Clinical trial NCT03859323
Conditions: Healthy Volunteers
Sponsor: Shire
Start date: 2019-03-26; Completion date: 2020-01-06
Enrollment: 104 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the study is to assess the safety and tolerability of single and multiple ascending subcutaneous (SC) doses of SHP681 in healthy adult participants.

Detailed description:
The study consists of a single ascending dose (SAD) portion and a multiple ascending dose (MAD) portion.

The study duration for the SAD portion of the study consists of a screening period of up to 28 days and 1 treatment period of 29 days. SAD portion of the study contains 5 cohorts and dose escalation will proceed sequentially to assess the following single SC doses of SHP681 or SHP681 matched placebo: 0.2 milligram per kilogram (mg/kg), 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg.

The study duration of the MAD portion comprises of a screening period up to 28 days and a treatment period of 57 days for each cohort. MAD portion of the study contains 6 cohorts and dose escalation will proceed sequentially to assess the following SC doses of SHP681 or SHP681 matched placebo: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg once weekly for 5 weeks till 5 cohorts and the 6th cohort will receive 4 mg/kg SHP681 or matched placebo every 2 weeks over a 6-week period (3 doses).

Arms: arm 1: Participants will receive single subcutaneous (SC) injection of 0.2 mg/kg SHP681 in the abdomen. arm 2: Participants will receive single SC injection of 0.5 mg/kg SHP681 in the abdomen. arm 3: Participants will receive single SC injection of 1 mg/kg SHP681 in the abdomen. arm 4: Participants will receive single SC injection of 2 mg/kg SHP681 in the abdomen. arm 5: Participants will receive single SC injection of 4 mg/kg SHP681 in the abdomen. arm 6: Participants will receive single SC injection of placebo matched to SHP681 in the abdomen. arm 7: Participants will receive SC injection of 0.2 mg/kg SHP681 once weekly for 5 weeks in the abdomen. arm 8: Participants will receive SC injection of 0.5 mg/kg SHP681 once weekly for 5 weeks in the abdomen. arm 9: Participants will receive SC injection of 1 mg/kg SHP681 once weekly for 5 weeks in the abdomen. arm 10: Participants will receive SC injection of 2 mg/kg SHP681 once weekly for 5 weeks in the abdomen. arm 11: Participants will receive SC injection of 4 mg/kg SHP681 once weekly for 5 weeks in the abdomen. arm 12: Participants will receive SC injection of placebo matched to SHP681 once weekly for 5 weeks in the abdomen.
Interventions: intervention 1: SHP681 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive SC injection of SHP681 in the abdomen. intervention 2: Participants will receive SC injection of placebo matched to SHP681 in the abdomen.

Protocol documents:
Prot_000.pdf: 
PROTOCOL: SHP681-101
TITLE:
A Randomized, Double-blind, Placebo-controlled, Phase 1 Study to 
Assess the Safety, Tolerability, and Pharmacokinetics of Ascending, 
Subcutaneous, Single and Multiple Doses of SHP681 (GLP-2 analog-Fc 
fusion) in Healthy Adult Subjects
DRUG:
SHP681 (Glucagon-like peptide-2 (GLP-2) analog-Fc fusion protein)
IND:
139424
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire Human Genetic Therapies, Inc. (Shire)
300 Shire Way, Lexington, MA 02421 USA 
PRINCIPAL/
COORDINATING
INVESTIGATOR:
PROTOCOL
Original Protocol: 29 Oct 2018
HISTORY:
Amendment 1: 11 Feb 2019
Amendment 2: 10 May 2019
Amendment 3: 08 Oct 2019
Amendment 4: 19 Nov 2019
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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Protocol
Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
19 Nov 2019
Global/Country/Site
Specific
Glo
bal
Description of Change
Section(s) Affected by Change
Abnormal gallbladder wall thickness and gallbladder diameter which were 
noted in the subject above may be related to pharmacodynamic effects of 
SHP681. To characterize changes in the biliary tree caused by SHP681, 
abdominal ultrasound will be obtained during screening and at the end of 
treatment in the final MAD cohort.
Table 7, Table 10, Table 11,
Section 3.1.2, Section 7.2.2.10, 
Section 9.9
Removed the analysis of crypt depth as this data was not collected.
Synopsis, Section 9.10
Clarified that PK samples drawn beyond Day 2 cannot deviate by more 
than ±10% of the specified time from the first dose.
Table 7, Table 9, Table 10, 
Section 7.1, Section 7.2.3
Deleted the Day 43 abbreviated physical exam to be consistent with MAD 
cohorts 1-5 and overall schedule of assessments for MAD cohort 6.
Table 7
The visit windows were updated to allow for subject flexibility.
Table 7, Table 9, Table 10
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form 
within 24 hours to the Shire Global Drug Safety Department. Applicable fax numbers and e-mail 
address (drugsafety@shire.com) can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the contract research organization (CRO)/Shire medical monitor by
fax or e-mail using the details below.
For protocol- or safety-related issues, the investigator must contact the Shire 
medical monitor:
Telephone (24-hour coverage):
 
