circumferencef
X
X
X
X
X
Electrocardiogram
X 
X
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; 
S=site visit; T=telephone contact; W=week
a
Any subject who discontinues from the study before week 24 (EOT) (ie, early terminates) will undergo EOT procedures at the time of discontinuation and will complete a follow-up visit 4 weeks 
later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.
d
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected by 
a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the PN/IV 
prescription.
e
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
f
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
8-digit subject number, including subjects in the SOC treatment arm.  The first 4 digits consist of 
the study site number.  The last four digits will be assigned sequentially starting with 0001.  This 
number is the main identifier for subjects. 
Data collected during the study will be recorded in the subject’s eCRF by the investigational site 
staff.  The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.).  Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments).  In case of 
computerized source data, the investigator must provide Shire access to the subject files at each 
monitoring visit.  To ensure that data has been entered correctly on the eCRF, they will be 100% 
source-data verified by a site monitor from the sponsor/designee, who will notify the investigator 
regarding any questions or discrepant data.  The investigator or designee will be responsible for 
the timely recording of subject data into the eCRF.
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents.
The investigator or designee will review all eCRFs (including the termination page after the 
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the appropriate 
vendor.  Paper copies of laboratory reports and other non-eCRF data (eg, ECGs) will be signed 
and dated by the investigator and filed.
Diaries will be used by the subjects’ parent or guardian to record study information, including 
PN/IV support, enteral administration, urine output (as either collected or calculated volume), 
stool form and volume, and urine specific gravity. The subject diaries will provide the source 
documentation for the diary data that is to be recorded in the eCRF by the study staff.  Original 
diary data should be entered into the eCRF and takes precedence over data collected over the 
phone.
All data collected in this study will be entered into a study-specific database and submitted for 
statistical evaluation. The sites will be provided with eCRF completion guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that must be 
resolved at the study site in a timely manner. 
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor/designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.


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A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the database, 
the database will be ready for statistical analysis by the sponsor/designee.
7.2
Rescreening
Subjects may be rescreened only once and with prior sponsor approval. In the event of 
re-screening, a new subject number will be assigned.  Subjects who are rescreened will be 
reconsented.  See also Section 5.2.
7.3
Record Retention
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines.  These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject consent/assent 
documents, ECGs, photographs, and computer records) which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and evaluation of 
any study report.
The clinical investigators will maintain copies of these essential documents for approximately 10 
years or as dictated by local regulatory requirements or until instructed in writing by the sponsor 
that records may be destroyed or forwarded to the sponsor.  In accordance with regulatory 
guidelines, these records will be available for inspection and copying if requested by a properly 
authorized employee of the FDA/European Health Authorities.


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8
STATISTICAL METHODOLOGY AND SAMPLE SIZE
Detailed statistical analysis methods will be conducted as described in the statistical analysis 
plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in the 
clinical study report (CSR).
Because of the small size of the study population only descriptive statistics will be used to 
summarize data.  Accordingly, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum. For categorical variables, statistical summaries will include number of subjects 
and percentages.
8.1
Demographic and Baseline Variables
Demographic and/or other baseline variables obtained at the screening or baseline visit are listed 
below.

Demography (including age, sex, and race)

Medical history

SBS history, including remnant anatomy

GI-specific symptoms history

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), and height or length

Physical examination

Prior treatment(s)

Electrocardiogram (12-lead)

Laboratory test results:  hematology, coagulation, clinical chemistry, and urinalysis

Citrulline levels

Presence of antibodies to teduglutide and titer level, if present (teduglutide treatment arm
only)

Gastrointestinal imaging (UGI/SBFT, abdominal ultrasound, colonoscopy/sigmoidoscopy, 
fecal occult blood) (teduglutide treatment arm only)

Pregnancy testing for females of child-bearing potential (teduglutide treatment arm only)

Nutritional support prescriptions (eg, PN/IV and EN volume and calories, PN/IV hours per 
day and days per week)

Nutritional support diary data
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories by treatment arm) will be presented, as 
appropriate, to summarize the demographic and baseline variables. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name.  The number and percentage of subjects 
with specific prior medications will be summarized by treatment and SOC treatment arms.
Medical history (including surgical/procedural history) will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  The number and percentage of subjects with 


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specific histories will be summarized by system organ class and preferred term for each study 
arm.
8.2
Safety and Tolerability Variables
The safety and tolerability variables include:

Adverse events, including GI symptoms

Physical examination findings

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts

Electrocardiograms

Laboratory safety data (ie, clinical chemistry, coagulation, hematology, urinalysis), 
including the following lab tests at all clinic visits and interim safety labs to detect 
hepatoxicity signals:  AST, ALT, ALP, and bilirubin

Change in urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide (teduglutide treatment arm only)

GI-specific testing (teduglutide treatment arm only) including colonoscopy or 
sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment emergent AEs will be summarized by 
system organ class and preferred term for each treatment arm (teduglutide and SOC). The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and SAEs that resulted in a fatal outcome will 
be summarized by treatment arm and teduglutide dose group. AEs will also be summarized by 
treatment arm and dose group with regard to severity and, for the teduglutide dose groups,
relationship to study drug.  For AESIs, the CTCAE grading system will be used as described in 
Section 6.14.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit for each study arm.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment arm.
8.3
Pharmacokinetic Variables
The following pharmacokinetic parameters will be estimated using a population PK modeling 
approach:


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
Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUClast)

AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Time to Cmax (Tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, 
geometric mean, the number and percentage of subjects in specified categories) will be 
calculated to summarize the absolute values and change from baseline at each scheduled visit.
8.4
Efficacy/Pharmacodynamic Variables
The primary efficacy/PD endpoint is a reduction in PN/IV volume of at least 20% at week 24 
(or EOT) compared to baseline.
The following efficacy/PD parameters will be measured:

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or 
EOT) compared to baseline

Change from baseline (absolute and percent change) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories) at each clinic 
visit

Change from week 24 (or EOT) (absolute and percent change) in PN/IV support (volume 
and calories), citrulline, and enteral nutritional support (volume and calories) at week 28 
(or EOS)

Change in hours per day and days per week of PN/IV support

≥20% reduction in PN/IV volume at each clinic visit
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, the 
number and percentage of subjects in specified categories) will be calculated to summarize the 
absolute values and change from baseline at each scheduled visit for each study arm and 
teduglutide dose group.
8.5
Other Variables
Other variables will be analyzed by study arm and dose group, as appropriate, including:


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
Subject disposition

Duration of teduglutide exposure

Subjects will be considered compliant if teduglutide was taken according to protocol and
assigned dose group for ≥80% of doses.  Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment arm.

The number and percentage of subjects who complete the study, are lost to follow up, or 
discontinued from the study (including reason for study withdrawal) will be summarized 
by dose group.

The teduglutide dose duration will be summarized by dose group.
8.6
Analysis Populations, Data Sets, and Time Points
8.6.1
Analysis Populations
The efficacy population will consist of all enrolled subjects.
The safety population will include all subjects in the efficacy population who meet the 
following criteria:

Teduglutide treatment arm:  subjects who have received at least 1 dose of teduglutide and 
have undergone at least 1 safety assessment

SOC treatment arm:  subjects who have undergone at least 1 safety assessment
The per protocol population will consist of all subjects in the efficacy population who have 
completed the study through EOT (week 24) without incidence of a major protocol violation that 
could affect the efficacy/PD conclusions of the study
The PK population will consist of all enrolled subjects who receive at least one subcutaneous 
injection of teduglutide and have evaluable and interpretable PK data.
Detailed per-protocol evaluable definitions will be documented in the SAP.  Major protocol 
violations will be determined before database lock.
The primary population analyzed for efficacy/PD will be the efficacy population.  An additional 
per-protocol population analysis will also be performed as secondary/sensitivity analysis.
8.7
Statistical/Analytical Issues
8.7.1
Adjustments for Covariates
Not applicable for this study.
8.7.2
Handling of Dropouts or Missing Data
All subjects randomized will be included in the analyses. Missing safety parameters will not be 
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV volume 
will be detailed in the SAP.
8.7.3
Interim Analyses and Data Monitoring
No interim analyses are planned.


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An independent DMC will review the data on a routine basis and may have access to data from 
the study for safety assessment. Details of the roles and responsibilities of the DMC members 
and the structure and scope of the DMC meetings will be provided in a separate DMC Charter.
8.7.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Accordingly, no 
adjustment to the alpha will be made.
8.7.5
Use of an Efficacy Subset of Subjects
A per-protocol population will be analyzed for this study.
8.7.6
Examination of Subgroups
Data from subjects in the teduglutide dose groups will be analyzed according to age strata 
(subjects aged <1 year, 1 to <12 years, 12 to <17 years, and 17 to <18 years) and by glutamine 
use, separately.
8.8
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.
8.9
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final CSR.


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9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the current applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association Declaration of Helsinki and its 
amendments concerning medical research in humans.
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent 
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant material 
for the investigator to submit to the IRB for the protocol’s review and approval.  Verification of 
the IEC/IRB approval of the protocol and the written consent/assent form will be forwarded to 
the sponsor/designee.
The investigator will inform the IEC/IRB of subsequent protocol amendments and any SUSARs 
if the sponsor has assessed it as an unanticipated problem.  Approval for protocol amendments 
will be transmitted in writing to the investigator.
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information, Informed Consent and Assent
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate.
The investigator (or designee) will explain to the subject and/or the subject’s parent or guardian 
the nature of the study, the action of the test product, and any risks and benefits.  The subject 
and/or subject’s parent or guardian will be informed that participation is voluntary and that the 
subject can be withdrawn from the study at any time without prejudice to their subsequent care.
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor/designee will be identified only by subject number and initials, 
thereby ensuring that the subject’s identity remains unknown.  Where allowed, the subject’s date 
of birth will also be recorded. The subject and/or the subjects’ parent or guardian should be 
informed in writing, that the subject’s data will be stored and analyzed in a computer, with 
confidentiality maintained in accordance with national and local legislation.  Study site-specific 
information must be added to the consent/assent as appropriate.
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 


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access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, and 
a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed screening 
must also be maintained and be available for inspection.
9.4
Financial Disclosure
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” (February 
2013) provides guidance to industry on its final rule on financial disclosure that became effective 
02 February 1999 and was published as Title 21 Code of Federal Regulations Part 54.  This rule 
applies to all investigators participating in clinical studies to be submitted to the FDA in support 
of an application for market approval.  The financial disclosure statement must be updated if any 
relevant changes occur during the course of the study, again at the site close-out visit, and for 1 
year after the completion of the study.
According to the guidance, financial arrangements that must be disclosed are defined as the 
following:

Compensation made to the investigator in which the value of compensation could be 
affected by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or 
the investigator’s institution to support activities of the investigator exclusive of the costs 
of conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing 
research, compensation in the form of equipment or retainers for ongoing consultation, or 
honoraria) during the time the clinical investigator is carrying out the study and for 1 year 
after completion of the study
Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes the 
spouse and each dependent child of the investigator.  Participating investigators must provide 
this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA in 
support of a market application.  Companies must meet these financial disclosure requirements, 
and failure to do so may result in the refusal by the FDA to accept an application for market 
approval of the study drug.


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9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the sponsor 
and the investigator.  All changes must be documented as signed protocol amendments, or as a 
revised protocol.  Changes to the protocol may require notification to or approval by the 
IEC/IRB and the regulatory authorities before implementation. Local regulatory requirements 
must be followed.  Instructions for reporting deviations from the protocol can be found in the 
Study Reference Manual.
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site.
9.6
Investigator Obligations
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address 
which matches the address on the FDA Form 1572

Financial disclosure statement for the principal investigator, and subinvestigators (listed 
on the FDA Form 1572).  An updated financial disclosure statement must be provided at 
the study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study.

A copy of the original approval for conducting the study from the IEC/IRB. Renewals 
must be submitted at yearly intervals if the study is ongoing or as required by the 
institution.

A copy of the IEC/IRB-approved ICF/assent

IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and dated 
by the principal investigator for the study site.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
and/or for submission to regulatory agencies.  In addition, the sponsor reserves the right to 


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review data from this study relative to the potential release of proprietary information 30 days 
prior to submission to any publication or for any presentation.
9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all investigators 
for this study.  Roles, affiliations, and qualifications for the principal investigators will be 
included in the CSR appendices.  Where the signature of the principal investigator is required by 
regulatory authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


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10
REFERENCES
Buchman, A. L., Scolapio, J. & Fryer, J. 2003. AGA technical review on short bowel syndrome 
and intestinal transplantation. Gastroenterology, 124, 1111-34.
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Fleming, C. R., Witzke, D. J. & Beart, R. W., Jr. 1980. Catheter-related complications in patients 
receiving home parenteral nutrition. Ann Surg, 192, 593-9.
Jeppesen, P. B. & Mortensen, P. B. 2000. Intestinal failure defined by measurements of intestinal 
energy and wet weight absorption. Gut, 46, 701-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Messing, B., Crenn, P., Beau, P., Boutron-Ruault, M. C., Rambaud, J. C. & Matuchansky, C. 
1999. Long-term survival and parenteral nutrition dependence in adult patients with the 
short bowel syndrome. Gastroenterology, 117, 1043-50.
O'keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., De Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.


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Appendix 1
Guidelines for Nutritional Support Management during the Study 
(TED-C14-006)
Nutritional support adjustment in volume and calories should be considered at all planned visits.  
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric short bowel syndrome.  These parameters should be considered for managing 
nutritional support (PN/IV and EN) in terms of volume and calories during the treatment period.

Growth trajectory, including weight, height (or length), and head circumference (for 
children up to 36 months of age)

Other clinical evaluations
◦
Serum electrolytes
◦
BUN/creatinine levels
◦
Changes in stool frequency or volume, including mixed output
◦
Stool consistency (ie, Bristol Stool Scale)
◦
Urine specific gravity

General consideration to possible clinical deterioration in SBS
◦
Inability to maintain weight and growth velocity
◦
Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)
◦
Colic/vomiting frequency increased
◦
Electrolyte changes or imbalance
◦
Skin breakdown

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses.  Subjects should remain compliant with the nutritional support 
prescription in volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour Intake/Output measurement period prior to the subject’s scheduled 
visit, no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food or fluid intake, the investigator should consider 
this when adjusting the PN/EN support in volume and calories.


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Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers


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Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers


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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment


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Appendix 2
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
12 Mar 2015
Global
Amendment 1
22 Jun 2015
Global
Amendment 2
06 October 2015
Global
Amendment 3
25 February 2016
Global
Amendment 4*
15 March 2016
Global
*Amendment 4 was created because a quality control error was identified in amendment 3, in 
which one of the exclusion criterion was not replicated in the synopsis.
Note:  Administrative changes, typographical errors, and text changes made to increase 
readability are not listed in the table below.
Protocol Amendments
Summary of Change(s) Since Amendment 3 of Approved Protocol
Differences between amendment 
number 3 and amendment 
number 4
Amendment Date
15 Mar 2016
Global/Country/Site Specific
Global
A quality control error was identified in amendment 3, in which an exclusion criterion was not replicated in 
the synopsis.  Sections affected are the Synopsis and Section 4.2.2.
Note:  Administrative changes, typographical errors, and text changes made to increase 
readability are not listed in the table below.
Protocol Amendments
Summary of Change(s) Since Amendment 2 of Approved Protocol
Differences between amendment 
number 2 and amendment 
number 3
Amendment Date
25 Feb 2016
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Key study contacts have been updated
Page 2
Product Quality Complaints information has been updated
Page 3
Methodology has been clarified; no changes were made to the overall 
design; clarified terminology for treatment arm and dose group 
Synopsis
Protocol Section 3.1
Section 3.2
Statement added that subjects who complete the study may participate 
in a long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Protocol Section 3.1
Inclusion and Exclusion have been refined and clarified; there were no 
additional criteria added
Synopsis
Protocol Sections 4.2.1 and 4.2.2
Exclusion Criteria #11 has been updated to indicate that a subject 
would be excluded from the study if the subject had participated in a
clinical study of experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
Synopsis
Protocol Section 4.2.2
Number of subjects in the teduglutide treatment arms was changed 
from approximately 20 to approximately 26; the number of global 
Synopsis


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investigational sites was changed from approximately 20 to 
approximately 28.
Protocol Section 4.1
Language strengthened describing the number of subjects enrolling 
into the SOC treatment arm:  “attempts will be made to enroll” has 
been changed to “at least 8 subjects who are teduglutide-naïve will be 
enrolled”.
Synopsis
Protocol Section 4.1
Language has been added to indicate that attempts will be made to 
enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
Synopsis
Protocol Section 4.1
Section 5.2
Clarification that departing from the nutritional support adjustment 
guidelines provided in Appendix 1 will not constitute a protocol 
deviation.
Synopsis
Protocol Section 3.1
Section 6.4
Specified that randomization across teduglutide dose groups will be 
stratified by age subgroups. 
Synopsis
Protocol Section 3.1
Section 5.2
The requirement that teduglutide should be administered in the 
morning has been removed.
Protocol Section 5.3.2
Reviewing subject diaries has been included in the subject compliance 
with dosing check.
Protocol Section 5.3.3
Section 7.1
The definition of prior and concomitant medications has been 
expanded to include treatments.
Protocol Section 5.3.4, Section 
6.16;Table 6-2, Table 6-3, Table 
6-4, and Table 6-5
The Data Safety Monitoring Board has been replaced with a Data 
Monitoring Committee.
Synopsis
Protocol Section 4.4
A pharmacokinetic component has been added to the study as a 
criterion for evaluation.
Synopsis
Protocol Sections 6.1, 8.3, and 
8.6.1; Table 6-2
Adverse event and serious advent definitions and reporting procedures 
have been updated to align with Shire processes.  Definitions for 
abuse, misuse, overdose, and medication error have been added.
Protocol Sections 6.3 and 6.12; and 
subsections therein
Adverse events of special interest have been redefined and procedures 
for reporting them have been added.
Protocol Section 6.13
Dose interruption of individual subjects in the teduglutide treatment 
arm has been broken out according to known risks of teduglutide 
administration and to drug-induced liver injury
Protocol Sections 6.14 and added 
sections within; new Table 6-1
Criteria for DILI have been added.
Protocol Section 6.14.2
PT/INR testing has been added at screening for subjects in the 
teduglutide treatment arm and if DILI is suspected thereafter.
Protocol Section 6.6.1; Table 6-2
and Table 6-3
Dose discontinuation has been made absolute for an AE known to be a 
study drug risk that is of severity ≥Grade 3 and considered to be 
related to study drug; cases of severe hypersensitivity that are
determined to be related to study drug; DILI that is related to 
teduglutide, and pregnancy.  SAEs related to study drug are potential 
but not absolute reasons for dose discontinuation.
Protocol Section 6.14.2 and 
sections added within; new 
Table 6-1
Requirement added that female subjects of child-bearing potential in 
the teduglutide treatment arm have a serum-based pregnancy test at 
screening.
Protocol Section 6.17 and Table 
6-2


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Procedures for unblinding have been made consistent with the EMA 
GCP guidance that breaking of treatment code resides with the 
investigator in emergency situations 
Protocol Section 6.18
“Other nutrition (regular diet and drink)” has been removed from the 
Intake diary.
Protocol Section 6.6
Section 7.1
Decrease frequency of capturing Output diary data to the 48 hours of 
PN/IV and EN stability before every clinic visit and within 1 week of 
implementing a change in the PN/IV prescription.
Protocol Section 6.6; Table 6-2, 
Table 6-3, Table 6-4, and Table 
6-5
The need for a subject in the teduglutide treatment arm with a positive 
FOBT at week 12 without a readily identifiable cause to undergo a 
colonoscopy/sigmoidoscopy is now open to discussion with the Shire 
medical monitor.
Protocol Sections 6.5.3 and Table 
6-2
The requirement has been added that subjects who are rescreened 
must be reconsented.
Protocol Section 7.2
Definitions of analysis populations have been updated.
Protocol Section 8.6.1
Subgroup analyses have been added based on glutamine use and age 
strata, separately, for subjects in the teduglutide dose groups.
Protocol Section 8.7.6
Correct amendment 2 summary of change document which misstated 
that investigators no longer were required to assign CTCAE severity 
grades to adverse events that may lead to dose interruption.
Not applicable

Prot_005.pdf: 
 
 
 
 
A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 
17 Years of Age with Short Bowel Syndrome who are Dependent on 
Parenteral Support 
 
 
Clinical Study Protocol TED-C14-006 
Version 3.0 
 
 
 
Phase 3 
 
 
 
US IND# 058213  
US NDA# 203441 
EuDRACT #2015-002252-27 
 
 
 
NPS Pharmaceuticals, Inc. 
550 Hills Drive, 3rd Floor 
Bedminster, NJ 07921 
USA 
 
 
 
ISSUED: 
 
Amendment 2, version 3.0  
 
06 October 2015 
Amendment 1, version 2.0:  
 
22 June 2015 
Original Protocol version 1.0: 
 
12 March 2015 
 
 


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Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
Page 4 of 78 
 
Final v3.0 
06 October 2015 
SYNOPSIS 
Protocol TED-C14-006 
Title of Study: A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with 
Short Bowel Syndrome who are Dependent on Parenteral Support 
Protocol No: TED-C14-006 
Phase of development: 3 
Objectives: The objective of this clinical study is to evaluate the safety, tolerability, efficacy, 
and pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with short 
bowel syndrome (SBS) who are dependent on parenteral support. 
Methodology: This will be a double-blind, 2-arm study in which subjects will be randomized in 
a 1:1 ratio to receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks 
followed by 4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators 
and subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of 
care group, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up. The subjects in the standard of care group will follow the same visit schedule 
as the randomized subjects. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. After screening, the 24-week treatment period will consist of site visits at baseline, 
weekly for the first 2 weeks (Weeks 1 and 2), and then every other week through Week 12 
(Weeks 4, 6, 8, 10, and 12). For the remainder of the treatment period, visits at the sites will be 
conducted every 3 weeks (at Weeks 15, 18, 21, and 24). Telephone contacts will be made on all 
other weeks during the treatment period. At all site visits and telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed. A final visit will be 
scheduled at Week 28, 4 weeks following the end of treatment (EOT). Telephone contact will be 
made during the interim weeks from EOT to end of study (EOS) to monitor safety and any 
changes in nutritional support. 
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input and 
provided in the protocol) for decisions regarding PN/IV support reduction and advances in 
enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability. 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
Page 5 of 78 
 
Final v3.0 
06 October 2015 
Safety and tolerability results will be evaluated by a Data Safety Monitoring Board (DSMB) 
approximately every 3 months during the active study period (date of the first subject’s first dose 
to date of the last subject’s last dose).  The DSMB review will include all cumulative safety data 
(ie, adverse events, laboratory assessments, physical examinations, etc.) from study assessments 
through each cutoff period period. 
Number of Subjects:  Approximately 20 teduglutide-naïve subjects (at least 10 subjects per 
treatment arm) will be enrolled into the active treatment groups at approximately 
20 investigational sites globally. 
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in a standard of 
care group (who will not be treated with teduglutide) to serve as an observational cohort. 
Duration of Study:  There will be, at a minimum, a 2-week screening period followed by 
24 weeks of treatment. There will be one final scheduled clinic visit at Week 28, 4 weeks after 
the EOT (Week 24).  
The start of the clinical phase is defined as first subject consented.  The end of the clinical phase 
is defined as the last visit of the last subject. 
Diagnosis and main criteria for inclusion:  Male and female children and adolescents, through 
17 years of age, who satisfy the following inclusion and exclusion criteria will be enrolled in the 
study. 
Inclusion Criteria 
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures  
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures  
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)  
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening 
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
Page 6 of 78 
 
Final v3.0 
06 October 2015 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event. 
6. Sexually active female subjects of child-bearing potential (in the active treatment group only) 
must use medically acceptable methods of birth control during and for 4 weeks after the 
treatment period 
Exclusion Criteria 
1. Subjects who are not expected to be able to advance oral or tube feeding regimens  
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support  
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome) 
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related dysmotility disorders, that is the primary contributing factor to 
feeding intolerance and inability to reduce parenteral support, prior to screening. Dysmotility 
is defined as severe if it is expected to limit the advancement of enteral feeding. 
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done 
within 6 months prior to screening 
7. Major gastrointestinal surgical intervention including significant intestinal resection within 
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤ 10 cm, or endoscopic procedure is allowed) 
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer 
10. Pregnant or lactating female subjects (in the active treatment group only) 


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Final v3.0 
06 October 2015 
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide 
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening  
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit 
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit 
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject 
19. Body weight < 10 kg at screening and randomization visits 
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results during the screening period: 
a. Total bilirubin ≥ 2 x upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) ≥ 7 x ULN 
c. Alanine aminotransferase (ALT) ≥ 7 x ULN 
For subjects with Gilbert’s disease:  
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN 
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2. 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
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Final v3.0 
06 October 2015 
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements 
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease 
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are listed 
in the table below. 
 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
Page 9 of 78 
 
Final v3.0 
06 October 2015 
Examples of Excluded Diseases and Illnesses 
Body system 
Known conditions excluded 
Related to SBS 
• Ongoing radiation enteritis  
• Untreated celiac disease 
• Refractory or tropical sprue 
• Pseudo-obstruction 
Gastrointestinal  
• Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced 
or changed during the last 3 months 
• IBD that requires chronic systemic immunosuppressant 
therapy for symptom control  
• Tufting or autoimmune enteropathy or microvillous 
inclusion disease 
• Untreated pre-malignant or malignant change in GI 
tract identified by upper GI series, biopsy or 
polypectomy 
• Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome) 
• Intestinal or other major surgery scheduled within the 
time frame of the study 
• Chronic active pancreatitis  
• Cholecystitis 
Immune 
• Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency). 
Psychiatric 
• Alcohol or drug addiction within the previous year 
• Major uncontrolled psychiatric illness  
General 
• Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system) 
 
 
Test Product, Dose, and Mode of Administration: 
After randomization, daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will 
be administered to the subjects in the active treatment groups.  The dose calculation will be 
based on body weight measured at the Baseline Visit (Visit 2) and adjusted, as needed, based on 
body weight measured at Week 12 (Visit 14).  No other adjustments to dose will be made during 
the study period, unless discussed with the sponsor’s medical monitor. 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
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Final v3.0 
06 October 2015 
Teduglutide will be administered by subcutaneous (SC) injection once daily in the morning into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma will not be used. 
Reference Therapy, Dose and Mode of Administration: 
Not applicable. 
Criteria for Evaluation: 
Safety and tolerability: 
Safety and tolerability will be assessed by evaluation of: 
• Adverse events, including GI symptoms.  A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline.  GI symptoms will be 
recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject. 
• Physical examinations 
• Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts 
• Electrocardiograms 
• Laboratory safety data, including clinical chemistry, hematology and urinalysis  
• Change in urine output (collected or calculated volume) 
• Fecal output (by volume or number of bowel movements per day) 
• Antibodies to teduglutide (active treatment groups only). Samples for antibody analysis will 
be drawn at baseline and at the EOT (Week 24 or early termination) visits prior to the 
administration of teduglutide and at least 14 hours after the previous dose. One additional 
sample will be collected at the final visit 4 weeks after the EOT (EOS, Week 28). If subjects 
are determined to have positive/specific antibodies at Week 28 or EOS, they will be asked to 
return for a follow-up clinic visit 3 months post EOT for another antibody sample.  If the 
subjects continued to have positive/specific antibodies at 3 months post EOT, they will be 
asked to return for a follow-up visit 6 months post-treatment in order to determine their 
antibody status.   
• GI-specific testing (active treatment groups only) including colonoscopy or sigmoidoscopy,  
abdominal ultrasound, fecal occult blood testing, upper GI series with small bowel follow 
through 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
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Final v3.0 
06 October 2015 
Pharmacodynamics: 
The primary pharmacodynamic (PD) parameter is PN/IV volume reduction of at least 20% at 
24 weeks (or EOT) compared to baseline. 
Analysis of additional PD endpoints will include: 
• 100% reduction in PN/IV support (any subjects who are able to completely wean off PN/IV 
support) compared to baseline at EOT 
• Change from baseline (absolute and percent change) in PN/IV support (volume and calories), 
citrulline, and enteral nutritional support (volume and calories) over time  
• Change from Week 24 (or EOT) (absolute and percent change) in PN/IV support (volume 
and calories), citrulline, and enteral nutritional support (volume and calories) at Week 28 (or 
EOS)   
• Change in body weight, height (or length) and head circumference (up to 36 months of age). 
Derived variables will include height Z-score, weight Z-score, body mass index (BMI), and 
BMI Z-score 
• Fecal output (by volume or number of bowel movements per day) 
• Change in hours per day and days per week of PN/IV support  
• Proportion of responders (ie, subjects who achieve at least a 20% reduction in PN/IV 
volume) over time 
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input) for 
decisions regarding PN/IV support reduction and advances in enteral feeds based on weight gain, 
urine, and stool output in the setting of clinical stability. 
Statistical methods: 
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum.  For categorical variables, statistical summaries will include number of subjects 
and percentages. 
Demographics and baseline: 
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate. 


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Teduglutide (rDNA origin) for injection 
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Final v3.0 
06 October 2015 
Efficacy/Pharmacodynamics: 
Efficacy/pharmacodynamics data including reduction in PN/IV support, increase in enteral  
nutritional support, change in fecal output, change in citrulline, weight Z-score, height Z-score, 
BMI Z-score, hours per day or days per week of PN/IV support, and time to PN/IV reduction and 
advance in enteral support will be summarized by visit and time point. 
Safety: 
Safety data including clinical laboratory tests, physical examinations, concomitant medications, 
electrocardiogram monitoring, and vital signs assessments will be summarized by visit and time 
point.  Adverse events will also be collected and summarized. Descriptive statistics will be 
calculated for quantitative safety data as well as for the difference from baseline, if applicable.  
Frequency counts will be compiled for classification of qualitative safety data. 
 
 


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Pediatric Study TED-C14-006 – Amendment 2 
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Page 14 of 78 
 
Final v3.0 
06 October 2015 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE 
Protocol TED-C14-006 
I agree: 
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor, 
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics 
Committee (IEC) for the study protocol and any amendments thereof, written informed consent 
or updates thereof, subject recruitment procedures (eg, advertisements), and any other written 
information to be provided to the subjects, before initiating this clinical study, 
Not to implement any changes to, or deviations from the protocol without prior agreement 
from the sponsor and review and documented approval from the IRB/IEC, except to eliminate 
an immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study, 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies), 
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable), 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely, 
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions, 
To maintain drug records, electronic copies of case report forms, laboratory records, data 
sheets, correspondence records, and signed subject consent/assent documents for at least 
10 years or until instructed in writing by the sponsor that records may be destroyed or forwarded 
to the sponsor.   
 
 
Principal Investigator (Print Name) 
 
 
 
 
Principal Investigator (Signature) 
 
Date (DD MMM YYYY) 
 


Pediatric Study TED-C14-006 – Amendment 2 
Teduglutide (rDNA origin) for injection 
Page 15 of 78 
 
Final v3.0 
06 October 2015 
TABLE OF CONTENTS 
KEY SPONSOR CONTACTS ......................................................................................................2 
PRODUCT QUALITY COMPLAINTS ......................................................................................3 
SYNOPSIS ......................................................................................................................................4 
SIGNATURE PAGE ....................................................................................................................13 
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE ..................................14 
TABLE OF CONTENTS ............................................................................................................15 
LIST OF IN-TEXT TABLES AND FIGURES .........................................................................17 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................18 
1 INTRODUCTION..................................................................................................................19 
1.1 
Background .....................................................................................................................19 
1.2 
Rationale for the Clinical Study ......................................................................................21 
1.3 
Rationale for Study Design .............................................................................................23 
2 OBJECTIVES ........................................................................................................................25 
2.1 
Primary Objective ...........................................................................................................25 
3 STUDY DESIGN ....................................................................................................................25 
3.1 
Overall Design and Control Methods..............................................................................25 
3.2 
Study Duration ................................................................................................................28 
4 SUBJECT SELECTION AND PARTICIPATION ............................................................28 
4.1 
Number of Subjects .........................................................................................................28 
4.2 
Inclusion Criteria .............................................................................................................28 
4.3 
Exclusion Criteria ............................................................................................................29 
4.4 
Subject Withdrawal Criteria ............................................................................................32 
4.5 
Data Safety Monitoring Board ........................................................................................33 
5 TREATMENTS AND TREATMENT PLAN .....................................................................33 
5.1 
Treatment Administered ..................................................................................................33 
 
Identification of Investigational Product .................................................................34 
5.1.1
 
Packaging and Labeling ...........................................................................................34 
5.1.2
 
Storage, Accountability, and Stability .....................................................................34 
5.1.3
5.2 
Methods of Assigning Subjects to Treatment Groups ....................................................35 
5.3 
Dose Regimens ................................................................................................................36 
 
Selection of Doses in Study .....................................................................................36 
5.3.1


Pediatric Study TED-C14-006 – Amendment 2 
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Selection and Timing of Dose for Each Subject ......................................................36 
5.3.2
 
Compliance with Dosing Regimens.........................................................................37 
5.3.3
 
Prior and Concomitant Medications ........................................................................37 
5.3.4
6 STUDY EVALUATIONS AND PROCEDURES ...............................................................37 
6.1 
Evaluations for Safety and Tolerability ..........................................................................37 
 
Adverse Events ........................................................................................................38 
6.1.1
 
Serious Adverse Events ...........................................................................................40 
6.1.2
 
Unblinding ...............................................................................................................43 
6.1.3
 
Dose Interruption of Individual Subjects .................................................................44 
6.1.4
 
Early Termination of the Clinical Study ..................................................................45 
6.1.5
 
Laboratory Evaluations ............................................................................................45 
6.1.6
 
Physical Examinations .............................................................................................48 
6.1.7
 
Vital Signs and Body Weight ..................................................................................48 
6.1.8
 
Electrocardiograms ..................................................................................................49 
6.1.9
 Gastrointestinal-specific Testing .............................................................................49 
6.1.10
 Concomitant Medication Assessment ......................................................................50 
6.1.11
 Nutritional Support Usage .......................................................................................50 
6.1.12
 Diaries ......................................................................................................................51 
6.1.13
 Female Subjects of Child-bearing Potential ............................................................52 
6.1.14
7 DATA MANAGEMENT .......................................................................................................62 
7.1 
Data Collection ................................................................................................................62 
7.2 
Rescreening .....................................................................................................................63 
7.3 
Record Retention .............................................................................................................63 
8 STATISTICAL METHODOLOGY AND SAMPLE SIZE ...............................................63 
8.1 
Demographic and Baseline Variables .............................................................................64 
8.2 
Safety and Tolerability Variables ....................................................................................65 
8.3 
Pharmacodynamic Variables ...........................................................................................65 
8.4 
Other Variables ...............................................................................................................66 
8.5 
Analysis Populations, Data Sets, and Time Points..........................................................66 
 
Analysis Populations ................................................................................................66 
8.5.1
8.6 
Statistical/Analytical Issues.............................................................................................67 
 
Adjustments for Covariates......................................................................................67 
8.6.1
 
Handling of Dropouts or Missing Data ....................................................................67 
8.6.2
 
Interim Analyses and Data Monitoring....................................................................67 
8.6.3


Pediatric Study TED-C14-006 – Amendment 2 
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Final v3.0 
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Multiple Comparisons/Multiplicity .........................................................................67 
8.6.4
 
Use of an Efficacy Subset of Subjects .....................................................................67 
8.6.5
 
Examination of Subgroups .......................................................................................67 
8.6.6
8.7 
Determination of Sample Size.........................................................................................67 
8.8 
Changes to Planned Statistical Analyses .........................................................................67 
9 ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................68 
9.1 
Declaration of Helsinki and Ethical Review ...................................................................68 
9.2 
Subject Information, Informed Consent and Assent .......................................................68 
9.3 
Subject Data Protection ...................................................................................................68 
9.4 
Financial Disclosure ........................................................................................................69 
9.5 
Changes to the Protocol...................................................................................................70 
9.6 
Investigator Obligations ..................................................................................................70 
9.7 
Confidentiality/Publication of the Study .........................................................................71 
9.8 
Selection of a Primary Principal Investigator .................................................................71 
9.9 
Study Termination ...........................................................................................................71 
10 REFERENCES .......................................................................................................................72 
APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY ......................................................................................73 
APPENDIX 2: 
PROTOCOL HISTORY ................................................................................77 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 4-1  
Excluded Diseases and Illnesses ...............................................................................31 
Table 6-1 
Schedule of Evaluations and Procedures – Screening to Week 12 – Active 
Treatment Groups .....................................................................................................53 
Table 6-2 
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment 
Groups .......................................................................................................................56 
Table 6-3 
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard 
of Care Group ...........................................................................................................58 
Table 6-4 
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care 
Group ........................................................................................................................60 
 
Figure 3-1  Study Diagram ..........................................................................................................27 
 
 


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Final v3.0 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CrCl 
Creatinine Clearance 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EN 
Enteral nutrition 
EOS 
End of study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FOCBP 
Females of child-bearing potential 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GLP-2 
Glucagon-like peptide 2 
IB 
Investigator’s Brochure 
IBD 
Inflammatory bowel disease 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
PD 
Pharmacodynamic 
PN 
Parenteral nutrition 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBS 
Short bowel syndrome 
SC 
Subcutaneous 
SUSAR 
Suspected, unexpected, serious, adverse reaction 
t1/2 
Elimination half-life 
UGI/SBFT 
Upper GI series with small bowel follow through 
ULN 
Upper limit of normal 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Compound 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like 
peptide-2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native 
GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus.  As a 
result, teduglutide demonstrates resistance to degradation by dipeptidyl peptidase-IV and 
therefore maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to 
the native peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in 
animal studies and previous human clinical trials to increase villus height and crypt depth in 
the intestinal epithelium, thereby increasing the absorptive surface area of the intestines 
(Thymann et al, 2014; Tappenden et al, 2013).  The European Commission granted a 
centralised marketing authorization valid throughout the European Union for teduglutide 
(Revestive™) on 30 August 2012 and a New Drug Application (NDA) for teduglutide 
(Gattex®) was approved by the US Food and Drug Administration (FDA) on 
21 December 2012 for the treatment of adult patients with Short Bowel Syndrome (SBS) who 
are dependent on parenteral support. 
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes 
to the label which provide for long-term use of Gattex in adults. 
   
Preclinical Studies 
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in Cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated 
rats. Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those 
observed in studies conducted using adult animals (rodents and primates). No treatment-related 


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malignant tumors were noted in a 2-year carcinogenicity study in rats; treatment-related 
changes included benign tumors of the bile duct epithelium and adenomas of the jejunal 
mucosa in males treated at 35 mg/kg/day. The results from a second 2-year carcinogenicity 
study in Crl:CD1(ICR) mice were provided to the agency in a NDA Supplement which 
received agency approval on 26 June 2014. Subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day 
(about 20, 70, and 250 times the recommended daily human dose of 0.05 mg/kg, respectively) 
were studied and adenocarcinoma in the jejunum was present in males given a dose of 
12.5 mg/kg/day. 
Clinical Studies 
Two completed adult studies (CL0600-004 and CL0600-005) evaluated safety and tolerability 
of daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on 
parenteral nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, placebo-
controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed 
the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was a 
statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study.  At Week 24, the weekly reduction of 
PN/IV volume was similar in the 2 active groups (2.5 L each). The extension study, 
CL0600-005, assessed the long-term safety of teduglutide and the proportion of responders in 
the CL0600-004 study that maintained their response at the end of a further 28 weeks of 
treatment. The extension study also assessed the effects of teduglutide at 28 weeks on those 
subjects previously receiving placebo in Study CL0600-004. 
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day dose, 
teduglutide treatment in the initial phase 3 study, which included significant reductions in 
PN/IV.  Seventy-five percent of the subjects who previously responded to teduglutide 
treatment in Study CL0600-004 maintained this response or experienced further improved 
benefit from teduglutide treatment.  More than 60% of the subjects previously receiving 
placebo in Study CL0600-004 achieved a clinical response after switching to teduglutide 
treatment for 6 months.  The majority of adverse events (AEs) reflected the underlying disease 
and were not treatment-related. 
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which 
subjects were randomized to either teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The 
first stage of the study included a screening and optimization period and a stabilization period 
that demonstrated stable administration of PN/IV volume for a minimum of 4 weeks up to a 
maximum of 8 weeks. The second stage was a dosing period of 24 weeks. Subjects on 
0.05 mg/kg/day teduglutide achieved a higher responder rate (defined as a 20% to 100% 
reduction from baseline in PN/IV volume at Weeks 20 and 24) than the placebo-treated 
subjects (27/43 subjects, 62.8% and 13/43 subjects, 30.2%, respectively). This difference was 
clinically and statistically significant in both the Intention-to-Treat (ITT) (p = 0.002) and Per 


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Protocol (p < 0.001) populations. Generally, the incidence of treatment-emergent AEs 
(TEAEs) was distributed similarly across all treatment groups. The TEAEs with a higher 
incidence in the teduglutide group were mainly of GI origin. A long-term, open-label extension 
study (CL0600-021) assessed safety and efficacy for up to 24 additional months (ie, up to 
30 months of exposure for subjects who received teduglutide in Study CL0600-020). Overall, 
30 of 43 subjects who received teduglutide in Study CL0600-020 and entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide. Of these, 
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a 
PN/IV volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative 
to baseline prior to exposure to teduglutide at the beginning of Study CL0600-021. PN/IV 
frequency was reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 
30 months of treatment. Of the 39 subjects who entered Study CL0600-021 after receiving 
placebo in Study CL0600-020, 29 completed 24 months of treatment with teduglutide. The 
mean reduction in PN/IV volume was 3.11 L/week from baseline at the start of 
Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers achieved a 20% 
or greater reduction of parenteral support. Of the 12 subjects entering Study CL0600-021 
directly, 6 completed 24 months of treatment with teduglutide. The mean reduction in PN/IV 
volume was 4.0 L/week (a 39.4% reduction from baseline at the start of Study CL0600-021) 
and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of parenteral support. 
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and UK. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort. 
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose.  In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at Week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at Week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time. 
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts.  
There were no deaths during the study and no TESAEs related to teduglutide were reported.  
No discontinuations from study were due to adverse events. 
1.2 
Rationale for the Clinical Study 
Short bowel syndrome is a rare disorder. At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, 
market research performed in 2012 indicates that the true addressable adult patient population 


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is between 3000 to 5000 patients which qualifies SBS as an ultra-orphan condition. In addition 
to adult SBS patients, it is estimated that, at most, there are a few hundred children 1 year and 
older with SBS (Wales et al, 2004). As a result of congenital abnormalities or severe intestinal 
disease in children and adolescents, major surgical resections of the intestine can become 
necessary, resulting in SBS. Common causes of SBS in children include necrotizing 
enterocolitis (NEC) in infants, midgut volvulus, intestinal atresia, and gastroschisis (Duro et al, 
2008; Squires et al, 2012). New onset SBS in older children may stem from the same etiologies 
as in adults (ie, Crohn’s disease, trauma, cancer) but is far less common. As the characteristics 
are similar to the adult disease, pediatric SBS is defined as a disease where there is diminished 
absorptive capacity for fluids and/or nutrients, sometimes requiring a dependence on PN/IV 
support to maintain energy and clinical status. 
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able 
to adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al, 1999; Jeppesen 
et al, 2000), other patients with intestinal failure depend on PN/IV for nutritional support 
(Fleming et al, 1980; O’Keefe et al, 2006; Buchman et al, 2003).  Although PN/IV can provide 
this nutritional support for patients with compromised fluid and nutritional status, it is also 
associated with serious complications, such as infections and liver damage.  The risk for these 
effects increases over time with longer duration of PN/IV support. 
Treatment of both pediatric and adult patients is focused on achieving adequate intestinal 
absorption to allow for minimization or discontinuation of PN/IV support. Because children 
are at higher risk for intestinal failure-associated liver disease, reducing PN support is far more 
urgent in this population. About 30% of infants who develop SBS during the neonatal period 
become independent of PN/IV requirements by 12 months of age, and an additional 10% wean 
off PN/IV support by 24 months of age. After this time, intestinal adaptation and growth 
occurs much more slowly, and many children remain terminally dependent on PN/IV support. 
Due to the risks of intestinal failure-associated liver disease, catheter-related blood stream 
infections, central line-associated venous thrombosis and dwindling central venous access, 
achieving autonomy from parenteral support remains an urgent goal for all affected children 
(Khan et al, 2015; Squires et al, 2012).  
This study proposes to investigate the safe and appropriate use of teduglutide in the pediatric 
population for up to 24 weeks for the purpose of providing longer-term data in regard to safety 
and potential to explore further efficacy including PN reduction and ability to completely wean 
off parenteral support.  This protocol was developed with input from expert advisors from 
intestinal rehabilitation centers who offered advice on the most appropriate use of teduglutide 
in pediatric patients.  The aim of teduglutide treatment is to increase absorptive capacity in 
order to yield decreases in parenteral support.  The experts anticipated that there would be 
several direct benefits from decreased parenteral support, including less exposure to PN/IV 


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constituents, less central line manipulation with lower risk of infection, and more time to focus 
on oral rehabilitation strategies. 
1.3 
Rationale for Study Design  
Dose 
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily (QD) in adult SBS subjects requiring PN. The recommended clinical 
dosage for the adult SBS patient population is 0.05 mg/kg QD. The completed 12 week 
pediatric study (TED-C13-003) included doses of 0.0125, 0.025, and 0.05 mg/kg/day. It 
demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a 
favorable benefit/risk profile. In addition, population pharmacokinetic (PK) modeling and 
simulations were conducted to determine the effective dose to be used in pediatric subjects 
using data in 8 adult clinical studies including adult Phase 1 studies and Phases 2/3 studies as 
well as the pediatric study, TED-C13-003. The analysis suggested that pediatric patients ages 
1 to 17 years old are likely to require the same dose as used in adults, namely 0.05 mg/kg/day. 
To further explore additional safety and efficacy of 0.025 and 0.05 mg/kg/day doses, a 
24-week study is currently proposed. 
Treatment Duration/Design 
Safety, tolerability and pharmacodynamic measures over a 24-week period will be the main 
outcomes of the current study. The main pharmacodynamic (PD) effect of teduglutide to be 
measured in children will include a decrease in the volume of PN/IV requirement. 
Measurement of a decrease in PN/IV volume requirements was the primary endpoint in the 
adult SBS clinical studies and can be used in children with SBS who are dependent on PN/IV 
support. 
A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of treatment was used as the primary endpoint in the adult clinical development 
program during pivotal Phase 3 studies and the previous pediatric study and will be the same 
endpoint used in the current pediatric study. 
The current study will employ a double-blind, 2 arm design with treatment of either 
0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for up to 24 weeks.  The 24-week treatment 
period will provide further information on longer term safety and additional efficacy including 
complete weaning of treatment beyond the 12-week period previously evaluated in the first 
pediatric study. 
Thus, this study is designed to provide further information on the safety and PD profile of 
teduglutide in pediatric subjects treated for up to 24 weeks. 


