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
Phase: PHASE3
Conditions: Short Bowel Syndrome
Sponsor: Shire

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

Shire
Confidential
Page 7
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 8
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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.

Shire
Confidential
Page 9
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 11
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 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)

Shire
Confidential
Page 12
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 13
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 14
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 15
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 16
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 17
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 18
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 19
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 20
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 21
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 22
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 23
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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. 

Shire
Confidential
Page 24
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 25
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 26
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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).

Shire
Confidential
Page 27
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
Figure 3-1
Study Diagram
Note:  Subjects in both treatment arms (SOC and teduglutide) will follow the same visit schedule.

Shire
Confidential
Page 28
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 29
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 30
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 31
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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:

Shire
Confidential
Page 32
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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.

Shire
Confidential
Page 33
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 34
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 35
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 36
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 37
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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:

Shire
Confidential
Page 38
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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 

Shire
Confidential
Page 39
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 40
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 41
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 42
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 43
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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

Shire
Confidential
Page 44
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 45
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 46
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 47
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 48
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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)

Shire
Confidential
Page 49
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 50
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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).

Shire
Confidential
Page 51
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 52
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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)

Shire
Confidential
Page 53
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 54
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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).

Shire
Confidential
Page 55
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 56
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 57
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 58
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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).

Shire
Confidential
Page 59
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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).

Shire
Confidential
Page 60
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 61
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 62
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 63
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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:

Shire
Confidential
Page 64
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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:

Shire
Confidential
Page 65
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016

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.

Shire
Confidential
Page 66
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 67
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 68
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 69
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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 

Shire
Confidential
Page 70
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 71
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 72
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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.

Shire
Confidential
Page 73
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers

Shire
Confidential
Page 74
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers

Shire
Confidential
Page 75
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment

Shire
Confidential
Page 76
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 77
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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

Shire
Confidential
Page 78
Pediatric Study TED-C14-006 – Amendment 4
Version 5.0 / 15 Mar 2016
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