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ADDITIONAL CONTACT INFORMATION
In case of any other issues, including non-safety-related issues or if the medical
monitor is unable to be reached, the investigator must contact the Shire Study Lead:
Telephone:
 (business hours)
 (24-hour coverage) 
If unavailable, please contact:
Telephone: 
 (business hours)
 (24-hour coverage)
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE ..................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
ADDITIONAL CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................20
1.
BACKGROUND INFORMATION ......................................................................................36
1.1
Indication and Current Treatment Options ..................................................................36
1.2
Product Background.....................................................................................................37
1.2.1
Preclinical Information ......................................................................................37
1.2.2
Clinical Information...........................................................................................37
1.3
Risk/Benefit and Ethical Assessment ..........................................................................37
2.
STUDY OBJECTIVES AND PURPOSE .............................................................................38
2.1
Rationale for the Study ................................................................................................38
2.2
Study Objectives ..........................................................................................................38
2.2.1
Primary Objectives.............................................................................................38
2.2.2
Secondary Objectives.........................................................................................38
2.2.3
Exploratory Objectives ......................................................................................38
3.
STUDY DESIGN...................................................................................................................39
3.1
Study Design and Flow Chart......................................................................................39
3.1.1
Dose selection, rationale and administration......................................................40
3.1.2
Screening and Treatment Period........................................................................41
3.2
Duration and Study Completion Definition.................................................................42
3.3
Sites and Regions.........................................................................................................43
4.
STUDY POPULATION........................................................................................................44
4.1
Inclusion Criteria .........................................................................................................44
4.2
Exclusion Criteria ........................................................................................................44
4.3
Restrictions ..................................................................................................................46
4.4
Reproductive Potential.................................................................................................46
4.4.1
Female Contraception........................................................................................46
4.4.2
Male Contraception............................................................................................47
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4.5
Discontinuation of Subjects.........................................................................................47
4.5.1
Reasons for Discontinuation..............................................................................47
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.............................48
4.5.3
Stopping Criteria for Dose Escalation ...............................................................48
5.
PRIOR AND CONCOMITANT TREATMENT ..................................................................50
5.1
Prior Treatment ............................................................................................................50
5.2
Concomitant Treatment ...............................................................................................50
5.2.1
Permitted Treatment...........................................................................................50
5.2.2
Prohibited Treatment..........................................................................................50
6.
INVESTIGATIONAL PRODUCT........................................................................................51
6.1
Identity of Investigational Product...............................................................................51
6.1.1
Blinding the Treatment Assignment..................................................................51
6.2
Administration of Investigational Product(s)...............................................................52
6.2.1
Allocation of Subjects to Treatment ..................................................................52
6.2.2
Dosing................................................................................................................53
6.2.3
Unblinding the Treatment Assignment..............................................................53
6.2.4
Labeling .............................................................................................................54
6.2.5
Packaging...........................................................................................................54
6.2.6
Storage ...............................................................................................................54
6.3
Drug Accountability.....................................................................................................55
6.4
Subject Compliance .....................................................................................................56
6.5
Retention of Bioavailability and Bioequivalence Testing Samples.............................56
7.
STUDY PROCEDURES .......................................................................................................57
7.1
Study Schedule.............................................................................................................57
7.1.1
Screening Period................................................................................................57
7.1.2
Treatment Period................................................................................................58
7.1.3
Follow-up Period ...............................................................................................59
7.1.4
Additional Care of Subjects after the Study ......................................................59
7.2
Study Evaluations and Procedures...............................................................................59
7.2.1
Demographic and Other Baseline Characteristics .............................................59
7.2.2
Safety .................................................................................................................59
7.2.3
Pharmacokinetic Procedures..............................................................................65
7.2.4
Pharmacodynamic Assessments ........................................................................66
7.2.5
Pharmacogenomic Assessments ........................................................................66
7.2.6
Exploratory Assessments...................................................................................67
7.2.7
Volume of Blood to be Drawn from Each Subject............................................68
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ...................................69
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8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events...........................................................................................................................69
8.1.1
Severity Categorization......................................................................................69
8.1.2
Relationship Categorization...............................................................................70
8.1.3
Outcome Categorization ....................................................................................70
8.1.4
Clinical Laboratory and Other Safety Evaluations............................................70
8.1.5
Pregnancy...........................................................................................................71
8.1.6
Abuse, Misuse, Overdose, and Medication Error..............................................71
8.2
Serious Adverse Event Procedures..............................................................................72
8.2.1
Reference Safety Information............................................................................72
8.2.2
Reporting Procedures.........................................................................................72
8.2.3
Serious Adverse Event Definition .....................................................................73
8.2.4
Serious Adverse Event Collection Time Frame.................................................73
8.2.5
Serious Adverse Event Onset and Resolution Dates .........................................74
8.2.6
Fatal Outcome....................................................................................................74
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting ....................................................................................................74
9.
DATA MANAGEMENT AND STATISTICAL METHODS ..............................................75
9.1
Data Collection ............................................................................................................75
9.2
Clinical Data Management ..........................................................................................75
9.3
Data Handling Considerations.....................................................................................75
9.4
Statistical Analysis Process..........................................................................................75
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........76
9.6
Sample Size Calculation and Power Considerations ...................................................77
9.7
Study Population..........................................................................................................77
9.8
Pharmacokinetic Analyses...........................................................................................78
9.8.1
Pharmacokinetic Analysis..................................................................................78
9.9
Safety Analyses............................................................................................................80
9.10
Exploratory Analysis ...................................................................................................81
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ..........................................82
10.1
Sponsor’s Responsibilities...........................................................................................82
10.1.1
Good Clinical Practice Compliance...................................................................82
10.1.2
Public Posting of Study Information..................................................................82
10.1.3
Indemnity/Liability and Insurance.....................................................................82
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees.......................................82
10.1.5
Study Suspension, Termination, and Completion..............................................83
10.2
Investigator’s Responsibilities.....................................................................................83
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ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
-hCG
beta-human chorionic gonadotropin
CRC
clinical research center
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
EC
ethics committee 
ECG
electrocardiogram 
EU
European Union
FDA
Food and Drug Administration
FIH
first in human
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonisation
IP
investigational product
IRB
Institutional Review Board
MAD
multiple ascending dose
nADA
neutralizing anti-drug antibody
PK
pharmacokinetic
SAD
single ascending dose 
SAE
serious adverse event 
SAP
statistical analysis plan 
SC
subcutaneous
SBS
short bowel syndrome
US
United States
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STUDY SYNOPSIS
Protocol number: SHP681-101
Drug: SHP681
Title of the study: A Randomized, Double-blind, Placebo-controlled, Phase 1 Study to Assess the Safety,
Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and Multiple Doses of SHP681 (GLP-2 
analog-Fc fusion) in Healthy Adult Subjects
Number of subjects (total and for each treatment arm):
A total of 102 subjects (30 for the single ascending dose [SAD] portion and 72 subjects for the multiple 
ascending dose [MAD] portion) are planned to be enrolled for this study.
Investigator(s): 
Site(s) and Region(s):
Study period (planned):
Feb 2019-Jan 2020
Clinical phase:
1
Objectives:
Primary: To assess the safety and tolerability of single and multiple, ascending, subcutaneous (SC) doses of
SHP681 in healthy adult subjects
Secondary: To characterize the pharmacokinetics (PK) of SHP681 following single and multiple, ascending SC 
doses in healthy adult subjects
Rationale:
SHP681 has been engineered with a significant half-life extension compared to teduglutide. This extended 
half-life is expected to allow once weekly injection with similar safety and efficacy as teduglutide.
The present study is a first in human study to assess the safety, tolerability, and pharmacokinetics of SHP681 
when administered as single and multiple ascending SC doses.
Investigational product, dose, and mode of administration:

Investigational product (IP): SHP681 refers to a glucagon-like peptide-2 (GLP-2) analog-Fc fusion protein, 
abbreviated as GLP-2 analog-Fc fusion. The IP will be referred to as SHP681 through this document

SAD portion of the study- Dose escalation with single SC doses of SHP681: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 
2 mg/kg, and 4 mg/kg vs. placebo.