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Subject Population 
The current significant unmet medical need is for patients over age 1 year who remain 
dependent on parenteral support. These patients reach a plateau in their ability to advance 
oral/enteral feeds or decrease PN/IV support and are not expected to achieve spontaneous 
adaptation. The subjects in the study will be children whose intestines have not reached full 
enteral adaptation and whose PN/IV requirement had been stable without any clinically 
meaningful or substantial reduction in parenteral support for the 3 months prior to baseline. 
Therefore, this study will be performed in PN/IV-dependent children with SBS through 
17 years of age who have demonstrated that they have reached a plateau with regard to their 
ability to fully continue intestinal adaptation in terms of their ability to advance feeds and 
subsequently reduce their needs for parenteral support.  Stability for these subjects will be 
defined as at least 3 months in which patients still are requiring at least 30% of their volume 
and/or calories from PN/IV with no clinically meaningful change in advances in their enteral 
feeds (specialized nutrition such as formula via mouth or tube). 
This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000). 
Gastrointestinal Screening Measures 
Pediatric SBS patients who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for obstruction due to history of surgery. Teduglutide has 
been found to have a targeted intenstinotrophic effect on the GI tract and areas of special 
interest in regards to safety have been identified throughout the development program. Taking 
into account the patient population and the pharmacologic effect of teduglutide, GI-specific 
screening tests that are usually part of the routine care of these subjects will be performed on 
subjects in the active treatment groups to ensure safety. These include: abdominal ultrasound, 
upper GI series with small bowel follow through (UGI/SBFT), fecal occult blood testing, and 
colonoscopy/sigmoidoscopy. 
General Guidance for Nutritional Support Adjustment 
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status, which will include measures of weight, hydration status, and stool 
output.  The pharmacodynamic endpoint for this study is a ≥ 20% reduction in PN/IV support 
guided by clinical status.  A suggested guidance for nutrition support adjustment is provided in 
Appendix 1 and should be followed by all sites to ensure uniform care across study sites and 
participants. 


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2 
OBJECTIVES 
2.1 
Primary Objective 
The objective of this clinical study is to evaluate the safety, tolerability, efficacy, and 
pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with SBS who 
are dependent on parenteral support. 
See Section 8.2 and Section 8.3 for further details of the variables being measured. 
3 
STUDY DESIGN 
3.1 
Overall Design and Control Methods 
This will be a double-blind, 2-arm study in which subjects will be randomized in a 1:1 ratio to 
receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks followed by 
4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators and 
subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of care 
group, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up.  The subjects in the standard of care group will follow the same visit 
schedule as the randomized subjects. 
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters.  After screening, the 24-week treatment period will consist of visits at baseline, 
weekly for the first 2 weeks (Weeks 1 and 2), and then every other week through Week 12 
(Weeks 4, 6, 8, 10, and 12).  For the remainder of the treatment period, visits at the sites will be 
conducted every 3 weeks (at Weeks 15, 18, 21, and 24).  Telephone contacts will be made on 
all other weeks during the treatment period.  At all site visits and telephone contacts, safety 
will be monitored and nutritional support will be reviewed and adjusted as needed. A final visit 
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone 
contact will be made during the interim weeks from EOT to end of study (EOS), to monitor 
safety and any changes in nutritional support.  If necessary, unscheduled visits can be arranged 
in place of the telephone contacts.  Schedules of study parameters are displayed in Table 6-1 
and Table 6-2. 
To maintain consistency across all centers, sites and subjects (treated and standard of care) 
must follow the nutritional support adjustment guidelines (developed with SBS expert input 
and provided in Appendix 1) for decisions regarding PN/IV support reduction and advances in 
enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability. 
At the conclusion of the follow-up period (Week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post 
EOT for another antibody sample.  If the subjects continue to have positive/specific antibodies 


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at 3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status.  
Safety and tolerability results will be evaluated by a Data Safety Monitoring Board (DSMB) 
approximately every 3 months during the active study period (date of the first subject’s first 
dose to date of the last subject’s last dose).  The DSMB review will include all cumulative 
safety data (ie, adverse events, laboratory assessments, physical examinations, etc.) from study 
assessments through each cutoff period.  
A schematic representation of the study design is displayed in Figure 3-1.


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Figure 3-1  
Study Diagram 
 
 
Note:  The Standard of Care group follows the same visit schedule as the active treatment groups.


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3.2 
Study Duration 
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment.  
Attempts should be made to limit the screening period to 4 weeks. There will be one final 
scheduled clinic visit at Week 28, 4 weeks after EOT (Week 24).  
The start of the clinical phase is defined as first subject consented.  The end of the clinical 
phase is defined as the last visit of the last subject. 
4 
SUBJECT SELECTION AND PARTICIPATION 
4.1 
Number of Subjects 
Approximately 20 teduglutide-naïve subjects (minimum 10 subjects per treatment arm) will be 
enrolled into the active treatment groups.   
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in the standard of 
care group (who will not be treated with teduglutide) to serve as an observational cohort.   
Subjects will be enrolled at approximately 20 investigational sites globally. 
4.2 
Inclusion Criteria 
Male and female children and adolescents, through 17 years of age, who meet the following 
inclusion criteria will be enrolled in the study. 
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures 
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)  
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening 
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds)  for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior 
to the event. 


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6. Sexually active female subjects of child-bearing potential (in the active treatment group 
only) must use medically acceptable methods of birth control during and for 4 weeks after 
the treatment period 
4.3 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria at baseline are not eligible for 
enrollment into the study: 
1. Subjects who are not expected to be able to advance oral or tube feeding regimens  
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening 
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome) 
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related dysmotility disorders, that is the primary contributing factor to 
feeding intolerance and inability to reduce parenteral support, prior to screening. 
Dysmotility is defined as severe if it is expected to limit the advancement of enteral 
feeding. 
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening 
7. Major gastrointestinal surgical intervention including significant intestinal resection within 
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤ 10 cm, or endoscopic procedure is allowed) 
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation 
9. History of cancer or clinically significant lymphoproliferative disease, not including 
resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and 
surgically resected cancer 
10. Pregnant or lactating female subjects (in the active treatment group only) 


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11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide 
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2) 
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening 
14. Previous use of octreotide, or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months 
prior to screening 
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit 
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening 
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) 
within 3 months prior to the screening visit 
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject 
19. Body weight < 10 kg at the screening and randomization visits 
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any 
of the below laboratory test results during the screening period: 
a. Total bilirubin ≥ 2 x upper limit of normal (ULN) 
b. Aspartate aminotransferase (AST) ≥ 7 x ULN 
c. Alanine aminotransferase (ALT) ≥ 7 x ULN 
For subjects with Gilbert’s disease:  
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN 


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21. Signs of known continuous active or unstable, clinically significant renal dysfunction 
shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2. 
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to 
the study visit schedule and other protocol requirements 
23. Unstable, clinically significant active, untreated pancreatic or biliary disease 
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of 
the study results.  Examples of potential disease states/illnesses that may be excluded are 
listed in the table below. 
Table 4-1  
Excluded Diseases and Illnesses 
Body system 
Known conditions excluded 
Related to SBS 
• Ongoing radiation enteritis  
• Untreated celiac disease 
• Refractory or tropical sprue 
• Pseudo-obstruction 
Gastrointestinal  
• Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced 
or changed during the last 3 months 
• IBD that requires chronic systemic immunosuppressant 
therapy for symptom control  
• Tufting or autoimmune enteropathy or microvillous 
inclusion disease 
• Untreated pre-malignant or malignant change in GI 
tract identified by upper GI series, biopsy or 
polypectomy 
• Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome) 
• Intestinal or other major surgery scheduled within the 
time frame of the study 
• Chronic active pancreatitis  
• Cholecystitis 


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Table 4-1  
Excluded Diseases and Illnesses 
Body system 
Known conditions excluded 
Immune 
• Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency) 
Psychiatric 
• Alcohol or drug addiction within the previous year 
• Major uncontrolled psychiatric illness 
General 
• Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system) 
 
4.4 
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
sponsor’s Medical Monitor prior to the patient discontinuing/withdrawing.  A subject may (but 
not automatically) be withdrawn from the study under any of the following circumstances: 
• Withdrawal of informed consent and/or assent when applicable 
• If, in the opinion of the investigator, Institutional Review Board (IRB) or the sponsor, it is 
no longer in the subject’s best interest to continue in the study 
• Subject no longer meets all inclusion criteria or meets any criterion for exclusion 
• Lack of compliance with study procedures or study drug administration, as determined by 
the investigator 
• Occurrence of a serious adverse event (SAE) determined by the investigator to be possibly 
related to study drug and not alleviated with treatment of symptoms 
• Adverse event (including Grade 3 or 4 events of special interest [Section 6.1.4]) 
• Hypersensitivity determined by the investigator to be possibly related to study drug 
• Administrative reasons 
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.1.1.  Reasons for discontinuation other 
than AEs must be reported within 4 weeks of the EOS date in order to be included in the 
database.  Any reason for discontinuation obtained after this time will be included in the 


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subject’s medical record only, unless the EOS visit date is amended and the database remains 
open. 
As far as possible, all examinations scheduled for the EOT evaluations must be performed on 
all subjects who participate even if they do not complete the study according to the protocol. 
Any subject who discontinues treatment prematurely will be asked to return 4 weeks later for 
the EOS visit and will be contacted weekly for wellness checks during the interim period 
between EOT and EOS.  
4.5 
Data Safety Monitoring Board 
The DSMB for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006). 
The DSMB will be an external, independent board comprised of physicians with relevant 
training. The DSMB will be restricted to individuals free of significant conflicts of interest, 
including, but not limited to, financial, scientific, or regulatory in nature. The DSMB will be 
governed by a Charter agreed to by members of the Board and the sponsor. Members of the 
Board may not be study investigators or be employed at the same institution as a study 
investigator, individuals employed by the sponsor, independent contractors hired by the 
sponsor, or members of regulatory agencies. The DSMB may make recommendations to the 
sponsor regarding study aspects including stopping, modifying or continuing the study; 
however, the sponsor will have the final responsibility to determine whether the study should 
be modified or temporarily or permanently stopped.  
The DSMB members will review the data approximately every 3 months during the active 
study period (date of the first subject’s first dose to date of the last subject’s last dose).  The 
DSMB review will include all cumulative safety data (ie, adverse events, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
5 
TREATMENTS AND TREATMENT PLAN 
5.1 
Treatment Administered 
Daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will be administered 
once daily in the morning to the subjects in the active treatment groups.  The dose calculation 
will be based on body weight measured at the Baseline Visit (Visit 2) and adjusted, as needed, 
based on body weight measured at Week 12 (Visit 14).  No other adjustments to dose will be 
made during the study period, unless discussed with the sponsor’s medical monitor.  
Teduglutide will be administered by SC injection into 1 of the 4 quadrants of the abdomen (in 
subjects without a stoma) or either thigh or arm.  For subjects with a stoma, the quadrant of the 
abdomen containing the stoma will not be used.  


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Identification of Investigational Product 
5.1.1
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled 
syringe.  The 5-mg vial is 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is 
5 mg/mL. A maximum of 0.38 mL of reconstituted solution can be withdrawn from the vial. 
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients. 
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength. 
 
Packaging and Labeling 
5.1.2
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Study drug vial will be supplied in kits containing 7 vials and labeled with the 
protocol number, the investigational drug warning, general dosage instructions, storage 
conditions, expiry date, kit number, lot number, and company name.  Space will be provided 
for recording study site and subject numbers at the study site.  Ancillary supply kits containing 
syringes with needles for injection and reconstitution, sterile water, and alcohol swabs will also 
be provided. 
All study drug used in this study will be manufactured, tested, labeled, and released according 
to current legal requirements and Good Manufacturing Practice. 
 
Storage, Accountability, and Stability 
5.1.3
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures.  Study drug will be shipped once the first subject 
at a site is screened. Upon receipt, the study site’s pharmacist or delegate is responsible for 
ensuring that all study drug received at the site is inventoried and accounted for throughout the 
study.  A copy of the shipping documents must be maintained for the investigator’s records. 
Study drug must be kept in a locked area with access restricted to specific study personnel.  
Study drug will be stored refrigerated at a temperature between 2 to 8 oC (35.6 to 46.4 oF) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated 
or up to a controlled room temperature (acceptable range of 2 to 25 oC, or 35.6 to 77 oF).  
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature.  If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated. 


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Study drug kits will be dispensed at each of the study visits at which the subject is required to 
be at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough 
kits will be supplied to cover the period to the next planned study visit.  Additional study kits 
will be provided as necessary. 
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies.  This record will be made available to the sponsor’s site monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded and will 
include an explanation.  All supplies sent to the investigator must be accounted for and in no 
case will clinical supplies be used in any unauthorized situation. 
All used and unused study drug vials must be returned by the subjects and/or parent/guardian 
and will be retained at the site. All original containers, whether empty or containing study drug 
will be returned to the pharmacy. Returned study drugs will NOT be relabeled or reassigned 
for use by other subjects. Contents of the study drug containers will not be combined. All used 
and unused vials must be returned to the distribution center according to the sponsor’s 
instruction. No vial/kit may be destroyed on site. 
5.2 
Methods of Assigning Subjects to Treatment Groups 
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of 
the study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These 
numbers will be used to identify the subjects throughout the study period, including any 
subjects in the standard of care group.   
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the dosing cohort or the 
standard of care group.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all Inclusion/Exclusion criteria.  If the subject or 
subject’s parent/guardian/caretaker decides to participate in the dosing cohort, the investigator 
or designee will request the subject be randomized at the Baseline Visit using an interactive 
web response system (IWRS) at a 1:1 ratio, centrally administered as described in the IWRS 
Manual of Procedures.  Subject numbers for patients enrolling in the standard of care group 
will also be assigned via the IWRS. 
Study drug kits will be assigned through IWRS to each subject at each on-site visit through 
completion of the dosing period. The IWRS will automatically assign the correct number of 
kits for each visit based on the date of randomization.  If additional kits are needed (eg., subject 
is going on holiday), the IWRS and the sponsor will need to be notified so that the additional 
kits can be assigned.  Subjects will be randomized across centers rather than within a center. 
Those subjects opting for the standard of care group will continue in the study but without the 
study drug. 


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5.3 
Dose Regimens 
Teduglutide will be supplied in 2 strengths: 
• 5.0 mg/vial for subjects receiving 0.05 mg/kg/day of teduglutide 
• 2.5 mg/vial for subjects requiring 0.025 mg/kg/day 
Subjects in the active treatment groups are to have the study drug administered once daily in 
the morning by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or 
arm, for 24 weeks.  For subjects with a stoma, the quadrant of the abdomen containing the 
stoma will not be used. The initial dose will be calculated based on body weight measured at 
the Baseline Visit (Visit 2). 
 
Selection of Doses in Study 
5.3.1
A recently completed 12-week pediatric study (TED-C13-003) that included doses of 0.0125, 
0.025, and 0.05 mg/kg/day demonstrated a favorable risk/benefit profile at the 2 higher doses 
with PN/IV volume reduction and advance in feeds observed. In addition, modeling and 
simulation data from previously completed studies suggested that pediatric patients are likely 
to require the same dose as used in adults (ie, 0.05 mg/kg daily). 
This study will evaluate teduglutide doses of 0.05 mg/kg and 0.025 mg/kg administered daily 
for 24 weeks. 
 
Selection and Timing of Dose for Each Subject 
5.3.2
The study drug will be administered in the morning immediately after reconstitution by SC 
injection into 1 of the 4 quadrants of the abdomen or into either thigh or arm. The first SC 
injection should be administered under the supervision of the investigator or designee and the 
subject observed for hypersensitivity reactions for at least 4 hours during their initial dosing 
visit.  The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be 
specified and recorded in the eCRF.  Detailed instructions for reconstitution and injection of 
the study drug can be found in the Dosing Instructions.  Each day, the injection site should be 
changed.  For subjects with a stoma, the abdominal quadrant in which the stoma is situated 
should be avoided. 
The subject should be dosed at approximately the same time each day, preferably in the 
morning.  If a morning dose is forgotten, that day’s dose should be administered as soon as 
possible, even if this is later in the day or evening.  Consecutive doses should be separated by 
at least 12 hours.   
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily study drug dosing regimen.  Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, a lapse in study drug delivery, etc.   


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Compliance with Dosing Regimens 
5.3.3
Subject compliance with study drug dosing will be monitored by the sponsor/designee by 
counting and examining used and unused vials.  In addition, compliance will be checked by 
site personnel at every visit by asking the subject or the subject’s parent or guardian if they 
have administered the study drug according to instructions.  If any doses have been missed, the 
reason for missed dose should be documented in the subject’s source documentation including, 
as applicable, the eCRF. 
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered. 
 
Prior and Concomitant Medications 
5.3.4
The administration of all medications including prior and concomitant medications must be 
recorded in the appropriate sections of the eCRF. 
Prior medications are those taken by the subject within 14 days before the first dose of study 
drug and discontinued prior to first dose of study drug.  
Concomitant medications are those taken by the subject anytime during the treatment period, 
after the first dose of study drug.  
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation. 
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens.  Down-titration of concomitant medications should be 
considered when drugs, especially those with a narrow therapeutic range, are given at dosages 
that are higher than usual. 
6 
STUDY EVALUATIONS AND PROCEDURES 
6.1 
Evaluations for Safety and Tolerability 
Safety variables will be assessed by the following evaluations, according to Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2.  Safety variables for the 
standard of care group are displayed in Table 6-3 and Table 6-4. 
• Adverse events, including GI symptoms.  A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline.  GI symptoms will be 


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recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject. 
• Physical examinations 
• Vital signs, including temperature, heart rate, and blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts 
• Electrocardiograms 
• Laboratory safety data, including clinical chemistries, hematology, and urinalysis 
• Change in urine output (collected or calculated volume) 
• Fecal output (by volume or number of bowel movements per day) 
• Antibodies to teduglutide (active treatment groups only).  Samples for antibody analysis 
will be drawn at baseline and at the EOT (Week 24 or early termination) visits prior to the 
administration of teduglutide and at least 14 hours after the previous dose.  One additional 
sample will be collected at the final visit 4 weeks after the EOT (EOS, Week 28).  If 
subjects are determined to have positive/specific antibodies at Week 28 or EOS, they will 
be asked to return for a follow-up clinic visit 3 months post EOT for another antibody 
sample.  If the subjects continued to have positive/specific antibodies at 3 months post 
EOT, they will be asked to return for a follow-up visit 6 months post-treatment in order to 
determine their antibody status.  
• GI-specific testing (active treatment groups only) including colonoscopy or sigmoidoscopy,  
abdominal ultrasound, fecal occult blood testing, UGI/SBFT 
 
Adverse Events 
6.1.1
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study. 
6.1.1.1 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily have to 
have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product. 


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An AE includes: 
• An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant 
electrocardiogram (ECG) abnormality 
• An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study drug administration 
• Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures 
An AE does not include: 
• The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder 
• A pre-existing disease or condition, present at the start of the study, that does not worsen 
6.1.1.2 
Procedures for Reporting Adverse Events 
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs 
and SAEs will be recorded from the signing of the informed consent form (ICF) and, if 
applicable, the informed assent form, through the last study visit (Visit 28 or EOS).  SAEs will 
be monitored with a telephone call by the investigator, as necessary, for approximately 4 weeks 
after the last dose of study drug or until resolution or until the SAE is judged by the 
investigator to have stabilized.    
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  Also recorded are:  
• Start and stop date and time 
• Whether the event is continuing 
• Frequency (intermittent, continuous) 
• Intensity (mild, moderate, severe) 
o 
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities 
o 
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities 


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o 
Severe:  requires vigorous therapeutic intervention and interrupts usual activities; 
hospitalization may or may not be required. 
• Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out) 
• Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.1.2 below 
• Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy)  
• Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome. 
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized. 
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they: 
• Are considered clinically significant by the investigator 
• Fulfill SAE criteria, and/or 
• Cause subject discontinuation from the study 
 
Serious Adverse Events 
6.1.2
A serious event must be reported as described in Section 6.1.2.2 and recorded on the sponsor’s 
SAE Form.  An SAE requires expeditious handling to comply with regulatory requirements.  
Any SAEs occurring from the signing of the ICF through last study visit and 4 weeks after the 
last dose of study drug will be captured and must be reported within 24 hours after the 
investigator or the investigator’s site personnel is made aware of the event. 
6.1.2.1 
Serious Adverse Event Definition 
An SAE is an AE that results in any of the following outcomes: 
• Death  
• Is life-threatening.  A life-threatening AE is any AE that places the subject - in the 
investigator’s opinion - at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more serious form, might have caused 
death. 
• Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions 


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• Hospitalization or prolongation of existing hospitalization 
• Congenital anomaly/birth defect 
• Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. 
Scheduled and/or elective hospitalizations occurring under the following circumstances will 
not be defined as SAEs for this clinical study: 
• Planned before entry into the clinical study 
• Are for elective treatment of a condition unrelated to the studied indication or its treatment 
• Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling 
the previous criteria) 
• Are part of the normal treatment or monitoring of the studied indication and not associated 
with any deterioration in condition 
Any laboratory test result that meets the criteria for an SAE must also be recorded in an SAE 
report so that the sponsor/designee can collect additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome. 
Overdose 
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form (Section 6.1.2.2).   
6.1.2.2 
Procedures for Reporting Serious Adverse Events 
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event.  Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors unless they 
result in an SAE.  
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 


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Pharmacovigilance and Risk Management Department. A copy of the Shire Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form (and any 
applicable follow-up reports) must also be sent to the Shire Medical Monitor using the details 
specified in the emergency contact information section at the beginning of the protocol.  
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator and/or the investigator’s site personnel at any interval after the study has 
completed must be reported to Shire’s Pharmacovigilance and Risk Management Department 
within 24 hours of the first awareness of the event. 
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but a serious event criterion.  The SAE term is the medical event that led to the 
hospitalization.  Surgery is not an adverse event, but the event that required the subject to have 
surgery is the SAE term.  Death is not an SAE, but an outcome. 
The sponsor/designee will provide a FAX cover sheet for the investigators in the study 
reference manual (ie, Investigator Site File). 
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form. 
All SAEs must be reported, whether or not they are considered causally related to the study 
drug.  Appropriate clinical, diagnostic, and laboratory measures should be performed to 
delineate the cause of the SAE in question and the results reported.  Follow-up for the SAE 
should occur at appropriate intervals until the event/laboratory abnormality: 
• Returns to baseline or 
• Becomes stable to a clinically acceptable level that is safe for the subject. 
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the sponsor’s SAE 
form.  The investigator should make the causality assessment based on the information 
available at the time of the event.  The causality can be updated at a future date if additional 
information is received. 
The causality categories are: 
Not related 
• May or may not follow a reasonable temporal sequence from administration of the study 
product 
• Is biologically implausible and does not follow a known response pattern to the suspect 
study product (if response pattern is previously known) 


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• Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject 
Related  
• A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• Follows a reasonable temporal sequence from administration of the study product 
• May follow a known response pattern to the study product (if response pattern is previously 
known) 
• Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject, if applicable 
• Recurs upon rechallenge after withholding and then reintroducing study product 
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Investigator Site File. 
As required by International Conference of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Causality, while assessed, 
does not negate reporting requirements to the sponsor.  An AE, whether serious or not serious, 
is designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator Brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 
expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined. 
Upon receiving such notices, the investigator must review and retain the notice.   
The investigator should also comply with the Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) procedures for reporting any other safety information. 
The sponsor/designee will be responsible for submitting SUSAR reports to the appropriate 
health authorities.  These reports will be submitted within the expedited timeframe.  All fatal 
and life-threatening SUSAR reports will be submitted by the sponsor or designee within 7 days 
of receipt (Day 0) of the initial report.  All other SUSAR reports will be submitted by Day 15 
following the event. 
 
Unblinding 
6.1.3
If a subject becomes pregnant or seriously ill during the study, the blind should be broken only 
if knowledge of the study medication dose administered will affect treatment options available 


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to the subject.  Before breaking the blind, the investigator should contact the sponsor’s Medical 
Monitor/designee for discussion on whether unblinding of the subject is warranted.  If 
warranted, the principal investigator or designee will place an unblinding call to the IWRS to 
receive treatment assignment information.  In the case of an extreme emergency and if the 
Medical Monitor is immediately unreachable, the investigator should break the blind through 
the IWRS. Please see the Investigator Site File for further details. 
In the event prior authorization from the sponsor’s Medical Monitor is not possible, the 
sponsor’s Medical Monitor must be notified by telephone immediately, but no later than 
24 hours following the unblinding of any subject for any reason.  A record should be kept of 
when the blind was broken, who broke it, and why. 
 
Dose Interruption of Individual Subjects 
6.1.4
Teduglutide administration for an individual subject may need to be stopped if the subject has 
an adverse event of special interest (see risks in table below) that is severe in intensity [Grade 3 
or higher as defined by the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (CTCAE)].  This may occur if an event is attributable to study drug or a 
subject experiences an unexplained CTCAE Grade 3 or higher that is not reasonably related to 
the underlying disease process.  The determination of length of the discontinuation, temporary 
or permanent, depends on the clinical situation.   
Investigators and the DSMB should be guided by the descriptions of Grade 3 and 4 events 
below, as they relate to identified risks associated with the administration of teduglutide. 
Identified Risk 
Grade 3 Description 
Grade 4 Description 
Gastrointestinal Disorders 
Colorectal polyps 
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living 
Life-threatening consequences; urgent 
intervention indicated 
Intestinal Obstruction 
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self-care activities of daily 
living; disabling 
Life-threatening  consequences; urgent 
operative intervention indicated 
Gallbladder and Bile Duct Disease 
Cholecystitis 
Severe symptoms; radiologic, 
endoscopic or elective operative 
intervention indicated 
Life-threatening consequences; urgent 
operative intervention indicated 
Gallbladder 
perforation 
Not Applicable 
Life-threatening consequences; urgent 
intervention indicated 
Gallbladder 
obstruction 
Symptomatic and severely altered 
gastrointestinal function; tube 
feeding, total parenteral nutrition or 
hospitalization indicated; nonemergent 
operative intervention indicated 
Life-threatening consequences; urgent 
operative intervention indicated 


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Identified Risk 
Grade 3 Description 
Grade 4 Description 
Gallbladder infection 
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic, endoscopic, or operative 
intervention indicated 
Life-threatening consequences; urgent 
intervention indicated 
Alkaline Phosphatase 
increased 
> 5.0 to 20.0 x Upper limit of normal 
> 20.0 x Upper limit of normal 
Blood bilirubin 
increased 
> 3.0 to 10.0 x Upper limit of normal 
> 10.0 x Upper limit of normal 
Bile duct stenosis 
Severely altered gastrointestinal 
function; radiologic, endoscopic or 
elective operative intervention 
indicated 
Life-threatening consequences; urgent 
operative intervention indicated 
Pancreatic Disease 
Pancreatitis 
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support) 
Life-threatening consequences; urgent 
intervention indicated 
Pancreatic duct 
stenosis 
Severely altered gastrointestinal 
function; tube feeding or hospitalization 
indicated; elective operative 
intervention indicated 
Life-threatening consequences; urgent 
operative intervention indicated 
Pancreas infection 
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic or operative 
intervention indicated 
Life-threatening consequences; urgent 
intervention indicated 
Serum amylase 
increaseda 
> 2.0 to 5.0 x Upper limit of normal 
> 5.0 x Upper limit of normal 
Lipase increaseda 
> 2.0 to 5.0 x Upper limit of normal 
> 5.0 x Upper limit of normal 
Cardiovascular Disease 
Heart failure 
Severe with symptoms at rest or with 
minimal activity or exertion; 
intervention indicated 
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support) 
aIn the setting of clinically acute and symptomatic pancreatitis  
Source:  Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010 
 
 
Early Termination of the Clinical Study 
6.1.5
The DSMB may recommend stopping the study if: 
• ≥ 2 subjects being administered study drug develop the same CTCAE Grade 3 or 
• 1 subject develops a CTCAE Grade 4 adverse event which is attributable to study drug 
or is not reasonably related to the underlying disease process 
 
Laboratory Evaluations 
6.1.6
The following laboratory parameters will be examined according to the Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2 (Table 6-3 and Table 6-4 
for the standard of care group).  While not all abnormal laboratory results would be considered 


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clinically significant as determined by the investigator (ie, those that are associated with the 
disease state and were present at baseline), those that are determined to be a clinically 
significant change (ie, worsening) from baseline or known medical history will be considered 
adverse events.  All such abnormal laboratory values that are considered AEs must be recorded 
on the appropriate eCRF.  A result outside of the normal range may be repeated for 
confirmation.  Any laboratory test result that meets the criteria for an SAE (Section 6.1.2) must 
also be recorded in an SAE report so that the sponsor/designee can collect additional 
information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome. 
Laboratory collections that are required at intervals that do not coincide with clinic visits 
(ie, for safety lab assessments done following PN/IV adjustments) may be obtained by a Home 
Health Agency at subjects’ homes.  
 
 


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6.1.6.1 
Safety Laboratory Tests and Procedures 
Hematology 
Serum Chemistry 
Albumin 
Alkaline phosphatase 
ALT 
Amylase 
AST  
Bicarbonate 
Bilirubin (total and indirect) 
Blood urea nitrogen  
Calcium (total) 
Chloride 
Cholesterol 
Citrulline (plasma) 
Creatinine 
C-reactive protein  
Estimated Glomerular Filtration Rate [eGFR] 
(Schwartz formula) 
Glucose 
Gamma glutamyl transferase  
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Triglycerides 
Uric acid 
Urinalysis 
Blood 
Glucose 
Leucocytes 
Microscopic analysis 
Specific gravity 
pH and osmolality 
Protein 
Sodium 
Pregnancy tests (females of child-bearing 
potential) – for active treatment group only 
Procedures 
Upper GI series with small bowel follow through 
Abdominal ultrasound 
Colonoscopy/sigmoidoscopy (subjects 12 years and older or if fecal occult blood testing 
result is positive regardless of age without a documented or known etiology to explain the 
fecal positive results, ie, fissures, etc.). 
Fecal occult blood testing 
Hemoglobin 
Hematocrit 
Platelets 
Red blood cell (RBC) count 
White blood cell (WBC) count with differential 
RBC morphology, if needed 


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6.1.6.2 
Plasma Citrulline 
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2). Citrulline should be 
collected 2 to 4 hours postprandially, whenever possible. Blood samples for citrulline may be 
drawn from a central line or from peripheral access. The samples will be processed according 
to instructions in the Laboratory Manual and will be collected from subjects from both active 
treatment and standard of care groups who participate in this study.  
6.1.6.3 
Antibodies to Teduglutide 
Blood samples will be drawn only from the active treatment groups for the analysis of 
positive/specific antibodies to teduglutide according to the Schedules of Evaluations and 
Procedures (Table 6-1 and Table 6-2). Blood samples for antibodies may be drawn from a 
central line or from peripheral access. 
 
Physical Examinations 
6.1.7
Complete and comprehensive physical examinations will be performed by a medically 
qualified person during the study to assess the subject’s physical status, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2) (Table 6-3 and Table 6-4 
for the standard of care group). 
Any significant finding at baseline, such as hepatomegaly, should be included in the subject’s 
medical history eCRF. Any clinically significant changes from baseline (in the opinion of the 
investigator) noted during the physical examinations, whether or not these procedures are 
required by the protocol, should be recorded on the appropriate AE page of the eCRF. This will 
assist the sponsor/designee in collecting additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome. 
 
Vital Signs and Body Weight  
6.1.8
Vital signs will be measured according to the Schedules of Evaluations and Procedures (Table 
6-1 and Table 6-2) (Table 6-3 and Table 6-4 for the standard of care group).  Measurements 
will include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body 
temperature (oC/oF).  Body weight (kg) will also be recorded on the eCRF; subjects should be 
weighed on the same scale at each study visit. Height (or length [cm]) and head circumference 
(in cm for subjects ≤ 36 months of age) will be measured at selected visits. 
A height Z-score, weight Z-score, BMI, and BMI Z-score will be calculated by the sponsor 
using the site-provided height and weight data collected at each site visit. 
Any clinically significant changes (ie, worsening) in the opinion of the investigator noted in 
vital signs assessments (ie, those that are associated with the disease state and were present at 
baseline), should be recorded on the appropriate AE page of the eCRF.  This will assist the 


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sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome. 
 
Electrocardiograms 
6.1.9
Twelve-lead electrocardiograms will be performed according to the Schedules of Evaluations 
and Procedures (Table 6-1 and Table 6-2; Table 6-3 and Table 6-4 for the standard of care 
group).  The ECG tracing will be read by a local experienced physician.  Results (normal, 
abnormal not clinically significant, and abnormal clinically significant with description of the 
finding) will be recorded on the eCRFs. 
Any clinically significant changes from baseline (in the opinion of the investigator) noted 
during the ECG evaluations should be recorded on the appropriate AE page of the eCRF.  This 
will assist the sponsor/designee in collecting additional information about that abnormality, 
including information regarding relationship to study drug or other causes, any action taken, 
and outcome. 
 
Gastrointestinal-specific Testing 
6.1.10
Gastrointestinal testing will be done for all subjects in the active treatment group only during 
or prior to the screening period, as indicated below. Follow-up testing will be performed as 
necessary according to the guidelines noted below. See Table 6-1 and Table 6-2 for details and 
scheduling. 
6.1.10.1 
Upper Gastrointestinal Series with Contrast 
An upper GI with small bowel follow through will be performed following the ingestion of 
barium contrast material.  Results from procedures performed within 6 months prior to Visit 1 
will also be acceptable. 
6.1.10.2 
Abdominal Ultrasound 
An abdominal ultrasound will be performed.  Results from procedures performed within 
6 months prior to Visit 1 will also be acceptable. 
6.1.10.3 
Fecal Occult Blood Testing 
Fecal occult blood testing will be performed at screening, Week 12, and at the end of 
treatment. Subjects with positive results for fecal occult blood for whom a cause is not readily 
identified (eg, anal fissure) will undergo a confirmatory colonoscopy/sigmoidoscopy. If no 
known underlying documented etiology can be attributed to this finding, the results should be 
discussed with the sponsor’s Medical Monitor. 
• Subjects with negative endoscopy findings may enroll in the study. 
• Subjects with positive endoscopy findings who receive treatment may enroll in the study. 


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• Subjects with positive endoscopy findings who do not receive treatment will be excluded 
from the study. 
• In those subjects with positive results for fecal occult blood at the end of the study, the 
investigator will have to determine the cause for the finding and may perform an additional 
colonoscopy/sigmoidoscopy, if clinically warranted. 
6.1.10.4 
Colonoscopy/Sigmoidoscopy 
Subjects age 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children under the age of 12 years may also undergo the procedure if they had a positive result 
on the fecal occult blood testing (see above).  Results from procedures performed within 1 year 
prior to Visit 1 will also be acceptable for the screening measurement. 
 
Concomitant Medication Assessment 
6.1.11
The subject’s usage of concomitant medication will be assessed at each clinic visit and the 
details of any medications and changes in medication or dosage of medications will be 
recorded on the eCRF. 
 
Nutritional Support Usage 
6.1.12
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status which will include measures for weight, linear growth, hydration 
status, and safety laboratory results. The pharmacodynamic endpoints for this study include 
decreases in PN/IV volume reduction including a ≥ 20% or greater reduction up to 100% 
reduction (or complete weaning) in PN/IV support guided by clinical status. A 20% decrease in 
PN/IV volume over 24 weeks is considered clinically meaningful to these PN/IV-dependent 
children who have plateaued in their ability to wean PN/IV and advance their oral/enteral 
feeds. A decrease of this magnitude may translate to several hours a day for more age-
appropriate activities or an opportunity to introduce an extra oral/enteral feed to encourage oral 
rehabilitation. A guidance for nutrition support adjustment to be followed for this protocol is 
provided in Appendix 1. 
Evaluation of each subject’s nutritional support will be made during screening and at all visits 
at the study site.  The following information will be collected and can be used to evaluate each 
subject’s nutritional support: 
• Daily PN/IV support volume and calories 
• Daily EN volume and calories (oral or tube feeds, including formula and specialized 
electrolyte solution) 
• Other nutritional intake (regular diet and drink)  
• 48-hour urine output prior to each phone and site visit 


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• 48-hour stool output (by volume or daily stool count) and stool consistency, prior to 
each phone and site visit 
 
Diaries 
6.1.13
Subjects or subjects’ parent or guardian will be required to complete the following: 
• Intake Diaries, completed daily, which will include:  
o PN/IV volume and calories (days per week, hours per day) 
o EN (formula and specialized electrolyte solutions) volume and calories (days 
per week, hours per day) 
o Other Nutrition (regular diet and drink) intake (to be converted into calories by 
site personnel) 
• Urine/Stool Output Diary, completed for 2 days (48 hours) just prior to every scheduled 
clinic visit and telephone contact, consisting of :   
o Collection of urine data:   
 For those who are toilet trained and NOT IN DIAPERS:  All urine 
output should be measured and recorded in mL.  The subject or parent 
will perform dipstick specific gravity tests on the first urine produced 
after the daily infusions of  PN/IV support. 
 For those who are not toilet trained and IN DIAPERS:  The weight of all 
urine-only diapers will be recorded. Volume will be calculated based on 
the formula: 1g (scale weight) = 1 mL or 1 cc.  At the discretion of the 
investigator, the parent may be asked to collect the first void after the 
daily infusion of PN/IV support to measure the specific gravity. 
o Collection of stool output data (including stool only and mixed urine/stool 
diapers):  
 For those who are toilet trained and NOT IN DIAPERS:  Daily stool 
count will be recorded.   
 For those who are not toilet trained and IN DIAPERS: The weight of all 
diapers that contain stool (including diapers that contain mixed stool and 
urine) will be recorded as stool output.  Stool volume will be calculated 
based on the formula: 1 g (scale weight = 1 mL or 1 cc). 
 All ostomy output will be recorded as stool output and measured in cc or 
mL.  
 In addition all subjects (toilet trained or not) will report on the average 
consistency (form) of the stool passed each day during the 48-hour 


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period.  The subject or parent will use the Bristol Stool Form Scale 
(Lewis and Heaton, 1997) to make the assessment.    
During the screening period, these diaries focusing on Intake and Output will be completed 
every day. 
All diaries will be reviewed by the investigator or their designee at each visit or telephone 
contact to assess clinical status and opportunity for PN/IV changes and advance in feeds.  At 
each visit, the diaries will be reviewed for completeness and accuracy of the data. 
 
Female Subjects of Child-bearing Potential 
6.1.14
Any female subject in an active treatment group who has reached menarche must have a 
negative urine pregnancy test to enroll or continue in the study. Pregnancy tests will be 
performed at screening and at all study visits.  Female subjects in the standard of care group 
subjects will not be required to undergo pregnancy testing.  Sexually active females of child-
bearing potential (FOCBP) must use medically acceptable methods of birth control during and 
for 4 weeks after the treatment period (eg, true abstinence1, oral contraceptive pills, barrier 
methods with spermicide) in a manner such that the risk of failure is minimized.  The 
investigator will discuss these methods as well as their side effects with the subject. 
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy.  
In the event a subject becomes pregnant during the study, study drug will be discontinued and a 
Pregnancy Form will be completed to capture potential drug exposure during pregnancy.  The 
pregnancy will be reported within 24 hours of becoming aware of the condition.  The subject 
will be followed until an outcome is known (ie, normal delivery, abnormal delivery, 
spontaneous abortion (miscarriage), voluntary abortion, or therapeutic abortion).  If a pregnant 
subject also experiences an SAE, the SAE form will be completed and submitted within 
24 hours as discussed above. 
In the event a female partner of a subject becomes pregnant within 4 weeks after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator and a supplemental SAE form will be completed to 
capture the event. 
 
                                                 
1 True abstinence:  Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception). 


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Table 6-1 
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups 
Procedures 
Screen-
ing 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week  
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week  
12 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Type 
Site 
Site 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
 Phone  
Site 
Study Day 
≥-14 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
Visit Window (days) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBS history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense drugc 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense GI 
Symptoms History 
Worksheet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review GI 
Symptoms History 
Worksheet 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Upper GI with small 
bowel follow 
throughd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal 
ultrasoundd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fecal occult blood 
testing e  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Colonoscopy/ 
Sigmoidoscopye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Citrullinef 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense Intake and 
Urine/Stool Output 
Diaries 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 


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Final v3.0 
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Table 6-1 
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups 
Procedures 
Screen-
ing 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week  
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week  
12 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Type 
Site 
Site 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
 Phone  
Site 
Study Day 
≥-14 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
Visit Window (days) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Review Intake and 
Output Diariesg, h, 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review nutritional 
support usage i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional support 
adjustment (as 
needed)j 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testingk 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Physical examination 
and vital signs 
including weight 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height (length) and 
head circumferencel 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety laboratory 
testsm 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
Antibodies to 
teduglutiden 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 6-1 
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups 
Procedures 
Screen-
ing 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week  
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week  
12 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Type 
Site 
Site 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
 Phone  
Site 
Study Day 
≥-14 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
Visit Window (days) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
eCRF = electronic case report form; EN = enteral nutrition; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; 
SC = subcutaneous  
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure. 
b Randomization and therapy assignment is to be completed prior to drug dispensing.  
c The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at least 
4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF.  The dose of study medication will be re-
evaluated at Week 12, based on weight gain/loss. 
d If they have not been performed within 6 months of the baseline visit, upper GI with small bowel follow through and abdominal ultrasound can be performed on all active cohort 
subjects at any time after signing of consent but must be completed and results available and reviewed prior to the baseline visit.  
e Fecal occult blood test will be performed on all active cohort subjects after signing of consent. Colonoscopy/sigmoidoscopy will be conducted on all subjects 12 years of age and 
older and any subjects who have a positive fecal occult blood result without etiology to explain.  Results of colonoscopies done within the prior year may also be used.  
f Citrulline should be collected 2 to 4 hours postprandially, whenever possible. 
g Intake Diaries will collect data on  PN/IV support volume, EN feeds (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.   
h Urine/Stool Output Diary will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact.  
i Nutritional support includes PN/IV, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink. 
j Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1. 
k Female subjects of child-bearing potential 
l Head circumference is to be collected as appropriate (ie, up to 36 months of age).  
m At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. For safety lab assessment done approximately 7 days following any PN/IV 
adjustment and/or in between site visits, safety labs consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety 
labs performed at alternate times in between site visits may be collected by a Home Health Agency and processed for submission to the central lab. 
n Antibody collection is to be done prior to first study drug administration at study site. 
 
 
 
 


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Table 6-2 
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups 
Procedures 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
Week 
17 
Week 
18 
Week 
19 
Week 
20 
Week 
21 
Week 
22 
Week 
23 
Week 24 
(or 
EOT/ET)k 
Weeks 
25-27l 
Week 
28 (or 
EOS) 
Visit Number: 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27-29 
30 
Visit Type 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
 Phone  
Site 
Phone 
Site 
Study Day 
91 
98 
105 
112 
119 
126 
133 
140 
147 
154 
161 
168 
175, 182, 
189 
196 
Visit Window 
(days) 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
Dispense drug 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Fecal occult blood 
testinga 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Colonoscopy/ 
Sigmoidoscopya 
 
 
 
 
 
 
 
 
 
 
 
(X) 
 
 
Citrullineb 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense Intake and 
Urine/Stool Output 
Diaries 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Review Intake and 
Urine/Stool Output 
Diaries and 
nutritional support 
usage c d, e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional support 
adjustment (as 
needed)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testingg 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Physical 
examination and 
vital signs, 
including weight 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Height (length) and 
head circumferenceh 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 


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Table 6-2 
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups 
Procedures 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
Week 
17 
Week 
18 
Week 
19 
Week 
20 
Week 
21 
Week 
22 
Week 
23 
Week 24 
(or 
EOT/ET)k 
Weeks 
25-27l 
Week 
28 (or 
EOS) 
Visit Number: 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27-29 
30 
Visit Type 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
 Phone  
Site 
Phone 
Site 
Study Day 
91 
98 
105 
112 
119 
126 
133 
140 
147 
154 
161 
168 
175, 182, 
189 
196 
Visit Window 
(days) 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X 
Safety laboratory 
testsi 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X)  
(X) 
X 
(X) 
X 
Antibodies to 
teduglutidej 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EN = enteral nutrition; EOS = end of study; EOT = end of treatment; ET = early termination; PN/IV = parenteral nutrition/intravenous fluid  
a If fecal/occult blood is positive without explanation, then a colonoscopy/sigmoidoscopy may be warranted  
b Citrulline should be collected 2 to 4 hours postprandially, whenever possible. 
c Intake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.     
d Urine/Stool Output Diary will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact. 
e Nutritional support includes PN/IV, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink. 
f Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance for 
nutrition support adjustment provided in Appendix 1. 
g Female subjects of child-bearing potential  
h Head circumference is to be collected as appropriate (ie, up to 36 months of age).  
i At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. For safety lab assessment done approximately 7 days following any PN/IV adjustment 
and/or in between site visits, safety labs consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety labs performed 
at alternate times in between site visits may be collected by a Home Health Agency and processed for submission to the central lab. 
j Antibody blood draw is to be taken prior to the last dose of study drug, at least 14 hours following the previous dose of study drug. Subjects who test positive/specific for 
antibodies to teduglutide at the Week 28 visit will have follow-up blood draws for positive/specific antibodies to teduglutide at approximately 3 months following the last dose of 
study drug. If antibodies are still positive/specific they will be collected again approximately 6 months after the last dose of study drug.  
k If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later. 
l A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an Unscheduled Visit. 