MAD portion of the study- Sequential dose escalation of SC doses of SHP681: 0.2 mg/kg, 0.5 mg/kg, 
1 mg/kg, 2 mg/kg, and 4 mg/kg. Each of the first 5 MAD cohorts will receive SHP681 (or placebo) once 
weekly for 5 weeks. The 6th MAD cohort will receive 4 mg/kg SHP681 once every 2 weeks for 6 weeks 
(3 doses). 

All subjects (both SAD and MAD portions) will have the IP administered in the abdomen.
Methodology:
SAD- Part 1: The plan is to enroll 30 subjects in 5 cohorts. Each cohort will include 6 subjects. Subjects will be 
randomized within each cohort such that 5 subjects receive SHP681 and 1 subject receives placebo. Dose 
escalation will proceed sequentially to assess the following SC doses of SHP681: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 
2 mg/kg, and 4 mg/kg. After a single administration of SHP681 or placebo in each cohort, if the dose is assessed 
as safe and tolerable during a dose escalation meeting, the next cohort will be administered a SC dose of SHP681 
at the next higher dose level or placebo. During dose escalation, protocol defined dose levels may be reduced, 
repeated, discontinued, or an intermediate increase may be added depending on the outcome of the blinded safety 
data review between dose escalations. Upon completion of these 5-dose cohorts, additional doses may be studied 
based on emergent safety data.
The study duration of the SAD portion of the study will consist of a screening period of up to 28 days and 
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Exclusion Criteria:
1. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or psychiatric
disease, gallbladder removal, or current or recurrent disease that could affect the action, absorption, or 
disposition of the investigational product, or clinical or laboratory assessments.
2. Current or relevant medical history of physical or psychiatric illness, any medical disorder that may require 
treatment or render the subject unlikely to complete the study, or any condition that presents undue risk 
from the investigational product or procedures.
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related 
compounds, or any of the stated ingredients.
4. Significant illness, as judged by the investigator, within 2 weeks of the first dose of investigational product.
5. Known history of alcohol or other substance abuse within the last year.
6. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first
dose of investigational product.
7. Within 30 days prior to the first dose of investigational product:
a.
Have used an investigational product (if elimination half-life is <6 days, otherwise 5 half-lives).
b.
Have been enrolled in a clinical study.
c.
Have had any substantial changes in eating habits, as assessed by the investigator.
8. Use of DPP-4 inhibitors within 30 days or 5 half-lives, whichever is greater, prior to administration of the 
investigational product.
9. Confirmed systolic blood pressure >139mmHg or <89mmHg, and diastolic blood pressure >89 mmHg or 
<49 mmHg.
10. Twelve-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 450 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTcF values should be used to determine the 
subject’s eligibility.
11. Positive screen for alcohol or illicit drugs at screening or Day -1.
12. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. Female subjects 
who consume more than 14 units of alcohol per week or 2 units per day. (1 alcohol unit=1 beer or 1 wine 
(5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz alcohol).
13. Positive HIV, HBsAg, or HCV antibody screen.
14. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing products in any form 
(eg, gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to 
receiving the first dose of investigational product.
15. Routine consumption of more than 2 units of caffeine per day or subjects who report developing
headaches associated with caffeine withdrawal. (1 caffeine unit is contained in the following items: one
6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 12 oz cup of tea, three 1 oz (85 g)
chocolate bars. Decaffeinated coffee, tea, or cola are not considered to contain caffeine).
16. Prior screen failure (unless Sponsor approval is given), randomization, participation, or enrollment in this
study or prior exposure to any GLP-2 analogs.
17. Unresected GI polyp, known polyposis condition, or premalignant changes in the GI tract.
18. Any history of malignancy in the GI tract or treatment for any other malignancy in the previous 5 years.
19. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations; with the 
exception of hormonal replacement therapy or hormonal contraceptives and occasional use of ibuprofen or 
acetaminophen and pre-approved medication for sedation or other medications required during or after the 
endoscopy). Current use is defined as use within 14 days of the first dose of investigational product.
20. Findings of subclinical hepatobiliary disease, such as gallstones, on abdominal ultrasound at screening as 
determined by the Investigator in consultation with the Medical Monitor.
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Maximum duration of subject involvement in the study: 
SAD-Part1

Planned duration of screening period: 28 days

Planned duration of treatment period: 29 days
The maximum total duration of study participation for a subject is 57 days (approximately 2 months)
MAD-Part2

Planned duration of screening period: 28 days

Planned duration of treatment period: 57 days
The maximum total duration of study participation for a subject is 85 days (approximately 3 months)
Endpoints and statistical analysis:
Endpoints and Statistical Analysis
Subject populations are separately defined to analyze the data in the SAD portion and the MAD portion:
SAD

The SAD safety analysis data set includes subjects who have received at least 1 dose of SHP681or placebo in 
the SAD portion.

The SAD PK analysis data set consists of subjects who have received at least 1 dose of SHP681 and have at 
least 1 evaluable post-dose PK concentration value in the SAD portion.
MAD

The MAD safety analysis data set includes subjects who have received at least 1 dose of SHP681or placebo 
in the MAD portion.

The MAD PK analysis data set consists of subjects who have received at least 1 dose of SHP681 and have at
least 1 evaluable post-dose PK concentration value in the MAD portion.
Pharmacokinetic Endpoints:

Pharmacokinetic parameters including exposure and property parameters will be calculated for individual
subjects using plasma SHP681 concentration-time data and non-compartmental analysis for both SAD and
MAD parts and all calculations will be based on actual sampling times. Effect of anti-drug antibody (ADA)
and neutralizing anti-drug antibody (nADA) on PK will be evaluated. 
The PK analysis will be based on the PK analysis set.
Pharmacokinetic parameters will be calculated from plasma SHP681 concentration-time data using 
non-compartmental methods and all calculations will be based on actual sampling times. Pharmacokinetic 
parameters will include, but not be limited to, the following:
SAD
Cmax:
Maximum concentration occurring at tmax
tlast:
Time of the last measurable concentration
tmax:
Time of maximum observed concentration sampled during a dosing interval
AUC0-last:
Area under the curve from the time of dosing to the last measurable concentration
AUC0-∞:
Area under the curve extrapolated to infinity
t1/2:
Terminal half-life
z:
First order rate constant associated with the terminal (log-linear) portion of the curve
CL/F:
Apparent total body clearance for extravascular administration divided by the fraction of dose
absorbed calculated as dose divided by AUC0-∞.
Vz/F:
Apparent volume of distribution following extravascular administration divided by the fraction
of dose absorbed calculated as CL/F divided by z.
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MAD
Post first dose
AUC0-24: Area under the curve from the time of dosing to the 24 hours post first dose
Cmax,24: Maximum concentration occurring during 24 hours after first dose
tmax,24: Time of maximum observed concentration during 24 hours after first dose
Between the first dose and last dose
Ctrough:
Observed concentration at the end of each dosing interval
(immediately before next dose for the first 5 cohorts and immediately before 2nd and 3rd dose of 
the 6th MAD cohort)
Post last dose
Cmax:
Maximum concentration during the dosing interval occurring at tmax
Tlast:
Time of the last measurable concentration
tmax:
Time of maximum observed concentration during the dosing interval
AUCtau: Area under the curve for the defined interval between doses (only calculated if interpretable)
AUC0-last: Area under the curve from the time of dosing to the last measurable concentration post last dose
AUC0-∞: Area under the curve (post last dose) extrapolated to infinity, calculated using the observed value of the
last non-zero concentrations (only calculated if interpretable)
t1/2
Terminal half-life
z
First order rate constant associated with the terminal (log-linear) portion of the curve
CL/F
Apparent total body clearance following extravascular administration divided by the fraction of
dose absorbed calculated as dose divided by AUCtau
Vz/F
Apparent volume of distribution following extravascular administration divided by the fraction
of dose absorbed calculated as CL/F divided by z
Safety Endpoints:
For both the SAD and MAD portions, the safety and tolerability of escalating SC doses of SHP681 will be
evaluated by examining for each cohort: number, severity, seriousness and causality of all treatment-emergent
adverse events (TEAEs), including injection site and hypersensitivity reactions, changes in vital signs, ECGs,
abdominal ultrasounds, and clinical laboratory results (hematology, chemistry, and urinalysis) from baseline to
post-baseline timepoints, incidence of anti-drug antibodies (ADA) to SHP681 and incidence of neutralizing anti-
drug antibodies (nADA) to SHP681.
Sample Size Justification:
SAD
It is planned that dose escalation will proceed for up to 5 dose levels. Each cohort will include 5 subjects treated
with SHP681 and 1 subject treated with placebo for a planned total of 30 subjects. However, if dose levels are
repeated, modified, or not conducted or if additional dose levels are studied, the total number of subjects may
change. The number of subjects is expected to provide reasonable information on initial testing of SHP681 for
safety and PK while exposing as few subjects as possible to investigational drug materials. The number of subjects
in this study is not based on statistical hypothesis testing and power considerations as this is the first in human
study. The statistical analyses are primarily descriptive, and no hypothesis testing is specified for this portion.
MAD
It is planned that the MAD portion of the study will include 6 cohorts. Each cohort will include 10 subjects treated
with SHP681 and 2 subjects treated with placebo for a planned total of 72 subjects. The number of subjects is
expected to provide reasonable information on initial testing of SHP681 for safety and PK while exposing as few
subjects as possible to investigational drug materials. The number of subjects in this study is not based on 
For non-commercial use only


For non-commercial use only


For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
STUDY SCHEDULE(S)
Table 1
Schedule of Assessments (SAD Portion)
Visit
Screening
Treatment Period (All Cohorts)
Study Day
–28 to -2
-1
1
2
3
4
5
6
8
11
15
22
29
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical/medication history
X
Physical examination (Including Height and
Weight)a,b
X
X
X
X
Vital signs (body temperature, blood
pressure, pulse)a,c
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a, d
X
X
X
X
X
X
X
Biochemistry, hematology, and urinalysisa, j, l
X
X
X
X
X
Xm
X
HIV, HBsAg, and HCV antibodies
X
Pregnancy test (women only)a, e
X
X
X
X
X
X
X
Urine drug and alcohol screeningf
X
X
X
X
X
X
Randomization
Xi
SHP681 or placebo administration
X
Pharmacokinetic blood samplingg
X
X
X
X
X
X
X
X
X
X
X
ADA and nADA sampling
X
X
Admit to CRC
X
Discharge from CRCh
X
Outpatient visit
Xk
Xk
Xk
Xk
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 1
Schedule of Assessments (SAD Portion)
Visit
Screening
Treatment Period (All Cohorts)
Study Day
–28 to -2
-1
1
2
3
4
5
6
8
11
15
22
29
β-hCG=beta human chorionic gonadotropin; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a In the event a subject prematurely withdraws or is discontinued from the study, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; these assessments should be performed within 15 minutes of the planned timepoint. The subject should not have 
exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to collection. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG.
e Serum β-hCG test at screening is required for all women. Urine pregnancy test is required for all women at subsequent scheduled timepoints
f Drugs of abuse at screening and drugs of abuse and alcohol on Day -1, Day 11, Day 15, Day 22, and Day 29; a breathalyzer test for alcohol may be done if more convenient than 
a urine alcohol test.
g See Table 2 for detailed collection timepoints.
h Subject to be discharged following the completion of all assessments on Day 8.
i Randomization to SHP681 or placebo will occur on Day -1 or Day 1 only.
j Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
k A window of +/- 1 day is allowed for outpatient visits on Days 11, 15, 22, and 29 to allow for subject flexibility.
l Full thyroid panel (T3, T4, TSH, Free T3 and Thyroxine-binding globulin [TBG]) on Day 1 (Predose), Day 8 and Day 15.
m On Day 15, only a full thyroid panel (T3, T4, TSH, Free T3, and Thyroxine-binding globulin [TBG]) will be collected.
For non-commercial use only