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Table 6-3 
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Group 
Procedures 
Screen-
ing 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week  
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week  
12 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Type 
Site 
Site 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
 Phone  
Site 
Study Day 
≥-14 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
Visit Window (days) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBS history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense GI 
Symptoms History 
Worksheet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review GI 
Symptoms History 
Worksheet 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Citrullineb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense Intake and 
Urine/Stool Output 
Diaries 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Review Intake and 
Output Diariesc, d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review nutritional 
support usage e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional support 
adjustment (as 
needed)f 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
and vital signs 
including weight 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 


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Final v3.0 
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Table 6-3 
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Group 
Procedures 
Screen-
ing 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week  
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week  
12 
Visit Number: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Visit Type 
Site 
Site 
Site 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
Phone 
Site 
 Phone  
Site 
Study Day 
≥-14 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
Visit Window (days) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Height (length) and 
head circumferenceg 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Safety laboratory 
testsh 
X 
X 
X 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EN = enteral nutrition; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome  
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure. 
b Citrulline should be collected 2 to 4 hours postprandially, whenever possible. 
c Intake Diaries will collect data on PN/IV support volume, EN feeds (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.   
d Urine/Stool Output Diary will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact.  
e Nutritional support includes PN/IV, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink. 
f Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1. 
g Head circumference is to be collected as appropriate (ie, up to 36 months of age).  
h At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. For safety lab assessment done approximately 7 days following any PN/IV 
adjustment and/or in between site visits, safety labs consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety 
labs performed at alternate times in between site visits may be collected by a Home Health Agency and processed for submission to the central lab. 
 
 
 
 


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Teduglutide (rDNA origin) for injection 
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Table 6-4 
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Group 
Procedures 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
Week 
17 
Week 
18 
Week 
19 
Week 
20 
Week 
21 
Week 
22 
Week 
23 
Week 24 
(or 
EOT/ET)h 
Weeks 
25-27i 
Week 
28 (or 
EOS) 
Visit Number: 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27-29 
30 
Visit Type 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
 Phone  
Site 
Phone 
Site 
Study Day 
91 
98 
105 
112 
119 
126 
133 
140 
147 
154 
161 
168 
175, 182, 
189 
196 
Visit Window 
(days) 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
Citrullinea 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Dispense Intake and 
Urine/Stool Output 
Diaries 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Review Intake and 
Urine/Stool Output 
Diaries and 
nutritional support 
usage b, c, d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nutritional support 
adjustment (as 
needed)e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination and 
vital signs, 
including weight 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Height (length) and 
head circumferencef 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X 
Safety laboratory 
testsg 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X) 
(X) 
X 
(X)  
(X) 
X 
(X) 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Pediatric Study TED-C14-006 – Amendment 2 
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Final v3.0 
06 October 2015 
Table 6-4 
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Group 
Procedures 
Week 
13 
Week 
14 
Week 
15 
Week 
16 
Week 
17 
Week 
18 
Week 
19 
Week 
20 
Week 
21 
Week 
22 
Week 
23 
Week 24 
(or 
EOT/ET)h 
Weeks 
25-27i 
Week 
28 (or 
EOS) 
Visit Number: 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27-29 
30 
Visit Type 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
Phone 
Site 
Phone 
 Phone  
Site 
Phone 
Site 
Study Day 
91 
98 
105 
112 
119 
126 
133 
140 
147 
154 
161 
168 
175, 182, 
189 
196 
Visit Window 
(days) 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 4 
EN = enteral nutrition; EOS = end of study; EOT = end of treatment; ET = early termination; PN/IV = parenteral nutrition/intravenous fluid  
a Citrulline should be collected 2 to 4 hours postprandially, whenever possible. 
b Intake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.     
c Urine/Stool Output Diary will collect data on urine and stool output for the 48 hours prior to the next scheduled visit or telephone contact. 
d Nutritional support includes PN/IV and EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink. 
e Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance for 
nutrition support adjustment provided in Appendix 1. 
f Head circumference is to be collected as appropriate (ie, up to 36 months of age).  
g At site visits, safety lab assessments consist of serum chemistry, hematology and urinalysis. For safety lab assessment done approximately 7 days following any PN/IV adjustment 
and/or in between site visits, safety labs consist of serum chemistry and urinalysis. Safety labs performed during site visits must be processed via central lab. Safety labs performed 
at alternate times in between site visits may be collected by a Home Health Agency and processed for submission to the central lab. 
h If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination and a follow-up visit should be scheduled 4 weeks later. 
i A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an Unscheduled Visit. 


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Teduglutide (rDNA origin) for injection 
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7 
DATA MANAGEMENT 
7.1 
Data Collection 
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
8-digit subject number, including subjects in the standard of care group.  The first 4 digits 
consist of the study site number.  The last four digits will be assigned sequentially starting with 
0001.  This number is the main identifier for subjects.  
Data collected during the study will be recorded in the subject’s eCRF by the investigational 
site staff.  The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.).  Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments).  In case 
of computerized source data, the investigator must provide the sponsor access to the subject 
files at each monitoring visit.  To ensure that data has been entered correctly on the eCRF, they 
will be 100% source-data verified by a site monitor from the sponsor/designee, who will notify 
the investigator regarding any questions or discrepant data.  The investigator or designee will 
be responsible for the timely recording of subject data into the eCRF.  
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents. 
The investigator or designee will review all eCRFs (including the termination page after the 
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the 
appropriate vendor for assimilation into the database.  Paper copies of laboratory reports and 
other non-eCRF data (eg, ECGs) will be signed and dated by the investigator and filed.  
Diaries will be used by the subjects’ parent or guardian to record study information, including 
PN/IV support, enteral administration, regular diet/drink intake, urine output (as either 
collected or calculated volume), stool form and volume, and urine specific gravity. The time of 
the dose should be captured in the appropriate area in the subject diary (ie, Daily [yes/no], 
Morning [yes/no], and option for other). The subject diaries will provide the source 
documentation for the diary data that is to be recorded in the eCRF by the study staff.  
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with eCRF guidelines outlining 
the specific procedures to use when entering the data into the clinical database. Data validation 
and edit checks will be conducted on the data. Any discrepancies will generate queries that 
must be resolved at the study site in a timely manner.  


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Teduglutide (rDNA origin) for injection 
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When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once 
the sponsor/designee acknowledges that all data are acceptable, the data will be declared a 
“clean file,” and the data will be frozen/locked. 
A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the 
database, the database will be ready for statistical analysis by the sponsor/designee. 
7.2 
Rescreening 
At the discretion of the investigator, subjects who fail screening may be re-screened one time 
with prior sponsor approval. In the event of re-screening, a new subject number will be 
assigned. 
7.3 
Record Retention 
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines.  These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject 
consent/assent documents, ECGs, photographs, and computer records) which are a result of the 
original observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report. 
The clinical investigators will maintain copies of these essential documents for approximately 
10 years or as dictated by local regulatory requirements or until instructed in writing by the 
sponsor that records may be destroyed or forwarded to the sponsor.  In accordance with 
regulatory guidelines, these records will be available for inspection and copying if requested by 
a properly authorized employee of the FDA/European Health Authorities. 
8 
STATISTICAL METHODOLOGY AND SAMPLE SIZE 
Detailed statistical analysis methods will be conducted as described in the Statistical Analysis 
Plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in 
the clinical study report (CSR).  
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. 
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. For categorical variables, statistical summaries will include number 
of subjects and percentages. 


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8.1 
Demographic and Baseline Variables 
Demographic and/or other Baseline variables obtained at the screening and baseline visit are 
listed below.  Abnormal findings of clinical significance (if any) will be recorded as past 
medical history. 
• Demography (including age, sex, and race) 
• Medical history 
• SBS history, including remnant anatomy 
• Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts 
• Physical examination 
• Prior medications (medications used within 14 days prior to screening and discontinued 
prior to first dose of study drug), including drug name, dose, route, reason for use, and 
therapy dates.  Medications used during the treatment period (after the first dose of study 
drug) will be recorded as concomitant medications. 
• Electrocardiogram (12-lead) variables will include general findings of 
(normal/abnormal/abnormal, clinically significant).  The cause of any clinically significant 
ECG will be specified.  
• Laboratory test results:  Serum chemistries, hematology, and urinalysis 
• Citrulline levels 
• Presence of antibodies to teduglutide and titer level, if present (active treatment groups 
only) 
• Gastrointestinal imaging (UGI/SBFT, abdominal ultrasound, colonoscopy/sigmoidoscopy, 
fecal occult blood) (active treatment groups only) 
• Pregnancy testing for females of child-bearing potential (active treatment groups only) 
• Nutritional support (eg, PN/IV volume and calorie usage) 
• Data entered in the nutritional diaries 
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and 
the number and percentage of subjects in specified categories by treatment group) will be 
presented, as appropriate, to summarize the demographic and baseline variables.  
Prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary with regard to drug class and drug name.  The number and 
percentage of subjects with specific prior medications will be summarized by treatment group.  


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Medical history (including surgical history) will be coded using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA).  The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term 
for each treatment group. 
8.2 
Safety and Tolerability Variables 
The safety and tolerability variables include: 
• Adverse events, including GI symptoms  
• Physical examination 
• Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts 
• Electrocardiograms 
• Laboratory safety data, including clinical chemistries, hematology and urinalysis 
• Change in urine output (collected or calculated volume) 
• Fecal output (by volume or number of bowel movements per day)  
• Antibodies to teduglutide (active treatment group only 
• GI-specific testing (active treatment groups only) including colonoscopy or sigmoidoscopy,  
abdominal ultrasound, fecal occult blood testing, UGI/SBFT 
Adverse events will be coded using the current version of MedDRA. Treatment emergent AEs 
will be summarized by system organ class and preferred term for each treatment group. The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and AEs that lead to death will be 
summarized by treatment group. AEs will also be summarized by treatment group with regard 
to intensity and relationship to study drug.  For AEs of special interest, the CTCAE grading 
system will be used as described in Section 6.1.4. 
For laboratory tests, vital signs, body weight, ECG, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit for each treatment group. 
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment group. 
8.3 
Pharmacodynamic Variables 
The following pharmacodynamic parameters will be measured: 
• PN/IV volume reduction of at least 20% at 24 weeks (or EOT) compared to baseline  


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• 100% reduction in PN/IV support (any subjects who are able to completely wean off PN/IV 
support) compared to baseline at EOT 
• Change from baseline (absolute and percent change) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories) over time  
• Change from Week 24 (or EOT) (absolute and percent change) in PN/IV support (volume 
and calories), citrulline, and enteral nutritional support (volume and calories) at Week 28 
(or EOS)   
• Change in body weight, height (or length) and head circumference (up to 36 months of 
age). Derived variables will include height Z-score, weight Z-score, body mass index 
(BMI), and BMI Z-score 
• Fecal output (by volume or number of bowel movements per day) 
• Change in hours per day and days per week of PN/IV support   
• Proportion of responders (ie, subjects who achieve at least a 20% reduction in PN/IV 
volume) over time 
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, the 
number and percentage of subjects in specified categories) will be calculated to summarize the 
absolute values and change from baseline at each scheduled visit for each treatment group. 
8.4 
Other Variables  
Other variables will be analyzed by treatment group including: 
• Subject disposition 
• Duration of study drug exposure 
• Subjects will be considered compliant if study drug was taken according to protocol and 
assigned treatment group for ≥ 80% of doses.  Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment group. 
• The number and percentage of subjects who complete the study, are lost to follow up, or 
discontinued from the study (including reason for study withdrawal) will be summarized by 
treatment group. 
• The study drug dose by duration will be summarized by treatment group.   
8.5 
Analysis Populations, Data Sets, and Time Points 
 
Analysis Populations 
8.5.1
The ITT population is defined as any subjects who were randomized into the study.  The safety 
population is defined as the subset of ITT with subjects who received at least one 


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administration of study drug with any safety follow-up.  The primary population analyzed for 
efficacy will be the ITT population.  An additional per-protocol population analysis will also 
be performed as secondary/sensitivity analysis.  Detailed per-protocol evaluable definitions 
will be documented in the SAP. 
8.6 
Statistical/Analytical Issues 
 
Adjustments for Covariates 
8.6.1
No baseline stratification parameter is employed in this study. 
 
Handling of Dropouts or Missing Data 
8.6.2
All subjects randomized will be included in the analyses. Missing safety parameters will not be 
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV 
volume will be detailed in the SAP. 
 
Interim Analyses and Data Monitoring 
8.6.3
No interim analyses are planned. 
An independent DSMB will review the data on a routine basis and may have access to data 
from the study for safety assessment. Details of the roles and responsibilities of the DSMB 
members and the structure and scope of the DSMB meetings will be provided in a separate 
DSMB Charter. 
 
Multiple Comparisons/Multiplicity 
8.6.4
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be 
no adjustment for alpha level. 
 
Use of an Efficacy Subset of Subjects 
8.6.5
A per-protocol population will be analyzed for this study. 
 
Examination of Subgroups 
8.6.6
Because a small number of subjects are expected at each study site, data from all study sites 
will be pooled. 
8.7 
Determination of Sample Size 
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation. 
8.8 
Changes to Planned Statistical Analyses 
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified 
in the final CSR.  


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Teduglutide (rDNA origin) for injection 
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9 
ADMINISTRATIVE AND ETHICAL REQUIREMENTS 
9.1 
Declaration of Helsinki and Ethical Review 
This protocol will be conducted in accordance with the current applicable ICH Guidelines, 
Good Clinical Practice, and the World Medical Association Declaration of Helsinki and its 
amendments concerning medical research in humans. 
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent 
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant 
material for the investigator to submit to the IRB for the protocol’s review and approval.  
Verification of the IEC/IRB approval of the protocol and the written consent/assent form will 
be forwarded to the sponsor/designee. 
The investigator will inform the IEC/IRB of subsequent protocol amendments and any 
SUSARs if the sponsor has assessed it as an unanticipated problem.  Approval for protocol 
amendments will be transmitted in writing to the investigator. 
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study. 
9.2 
Subject Information, Informed Consent and Assent 
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate. 
The investigator (or designee) will explain to the subject and/or the subject’s parent or 
guardian the nature of the study, the action of the test product, and any risks and benefits.  The 
subject and/or subject’s parent or guardian will be informed that participation is voluntary and 
that the subject can be withdrawn from the study at any time without prejudice to their 
subsequent care. 
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records. 
9.3 
Subject Data Protection 
All data provided to the sponsor/designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  Where allowed, the 
subject’s date of birth will also be recorded. The subject and/or the subjects’ parent or guardian 
should be informed in writing, that the subject’s data will be stored and analyzed in a 


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computer, with confidentiality maintained in accordance with national and local legislation.  
Study site-specific information must be added to the consent/assent as appropriate. 
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 
access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes. 
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, 
and a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed 
screening must also be maintained and be available for inspection. 
9.4 
Financial Disclosure 
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” 
(February 2013) provides guidance to industry on its final rule on financial disclosure that 
became effective 02 February 1999 and was published as Title 21 Code of Federal Regulations 
Part 54.  This rule applies to all investigators participating in clinical studies to be submitted to 
the FDA in support of an application for market approval.  The financial disclosure statement 
must be updated if any relevant changes occur during the course of the study, again at the site 
close-out visit, and for 1 year after the completion of the study. 
According to the guidance, financial arrangements that must be disclosed are defined as the 
following: 
• Compensation made to the investigator in which the value of compensation could be 
affected by study outcome  
• A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement 
• Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices)  
• An equity interest in a publicly held company that exceeds $50,000 in value  
• Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or the 
investigator’s institution to support activities of the investigator exclusive of the costs of 
conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing research, 
compensation in the form of equipment or retainers for ongoing consultation, or honoraria) 
during the time the clinical investigator is carrying out the study and for 1 year after 
completion of the study 


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Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes 
the spouse and each dependent child of the investigator.  Participating investigators must 
provide this information and complete necessary documentation as requested by the sponsor. 
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA 
in support of a market application.  Companies must meet these financial disclosure 
requirements, and failure to do so may result in the refusal by the FDA to accept an application 
for market approval of the study drug. 
9.5 
Changes to the Protocol 
No change in the study procedures shall be effected without the mutual agreement of the 
sponsor and the investigator.  All changes must be documented as signed protocol 
amendments, or as a revised protocol.  Changes to the protocol may require notification to or 
approval by the IEC/IRB and the regulatory authorities before implementation. Local 
regulatory requirements must be followed.  Instructions for reporting deviations from the 
protocol can be found in the Study Reference Manual. 
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site. 
9.6 
Investigator Obligations 
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study: 
• 
A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA. 
• 
A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address which 
matches the address on the FDA Form 1572 
• 
Financial disclosure statement for the principal investigator, and subinvestigators (listed on 
the FDA Form 1572).  An updated financial disclosure statement must be provided at the 
study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study. 
• 
A copy of the original approval for conducting the study from the IEC/IRB. Renewals must 
be submitted at yearly intervals if the study is ongoing or as required by the institution. 
• 
A copy of the IEC/IRB-approved ICF/assent 


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• 
IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial 
• 
Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively 
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and 
dated by the principal investigator for the study site. 
9.7 
Confidentiality/Publication of the Study 
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential. 
The data generated by this clinical study are the property of the sponsor.  These data may be 
used by the sponsor, now and in the future, for presentation or publication at the sponsor’s 
discretion and/or for submission to regulatory agencies.  In addition, the sponsor reserves the 
right to review data from this study relative to the potential release of proprietary information 
30 days prior to submission to any publication or for any presentation. 
9.8 
Selection of a Primary Principal Investigator 
The sponsor will select one primary principal investigator as a representative of all 
investigators for this study.  Roles, affiliations, and qualifications for the principal investigators 
will be included in the CSR appendices.  Where the signature of the principal investigator is 
required by regulatory authorities, this will also be included in the CSR appendices. 
9.9 
Study Termination 
The sponsor reserves the right to discontinue the study for medical and/or administrative 
reasons at any time. 
 
 


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10 
REFERENCES 
Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and 
intestinal transplantation. Gastroenterology. 2003;124:1111-1134. 
Common Terminology Criteria for Adverse Events (CTCAE).  US Department of Health and 
Human Services, National Institutes of Health, National Cancer Institute. Version 4.03, 
June 14, 2010. 
Duro D, Kamin D, Duggan C.  Overview of Pediatric Short Bowel Syndrome.  J Pediatr 
Gastro and Nutr. 2008;47:S33-S36. 
Fleming CR, Witzke D, Beart RW Jr.  Catheter-related complications in patients receiving 
home parenteral nutrition. Ann Surg. 1980 Nov;192(5):593-599. 
Jeppesen PB, Langholz E, Mortensen PB.  Intestinal failure defined by measurements of 
intestinal energy and wet weight absorption.  Gut. 2000;46:701-706. 
Khan FA, Squires RH, Litman HJ, et al. Predictors of enteral autonomy in children with 
intestinal failure:  a multicenter cohort study.  J Pediatr. 2015 Jul; 167(1): 29-34. 
 
Lewis SJ and Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924. 
Messing B, Crenn P, Beau P, Boutron-Ruault MC, Rambaud J-C, Matuchansky C.  Long-term 
survival and parenteral nutrition dependence in adult patients with the short bowel syndrome. 
Gastroenterology. 1999;117:1043-1050. 
O’Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel 
syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol 
Hepatol. 2006;4:6-10. 
Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: 
initial report from the Pediatric Intestinal Failure Consortium. J Pediatr. 2012 Oct;161(4): 
723-728. 
 
Tappenden KA, Edelman J, Joelsson B. Teduglutide enhances structural adaptation of the 
small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol. 2013 
Aug; 47(7):602-607. 
 
Thymann T, Stoll B, Mecklenburg L, et al. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr. 2014 Jun;58(6):694-702.  
 
Wales PW, deSilva N, Kim J, Lecce L, To T, Moore A. Neonatal short bowel syndrome:  
population-based estimates of incidence and mortality rates. J Pediatr Surg. 2004 
May;39(5):690-695. 
 


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APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY 
Please consider the following clinical parameters identified as markers for adequate 
management of pediatric short bowel syndrome.  These parameters should also be considered 
for managing nutritional support (PN/IV and/or oral/enteral feeding) in terms of volume and 
calories during the treatment period.   
• Considerations to adjust nutritional support in volume and calories will be made at all 
planned visits. 
• Maintaining growth (including weight and length and head circumference [for children up 
to 36 months of age]) by the subjects trending along their growth chart and adjusting 
calories/volumes to maintain appropriate growth. 
• Other clinical evaluations 
o Normal serum electrolytes 
o Stable BUN/creatinine levels 
o Decrease in stool frequency or volume, including mixed output 
o Stool consistency (ie, Bristol Stool Scale) 
o Urine specific gravity 
• General consideration to possible clinical deterioration in SBS 
o Inability to maintain weight and growth velocity 
o Diarrhea (≥10 bowel movements per day, ≥ 80 mL/kg/day from an ostomy, or 
≥ 75 mL/kg/day mixed output) 
o Colic/vomiting frequency increased 
o Electrolyte changes or imbalance 
o Skin breakdown  
• Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses.  Subjects should remain compliant with the nutritional support prescription 
in volume and calories during the study. 
• Nutritional support constituents may be adjusted at the discretion of the investigator. 
• During the 48-hour Intake/Output measurement period prior to the subject’s scheduled 
visit, no further changes to the prescribed nutritional support should be made. 
• If there is a change in EN or other oral fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories. 
 
 


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Figure A-1 
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers 
 
  
  


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Figure A-2 
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers 
 
 
 
 
 


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Final v3.0 
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Figure A-3 
Clinical Dehydration Assessment and PN/EN Adjustment 
 
 
 
 


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APPENDIX 2: PROTOCOL HISTORY  
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
12 Mar 2015 
Global 
Amendment 1 
22 Jun 2015 
Global 
 
Note:  Administrative changes, typographical errors, and otherwise minor text changes made to 
increase readability are not listed. 
Protocol Amendments 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number 
2 
Amendment Date 
06 October 2015 
Global/Country/Site Specific 
Global 
 
Description of Change 
Section(s) Affected by Change 
Key study contacts have been added 
Page 2 
Product Quality Complaints information has been added 
Page 3 
Methodology has been clarified; there were no changes to the overall 
design 
Synopsis 
Protocol Section 3.1 
Inclusion and Exclusion have been refined and clarified; there were no 
additional criteria added 
Synopsis 
Protocol Sections 4.2 and 4.3 
Exclusion Criteria #21 has been changed to indicate that subjects with 
active or unstable renal dysfunction meet laboratory criteria of an eGFR 
of at least 50 mL/min/1.73 m2; creatinine clearance is no longer a basis 
for exclusion. 
Synopsis 
Protocol Section 4.3 
Administration of investigational product has been modified to allow for a 
dose adjustment at Week 12, if warranted based on subjects’ weight 
gain/loss over the initial 12-week treatment period. 
Synopsis 
Protocol Section 5.1 
Study endpoints have been streamlined and redundancies removed.  
Safety and pharmacodynamics endpoints have been realigned, as 
appropriate.  No additional endpoints have been added and nor existing 
endpoints eliminated. 
Synopsis 
Protocol Sections 6.1, 8.2, and 8.3 
Height and BMI Z-scores have been added to the parameters being 
calculated by the sponsor based on vital signs measurements of height and 
weight. 
Synopsis and Protocol Sections 6.1.8 
and 8.3 
Study signatories have been amended as appropriate. 
Protocol signature page, Page 13 
Background information and study rationales have been updated based on 
current information and the availability of final results of the prior 
pediatric study 
Protocol Sections 1.1, 1.2, 1.3, and 
5.3.1 
Procedures for subjects who terminate early from the study have been 
clarified. 
Protocol Section 4.4 
Data Safety Monitoring Board requirements and expectations have been 
clarified. 
Protocol Section 4.5 
Initial study drug shipment requirements have been clarified. 
Protocol Section 5.1.3 
Subject number assignment has been clarified. 
Protocol Section 5.2 
Prior and concomitant medications have been defined 
Protocol Sections 5.3.4 and 8.1 


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Description of Change 
Section(s) Affected by Change 
Procedures for reporting serious adverse events have been revised in order 
to comply with Shire procedures. 
Protocol Section 6.1.2.2 
Investigators will no longer be required to assign CTCAE severity grades 
to treatment-emergent adverse events of special interest.  The normal AE 
reporting process will prevail. 
Protocol Section 6.1.4 
A provision has been made for safety laboratory blood draws to be done 
by a Home Health Agency for measurements that are required at times 
that do not coincide with clinic visits. 
Protocol Section 6.1.6 
Specification that samples for antibody analysis may be drawn from either 
peripheral venous access or a central line has been added. 
Protocol Section 6.1.6.3 
Clarification made that electrocardiograms will be required for subjects in 
the standard of care group 
Tables 6-3 and 6-4 
Urine and stool collection will be done for 48 hours prior to all scheduled 
visits (phone and clinic) rather than for 72 hours 
Protocol Sections 6.1.12 and 6.1.13; 
Tables 6-1, 6-2, 6-3, and 6-4 
Information captured by subjects in the Study Diaries has been clarified. 
Protocol Section 6.1.13 
Collection of urine specific gravity for children in diapers is now 
requested of parents at the discretion of the investigator 
Protocol Section 6.1.13 
Schedules of Evaluations and Procedures have been revised to increase 
readability and correct entries, as appropriate. 
Protocol Tables 6-1, 6-2, 6-3, and 
6-4 
The ability to re-screen subjects one time with sponsor approval has been 
specified. 
Protocol Section 7.2 
Disclosure that, as allowed, subjects’ dates of birth will be recorded, was 
added. 
Protocol Section 9.3 
Specifications for the management of nutritional support has been updated 
based on expert opinion.   
Protocol Appendix 1 and Figures 
A-1, A-2, and A-3 
 
 

Prot_002.pdf: 
A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic 
Study Investigating Two Doses of Teduglutide in Pediatric Subjects 
Through 17 Years of Age with Short Bowel Syndrome who are 
Dependent on Parenteral Support
Clinical Study Protocol TED-C14-006
Version 4.0
Phase 3
US IND# 058213 
US NDA# 203441
EuDRACT #2015-002252-27
NPS Pharmaceuticals, Inc.*
300 Shire Way Lexington, MA 02421 USA
(*NPS Pharmaceuticals was acquired by Shire, Inc on 21 February 2015)
ISSUED:
Amendment 3, version 4.0
25 February 2016
Amendment 2, version 3.0
06 October 2015
Amendment 1, version 2.0:
22 June 2015
Original Protocol version 1.0:
12 March 2015
SPONSOR
NPS Pharmaceuticals, Inc.*
300 Shire Way Lexington, MA 02421 USA
(*NPS Pharmaceuticals was acquired by Shire, Inc on 21 February 2015)


S hire
C o nfi de nti al
P a ge 2
Pe di atric St u d y T E D -C 1 4 -0 0 6 – A m e n d me nt 3
Versi o n 4. 0 / 2 5 Fe b 2 0 1 6
K E Y S P O N S O R C O N T A C T S

Q ui ntiles Me dic al S u p p ort
, M D –
P H :
 ( me dical emer ge ncies – U S & Ca na da)
P H :
 (me dical e mer ge ncies – gl o bal)

S hire Me dic al M o nit or
, M D, P h D –
P H :
 ( M-F, 9 a m t o 5 p m E S T)
Fa x:
T O R E P O R T A S E RI O U S A D V E R S E E V E N T :
Gl o b al P h ar m ac o vi gil a nce a n d Ris k M a n a ge me nt
P P D
Sca n a n d e -mail:
Fa x:
 ( Gl o bal)
Fa x:
 ( N ort h A merica)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire
C o nfi de nti al
P a ge 3
Pe di atric St u d y T E D -C 1 4 -0 0 6 – A m e n d me nt 3
Versi o n 4. 0 / 2 5 Fe b 2 0 1 6
P R O D U C T Q U A LI T Y C O M P L AI N T S
I n vesti gat ors are re q uire d t o re p ort i n vesti gati o nal pr o d uct q ualit y c o m plai nts t o S hire wit hi n 
2 4 h o urs. T his i ncl u des a n y  i nsta nces w herei n t he q ualit y or perf or ma nce of a S hire pr o d uct 
( mar kete d or i n vesti gati o nal) d oes n ot meet e x pectati o ns (e g, i na de quate or fa ult y  cl os ure, 
pr o d uct c o nta mi nati o n) or t hat t he pr o d uct di d n ot meet t he s pecificati o ns defi ne d i n t he 
a p plicati o n f or t he pr o d uct (e g, wr o n g pr o d uct s uc h t hat t he la bel a n d c o nte nts are differe nt 
pr o d ucts).  F or i nstr ucti o ns o n re p orti n g A Es re late d t o pr o d uct c o m plai nts, see Secti o n 6. 3 .
Please use t he i nf or mati o n bel o w as a p plica ble t o re p ort t he Pr o d uct Q ualit y C o m plai nt:
Ori gi n of Pr o d uct Q ualit y C o m plai nt
E- mail A d dress
U nite d States
Rest of W orl d
P P D
Tele p h o ne n u m bers ( pr o vi de d f or refere nce):   
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P P D
P P D


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Pediatric Study TED-C14-006 – Amendment 3
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SYNOPSIS
Protocol TED-C14-006
Title of Study: A 24-week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Protocol No: TED-C14-006
Development phase: 3
Objective: The objective of this clinical study is to evaluate the safety, tolerability,
pharmacokinetics, and efficacy/pharmacodynamics of teduglutide in pediatric subjects through
17 years of age with short bowel syndrome (SBS) and who are dependent on parenteral support.
Methodology: This study will include 2 treatment arms:  a teduglutide treatment arm and a 
standard of care treatment arm.  Subjects in both arms will participate in a 2-week minimum 
screening period, a 24-week treatment period, and a 4-week follow-up period.  During the 
screening period, subjects will choose into which arm to enroll.  During the 24-week treatment 
period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; while 
those in the teduglutide treatment arm will receive daily subcutaneous (SC) injections of 
teduglutide (study drug) in addition to standard medical therapy.  These subjects will be 
randomized 1:1 in a double-blinded manner into two parallel dose groups:  0.025 mg/kg/day and
0.05 teduglutide.  Randomization across dose groups will be stratified by age:  <1 year, 1 to 
<12 years, 12 to <17 years, and 17 to <18 years.
Each subject will be screened minimally for 2 weeks before the baseline visit (day 0) to allow 
adequate time to verify enrollment eligibility.  Subjects in both arms will follow the same visit 
schedule. After the screening period, subjects will visit the site at baseline (day 0), weekly for 
the first 2 weeks (ie, weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 
10, and 12). For the remainder of the treatment period, subjects will visit the sites once every 
3 weeks (ie, weeks 15, 18, 21, and 24). For all other study weeks, subjects will be contacted by 
telephone. At all site visits and telephone contacts, safety will be monitored and nutritional 
support will be reviewed and adjusted as needed. At the end of the treatment period (week 
24/EOT), all subjects will enter a 4-week follow-up period until the end of study (week 28/EOS) 
during which time no study drug (ie, teduglutide) will be administered.  A final visit will occur at 
week 28, 4 weeks after EOT. Telephone contact will be made during the weeks from EOT to 
EOS to monitor safety and any changes in nutritional support.
All subjects who complete the study, including those in the SOC treatment arm, may participate 
in a long-term extension study in which eligible subjects could receive teduglutide.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) 
for decisions regarding PN/IV support reduction and advances in enteral feeds based on weight 
gain, urine and stool output, and clinical stability.  Any departure from the guidelines will not
constitute a protocol deviation.


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Pediatric Study TED-C14-006 – Amendment 3
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If a blood sample is positive for antibodies to teduglutide at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) that 
will convene approximately every 3 months during the treatment period.  The treatment period 
for the study is defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT. The DMC committee members will include all cumulative 
safety data from study assessments through the end of each review period.
Number of Subjects:  Approximately 26 subjects who are teduglutide-naïve (a minimum of 
10 subjects per teduglutide dose arm) will be enrolled into the teduglutide treatment arm and at 
least 8 subjects who are teduglutide-naïve will be enrolled into the SOC treatment arm.  
Enrollment will proceed at approximately 28 investigational sites globally.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
Duration of Study:  For each subject, the study duration will be a minimum of 30 weeks:

2-week minimum screening period

24-week treatment period

4-week follow-up period
A subject will be considered enrolled in the study at the baseline visit (day 0) when the choice of 
treatment arm (ie, teduglutide or SOC) has been made.
Criteria for inclusion/exclusion:  Male and female children and adolescents through 17 years of 
age, who satisfy all of the following inclusion criteria and none of the following exclusion 
criteria are eligible to be enrolled in this study.
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures 
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
6. Sexually active female subjects of child-bearing potential (in the teduglutide treatment arm
only) must use medically acceptable methods of birth control during and 4 weeks after the 
treatment period


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Pediatric Study TED-C14-006 – Amendment 3
Version 4.0 / 25 Feb 2016
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria are met:
1. Subjects who are not expected to be able to advance oral or tube feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done 
within 6 months prior to screening
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to the screening visit (insertion of feeding tube, anastomotic ulcer repair, minor intestinal 
resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the teduglutide treatment arm only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject


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Pediatric Study TED-C14-006 – Amendment 3
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19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
a.
Total bilirubin (TBL) ≥2x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7x ULN
c.
Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are 
provided in Table 4-1.
Test Product, Dose, and Mode of Administration
Subjects who elect to receive teduglutide treatment will be randomized 1:1 in a double-blinded 
manner into two dose groups:  0.025 mg/kg/day and 0.05 mg/kg/day.  The dose calculation will 
be based on subject body weight measured at the baseline visit (visit 2) and adjusted, as needed, 
based on measurements made at week 12 (visit 14).  Subjects in both dose groups of the 
teduglutide treatment arm will receive 0.005 mL/kg of reconstituted study drug at a blinded 
concentration.  No other adjustments to the dose will be made during the treatment period, unless 
discussed with the Shire medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.
Reference Therapy, Dose, and Mode of Administration:  Not applicable
Criteria for Evaluation
Pharmacokinetics:  Subjects in the teduglutide treatment arm only
For the PK evaluation, blood will be collected at the clinic on day 0 when the subject receives 
the first dose of teduglutide.  Blood sampling will occur at the following timepoints:  predose 
and 1, 2, and 4 hours postdose.  In smaller children for whom blood sampling may impose 
unacceptable phlebotomy volume, the number of PK samples may be reduced.
If a subject is unable to provide blood samples at baseline (day 0) on the first day of treatment, 
then blood may be collected for PK analysis during any other future clinic visit while the subject 
is still receiving treatment with teduglutide.
Safety and tolerability
Safety and tolerability will be assessed by evaluating the following:


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Pediatric Study TED-C14-006 – Amendment 3
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
Assessment of adverse events including those pertaining to GI symptoms

Physical examinations

Vital signs, including temperature, heart rate, blood pressure

Body weight, height (or length), head circumference (up to 36 months of age), body mass 
index (BMI); z-scores will be calculated for height (or length), weight, head 
circumference, and BMI

Electrocardiograms

Laboratory safety data (ie, clinical chemistry, hematology, urinalysis)

Urine output

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide (teduglutide treatment arm only)

GI-specific testing (teduglutide treatment arm only) including colonoscopy or
sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, upper GI series with 
small bowel follow through
Efficacy/pharmacodynamics
The primary efficacy/PD endpoint is a reduction in PN/IV volume of at least 20% at week 24 
(or EOT) compared to baseline.
Additional PD endpoints include:

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or 
EOT) compared to baseline

Changes (absolute and percent change) from baseline in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories), separately, at 
each clinic visit

Changes (absolute and percent change) from week 24 (or EOT) in PN/IV support
(volume and calories), citrulline, and enteral nutritional support (volume and calories), 
separately, to week 28 (or EOS)

Change in hours per day and days per week of PN/IV support

≥20% reduction in PN/IV volume at each clinic visit
Statistical methods
Because of the small size of the study population only descriptive statistics will be used to 
summarize data.  Accordingly, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum.  For categorical variables, statistical summaries will include number of subjects 
and percentages.
Demographics and baseline
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate.
Pharmacokinetics


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Pediatric Study TED-C14-006 – Amendment 3
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The PK parameters will be estimated based on measured teduglutide plasma concentrations using 
a population PK modeling approach.
Safety
Safety data will include clinical laboratory test results; physical examinations; measurements of
weight, height or length, and head circumference (if applicable); vital signs; concomitant 
medications; and electrocardiogram monitoring. Adverse events will be collected and 
summarized. Descriptive statistics will be calculated for quantitative safety data as well as for 
the difference from baseline, if applicable.  Frequency counts will be compiled for classification 
of qualitative safety data.
Efficacy/Pharmacodynamics
Efficacy/pharmacodynamics data will include changes in PN/IV support, enteral nutritional 
support, citrulline, and hours per day or days per week of PN/IV support and will be summarized 
by visit and time point.


S hir e 
C o nfi d e nti al 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 3 
P a g e 1 0 
V ersi o n 4. 0 I 2 5 F e b 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
Re vie we d a n d A p pr o v e d: 
 
 
S hir e , I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h ar m a c o vi gil a n c e 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n , M A 0 2 4 2 1 
, P h D 
 
S h ire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n , M A 0 2 4 2 1 
, P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Zli hl er w e g t O 
6 3 0 0 Z u g 
S wit z erl a n d 
, M D, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n , M A 0 2 4 2 1 
Si g n at ur e 
D ¥at e 
' 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hir e 
C o nfi d e nti al 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 3 
P a g e 1 0 
V ersi o n 4. 0 I 2 5 F e b 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o v e d: 
 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h ar m a c o vi gil a n c e 
S hir e, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h D 
 
S hir e, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Z a hl er w e g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
, M D, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hi r e 
C o nfi de nti al 
P e di atri c St u d y T E D- C 1 4- 0 0 6- A m e n d m e nt 3 
P a g e 1 0 
V ersi o n 4. 0 I 2 5 F e b 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o v e d: 
 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h ar m a c o vi gil a n c e 
S hire, I nc. 
3 0 0 S hir e Wa y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h D 
 
S hire, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h ar m D 
 
S hire I nt er n ati o n al G m b H 
Zii hler we g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
 M D, P h D 
 
S hire, I n c. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire 
C o nfi de nti al 
P e di atri c St u d y T E D- CI 4- 0 0 6- A m e n d m e nt 3 
P a g e 1 0 
V ersi o n 4. 0 1 2 5 F e b 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- Cl 4- 0 0 6 
R e vie we d a n d A p pr o v e d: 
 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, M D 
Gl o b al P h a n n a c o vi gil a n c e 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Z a hl er w e g I 0 
6 3 0 0 Z u g 
S wit z erl a n d 
, M D, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
Si g n at ur e 
Si g n at ur e 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M Y Y Y Y) 
D at e 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire 
C o nfi de nti al 
Pe di atric St u d y T E D- CI 4- 0 0 6- A me n d me nt 3 
P a g el O 
Versi o n 4. 0/ 2 5 Fe b 2 0 1 6 
SI G N A T U R E S F O R P R O T O C O L T E D- C 1 4- 0 0 6 
R e vi e w e d a n d A p pr o ve d: 
 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 M D 
Gl o bal P h ar m a c o vi gil a n c e 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
 P h D 
 
S hire, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
, P h ar m D 
 
S hir e I nt er n ati o n al G m b H 
Zfi hler we g 1 0 
6 3 0 0 Z u g 
S wit z erl a n d 
, M D, P h D 
 
S hir e, I nc. 
3 0 0 S hir e W a y 
L e xi n gt o n, M A 0 2 4 2 1 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
Date 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Si g n at ur e 
D at e 
( D D M M M Y Y Y Y) 
Date 
( D D M M M 
P P D
Y Y Y Y) 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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Pediatric Study TED-C14-006 – Amendment 3
Version 4.0 / 25 Feb 2016
PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL TED-C14-006
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics Committee 
(IEC) for the study protocol and any amendments thereof, written informed consent or updates 
thereof, subject recruitment procedures (eg, advertisements), and any other written information 
to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement from 
the sponsor and review and documented approval from the IRB/IEC, except to eliminate an
immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data sheets, 
correspondence records, and signed subject consent/assent documents for at least 10 years or 
until instructed in writing by the sponsor that records may be destroyed or forwarded to the 
sponsor.
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................4
SIGNATURES FOR PROTOCOL TED-C14-006........................................................................10
PRINCIPAL INVESTIGATOR AGREEMENT FOR PROTOCOL TED-C14-006....................11
TABLE OF CONTENTS...............................................................................................................12
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................15
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................16
1
INTRODUCTION .................................................................................................................18
1.1 Background........................................................................................................................18
1.2 Rationale for the Clinical Study.........................................................................................20
1.3 Rationale for Study Design................................................................................................21
2
OBJECTIVES........................................................................................................................24
2.1 Primary Objective..............................................................................................................24
3
STUDY DESIGN...................................................................................................................25
3.1 Overall Design and Control Methods ................................................................................25
3.2 Study Duration...................................................................................................................28
4
SUBJECT SELECTION AND PARTICIPATION...............................................................29
4.1 Number of Subjects............................................................................................................29
4.2 Criteria for Inclusion/Exclusion.........................................................................................29
4.2.1
Inclusion Criteria ...............................................................................................29
4.2.2
Exclusion Criteria ..............................................................................................29
4.3 Subject Withdrawal Criteria ..............................................................................................31
4.4 Data Monitoring Committee..............................................................................................32
5
TREATMENTS AND TREATMENT PLAN.......................................................................33
5.1 Treatment Administered ....................................................................................................33
5.1.1
Identification of Investigational Product ...........................................................33
5.1.2
Packaging and Labeling.....................................................................................33
5.1.3
Storage, Accountability, and Stability...............................................................33
5.2 Methods of Assigning Subjects to Study Treatment Arms................................................34
5.3 Dose Regimens ..................................................................................................................35
5.3.1
Selection of Doses in Study...............................................................................35
5.3.2
Selection and Timing of Dose for Each Subject in the Teduglutide 
Treatment Arm...................................................................................................35
5.3.3
Compliance with Dosing Regimens ..................................................................36
5.3.4
Prior and Concomitant Treatments....................................................................36
6
STUDY EVALUATIONS AND PROCEDURES ................................................................37
6.1 Pharmacokinetics...............................................................................................................37
6.2 GI-specific Symptoms History ..........................................................................................37


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6.3 Diaries................................................................................................................................37
6.4 Nutritional Support ............................................................................................................38
6.5 Gastrointestinal-specific Testing .......................................................................................38
6.5.1
Upper Gastrointestinal Series with Contrast......................................................39
6.5.2
Abdominal Ultrasound.......................................................................................39
6.5.3
Fecal Occult Blood Testing ...............................................................................39
6.5.4
Colonoscopy/Sigmoidoscopy ............................................................................39
6.6 Laboratory Evaluations......................................................................................................39
6.6.1
Laboratory Tests ................................................................................................40
6.6.1.1
Plasma Citrulline......................................................................................40
6.6.1.2
Antibodies to Teduglutide........................................................................40
6.7 Physical Examinations.......................................................................................................41
6.8 Body and Weight Measurements.......................................................................................41
6.9 Vital Signs..........................................................................................................................41
6.10
Electrocardiograms ......................................................................................................41
6.11
Adverse Events ............................................................................................................41
6.11.1
Adverse Event Definition ..................................................................................42
6.11.2
Procedures for Reporting Adverse Events.........................................................42
6.11.3
Relationship to study drug (not related, related)................................................43
6.11.4
Abuse, Misuse, Overdose, and Medication Error..............................................44
6.12
Serious Adverse Events ...............................................................................................44
6.12.1
Serious Adverse Event Definition .....................................................................45
6.12.2
Procedures for Reporting Serious Adverse Events............................................45
6.13
Adverse Events of Special Interest ..............................................................................47
6.14
Dose Interruption of Individual Subjects in the Teduglutide Treatment Arm.............47
6.14.1
Dose Interruption Criteria Based on Known Risks of Teduglutide...................47
6.14.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ......................49
6.15
Early Termination of the Clinical Study......................................................................49
6.16
Prior and Concomitant Treatments..............................................................................50
6.17
Female Subjects of Child-bearing Potential ................................................................50
6.18
Unblinding ...................................................................................................................50
7
DATA MANAGEMENT.......................................................................................................60
7.1 Data Collection ..................................................................................................................60
7.2 Rescreening........................................................................................................................61
7.3 Record Retention ...............................................................................................................61
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE ..................................................62
8.1 Demographic and Baseline Variables................................................................................62
8.2 Safety and Tolerability Variables ......................................................................................63


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8.3 Pharmacokinetic Variables ................................................................................................63
8.4 Efficacy/Pharmacodynamic Variables...............................................................................64
8.5 Other Variables ..................................................................................................................64
8.6 Analysis Populations, Data Sets, and Time Points ............................................................65
8.6.1
Analysis Populations..........................................................................................65
8.7 Statistical/Analytical Issues ...............................................................................................65
8.7.1
Adjustments for Covariates ...............................................................................65
8.7.2
Handling of Dropouts or Missing Data..............................................................65
8.7.3
Interim Analyses and Data Monitoring .............................................................65
8.7.4
Multiple Comparisons/Multiplicity ...................................................................66
8.7.5
Use of an Efficacy Subset of Subjects...............................................................66
8.7.6
Examination of Subgroups.................................................................................66
8.8 Determination of Sample Size ...........................................................................................66
8.9 Changes to Planned Statistical Analyses ...........................................................................66
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS..................................................67
9.1 Declaration of Helsinki and Ethical Review......................................................................67
9.2 Subject Information, Informed Consent and Assent..........................................................67
9.3 Subject Data Protection......................................................................................................67
9.4 Financial Disclosure...........................................................................................................68
9.5 Changes to the Protocol .....................................................................................................69
9.6 Investigator Obligations.....................................................................................................69
9.7 Confidentiality/Publication of the Study ...........................................................................69
9.8 Selection of a Primary Principal Investigator....................................................................70
9.9 Study Termination .............................................................................................................70
10
REFERENCES ......................................................................................................................71


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LIST OF IN-TEXT TABLES AND FIGURES
In-Text Tables
Table 4-1
Excluded Diseases and Illnesses............................................................................31
Table 6-1
Adverse Events that May Lead to Dose Interruption.............................................48
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm –
Screening to Week 12 ............................................................................................52
Table 6-3
Schedule of Events in the Teduglutide Treatment Arm –
Weeks 13 to 28 (EOT)...........................................................................................55
Table 6-4
Schedule of Events in the Standard of Care Treatment Arm –
Screening to Week 12 ............................................................................................57
Table 6-5
Schedule of Events in the Standard of Care Arm – Weeks 13 to 28 (EOT)..........59
In-Text Figures
Figure 3-1
Study Diagram ......................................................................................................27


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Pediatric Study TED-C14-006 – Amendment 3
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-inf
AUC from zero to infinity
AUClast
AUC from zero to the last measurable concentration
AUC
AUC at steady state
CL/F
apparent clearance
Cmax
maximum plasma concentration
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
FDA
Food and Drug Administration
FOCBP
female (subjects) of child-bearing potential
GI
gastrointestinal
GLP-2
glucagon-like peptide 2
IB
Investigator’s brochure
IBD
inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IV
Intravenous fluids
IWRS
Interactive Web Response System
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
PD
pharmacodynamic
PK
pharmacokinetic
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
Short bowel syndrome


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Abbreviation
Definition
SC
subcutaneous
SOC
standard of care
SUSAR
suspected, unexpected, serious, adverse reaction
t1/2
terminal-phase half-life
TEAEs
treatment-emergent adverse events
Tmax
time to Cmax
UGI/SBFT
upper GI series with small bowel follow through
ULN
upper limit of normal
Vλz/F
apparent volume of distribution


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1
INTRODUCTION
1.1
Background
Compound
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide-
2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native GLP-2 
in the substitution of glycine for alanine at the second position at the N-terminus.  As a result, 
teduglutide demonstrates resistance to degradation by dipeptidyl peptidase-IV and therefore 
maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Thymann et 
al. 2014; Tappenden et al. 2013).  The European Commission granted a centralized marketing 
authorization valid throughout the European Union for teduglutide (Revestive™) on 30 August 
2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by the US 
Food and Drug Administration (FDA) on 21 December 2012 for the treatment of adult patients 
with Short Bowel Syndrome (SBS) who are dependent on parenteral support.
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes to 
the label which provide for long-term use of Gattex in adults.
Preclinical Studies
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated rats. 
Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those observed 
in studies conducted using adult animals (rodents and primates). No treatment-related malignant 
tumors were noted in a 2-year carcinogenicity study in rats; treatment-related changes included 
benign tumors of the bile duct epithelium and adenomas of the jejunal mucosa in males treated at 
35 mg/kg/day. The results from a second 2-year carcinogenicity study in Crl:CD1(ICR) mice 
were provided to the FDA in a NDA Supplement which received agency approval on 26 June 
2014. Subcutaneous doses of 1, 3.5, and 12.5 mg/kg/day (about 20, 70, and 250 times the 
recommended daily human dose of 0.05 mg/kg, respectively) were studied and adenocarcinoma 
in the jejunum was observed in males given a dose of 12.5 mg/kg/day.