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CONFIDENTIAL
Page 22
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 2
Detailed Schedule of Assessments for SAD
Study Day
Day 1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
8
Day
11
Day
15
Day
22
Day
29
Hour (relative to dosing time)
Pre 
dose
0
3
6
12
24
48
72
96
120
168
240
336
504
672
Physical examination (Including Height and Weight)a, b
X
X
Vital signs (body temperature , blood pressure, pulse)a, c
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a,d
Xe
X
X
X
X
X
X
X
Biochemistry, hematology, and urinalysisa, f, g
Xe
X
X
Xh
X
SHP681 or placebo administration
X
Pharmacokinetic blood sampling
Xe
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA and nADA blood sampling
Xe
X
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e These assessments should be performed within 30 minutes prior to dose administration.
f Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
g Full thyroid panel (T3, T4, TSH, Free T3 and Thyroxine-binding globulin [TBG]) on Day 1 (Predose), Day 8 and Day 15.
h On Day 15, only a full thyroid panel (T3, T4, TSH, Free T3, and Thyroxine-binding globulin [TBG]) will be collected.
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 3
Schedule of Assessments (MAD Portion for Cohorts 1-5)-Part 1
Visit
Screening
Treatment Period (Cohorts 1-5)
Study Day
–28 to -2
-1
1
2
3
4
7
8
10
14
15
18
21
22
24
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical/medication history
X
Physical examination (Including Height and Weight) 
a,b
X
X
X
Xk
Xk
Xk
Vital signs (body temperature, blood pressure, 
pulse)a,c
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a,d
X
X
X
X
X
X
X
X
X
Biochemistry, hematology, and urinalysisa,l
X
X
X
X
X
X
X
X
HIV, HBsAg, and HCV antibodies
X
Pregnancy test (women only)a, e
X
X
X
X
X
X
X
X
X
Urine drug and alcohol screeningf
X
X
X
X
X
Randomization
Xj
SHP681 or placebo administration
X
X
X
X
Pharmacokinetic blood samplingg
X
X
X
X
X
ADA and nADA blood sampling
X
X
X
X
X
Admit to CRC
X
X
X
X
Discharge from CRCi
X
X
X
X
Outpatient visit
Upper GI endoscopy with biopsy
X
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
βhCG=beta human chorionic gonadotropin; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a In the event a subject prematurely withdraws or is discontinued from the study, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; these assessments should be performed within 15 minutes of the planned timepoint. The subject should not have 
exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to collection. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG.
e Serum β-hCG test at screening is required for all women. Urine pregnancy test is required for all women at subsequent scheduled timepoints
f Drugs of abuse at screening and drugs of abuse and alcohol on Day -1, Day 7, Day 14, Day 21, Day 28; Day 39, Day 43, Day 50, Day 57 a breathalyzer test may be done if more 
convenient than a urine alcohol test.
g See Table 4 and Table 5 for detailed collection timepoints. 
h Subjects must fast for at least 8 hours prior to collection
i Subject to be discharged following the last assessment on study days noted. The inhouse period may be revised due to operational issues pending approval by the PI and Sponsor.
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 3
Schedule of Assessments (MAD Portion for Cohorts 1-5)-Part 1
Visit
Screening
Treatment Period (Cohorts 1-5)
Study Day
–28 to -2
-1
1
2
3
4
7
8
10
14
15
18
21
22
24
j Randomization to SHP681 or placebo will occur on Day -1 or Day 1 only.
k Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
l Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
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CONFIDENTIAL
Page 25
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 3
Schedule of Assessments (MAD Portion for Cohorts 1-5)-Part 2
Visit
Treatment Period (Cohorts 1-5)
Study Day
28
29
30
31
32
33
34
36
39
43
50
57
Informed consent
Inclusion/exclusion criteria
X
Demographics and medical/medication history
Physical examination (Including Height and Weight) a,b
Xj
X
Xj
X
Vital signs (body temperature, blood pressure, pulse)a,c
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a, d
X
X
X
X
X
X
Biochemistry, hematology, and urinalysisa, l
X
X
X
X
X
HIV, HBsAg, and HCV antibodies
Pregnancy test (women only)a, e
X
X
X
X
X
X
Urine drug and alcohol screeningf
X
X
X
X
X
Randomization
SHP681 or placebo administration
X
Pharmacokinetic blood samplingg
X
X
X
X
X
X
X
X
X
X
X
ADA and nADA blood sampling
X
X
X
X
X
Admit to CRC
X
Discharge from CRCi
X
Outpatient visit
Xm
Xm
Xm
Xm
Upper GI endoscopy with biopsy
Xk
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 3
Schedule of Assessments (MAD Portion for Cohorts 1-5)-Part 2
Visit
Treatment Period (Cohorts 1-5)
Study Day
28
29
30
31
32
33
34
36
39
43
50
57
βhCG=beta human chorionic gonadotropin; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a In the event a subject prematurely withdraws or is discontinued from the study, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for at 
least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure throughout the 
study.
d 12-lead electrocardiograms will be performed at each timepoint; these assessments should be performed within 15 minutes of the planned timepoint. The subject should not have 
exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting 
the ECG.
e Serum β-hCG test at screening is required for all women. Urine pregnancy test is required for all women at subsequent scheduled timepoints.
f Drugs of abuse at screening and drugs of abuse and alcohol on Day -1, Day 7, Day 14, Day 21, Day 28; Day 39, Day 43, Day 50, Day 57 a breathalyzer test may be done if more 
convenient than a urine alcohol test.
g See Table 6 for detailed collection timepoints. PK timepoints post day 33 can have a -/+ one day window.
h Subjects must fast for at least 8 hours prior to collection
i Subject to be discharged following the last assessment on study days noted. The inhouse period may be revised due to operational issues pending approval by the PI and Sponsor.
j Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted
k This procedure will be performed on Day 36 (ie, window of +/-3 days).
l Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
m A window of +/- 1 day is allowed for outpatient visits on Days 39, 43, 50, and 57 to allow for subject flexibility.
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CONFIDENTIAL
Page 27
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 4
Detailed Schedule of Assessments for MAD Cohorts 1-5 (Day 1 to Day 4)
Study Day
Day 1
Day 2
Day 3
Day 4
Hour (relative to dosing time)
Pre 
dose
0
3
6
12
24
48
72
Physical examination (Including Height and Weight)
a, b
Xg
Vital signs (body temperature, blood pressure, pulse)
a, c
X
f
X
X
X
X
X
X
Electrocardiogram(12-lead)a,d
X
f
X
X
X
X
X
X
Biochemistry, hematology,and urinalysis
a, h
X
f
X
X
SHP681 or placebo administration
X
Pharmacokinetic blood sampling
X
f
X
X
X
X
ADA and nADA blood sampling
X
f
X
f
Upper GI endoscopy with biopsy
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
For non-commercial use only


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CONFIDENTIAL
Page 28
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 5
Detailed Schedule of Assessments for MAD Cohorts 1-5 (Day 7 to Day 22)
Study Day
Day 7
Day 8
Day 14
Day 15
Day 21
Day 22
Hour (relative to dosing time)
0
Predose
0
0
Predose
0
0
Predose
0
Physical examination (Including Height and Weight)
a, b
Xg
Xg
Xg
Vital signs (body temperature, blood pressure, pulse)
a, c
X
X
f
X
X
g
X
X
g
Electrocardiogram (12-lead)a,d
X
f
X
g
X
g
Biochemistry, hematology,and urinalysisa, h
Xf
X
X
SHP681 or placebo administration
X
X
X
Pharmacokinetic blood sampling
X
f
X
g
X
g
ADA and nADA blood sampling
X
f
X
g
X
g
Upper GI endoscopy with biopsy
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
For non-commercial use only


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CONFIDENTIAL
Page 29
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 6         Detailed Schedule of Assessments for MAD Cohorts 1-5 (Day 28 to Day 57)
Study Day
Day
28
Day 29
Day
30
Day
31
Day
32
Day
33
Day
34
Day
36
Day
39
Day
43
Day
50
Day
57
Hour (relative to dosing time)
0
Predose
0
3
6
12
24
48
72
96
120
168
240
336
504
672
Physical examination (Including 
Height and Weight)
a, b
Xg
Xg
Xg
X
Vital signs (body temperature , 
blood pressure, pulse)
a, c
X
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a,d
X
X
f
X
X
X
X
X
X
X
Biochemistry, hematology, and 
urinalysisa, i
X
X
f
X
X
X
SHP681 or placebo
administration
X
Pharmacokinetic blood sampling
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA and nADA blood sampling
X
f
X
X
X
X
Upper GI endoscopy with biopsy
Xh
Adverse events/serious adverse 
eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h This procedure will be performed on Day 36 (ie, window of +/- 3 days).
i Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
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For non-commercial use only