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Clinical Studies
Two completed adult studies (CL0600-004 and CL0600-005) evaluated safety and tolerability of 
daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on parenteral 
nutrition/intravenous fluids (PN/IV). Study CL0600-004, a double-blind, placebo-controlled 
study in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed the effects of 
teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV. There was a statistically 
significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) by using a 
graded response at the end of the study.  At week 24, the weekly reduction of PN/IV volume was 
similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, assessed the long-
term safety of teduglutide and the proportion of responders in the CL0600-004 study that 
maintained their response at the end of a further 28 weeks of treatment. The extension study also 
assessed the effects of teduglutide at 28 weeks on those subjects previously receiving placebo in 
Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial phase 3 study, which included significant reductions in PN/IV.  
Seventy-five percent of the subjects who previously responded to teduglutide treatment in Study 
CL0600-004 maintained this response or experienced further improved benefit from teduglutide 
treatment.  More than 60% of the subjects’ previously receiving placebo in Study CL0600-004 
achieved a clinical response after switching to teduglutide treatment for 6 months. Most of the 
adverse events (AEs) reflected the underlying disease and were not treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PN/IV volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PN/IV 
volume at weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus
13/43 subjects [30.2%], respectively). This difference was clinically and statistically significant 
in both the intention-to-treat (ITT) (p = 0.002) and per protocol (p < 0.001) populations. 
Generally, the incidence of treatment-emergent AEs (TEAEs) was distributed similarly across all 
treatment groups. The TEAEs with a higher incidence in the teduglutide group were mainly of 
GI origin. A long-term, open-label extension study (CL0600-021) assessed safety and efficacy 
for up to 24 additional months (ie, up to 30 months of exposure for subjects who received 
teduglutide in Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in 
Study CL0600-020 and entered Study CL0600-021 completed a total of 30 months of treatment 
with teduglutide. Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral 
support resulting in a PN/IV volume reduction of 7.55 L/week, corresponding to a mean 
reduction of 65.6% relative to baseline prior to exposure to teduglutide at the beginning of 
Study CL0600-021. PN/IV frequency was reduced by at least 1 day per week in 21 of 30 subjects 
(70%) who completed 30 months of treatment. Of the 39 subjects who entered 
Study CL0600-021 after receiving placebo in Study CL0600-020, 29 completed 24 months of 
treatment with teduglutide. The mean reduction in PN/IV volume was 3.11 L/week from baseline 
at the start of Study CL0600-021 (a 28% reduction). Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support. Of the 12 subjects entering 


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Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide. The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support.
One phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and UK. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose.  In the 0.025 mg/kg/day 
cohort there was a reduction in PN/IV volume at week 12 of 37%, including complete 
independence from PN/IV support in 1 subject, and a reduction of 3.94 hours per day infusion 
time. In the 0.05 mg/kg/day cohort there was a reduction in PN/IV volume at week 12 of 39%, 
including complete independence from PN/IV support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.
Teduglutide was generally safe and well tolerated by pediatric subjects in all dosing cohorts.  
There were no deaths during the study and no TESAEs related to teduglutide were reported.  No 
discontinuations from study were due to adverse events.
1.2
Rationale for the Clinical Study
Short bowel syndrome is a rare disorder. At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, market 
research performed in 2012 indicates that the true addressable adult patient population is 
between 3000 to 5000 patients qualifying SBS as an ultra-orphan condition. In addition to adult 
SBS patients, it is estimated that, at most, there are a few hundred children 1 year and older with 
SBS (Wales et al. 2004). As a result of congenital abnormalities or severe intestinal disease in 
children and adolescents, major surgical resections of the intestine can become necessary, 
resulting in SBS. Common causes of SBS in children include necrotizing enterocolitis (NEC) in 
infants, midgut volvulus, intestinal atresia, and gastroschisis (Duro et al. 2008; Squires et al. 
2012). New onset SBS in older children may stem from the same etiologies as in adults (ie, 
Crohn’s disease, trauma, cancer) but is far less common. As the characteristics are similar to the 
adult disease, pediatric SBS is defined as a disease where there is diminished absorptive capacity 
for fluids and/or nutrients, sometimes requiring a dependence on PN/IV support to maintain 
energy and clinical status.
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able to 
adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al. 1999; Jeppesen 
and Mortensen 2000), other patients with intestinal failure depend on PN/IV for nutritional 
support (Fleming et al. 1980; O'Keefe et al. 2006; Buchman et al. 2003).  Although PN/IV can 
provide this nutritional support for patients with compromised fluid and nutritional status, it is 
also associated with serious complications, such as infections and liver damage.  The risk for 
these effects increases over time with longer duration of PN/IV support.


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Treatment of both pediatric and adult patients is focused on achieving adequate intestinal 
absorption to allow for minimization or discontinuation of PN/IV support. Because children are 
at higher risk for intestinal failure-associated liver disease, reducing PN support is far more 
urgent in this population. About 30% of infants who develop SBS during the neonatal period 
become independent of PN/IV requirements by 12 months of age, and an additional 10% wean 
off PN/IV support by 24 months of age. After this time, intestinal adaptation and growth occurs 
much more slowly, and many children remain terminally dependent on PN/IV support. Due to 
the risks of intestinal failure-associated liver disease, catheter-related blood stream infections, 
central line-associated venous thrombosis and dwindling central venous access, achieving 
autonomy from parenteral support remains an urgent goal for all affected children (Khan et al. 
2015; Squires et al. 2012).
This study proposes to investigate the safe and appropriate use of teduglutide in the pediatric 
population for up to 24 weeks of administration for the purpose of providing longer-term data in 
regard to safety and the potential to explore further efficacy including PN reduction and ability to 
completely wean off parenteral support.  This protocol was developed with input from expert 
advisors from intestinal rehabilitation centers who offered advice on the most appropriate use of 
teduglutide in pediatric patients.  The aim of teduglutide treatment is to increase absorptive 
capacity in order to yield decreases in parenteral support requirements.  The experts anticipated 
that there would be several direct benefits from decreased parenteral support, including less 
exposure to PN/IV constituents, less central line manipulation with lower risk of infection, and 
more time to focus on oral rehabilitation strategies.
1.3
Rationale for Study Design
Dose
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily in adult SBS subjects requiring PN. The recommended daily clinical 
dosage for the adult SBS patient population is 0.05 mg/kg. The completed 12 week pediatric 
study (TED-C13-003) included doses of 0.0125, 0.025, and 0.05 mg/kg/day. It demonstrated that 
teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk 
profile. In addition, population pharmacokinetic (PK) modeling and simulations were conducted 
to determine the effective dose to be used in pediatric subjects using data in 8 adult clinical 
studies including adult phase 1 studies and phases 2/3 studies as well as the pediatric phase 3 
study, TED-C13-003. The analysis suggested that pediatric patients aged 1 to 17 years were 
likely to require the same dose as that used in adults, namely 0.05 mg/kg/day. To further explore 
additional safety and efficacy of 0.025 and 0.05 mg/kg/day doses, a 24-week study is currently 
proposed.
Treatment Duration/Design
Safety, tolerability, pharmacokinetics, and efficacy/PD measures will be the main outcomes of 
the current study. The main efficacy/PD effect of teduglutide to be measured in children is a 
decrease in the volume of PN/IV support. Measurement of a decrease in PN/IV volume was the 
primary endpoint in the adult SBS clinical studies and can be used in children with SBS who are 
dependent on PN/IV support.


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A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of treatment was used as the primary endpoint in the adult clinical development program 
during pivotal phase 3 studies and the previous pediatric study and will be the same endpoint 
used in the current pediatric study.  A 20% decrease in PN/IV volume over 24 weeks is 
considered clinically meaningful to these PN/IV-dependent children who have plateaued in their 
ability to wean PN/IV requirements and advance their oral/enteral feeds.  A decrease of this 
magnitude may allow a child several hours a day for more age-appropriate activities or an 
opportunity to introduce an extra oral/enteral feed to encourage oral rehabilitation.
This study will include 2 treatment arms:  a teduglutide treatment arm and a standard of care 
treatment arm.  Subjects in both arms will participate in a 24-week treatment period and a 4-
week follow-up period.  The teduglutide treatment arm will have a double-blind, parallel group 
design in which subjects are randomized 1:1 to teduglutide at either 0.025 mg/kg/day or 0.05 
mg/kg/day subcutaneous injection for 24 weeks.  The 24-week teduglutide treatment period will 
provide additional pharmacokinetic, safety, tolerability, and efficacy data beyond that which was 
collected in the previous 12-week pediatric study (TED-C13-003).
Thus, this study is designed to provide further information on the safety, PK, and efficacy/PD 
profile of teduglutide in pediatric subjects treated for up to 24 weeks.
Subject Population
The current significant unmet medical need is for children who remain dependent on parenteral 
support. Patients who reach a plateau in their ability to advance oral/enteral feeds or decrease 
PN/IV support are not expected to achieve spontaneous adaptation. The subjects in the study will 
be children who have not reached full enteral autonomy and whose PN/IV requirements had been 
stable without any clinically meaningful or substantial reduction in parenteral support for the 
3 months prior to, and during, screening.
This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000).
Gastrointestinal Screening Measures
Pediatric patients with SBS who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for small bowel obstruction due to history of intestinal surgery. 
Teduglutide has been found to have a targeted intenstinotrophic effect on the GI tract and areas 
of special interest in regards to safety have been identified throughout the development program. 
Taking into account the patient population and the pharmacologic effect of teduglutide, 
GI-specific screening tests that are usually part of the routine care of these subjects will be 
performed on subjects in the treatment arms only to ensure safety. These include: abdominal 
ultrasound, upper GI series with small bowel follow through (UGI/SBFT), fecal occult blood 
testing, and colonoscopy/sigmoidoscopy.
General Guidance for Nutritional Support Adjustment
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status and will include measures of weight, hydration status, and stool output.  
Because the primary efficacy/PD endpoint for this study is a reduction in PN/IV volume of at 
least 20% at week 24 (or EOT) compared to baseline, guidelines for nutritional support 
adjustment, including a weaning algorithm, are provided in Appendix 1.  These guidelines were 


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developed with input from SBS experts.  All attempts should be made to follow these guidelines 
to ensure uniform care across study sites and participants; however, a departure from the 
guidelines will not constitute a protocol deviation. 


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2
OBJECTIVES
2.1
Primary Objective
The objective of this clinical study is to evaluate the safety, pharmacokinetics, and efficacy/PD 
of teduglutide in pediatric subjects through 17 years of age with short bowel syndrome (SBS) 
and who are dependent on parenteral support.
Details of study assessments are provided in Sections 8.2 and 8.4.


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3
STUDY DESIGN
3.1
Overall Design and Control Methods
This study will include 2 treatment arms:  a teduglutide treatment arm and a standard of care 
treatment arm.  Subjects in both arms will participate in a 2-week minimum screening period, a 
24-week treatment period, and a 4-week follow-up period.  During the screening period, subjects 
will choose into which arm to enroll.  During the 24-week treatment period, subjects in the 
SOC treatment arm will receive standard medical therapy for SBS; while those in the teduglutide 
treatment arm will receive daily subcutaneous injections of teduglutide (study drug) in addition 
to standard medical therapy.  These subjects will be randomized 1:1 in a double-blinded manner 
into two parallel dose groups:  0.025 mg/kg/day and 0.05 teduglutide.  Randomization across 
dose groups will be stratified by age:  <1 year, 1 to <12 years, 12 to <17 years, and 17 to 
<18 years.
Each subject will be screened minimally for 2 weeks before the baseline visit (day 0) to allow 
adequate time to verify enrollment eligibility.  Subjects in both arms will follow the same visit 
schedule. After the screening period, subjects will visit the site at baseline (day 0), weekly for 
the first 2 weeks (ie, weeks 1 and 2), and then every other week through week 12 (weeks 4, 6, 8, 
10, and 12).  For the remainder of the treatment period, subjects will visit the sites once every 
3 weeks (ie, weeks 15, 18, 21, and 24).  For all other study weeks, subjects will be contacted by 
telephone.  At all site visits and telephone contacts, safety will be monitored and nutritional 
support will be reviewed and adjusted as needed.  At the end of the treatment period (week 
24/EOT), all subjects will enter a 4-week follow-up period until the end of study (week 28/EOS) 
during which time no study drug (ie, teduglutide) will be administered.  A final visit will occur at 
week 28, 4 weeks after EOT.  Telephone contact will be made during the weeks from EOT to 
EOS to monitor safety and any changes in nutritional support.
All subjects who complete the study, including those in the SOC treatment arm, may participate 
in a long-term extension study in which eligible subjects could receive teduglutide.
To maintain consistency across all centers, all attempts should be made to follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) 
for decisions regarding PN/IV support reduction and advances in enteral feeds based on weight 
gain, urine and stool output, and clinical stability.  Any departure from the guidelines will not 
constitute a protocol deviation.
If a blood sample is positive for antibodies to teduglutide at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.
Safety and tolerability results will be evaluated by a Data Monitoring Committee (DMC) that 
will convene approximately every 3 months during the treatment period.  The treatment period 
for the study is defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT.  The DMC’s data review will include all cumulative safety data 
from study assessments through the end of each review period.
A schematic of the study design is displayed in Figure 3-1.


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Timing of study visits and evaluations can be found in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).


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Figure 3-1
Study Diagram
Note:  Subjects in both treatment arms (SOC and teduglutide) will follow the same visit schedule.


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3.2
Study Duration
A 2-week minimum screening period will be followed by 24 weeks of teduglutide treatment for 
all subjects.  At EOT, all subjects will enter the follow-up period, during which time subjects 
will have a final site visit at week 28 (EOS), 4 weeks after EOT (ie, week 24).
A subject will be considered enrolled in the study at the baseline visit (day 0) when the choice of 
treatment arm (ie, teduglutide or SOC) has been made.


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4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects
Approximately 26 subjects who are teduglutide-naïve (a minimum of 10 subjects per teduglutide 
dose group) will be enrolled into the teduglutide treatment arm and at least 8 subjects who are 
teduglutide-naïve will be enrolled into the SOC treatment arm.  Enrollment will proceed at 
approximately 28 investigational sites globally.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
4.2
Criteria for Inclusion/Exclusion
Male and female children and adolescents through 17 years of age, who satisfy all of the 
following inclusion criteria and none of the following exclusion criteria are eligible to be 
enrolled in this study.
4.2.1
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures 
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures 
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support, defined as inability to significantly reduce PN/IV support, usually 
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or 
advance in feeds) for at least 3 months prior to and during screening, as assessed by the 
investigator.  Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PN/IV support returns to within 10% of baseline prior to 
the event.
6. Sexually active female subjects of child-bearing potential (in the teduglutide treatment arm 
only) must use medically acceptable methods of birth control during and 4 weeks after the 
treatment period
4.2.2
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support
4. Unstable absorption due to cystic fibrosis or known DNA abnormalities (eg, Familial 
Adenomatous Polyposis, Fanconi-Bickel syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.


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6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done 
within 6 months prior to screening
7. Major GI surgical intervention including significant intestinal resection within 3 months prior 
to the screening visit (insertion of feeding tube, anastomotic ulcer repair, minor intestinal 
resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the teduglutide treatment arm only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, 
prior to screening and for the duration of the study
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months 
prior to screening
14. Previous use of octreotide or dipeptidyl peptidase-4 (DPP-4) inhibitors within 3 months prior 
to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF]) within the 6 months prior to the screening visit
16. Subjects with inflammatory bowel disease (IBD) who require chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented 
infection-related catheter sepsis, clots, bowel obstruction, severe water-electrolyte 
disturbances) within 3 months prior to the screening visit
18. Any major unscheduled hospital admission which affects parenteral support requirements 
within 1 month prior to or during screening, excluding uncomplicated treatment of 
bacteremia, central line replacement/repair, or issues of similar magnitude in an otherwise 
stable subject
19. Body weight <10 kg at screening and baseline visits
20. Signs of active, severe, or unstable clinically significant hepatic impairment during the 
screening period, indicative by any of the following laboratory test results:
e.
Total bilirubin (TBL) ≥2x upper limit of normal (ULN)
f.
Aspartate aminotransferase (AST) ≥7x ULN
g. Alanine aminotransferase (ALT) ≥7x ULN
For subjects with Gilbert’s disease:
h. Indirect (unconjugated) bilirubin ≥2x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by results of an estimated glomerular filtration rate (eGFR) below 50 mL/min/1.73 m2
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant, active, untreated pancreatic or biliary disease


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24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are listed 
in Table 4-1.
Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal

Active IBD which requires chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months

Tufting or autoimmune enteropathy or microvillus inclusion 
disease

Untreated pre-malignant or malignant change in GI tract 
identified by upper GI series, biopsy or polypectomy

Known polyposis conditions (ie, familial adenomatous 
polyposis, Peutz-Jeghers syndrome, Turcot syndrome, 
Juvenile polyposis syndrome, Cowden disease, Bannayan-
Riley-Ruvalcaba syndrome, Gardner’s syndrome, Cronkhite-
Canada syndrome)

Intestinal or other major surgery scheduled within the time 
frame of the study

Chronic active pancreatitis

Cholecystitis
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic diseases 
(eg, cardiovascular, respiratory, renal, infectious, endocrine, 
hepatic, or central nervous system)
GI=gastrointestinal; IBD=inflammatory bowel disease; SBS=short bowel syndrome
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
Shire’s medical monitor prior to the patient discontinuing/withdrawing.  A subject may (but not 
automatically) be withdrawn from the study under any of the following circumstances:


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
Withdrawal of informed consent and/or assent when applicable

If, in the opinion of the investigator, IRB or the sponsor, it is no longer in the subject’s 
best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any of the exclusionary criterion

Lack of compliance with study procedures or study drug administration, as determined by 
the investigator

Occurrence of a serious adverse event (SAE) determined by the investigator to be related 
to study drug and not alleviated with treatment of symptoms

AEs resulting in dose interruption (Section 6.14)

Hypersensitivity determined by the investigator to be related to study drug

Administrative reasons
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.3.
As far as possible, all examinations scheduled for the EOT evaluations must be performed on all 
subjects who participate even if they do not complete the study according to the protocol (ie, 
early terminate [ET]). Any subject who discontinues treatment prematurely will be asked to 
return 4 weeks later for the EOS visit and will be contacted weekly for wellness checks during 
the interim period between EOT and EOS.
4.4
Data Monitoring Committee
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
charter agreed to by members of the committee and the sponsor. Committee members may not 
be study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying, or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
The DMC members will review the data approximately every 3 months during the study’s
treatment period (defined as the date of the first subject’s baseline visit to the date of the last 
subject’s visit at week 24/EOT).  DMC’s data review will include all cumulative safety data from 
study assessments through the end of each review period.


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5
TREATMENTS AND TREATMENT PLAN
5.1
Treatment Administered
Subjects who elect to receive teduglutide treatment will be randomized 1:1 in a double-blinded 
manner into one of two dose groups:  0.025 mg/kg/day or 0.05 mg/kg/day.  The dose calculation 
will be based on subject body weight measured at the baseline visit (day 0/visit 2) and adjusted, 
as needed, based on measurements made at week 12 (visit 14).  Subjects in both dose groups of 
the teduglutide treatment arm will receive 0.005 mL/kg of reconstituted study drug at a blinded 
concentration.  No other adjustments to the dose will be made during the treatment period, unless 
discussed with the Shire medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.
5.1.1
Identification of Investigational Product
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.  
The 5-mg vial is a 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is a 5 mg/mL
solution upon reconstitution.
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients.
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength.
5.1.2
Packaging and Labeling
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements.  Sterile water for injection syringes will also 
be provided separately and will be labeled in accordance with the applicable regulatory 
requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
5.1.3
Storage, Accountability, and Stability
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures.  Study drug will be shipped once the first subject at a 
site is screened. Upon receipt, the study site’s pharmacist or delegate is responsible for ensuring 
that all study drug received at the site is inventoried and accounted for throughout the study.  A 
copy of the shipping documents must be maintained for the investigator’s records.
Study drug must be kept in a locked area with access restricted to specific study personnel.  
Study drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated or 


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up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F).  
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature.  If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated.
Study drug kits will be dispensed at each of the study visits at which the subject is required to be 
at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough kits 
will be supplied to cover the period to the next planned study visit.  Additional study kits will be 
provided as necessary.
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies.  This record will be made available to the sponsor’s site monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded and will 
include an explanation.  All supplies sent to the investigator must be accounted for and in no case 
will clinical supplies be used in any unauthorized situation.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian and 
will be retained at the site. All original containers, whether empty or containing study drug will 
be returned to the pharmacy. Returned study drugs will NOT be relabeled or reassigned for use 
by other subjects. Contents of the study drug containers will not be combined. All used and
unused vials must be returned to the distribution center according to the sponsor’s instruction. 
No vial/kit may be destroyed on site without approval by the sponsor.
Please see the Pharmacy Manual for additional information.
5.2
Methods of Assigning Subjects to Study Treatment Arms
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of the 
study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These 
numbers will be used to identify the subjects in the teduglutide treatment arm and those in the
SOC treatment arm.  Subjects may be rescreened only once and with prior sponsor approval.  See 
Section 7.2 for rescreening instructions.
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the teduglutide treatment arm or 
the SOC treatment arm.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all inclusion criteria and none of the exclusion criteria.
If the subject or subject’s parent/guardian/caretaker decides to participate in the study and 
receive study drug (defined as treatment with teduglutide), then the investigator or designee will 
request that the subject be randomized to a teduglutide dose group using an interactive web 
response system (IWRS) centrally administered as described in the IWRS Manual of Procedures.  
Subjects in teduglutide treatment arm will be double-blinded and randomized at the baseline visit 
(day 0) 1:1 into parallel dose groups of either 0.025 mg/kg/day or 0.05 mg/kg/day.  To ensure 
balance across dose groups, randomization will be stratified by the following age subgroups:  
<1 year, 1 to <12 years, 12 to <17 years, and 17 to <18 years.
Attempts will be made to enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.


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Study drug kits will be assigned through IWRS to each subject at each site visit through 
completion of the treatment period. The IWRS will automatically assign the correct number of 
kits for each visit based on the randomization date.  If additional kits are needed (eg, subject is 
going on holiday), then the IWRS and the sponsor must be notified to assign additional kits.  
Subjects will be randomized across centers rather than within a center.
5.3
Dose Regimens
Study drug will be supplied in 2 powder strengths:

5.0 mg/vial for subjects randomized to 0.05 mg/kg/day teduglutide

2.5 mg/vial for subjects randomized to 0.025 mg/kg/day teduglutide
Subjects in the teduglutide dose groups will be administered study drug for 24 weeks by SC 
injection.  See Section 5.3.2 for more detail.  The dose calculation will be based on subject
weight measured at the baseline visit (day 0/visit 2), and adjusted as needed, based on weight 
measured at week 12 (visit 14).  No other adjustments will be made during the treatment period 
unless discussed with the Shire medical monitor.
5.3.1
Selection of Doses in Study
A recently completed 12-week pediatric study (TED-C13-003) that included doses of 0.0125, 
0.025, and 0.05 mg/kg/day demonstrated a favorable risk/benefit profile at the 2 higher doses as 
evident by reduction in PN/IV volume and advance in feeds. Furthermore, results from
modeling and simulation data of previously completed studies indicate that pediatric patients are 
likely to require the same dose as adults (ie, 0.05 mg/kg daily).
This study will evaluate teduglutide doses of 0.05 mg/kg and 0.025 mg/kg administered daily for 
24 weeks.
5.3.2
Selection and Timing of Dose for Each Subject in the Teduglutide Treatment Arm
Teduglutide will be administered after reconstitution by SC injection into 1 of the 4 quadrants of 
the abdomen (in subjects without a stoma) or into either the thigh or arm.  For subjects with a 
stoma, the quadrant of the abdomen containing the stoma should not be used. The first SC 
injection should be administered under the supervision of the investigator or designee and the 
subject observed for hypersensitivity reactions for at least 4 hours after teduglutide 
administration during their initial dosing visit.  The site of administration (arm, thigh, abdomen) 
of the first teduglutide dose must be specified and recorded in the eCRF.  Detailed instructions 
for reconstitution and injection of teduglutide can be found in the Dosing Instructions.  Each day, 
the injection site should be rotated.
The subject should be dosed at approximately the same time each day.  If a dose is forgotten, that 
day’s dose should be administered as soon as possible, even if this is later in the day or evening.  
Consecutive doses should be separated by at least 12 hours.
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily teduglutide dosing regimen.  Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, a lapse in teduglutide delivery, etc.


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5.3.3
Compliance with Dosing Regimens
Subject compliance with teduglutide dosing will be monitored by the sponsor/designee by 
counting and examining used and unused vials.  In addition, compliance will be checked by site 
personnel at every visit by reviewing the subject diaries and asking the subject or the subject’s 
parent or guardian if they have administered teduglutide according to instructions.  If any doses 
have been missed, the reason for missed dose should be documented in the subject’s source 
documentation including, as applicable, the eCRF.
5.3.4
Prior and Concomitant Treatments
All non-study treatments, including medications, herbal treatments, vitamins, invasive and 
diagnostic procedures, received within 14 days before screening through week 28 (EOS) or final 
study contact must be recorded on the appropriate section of the eCRF.
Prior treatment includes all treatments (medications, herbal treatments, vitamins, invasive and 
diagnostic procedures) received within the 14 days before screening.
Concomitant treatments will be assessed at each site visit and will include all non-study 
treatments (medications, herbal treatments, vitamins, invasive and diagnostic procedures) 
received between the first teduglutide dose (teduglutide treatment arm) or day 0 (SOC treatment 
arm) though week 28 (EOS), or the end of the follow-up period. Details of medication changes 
and/or dosages will be recorded on the eCRF.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin).  Accordingly, due consideration should be given to 
modifying concomitant medication regimens.  Down-titration of concomitant medications should 
be considered when drugs, especially those with a narrow therapeutic range, are prescribed at 
dosages that are higher than usual.


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6
STUDY EVALUATIONS AND PROCEDURES
6.1
Pharmacokinetics
Blood samples for PK analysis should be collected at baseline (day 0).  If a subject is unable to 
provide blood samples for PK at the baseline visit (day 0), then PK samples may be collected 
during any other future site visit while the subject is still receiving treatment with teduglutide.
Pharmacokinetic variables are listed in Section 8.3.  Instructions for sample collection and 
handling are included in the Laboratory Manual.
Blood will be drawn predose and 1, 2, and 4 hours postdose.  In smaller children for whom blood 
sampling may impose unacceptable phlebotomy volume, the number of PK samples may be 
reduced.  For example, the sampling timepoints postdose may be reduced from 3 to 2.  The 
decision to reduce blood sampling postdose timepoints will be made by the investigator and the 
Shire medical monitor.
The time points indicated for PK blood draws should be adhered to as closely as possible. 
However, it is recognized that some deviations from these time points may occur. The 
investigator or designee should keep deviations to a minimum and be guided by the following 
collection windows:

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 
14 hours after the previous dose (if the PK blood draw does not occur at day 0)

1-hour postdose draw: ±10 minutes

2-hour postdose draw: ±10 minutes

4-hour postdose draw: ±30 minutes
The actual date and time of teduglutide administration and blood draw must be documented on 
the PK blood sampling eCRF.
If a subject is unable to provide blood samples for PK at the baseline visit (day 0), then PK 
samples may be collected during any other future site visit while the subject is still receiving
treatment with teduglutide.
6.2
GI-specific Symptoms History
GI symptoms during the screening period will be recorded by the subject/parent/guardian in a 
GI-Specific Symptoms History diary on a daily basis.  At the baseline visit, the investigator or 
sub-investigator will review the GI-symptoms diary and summarize the findings.
6.3
Diaries
Intake diaries will be used to collect and evaluate each subject’s nutritional support.
The subject/parent/guardian will complete the appropriate fields of the PN/IV and enteral 
nutrition (formula) sections of the Intake diary.
Intake diary:  The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through week 28/EOS:


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
PN/IV volume and infusion duration

EN (formula) volume
Site personnel will determine the actual PN/IV and EN daily calories based on diary entries.
Output diary:  Urine and stool output should be recorded in the output diary over a 48 hour 
period of PN/IV and EN stability before every clinic visit and within 1 week of implementing a 
change in the PN/IV prescription.

Urine data

Toilet-trained subjects WHO DO NOT WEAR DIAPERS
Measure and record all urine output in mL or cc.  The subject or parent will perform 
dipstick specific gravity tests on the first urine produced after the daily infusions of 
PN/IV support.

Nontoilet-trained subjects WHO WEAR DIAPERS
Measure and record the weight of all urine-only diapers.  Urine volume will be 
calculated using the following formula:  1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first void after the 
daily PN/IV infusion to measure specific gravity.
Stool data (includes diapers with mixed urine and stool)

Toilet-trained subjects WHO DO NOT WEAR DIAPERS
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see Output diary)

Nontoilet-trained subjects WHO WEAR DIAPERS
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form Scale 
(see Output diary).  Stool volume will be calculated using the formula:
1 g (scale weight = 1 mL or 1 cc)
All ostomy output volume should be recorded.  Ostomy output will not be scored using the 
Bristol scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PN/IV reduction and advance in feeds.
6.4
Nutritional Support
Nutritional support includes PN/IV and EN.  Advances in enteral nutrition and/or reductions to 
PN/IV support will be based on clinical status, including weight, linear growth, hydration status, 
and safety laboratory results.  Guidelines for nutrition support adjustment, including a weaning 
algorithm, are provided in Appendix 1.
Intake diaries will be used to collect each subject’s nutritional support.  The following 
information will be collected and can be used to evaluate each subject’s nutritional support:
6.5
Gastrointestinal-specific Testing
Only subjects in the teduglutide treatment arm will undergo GI-specific testing.  GI-specific 
testing includes upper GI with small bowel follow through, abdominal ultrasound, FOBT, and 


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colonoscopy/sigmoidoscopy.  These procedures will be performed during or before screening 
(visit 1).
Follow-up testing will be performed as necessary according to the guidelines provided. See 
Table 6-2 and Table 6-3 for details and scheduling.
6.5.1
Upper Gastrointestinal Series with Contrast
An upper GI with small bowel follow through will be performed following the ingestion of 
barium contrast material.  Results from procedures performed within 6 months prior to visit 1 are 
acceptable also.
6.5.2
Abdominal Ultrasound
An abdominal ultrasound will be performed.  Results from procedures performed within the 
6 months before screening (visit 1) are also acceptable.
6.5.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening, week 12, and week 24 (EOT). Subjects 
with positive FOBT results at screening or at week 24 for whom a readily detectable cause 
cannot be not identified (eg, anal fissure) will undergo a colonoscopy/sigmoidoscopy.  Subjects 
with positive FOBT results at week 12 for which a cause is not identified by a physical exam will 
be discussed with the Shire medical monitor.  If clinically indicated, an 
esophagogastroduodenoscopy (EGD) may also be performed.
Subjects with negative endoscopy findings at screening may enroll in the study.
Subjects with positive endoscopy findings at screening who receive treatment may enroll in the 
study if following consultation with Shire’s medical monitor, the subject is considered 
appropriate to be enrolled in the study.
Subjects with positive endoscopy findings at screening who do not receive treatment will be 
excluded from the study if following consultation with Shire’s medical monitor, the subject is 
considered inappropriate to be enrolled in the study.
6.5.4
Colonoscopy/Sigmoidoscopy
Subjects who are 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children younger than 12 years will undergo the procedure if they test positive for fecal occult 
blood at screening and if the source is not identified by physical exam (see Section 6.5.3).
If the FOBT is negative at screening and the procedure was performed within 1 year before the 
screening visit (visit 1), then those prior results are acceptable for the screening assessment.
6.6
Laboratory Evaluations
The following laboratory evaluations will be performed according to the Schedules of Events
(Table 6-2 and Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the 
SOC treatment arm).  A result outside of the normal range may be repeated for confirmation.
Laboratory collections that are required at intervals that do not coincide with clinic visits (ie, for 
lab assessments done following PN/IV adjustments) may be obtained by a Home Health Agency 
at subjects’ homes.


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6.6.1
Laboratory Tests
Hematology
Hemoglobin
Hematocrit
Platelets
Red blood cell (RBC) count
RBC morphology, if necessary
White blood cell (WBC) count with differential
Coagulation
PT/INR will be measured in subjects in the teduglutide treatment arm at screening and 
subsequently if DILI is suspected (Section 6.14.2)
Clinical Chemistry
Albumin
ALP
ALT
Amylase
AST
Bicarbonate
Bilirubin (total and direct)
Blood urea nitrogen
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma) (Section 6.6.1.1)
Creatinine
C-reactive protein
eGFR (Schwartz formula)
Glucose
Gamma glutamyl transferase
HCG for FOCBP in the teduglutide treatment 
arm (serum at screening only; Section 6.17)
Lipase
Magnesium
Phosphorous
Potassium
Sodium
Triglycerides
Uric acid
Urinalysis
Blood
Glucose
HCG for FOCBP in the teduglutide 
treatment arm (Section 6.17)
Leukocytes
Microscopic analysis
pH and osmolality
Protein
Sodium
Specific gravity
For children in diapers, urine specimen collection should be attempted as part of the safety 
labs, but lack of urinalysis will not constitute a protocol deviation.
6.6.1.1
Plasma Citrulline
Plasma citrulline levels will be measured as a biomarker of enterocyte mass.  Blood will be 
collected from all subjects 2 to 4 hours postprandial, whenever possible, timepoints specified in 
the Schedule of Events (Table 6-2 and Table 6-3 for the teduglutide treatment arm and Table 6-4
and Table 6-5 for the SOC treatment arm).  Samples may be drawn from a central line or from 
peripheral access and processed according to instructions in the Laboratory Manual. 
6.6.1.2
Antibodies to Teduglutide
Blood will be sampled from subjects in the teduglutide treatment arm to test for antibodies to 
teduglutide.  Samples will be taken before teduglutide administration at the baseline visit (day 0) 
and ≥14 hours after the previous dose at the EOT visit (week 24 or ET); samples may be drawn 


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from a central line or from peripheral access.  One additional sample will be collected at the final 
visit, 4 weeks after the EOT (ie, week 28/EOS).
If a blood sample is positive for anti-teduglutide antibodies at week 28 or EOS, then the subject 
will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 
6 months after EOT.
6.7
Physical Examinations
Complete and comprehensive physical examinations will be performed by a medically qualified 
professional during the study to assess the subject’s physical status.  Timing of physical 
examinations is presented in the Schedules of Events (Table 6-2 and Table 6-3 for the 
teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment arm).
6.8
Body and Weight Measurements
Body measurements will be recorded on the appropriate section of the eCRF.  Subjects should be 
weighed in kilograms on the same scale at each site visit.  Height and body length and head 
circumference (subjects ≤36 months old) will be measured at selected visits.
BMI and z-scores for height/length, weight, head circumference, and BMI will be calculated by 
the sponsor.
Timing of body measurements and weight is provided in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).
6.9
Vital Signs
Examinations will be made at the timepoints specified in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).
Measurements will include systolic and diastolic blood pressure (mmHg), pulse (beats per 
minute), and body temperature (°C/°F).
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
6.10
Electrocardiograms
Examinations will be made at the timepoints specified in the Schedules of Events (Table 6-2 and 
Table 6-3 for the teduglutide treatment arm and Table 6-4 and Table 6-5 for the SOC treatment 
arm).  The ECG tracing will be read by a local experienced physician.  Results (normal, 
abnormal not clinically significant, and abnormal clinically significant with description of the 
finding) will be recorded on the eCRF.
6.11
Adverse Events
Timing of all safety/tolerability evaluations is presented in the Schedule of Events (Table 6-2 and 
Table 6-3 for the treatment arms and Table 6-4 and Table 6-5 for the SOC treatment arm).


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During the study, the investigator is responsible for the detection and documentation of any and 
all AEs or SAEs as defined in this protocol.
6.11.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product.  An AE does not necessarily have a causal relationship 
with study drug treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant 
electrocardiogram (ECG) abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study evaluations have begun (after signing of the ICF)

Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease 
or disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen
6.11.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs and 
SAEs will be recorded from the time of the signing of the informed consent form (ICF) and, if 
applicable, the informed assent form, through the last study visit (visit 28 or EOS).  SAEs will be 
monitored with a telephone call by the investigator, as necessary, for approximately 4 weeks 
after the last dose of study drug or until resolution or until the SAE is judged by the investigator 
to have stabilized.
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes,
and abnormal ECG).  The following features are recorded also:

Onset and stop date and time

Frequency (intermittent, continuous)

Severity (mild, moderate, severe)

Mild:  usually transient, requiring no special treatment and generally not 
interfering with usual daily activities


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
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs 
usual activities

Severe:  requires vigorous therapeutic intervention and interrupts usual activities; 
hospitalization may or may not be required.

Note that the severity of adverse events that constitute dose interruption criteria 
will also be evaluated using the NCI CTCAE grading criteria (Section 6.14)
6.11.3
Relationship to study drug (not related, related)
A physician/investigator must make the assessment of relationship to investigational product for 
each AE.  The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product.  If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”.  Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”.  The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the investigational product 
is compelling and/or follows a known or suspected response pattern to that product, and the event 
cannot be explained by the subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic relationship 
exists between the investigational product and the event.

Whether the AE is serious (ie, an SAE).  An event identified as an SAE should be 
reported on the form entitled “Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol” (Section 6.12)

Actions taken with regards to study drug:   none; study drug dose changed, interrupted, or 
permanently discontinued/withdrawn

Other action taken

Outcome:  fatal; not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; recovering/resolving; unknown
Adverse events that are related to study drug that are not resolved at EOT will be followed until 
the event resolves or stabilizes, as judged by the investigator.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if:


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
The investigator considers the finding to be a clinically significant change from the 
baseline visit (day 0)

The finding fulfill SAE criteria, and/or

The finding results in the subject discontinuation
6.11.4
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE.  Note: The 
24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.
Abuse – Persistent or sporadic intentional intake of investigational product when used for a non-
medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that may be 
detrimental to the individual and/or society
Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed at 
the dose prescribed by the protocol)
Overdose – Administration of a dose greater than the allocated dose of study drug or at a 
frequency greater than the dosing interval specified by the protocol
Medication Error – An error made in prescribing, dispensing, administration, and/or use of an 
investigational product.  For studies, medication errors are reportable to the sponsor only as 
defined below.

Cases of subjects missing doses of the investigational product are not considered 
reportable as medication errors.

Medication errors should be collected and reported for all products under investigation.

The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.

The administration and/or use of an expired investigational product should be considered 
as a reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
6.12
Serious Adverse Events
An SAE must be reported as described in Section 6.12.2 and recorded on the sponsor’s form
entitled “Shire Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-
serious AEs as Required by Protocol”.  An SAE requires expeditious handling to comply with 
regulatory requirements.  Any SAE that occurs from the time of the signing of the ICF through 
last study visit (visit 28 or EOS) will be captured and must be reported within 24 hours after the 
investigator or the investigator’s site personnel is made aware of the event.


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Note:  The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless they result in an SAE.
6.12.1
Serious Adverse Event Definition
An SAE is an AE that has any of the following outcomes:

Death

Is life-threatening: a life-threatening AE is any AE that places the subject – in the 
investigator’s opinion – at immediate risk of death from the reaction as it occurred.  It 
does not include a reaction that, had it occurred in a more serious form, might have 
caused death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal 
life functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will not 
be defined as SAEs for this clinical study:

Planned before entry into the clinical study

Are for elective treatment of a condition unrelated to the studied indication or its 
treatment

Occur on an emergency, outpatient basis and do not result in admission (unless fulfilling 
the previous criteria)

Are part of the normal treatment or monitoring of the studied indication and not 
associated with any deterioration in condition
Any laboratory test result that meets the criteria for an SAE must also be recorded on the 
sponsor’s form entitled “Shire Clinical Study Adverse Event Form for Serious Adverse Events 
(SAEs) and Non-serious AEs as Required by Protocol” so that the sponsor/designee can collect 
additional information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome.
6.12.2
Procedures for Reporting Serious Adverse Events
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire medical monitor within 
24 hours of the first awareness of the event.  Note: The 24-hour reporting requirement for SAEs 
does not apply to reports of abuse, misuse, overdose, or medication errors unless the event results 
in an SAE.


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The investigator must complete, sign, and date the form entitled “Shire Clinical Study Serious 
Adverse Event and Non-serious AEs Required by Protocol” and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 
Pharmacovigilance and Risk Management Department. A copy of the sponsor’s form (and any
applicable follow-up reports) must also be sent to the Shire medical monitor using the details 
specified in the key sponsor contact information provided at the beginning of the protocol.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator and/or the investigator’s site personnel at any interval after the study has completed 
must be reported to Shire’s Pharmacovigilance and Risk Management Department within 
24 hours of the first awareness of the event.
All SAEs must be reported, whether or not they are considered causally related to the study drug.  
Appropriate clinical, diagnostic, and laboratory measures should be performed to delineate the 
cause of the SAE in question and the results reported.  Follow-up for the SAE should occur at 
appropriate intervals until the event/laboratory abnormality:

Returns to baseline
or

Becomes stable to a clinically acceptable level that is safe for the subject
The investigator is required to assess the causal relationship of each reported SAE to the study 
drug (see below).  A causality assessment should always be included on the “Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” form.  The investigator should make the causality assessment based on 
the information available at the time of the event.  The causality can be updated at a future date if 
additional information is received.
Relationship of an AE to investigational product is to be determined by the 
physician/investigator based on the definitions of “related” and “not related” provided in 
Section 6.11.2.
Contact information for SAE reporting and emergency contact details can be found in the key 
sponsor contact information provided at the beginning of the protocol and in the Investigator Site 
File.
As required by International Council of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Lack of causality does not 
negate SAE reporting requirements to the sponsor.  An AE, whether serious or not serious, is 
designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator’s brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 
expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.


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The investigator should also comply with the IEC/IRB procedures for reporting any other safety 
information.
The sponsor/designee will be responsible for submitting SUSAR reports to the appropriate health 
authorities.  These reports will be submitted within the expedited timeframe.  All fatal and life-
threatening SUSAR reports will be submitted by the sponsor or designee within 7 days of receipt 
(day 0) of the initial report.  All other SUSAR reports will be submitted by day 15 following the 
event.
6.13
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the sponsor’s product or program and for which ongoing monitoring 
and immediate notification by the investigator to the sponsor is required.
The AESIs that require expedited reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the gastrointestinal tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AESIs, the sponsor will be informed within 24 hours as per the SAE notification instructions 
described in Section 6.12.2 even if the event does not fulfill the serious criterion.
6.14
Dose Interruption of Individual Subjects in the Teduglutide Treatment Arm
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted.  Attempts should be make to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but 
are not limited to hospitalization, incidents of certain AEs, SAEs considered to be related to the 
study drug, a lapse in investigational product delivery, etc.
Study drug (teduglutide) must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include anti-teduglutide antibodies, mild injection site 
reactions or mild symptoms that according to the investigator do not pose a significant 
risk to the subject.

An AE listed in Table 6-1 that is of NCI CTCAE severity Grade 3 or 4 and considered to 
be related to study drug administration

Confirmed drug-induced liver injury (DILI) related to teduglutide (See Section 6.14.2).
6.14.1
Dose Interruption Criteria Based on Known Risks of Teduglutide
The study drug may be discontinued if the subject has an adverse event listed in Table 6-1 that is 
of severity ≥Grade 3 per the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (NCI CTCAE).  All such AEs should be discussed with Shire’s medical monitor 
as soon as possible. Teduglutide administration must be discontinued if the AE is considered 
related to study drug. The length of discontinuation, whether it is temporary or permanent, 
depends on the clinical situation.


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Investigators and the DMC members should be guided by the descriptions of Grade 3 and 4 
events presented in Table 6-1.
Table 6-1
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal disorders
Colorectal polyps
Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of existing 
hospitalization indicated; disabling; limiting self-care 
activities of daily living
Life-threatening consequences;
urgent intervention indicated
Intestinal 
Obstruction
Hospitalization indicated; elective operative intervention 
indicated; limiting self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct diseases
Cholecystitis
Severe symptoms; radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Gallbladder 
perforation
Not Applicable
Life-threatening consequences;
urgent intervention indicated
Gallbladder 
obstruction
Symptomatic and severely altered gastrointestinal 
function; tube feeding, total parenteral nutrition or
hospitalization indicated; nonemergent operative 
intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Gallbladder 
infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative intervention 
indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline 
Phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin 
increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; radiologic, 
endoscopic, or elective operative intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Pancreatic diseases
Pancreatitis
Severe pain; vomiting; medical intervention indicated 
(eg, analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Pancreatic duct 
stenosis
Severely altered gastrointestinal function; tube feeding 
or hospitalization indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or antiviral 
intervention indicated; radiologic or operative
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase 
increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Cardiovascular diseases
Heart failure
Severe with symptoms at rest or with minimal 
activity or exertion; intervention indicated
Life-threatening consequences;
urgent intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)


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Table 6-1
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
ULN=upper limit of normal
a
In the setting of clinically acute and symptomatic pancreatitis 
Source:  Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
6.14.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (TBL >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (TBL >2x ULN or INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification labs and an inquiry should be made 
as to the presence of clinical symptoms consistent with new liver injury.  The subject should be 
followed closely to determine the trajectory of the laboratory abnormalities and to evaluate the 
cause of liver injury. This evaluation may include, as clinically indicated, consideration of 
sepsis, acute viral hepatitis (eg, HepA IgM, HepB sAg, HepC Ab, CMV IgM, EBV antibody 
panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis (ANA, anti-SMA or anti-
actin ab, anti-LKM), intestinal failure associated liver disease, cardiovascular causes such as 
ischemic hepatitis, and concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with Shire medical monitor.
Tedulgutide administration must be discontinued if DILI is confirmed and deemed related to 
study drug.
6.15
Early Termination of the Clinical Study
The DMC members may recommend stopping the study if:

≥2 subjects being administered study drug develop the same event listed in Table 6-1 of 
severity CTCAE Grade 3
or


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
1 subject develops an event listed in Table 6-1 of severity CTCAE Grade 4 that is 
attributable to teduglutide or is not reasonably related to the underlying disease process
6.16
Prior and Concomitant Treatments
All non-study treatments, including invasive and diagnostic procedures, herbal treatment, and 
vitamins received within 14 days before screening through week 28 or final study contact must 
be recorded on the appropriate section of the eCRF.  The following information should be 
included, as appropriate:

Medication name, route, dose, indication, dates used

Procedure type, reason, dates
Changes in any medication and/or dosage will be recorded on the eCRF.  See also Sections 5.3.4
and 8.1.
6.17
Female Subjects of Child-bearing Potential
Any female subject in the teduglutide treatment arm who has reached menarche must have a 
negative serum pregnancy test to enroll or continue in the study. Pregnancy tests will be 
performed at screening (serum HCG) and at all subsequent clinic visits (urine HCG).  Female 
subjects in the standard of care treatment arm will not be required to undergo pregnancy testing.  
Sexually active females of child-bearing potential (FOCBP) must use medically acceptable 
methods of birth control during and for 4 weeks after the treatment period (eg, true abstinence1, 
oral contraceptive pills, barrier methods with spermicide) in a manner such that the risk of failure 
is minimized.  The investigator will discuss these methods as well as their side effects with the 
subject.  If a pregnant subject also reports an SAE, then the SAE form will be completed and 
submitted within 24 hours.
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
discontinued immediately, unless clearly needed, and a Pregnancy Report Form should be 
completed to capture potential drug exposure during pregnancy.  The pregnancy should be 
reported within 24 hours of becoming aware of the condition.  The subject should be followed 
until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous abortion 
(miscarriage), voluntary abortion, or therapeutic abortion).
6.18
Unblinding
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the dose of the investigational product is required for further 
                                                
1 True abstinence:  Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception).


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treatment of the subject.  If warranted, the principal investigator or designee will place an 
unblinding call to the IWRS to receive treatment assignment information. The investigator 
should contact the Shire medical monitor as soon as possible after the investigator has been 
unblinded.  Greater detail is provided in the Investigator Site File.
In the event that the treatment assignment is broken, the date, the name of the person who broke 
the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents.  Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes.


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
Informed consent/assenta
X
Eligibility
X
X
Demographics
X
Medical/Surgical history
X
Electrocardiogram
X
X
Short bowel syndrome history
X
Upper GI with small bowel follow through and 
abdominal ultrasoundb
X
Fecal occult blood testc 
X
X
Colonoscopy/Sigmoidoscopyc
(X)
(X)
Provide GI-specific symptoms history diary
X
Review GI-specific symptoms history diary
X
Randomizationd
X
Dispense druge
X
X
X
X
X
X
X
X
Pharmacokinetic samplingf
Xf
Safety laboratory testingg
Xh
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Pregnancy testh
X
X
X
X
X
X
X
X
X
Citrulline testi
X
X
Antibodies to teduglutidej
X
Provide intake and output diaries
X
X
X
X
X
X
X
X
X
Review diaries and nutritional supportk
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportl
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
PE/Vitals/Weight
X
X
X
X
X
X
X
X
X
Height (or length) and head circumferencem
X
X
X
X
X
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; BL=baseline; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; S=site; 
SRN=screening; T=telephone; W=week
Note:  Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate subject visits to the site.
a
Informed consent/assent must be obtained before performing any study-related procedure.
b
If the subject has undergone an upper GI with small bowel follow through and/or an abdominal ultrasound within the 6 months before visit 1 (screening), then those test results will be acceptable 
for the screening assessments.  If the subject has not had these procedures within the 6 months before visit 1 (screening), then the procedure(s) will be performed any time after providing 
informed consent with the results available and reviewed before the baseline visit (day 0).
c
All subjects enrolled in a treatment arm will have an FOBT after providing consent/assent.  Subjects with positive FOBT at screening for whom a readily detectable cause cannot be not identified 
(eg, anal fissure) will undergo a colonoscopy/sigmoidoscopy.  Colonoscopy/sigmoidoscopy will be conducted at screening on all subjects 12 years of age and older; however if the screening 
FOBT is negative and the subject has undergone the procedure within 1 year before visit 1 (screening), then that result will be acceptable for the screening assessment (See Section 6.5.4).  
Subjects with positive FOBT results at week 12 for which a cause is not identified by a physical exam will be discussed with the Shire medical monitor (See Section 6.5.3).
d
Treatment arm assignment and randomization and will be completed before dispensing teduglutide.
e
The first subcutaneous injection of teduglutide will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at 
least 4 hours. The site of administration (arm, thigh, abdomen) must be specified and recorded in the eCRF.  Teduglutide dose may be adjusted based on weight at week 12.
f
See Section 6.1 for PK blood draw timepoints.  If a subject is unable to provide blood samples for PK at the baseline visit (day 0), then PK samples may be collected during any other future site 
visit while the subject is still receiving treatment with teduglutide.
g
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab. Safety labs performed at phone visits may be collected 
by a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should 
be attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed approximately within 5-7 days of any adjustment to the PN/IV 
prescription.  For all subjects in the teduglutide treatment arm, PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
h
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine thereafter.
i
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible, and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
j
For antibody testing, blood will be obtained from subjects in the teduglutide treatment arm at the site before receiving the first dose of teduglutide. Blood samples may be drawn from a central 
line or from peripheral access (See Section 6.6.1.2).
k
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
l
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.


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Schedules of Events
Table 6-2
Schedule of Events in the Teduglutide Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
m
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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Table 6-3
Schedule of Events in the Teduglutide Treatment Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense drug
X
X
X
Provide intake and output diaries
X
X
X
X
Review diaries and nutritional supportb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testingd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Pregnancy teste
X
X
X
X
X
Citrulline testf
X
X
PE/vitals/weight/height (or length)/head 
circumferenceg
X
X
X
X
X
Fecal occult blood testh
X
Colonoscopy/Sigmoidoscopy
(X)
Electrocardiogram
X 
X
Antibodies to teduglutidei
X
X
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; S=site visit; 
T=telephone contact; W=week
a
Any subject who discontinues from the study before week 24 (EOT) (ie, early terminates) will undergo EOT procedures at the time of discontinuation and will complete a follow-up visit 4 weeks 
later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.


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Table 6-3
Schedule of Events in the Teduglutide Treatment Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
d
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected by 
a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the PN/IV 
prescription.  For all subjects in the teduglutide treatment arm, PT/INR will be tested at screening and if drug-induced liver injury is suspected thereafter.
e
All female subjects of child-bearing potential will be tested for pregnancy:  serum testing at screening; urine thereafter.
f
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
g
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).
h
Subjects with positive FOBT at week 24 (EOT)/ET for whom a readily detectable cause cannot be identified (eg, anal fissure) will undergo a confirmatory colonoscopy/sigmoidoscopy.  See 
Section 6.5.3.
i
Blood draw to test for antibodies to teduglutide before the last dose of teduglutide, ≥14 hours after the previous dose of teduglutide. If a blood sample is positive for antibodies at week 28 or EOS, 
then the subject will be retested 3 months after EOT.  If that sample is positive, then the subject will be retested 6 months after EOT.


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Table 6-4
Schedule of Events in the Standard of Care Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
Informed consent/assenta
X
Eligibility
X
X
Demographics
X
Medical/Surgical history
X
Electrocardiogram
X
X
Short bowel syndrome history
X
Provide GI-specific symptoms history diary
X
Review GI-specific symptoms history diary
X
Safety laboratory testingb
X
X
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
X
Citrulline testc
X
X
Provide intake and output diaries
X
X
X
X
X
X
X
X
X
Review diaries and nutritional supportd
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportg
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
PE/Vitals/Weight
X
X
X
X
X
X
X
X
X
Height (or length) and head circumferenceh
X
X
X
X
X
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)=as needed; AE=adverse event; BL=baseline; eCRF=electronic case report form; EN=enteral nutrition; GI=gastrointestinal; PE=physical examination; PN/IV=parenteral nutrition/intravenous 
fluid; S=site; SRN=screening; T=telephone; W=week
Note:  Unshaded columns indicate that the site will contact the subject by telephone; shaded columns indicate subject visits to the site.
a
Informed consent/assent must be obtained before performing any study-related procedure.
b
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected 
by a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should 
be attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the 
PN/IV prescription.
c
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
d
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 


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Table 6-4
Schedule of Events in the Standard of Care Treatment Arm – Screening to Week 12
Screening
Baseline
Treatment period
Study week
SRN
BL
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
Visit Number/Type: S=site/T=telephone
1/S
2/S
3/S
4/S
5/T
6/S
7/T
8/S
9/T
10/S
11/T
12/S
13/T
14/S
Study day±window
≥-14
0
7±2
14±2
21±3
28±3
35±3
42±3
49±3
56±3
63±3
70±3
77±3
84±3
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
e
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.
f
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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Table 6-5
Schedule of Events in the Standard of Care Arm – Weeks 13 to 28 (EOT)
Treatment period
Follow-up period
Week number
W13
W14
W15
W16
W17
W18
W19
W20
W21
W22
W23
W24
EOT
ETa
W25
W26
W27
W28
EOS
Visit number/type
S=site; T=telephone
15/T
16/T
17/S
18/T
19/T
20/S
21/T
22/T
23/S
24/T
25/T
26/S
27/T
28/T
29/T
30/S
Study day
±window (day)
91
±3
98
±3
105
±3
112
±3
119
±3
126
±3
133
±3
140
±3
147
±3
154
±3
161
±3
168
±3
175±3
182±3
189±3
196
±4
Adverse event collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications/procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Provide Intake and Output diaries
X
X
X
X
Diary and nutritional support reviewb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional supportc
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory testingd
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
(X)
X
(X)
X
Citrulline teste
X
X
PE/vitals/weight/height (or length)/head 
circumferencef
X
X
X
X
X
Electrocardiogram
X 
X
(X)=as needed; EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; PE=physical examination; PN/IV=parenteral nutrition/intravenous fluid; 
S=site visit; T=telephone contact; W=week
a
Any subject who discontinues from the study before week 24 (EOT) (ie, early terminates) will undergo EOT procedures at the time of discontinuation and will complete a follow-up visit 4 weeks 
later.
b
The volume and hours per day of PN/IV support and EN (formula) will be recorded on the intake diary every day during the study (Section 6.6).  Urine and stool output should be recorded in the 
output diary over a 48 hour period of PN/IV and EN stability before every clinic visit and within 1 week of each change in PN/IV prescription.  (See Section 6.6 for more detail).  Nutritional 
support includes PN/IV and EN (formula) (See Section 6.4).
c
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data and according to the guidelines provided in Appendix 1.
d
Safety lab assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central lab.  Safety labs performed at phone visits may be collected by 
a Home Health Agency and submitted to a central lab or performed locally and will consist of clinical chemistry and urinalysis only.  For children in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.  Safety labs must be performed within approximately 5-7 days of any adjustment to the PN/IV 
prescription.
e
Blood samples for measuring citrulline levels should be collected 2 to 4 hours postprandial, whenever possible and may be drawn from a central line or from peripheral access (Section 6.6.1.1).
f
Head circumference will be measured in subjects 36 months of age and younger (Section 6.8).


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7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
8-digit subject number, including subjects in the SOC treatment arm.  The first 4 digits consist of 
the study site number.  The last four digits will be assigned sequentially starting with 0001.  This 
number is the main identifier for subjects. 
Data collected during the study will be recorded in the subject’s eCRF by the investigational site 
staff.  The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.).  Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments).  In case of 
computerized source data, the investigator must provide Shire access to the subject files at each 
monitoring visit.  To ensure that data has been entered correctly on the eCRF, they will be 100% 
source-data verified by a site monitor from the sponsor/designee, who will notify the investigator 
regarding any questions or discrepant data.  The investigator or designee will be responsible for 
the timely recording of subject data into the eCRF.
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents.
The investigator or designee will review all eCRFs (including the termination page after the 
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the appropriate 
vendor.  Paper copies of laboratory reports and other non-eCRF data (eg, ECGs) will be signed 
and dated by the investigator and filed.
Diaries will be used by the subjects’ parent or guardian to record study information, including 
PN/IV support, enteral administration, urine output (as either collected or calculated volume), 
stool form and volume, and urine specific gravity. The subject diaries will provide the source 
documentation for the diary data that is to be recorded in the eCRF by the study staff.  Original 
diary data should be entered into the eCRF and takes precedence over data collected over the 
phone.
All data collected in this study will be entered into a study-specific database and submitted for 
statistical evaluation. The sites will be provided with eCRF completion guidelines outlining the 
specific procedures to use when entering the data into the clinical database. Data validation and 
edit checks will be conducted on the data. Any discrepancies will generate queries that must be 
resolved at the study site in a timely manner. 
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once the 
sponsor/designee acknowledges that all data are acceptable, the data will be declared a “clean 
file,” and the data will be frozen/locked.


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A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the database, 
the database will be ready for statistical analysis by the sponsor/designee.
7.2
Rescreening
Subjects may be rescreened only once and with prior sponsor approval. In the event of 
re-screening, a new subject number will be assigned.  Subjects who are rescreened will be 
reconsented.  See also Section 5.2.
7.3
Record Retention
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines.  These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject consent/assent 
documents, ECGs, photographs, and computer records) which are a result of the original 
observations and activities of the study and are necessary for the reconstruction and evaluation of 
any study report.
The clinical investigators will maintain copies of these essential documents for approximately 10 
years or as dictated by local regulatory requirements or until instructed in writing by the sponsor 
that records may be destroyed or forwarded to the sponsor.  In accordance with regulatory 
guidelines, these records will be available for inspection and copying if requested by a properly 
authorized employee of the FDA/European Health Authorities.


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8
STATISTICAL METHODOLOGY AND SAMPLE SIZE
Detailed statistical analysis methods will be conducted as described in the statistical analysis 
plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in the 
clinical study report (CSR).
Because of the small size of the study population only descriptive statistics will be used to 
summarize data.  Accordingly, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum. For categorical variables, statistical summaries will include number of subjects 
and percentages.
8.1
Demographic and Baseline Variables
Demographic and/or other baseline variables obtained at the screening or baseline visit are listed 
below.

Demography (including age, sex, and race)

Medical history

SBS history, including remnant anatomy

GI-specific symptoms history

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), and height or length

Physical examination

Prior treatment(s)

Electrocardiogram (12-lead)

Laboratory test results:  hematology, coagulation, clinical chemistry, and urinalysis

Citrulline levels

Presence of antibodies to teduglutide and titer level, if present (teduglutide treatment arm
only)

Gastrointestinal imaging (UGI/SBFT, abdominal ultrasound, colonoscopy/sigmoidoscopy, 
fecal occult blood) (teduglutide treatment arm only)

Pregnancy testing for females of child-bearing potential (teduglutide treatment arm only)

Nutritional support prescriptions (eg, PN/IV and EN volume and calories, PN/IV hours per 
day and days per week)

Nutritional support diary data
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and the 
number and percentage of subjects in specified categories by treatment arm) will be presented, as 
appropriate, to summarize the demographic and baseline variables. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary with regard to drug class and drug name.  The number and percentage of subjects 
with specific prior medications will be summarized by treatment and SOC treatment arms.
Medical history (including surgical/procedural history) will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  The number and percentage of subjects with 


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specific histories will be summarized by system organ class and preferred term for each study 
arm.
8.2
Safety and Tolerability Variables
The safety and tolerability variables include:

Adverse events, including GI symptoms

Physical examination findings

Vital signs, including temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height or length, and trends on growth charts

Electrocardiograms

Laboratory safety data (ie, clinical chemistry, coagulation, hematology, urinalysis), 
including the following lab tests at all clinic visits and interim safety labs to detect 
hepatoxicity signals:  AST, ALT, ALP, and bilirubin

Change in urine output (measured volume)

Fecal output (by volume or number of bowel movements per day)

Antibodies to teduglutide (teduglutide treatment arm only)

GI-specific testing (teduglutide treatment arm only) including colonoscopy or 
sigmoidoscopy, abdominal ultrasound, fecal occult blood testing, UGI/SBFT
Adverse events will be coded using MedDRA. Treatment emergent AEs will be summarized by 
system organ class and preferred term for each treatment arm (teduglutide and SOC). The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and SAEs that resulted in a fatal outcome will 
be summarized by treatment arm and teduglutide dose group. AEs will also be summarized by 
treatment arm and dose group with regard to severity and, for the teduglutide dose groups,
relationship to study drug.  For AESIs, the CTCAE grading system will be used as described in 
Section 6.14.
For laboratory tests, vital signs, body weight, ECG, and output diary variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit for each study arm.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment arm.
8.3
Pharmacokinetic Variables
The following pharmacokinetic parameters will be estimated using a population PK modeling 
approach:


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
Area under the plasma concentration-time curve (AUC) of zero to infinity (0–inf)

AUC from zero to the last measurable concentration (AUClast)

AUC at steady state (AUCss)

Maximum plasma concentration (Cmax)

Time to Cmax (Tmax)

Terminal-phase half-life (t1/2)

Apparent clearance (CL/F)

Apparent volume of distribution (Vλz/F)
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, 
geometric mean, the number and percentage of subjects in specified categories) will be 
calculated to summarize the absolute values and change from baseline at each scheduled visit.
8.4
Efficacy/Pharmacodynamic Variables
The primary efficacy/PD endpoint is a reduction in PN/IV volume of at least 20% at week 24 
(or EOT) compared to baseline.
The following efficacy/PD parameters will be measured:

100% reduction in PN/IV volume (complete weaning of PN/IV support) at week 24 (or 
EOT) compared to baseline

Change from baseline (absolute and percent change) in PN/IV support (volume and 
calories), citrulline, and enteral nutritional support (volume and calories) at each clinic 
visit

Change from week 24 (or EOT) (absolute and percent change) in PN/IV support (volume 
and calories), citrulline, and enteral nutritional support (volume and calories) at week 28 
(or EOS)

Change in hours per day and days per week of PN/IV support

≥20% reduction in PN/IV volume at each clinic visit
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, the 
number and percentage of subjects in specified categories) will be calculated to summarize the 
absolute values and change from baseline at each scheduled visit for each study arm and 
teduglutide dose group.
8.5
Other Variables
Other variables will be analyzed by study arm and dose group, as appropriate, including:


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
Subject disposition

Duration of teduglutide exposure

Subjects will be considered compliant if teduglutide was taken according to protocol and
assigned dose group for ≥80% of doses.  Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment arm.

The number and percentage of subjects who complete the study, are lost to follow up, or 
discontinued from the study (including reason for study withdrawal) will be summarized 
by dose group.

The teduglutide dose duration will be summarized by dose group.
8.6
Analysis Populations, Data Sets, and Time Points
8.6.1
Analysis Populations
The efficacy population will consist of all enrolled subjects.
The safety population will include all subjects in the efficacy population who meet the 
following criteria:

Teduglutide treatment arm:  subjects who have received at least 1 dose of teduglutide and 
have undergone at least 1 safety assessment

SOC treatment arm:  subjects who have undergone at least 1 safety assessment
The per protocol population will consist of all subjects in the efficacy population who have 
completed the study through EOT (week 24) without incidence of a major protocol violation that 
could affect the efficacy/PD conclusions of the study
The PK population will consist of all enrolled subjects who receive at least one subcutaneous 
injection of teduglutide and have evaluable and interpretable PK data.
Detailed per-protocol evaluable definitions will be documented in the SAP.  Major protocol 
violations will be determined before database lock.
The primary population analyzed for efficacy/PD will be the efficacy population.  An additional 
per-protocol population analysis will also be performed as secondary/sensitivity analysis.
8.7
Statistical/Analytical Issues
8.7.1
Adjustments for Covariates
Not applicable for this study.
8.7.2
Handling of Dropouts or Missing Data
All subjects randomized will be included in the analyses. Missing safety parameters will not be 
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV volume 
will be detailed in the SAP.
8.7.3
Interim Analyses and Data Monitoring
No interim analyses are planned.


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An independent DMC will review the data on a routine basis and may have access to data from 
the study for safety assessment. Details of the roles and responsibilities of the DMC members 
and the structure and scope of the DMC meetings will be provided in a separate DMC Charter.
8.7.4
Multiple Comparisons/Multiplicity
Given the small sample size, no hypothesis testing will be conducted. Accordingly, no 
adjustment to the alpha will be made.
8.7.5
Use of an Efficacy Subset of Subjects
A per-protocol population will be analyzed for this study.
8.7.6
Examination of Subgroups
Data from subjects in the teduglutide dose groups will be analyzed according to age strata 
(subjects aged <1 year, 1 to <12 years, 12 to <17 years, and 17 to <18 years) and by glutamine 
use, separately.
8.8
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.
8.9
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified in 
the final CSR.


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9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the current applicable ICH Guidelines, Good 
Clinical Practice, and the World Medical Association Declaration of Helsinki and its 
amendments concerning medical research in humans.
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent 
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant material 
for the investigator to submit to the IRB for the protocol’s review and approval.  Verification of 
the IEC/IRB approval of the protocol and the written consent/assent form will be forwarded to 
the sponsor/designee.
The investigator will inform the IEC/IRB of subsequent protocol amendments and any SUSARs 
if the sponsor has assessed it as an unanticipated problem.  Approval for protocol amendments 
will be transmitted in writing to the investigator.
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information, Informed Consent and Assent
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate.
The investigator (or designee) will explain to the subject and/or the subject’s parent or guardian 
the nature of the study, the action of the test product, and any risks and benefits.  The subject 
and/or subject’s parent or guardian will be informed that participation is voluntary and that the 
subject can be withdrawn from the study at any time without prejudice to their subsequent care.
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor/designee will be identified only by subject number and initials, 
thereby ensuring that the subject’s identity remains unknown.  Where allowed, the subject’s date 
of birth will also be recorded. The subject and/or the subjects’ parent or guardian should be 
informed in writing, that the subject’s data will be stored and analyzed in a computer, with 
confidentiality maintained in accordance with national and local legislation.  Study site-specific 
information must be added to the consent/assent as appropriate.
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 


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access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, and 
a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed screening 
must also be maintained and be available for inspection.
9.4
Financial Disclosure
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” (February 
2013) provides guidance to industry on its final rule on financial disclosure that became effective 
02 February 1999 and was published as Title 21 Code of Federal Regulations Part 54.  This rule 
applies to all investigators participating in clinical studies to be submitted to the FDA in support 
of an application for market approval.  The financial disclosure statement must be updated if any 
relevant changes occur during the course of the study, again at the site close-out visit, and for 1 
year after the completion of the study.
According to the guidance, financial arrangements that must be disclosed are defined as the 
following:

Compensation made to the investigator in which the value of compensation could be 
affected by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or 
the investigator’s institution to support activities of the investigator exclusive of the costs 
of conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing 
research, compensation in the form of equipment or retainers for ongoing consultation, or 
honoraria) during the time the clinical investigator is carrying out the study and for 1 year 
after completion of the study
Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes the 
spouse and each dependent child of the investigator.  Participating investigators must provide 
this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA in 
support of a market application.  Companies must meet these financial disclosure requirements, 
and failure to do so may result in the refusal by the FDA to accept an application for market 
approval of the study drug.


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9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the sponsor 
and the investigator.  All changes must be documented as signed protocol amendments, or as a 
revised protocol.  Changes to the protocol may require notification to or approval by the 
IEC/IRB and the regulatory authorities before implementation. Local regulatory requirements 
must be followed.  Instructions for reporting deviations from the protocol can be found in the 
Study Reference Manual.
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site.
9.6
Investigator Obligations
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address 
which matches the address on the FDA Form 1572

Financial disclosure statement for the principal investigator, and subinvestigators (listed 
on the FDA Form 1572).  An updated financial disclosure statement must be provided at 
the study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study.

A copy of the original approval for conducting the study from the IEC/IRB. Renewals 
must be submitted at yearly intervals if the study is ongoing or as required by the 
institution.

A copy of the IEC/IRB-approved ICF/assent

IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and dated 
by the principal investigator for the study site.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be used 
by the sponsor, now and in the future, for presentation or publication at the sponsor’s discretion 
and/or for submission to regulatory agencies.  In addition, the sponsor reserves the right to 


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review data from this study relative to the potential release of proprietary information 30 days 
prior to submission to any publication or for any presentation.
9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all investigators 
for this study.  Roles, affiliations, and qualifications for the principal investigators will be 
included in the CSR appendices.  Where the signature of the principal investigator is required by 
regulatory authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative reasons 
at any time.


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10
REFERENCES
Buchman, A. L., Scolapio, J. & Fryer, J. 2003. AGA technical review on short bowel syndrome 
and intestinal transplantation. Gastroenterology, 124, 1111-34.
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
Fleming, C. R., Witzke, D. J. & Beart, R. W., Jr. 1980. Catheter-related complications in patients 
receiving home parenteral nutrition. Ann Surg, 192, 593-9.
Jeppesen, P. B. & Mortensen, P. B. 2000. Intestinal failure defined by measurements of intestinal 
energy and wet weight absorption. Gut, 46, 701-6.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Messing, B., Crenn, P., Beau, P., Boutron-Ruault, M. C., Rambaud, J. C. & Matuchansky, C. 
1999. Long-term survival and parenteral nutrition dependence in adult patients with the 
short bowel syndrome. Gastroenterology, 117, 1043-50.
O'keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., De Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.


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Appendix 1
Guidelines for Nutritional Support Management during the Study 
(TED-C14-006)
Nutritional support adjustment in volume and calories should be considered at all planned visits.  
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric short bowel syndrome.  These parameters should be considered for managing 
nutritional support (PN/IV and EN) in terms of volume and calories during the treatment period.

Growth trajectory, including weight, height (or length), and head circumference (for 
children up to 36 months of age)

Other clinical evaluations
◦
Serum electrolytes
◦
BUN/creatinine levels
◦
Changes in stool frequency or volume, including mixed output
◦
Stool consistency (ie, Bristol Stool Scale)
◦
Urine specific gravity

General consideration to possible clinical deterioration in SBS
◦
Inability to maintain weight and growth velocity
◦
Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)
◦
Colic/vomiting frequency increased
◦
Electrolyte changes or imbalance
◦
Skin breakdown


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
Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses.  Subjects should remain compliant with the nutritional support 
prescription in volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour Intake/Output measurement period prior to the subject’s scheduled 
visit, no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other fluid intake, the investigator should consider this when 
adjusting the PN/EN support in volume and calories.
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers


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Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers


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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment


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Appendix 2
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
12 Mar 2015
Global
Amendment 1
22 Jun 2015
Global
Amendment 2
06 October 2015
Global
Amendment 3
25 February 2016
Global
Note:  Administrative changes, typographical errors, and text changes made to increase 
readability are not listed.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
25 February 2016
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Key study contacts have been updated
Page 2
Product Quality Complaints information has been updated
Page 3
Methodology has been clarified; no changes were made to the overall 
design; clarified terminology for treatment arm and dose group 
Synopsis
Protocol Section 3.1
Section 3.2
Statement added that subjects who complete the study may participate 
in a long-term extension study in which eligible subjects could receive 
teduglutide.
Synopsis
Protocol Section 3.1
Inclusion and Exclusion have been refined and clarified; there were no 
additional criteria added
Synopsis
Protocol Sections 4.2 and 4.3
Exclusion Criteria #11 has been updated to indicate that a subject 
would be excluded from the study if the subject had participated in a
clinical study of experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
Synopsis
Protocol Section 4.3
Number of subjects in the teduglutide treatment arms was changed 
from approximately 20 to approximately 26; the number of global 
investigational sites was changed from approximately 20 to 
approximately 28.
Synopsis
Protocol Section 4.1
Language strengthened describing the number of subjects enrolling 
into the SOC treatment arm:  “attempts will be made to enroll” has 
been changed to “at least 8 subjects who are teduglutide-naïve will be 
enrolled”.
Synopsis
Protocol Section 4.1
Language has been added to indicate that attempts will be made to 
enroll into each teduglutide dose group at least 1 subject younger than 
1 year and at least 2 subjects aged 12 to <17 years.
Synopsis
Protocol Section 4.1
Section 5.2
Clarification that departing from the nutritional support adjustment 
guidelines provided in Appendix 1 will not constitute a protocol 
Synopsis


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Description of Change
Section(s) Affected by Change
deviation.
Protocol Section 3.1
Section 6.4
Specified that randomization across teduglutide dose groups will be 
stratified by age subgroups. 
Synopsis
Protocol Section 3.1
Section 5.2
The requirement that teduglutide should be administered in the 
morning has been removed.
Protocol Section 5.3.2
Reviewing subject diaries has been included in the subject compliance 
with dosing check.
Protocol Section 5.3.3
Section 7.1
The definition of prior and concomitant medications has been 
expanded to include treatments.
Protocol Section 5.3.4, Section 
6.16;Table 6-2, Table 6-3, Table 
6-4, and Table 6-5
The Data Safety Monitoring Board has been replaced with a Data 
Monitoring Committee.
Synopsis
Protocol Section 4.5
A pharmacokinetic component has been added to the study as a 
criterion for evaluation.
Synopsis
Protocol Sections 6.1, 8.3, and 
8.6.1; Table 6-2
Adverse event and serious advent definitions and reporting procedures 
have been updated to align with Shire processes.  Definitions for 
abuse, misuse, overdose, and medication error have been added.
Protocol Sections 6.3 and 6.12; and 
subsections therein
Adverse events of special interest have been redefined and procedures 
for reporting them have been added.
Protocol Section 6.13
Dose interruption of individual subjects in the teduglutide treatment 
arm has been broken out according to known risks of teduglutide 
administration and to drug-induced liver injury
Protocol Sections 6.14 and added 
sections within; new Table 6-1
Criteria for DILI have been added.
Protocol Section 6.14.2
PT/INR testing has been added at screening for subjects in the 
teduglutide treatment arm and if DILI is suspected thereafter.
Protocol Section 6.6.1; Table 6-2
and Table 6-3
Dose discontinuation has been made absolute for an AE known to be a 
study drug risk that is of severity ≥Grade 3 and considered to be 
related to study drug; cases of severe hypersensitivity that are
determined to be related to study drug; DILI that is related to 
teduglutide, and pregnancy.  SAEs related to study drug are potential 
but not absolute reasons for dose discontinuation.
Protocol Section 6.14.2 and 
sections added within; new 
Table 6-1
Requirement added that female subjects of child-bearing potential in 
the teduglutide treatment arm have a serum-based pregnancy test at 
screening.
Protocol Section 6.17 and Table 
6-2
Procedures for unblinding have been made consistent with the EMA 
GCP guidance that breaking of treatment code resides with the 
investigator in emergency situations 
Protocol Section 6.18
“Other nutrition (regular diet and drink)” has been removed from the 
Intake diary.
Protocol Section 6.6
Section 7.1
Decrease frequency of capturing Output diary data to the 48 hours of 
PN/IV and EN stability before every clinic visit and within 1 week of 
implementing a change in the PN/IV prescription.
Protocol Section 6.6; Table 6-2, 
Table 6-3, Table 6-4, and Table 
6-5
The need for a subject in the teduglutide treatment arm with a positive 
Protocol Sections 6.5.3 and Table 


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Description of Change
Section(s) Affected by Change
FOBT at week 12 without a readily identifiable cause to undergo a 
colonoscopy/sigmoidoscopy is now open to discussion with the Shire 
medical monitor.
6-2
The requirement has been added that subjects who are rescreened 
must be reconsented.
Protocol Section 7.2
Definitions of analysis populations have been updated.
Protocol Section 8.6.1
Subgroup analyses have been added based on glutamine use and age 
strata, separately, for subjects in the teduglutide dose groups.
Protocol Section 8.7.6
Correct amendment 2 summary of change document which mistated 
that investigators no longer were required to assign CTCAE severity 
grades to adverse events that may lead to dose interruption.
Not applicable

Prot_001.pdf: 
A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study
Investigating Two Doses of Teduglutide in Pediatric Subjects Through
17 Years of Age with Short Bowel Syndrome who are Dependent on 
Parenteral Support
Clinical Study Protocol TED-C14-006
Version 2.0
Phase 3
US IND# 058213 
US NDA# 203441
EuDRACT #2015-002252-27
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ 07921
USA
ISSUED:
Amendment 1, version 2.0:
22 June 2015
Original Protocol version 1.0:
12 March 2015


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 2 of 71
Final v2.0
22 June 2015
SYNOPSIS
Protocol TED-C14-006
Title of Study: A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Protocol No: TED-C14-006
Phase of development: 3
Objectives: The objective of this clinical study is to evaluate the safety, tolerability, efficacy, 
and pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with short 
bowel syndrome (SBS) who are dependent on parenteral support.
Methodology: This will be a double-blind, 2 arm study in which subjects will be randomized in 
a 1:1 ratio to receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks
followed by 4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators 
and subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of
care cohort, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up. The subjects in the standard of care cohort will follow the same visit schedule 
as the randomized subjects.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. After screening, the 24-week treatment period will consist of site visits at baseline, 
weekly for the first 2 weeks, and then every other week for the next 8 weeks (through Week 12).  
From Weeks 13 to 24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  
Telephone contacts will be made on all other weeks during the treatment period.  A final visit 
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone contact 
will be made during the interim weeks from EOT to end of study (EOS).
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input and 
provided in the protocol) for decisions regarding parenteral nutrition/intravenous (PN/IV)
support reduction and advances in enteral feeds based on weight gain, urine, and stool output in 
the setting of clinical stability.


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Final v2.0
22June 2015
Number of Subjects:  Approximately 20 teduglutide-naïve subjects (at least 10 subjects per 
treatment arm) will be enrolled into the active treatment groups at approximately 10 to 
20 investigational sites globally.
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in a standard of 
care cohort (who will not be treated with teduglutide) to serve as an observational cohort.
Duration of Study:  There will be, at a minimum, a 2-week screening period followed by 
24 weeks of on-treatment study visits. There will be one final scheduled visit at Week 28, 
4 weeks after the EOT (Week 24).  
The proposed duration of the clinical phase is from July 2015 through December 2016.  The start 
of the clinical phase is defined as first subject screened.  The end of the clinical phase is defined 
as the last visit of the last subject.
Diagnosis and main criteria for inclusion: Male and female children and adolescents, through 
17 years of age, who meet the following inclusion and exclusion criteria will be enrolled in the 
study.
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce PN/IV 
support, usually associated with minimal or no advance in enteral feeds [ie, 10% or less 
change in PN or advance in feeds])  prior to screening, as assessed by the investigator
6. Female subjects of child-bearing potential (in the active treatment group only) must use 
medically acceptable methods of birth control during and for 30 days after the treatment 
period.


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Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
(ie, subjects with oral aversion)
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA 
abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support, prior to screening
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done
within 6 months prior to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the active treatment group only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)


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13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase-IV (DPP-IV) inhibitors within 3 months
prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements 
within 1 month prior to the screening visit (up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, are 
allowed)
19. Body weight < 10 kg at screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by any of the below laboratory test results during the screening period:
a.
Serum creatinine ≥ 2 x ULN 
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of chronic renal disease who must then 
have a screening creatinine clearance (CrCl) < 50 mL/min or, if CrCl cannot be measured, 
an eGFR level below 40 mL/min/1.73 m2.


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22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are listed 
in the table below.
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Tufting or autoimmune enteropathy or microvillous 
inclusion disease

Untreated pre-malignant or malignant change in upper 
GI, biopsy or polypectomy 

Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, 
Turcot syndrome, Juvenile polyposis syndrome, 
Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada 
syndrome, Eversmeyerous polypius)
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency).
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system)
Test Product, Dose, and Mode of Administration:
After randomization, daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will 
be administered to the subjects in the active treatment cohorts.  The dose calculation will be 


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based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose will be 
made during the study period, unless discussed with the NPS medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily in the morning into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma will not be used.
Reference Therapy, Dose and Mode of Administration:
Not applicable.
Criteria for Evaluation:
Safety and tolerability:
Safety and tolerability will be assessed by evaluation of:

Adverse events, including GI symptoms. A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline.  GI symptoms will be 
recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject.

Physical examinations

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide (active treatment groups only).  Samples for antibody analysis will 
be drawn at baseline and at the EOT (Week 24) and EOS (Week 28) visits prior to the 
administration of teduglutide and at least 14 hours after the previous dose.  One sample will 
be collected at the final visit 4 weeks after the EOT (EOS, Week 28).  Any subjects testing 
positive for antibodies specific to teduglutide (positive/specific antibodies) at Week 28 will 
have follow-up visits 3 and/or 6 months after the last dose of study drug to assess antibody 
status.

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (where collection is possible)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing upper GI series with small bowel follow-through


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Pharmacodynamics:
The primary pharmacodynamic (PD) parameter is parenteral support reduction of 20% to 100% 
at 24 weeks (or EOT) compared to baseline.
Analysis of additional PD endpoints will include:

100% reduction in PN/IV volume support (any subjects who are able to completely wean off
PN/IV support) compared to baseline at EOS

A decrease in parenteral support (calories and volume)

An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 (or EOS)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT) 
compared to Week 28 (or EOS)

Change in urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months (as applicable) after EOT compared to baseline for 
those subjects who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of response (PN/IV reduction and advance in enteral support) at each visit.

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks.
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input) for 
decisions regarding PN/IV support reduction and advances in enteral feeds based on weight gain, 
urine, and stool output in the setting of clinical stability.
Safety and tolerability will be evaluated by a data safety monitoring board (DSMB) every 
3 months during the active study period.  The DSMB review will include all cumulative safety 
data (ie, adverse events, laboratory assessments, physical examinations, etc.) from study 
assessments through each cutoff period including any reasons for dose adjustment and 
discontinuations.


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Statistical methods:
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum. For categorical variables, statistical summaries will include number of subjects 
and percentages.
Demographics and baseline:
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate.
Efficacy/Pharmacodynamics:
Efficacy/pharmacodynamics data including reduction in parenteral support, increase in enteral  
nutritional tolerance, change in PN/IV support, citrulline, enteral support, urine output, weight,
height, hours per day or days per week of PN/IV support, and time to PN/IV reduction and 
advance in enteral support will be summarized by visit and time point.
Safety:
Safety data including clinical laboratory tests, physical examinations, concomitant medications, 
electrocardiogram monitoring, and vital signs assessments will be summarized by visit and time 
point.  Adverse events will also be collected and summarized, including Grade 3 and 4 adverse 
events of special interest, based on Common Terminology Criteria for Adverse Events (CTCAE) 
criteria.  Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable.  Frequency counts will be compiled for classification of 
qualitative safety data.