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CONFIDENTIAL
Page 31
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 7
Schedule of Assessments for 6th MAD Cohort (Day 1 to Day 57)
Visit
Screening
Treatment Period (Cohort 6)
Study Day
-28
-1
1
2
3
4
8
14
15
18
22 n
28
29
30
31
32
33
34
36
39
43
50 o
57 p
Discharge from 
CRCi
X
X
X
Outpatient visit
X
X
X
X
X
X
Upper GI 
endoscopy with 
biopsy
X
Xl
Abdominal 
ultrasounda
X
Xl
Adverse 
events/serious 
adverse eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
βhCG=beta human chorionic gonadotropin; CRC=clinical research center; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus
a In the event a subject prematurely withdraws or is discontinued from the study, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for at 
least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure throughout the 
study.
d 12-lead electrocardiograms will be performed at each timepoint; these assessments should be performed within 15 minutes of the planned timepoint. The subject should not have 
exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the 
ECG.
e Serum β-hCG test at screening is required for all women. Urine pregnancy test is required for all women at subsequent scheduled timepoints
f Drugs of abuse at screening and drugs of abuse and alcohol on the remainder of study days as indicated. A breathalyzer test may be done if more convenient than a urine alcohol test.
g See Table 8, Table 9, and Table 10 for detailed collection timepoints. PK samples drawn beyond Day 2 cannot deviate by more than ±10% of the specified time from the first dose.
h Subjects must fast for at least 8 hours prior to collection
i Subject to be discharged following the last assessment on study days noted. The inhouse period may be revised due to operational issues pending approval by the PI and Sponsor.
j Randomization to SHP681 or placebo will occur on Day -1 or Day 1 only.
k Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and skin) 
on study days noted.
l This procedure will be performed on Day 36 (window of +/-3 days).
m Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
n A window of + / - 2 days is allowed for Day 22 visit to allow for subject flexibility.
o A window of +/- 3 days is allowed for Day 50 visit to allow for subject flexibility.
p A window of +/- 4 days is allowed for Day 57 visit to allow for subject flexibility.
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CONFIDENTIAL
Page 32
SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Table 8
Detailed Schedule of Assessments for MAD Cohort 6 (Day 1 to Day 4)
Study Day
Day 1
Day 2
Day 3
Day 4
Hour (relative to dosing time)
Pre 
dose
0
3
6
12
24
48
72
Physical examination (Including Height and Weight)
a, b
Xg
Vital signs (body temperature, blood pressure, pulse)
a, c
X
f
X
X
X
X
X
X
Electrocardiogram(12-lead)a,d
X
f
X
X
X
X
X
X
Biochemistry, hematology,and urinalysis
a, h
X
f
X
X
SHP681 or placebo administration
X
Pharmacokinetic blood sampling
X
f
X
X
X
X
ADA and nADA blood sampling
X
f
X
f
Upper GI endoscopy with biopsy
Adverse events/serious adverse eventsa
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
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Table 9
Detailed Schedule of Assessments for MAD Cohort 6 (Day 8 to Day 22)
Study Day
Day 8
Day 14
Day 15
Day 22i
Hour (relative to dosing time)
0
0
Predose
0
0
Physical examination (Including Height and Weight)
a, b
Xg
Xg
Xg
Vital signs (body temperature, blood pressure, pulse)
a, c
X
X
X
f
X
Electrocardiogram (12-lead)a,d
X
Xf
X
Biochemistry, hematology,and urinalysisa, h
X
Xf
X
SHP681 or placebo administration
X
Pharmacokinetic blood samplingj
Xf
ADA and nADA blood sampling
X
Xf
X
Upper GI endoscopy with biopsy
Adverse events/serious adverse eventsa
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
i A window of + / - 2 days is allowed for Day 22 visit to allow for subject flexibility.
j PK samples drawn beyond Day 2 cannot deviate by more than ±10% of the specified time from the first dose.
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Table 10
Detailed Schedule of Assessments for MAD Cohort 6 (Day 28 to Day 57)
Study Day
Day
28
Day 29
Day
30
Day
31
Day
32
Day
33
Day 
34
Day 
36
Day
39
Day
43
Day
50j
Day
57 k
Hour (relative to dosing time)
0
Predose
0
3
6
12
24
48
72
96
120
168
240
336
504
672
Physical examination (Including 
Height and Weight)
a, b
Xg
Xg
Xg
X
Vital signs (body temperature, 
blood pressure, pulse)
a, c
X
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (12-lead)a,d
X
X
f
X
X
X
X
X
X
X
Biochemistry, hematology, and 
urinalysisa, i
X
X
f
X
X
X
SHP681 or placebo
administration
X
Pharmacokinetic blood samplingl
X
f
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA and nADA blood sampling
X
f
X
X
X
X
Upper GI endoscopy with biopsy
Xh
Abdominal ultrasounda
Xh
Adverse events/serious adverse 
eventsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a In the event a subject is prematurely discontinued from the study or withdraws, every attempt should be made to complete these assessments.
b Height will be recorded at the screening visit only.
c Vital signs will be obtained while the subject is seated for 5 minutes on study days noted. Oral temperature should be taken by placing a digital thermometer under the tongue for 
at least 30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be used. Whichever procedure is used should be the same procedure 
throughout the study.
d 12-lead electrocardiograms will be performed at each timepoint; the subject should not have exercised or consumed caffeine, alcohol, or nicotine within 30 minutes prior to 
collection. The subject must be resting in the supine position for at least 5 minutes prior to collecting the ECG.
e Subjects must fast for at least 8 hours prior to collection.
f These assessments should be performed within 30 minutes prior to dose administration.
g Abbreviated physical exam will be performed (includes minimally general appearance; head, eyes, ears, nose, and throat; cardiovascular; respiratory; neurological; abdomen; and 
skin) on study days noted.
h This procedure will be performed on Day 36 (window of +/-3 days).
i Urine collections should be from the first void of the day while the subjects are confined to the unit; during outpatient visits, urine may be obtained at any time during the visit.
j A window of +/- 3 days is allowed for Day 50 visit to allow for subject flexibility.
k A window of +/- 4 days is allowed for Day 57 visit to allow for subject flexibility.
l PK samples drawn beyond Day 2 cannot deviate by more than ±10% of the specified time from the first dose.
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Table 11
Early Discontinuation Assessments
Study Procedure
Early Discontinuation Visita,b
Concomitant medications
X
Physical examination (including weight)c
X
Vital signs (blood pressure, pulse)d
X
Biochemistry, hematology, and urinalysis
X
Pregnancy testinge
X
Abdominal ultrasound
X
ADA and nADA blood sampling
X
Adverse events/serious adverse eventsf
X
a Rules for data collection when subjects are discontinued from the study are provided in Section 4.5 of the protocol.
b The early discontinuation visit will be conducted at 28 (±7) days after the last dose of investigational product
c Abbreviated physical exam on all subjects (includes minimally general appearance; head, eyes, ears, nose, and throat; 
cardiovascular; respiratory; neurological; abdomen; and skin).
d Vital signs will be measured with the subject in a seated position using standard methods/equipment at the CPU. Subjects 
should be in a seated position for at least 5 minutes prior to the procedure. Vital signs should be measured before the collection of 
blood (eg, safety labs).
eA urine pregnancy test will be performed for all female subjects.
fAll AEs are collected from the time the informed consent is signed through 7 days after the last dose of investigational product. 
Investigators will report all SAEs that occur ≤30 days after the last dose of investigational product and related SAEs that occur 
>30 days after the last dose of investigational product to Shire Global Safety Department.
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1. BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options
SHP681 is the Glucagon-like peptide-2 (GLP-2) analog-Fc fusion protein, abbreviated as 
GLP-2 analog-Fc fusion. The IP will be called SHP681 through this document.
SHP681, a long acting glucagon like peptide-2 (GLP-2) analog, is being developed for treating 