Pe diatric St u d y T E D -C 1 4 -0 0 6 – A me n d me nt 1
Te d u gl uti de (r D N A ori gi n) f or i njecti o n
Pa ge 1 0 of 7 1
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SI G N A T U R E P A G E
Pr ot oc ol T E D -C 1 4- 0 0 6
Re vie we d a n d A p pr o ve d:
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O perati o ns
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
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Date 
( D D M M M
Y Y Y Y)
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N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
, P h D
, Bi o metrics a n d Data 
Ma na ge me nt
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
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Date 
( D D M M M
Y Y Y Y)
, B S, R A C 
, Re g ulat or y Affairs 
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
, M D
, Cli nical 
De vel o p me nt 
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
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Date 
( D D M M M
Y Y Y Y )
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol TED-C14-006
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics 
Committee (IEC) for the study protocol and any amendments thereof, written informed consent 
or updates thereof, subject recruitment procedures (eg, advertisements), and any other written 
information to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement 
from the sponsor and review and documented approval from the IRB/IEC, except to eliminate 
an immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data 
sheets, correspondence records, and signed subject consent/assent documents for at least 
5 years or until instructed in writing by the sponsor that records may be destroyed or forwarded 
to the sponsor.  
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


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TABLE OF CONTENTS
SYNOPSIS......................................................................................................................................2
SIGNATURE PAGE....................................................................................................................10
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE..................................11
TABLE OF CONTENTS ............................................................................................................12
LIST OF IN-TEXT TABLES AND FIGURES.........................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................15
1
INTRODUCTION..................................................................................................................16
1.1
Background .....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design .............................................................................................19
2
OBJECTIVES ........................................................................................................................21
2.1
Primary Objective ...........................................................................................................21
3
STUDY DESIGN....................................................................................................................21
3.1
Overall Design and Control Methods..............................................................................21
3.2
Study Duration ................................................................................................................25
4
SUBJECT SELECTION AND PARTICIPATION ............................................................25
4.1
Number of Subjects.........................................................................................................25
4.2
Inclusion Criteria.............................................................................................................25
4.3
Exclusion Criteria............................................................................................................26
4.4
Subject Withdrawal Criteria............................................................................................29
4.5
Data Safety Monitoring Board ........................................................................................30
5
TREATMENTS AND TREATMENT PLAN .....................................................................30
5.1
Treatment Administered..................................................................................................30
Identification of Investigational Product .................................................................30
5.1.1
Packaging and Labeling...........................................................................................31
5.1.2
Storage, Accountability, and Stability .....................................................................31
5.1.3
5.2
Methods of Assigning Subjects to Treatment Groups ....................................................32
5.3
Dose Regimens................................................................................................................32
Selection of Doses in Study .....................................................................................33
5.3.1
Selection and Timing of Dose for Each Subject......................................................33
5.3.2
Compliance with Dosing Regimens.........................................................................33
5.3.3


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Prior and Concomitant Medications ........................................................................34
5.3.4
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................34
6.1
Evaluations for Safety and Tolerability ..........................................................................34
Adverse Events ........................................................................................................35
6.1.1
Serious Adverse Events ...........................................................................................37
6.1.2
Unblinding ...............................................................................................................40
6.1.3
Dose Interruption of Individual Subjects.................................................................40
6.1.4
Early Termination of the Clinical Study..................................................................42
6.1.5
Laboratory Evaluations............................................................................................42
6.1.6
Physical Examinations.............................................................................................44
6.1.7
Vital Signs and Body Weight ..................................................................................44
6.1.8
Electrocardiograms ..................................................................................................45
6.1.9
Gastrointestinal-specific Testing .............................................................................45
6.1.10
Concomitant Medication Assessment......................................................................46
6.1.11
Nutritional Support Usage .......................................................................................46
6.1.12
Diaries......................................................................................................................47
6.1.13
Female Subjects of Child-bearing Potential ............................................................48
6.1.14
7
DATA MANAGEMENT.......................................................................................................58
7.1
Data Collection................................................................................................................58
7.2
Record Retention.............................................................................................................59
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE ...............................................59
8.1
Demographic and Baseline Variables .............................................................................59
8.2
Safety and Tolerability Variables....................................................................................61
8.3
Pharmacodynamic Variables...........................................................................................61
8.4
Other Variables ...............................................................................................................62
8.5
Analysis Populations, Data Sets, and Time Points..........................................................63
Analysis Populations................................................................................................63
8.5.1
8.6
Statistical/Analytical Issues.............................................................................................63
Adjustments for Covariates......................................................................................63
8.6.1
Handling of Dropouts or Missing Data....................................................................63
8.6.2
Interim Analyses and Data Monitoring....................................................................63
8.6.3
Multiple Comparisons/Multiplicity .........................................................................63
8.6.4
Use of an Efficacy Subset of Subjects .....................................................................63
8.6.5
Examination of Subgroups.......................................................................................63
8.6.6


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8.7
Determination of Sample Size.........................................................................................63
8.8
Changes to Planned Statistical Analyses.........................................................................64
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................64
9.1
Declaration of Helsinki and Ethical Review...................................................................64
9.2
Subject Information, Informed Consent and Assent.......................................................64
9.3
Subject Data Protection...................................................................................................65
9.4
Financial Disclosure........................................................................................................65
9.5
Changes to the Protocol...................................................................................................66
9.6
Investigator Obligations..................................................................................................66
9.7
Confidentiality/Publication of the Study.........................................................................67
9.8
Selection of a Primary Principal Investigator .................................................................67
9.9
Study Termination...........................................................................................................67
10 REFERENCES.......................................................................................................................68
APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY......................................................................................69
LIST OF IN-TEXT TABLES AND FIGURES
Table 4-1 
Excluded Diseases and Illnesses............................................................................28
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active 
Treatment Groups ..................................................................................................49
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment 
Groups....................................................................................................................52
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard 
of Care Cohort........................................................................................................54
Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care 
Cohort ....................................................................................................................56
Figure 3-1 
Study Diagram .......................................................................................................23
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet Trained and in Diapers ....69
Figure A-2
Weaning Algorithm for Subjects Who Are Toilet Trained and not in Diapers.....70
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment...................................71


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CrCl
Creatinine Clearance
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
EN
Enteral nutrition
EOS
End of study
EOT
End of treatment
FDA
Food and Drug Administration
FOCBP
Females of child-bearing potential
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP-2
Glucagon-like peptide 2
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
NOAEL
No Observed Adverse Effect Level
NPS
NPS Pharmaceuticals, Inc.
PD
Pharmacodynamic
PK
Pharmacokinetic
PN
Parenteral nutrition
QD
Once daily
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SMT
Safety Management Team 
SUSAR
Suspected, unexpected, serious, adverse reaction
ULN
Upper limit of normal
WMA
World Medical Association


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1
INTRODUCTION
1.1
Background
Compound
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like 
peptide-2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native 
GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus.  As a 
result, teduglutide demonstrates resistance to degradation by dipeptidyl peptidase-IV and 
therefore maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to 
the native peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in 
animal studies and previous human clinical trials to increase villus height and crypt depth in 
the intestinal epithelium, thereby increasing the absorptive surface area of the intestines.  The 
European Commission granted a centralised marketing authorization valid throughout the 
European Union for teduglutide (Revestive™) on 30 August 2012 and a New Drug Application 
(NDA) for teduglutide (Gattex®) was approved by the US Food and Drug Administration 
(FDA) on 21 December 2012 for the treatment of adult patients with Short Bowel Syndrome 
(SBS) who are dependent on parenteral support.
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes 
to the label which provide for long-term use of Gattex.
Preclinical Studies
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in Cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated 
rats. Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those 
observed in studies conducted using adult animals (rodents and primates). No treatment-related 
malignant tumors were noted in a 2-year carcinogenicity study in rats; treatment-related 
changes included benign tumors of the bile duct epithelium and adenomas of the jejunal 
mucosa in males treated at 35 mg/kg/day. The results from a second 2-year carcinogenicity 


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study in Crl:CD1(ICR) mice were provided to the agency in a NDA Supplement which 
received agency approval on 26 June 2014. Subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day 
(about 20, 70, and 250 times the recommended daily human dose of 0.05 mg/kg, respectively) 
were studied and adenocarcinoma in the jejunum was present in males given a dose of 
12.5 mg/kg/day.
Clinical Studies
Two completed studies (CL0600-004 and CL0600-005) evaluated safety and tolerability of 
daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on 
parenteral nutrition/intravenous fluids (PN/IV).  Study CL0600-004, a double-blind, placebo-
controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed 
the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV.  There was a 
statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study.  The reduction of PN/IV volume was 
similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, assessed the 
long-term safety of teduglutide and the proportion of responders in the CL0600-004 study that 
maintained their response at the end of a further 28 weeks of treatment.  The extension study 
also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day dose, 
teduglutide treatment in the initial phase 3 study, which included significant reductions in 
PN/IV.  There was 75% of the subjects who previously responded to teduglutide treatment in 
Study CL0600-004 who maintained this response or experienced further improved benefit 
from teduglutide treatment.  More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. The majority of adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which 
subjects were randomized to either teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio.  The 
first stage of the study included a screening and optimization period and a stabilization period 
that demonstrated stable administration of PN/IV volume for a minimum of 4 weeks up to a 
maximum of 8 weeks.  The second stage was a dosing period of 24 weeks.  Subjects on 
0.05 mg/kg/day teduglutide achieved a higher responder rate (defined as a 20% to 100% 
reduction from baseline in PN/IV volume at Weeks 20 and 24) than the placebo-treated 
subjects (27/43 subjects, 62.8% and 13/43 subjects, 30.2%, respectively).  This difference was 
clinically and statistically significant in both the Intent-to-Treat (ITT) (p = 0.002) and Per 
Protocol (p < 0.001) populations.  Generally, the incidence of treatment-emergent AEs 
(TEAEs) was distributed similarly across all treatment groups.  The TEAEs with a higher 
incidence in the teduglutide group were mainly of GI origin.  A long-term, open-label 


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extension study (CL0600-021) assessed safety and efficacy for up to 24 additional months 
(ie, up to 30 months of exposure for subjects who received teduglutide in Study CL0600-020).
Overall, 30 of 43 subjects who received teduglutide in Study CL0600-020 and entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide.  Of these,
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a 
PN/IV volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative 
to baseline prior to exposure to teduglutide at the beginning of Study CL0600-021.  PN/IV 
frequency was reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 
30 months of treatment.  Of the 39 subjects who entered Study CL0600-021 after receiving 
placebo in Study CL0600-020, 29 completed 24 months of treatment with teduglutide.  The 
mean reduction in PN/IV volume was 3.11 L/week from baseline at the start of 
Study CL0600-021 (an additional 28% reduction).  Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support.  Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide.  The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support
1.2
Rationale for the Clinical Study
Short bowel syndrome is a rare disorder.  At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, 
market research performed in 2012 indicates that the true addressable adult patient population 
is between 3000 to 5000 patients which qualifies SBS as an ultra-orphan condition.  In addition 
to adult SBS patients, it is estimated that, at most, there are a few hundred children 1 year and 
older with SBS.  As a result of congenital abnormalities or severe intestinal disease in children 
and adolescents, major surgical resections of the intestine can become necessary, resulting in 
SBS.  Common causes of SBS in children include necrotizing enterocolitis (NEC) in infants, 
midgut volvulus (volvulus), intestinal atresia, and gastroschisis (Duro et al, 2008).  SBS in 
older children may stem from the same etiologies as in adults (ie, Crohn’s disease, trauma, 
cancer). As the characteristics are similar to the adult disease, pediatric SBS is defined as a 
disease where there is diminished absorptive capacity for fluids and/or nutrients, sometimes 
requiring a dependence on PN/IV support to maintain energy and clinical status.
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able 
to adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al, 1999; Jeppesen
et al, 2000), other patients with intestinal failure depend on PN/IV for nutritional support 
(Fleming et al, 1980; O’Keefe et al, 2006; Buchman et al, 2003).  Although PN/IV can provide 
this nutritional support for patients with compromised fluid and nutritional status, it is also 


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associated with serious complications, such as infections and liver damage.  The risk for these 
effects increases over time with longer duration of PN/IV support.
The same treatment options are currently available for children and the same associated risks 
prevail.  Treatment of both pediatric and adult patients is focused on achieving adequate 
intestinal absorption to allow for minimization or discontinuation of PN/IV support.  This is 
achieved far more successfully in infants who develop SBS during the neonatal period and 
frequently come off their PN/IV requirements within 6 to 12 months of their initial surgical 
insult such that they achieve enteral autonomy by age 1 year.  Recent data suggest that up to 
85% of patients achieve spontaneous adaptation by age 1 year.
In the US, data from the Organ Procurement and Transplant Network reflect improvement in 
the medical and non-transplant surgical management of intestinal failure after 2010.  The peak
number of pediatric intestinal transplants in North America occurred between 2004 to 2009 (up 
to 111 in 2007) with falling levels from about 2010 onward (52 to 62 transplants annually). In 
2012, 56 transplants took place and in 2013, 36 transplants took place.
This study proposes to investigate the safe and appropriate use of teduglutide in the pediatric 
population for up to 24 weeks for the purpose of providing longer-term data in regard to safety 
and potential to explore further efficacy including PN reduction and ability to completely wean 
off parenteral support.  This protocol was developed with input from expert advisors from 
intestinal rehabilitation centers who offered advice on the most appropriate use of teduglutide
in pediatric patients.  The aim of teduglutide treatment is to increase absorptive capacity in 
order to yield decreases in parenteral support.  The experts anticipated that there would be 
several direct benefits from decreased parenteral support, including less exposure to PN/IV 
constituents, less central line manipulation with lower risk of infection, and more time to focus 
on oral rehabilitation strategies.
1.3
Rationale for Study Design 
Dose
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily (QD) in adult SBS subjects requiring PN.  The recommended clinical 
dosage for the adult SBS patient population is 0.05 mg/kg QD.  Population pharmacokinetic 
(PK) modeling and simulations were conducted to determine the dose to be used in pediatric 
subjects.  Subcutaneous dosing of teduglutide in pediatric patients with SBS was based on data 
collected in 5 adult Phase 1 studies and 3 adult Phases 2/3 studies, as well as an adult 
population PK meta-analysis. The PK results from the adult SBS clinical program also were 
used to model and simulate PK parameters in pediatric SBS patients to provide guidance on 
pediatric dosing for teduglutide.  An ongoing 12 week pediatric study (TED-C13-003) includes 
doses of 0.0125, 0.025, and 0.05 mg/kg/day.  Interim data evaluated by the DSMB has 
concluded that all three doses are safe and tolerable with trends of PN/IV volume reduction 


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and advance in feeds observed. Modeling and simulation data from previously completed
studies suggested that pediatric patients are likely to require the same dose as used in adults 
and that the 0.05 mg/kg/day adult dose will be sufficient to provide similar blood levels in all 
subjects over 1 year of age.  To further explore additional safety and efficacy, a 24 week study 
is currently proposed.
Treatment Duration/Design
Safety, tolerability and pharmacodynamic measures over a 24-week period will be the main 
outcomes of the current study.  The main PD effect of teduglutide to be measured in children 
will include a decrease in the volume of PN/IV requirement.  Measurement of a decrease in 
PN/IV volume requirements was the primary endpoint in the adult SBS clinical studies and can 
be used in children with SBS who are dependent on PN/IV support.
A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of 24 weeks of treatment was used as the primary endpoint in the adult clinical 
development program during pivotal Phase 3 studies and will be the same endpoint used in the 
current pediatric study.
The current study will employ a double-blind, 2 arm design with treatment of either 
0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for up to 24 weeks.  The 24-week treatment 
period will provide further information on longer term safety and additional efficacy including 
complete weaning of treatment beyond the 12-week period previously evaluated in the first 
pediatric study.
Thus, this study is designed to provide further information on the safety and PD profile of 
teduglutide in pediatric subjects treated for up to 24 weeks.
Subject Population
The current significant unmet medical need is for patients over age 1 year who remain 
dependent on parenteral support.  These patients reach a plateau in their ability to advance 
oral/enteral feeds or decrease PN/IV support and are not expected to achieve spontaneous 
adaptation.  The subjects in the study will be children whose intestines have not reached full 
enteral adaptation after 12 months of PN/IV treatment and whose PN/IV requirement had been 
stable without any clinically meaningful or substantial reduction in parenteral support for the 
3 months prior to study enrollment.
Therefore, this study will be performed in PN/IV-dependent children with SBS through 
17 years of age who have demonstrated that they have reached a plateau with regard to their 
ability to fully continue intestinal adaptation in terms of their ability to advance feeds and 
subsequently reduce their needs for parenteral support.  Stability for these subjects will be
defined as at least 3 months in which patients still are requiring at least 30% of their volume 
and/or calories from PN/IV with no clinically meaningful change in advances in their enteral 
feeds (specialized nutrition such as formula via mouth or tube).


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This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000).
Gastrointestinal Screening Measures
Pediatric SBS patients who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for obstruction due to history of surgery. Teduglutide has 
been found to have a targeted intenstinotrophic effect on the GI tract and areas of special 
interest in regards to safety have been identified throughout the development program. Taken 
into account the patient population and the pharmacologic effect of teduglutide, GI-specific 
screening tests which are usually part of the routine care of these subjects will be performed on 
subjects in the active treatment groups to ensure safety. These include: abdominal ultrasound, 
upper GI series with contrast, fecal occult blood testing, and, if deemed clinically relevant, 
colonoscopy/sigmoidoscopy.
General Guidance for Nutritional Support Adjustment
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status, which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoint for this study is a ≥20% reduction in PN/IV support guided 
by clinical status. A suggested guidance for nutrition support adjustment is provided in 
Appendix 1 and should be followed by all sites to ensure uniform care across study sites and 
participants.
2
OBJECTIVES
2.1
Primary Objective
The objective of this clinical study is to evaluate the safety, tolerability, efficacy, and 
pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with SBS who 
are dependent on parenteral support.
See Section 8.2 and Section 8.3 for further details of the variables being measured.
3
STUDY DESIGN
3.1
Overall Design and Control Methods
This will be a double-blind, 2 arm study in which subjects will be randomized in a 1:1 ratio to 
receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks followed by 
4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators and 
subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of care 
cohort, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up.  The subjects in the standard of care cohort will follow the same visit 
schedule as the randomized subjects.


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All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters.  After screening, the 24-week treatment period will consist of visits at baseline, 
weekly for the first 2 weeks, and then every other week through Week 12.  From Weeks 13 to 
24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  Telephone contacts will 
be made on all other weeks during the treatment period in order to monitor safety.  A final visit
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone 
contact will be made during the interim weeks from EOT to end of study (EOS).  If necessary, 
unscheduled visits can be arranged in place of the telephone contacts.  Schedules of study 
parameters are displayed in Table 6-1 and Table 6-2.
To maintain consistency across all centers, sites and subjects (treated and standard of care) 
must follow the nutritional support adjustment guidelines (developed with SBS expert input 
and provided in Appendix 1) for decisions regarding PN/IV support reduction and advances in 
enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
At the conclusion of the follow-up period (Week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post
EOT for another antibody sample. If the subjects continued to have positive/specific antibodies
at 3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. At all follow-up visits, an assessment 
of the subject’s current PN/IV support and an adverse event determination will be conducted.
Safety and tolerability results will be evaluated by a DSMB every 3 months during the active 
study period (date of the first subject’s first dose to date of the last subject’s last dose).  The 
DSMB review will include all cumulative safety data (ie, adverse events, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period 
including any reasons for dose adjustment and discontinuations.
A schematic representation of the study design is displayed in Figure 3-1.


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Figure 3-1
Study Diagram
Note:  The Standard of Care cohort follows the same visit schedule as the active treatment groups.


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3.2
Study Duration
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment.  
There will be one final scheduled visit 4 weeks after the end of treatment. Those subjects who 
test positive for teduglutide-specific antibodies at the 4-week follow up visit (Week 28) will be 
asked to return for additional follow-up visit(s) as described in Section 6.1 in order to 
determine their antibody status.
The proposed duration of the clinical phase is from July 2015 through December 2016.  The 
start of the clinical phase is defined as first subject screened.  The end of the clinical phase is 
defined as the last visit of the last subject.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects
Approximately 20-30 teduglutide-naïve subjects (minimum 10 subjects per treatment arm) will 
be enrolled into the active treatment groups.  
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in the standard of 
care cohort.  
Subjects will be enrolled at approximately 10 to 20 investigational sites globally.
4.2
Inclusion Criteria
Male and female children and adolescents, through 17 years of age, who meet the following 
inclusion criteria will be enrolled in the study.
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject prior to any study-related procedures 
(as deemed appropriate by the Ethics Committee/Institutional Review Board)
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce 
PN/IV support, usually associated with minimal or no advance in enteral feeds [ie, 10% or 
less change in PN or advance in feeds])  prior to screening, as assessed by the investigator


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6. Sexually active female subjects of child-bearing potential (in the active treatment group 
only) must use medically acceptable methods of birth control during and for 30 days after 
the treatment period
4.3
Exclusion Criteria
Subjects who meet any of the following exclusion criteria at baseline are not eligible for 
enrollment into the study:
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
(ie, subjects with oral aversion)
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support prior to screening
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including 
resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and 
surgically resected cancer
10. Pregnant or lactating female subjects (in the active treatment group only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 


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screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase-IV (DPP-IV) inhibitors within 3 months 
prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy
(eg, antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) 
within 3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements
within 1 month prior to the screening visit(up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, 
are allowed)
19. Body weight < 10 kg at the screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any 
of the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction
shown by any of the below laboratory test results during the screening period:


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a.
Serum creatinine ≥ 2 x ULN
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of chronic renal disease who must then 
have a screening creatinine clearance (CrCl) < 50 mL/min or, if CrCl cannot be measured, 
an eGFR level below 40 mL/min/1.73 m2.  
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to 
the study visit schedule and other protocol requirements
23. Unstable, clinically significant active, untreated pancreatic or biliary disease
24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of 
the study results.  Examples of potential disease states/illnesses that may be excluded are 
listed in the table below.
Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS
Ongoing radiation enteritis 
Untreated celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal 
Active IBD which required chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months
IBD that required chronic systemic immunosuppressant 
therapy for symptom control 
Tufting or autoimmune enteropathy or microvillous 
inclusion disease
Untreated pre-malignant or malignant change in upper GI, 
biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, Turcot 
syndrome, Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome, Eversmeyerous 
polypius)
Intestinal or other major surgery scheduled within the time 
frame of the study
Chronic active pancreatitis 
Cholecystitis


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Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Immune
Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, infectious, 
endocrine, hepatic, or central nervous system)
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
NPS Medical Monitor prior to the patient discontinuing/withdrawing.  A subject may (but not 
automatically) be withdrawn from the study under any of the following circumstances:

Withdrawal of informed consent and/or assent when applicable

If, in the opinion of the investigator, Institutional Review Board (IRB) or NPS, it is no 
longer in the subject’s best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any criterion for exclusion

Lack of compliance with study procedures or study drug administration, as determined by 
the investigator

Occurrence of a serious adverse event (SAE) determined by the investigator to be possibly 
related to study drug and not alleviated with treatment of symptoms

Adverse event (including Grade 3 or 4 events of special interest [Section 6.1.4])

Hypersensitivity determined by the investigator to be possibly related to study drug

Administrative reasons
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.1.1.  Reasons for discontinuation other 
than AEs must be reported within 4 weeks of the EOS date in order to be included in the 
database.  Any reason for discontinuation obtained after this time will be included in the 
subject’s medical record only unless the EOS visit date is amended and the database remains 
open.


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As far as possible, all examinations scheduled for the EOT evaluations must be performed on 
all subjects who participate even if they do not complete the study according to the protocol.
4.5
Data Safety Monitoring Board
The DSMB for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DSMB will be an external, independent board comprised of physicians with relevant 
training and an independent statistician (not associated with NPS, study sites, or investigators). 
The DSMB will be restricted to individuals free of significant conflicts of interest, including, 
but not limited to, financial, scientific, or regulatory in nature. The DSMB will be governed by 
a Charter agreed to by members of the Board and the sponsor. Members of the Board may not 
be study investigators, individuals employed by NPS, independent contractors hired by NPS, or 
members of regulatory agencies. The DSMB may serve as an advisory board to NPS; however, 
NPS will have the final responsibility to determine whether the study should be modified or 
temporarily or permanently stopped. 
The DSMB members will review the data approximately every 3 months after the beginning of 
dosing of the first subject and then approximately every 3 months thereafter.  The DSMB will 
be provided the following:  1) all cumulative safety data from the study for safety assessments; 
2) data related to pharmacodynamics and the nutritional progress (ie, any changes in the use of 
PN/IV and/or enteral nutrition) of each subject; and 3) any other data supporting the decision to 
discontinue teduglutide throughout the study.
5
TREATMENTS AND TREATMENT PLAN
5.1
Treatment Administered
Daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will be administered 
once daily in the morning to the subjects in the active treatment cohorts.  The dose calculation 
will be based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose 
will be made during the study period. Teduglutide will be administered by SC injection into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma will not be used.
Identification of Investigational Product
5.1.1
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled 
syringe.  The 5-mg vial is 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is 
5 mg/mL. A maximum of 0.38 mL of reconstituted solution can be withdrawn from the vial.


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In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients.
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength.
Packaging and Labeling
5.1.2
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Study drug vial will be supplied in kits containing 7 vials and labeled with the 
protocol number, the investigational drug warning, general dosage instructions, storage 
conditions, expiry date, kit number, lot number, and company name.  Space will be provided 
for recording study site and subject numbers at the study site. Ancillary supply kits containing 
syringes with needles for injection and reconstitution, sterile water, and alcohol swabs will also 
be provided.
All study drug used in this study will be manufactured, tested, labeled, and released according 
to current legal requirements and Good Manufacturing Practice (GMP).
Storage, Accountability, and Stability
5.1.3
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures.  Upon receipt, the study site’s pharmacist or 
delegate is responsible for ensuring that all study drug received at the site is inventoried and 
accounted for throughout the study.  A copy of the shipping documents must be maintained for 
the investigator’s records.
Study drug must be kept in a locked area with access restricted to specific study personnel.  
Study drug will be stored refrigerated at a temperature between 2 to 8 oC (35.6 to 46.4 oF) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated 
up to a controlled room temperature (acceptable range of 2 to 25 oC, or 35.6 to 77 oF).  
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated.
Study drug kits will be dispensed at each of the study visits at which the subject is required to 
be at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough 
kits will be supplied to cover the period to the next planned study visit. Additional study kits
will be provided as necessary.
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies.  This record will be made available to the sponsor’s site monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded and will 


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include an explanation. All supplies sent to the investigator must be accounted for and in no 
case will clinical supplies be used in any unauthorized situation.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian
and will be retained at the site. All original containers, whether empty or containing study drug 
will be returned to the pharmacy.  Returned study drugs will NOT be relabeled or reassigned 
for use by other subjects.  Contents of the study drug containers will not be combined.  All
usedf and unused vials must be returned to the distribution center according to the sponsor’s 
instruction.  No vial/kit may be destroyed on site.
5.2
Methods of Assigning Subjects to Treatment Groups
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of 
the study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These
numbers will be used to identify the subjects throughout the study period, including any 
subjects in the standard of care cohort.  
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the dosing cohort or the 
standard of care cohort.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all Inclusion/Exclusion criteria.  If the subject or 
subject’s parent/guardian/caretaker decides to participate in the dosing cohort, the investigator 
or designee will request the subject be randomized at the Baseline Visit using an interactive 
voice response system (IVRS) at a 1:1 ratio, centrally administered as described in the IVRS 
Manual of Procedures.
Study drug kits will be assigned through IVRS to each subject at each on-site visit through
completion of the dosing period. The IVRS will automatically assign the correct number of kits 
for each visit based on the date of randomization. If additional kits are needed (eg., subject is 
going on holiday), the IVRS and NPS will need to be notified so that the additional kits can be 
assigned.  Subjects will be randomized across centers rather than within center.
Those subjects opting for the standard of care cohort will continue in the study but without the 
study drug.
5.3
Dose Regimens
Teduglutide will be supplied in 2 strengths:

5.0 mg/vial for subjects receiving 0.05 mg/kg/day of teduglutide

2.5 mg/vial for subjects requiring 0.025 mg/kg/day
Subjects in the active treatment groups are to have the study drug administered daily in the 
morning by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or arm, 
for 24 weeks. For subjects with a stoma, the quadrant of the abdomen containing the stoma 


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will not be used. The initial dose will be calculated based on body weight measured at the 
Baseline Visit (Visit 2).
Selection of Doses in Study
5.3.1
A recently completed 12-week pediatric study (TED-C13-003) included doses of 0.0125, 
0.025, and 0.05 mg/kg/day.  Data evaluated by the DSMB concluded that all 3 doses were safe 
and tolerable with trends of PN/IV volume reduction and advance in feeds observed.  Modeling 
and simulation data from previously completed studies suggested that pediatric patients are 
likely to require the same dose as used in adults and that the 0.05 mg/kg/day adult dose will be 
sufficient to provide similar blood levels in all subjects over 1 year of age.  
Selection and Timing of Dose for Each Subject
5.3.2
The study drug will be administered immediately after reconstitution by SC injection into 1 of 
the 4 quadrants of the abdomen or into either thigh or arm. The first SC injection should be 
administered under the supervision of the investigator or designee and the subject observed for 
hypersensitivity reactions for at least 4 hours during their initial dosing visit. The site of 
administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and 
recorded in the eCRF.  Detailed instructions for reconstitution and injection of the study drug 
can be found in the Injection Instructions. Each day, the injection site should be changed. For 
subjects with a stoma, the abdominal quadrant in which the stoma is situated should be 
avoided.
The subject should be dosed at approximately the same time each day, preferably in the 
morning. If a morning dose is forgotten, that day’s dose should be administered as soon as
possible, even if this is later in the day or evening. Consecutive doses should be separated by 
approximately 12 hours.  The time of the dose should be captured in the appropriate area in the 
subject diary (ie, Daily [yes/no], Morning [yes/no], and option for other).
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily study drug dosing regimen. Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, forgotten doses, lapse in study drug delivery, 
etc.  A single discontinuation period of study drug should not exceed 10 consecutive days. 
Dosage interruptions of study drug for a maximum of 21 days total during the entire 24 weeks 
are permissible.
Compliance with Dosing Regimens
5.3.3
Subject compliance with study drug dosing will be monitored by the sponsor /designee by 
counting and examining used and unused vials. In addition, compliance will be checked by 
site personnel at every visit by asking the subject or the subject’s parent or guardian if they 
have administered the study drug according to instructions.  If any doses have been missed, the 


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reason for missed dose should be documented in the subject’s source documentation including, 
as applicable, the eCRF.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
Prior and Concomitant Medications
5.3.4
The administration of all medications including concomitant medications must be recorded in 
the appropriate sections of the eCRF.
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, including those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
6.1
Evaluations for Safety and Tolerability
Safety variables will be assessed by the following evaluations, according to Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2, with opportunities for more 
frequent tests as clinically necessary.  Safety variables for the standard of care cohort are 
displayed in Table 6-3 and Table 6-4.

Adverse events, including GI symptoms.  A GI Symptom History Worksheet will be
completed daily during the screening period, prior to baseline.  GI symptoms will be 
recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject.

Physical examinations

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide (active treatment groups only).  Samples for antibody analysis 
will be drawn at baseline and at the EOT (Week 24) and EOS (Week 28) visits prior to the 


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administration of teduglutide and at least 14 hours after the previous dose.  One sample will 
be collected at the final visit 4 weeks after the EOT (EOS, Week 28).  Any subjects testing 
positive for antibodies specific to teduglutide (positive/specific antibodies) at Week 28 will 
have follow-up visits 3 and/or 6 months after the last dose of study drug to assess antibody 
status.

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (when available)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy), abdominal 
ultrasound, fecal occult blood testing, upper GI series with small bowel follow-through
Adverse Events
6.1.1
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study.
6.1.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily have to 
have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study drug administration

Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen


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Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form. This information will be 
shared with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.1.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs 
and SAEs will be recorded from the signing of the informed consent form (ICF) and, if 
applicable, the informed assent form, through the last study visit or the last study required 
procedure (including study visit).  SAEs will be monitored with a telephone call by the 
investigator, as necessary, for approximately 4 weeks after the last dose of study drug or until 
resolution or until the SAE is judged by the investigator to have stabilized.   
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  Also recorded are: 

Start and stop date and time

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities;
hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out)

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.1.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 


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
Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study
Serious Adverse Events
6.1.2
A serious event must be reported as described in Section 6.1.2.2 and recorded on the sponsor’s 
SAE Form.  An SAE requires expeditious handling to comply with regulatory requirements.  
Any SAEs occurring from the signing of the ICF through 30 days after the last dose of study 
drug will be captured and must be reported within 24 hours after the investigator is made aware 
of the event.
6.1.2.1
Serious Adverse Event Definition
An SAE is an AE that results in any of the following outcomes:

Death 

Is life-threatening.  A life-threatening AE is any AE that places the subject - in the 
investigator’s opinion - at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more serious form, might have caused 
death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.


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Scheduled and/or elective hospitalizations occurring under the following circumstances will 
not be defined as SAEs for this clinical study:

planned before entry into the clinical study

are for elective treatment of a condition unrelated to the studied indication or its treatment

occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

are part of the normal treatment or monitoring of the studied indication and not associated 
with any deterioration in condition
Any laboratory test result that meets the criteria for an SAE must also be recorded in an SAE 
report so that the sponsor/designee can collect additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
6.1.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
ICF/assent is signed through 30 days after the study drug is completed, the investigator must 
notify the sponsor.  The SAE information, including the time and date that the investigator 
became aware of the event, must be entered into the SAE reporting system and supplemental 
data (eg, medical records or lab values, if applicable) faxed to the sponsor. This ensures timely 
reporting of applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but a serious event criterion.  The SAE term is the medical event that led to the 
hospitalization.  Surgery is not an adverse event, but the event that required the subject to have 
surgery is the SAE term.  Death is not an SAE, but an outcome.
The sponsor/designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study 
drug.  Appropriate clinical, diagnostic, and laboratory measures should be performed to 
delineate the cause of the SAE in question and the results reported.  Follow-up for the SAE 
should occur at appropriate intervals until the event/laboratory abnormality:


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
Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the sponsor’s SAE 
form.  The investigator should make the causality assessment based on the information 
available at the time of the event.  The causality can be updated at a future date if additional 
information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect 
study product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related)

A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Study Reference Manual.
As required by International Conference of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Causality, while assessed, 
does not negate reporting requirements to the sponsor.  An AE, whether serious or not serious, 
is designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator Brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 


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expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.  As per 
regulatory guidance, if it is determined that there is an unanticipated signal, the NPS SMT will 
analyze the data and prepare a summary supporting the determination and interpretation of the 
findings.  The sponsor/designee will send this summary to the investigators with instructions to 
provide it to their IEC/IRB.
The investigator should also comply with the IEC/IRB procedures for reporting any other 
safety information (ie, autopsy reports).
NPS Pharmaceuticals (sponsor) will be responsible for submitting SUSAR reports to the 
appropriate health authorities.  These reports will be submitted within the expedited timeframe.  
All fatal and life-threatening SUSAR reports will be submitted by the sponsor or designee 
within 7 days of receipt (Day 0) of the initial report.  All other SUSAR reports will be 
submitted by Day 15 following the event.
Unblinding
6.1.3
If a subject becomes pregnant or seriously ill during the study, the blind should be broken only 
if knowledge of the study medication administered will affect treatment options available to the 
subject.  Before breaking the blind, the investigator should contact the NPS Medical Monitor 
for discussion on whether unblinding of the subject is warranted.  If warranted, the principal 
investigator or the sponsor or designee will place an unblinding call to the IVRS to receive 
treatment assignment information.  In the case of an extreme emergency and if the Medical 
Monitor is immediately unreachable, the investigator should break the blind through the IVRS. 
Please see Manual of Procedures for further details.
In the event prior authorization from the NPS Medical Monitor is not possible, the NPS 
Medical Monitor must be notified by telephone immediately, but no later than 24 hours 
following the unblinding of any subject for any reason.  A record should be kept of when the 
blind was broken, who broke it, and why.
Dose Interruption of Individual Subjects
6.1.4
Teduglutide administration for an individual subject may need to be stopped if the subject has 
an adverse event of special interest (see risks in table below) that is Grade 3 or higher as 
defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE).  This may occur if an event is attributable to study drug or a subject experiences an 
unexplained CTCAE Grade 3 or higher that is not reasonably related to the underlying disease 
process. The determination of length of the discontinuation, temporary or permanent, depends 
on the clinical situation. A treatment-emergent SAE of special interest that leads to study drug 


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interruption/discontinuation will be assigned a Grade 3 or 4, if applicable, by the investigator 
during the SAE reporting and follow-up process.
Investigators and the DSMB should be guided by the descriptions of Grade 3 and 4 events 
below, as they relate to identified risks associated with the administration of teduglutide.
Identified Risk
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent
intervention indicated
Intestinal Obstruction
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self-care activities of daily 
living; disabling
Life-threatening  consequences; urgent
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder 
perforation
Not Applicable
Life-threatening consequences; urgent
intervention indicated
Gallbladder 
obstruction
Symptomatic and severely altered 
gastrointestinal function; tube
feeding, total parenteral nutrition or
hospitalization indicated; nonemergent
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline Phosphatase 
increased
> 5.0 to 20.0 x Upper limit of normal
> 20.0 x Upper limit of normal
Blood bilirubin 
increased
> 3.0 to 10.0 x Upper limit of normal
> 10.0 x Upper limit of normal
Bile duct stenosis
Severely altered gastrointestinal
function; radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
Pancreatic duct 
stenosis
Severely altered gastrointestinal
function; tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated


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Identified Risk
Grade 3 Description
Grade 4 Description
Pancreas infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase 
increaseda
> 2.0 to 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal
Lipase increaseda
> 2.0 to 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; 
intervention indicated
Life-threatening consequences; urgent
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
aIn the setting of clinically acute and symptomatic pancreatitis 
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
Early Termination of the Clinical Study
6.1.5
The DSMB may recommend to stop the study if:

≥ 2 subjects being administered study drug develop the same CTCAE Grade 3 or

1 subject develops a CTCAE Grade 4 adverse event which is attributable to study drug 
or is not reasonably related to the underlying disease process
Laboratory Evaluations
6.1.6
The following laboratory parameters will be examined according to the Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2 (Table 6-3 and Table 6-4
for the standard of care cohort). While not all abnormal laboratory results would be considered 
clinically significant as determined by the investigator (ie, those that are associated with the 
disease state and were present at baseline), those that are determined to be a clinically 
significant change (ie, worsening) from baseline or known medical history will be considered 
adverse events.  All such abnormal laboratory values that are considered AEs must be recorded 
on the appropriate eCRF.  A result outside of the normal range may be repeated for 
confirmation.  Any laboratory test result that meets the criteria for an SAE (Section 6.1.2) must 
also be recorded in an SAE report so that the sponsor/designee can collect additional 
information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome.


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6.1.6.1
Safety Laboratory Tests and Procedures
Hematology
Serum Chemistry
Albumin
Alkaline phosphatase
ALT
Amylase
AST 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
Creatinine
Creatinine clearance
C-reactive protein 
Creatinine clearance (or Glomerular Filtration 
Rate [GFR])
Glucose
Gamma glutamyl transferase 
Lipase
Magnesium
Phosphate
Potassium
Sodium
Triglycerides
Uric acid
Urinalysis
Blood
Glucose
Leucocytes
Microscopic analysis
Specific gravity
pH and osmolality
Protein
Sodium
Pregnancy tests (females of child-bearing 
potential) – for active treatment group only
Procedures
Upper GI with contrast
Abdominal ultrasound
Colonoscopy/sigmoidoscopy (subjects 12 years and older or if fecal occult blood testing 
result is positive regardless of age without a documented or known etiology to explain the 
fecal positive results, ie, fissures, etc.).
Fecal occult blood testing
Hemoglobin
Hematocrit
Platelets
Red blood cell (RBC) count
White blood cell (WBC) count with differential


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6.1.6.2
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2).  If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the Laboratory Manual and will be 
collected from subjects from both active treatment and standard of care groups who participate 
in this study.
6.1.6.3
Antibodies to Teduglutide
Blood samples will be drawn only from the active treatment groups for the analysis of 
positive/specific antibodies to teduglutide according to the Schedules of Evaluations and 
Procedures (Table 6-1 and Table 6-2).
Physical Examinations
6.1.7
Complete and comprehensive physical examinations will be performed by a medically 
qualified person during the study to assess the subject’s physical status, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2) (Table 6-3 and Table 6-4
for the standard of care cohort).
Any significant finding at baseline should be included in the subject’s medical history eCRF, 
including known lab abnormalities such as decreased hemoglobin as part of anemia, history of 
elevated liver enzymes, etc. Any clinically significant changes from baseline (in the opinion of 
the investigator) noted during the physical examinations, whether or not these procedures are 
required by the protocol, should be recorded on the appropriate AE page of the eCRF. This 
will assist the sponsor/designee in collecting additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
Vital Signs and Body Weight 
6.1.8
Vital signs will be measured according to the Schedules of Evaluations and Procedures (Table 
6-1 and Table 6-2) (Table 6-3 and Table 6-4 for the standard of care cohort). Measurements 
will include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body 
temperature (oC/oF).  Body weight (kg), height (length [cm]), and head circumference (in cm
for subjects ≤ 36 months of age) will also be recorded on the eCRF.   Subjects should be 
weighed on the same scale at each study visit.
A weight Z-score will be calculated using the site-provided height and weight data collected at
each site visit.
Any clinically significant changes (ie, worsening) in the opinion of the investigator noted in 
vital signs assessments (ie, those that are associated with the disease state and were present at 
baseline), should be recorded on the appropriate AE page of the eCRF. This will assist the 


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 44 of 71
Final v2.0
22June 2015
sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome.,
Electrocardiograms
6.1.9
Twelve-lead electrocardiograms will be performed according to the Schedules of Evaluations 
and Procedures (Table 6-1 and Table 6-2; Table 6-3 and Table 6-4 for the standard of care 
cohort). The ECG tracing will be read by a local experienced physician. Results (normal, 
abnormal not clinically significant, and abnormal clinically significant with description of the 
finding) will be recorded on the eCRFs.
Any clinically significant changes (in the opinion of the investigator) noted during the ECG 
evaluations should be recorded on the appropriate AE page of the eCRF. This will assist the 
sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to study drug or other causes, any action taken, and 
outcome.
Gastrointestinal-specific Testing
6.1.10
Gastrointestinal testing will be done for all subjects in the active treatment group during the 
screening period, as needed.  Follow-up testing will be performed as necessary according to the 
guidelines noted below. See Table 6-1 and Table 6-2 for details and scheduling.
6.1.10.1
Upper Gastrointestinal Series with Contrast
An upper GI with small bowel follow through (UGI/SBFT) will be performed following the 
ingestion of barium contrast material.  Results from procedures performed within 6 months 
prior to Visit 1 will also be acceptable.
6.1.10.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to Visit 1 will also be acceptable.
6.1.10.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening and at the end of treatment. Subjects
with positive results for fecal occult blood will undergo a confirmatory 
colonoscopy/sigmoidoscopy.  If no known underlying documented etiology can be attributed to 
this finding, the results should be discussed with the NPS Medical Monitor.

Subjects with negative scope results may enroll in the study

Subjects with positive scope results who receive treatment may enroll in the study

Subjects with positive scope results who do not receive treatment will be excluded from the 
study


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 45 of 71
Final v2.0
22June 2015

In those subjects with positive results for fecal occult blood at the end of the study, the 
investigator will have to determine the cause for the finding and may perform an additional 
colonoscopy/sigmoidoscopy, if clinically warranted.
6.1.10.4
Colonoscopy/Sigmoidoscopy
Subjects age 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children under the age of 12 years will also undergo the procedure if they had a positive result 
on the fecal occult blood testing (see above). Results from procedures performed within 1 year
prior to Visit 1 will also be acceptable.
Concomitant Medication Assessment
6.1.11
The subject’s usage of concomitant medication will be assessed at each clinic visit and the 
details of any medications and changes in medication or dosage of medications will be 
recorded on the eCRF.
Nutritional Support Usage
6.1.12
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoints for this study include decreases in PN/IV volume reduction 
including a ≥ 20% or greater reduction up to 100% reduction (or complete weaning) in PN/IV 
support guided by clinical status.  A 20% decrease in PN/IV volume over 24 weeks is 
considered clinically meaningful to these PN/IV-dependent children who have plateaued in 
their ability to wean PN/IV and advance their oral/enteral feeds.  A decrease of this magnitude 
may translate to several hours a day for more age-appropriate activities or an opportunity to 
introduce an extra oral/enteral feed to encourage oral rehabilitation. A guidance for nutrition 
support adjustment to be followed for this protocol is provided in Appendix 1.
Evaluation of each subject’s nutritional support will be made during screening and at all visits 
at the study site.  The following information will be collected and can be used to evaluate each 
subject’s nutritional support:

Daily PN/IV support volume and calories

Daily enteral nutrition (EN) volume and calories (oral or tube feeds, including formula 
and specialized electrolyte solution)

Other nutritional intake (regular diet and drink)

72-hour urine output prior to each phone and site visit

72-hour stool output collected by volume, stool count, or stool consistency (when 
available)


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 46 of 71
Final v2.0
22June 2015
Diaries
6.1.13
Subjects or subjects’ parent or guardian will be required to complete the following:

Intake Diaries, completed daily, which will include:
o
PN/IV volume and calories (days per week, hours per day)
o
EN (formula and specialized electrolyte solutions) volume and calories (days 
per week, hours per day)
o
Other Nutrition (regular diet and drink) intake

Urine/Stool Output Diary, completed for 3 days (72 hours) just prior to the upcoming 
scheduled visit or telephone contact, consisting of :  
o
Collection of urine data:

For those who are toilet trained and NOT in diapers: urine volume 

For those who are NOT toilet trained and in diapers:  measure of urine 
volume/weight from urine-only diapers.  Volume will be calculated 
based on the formula:  1g (scale weight) = 1 ml or 1 cc.  

The subject/parent of subject will also be required to perform dipstick 
specific gravity tests on the first urine produced after the completion of 
the previous day’s/or overnight PN/IV support at the end of each day 
during the 72-hour collection periods.  
o
Collection of stool output data (including stool only and mixed urine/stool 
diapers):

For those who are toilet trained and NOT in diapers:  a stool count will 
be attempted.  

For those who are NOT toilet trained and in diapers: stool volume 
(including diapers that are stool only or mixed stool/urine).  Stool 
volume will be calculated based on the formula: 1 g (scale weight 
= 1 ml or 1 cc

Ostomy output will only be used if no stool is passed via the rectum 
(applicable to those subjects without a colon).  Ostomy output will be 
measured in cc or ml.   

In addition all subjects (toilet trained or not) will report on the average 
consistency (form) of the stool passed each day during the 72-hour 
period.  The subjects/parent of subject will use the Bristol Stool Form 
Scale (Lewis and Heaton, 1997) to make the assessment.  


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 47 of 71
Final v2.0
22June 2015
During the screening period, these diaries focusing on Intake and Output will be completed 
every day.
All diaries will be reviewed by the investigator or their designee at each visit or telephone 
contact to assess clinical status and opportunity for PN/IV changes and advance in feeds.  At 
each visit, the diaries will be reviewed for completeness and accuracy of the data.
Female Subjects of Child-bearing Potential
6.1.14
Any female subject in an active treatment group who has reached menarche must have a 
negative urine pregnancy test to enroll or continue in the study. Pregnancy tests will be 
performed at screening and at all study visits. Female subjects in the standard of care group
subjects will not be required to undergo pregnancy testing.  Sexually active females of child-
bearing potential (FOCBP) must use medically acceptable methods of birth control during and 
for 30 days after the treatment period (eg, true abstinence1, oral contraceptive pills, barrier 
methods with spermicide) in a manner such that the risk of failure is minimized.  The 
investigator will discuss these methods as well as their side effects with the subject.
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control 
during and for 30 days after the treatment.
In the event a subject becomes pregnant during the study, study drug will be discontinued and a 
Pregnancy Form will be completed to capture potential drug exposure during pregnancy.  The 
pregnancy will be reported within 24 hours of becoming aware of the condition.  The subject 
will be followed until an outcome is known (ie, normal delivery, abnormal delivery, 
spontaneous abortion (miscarriage), voluntary abortion, or therapeutic abortion).  If a pregnant 
subject also experiences an SAE, the SAE form will be completed and submitted within 
24 hours as discussed above.
In the event a female partner of a subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator and a supplemental SAE form will be completed to 
capture the event.
                                                
1 True abstinence:  Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception).


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 48 of 71
Final v2.0
22 June 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Review nutritional 
support usageb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Upper GI with small 
bowel follow 
throughd
X
Abdominal 
ultrasoundd
X
Fecal occult blood 
testingd,e
X
X
Colonoscopy/ 
Sigmoidoscopyd,e
X
Vital signs including 
body weight and head 
circumferencef
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
tests
X
X
(X)g
(X)g
(X)g
X
(X)g
(X)g
(X)g
X
(X)g
(X)g
(X)g
X


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 49 of 71
Final v2.0
22June 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Pregnancy testingh
X
X
X
X
X
X
X
X
X
Citrullinei
X
X
Antibodies to 
teduglutidej
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense GI 
Symptoms History 
Worksheet
X
Dispense Intake
Diaries
X
X
X
X
X
X
X
X
X
Dispense Urine/Stool 
Output Diary
X
X
X
X
X
X
X
X
X
Review GI 
Symptoms History 
Worksheet
X
Review Intake
Diariesk
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool
Output Diaryl
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomizationm
X
Drug dispensingn
X
X
X
X
X
X
X
X


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 50 of 71
Final v2.0
22June 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
eCRF = electronic case report form; EN = enteral feeds; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
c Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
d If it is necessary to perform the upper GI with small bowel follow-through, abdominal ultrasound, fecal occult blood testing, and/or colonoscopy/sigmoidoscopy, these tests can 
be performed at any time after signing of consent but must be completed and results available prior to the baseline visit. The results must be available and reviewed prior to the 
baseline visit.
e Colonoscopy/sigmoidoscopy will be conducted on subjects 12 years of age and older or subjects who have a positive fecal occult blood result without etiology to explain.  Results 
of colonoscopies done within the prior year may also be used.
f Head circumference is to be collected as appropriate (ie, up to 36 months of age).
g Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
h Female subjects of child-bearing potential only 
iCitrulline should be collected 2 to 4 hours post prandially, whenever possible.
j Antibody collection to be done prior to first study drug administration at study site.
k Intake Diaries will collect data on  PN/IV support volume, EN feeds (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
l Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
mRandomization and therapy assignment is to be completed prior to drug dispensing.
n The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at least 
4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF.


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 51 of 71
Final v2.0
22June 2015
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)j
Week 
28j
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Review nutritional 
support usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Fecal occult blood 
testing
Xk
Colonoscopy/ 
Sigmoidoscopy
(X)k
Vital signs including 
body weight and head 
circumferencec
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
tests
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Pregnancy testinge
X
X
X
X
X
Citrullinef
X
X
Antibodies to 
teduglutide
Xg
Xg
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Intake
Diaries
X
X
X
X


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 52 of 71
Final v2.0
22June 2015
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)j
Week 
28j
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Dispense Urine/Stool
Output Diary
X
X
X
X
Review Intake 
Diariesh
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryi
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and , EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
b Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
c Head circumference is to be collected as appropriate (ie, up to 36 months of age).
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Female subjects of child-bearing potential only
f Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
g EOT antibody blood draw is to be taken prior to the last dose of study drug, at least 14 hours following the previous dose of study drug. Subjects who test positive/specific for 
antibodies to teduglutide at the Week 28 visit will have follow-up blood draws for positive/specific antibodies to teduglutide at approximately 3 months following the last dose of 
study drug. If antibodies are still positive/specific they will be collected again approximately 6 months after the last dose of study drug.  Adverse events and PN/IV support will 
also be assessed at these visits.
hIntake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.    
iUrine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
j During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.
k If fecal/occult blood is positive without explanation, then a colonoscopy/sigmoidoscopy may be warranted.


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 53 of 71
Final v2.0
22June 2015
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Review Nutritional 
support usageb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs including 
body weight and head 
circumferenced
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests
X
X
(X)e
(X)e
(X)e
X
(X)e
X
(X)e
X
Citrullinef
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense GI 
Symptoms History 
Worksheet
X
Dispense Intake 
Diaries
X
X
X
X
X
X
X
X
X


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 54 of 71
Final v2.0
22June 2015
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Dispense Urine/Stool 
Output Diary
X
X
X
X
X
X
X
X
X
Review GI 
Symptoms History 
Worksheet
X
Review Intake 
Diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryh
X
X
X
X
X
X
X
X
EN = enteral feeds; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV and EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink
c Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment  provided in Appendix 1.
d Head circumference is to be collected as appropriate (ie, up to 36 months of age).
e Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
f Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
g Intake Diaries will collect data on  PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
h Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.


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Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Cohort
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)h
Week 
28h
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Nutritional support
usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signs including 
body weight and head 
circumferencec
X
X
X
X
X
Safety laboratory 
tests
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Citrullinee
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Intake 
Diaries
X
X
X
X
Dispense Urine/Stool 
Output Diary
X
X
X
X
Review Intake
Diariesf
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryh
X
X
X
X
X


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Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Cohort
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)h
Week 
28h
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
b Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
c Head circumference is to be collected as appropriate (ie, up to 36 months of age).
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
f Intake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
g Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
h During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.


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7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
eight-digit subject number, including subjects in the standard of care cohort.  The first four 
digits consist of the study site number.  The last four digits will be assigned sequentially 
starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s eCRF by the investigational 
site staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case 
of computerized source data, the investigator must provide the sponsor access to the subject 
files at each monitoring visit. To ensure that data has been entered correctly on the eCRF, they 
will be 100% source-data verified by a site monitor from the sponsor/designee, who will notify 
the investigator regarding any questions or discrepant data. The investigator or designee will 
be responsible for the timely recording of subject data into the eCRF. 
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents.
The investigator or designee will review all eCRFs (including the termination page after the 
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the 
appropriate vendor for assimilation into the database. Paper copies of laboratory reports and 
other non-eCRF data (eg, ECGs) will be signed and dated by the investigator and filed. 
Diaries will be used by the subjects’ parent or guardian to record study information, including
PN/IV support, enteral administration, regular diet/drink intake, urine output (as either 
collected or calculated volume), stool form, and urine specific gravity.  The time of the dose 
should be captured in the appropriate area in the subject diary (ie, Daily [yes/no], Morning 
[yes/no], and option for other). The subject diaries will provide the source documentation for 
the diary data that is to be recorded in the eCRF by the study staff.
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with eCRF guidelines outlining 
the specific procedures to use when entering the data into the clinical database. Data validation 
and edit checks will be conducted on the data. Any discrepancies will generate queries that 
must be resolved at the study site in a timely manner. 


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When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once 
the sponsor/designee acknowledges that all data are acceptable, the data will be declared a 
“clean file,” and the data will be frozen/locked.
A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the 
database, the database will be ready for statistical analysis by NPS or designee.
7.2
Record Retention
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines. These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject 
consent/assent documents, ECGs, photographs, and computer records) which are a result of the 
original observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report.
The clinical investigators will maintain copies of these essential documents for approximately 
10 years or as dictated by local regulatory requirements or until instructed in writing by the 
sponsor that records may be destroyed or forwarded to the sponsor.  In accordance with 
regulatory guidelines, these records will be available for inspection and copying if requested by 
a properly authorized employee of the FDA/EU Health Authorities.
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE
Detailed statistical analysis methods will be conducted as described in the Statistical Analysis 
Plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in 
the clinical study report (CSR). 
Due to the limited size of the study population descriptive statistics will be used with a goal of
summarizing the sample which discourages the use of inferential statistics.
Continuous variables, including those assessed on a discrete scale, will be summarized using
descriptive statistics including number of subjects, mean, median, standard deviation,
maximum, and minimum. For categorical variables, statistical summaries will include number
of subjects and percentages.
8.1
Demographic and Baseline Variables
Demographic and/or other Baseline variables obtained at the screening and baseline visit are 
listed below.  Abnormal findings of clinical significance (if any) will be recorded as past 
medical history.


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
Demography (including age, sex, and race)

Medical history

SBS history, including remnant anatomy

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Physical examination

Prior medications (medications used within 14 days prior to screening), including drug 
name, dose, route, reason for use, and therapy dates.  Medications used concomitantly will 
be recorded as concomitant medications.

Electrocardiogram (12-lead) variables will include general findings of
(normal/abnormal/abnormal, clinically significant).  The cause of any clinically significant 
ECG will be specified.

Laboratory test results:  Serum chemistries, hematology, and urinalysis

Citrulline levels

Presence of antibodies to teduglutide and titer level, if present (active treatment groups 
only)

Gastrointestinal imaging (upper GI with contrast, abdominal ultrasound, 
colonoscopy/sigmoidoscopy, fecal occult blood) (active treatment groups only)

Pregnancy testing for children of child-bearing potential (active treatment groups only)

Nutritional support (eg, PN/IV volume and calorie usage)

Data entered in the nutritional diaries
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and 
the number and percentage of subjects in specified categories by treatment group) will be 
presented, as appropriate, to summarize the demographic and baseline variables. 
Prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary with regard to drug class and drug name.  The number and 
percentage of subjects with specific prior medications will be summarized by treatment group. 
Medical history (including surgical history) will be coded using the current version of the
Medical Dictionary for Regulatory Activities (MedDRA).  The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term 
for each treatment group.


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8.2
Safety and Tolerability Variables
The safety and tolerability variables include:

Adverse events, including GI symptoms 

Physical examination

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose 

Antibodies to teduglutide

Oral/enteral feeding tolerance

Nutritional intake and urinary/fecal output (intake/output) (when available)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing and upper GI series with small bowel follow-through
Adverse events will be coded using the current version of MedDRA. Treatment emergent AEs 
will be summarized by system organ class and preferred term for each treatment group. The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and AEs that lead to death will be 
summarized by treatment group. AEs will also be summarized by treatment group with regard 
to intensity and relationship to study drug.  For AEs of special interest, the CTCAE grading 
system will be used as described in Section 6.1.4.
For laboratory tests, vital signs, body weight, ECG, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit for each treatment group.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment group.
8.3
Pharmacodynamic Variables
The following pharmacodynamic parameters will be measured:

20% to 100% parenteral support reduction at Week 24 (EOT)

100% reduction in PN/IV volume support  (any subjects who are able to completely wean 
off PN/IV support) compared to baseline at EOS

A  decrease in parenteral support (calories and volume)


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
An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 
(or EOT)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 
(or EOS)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 
(or EOT) compared to Week 28 (or EOS)

Urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months (as applicable) after EOT compared to baseline 
for those subjects who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of  response (PN/IV reduction and advance in enteral support) at each visit

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, the 
number and percentage of subjects in specified categories) will be calculated to summarize the 
absolute values and change from baseline at each scheduled visit for each treatment group.
8.4
Other Variables 
Other variables will be analyzed by treatment group including:

Subject disposition

Duration of study drug exposure

Subjects will be considered compliant if study drug was taken according to protocol and 
assigned treatment group for ≥ 80% of doses. Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment group.

The number and percentage of subjects who complete the study, are lost to follow up, or
discontinued from the study (including reason for study withdrawal) will be summarized by 
treatment group

The study drug dose by duration will be summarized by treatment group.


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8.5
Analysis Populations, Data Sets, and Time Points
Analysis Populations
8.5.1
The intent-to-treat (ITT) population is defined as any subjects who were randomized into the
study.  The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow-up.  The primary population analyzed 
for efficacy will be the ITT population.  An additional per-protocol population analysis will 
also be performed as secondary/sensitivity analysis.  Detailed per-protocol evaluable 
definitions will be documented in the SAP.
8.6
Statistical/Analytical Issues
Adjustments for Covariates
8.6.1
No Baseline stratification parameter is employed in this study.
Handling of Dropouts or Missing Data
8.6.2
All subjects randomized will be included in the analyses. Missing safety parameters will not be
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV 
volume will be detailed in the SAP.
Interim Analyses and Data Monitoring
8.6.3
No interim analyses are planned.
An independent DSMB will review the data on a routine basis and may have access to data 
from the study for safety assessment. Details of the roles and responsibilities of the DSMB 
members and the structure and scope of the DSMB meetings will be provided in a separate 
DSMB Charter.
Multiple Comparisons/Multiplicity
8.6.4
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be 
no adjustment for alpha level.
Use of an Efficacy Subset of Subjects
8.6.5
A per-protocol population will be analyzed for this study.
Examination of Subgroups
8.6.6
Because a small number of subjects are expected at each study site, data from all study sites 
will be pooled.
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.


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8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified 
in the final CSR.
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the current applicable ICH Guidelines, 
Good Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki 
and its amendments concerning medical research in humans.
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant 
material for the investigator to submit to the IRB for the protocol’s review and approval.  
Verification of the IEC/IRB approval of the protocol and the written consent/assent form will 
be forwarded to the sponsor/designee.
The investigator will inform the IEC/IRB of subsequent protocol amendments and any 
SUSARs if the NPS SMT has assessed it as an unanticipated problem.  Approval for protocol 
amendments will be transmitted in writing to the investigator.
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information, Informed Consent and Assent
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate.
The investigator (or designee) will explain to the subject and/or the subject’s parent or 
guardian the nature of the study, the action of the test product, and any risks and benefits.  The 
subject and/or subject’s parent or guardian will be informed that participation is voluntary and 
that the subject can be withdrawn from the study at any time without prejudice to their 
subsequent care.
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records.


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9.3
Subject Data Protection
All data provided to the sponsor/designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  The subject and/or the 
subjects’ parent or guardian should be informed in writing, that the subject’s data will be stored 
and analyzed in a computer, with confidentiality maintained in accordance with national and 
local legislation.  Study site-specific information must be added to the consent/assent as 
appropriate.
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 
access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, 
and a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed 
screening must also be maintained and be available for inspection.
9.4
Financial Disclosure
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” 
(February 2013) provides guidance to industry on its final rule on financial disclosure that 
became effective 02 February 1999 and was published as Title 21 Code of Federal Regulations 
Part 54.  This rule applies to all investigators participating in clinical studies to be submitted to 
the FDA in support of an application for market approval.  The financial disclosure statement 
must be updated if any relevant changes occur during the course of the study, again at the site 
close-out visit, and for 1 year after the completion of the study.
According to the guidance, financial arrangements that must be disclosed are defined as the 
following:

Compensation made to the investigator in which the value of compensation could be 
affected by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or the 
investigator’s institution to support activities of the investigator exclusive of the costs of 


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conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing research, 
compensation in the form of equipment or retainers for ongoing consultation, or honoraria) 
during the time the clinical investigator is carrying out the study and for 1 year after 
completion of the study
Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes 
the spouse and each dependent child of the investigator.  Participating investigators must 
provide this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA 
in support of a market application.  Companies must meet these financial disclosure 
requirements, and failure to do so may result in the refusal by the FDA to accept an application 
for market approval of the study drug.
9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the 
sponsor and the investigator.  All changes must be documented as signed protocol 
amendments, or as a revised protocol.  Changes to the protocol may require notification to or 
approval by the IEC/IRB and the regulatory authorities before implementation. Local 
regulatory requirements must be followed.  Instructions for reporting deviations from the 
protocol can be found in the Study Reference Manual.
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site.
9.6
Investigator Obligations
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address which 
matches the address on the FDA Form 1572

Financial disclosure statement for the principal investigator, and subinvestigators (listed on 
the FDA Form 1572).  An updated financial disclosure statement must be provided at the 


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study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study.

A copy of the original approval for conducting the study from the IEC/IRB. Renewals must 
be submitted at yearly intervals if the study is ongoing or as required by the institution.

A copy of the IEC/IRB-approved ICF/assent

IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and 
dated by the principal investigator for the study site.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be 
used by the sponsor, now and in the future, for presentation or publication at the sponsor’s 
discretion and/or for submission to regulatory agencies.  In addition, the sponsor reserves the 
right to review data from this study relative to the potential release of proprietary information 
30 days prior to submission to any publication or for any presentation.
9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all 
investigators for this study.  Roles, affiliations, and qualifications for the principal investigators 
will be included in the CSR appendices.  Where the signature of the principal investigator is 
required by regulatory authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative 
reasons at any time.


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10
REFERENCES
Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and 
intestinal transplantation. Gastroenterology. 2003;124:1111-1134.
Common Terminology Criteria for Adverse Events (CTCAE).  US Department of Health and 
Human Services, National Institutes of Health, National Cancer Institute. Version 4.03, 
June 14, 2010.
Duro D, Kamin D, Duggan C.  Overview of Pediatric Short Bowel Syndrome.  J Pediatr Gastro 
and Nutr. 2008;47:S33-S36.
Fleming CR, Witzke D, Beart RW Jr.  Catheter-related Complications in patients Receiving 
Home Parenteral Nutrition. Ann Surg. 1980 Nov;192(5):593-599.
Jeppesen PB, Langholz E, Mortensen PB.  Intestinal failure defined by measurements of 
intestinal energy and wet weight absorption.  Gut. 2000;46:701-706.
Lewis SJ and Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924.
O’Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel 
syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol 
Hepatol. 2006;4:6-10.
Messing B, Crenn P, Beau PBoutron-Ruault MC, Rambaud J-C, Matuchansky C.  Long-term 
survival and parenteral nutrition dependence in adult patients with the short bowel syndrome. 
Gastroenterology. 1999;117:1043-1050.


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APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY
Please consider the following clinical parameters identified as markers for adequate 
management of pediatric short bowel syndrome.  These parameters should also be considered 
for managing nutritional support (PN/IV and/or oral/enteral feeding) in terms of volume and 
calories during the treatment period.  

Considerations to adjust nutritional support in volume and calories will be made at all 
planned visits.

Maintaining growth (including weight and length and head circumference [for children up 
to 36 months of age]) by the subjects trending along their growth chart and adjusting 
calories/volumes to maintain the trend.

Other clinical evaluations
o
Normal serum electrolytes
o
Stable BUN/creatinine levels
o
Increase in the Volume Intake/Output ratio, including mixed output that can be 
collected

General consideration to possible clinical deterioration in SBS
o
Ability to maintain weight and growth velocity
o
Diarrhea (> 50 mL/kg/day with ostomy or >80mg/kg/day without ostomy)
o
Colic/vomiting frequency increased
o
Electrolyte changes or imbalance
o
Skin breakdown (“butt rot”)

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses.  Subjects should remain compliant with the nutritional support prescription 
in volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 72-hour Intake/Output measurement period prior to the subject’s scheduled 
visit, no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other oral fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.


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Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers


Pediatric Study TED-C14-006 – Amendment 1
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Final v2.0
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Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers


Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 71 of 71
Final v2.0
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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment

Prot_000.pdf: 
A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study
Investigating Two Doses of Teduglutide in Pediatric Subjects Aged 1 Year
Through 17 Years With Short Bowel Syndrome who are Dependent on 
Parenteral Support
Clinical Study Protocol TED-C14-006
Version 1.0
Phase 3
US IND# 058213 
US NDA# 203441
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ 07921
USA
ISSUED:
Original Protocol version 1.0:
12 March 2015


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SYNOPSIS
Protocol TED-C14-006
Title of Study: A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Aged 1 Year Through 17 Years 
With Short Bowel Syndrome who are Dependent on Parenteral Support
Protocol No: TED-C14-006
Phase of development: 3
Objectives: The objective of this clinical study is to evaluate the safety, tolerability, efficacy, 
and pharmacodynamic effects of teduglutide in pediatric subjects (aged 1 year through 17 years) 
with short bowel syndrome (SBS) who are dependent on parenteral support.
Methodology: This will be a double-blind, 2 arm study in which subjects will be randomized in 
a 1:1 ratio to receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks.  
Dosing regimens will be blinded to both investigators and subjects.  In addition, an attempt will 
be made to enroll subjects in a separate standard of care cohort, which will serve as an 
observational cohort for the 24-week treatment period. The subjects in the standard of care 
cohort will follow the same visit schedule as the randomized subjects.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. After screening, the 24-week treatment period will consist of site visits at baseline, 
weekly for the first 2 weeks, and then every other week for the next 8 weeks (through Week 12).  
From Weeks 13 to 24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  
Telephone contacts will be made on all other weeks during the treatment period.  A final visit 
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone contact 
will be made during the interim weeks from EOT to end of study (EOS).
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input and 
provided in the protocol) for decisions regarding parenteral nutrition/intravenous (PN/IV)
support reduction and advances in enteral feeds based on weight gain, urine, and stool output in 
the setting of clinical stability.
Number of Subjects:  Approximately 20 teduglutide-naïve subjects (at least 10 subjects per 
treatment arm) will be enrolled at approximately 10 to 20 investigational sites globally.


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In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in a standard of 
care cohort (who will not be treated with teduglutide) to serve as an observational cohort.
Duration of Study:  There will be, at a minimum, a 2-week screening period followed by 
24 weeks of on-treatment study visits. There will be one final scheduled visit at Week 28, 
4 weeks after the EOT (Week 24).  
The proposed duration of the clinical phase is from July 2015 through December 2016.  The start 
of the clinical phase is defined as first subject screened.  The end of the clinical phase is defined 
as the last visit of the last subject.
Diagnosis and main criteria for inclusion: Male and female children and adolescents, aged 
1 year through 17 years, who meet the following inclusion and exclusion criteria will be enrolled 
in the study.
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) for at least 12 months prior 
to screening
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce PN/IV 
support, usually associated with minimal or no advance in enteral feeds [ie, 10% or less 
change in PN or advance in feeds])  prior to screening, as assessed by the investigator
6. Female subjects of child-bearing potential must use medically acceptable methods of birth 
control during and for 30 days after the treatment period.
Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens (ie, 
subjects with oral aversion)


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2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA 
abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support, prior to screening
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done
within 6 months prior to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase IV (DPP-IV) inhibitors within 3 months
prior to screening


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15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, 
antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements 
within 1 month prior to the screening visit (up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, are 
allowed)
19. Body weight < 10 kg at screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by any of the below laboratory test results during the screening period:
a.
Serum creatinine ≥ 2 x ULN 
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of creatinine clearance (CrCl) 
< 50 mL/min who, to verify, then will be required to have > 50 mL/min to participate in 
the study.  If a CrCl cannot be measured, an estimated glomerular filtration rate (eGFR) 
may be calculated.
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant active, untreated pancreatic or biliary disease


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24. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.  Examples of potential disease states/illnesses that may be excluded are listed 
in the table below.
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Tufting or autoimmune enteropathy or microvillous 
inclusion disease

Untreated pre-malignant or malignant change in upper 
GI, biopsy or polypectomy 

Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, 
Turcot syndrome, Juvenile polyposis syndrome, 
Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada 
syndrome, Eversmeyerous polypius)
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency).
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system)
Test Product, Dose, and Mode of Administration:
After randomization, daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will 
be administered to the subjects in the active treatment cohorts.  The dose calculation will be 
based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose will be 
made during the study period, unless discussed with the NPS medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily in the morning into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm.


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Reference Therapy, Dose and Mode of Administration:
Not applicable.
Criteria for Evaluation:
Safety and tolerability:
Safety and tolerability will be assessed by evaluation of:

Adverse events, including GI symptoms

Physical examinations

Vital signs, including body weight, heart rate, and blood pressure

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide.  Samples for antibody analysis will be drawn at baseline and at the 
EOT (Week 24) and EOS (Week 28) visits prior to the administration of teduglutide and at 
least 14 hours after the previous dose.  One sample will be collected at the final visit 4 weeks 
after the EOT (EOS, Week 28).  Any subjects testing positive for antibodies specific to 
teduglutide (positive/specific antibodies) at Week 28 will have follow-up visits 3 and/or 
6 months after the last dose of study drug to assess antibody status.

Maintaining weight, head circumference, and length trends on growth charts

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (where collection is possible)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing upper GI series with small bowel follow-through
Pharmacodynamics:
The primary pharmacodynamic (PD) parameter is parenteral support reduction of 20% to 100% 
at 24 weeks (or EOT) compared to baseline.
Analysis of additional PD endpoints will include:

100% reduction in PN/IV volume support (any subjects who are able to completely wean off
PN/IV support) compared to baseline at EOS

A decrease in parenteral support (calories and volume)

An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT)


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
Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 (or EOS)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT) 
compared to Week 28 (or EOS)

Change in urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months after EOT compared to baseline for those subjects 
who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of  response (PN/IV reduction and advance in enteral support) at each visit.

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks.
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input) for 
decisions regarding PN/IV support reduction and advances in enteral feeds based on weight gain, 
urine, and stool output in the setting of clinical stability.
Safety and tolerability will be evaluated by a data safety monitoring board (DSMB) every 
3 months during the active study period.  The DSMB review will include all cumulative safety 
data (ie, adverse events, laboratory assessments, physical examinations, etc.) from study 
assessments through each cutoff period including any reasons for dose adjustment and 
discontinuations.
Statistical methods:
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample. As such, no claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, 
and minimum. For categorical variables, statistical summaries will include number of subjects 
and percentages.
Demographics and baseline:
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate.


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Efficacy/Pharmacodynamics:
Efficacy/pharmacodynamics data including reduction in parenteral support, increase in enteral  
nutritional tolerance, change in PN/IV support, citrulline, enteral support, urine output, weight,
height, hours per day or days per week of PN/IV support, and time to PN/IV reduction and 
advance in enteral support will be summarized by visit and time point.
Safety:
Safety data including clinical laboratory tests, physical examinations, concomitant medications, 
electrocardiogram monitoring, and vital signs assessments will be summarized by visit and time 
point.  Adverse events will also be collected and summarized, including Grade 3 and 4 adverse 
events of special interest, based on Common Terminology Criteria for Adverse Events (CTCAE) 
criteria.  Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable.  Frequency counts will be compiled for classification of 
qualitative safety data.


Pe diatric St u d y T E D -C 1 4 - 0 0 6
Te d u gl uti de (r D N A ori gi n) f or i njecti o n
Pa ge 1 0 of 6 8
Fi nal v 1. 0
1 2 Marc h 2 0 1 5
SI G N A T U R E P A G E
Pr ot oc ol T E D -C 1 4- 0 0 6
Re vie we d a n d A p pr o ve d:
 M S
, Precli nical & 
O perati o ns
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
, R P h, P h D
, Gl o bal P har mac o vi gila nce 
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
, P h D
, Bi o metrics a n d Data 
Ma na ge me nt
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
, B S, R A C 
, Re g ulat or y Affairs 
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y)
 M D
, Cli nical 
De vel o p me nt 
N P S P har mace uticals, I nc.
5 5 0 Hills Dri ve, 3 r d Fl o or
Be d mi nster, NJ 0 7 9 2 1
Si g nat ure
Date 
( D D M M M
Y Y Y Y )
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol TED-C14-006
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics 
Committee (IEC) for the study protocol and any amendments thereof, written informed consent 
or updates thereof, subject recruitment procedures (eg, advertisements), and any other written 
information to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement 
from the sponsor and review and documented approval from the IRB/IEC, except to eliminate 
an immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data 
sheets, correspondence records, and signed subject consent/assent documents for at least 
5 years or until instructed in writing by the sponsor that records may be destroyed or forwarded 
to the sponsor.  
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)


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TABLE OF CONTENTS
SYNOPSIS....................................................................................................................................2
SIGNATURE PAGE..................................................................................................................10
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE................................11
LIST OF IN-TEXT TABLES AND FIGURES.......................................................................14
1
INTRODUCTION................................................................................................................16
1.1
Background ...................................................................................................................16
1.2
Rationale for the Clinical Study....................................................................................18
1.3
Rationale for Study Design ...........................................................................................19
2
OBJECTIVES ......................................................................................................................21
2.1
Primary Objective .........................................................................................................21
3
STUDY DESIGN..................................................................................................................21
3.1
Overall Design and Control Methods............................................................................21
3.2
Study Duration ..............................................................................................................24
4
SUBJECT SELECTION AND PARTICIPATION ..........................................................24
4.1
Number of Subjects.......................................................................................................24
4.2
Inclusion Criteria...........................................................................................................24
4.3
Exclusion Criteria..........................................................................................................25
4.4
Subject Withdrawal Criteria..........................................................................................28
4.5
Data Safety Monitoring Board ......................................................................................29
5
TREATMENTS AND TREATMENT PLAN ...................................................................29
5.1
Treatment Administered................................................................................................29
Identification of Investigational Product ...............................................................29
5.1.1
Packaging and Labeling.........................................................................................30
5.1.2
Storage, Accountability, and Stability ...................................................................30
5.1.3
5.2
Methods of Assigning Subjects to Treatment Groups ..................................................31
5.3
Dose Regimens..............................................................................................................31
Selection of Doses in Study ...................................................................................32
5.3.1
Selection and Timing of Dose for Each Subject....................................................32
5.3.2
Compliance with Dosing Regimens.......................................................................32
5.3.3
Prior and Concomitant Medications ......................................................................33
5.3.4
6
STUDY EVALUATIONS AND PROCEDURES .............................................................33
6.1
Evaluations for Safety and Tolerability ........................................................................33


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Adverse Events ......................................................................................................34
6.1.1
Serious Adverse Events .........................................................................................36
6.1.2
Unblinding .............................................................................................................39
6.1.3
Dose Interruption of Individual Subjects...............................................................39
6.1.4
Early Termination of the Clinical Study................................................................41
6.1.5
Laboratory Evaluations..........................................................................................41
6.1.6
Physical Examinations...........................................................................................43
6.1.7
Vital Signs and Body Weight ................................................................................43
6.1.8
Electrocardiograms ................................................................................................43
6.1.9
Gastrointestinal-specific Testing ...........................................................................44
6.1.10
Concomitant Medication Assessment....................................................................45
6.1.11
Nutritional Support Usage .....................................................................................45
6.1.12
Diaries....................................................................................................................45
6.1.13
Female Subjects of Child-bearing Potential ..........................................................45
6.1.14
7
DATA MANAGEMENT.....................................................................................................55
7.1
Data Collection..............................................................................................................55
7.2
Record Retention...........................................................................................................56
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE .............................................56
8.1
Demographic and Baseline Variables ...........................................................................56
8.2
Safety and Tolerability Variables..................................................................................57
8.3
Pharmacodynamic Variables.........................................................................................58
8.4
Other Variables .............................................................................................................59
8.5
Analysis Populations, Data Sets, and Time Points........................................................59
8.6
Analysis Populations.....................................................................................................59
8.7
Statistical/Analytical Issues...........................................................................................60
Adjustments for Covariates....................................................................................60
8.7.1
Handling of Dropouts or Missing Data..................................................................60
8.7.2
Interim Analyses and Data Monitoring..................................................................60
8.7.3
Multiple Comparisons/Multiplicity .......................................................................60
8.7.4
Use of an Efficacy Subset of Subjects ...................................................................60
8.7.5
Examination of Subgroups.....................................................................................60
8.7.6
8.8
Determination of Sample Size.......................................................................................60
8.9
Changes to Planned Statistical Analyses.......................................................................60
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ............................................61


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9.1
Declaration of Helsinki and Ethical Review.................................................................61
9.2
Subject Information, Informed Consent and Assent.....................................................61
9.3
Subject Data Protection.................................................................................................61
9.4
Financial Disclosure......................................................................................................62
9.5
Changes to the Protocol.................................................................................................63
9.6
Investigator Obligations................................................................................................63
9.7
Confidentiality/Publication of the Study.......................................................................64
9.8
Selection of a Primary Principal Investigator ...............................................................64
9.9
Study Termination.........................................................................................................64
10 REFERENCES.....................................................................................................................65
APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY....................................................................................66
LIST OF IN-TEXT TABLES AND FIGURES
Table 4-1 
Excluded Diseases and Illnesses............................................................................27
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active 
Treatment Groups ..................................................................................................47
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment 
Groups....................................................................................................................50
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard 
of Care Cohort........................................................................................................52
Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care 
Cohort ....................................................................................................................54
Figure 3-1 
Study Diagram .......................................................................................................23


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CrCl
Creatinine Clearance
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
EOS
End of study
EOT
End of treatment
FDA
Food and Drug Administration
FOCBP
Females of child-bearing potential
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP-2
Glucagon-like peptide 2
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
NOAEL
No Observed Adverse Effect Level
NPS
NPS Pharmaceuticals, Inc.
PD
Pharmacodynamic
PK
Pharmacokinetic
PN
Parenteral nutrition
QD
Once daily
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SMT
Safety Management Team 
SUSAR
Suspected, unexpected, serious, adverse reaction
ULN
Upper limit of normal
WMA
World Medical Association


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1
INTRODUCTION
1.1
Background
Compound
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like 
peptide-2 (GLP-2) that regulates the functional and structural integrity of the cells lining the 
gastrointestinal (GI) tract.  Teduglutide is a 33-amino acid peptide that differs from native 
GLP-2 in the substitution of glycine for alanine at the second position at the N-terminus.  As a 
result, teduglutide demonstrates resistance to degradation by dipeptidyl peptidase 4 and 
therefore maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to 
the native peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in 
animal studies and previous human clinical trials to increase villus height and crypt depth in 
the intestinal epithelium, thereby increasing the absorptive surface area of the intestines.  The 
European Commission granted a centralised marketing authorization valid throughout the 
European Union for teduglutide (Revestive™) on 30 August 2012 and a New Drug Application 
(NDA) for teduglutide (Gattex®) was approved by the US Food and Drug Administration 
(FDA) on 21 December 2012 for the treatment of adult patients with Short Bowel Syndrome 
(SBS) who are dependent on parenteral support.
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes 
to the label which provide for long-term use of Gattex.
Preclinical Studies
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in Cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated 
rats. Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those 
observed in studies conducted using adult animals (rodents and primates). No treatment-related 
malignant tumors were noted in a 2-year carcinogenicity study in rats; treatment-related 
changes included benign tumors of the bile duct epithelium and adenomas of the jejunal 
mucosa in males treated at 35 mg/kg/day. The results from a second 2-year carcinogenicity 


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study in Crl:CD1(ICR) mice were provided to the agency in a NDA Supplement which 
received agency approval on 26 June 2014. Subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day 
(about 20, 70, and 250 times the recommended daily human dose of 0.05 mg/kg, respectively) 
were studied and adenocarcinoma in the jejunum was present in males given a dose of 
12.5 mg/kg/day.
Clinical Studies
Two completed studies (CL0600-004 and CL0600-005) evaluated safety and tolerability of 
daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on 
parenteral nutrition/intravenous fluids (PN/IV).  Study CL0600-004, a double-blind, placebo-
controlled study  in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed 
the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV.  There was a 
statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study.  The reduction of PN/IV volume was 
similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, assessed the 
long-term safety of teduglutide and the proportion of responders in the CL0600-004 study that 
maintained their response at the end of a further 28 weeks of treatment.  The extension study 
also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day dose, 
teduglutide treatment in the initial phase 3 study, which included significant reductions in 
PN/IV.  There was 75% of the subjects who previously responded to teduglutide treatment in 
Study CL0600-004 who maintained this response or experienced further improved benefit 
from teduglutide treatment.  More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. The majority of adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which 
subjects were randomized to either teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio.  The 
first stage of the study included a screening and optimization period and a stabilization period 
that demonstrated stable administration of PN/IV volume for a minimum of 4 weeks up to a 
maximum of 8 weeks.  The second stage was a dosing period of 24 weeks.  Subjects on 
0.05 mg/kg/day teduglutide achieved a higher responder rate (defined as a 20% to 100% 
reduction from baseline in PN/IV volume at Weeks 20 and 24) than the placebo-treated 
subjects (27/43 subjects, 62.8% and 13/43 subjects, 30.2%, respectively).  This difference was 
clinically and statistically significant in both the Intent-to-Treat (ITT) (p = 0.002) and Per 
Protocol  (p < 0.001) populations.  Generally, the incidence of treatment-emergent AEs 
(TEAEs) were distributed similarly across all treatment groups.  The TEAEs with a higher 
incidence in the teduglutide group were mainly of GI origin.  A long-term, open-label 


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extension study (CL0600-021) assessed safety and efficacy for up to 24 additional months 
(ie, up to 30 months of exposure for subjects who received teduglutide in Study CL0600-020).
Overall, 30 of 43 subjects who received teduglutide in Study CL0600-020 and entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide.  Of these,
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a 
PN/IV volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative 
to baseline prior to exposure to teduglutide at the beginning of Study CL0600-021.  PN/IV 
frequency was reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 
30 months of treatment.  Of the 39 subjects who entered Study CL0600-021 after receiving 
placebo in Study CL0600-020, 29 completed 24 months of treatment with teduglutide.  The 
mean reduction in PN/IV volume was 3.11 L/week from baseline at the start of 
Study CL0600-021 (an additional 28% reduction).  Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support.  Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide.  The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support
1.2
Rationale for the Clinical Study
Short bowel syndrome is a rare disorder.  At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, 
market research performed in 2012 indicates that the true addressable adult patient population 
is between 3000 to 5000 patients which qualifies SBS as an ultra-orphan condition.  In addition 
to adult SBS patients, it is estimated that, at most, there are a few hundred children 1 year and 
older with SBS.  As a result of congenital abnormalities or severe intestinal disease in children 
and adolescents, major surgical resections of the intestine can become necessary, resulting in 
SBS.  Common causes of SBS in children include necrotizing enterocolitis (NEC) in infants, 
midgut volvulus (volvulus), intestinal atresia, and gastroschisis (Duro et al, 2008).  SBS in 
older children may stem from the same etiologies as in adults (ie, Crohn’s disease, trauma, 
cancer). As the characteristics are similar to the adult disease, pediatric SBS is defined as a 
disease where there is diminished absorptive capacity for fluids and/or nutrients, sometimes 
requiring a dependence on PN/IV support to maintain energy and clinical status.
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able 
to adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al, 1999; Jeppesen
et al, 2000), other patients with intestinal failure depend on PN/IV for nutritional support 
(Fleming et al, 1980; O’Keefe et al, 2006; Buchman et al, 2003).  Although PN/IV can provide 
this nutritional support for patients with compromised fluid and nutritional status, it is also 


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associated with serious complications, such as infections and liver damage.  The risk for these 
effects increases over time with longer duration of PN/IV support.
The same treatment options are currently available for children and the same associated risks 
prevail.  Treatment of both pediatric and adult patients is focused on achieving adequate 
intestinal absorption to allow for minimization or discontinuation of PN/IV support.  This is 
achieved far more successfully in infants who develop SBS during the neonatal period and 
frequently come off their PN/IV requirements within 6 to 12 months of their initial surgical 
insult such that they achieve enteral autonomy by age 1 year.  Recent data suggest that up to 
85% of patients achieve spontaneous adaptation by age 1 year.
In the US, data from the Organ Procurement and Transplant Network reflect improvement in 
the medical and non-transplant surgical management of intestinal failure after 2010.  The peak
number of pediatric intestinal transplants in North America occurred between 2004 to 2009 (up 
to 111 in 2007) with falling levels from about 2010 onward (52 to 62 transplants annually). In 
2012, 56 transplants took place and in 2013, 36 transplants took place.
This study proposes to investigate the safe and approriate use of teduglutide in the pediatric 
population for up to 24 weeks for the purpose of providing longer-term data in regard to safety 
and potential to explore further efficacy including PN reduction and ability to completely wean 
off parenteral support.  This protocol was developed with input from expert advisors from 
intestinal rehabilitation centers who offered advice on the most appropriate use of teduglutide
in pediatric patients.  The aim of teduglutide treatment is to increase absorptive capacity in 
order to yield decreases in parenteral support.  The experts anticipated that there would be 
several direct benefits from decreased parenteral support, including less exposure to PN/IV 
constituents, less central line manipulation with lower risk of infection, and more time to focus 
on oral rehabilitation strategies.
1.3
Rationale for Study Design 
Dose
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily (QD) in adult SBS subjects requiring PN.  The recommended clinical 
dosage for the adult SBS patient population is 0.05 mg/kg QD.  Population pharmacokinetic 
(PK) modeling and simulations were conducted to determine the dose to be used in pediatric 
subjects.  Subcutaneous dosing of teduglutide in pediatric patients with SBS was based on data 
collected in 5 adult Phase 1 studies and 3 adult Phases 2/3 studies, as well as an adult 
population PK meta-analysis. The PK results from the adult SBS clinical program also were 
used to model and simulate PK parameters in pediatric SBS patients to provide guidance on 
pediatric dosing for teduglutide.  An ongoing 12 week pediatric study (TED-C13-003) includes 
doses of 0.0125, 0.025, and 0.05 mg/kg/day.  Interim data evaluated by the DSMB has 
concluded that all three doses are safe and tolerable with trends of PN/IV volume reduction 


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and advance in feeds observed. Modeling and simulation data from previously completed
studies suggested that pediatric patients are likely to require the same dose as used in adults 
and that the 0.05 mg/kg/day adult dose will be sufficient to provide similar blood levels in all 
subjects over 1 year of age.  To further explore additional safety and efficacy, a 24 week study 
is currently proposed.
Treatment Duration/Design
Safety, tolerability and pharmacodynamic measures over a 24-week period will be the main 
outcomes of the current study.  The main PD effect of teduglutide to be measured in children 
will include a decrease in the volume of PN/IV requirement.  Measurement of a decrease in 
PN/IV volume requirements was the primary endpoint in the adult SBS clinical studies and can 
be used in children with SBS who are dependent on PN/IV support.
A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of 24 weeks of treatment was used as the primary endpoint in the adult clinical 
development program during pivitol Phase 3 studies and will be the same endpoint used in the 
current pediatric study.
The current study will employ a double-blind, 2 arm design with treatment of either 
0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for up to 24 weeks.  The 24-week treatment 
period will provide further information on longer term safety and additional efficacy including 
complete weaning of treatment beyond the 12-week period previously evaluated in the first 
pediatric study.
Thus, this study is designed to provide further information on the safety and PD profile of 
teduglutide in pediatric subjects treated for up to 24 weeks.
Subject Population
The current significant unmet medical need is for patients over age 1 year who remain 
dependent on parenteral support.  These patients reach a plateau in their ability to advance 
oral/enteral feeds or decrease PN/IV support and are not expected to achieve spontaneous 
adaptation.  The subjects in the study will be children whose intestines have not reached full 
enteral adaptation after 12 months of PN/IV treatment and whose PN/IV requirement had been 
stable without any clinically meaningful or substantial reduction in parenteral support for the 
3 months prior to study enrollment.
Therefore, this study will be performed in PN/IV-dependent children with SBS aged 1 year
through 17 years who have demonstrated that they have reached a plateau with regard to their 
ability to fully continue intestinal adaptation in terms of their ability to advance feeds and 
subsequently reduce their needs for parenteral support.  Stability for these subjects will be
defined as at least 3 months in which patients still are requiring at least 30% of their volume 
and/or calories from PN/IV with no clinically meaningful change in advances in their enteral 
feeds (specialized nutrition such as formula via mouth or tube).


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This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000).
Gastrointestinal Screening Measures
Pediatric SBS patients who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for obstruction due to history of surgery. Teduglutide has 
been found to have a targeted intenstinotrophic effect on the GI tract and areas of special 
interest in regards to safety have been identified throughout the development program. Taken 
into account the patient population and the pharmacologic effect of teduglutide, GI-specific 
screening tests which are usually part of the routine care of these subjects will be performed to 
ensure safety. These include: abdominal ultrasound, upper GI series with contrast, fecal 
occult blood testing, and, if deemed clinically relevant, colonoscopy/sigmoidoscopy.
General Guidance for Nutritional Support Adjustment
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status, which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoint for this study is a ≥20% reduction in PN/IV support guided 
by clinical status. A suggested guidance for nutrition support adjustment is provided in 
Appendix 1 and should be followed by all sites to ensure uniform care across study sites and 
particpants.
2
OBJECTIVES
2.1
Primary Objective
The objective of this clinical study is to evaluate the safety, tolerability, efficacy, and 
pharmacodynamic effects of teduglutide in pediatric subjects (aged 1 year through 17 years) 
with SBS who are dependent on parenteral support.
See Section 8.2 and Section 8.3 for further details of the variables being measured.
3
STUDY DESIGN
3.1
Overall Design and Control Methods
This will be a double-blind, 2 arm study in which subjects will be randomized in a 1:1 ratio to 
receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks.  Dosing 
regimens will be blinded to both investigators and subjects.  In addition, an attempt will be 
made to enroll subjects in a separate standard of care cohort, which will serve as an 
observational cohort for the 24-week treatment period.  The subjects in the standard of care 
cohort will follow the same visit schedule as the randomized subjects.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 


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parameters.  After screening, the 24-week treatment period will consist of visits at baseline, 
weekly for the first 2 weeks, and then every other week through Week 12.  From Weeks 13 to 
24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  Telephone contacts will 
be made on all other weeks during the treatment period in order to monitor safety.  A final visit
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone 
contact will be made during the interim weeks from EOT to end of study (EOS).  If necessary, 
unscheduled visits can be arranged in place of the telephone contacts.  Schedules of study 
parameters are displayed in Table 6-1 and Table 6-2.
To maintain consistency across all centers, sites and subjects (treated and standard of care) 
must follow the nutritional support adjustment guidelines (developed with SBS expert input 
and provided in Appendix 1) for decisions regarding PN/IV support reduction and advances in 
enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
At the conclusion of the follow-up period (Week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post
EOT for another antibody sample. If the subjects continued to have positive/specific antibodies
at 3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. At all follow-up visits, an assessment 
of the subject’s current PN/IV support and an adverse event determination will be conducted.
Safety and tolerability results will be evaluated by a DSMB every 3 months during the active 
study period (date of the first subject’s first dose to date of the last subject’s last dose).  The 
DSMB review will include all cumulative safety data (ie, adverse events, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period 
including any reasons for dose adjustment and discontinuations.
A schematic representation of the study design is displayed in Figure 3-1.


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Figure 3-1
Study Diagram
Note:  The Standard of Care cohort will follow the same visit schedule as the active treatment groups.
10
Baseline
Visit
(Randomization)
4
8
18
21
12
15
24
28
6
2
Site Visit
Telephone Visit
3
1
10
4
8
18
21
12
15
24
28
6
2
3
1
Screening
Visit
Screening
Period 
(Minimum 2 weeks)
On-Treatment
Period (Weeks)
Off-
Treatment
Period
(Weeks)
Dose A
Dose B


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3.2
Study Duration
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment.  
There will be one final scheduled visit 4 weeks after the end of treatment. Those subjects who 
test positive for teduglutide-specific antibodies at the 4-week follow up visit (Week 28) will be 
asked to return for additional follow-up visit(s) as described in Section 6.1 in order to 
determine their antibody status.
The proposed duration of the clinical phase is from July 2015 through December 2016.  The 
start of the clinical phase is defined as first subject screened.  The end of the clinical phase is 
defined as the last visit of the last subject.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects
Approximately 20 teduglutide-naïve subjects (minimum 10 subjects per treatment arm) and up
to 8 teduglutide-naïve subjects in the standard of care cohort will be enrolled at approximately
10 to 20 investigational sites.
4.2
Inclusion Criteria
Male and female children and adolescents, aged 1 year through 17 years, who meet the 
following inclusion criteria will be enrolled in the study.
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject prior to any study-related procedures 
(as deemed appropriate by the Ethics Committee/Institutional Review Board)
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) for at least 12 months 
prior to screening
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce 
PN/IV support, usually associated with minimal or no advance in enteral feeds [ie, 10% or 
less change in PN or advance in feeds])  prior to screening, as assessed by the investigator
6. Sexually active female subjects of child-bearing potential must use medically acceptable 
methods of birth control during and for 30 days after the treatment period


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4.3
Exclusion Criteria
Subjects who meet any of the following exclusion criteria at baseline are not eligible for 
enrollment into the study:
1. Subjects who are not expected to be able to advance oral or tube feeding regimens (ie, 
subjects with oral aversion)
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support prior to screening
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including 
resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and 
surgically resected cancer
10. Pregnant or lactating female subjects
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)


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13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase IV (DPP-IV) inhibitors within 3 months 
prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy (eg, 
antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) 
within 3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements
within 1 month prior to the screening visit(up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, 
are allowed)
19. Body weight < 10 kg at the screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any 
of the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
20. Signs of known continuous active or unstable, clinically significant renal dysfunction
shown by any of the below laboratory test results during the screening period:
a.
Serum creatinine ≥ 2 x ULN
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of creatinine clearance (CrCl) 
< 50 mL/min who, to verify, then will be required to have > 50 mL/min to participate in 


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the study.  If a CrCl cannot be measured, an estimated glomerular filtration rate (eGFR) 
may be calculated.
21. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to 
the study visit schedule and other protocol requirements
22. Unstable, clinically significant active, untreated pancreatic or biliary disease
23. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of 
the study results.  Examples of potential disease states/illnesses that may be excluded are 
listed in the table below.
Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS
Ongoing radiation enteritis 
Celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal 
Active IBD which required chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months
IBD that required chronic systemic immunosuppressant 
therapy for symptom control 
Tufting or autoimmune enteropathy or microvillous 
inclusion disease
Untreated pre-malignant or malignant change in upper GI, 
biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, Turcot 
syndrome, Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome, Eversmeyerous 
polypius)
Intestinal or other major surgery scheduled within the time 
frame of the study
Chronic active pancreatitis 
Cholecystitis
Immune
Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)


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Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, infectious, 
endocrine, hepatic, or central nervous system)
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
NPS Medical Monitor prior to the patient discontinuing/withdrawing.  A subject may (but not 
automatically) be withdrawn from the study under any of the following circumstances:

Withdrawal of informed consent and/or assent when applicable

If, in the opinion of the investigator, Institutional Review Board (IRB) or NPS, it is no 
longer in the subject’s best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any criterion for exclusion

Lack of compliance with study procedures or study drug administration, as determined by 
the investigator

Occurrence of a serious adverse event (SAE) determined by the investigator to be possibly 
related to study drug and not alleviated with treatment of symptoms

Adverse event (including Grade 3 or 4 events of special interest [Section 6.1.4])

Hypersensitivity determined by the investigator to be possibly related to study drug

Administrative reasons
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.1.1.  Reasons for discontinuation other 
than AEs must be reported within 4 weeks of the EOS date in order to be included in the 
database.  Any reason for discontinuation obtained after this time will be included in the 
subject’s medical record only unless the EOS visit date is amended and the database remains 
open.


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As far as possible, all examinations scheduled for the EOT evaluations must be performed on 
all subjects who participate even if they do not complete the study according to the protocol.
4.5
Data Safety Monitoring Board
The DSMB for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DSMB will be an external, independent board comprised of physicians with relevant 
training and an independent statistician (not associated with NPS, study sites, or investigators). 
The DSMB will be restricted to individuals free of significant conflicts of interest, including, 
but not limited to, financial, scientific, or regulatory in nature. The DSMB will be governed by 
a Charter agreed to by members of the Board and the sponsor. Members of the Board may not 
be study investigators, individuals employed by NPS, independent contractors hired by NPS, or 
members of regulatory agencies. The DSMB may serve as an advisory board to NPS; however, 
NPS will have the final responsibility to determine whether the study should be modified or 
temporarily or permanently stopped. 
The DSMB members will review the data approximately every 3 months after the beginning of 
dosing of the first subject and then approximately every 3 months thereafter.  The DSMB will 
be provided the following:  1) all cumulative safety data from the study for safety assessments; 
2) data related to pharmacodynamics and the nutritional progress (ie, any changes in the use of 
PN/IV and/or enteral nutrition) of each subject; and 3) any other data supporting the decision to 
discontinue teduglutide throughout the study.
5
TREATMENTS AND TREATMENT PLAN
5.1
Treatment Administered
Daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will be administered 
once daily in the morning to the subjects in the active treatment cohorts.  The dose calculation 
will be based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose 
will be made during the study period. Teduglutide will be administered by SC injection into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm.
Identification of Investigational Product
5.1.1
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled 
syringe.  The 5-mg vial is 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is 
5 mg/mL. A maximum of 0.38 mL of reconstituted solution can be withdrawn from the vial.


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In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients.
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength.
Packaging and Labeling
5.1.2
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Study drug vial will be supplied in kits containing 7 vials and labeled with the 
protocol number, the investigational drug warning, general dosage instructions, storage 
conditions, expiry date, kit number, lot number, and company name.  Space will be provided 
for recording study site and subject numbers at the study site. Ancillary supply kits containing 
syringes with needles for injection and reconstitution, sterile water, and alcohol swabs will also 
be provided.
All study drug used in this study will be manufactured, tested, labeled, and released according 
to current legal requirements and Good Manufacturing Practice (GMP).
Storage, Accountability, and Stability
5.1.3
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures. Upon receipt, the study site’s pharmacist or 
delegate is responsible for ensuring that all study drug received at the site is inventoried and 
accounted for throughout the study.  A copy of the shipping documents must be maintained for 
the investigator’s records.
Study drug must be kept in a locked area with access restricted to specific study personnel.  
Study drug will be stored refrigerated at a temperature between 2 to 8 oC (35.6 to 46.4 oF) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated 
up to a controlled room temperature (acceptable range of 2 to 25 oC, or 35.6 to 77 oF).  
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated.
Study drug kits will be dispensed at each of the study visits at which the subject is required to 
be at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough 
kits will be supplied to cover the period to the next planned study visit. Additional study kits
will be provided as necessary.
The investigator is to keep a current record of the inventory and dispensing of all clinical 
supplies.  This record will be made available to the sponsor’s site monitor for the purpose of 
accounting for all clinical supplies. Any discrepancy or deficiency will be recorded and will 


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include an explanation. All supplies sent to the investigator must be accounted for and in no 
case will clinical supplies be used in any unauthorized situation.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian
and will be retained at the site. All original containers, whether empty or containing study drug 
will be returned to the pharmacy.  Returned study drugs will NOT be relabeled or reassigned 
for use by other subjects.  Contents of the study drug containers will not be combined.  All
study drug will be returned according to the sponsor’s instructions.
5.2
Methods of Assigning Subjects to Treatment Groups
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of 
the study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These
numbers will be used to identify the subjects throughout the study period, including any 
subjects in the standard of care cohort.  If a subject who participated in the previous teduglutide 
study, TED-C13-003, who was assigned and completed the study in the standard of care cohort 
wishes to participate, that subject will be assigned the 8-digit subject number used in the 
previous study.
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the dosing cohort or the 
standard of care cohort.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all Inclusion/Exclusion criteria.  If the subject or 
subject’s parent/guardian/caretaker decides to participate in the dosing cohort, the investigator 
or designee will request the subject be randomized at the Baseline Visit using an interactive 
voice response system (IVRS) at a 1:1 ratio, centrally administered as described in the IVRS 
Manual of Procedures.
Study drug kits will be assigned through IVRS to each subject at each on-site visit through
completion of the dosing period. The IVRS will automatically assign the correct number of kits 
for each visit based on the date of randomization. If additional kits are needed (eg., subject is 
going on holiday), the IVRS and NPS will need to be notified so that the additional kits can be 
assigned.  Subjects will be randomized across centers rather than within center.
Those subjects opting for the standard of care cohort will continue in the study but without the 
study drug.
5.3
Dose Regimens
Teduglutide will be supplied in 2 strengths:

5.0 mg/vial for subjects receiving 0.05 mg/kg/day of teduglutide

2.5 mg/vial for subjects requiring 0.025 mg/kg/day.


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Subjects in the active treatment groups are to have the study drug administered daily in the 
morning by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or arm, 
for 24 weeks. The initial dose will be calculated based on body weight measured at the 
Baseline Visit (Visit 2).
Selection of Doses in Study
5.3.1
A recently completed 12-week pediatric study (TED-C13-003) included doses of 0.0125, 
0.025, and 0.05 mg/kg/day.  Data evaluated by the DSMB concluded that all 3 doses were safe 
and tolerable with trends of PN/IV volume reduction and advance in feeds observed.  Modeling 
and simulation data from previously completed studies suggested that pediatric patients are 
likely to require the same dose as used in adults and that the 0.05 mg/kg/day adult dose will be 
sufficient to provide similar blood levels in all subjects over 1 year of age.  
Selection and Timing of Dose for Each Subject
5.3.2
The study drug will be administered immediately after reconstitution by SC injection into 1 of 
the 4 quadrants of the abdomen or into either thigh or arm. The first SC injection should be 
administered under the supervision of the investigator or designee and the subject observed for 
hypersensitivity reactions for at least 4 hours during their initial dosing visit. The site of 
administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and 
recorded in the eCRF.  Detailed instructions for reconstitution and injection of the study drug 
can be found in the Injection Instructions. Each day, the injection site should be changed. For 
subjects with a stoma, the abdominal quadrant in which the stoma is situated should be 
avoided.
The subject should be dosed at approximately the same time each day, preferably in the 
morning. If a morning dose is forgotten, that day’s dose should be administered as soon as
possible, even if this is later in the day or evening. Consecutive doses should be separated by 
approximately 12 hours.  The time of the dose should be captured in the appropriate area in the 
subject diary.
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily study drug dosing regimen. Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, forgotten doses, lapse in study drug delivery, 
etc.  A single discontinuation period of study drug should not exceed 10 consecutive days. 
Dosage interruptions of study drug for a maximum of 21 days total during the entire 24 weeks 
are permissible.
Compliance with Dosing Regimens
5.3.3
Subject compliance with study drug dosing will be monitored by the sponsor /designee by 
counting and examining used and unused vials. In addition, compliance will be checked by 
site personnel at every visit by asking the subject or the subject’s parent or guardian if they 


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have administered the study drug according to instructions.  If any doses have been missed, the 
reason for missed dose should be documented in the subject’s source documentation including, 
as applicable, the eCRF.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
Prior and Concomitant Medications
5.3.4
The administration of all medications including concomitant medications must be recorded in 
the appropriate sections of the eCRF.
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, including those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
6.1
Evaluations for Safety and Tolerability
Safety variables for the teduglutide dosing groups will be assessed by the following 
evaluations, according to Schedules of Evaluations and Procedures as outlined in Table 6-1 and
Table 6-2, with opportunities for more frequent tests as clinically necessary.  Safety variables 
for the standard of care cohort are displayed in Table 6-3 and Table 6-4.

Adverse events, including GI symptoms

Physical examinations

Vital signs, including body weight, heart rate, and blood pressure, head circumference, and 
length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide.  Samples for antibody analysis will be drawn at baseline and at 
the EOT (Week 24) and EOS (Week 28) visits prior to the administration of teduglutide 
and at least 14 hours after the previous dose.  One sample will be collected at the final visit 
4 weeks after the EOT (EOS, Week 28).  Any subjects testing positive for antibodies 


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specific to teduglutide (positive/specific antibodies) at Week 28 will have follow-up visits 
3 and/or 6 months after the last dose of study drug to assess antibody status.

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (when available)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy), abdominal 
ultrasound, fecal occult blood testing, upper GI series with small bowel follow-through
Adverse Events
6.1.1
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study.
6.1.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily have to 
have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study drug administration

Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen
Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form.  This information will be 
shared with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.


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6.1.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs 
and SAEs will be recorded from the signing of the informed consent form (ICF) through the 
last day of study drug dosing, or the last study required procedure (including study visit).  
SAEs will be monitored with a telephone call by the investigator, as necessary, for 
approximately 4 weeks after the last dose of study drug or until resolution or until the SAE is 
judged by the investigator to have stabilized.   
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  Also recorded are: 

Start and stop date and time

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities;
hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out)

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.1.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.


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Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study
Serious Adverse Events
6.1.2
A serious event must be reported as described in Section 6.1.2.2 and recorded on the sponsor’s 
SAE Form.  An SAE requires expeditious handling to comply with regulatory requirements.  
Any SAEs occurring from the signing of the ICF through 30 days after the last dose of study 
drug will be captured and must be reported within 24 hours after the investigator is made aware 
of the event.
6.1.2.1
Serious Adverse Event Definition
An SAE is an AE that results in any of the following outcomes:

Death 

Is life-threatening.  A life-threatening AE is any AE that places the subject - in the 
investigator’s opinion - at immediate risk of death from the reaction as it occurred.  It does
not include a reaction that, had it occurred in a more serious form, might have caused 
death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Scheduled and/or elective hospitalizations occurring under the following circumstances will 
not be defined as SAEs for this clinical study:

planned before entry into the clinical study

are for elective treatment of a condition unrelated to the studied indication or its treatment


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
occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

are part of the normal treatment or monitoring of the studied indication and not associated 
with any deterioration in condition
Any laboratory test result that meets the criteria for an SAE must also be recorded in an SAE 
report so that the sponsor/designee can collect additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
6.1.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
subject signs the ICF through 30 days after the study drug is completed, the investigator must 
notify the sponsor.  The SAE information, including the time and date that the investigator 
became aware of the event, must be entered into the SAE reporting system and supplemental 
data (eg, medical records or lab values, if applicable) faxed to the sponsor. This ensures timely 
reporting of applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but a serious event criterion.  The SAE term is the medical event that led to the 
hospitalization.  Surgery is not an adverse event, but the event that required the subject to have 
surgery is the SAE term.  Death is not an SAE, but an outcome.
The sponsor/designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study 
drug.  Appropriate clinical, diagnostic, and laboratory measures should be performed to 
delineate the cause of the SAE in question and the results reported. Follow-up for the SAE 
should occur at appropriate intervals until the event/laboratory abnormality:

Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the sponsor’s SAE 
form.  The investigator should make the causality assessment based on the information 


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available at the time of the event.  The causality can be updated at a future date if additional 
information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect 
study product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related)

A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Study Reference Manual.
As required by International Conference of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Causality, while assessed, 
does not negate reporting requirements to the sponsor.  An AE, whether serious or not serious, 
is designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator Brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 
expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.  As per 
regulatory guidance, if it is determined that there is an unanticipated signal, the NPS SMT will 
analyze the data and prepare a summary supporting the determination and interpretation of the 


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findings.  The sponsor/designee will send this summary to the investigators with instructions to 
provide it to their IEC/IRB.
The investigator should also comply with the IEC/IRB procedures for reporting any other 
safety information (ie, autopsy reports).
NPS Pharmaceuticals (sponsor) will be responsible for submitting SUSAR reports to the 
appropriate health authorities.  These reports will be submitted within the expedited timeframe.  
All fatal and life-threatening SUSAR reports will be submitted by the sponsor or designee 
within 7 days of receipt (Day 0) of the initial report.  All other SUSAR reports will be 
submitted by Day 15 following the event.
Unblinding
6.1.3
If a subject becomes pregnant or seriously ill during the study, the blind should be broken only 
if knowledge of the study medication administered will affect treatment options available to the 
subject.  Before breaking the blind, the investigator should contact the NPS Medical Monitor 
for discussion on whether unblinding of the subject is warranted.  If warranted, the sponsor will 
place an unblinding call to the IVRS to receive treatment assignment information.  In the case 
of an extreme emergency and if the Medical Monitor is immediately unreachable, the 
investigator should break the blind through the IVRS. Please see Manual of Procedures for 
further details.
In the event prior authorization from the NPS Medical Monitor is not possible, the NPS 
Medical Monitor must be notified by telephone immediately, but no later than 24 hours 
following the unblinding of any subject for any reason.  A record should be kept of when the 
blind was broken, who broke it, and why.
Dose Interruption of Individual Subjects
6.1.4
Teduglutide administration for an individual subject may need to be stopped if the subject has 
an adverse event of special interest (see risks in table below) that is Grade 3 or higher as 
defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE).  This may occur if an event is attributable to study drug or a subject experiences an 
unexplained CTCAE Grade 3 or higher that is not reasonably related to the underlying disease 
process. The determination of length of the discontinuation, temporary or permanent, depends 
on the clinical situation. A treatment-emergent SAE of special interest that leads to study drug 
interruption/discontinuation will be assigned a Grade 3 or 4, if applicable, by the investigator 
during the SAE reporting and follow-up process.
Investigators and the DSMB should be guided by the descriptions of Grade 3 and 4 events 
below, as they relate to identified risks associated with the administration of teduglutide.


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Identified Risk
Grade 3 Description
Grade 4 Description
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent
intervention indicated
Intestinal Obstruction
Hospitalization indicated; elective 
operative intervention indicated; 
limiting self-care activities of daily 
living; disabling
Life-threatening  consequences; urgent
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder 
perforation
Not Applicable
Life-threatening consequences; urgent
intervention indicated
Gallbladder 
obstruction
Symptomatic and severely altered 
gastrointestinal function; tube
feeding, total parenteral nutrition or
hospitalization indicated; nonemergent
operative intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Alkaline Phosphatase 
increased
> 5.0 to 20.0 x Upper limit of normal
> 20.0 x Upper limit of normal
Blood bilirubin 
increased
> 3.0 to 10.0 x Upper limit of normal
> 10.0 x Upper limit of normal
Bile duct stenosis
Severely altered gastrointestinal
function; radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
Pancreatic duct 
stenosis
Severely altered gastrointestinal
function; tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences; urgent
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences; urgent
intervention indicated
Serum amylase 
increaseda
> 2.0 to 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal
Lipase increaseda
> 2.0 to 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for subcutaneous injection
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Final v1.0
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Identified Risk
Grade 3 Description
Grade 4 Description
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; 
intervention indicated
Life-threatening consequences; urgent
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
aIn the setting of clinically acute and symptomatic pancreatitis 
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
Early Termination of the Clinical Study
6.1.5
The DSMB may recommend to stop the study if:

≥ 2 subjects being administered study drug develop the same CTCAE Grade 3 or

1 subject develops a CTCAE Grade 4 adverse event which is attributable to study drug 
or is not reasonably related to the underlying disease process
Laboratory Evaluations
6.1.6
The following laboratory parameters will be examined according to the Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2 (Table 6-3 and Table 6-4
for the standard of care cohort). While not all abnormal laboratory results would be considered 
clinically significant as determined by the investigator (ie, those that are associated with the 
disease state and were present at baseline), those that are determined to be a clinically 
significant change (ie, worsening) from baseline or known medical history will be considered 
adverse events.  All such abnormal laboratory values that are considered AEs must be recorded 
on the appropriate eCRF.  A result outside of the normal range may be repeated for 
confirmation.  Any laboratory test result that meets the criteria for an SAE (Section 6.1.2) must 
also be recorded in an SAE report so that the sponsor/designee can collect additional 
information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome.
6.1.6.1
Safety Laboratory Tests and Procedures
Hematology
Hemoglobin
Hematocrit
Platelets
Red blood cell (RBC) count
White blood cell (WBC) count with differential


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for subcutaneous injection
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Final v1.0
12 March 2015
Serum Chemistry
Albumin
Alkaline phosphatase
ALT
Amylase
AST 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
Creatinine
Creatinine clearance
C-reactive protein 
Creatinine clearance (or Glomerular Filtration 
Rate [GFR])
Glucose
Gamma glutamyl transferase 
Lipase
Magnesium
Phosphate
Potassium
Sodium
Triglycerides
Uric acid
Urinalysis
Blood
Glucose
Leucocytes
Microscopic analysis
pH and osmolality
Protein
Sodium
Pregnancy tests (females of child-bearing 
potential)
Procedures
Upper GI with contrast
Abdominal ultrasound
Colonoscopy/sigmoidoscopy (subjects 12 years and older or if fecal occult blood testing 
result is positive regardless of age without a documented or known etiology to explain the 
fecal positive results, ie, fissures, etc.).
Fecal occult blood testing
6.1.6.2
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2).  If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the Laboratory Manual.


Pediatric Study TED-C14-006
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Final v1.0
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6.1.6.3
Antibodies to Teduglutide
Blood samples will be drawn for the analysis of positive/specific antibodies to teduglutide
according to the Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2).
Physical Examinations
6.1.7
Complete and comprehensive physical examinations will be performed by a medically 
qualified person during the study to assess the subject’s physical status, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2) (Table 6-3 and Table 6-4
for the standard of care cohort).
Any significant finding at baseline should be included in the subject’s medical history eCRF, 
including known lab abnormalities such as decreased hemoglobin as part of anemia, history of 
elevated liver enzymes, etc. Any clinically significant changes from baseline (in the opinion of 
the investigator) noted during the physical examinations, whether or not these procedures are 
required by the protocol, should be recorded on the appropriate AE page of the eCRF. This 
will assist the sponsor/designee in collecting additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
Vital Signs and Body Weight 
6.1.8
Vital signs will be measured according to the Schedules of Evaluations and Procedures (Table 
6-1 and Table 6-2) (Table 6-3 and Table 6-4 for the standard of care cohort). Measurements 
will include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body 
temperature (oC), to be recorded after the subject has been sitting for 5 minutes.  Body weight
(kg), height (length [cm]), and head circumference (cm) will also be recorded on the eCRF.   
Subjects should be weighed on the same scale at each study visit.
Any clinically significant changes (ie, worsening) in the opinion of the investigator noted in 
vital signs assessments (ie, those that are associated with the disease state and were present at 
baseline), should be recorded on the appropriate AE page of the eCRF. This will assist the 
sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome.,
Electrocardiograms
6.1.9
Twelve-lead electrocardiograms will be performed according to the Schedules of Evaluations 
and Procedures (Table 6-1 and Table 6-2; Table 6-3 and Table 6-4 for the standard of care 
cohort). The ECG tracing will be read by a local experienced physician. Results (normal, 
abnormal not clinically significant, and abnormal clinically significant) will be recorded on the 
eCRFs.


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for subcutaneous injection
Page 44 of 68
Final v1.0
12 March 2015
Any clinically significant changes (in the opinion of the investigator) noted during the ECG 
evaluations should be recorded on the appropriate AE page of the eCRF. This will assist the 
sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to study drug or other causes, any action taken, and 
outcome.
Gastrointestinal-specific Testing
6.1.10
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. See Table 6-1
and Table 6-2 for details and scheduling.
6.1.10.1
Upper Gastrointestinal Series with Contrast
An upper GI with small bowel follow through (UGI/SBFT) will be performed following the 
ingestion of barium contrast material.  Results from procedures performed within 6 months 
prior to Visit 1 will also be acceptable.
6.1.10.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to Visit 1 will also be acceptable.
6.1.10.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening and at the end of treatment. Subjects
with positive results for fecal occult blood will undergo a confirmatory 
colonoscopy/sigmoidoscopy.  If no known underlying documented etiology can be attributed to 
this finding, the results should be discussed with the NPS Medical Monitor.

Subjects with negative scope results may enroll in the study

Subjects with positive scope results who receive treatment may enroll in the study

Subjects with positive scope results who do not receive treatment will be excluded from the 
study

In those subjects with positive results for fecal occult blood at the end of the study, the 
investigator will have to determine the cause for the finding and may perform an additional 
colonoscopy/sigmoidoscopy, if clinically warranted.
6.1.10.4
Colonoscopy/Sigmoidoscopy
Subjects age 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children under the age of 12 years will also undergo the procedure if they had a positive result 
on the fecal occult blood testing (see above). Results from procedures performed within 1 year
prior to Visit 1 will also be acceptable.


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for subcutaneous injection
Page 45 of 68
Final v1.0
12 March 2015
Concomitant Medication Assessment
6.1.11
The subject’s usage of concomitant medication will be assessed at each clinic visit and the 
details of any medications and changes in medication or dosage of medications will be 
recorded on the eCRF.
Nutritional Support Usage
6.1.12
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoints for this study include decreases in PN/IV volume reduction 
including a ≥ 20% or greater reduction up to 100% reduction (or complete weaning) in PN/IV 
support guided by clinical status.  A 20% decrease in PN/IV volume over 24 weeks is 
considered clinically meaningful to these PN/IV-dependent children who have plateaued in 
their ability to wean PN/IV and advance their oral/enteral feeds.  A decrease of this magnitude 
may translate to several hours a day for more age-appropriate activities or an opportunity to 
introduce an extra oral/enteral feed to encourage oral rehabilitation. A guidance for nutrition 
support adjustment to be followed for this protocol is provided in Appendix 1.
Evaluation of each subject’s nutritional support will be made during screening and at all visits 
at the study site.  The following information will be collected and can be used to evaluate each 
subject’s nutritional support:

PN/IV support volume and calories

Enteral nutrition volume and calories

72-hour EN/ oral fluid intake

72-hour urine output

72-hour stool output (when available)
Diaries
6.1.13
Subjects or subjects’ parent or guardian will record the subjects’ oral/enteral fluid intake, 
PN/IV support, and urine output on diaries throughout the screening period, the 24-week study 
period (or if early terminated, at the end of treatment), and 4 weeks after the end of treatment.
Subjects should bring completed diaries to each site visit.  Diaries should be completed during
the 72 hours prior to scheduled visits which will be reviewed by the investigator or their 
designee to assess clinical status and opportunity for PN/IV changes and advance in feeds.  At 
each visit, the diaries will be reviewed for completeness and accuracy of the data.
Female Subjects of Child-bearing Potential
6.1.14
Any female subject in an active treatment group who has reached menarche must have a 
negative urine pregnancy test to enroll or continue in the study. Pregnancy tests will be 


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for subcutaneous injection
Page 46 of 68
Final v1.0
12 March 2015
performed at screening and at all study visits.  Sexually active females of child-bearing 
potential (FOCBP) must use medically acceptable methods of birth control during and for 
30 days after the treatment period (eg, true abstinence1, oral contraceptive pills, barrier 
methods with spermicide) in a manner such that the risk of failure is minimized.  The 
investigator will discuss these methods as well as their side effects with the subject.
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control 
during and for 30 days after the treatment.
In the event a subject becomes pregnant during the study, study drug will be discontinued and 
an SAE form will be completed to capture potential drug exposure during pregnancy.  The 
SAE will be reported within 24 hours of becoming aware of the pregnancy.  The subject will 
be followed until an outcome is known (ie, normal delivery, abnormal delivery, spontaneous 
abortion (miscarriage), voluntary abortion, or therapeutic abortion).  If a pregnant subject also 
experiences an SAE, the SAE form will be completed and submitted within 24 hours as 
discussed above.
In the event a female partner of a subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator and a supplemental SAE form will be completed to 
capture the event.
                                                
1 True abstinence:  Abstention of sexual activity that is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not 
acceptable methods of contraception).


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for injection
Page 47 of 68
Final v1.0
12 March 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
1
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Review nutritional 
support usageb
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Upper GI with small 
bowel follow 
throughd
X
Abdominal 
ultrasound
X
Fecal occult blood 
testinge
X
X
Colonoscopy/ 
Sigmoidoscopye
X
Vital signs
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
testsf
X
X
(X)g
(X)g
(X)e
X
(X)g
X
(X)g
X


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for injection
Page 48 of 68
Final v1.0
12 March 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
1
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Pregnancy testingh
X
X
X
X
X
X
X
X
X
Citrullinei
X
X
Antibodies to 
teduglutidej
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Symptoms 
History Worksheet
X
Dispense Nutritional 
Diary
X
X
X
X
X
X
X
X
X
Review Symptoms 
History Worksheet
X
Review Nutritional 
Diaryk
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomizationl
X
Drug dispensingm
X
X
X
X
X
X
X
X


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for injection
Page 49 of 68
Final v1.0
12 March 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
1
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
EN = enteral feeds; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV and EN feeds (formula and fluids).
c Nutritional support adjustments can be made after review of the previous intake/output data and the subject’s safety lab data. A suggested guidance for nutrition support 
adjustment is provided in Appendix 1.
d If it is necessary to perform the upper GI with small bowel follow-through, abdominal ultrasound, fecal occult blood testing, and/or colonoscopy/sigmoidoscopy, these tests can 
be performed at anytime after signing of consent but prior to the baseline visit. The results must be available and reviewed prior to the baseline visit.
e Colonoscopy/sigmoidoscopy will be conducted on subjects 12 years of age and older or subjects who have a positive fecal occult blood result without etiology to explain.  Results 
of colonoscopies done within the prior year may also be used.
f Including electrolytes and glucose
g Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
h Female subjects of child-bearing potential only 
iCitrulline should be collected 2 to 4 hours post prandially, whenever possible.
j Collection to be done prior to first study drug administration at study site.
k Diaries will include recordings for oral/enteral dietary intake, PN/IV support volume, EN/ oral fluid intake and urine output..
lRandomization and therapy assignment is to be completed prior to drug dispensing.
m The first SC injection will be administered under the supervision of the investigator/designee after which the subject will be observed for hypersensitivity reactions for at least 
4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF.


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for injection
Page 50 of 68
Final v1.0
12 March 2015
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)i
Week 
28i
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Review nutritional 
support usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Fecal occult blood 
testing
Xj
Colonoscopy/ 
Sigmoidoscopy
(X)j
Vital signs
X
X
X
X
X
Body weight
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
testsc
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Pregnancy testinge
X
X
X
X
X
Citrullinef
X
X
Antibodies to 
teduglutide
Xg
Xg
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Nutritional 
Diary
X
X
X
X


Pediatric Study TED-C14-006
Teduglutide (rDNA origin) for injection
Page 51 of 68
Final v1.0
12 March 2015
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)i
Week 
28i
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Review of  
Nutritional Diaryh
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and EN feeds (formula and fluids).
b Nutritional support adjustments can be made after review of the previous 72 hour intake/output data and the subject’s safety lab data. A suggested guidance for nutrition support 
adjustment is provided.
c Including electrolytes and glucose
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Female subjects of child-bearing potential only
f Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
g EOT antibody blood draw is to be taken prior to the last dose of study drug, at least 14 hours following the previous dose of study drug. Subjects who test positive/specific for 
antibodies to teduglutide at the Week 28 visit will have follow-up blood draws for positive/specific antibodies to teduglutide at approximately 3 months following the last dose of 
study drug. If antibodies are still positive/specific they will be collected again approximately 6 months after the last dose of study drug.  Adverse events and PN/IV support will 
also be assessed at these visits.
h Diaries will include recordings for oral/enteral dietary intake, PN/IV support volume, EN/oral fluid intake, stool/urine output.
i During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.
j If fecal/occult blood is positive without explanation, then a colonoscopy/sigmoidoscopy may be warranted.


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Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
1
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Nutritional support
usageb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
Safety laboratory 
testsd
X
X
(X)e
(X)e
(X)e
X
(X)e
X
(X)e
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Symptoms 
History Worksheet
X
Dispense Nutritional 
Diary
X
X
X
X
X
X
X
X
X
Review Symptoms 
History Worksheet
X


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Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
1
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Review of  
Nutritional Diaryf
X
X
X
X
X
X
X
X
X
X
X
X
X
EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV and EN feeds (formula and fluids).
c Nutritional support adjustments can be made after review of the previous intake/output data and the subject’s safety lab data. A suggested guidance for nutrition support 
adjustment is provided.
d Including electrolytes and glucose 
e Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
f Diaries will include recordings for oral/enteral dietary intake, PN/IV support volume, oral fluid intake, and stool/ urine output.


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Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Cohort
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)f
Week 
28f
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Nutritional support
usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Body weight
X
X
X
X
X
Safety laboratory 
testsc
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Nutritional 
Diary
X
X
X
X
Review of  
Nutritional Diarye
X
X
X
X
X
X
X
X
X
X
X
X
X
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and EN feeds (formula and fluids).
b Nutritional support adjustments can be made after review of the previous 72 hour intake/output data and the subject’s safety lab data. A suggested guidance for nutrition support 
adjustment is provided.
c Including electrolytes and glucose
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Diaries will include recordings for oral/enteral dietary intake, PN/IV support volume, EN/ oral fluid intake, and stool/urine output.
f During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.


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7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
eight-digit subject number, including subjects in the standard of care cohort.  The first four 
digits consist of the study site number.  The last four digits will be assigned sequentially 
starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s eCRF by the investigational 
site staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case 
of computerized source data, the investigator must provide the sponsor access to the subject 
files at each monitoring visit. To ensure that data has been entered correctly on the eCRF, they 
will be 100% source-data verified by a site monitor from the sponsor/designee, who will notify 
the investigator regarding any questions or discrepant data. The investigator or designee will 
be responsible for the timely recording of subject data into the eCRF. 
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents.
The investigator or designee will review all eCRFs (including the termination page after the
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the 
appropriate vendor for assimilation into the database. Paper copies of laboratory reports and 
other non-eCRF data (eg, ECGs) will be signed and dated by the investigator and filed. 
Diaries will be used by the subjects’ parent or guardian to record study information, including
PN/IV support, enteral administration, urine output (as either collected or calculated volume), 
and nutritional intake.
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with eCRF guidelines outlining 
the specific procedures to use when entering the data into the clinical database. Data validation 
and edit checks will be conducted on the data. Any discrepancies will generate queries that 
must be resolved at the study site in a timely manner. 
When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 


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defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once 
the sponsor/designee acknowledges that all data are acceptable, the data will be declared a 
“clean file,” and the data will be frozen/locked.
A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the 
database, the database will be ready for statistical analysis by NPS or designee.
7.2
Record Retention
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines. These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject 
consent/assent documents, ECGs, photographs, and computer records) which are a result of the 
original observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report.
The clinical investigators will maintain copies of these essential documents for approximately 
10 years or as dictated by local regulatory requirements or until instructed in writing by the 
sponsor that records may be destroyed or forwarded to the sponsor.  In accordance with 
regulatory guidelines, these records will be available for inspection and copying if requested by 
a properly authorized employee of the FDA/EU Health Authorities.
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE
Detailed statistical analysis methods will be conducted as described in the Statistical Analysis 
Plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in 
the clinical study report (CSR). 
Due to the limited size of the study population descriptive statistics will be used with a goal of
summarizing the sample which discourages the use of inferential statistics.
Continuous variables, including those assessed on a discrete scale, will be summarized using
descriptive statistics including number of subjects, mean, median, standard deviation,
maximum, and minimum. For categorical variables, statistical summaries will include number
of subjects and percentages.
8.1
Demographic and Baseline Variables
Demographic and/or other Baseline variables obtained at the screening and baseline visit are 
listed below.  Abnormal findings of clinical significance (if any) will be recorded as past 
medical history.


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
Demography (including age, sex, and race)

Medical history

SBS history, including remnant anatomy

Vital signs

Physical examination

Body weight

Prior medications (medications used within 14 days prior to screening), including drug 
name, dose, route, reason for use, and therapy dates.  Medications used concomitantly will 
be recorded as concomitant medications.

Electrocardiogram (12-lead) variables include general findings only (normal/abnormal)

Laboratory test results: Serum chemistries, hematology, and urinalysis

Citrulline levels

Presence of antibodies to teduglutide and titer level, if present

Gastrointestinal imaging (upper GI with contrast, abdominal ultrasound, 
colonoscopy/sigmoidoscopy)

Nutritional support (eg, PN/IV volume and calorie usage)

Data entered in the nutritional diaries
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and 
the number and percentage of subjects in specified categories by treatment group) will be 
presented, as appropriate, to summarize the demographic and baseline variables. 
Prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary with regard to drug class and drug name.  The number and
percentage of subjects with specific prior medications will be summarized by treatment group. 
Medical history (including surgical history) will be coded using the current version of the
Medical Dictionary for Regulatory Activities (MedDRA).  The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term 
for each treatment group.
8.2
Safety and Tolerability Variables
The safety and tolerability variables include:

Adverse events, including GI symptoms 

Physical examination


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
Vital signs, including body weight, heart rate, and blood pressure, head circumference, and 
length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose 

Antibodies to teduglutide.

Oral/enteral feeding tolerance

Nutritional intake and urinary/fecal output (intake/output)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing and upper GI series with small bowel follow-through
Adverse events will be coded using the current version of MedDRA. Treatment emergent AEs 
will be summarized by system organ class and preferred term for each treatment group. The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and AEs that lead to death will be 
summarized by treatment group. AEs will also be summarized by treatment group with regard 
to intensity and relationship to study drug.  For AEs of special interest, the CTCAE grading 
system will be used as described in Section 6.1.4.
For laboratory tests, vital signs, body weight, ECG, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the absolute 
values and change from baseline at each scheduled visit for each treatment group.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment group.
8.3
Pharmacodynamic Variables
The following pharmacodynamic parameters will be measured:

20% to 100% parenteral support reduction at Week 24 (EOT)

100% reduction in PN/IV volume support  (any subjects who are able to completely wean 
off PN/IV support) compared to baseline at EOS

A  decrease in parenteral support (calories and volume)

An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or 
EOT)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 (or 
EOS)


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
Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or 
EOT) compared to Week 28 (or EOS)

Urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months after EOT compared to baseline for those 
subjects who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of  response (PN/IV reduction and advance in enteral support) at each visit

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, the 
number and percentage of subjects in specified categories) will be calculated to summarize the 
absolute values and change from baseline at each scheduled visit for each treatment group.
8.4
Other Variables 
Other variables will be analyzed by treatment group including:

Subject disposition

Duration of study drug exposure

Subjects will be considered compliant if study drug was taken according to protocol and 
assigned treatment group for ≥ 80% of doses. Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment group.

The number and percentage of subjects who complete the study, are lost to follow up, or
discontinued from the study (including reason for study withdrawal) will be summarized by 
treatment group

The study drug dose by duration will be summarized by treatment group.
8.5
Analysis Populations, Data Sets, and Time Points
8.6
Analysis Populations
The intent-to-treat (ITT) population is defined as any subjects who were randomized into the
study.  The safety population is defined as the subset of ITT with subjects who received at least 
1 administration of study drug with any safety follow-up.  The primary population analyzed for 
efficacy will be the ITT population.  An additional per-protocol population analysis will also 


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be performed as secondary/sensitivity analysis.  Detailed per-protocol evaluable definitions 
will be documented in the SAP.
8.7
Statistical/Analytical Issues
Adjustments for Covariates
8.7.1
No Baseline stratification parameter is employed in this study.
Handling of Dropouts or Missing Data
8.7.2
All subjects randomized will be included in the analyses. Missing safety parameters will not be
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV 
volume will be detailed in the SAP.
Interim Analyses and Data Monitoring
8.7.3
No interim analyses are planned.
An independent DSMB will review the data on a routine basis and may have access to data 
from the study for safety assessment. Details of the roles and responsibilities of the DSMB 
members and the structure and scope of the DSMB meetings will be provided in a separate 
DSMB Charter.
Multiple Comparisons/Multiplicity
8.7.4
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be 
no adjustment for alpha level.
Use of an Efficacy Subset of Subjects
8.7.5
A per-protocol population will be analyzed for this study.
Examination of Subgroups
8.7.6
Because a small number of subjects are expected at each study site, data from all study sites 
will be pooled.
8.8
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.
8.9
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified 
in the final CSR.


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9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the current applicable ICH Guidelines, 
Good Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki 
and its amendments concerning medical research in humans.
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant 
material for the investigator to submit to the IRB for the protocol’s review and approval.  
Verification of the IEC/IRB approval of the protocol and the written consent/assent form will 
be forwarded to the sponsor/designee.
The investigator will inform the IEC/IRB of subsequent protocol amendments and any 
SUSARs if the NPS SMT has assessed it as an unanticipated problem.  Approval for protocol 
amendments will be transmitted in writing to the investigator.
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information, Informed Consent and Assent
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate.
The investigator (or designee) will explain to the subject and/or the subject’s parent or 
guardian the nature of the study, the action of the test product, and any risks and benefits.  The 
subject and/or subject’s parent or guardian will be informed that participation is voluntary and 
that the subject can be withdrawn from the study at any time without prejudice to their 
subsequent care.
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records.
9.3
Subject Data Protection
All data provided to the sponsor/designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  The subject and/or the 
subjects’ parent or guardian should be informed in writing, that the subject’s data will be stored 
and analyzed in a computer, with confidentiality maintained in accordance with national and 


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local legislation.  Study site-specific information must be added to the consent/assent as 
appropriate.
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 
access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, 
and a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed 
screening must also be maintained and be available for inspection.
9.4
Financial Disclosure
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” 
(February 2013) provides guidance to industry on its final rule on financial disclosure that 
became effective 02 February 1999 and was published as Title 21 Code of Federal Regulations 
Part 54.  This rule applies to all investigators participating in clinical studies to be submitted to 
the FDA in support of an application for market approval.  The financial disclosure statement 
must be updated if any relevant changes occur during the course of the study, again at the site 
close-out visit, and for 1 year after the completion of the study.
According to the guidance, financial arrangements that must be disclosed are defined as the 
following:

Compensation made to the investigator in which the value of compensation could be 
affected by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or the 
investigator’s institution to support activities of the investigator exclusive of the costs of 
conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing research, 
compensation in the form of equipment or retainers for ongoing consultation, or honoraria) 
during the time the clinical investigator is carrying out the study and for 1 year after 
completion of the study


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Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes 
the spouse and each dependent child of the investigator.  Participating investigators must 
provide this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA 
in support of a market application.  Companies must meet these financial disclosure 
requirements, and failure to do so may result in the refusal by the FDA to accept an application 
for market approval of the study drug.
9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the 
sponsor and the investigator.  All changes must be documented as signed protocol 
amendments, or as a revised protocol.  Changes to the protocol may require notification to or 
approval by the IEC/IRB and the regulatory authorities before implementation. Local 
regulatory requirements must be followed.  Instructions for reporting deviations from the 
protocol can be found in the Study Reference Manual.
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site.
9.6
Investigator Obligations
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address which 
matches the address on the FDA Form 1572

Financial disclosure statement for the principal investigator, and subinvestigators (listed on 
the FDA Form 1572).  An updated financial disclosure statement must be provided at the 
study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study.

A copy of the original approval for conducting the study from the IEC/IRB. Renewals must 
be submitted at yearly intervals if the study is ongoing or as required by the institution.

A copy of the IEC/IRB-approved ICF/assent


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
IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and 
dated by the principal investigator for the study site.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be 
used by the sponsor, now and in the future, for presentation or publication at the sponsor’s 
discretion and/or for submission to regulatory agencies.  In addition, the sponsor reserves the 
right to review data from this study relative to the potential release of proprietary information 
30 days prior to submission to any publication or for any presentation.
9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all 
investigators for this study.  Roles, affiliations, and qualifications for the principal investigators 
will be included in the CSR appendices.  Where the signature of the principal investigator is 
required by regulatory authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative 
reasons at any time.


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10
REFERENCES
Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and 
intestinal transplantation. Gastroenterology. 2003;124:1111-1134.
Common Terminology Criteria for Adverse Events (CTCAE).  US Department of health and 
Human Services, National Institutes of Health, National Cancer Institute. Version 4.03, June 
14, 2010.
Duro D, Kamin D, Duggan C.  Overview of Pediatric Short Bowel Syndrome.  J Pediatr Gastro 
and Nutr. 2008;47:S33-S36.
Fleming CR, Witzke D, Beart RW Jr.  Catheter-related Complications in patients Receiving 
Home Parenteral Nutrition. Ann Surg. 1980 Nov;192(5):593-599.
Jeppesen PB, Langholz E, Mortensen PB.  Intestinal failure defined by measurements of 
intestinal energy and wet weight absorption.  Gut. 2000;46:701-706.
O’Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel 
syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol 
Hepatol. 2006;4:6-10.
Messing B, Crenn P, Beau PBoutron-Ruault MC, Rambaud J-C, Matuchansky C.  Long-term 
survival and parenteral nutrition dependence in adult patients with the short bowel syndrome. 
Gastroenterology. 1999;117:1043-1050.


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APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY
Please consider the following clinical parameters identified as markers for adequate 
management of pediatric short bowel syndrome.  These parameters should also be considered 
for managing nutritional support (PN/IV and/or oral/enteral feeding) in terms of volume and 
calories during the treatment period.  

Considerations to adjust nutritional support in volume and calories will be made at all 
planned visits.

Maintaining growth (including weight, and head circumferenceand length, as appropriate) 
by the subjects trending along their growth chart and adjusting calories/volumes to 
maintain the trend.

Other clinical evaluations
o
Normal serum electrolytes
o
Stable BUN/creatinine levels
o
Increase in the Volume Intake/Output ratio, including mixed output that can be 
collected

General consideration to possible clinical deterioration in SBS
o
Ability to maintain weight and growth velocity
o
Diarrhea (> 50 mL/kg/day with ostomy or >80mg/kg/day without ostomy)
o
Colic/vomiting frequency increased
o
Electrolyte changes or imbalance
o
Skin breakdown (“butt rot”)

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses.  Subjects should remain compliant with the nutritional support prescription 
in volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 72-hour Intake/Output measurement period prior to your scheduled visit, no 
further changes to the prescribed nutritional support should be made.

If there is a change in EN/oral fluid intake, the investigator should consider this when 
adjusting the nutritional support in volume and calories.


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Figure 1
Weaning Algorithm for Subjects Who are Not Toilet Trained


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Figure 2
Weaning Algorithm for Subjects Who are Toilet Trained