patients with short bowel syndrome (SBS).
Short bowel syndrome is a rare, serious, disabling, socially incapacitating, and potentially
life-threatening condition (Nightingale and Woodward, 2006) resulting from surgical resection 
or congenital loss of most of the absorptive surface area of the small intestine (O' Keefe et al., 
2006). Short bowel syndrome is characterized by the inability to maintain protein-energy, fluid, 
electrolyte, or micronutrient balances when on a conventionally accepted, normal diet (O' Keefe 
et al., 2006). Causes of SBS in adults include Crohn's disease, mesenteric ischemia, volvulus, 
trauma, surgical complications, and cancer.
The prevalence of adults with intestinal failure due to SBS is estimated at 2-4 million, (Bakker et 
al., 1999; Kelly et al., 2014; Mughal and Irving, 1986) while the incidence of neonatal SBS is 
estimated at 24.5 per 100,000 live births (Wales et al., 2004). It is estimated that 83% of pediatric 
cases of SBS begin during infancy (Guarino and De Marco, 2003).
Patients with SBS are highly prone to malnutrition, diarrhea, dehydration, electrolyte 
disturbances, malabsorption of nutrients, gastric hypersecretion, metabolic acidosis, 
cholelithiasis, nephrolithiasis, steatorrhea, small bowel bacterial overgrowth and an inability to 
maintain weight due to the reduced intestinal capacity to absorb macronutrients, water, and 
electrolytes (Dudrick et al., 1991; Nightingale, 1999; Rombeau and Rolandelli, 1987; 
Shanbhogue and Molenaar, 1994; Vanderhoof and Langnas, 1997; Wilmore et al., 1997;
Nightingale and Woodward, 2006; O' Keefe et al., 2006). Complications common to SBS 
include d-lactic acidosis, hyperoxaluria, intestinal failure associated liver disease, and 
anastomotic ulcers.
Short bowel syndrome is the leading cause of intestinal failure, defined as the requirement for 
parenteral support (intravenous nutrition and/or fluids) to maintain health and/or growth (Pironi 
et al., 2016). Although parenteral support (PS) is considered life-saving, it is also well associated 
with serious complications such as catheter-associated bloodstream infections, catheter breakage, 
central venous thrombosis, metabolic bone disease, and liver disease. The risks of these 
complications increase commensurately with the duration of intestinal failure, and as a result, 
patients with intestinal failure have higher mortality rates than those with intestinal insufficiency
(Amiot et al., 2013; Goulet et al., 2005).
Some patients with SBS 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) such that they can attain enteral 
autonomy (independence from parenteral support) even though they continue to have symptoms 
of malabsorption (intestinal insufficiency).
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However, there are limits to the adaptive capacity of the small intestine, especially in cases 
where the distal ileum and colon have been removed. Such patients often have a compromised 
adaptive response due in part to deficiency in glucagon-like peptide 2 (GLP-2), a hormone 
produced by L-type enteroendocrine cells that reside in these segments of bowel.
In response to the presence of unabsorbed nutrients in the distal ileum and colon, L-type 
enteroendocrine cells release GLP-2, which acts on receptors in sub-epithelial myofibrobasts 
and enteric neurons. This triggers the release of growth factors that stimulate intestinal 
epithelial stem cell proliferation and inhibit epithelial apoptosis, resulting in increases in villus 
height and crypt depth, thereby increasing the absorptive surface area of the remaining gut. 
Other downstream effects include increases in splanchnic blood flow, inhibition of gastric acid 
production, and slowing of gastric emptying.
1.2
Product Background
Teduglutide is a recombinant human GLP-2 analog with an Ala2Gly substitution, which 
increases the half-life from 7 minutes to approximately 2 hours in healthy subjects and 
1.3 hours in adult SBS subjects.
SHP681 is a fusion protein containing 2 moieties of teduglutide, a polypeptide linker, and 
human IgG1Fc. Based on animal models, the predicted half-life in humans for SHP681 is 
approximately 4 days, which may allow once weekly dosing.
1.2.1
Preclinical Information
SHP681 demonstrated in animal models a longer half-life than teduglutide. The present study is 
a first in human (FIH) study to assess the safety, tolerability, and pharmacokinetics of SHP681 
when administered as single and multiple, ascending subcutaneous (SC) doses.
Refer to the Investigator’s Brochure provided under separate cover for more information.
1.2.2
Clinical Information
Teduglutide has been shown in clinical trials to reduce parenteral support requirements in 
patients with SBS. It is approved in the US (as Gattex®) for the treatment of adults with SBS 
who are dependent on parenteral support, and in Europe (as Revestive®) for treatment of 
patients aged 1 year and above with SBS who are stable following a period of intestinal 
adaptation after surgery. Teduglutide is administered at 0.05 mg/kg subcutaneous once daily.
Always refer to the latest version of the SHP681 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP681.
1.3
Risk/Benefit and Ethical Assessment
There is no anticipated benefit from taking part in this study.
Risks for subject exposure to SHP681 are listed in the current investigator brochure.
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3. STUDY DESIGN
3.1
Study Design and Flow Chart
This study is a randomized, double-blind, placebo-controlled, Phase 1 study to assess the safety 
and tolerability, and pharmacokinetics of SHP681 following single and multiple, ascending, SC 
doses in healthy adult subjects. This study will be conducted at a single center and 5 dose levels 
are planned for both the single-ascending dose (SAD) and multiple-ascending dose (MAD) parts 
of this study. A total of 102 subjects (30 for the SAD portion and 72 subjects for the MAD 
portion) are planned to be enrolled for this study.
The plan is to enroll in the SAD portion of the study 30 subjects in 5 cohorts. Each cohort will 
include 6 subjects. Subjects will be randomized within each cohort such that 5 subjects receive 
SHP681 and 1 subject receives placebo.
The MAD portion of this study may initiate upon completion of a pharmacokinetic and safety 
data review of SAD Cohort 1, SAD Cohort 2, and partial data from SAD Cohort 3 (see Part 1). 
The plan is to enroll 72 subjects within 6 MAD cohorts. Each cohort will include 12 subjects. 
Subjects will be randomized within each cohort such that 10 subjects receive SHP681 and 
2 subjects receive placebo.
The study design is shown in the study schema in Figure 1 and Figure 2.
Figure 1
Study Design Flow Chart for the SAD portion
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Figure 2
Study Design Flow Chart for the MAD portion
3.1.1
Dose selection, rationale and administration
SAD(Part1)
Dose escalation will proceed sequentially to assess the following SC doses of SHP681:
0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. After a single administration of SHP681 
or placebo in each cohort, if the dose is assessed as safe and tolerable during a dose escalation 
meeting, the next cohort will be administered a SC dose of SHP681 at the next higher dose level 
or placebo. All subjects will have the IP administered in the abdomen. During dose escalation, 
protocol defined dose levels may be reduced, repeated, discontinued, or an intermediate increase 
may be added depending on the outcome of the blinded safety data review between dose 
escalations. Upon completion of these 5-dose cohorts, additional doses may be studied based on 
emergent safety data.
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MAD (Part 2)
The MAD part will not commence until results of a pharmacokinetic and safety data review of 
SAD Cohort 1, SAD Cohort 2, and partial data from SAD Cohort 3 are available. Each cohort 
will receive SHP681 (or placebo) once weekly for 5 weeks. After the first cohort has been 
administered 2 doses of SHP681 (or placebo) over 2 weeks and the dose is assessed as safe and 
tolerable during a dose escalation meeting, the next MAD cohort will commence. All subjects 
will have the IP administered in the abdomen. Dose escalation will proceed sequentially to 
include the following SC doses: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg weekly.
An interim analysis was performed after the last subject from the 3rd MAD cohort completed the 
Day 39 visit, to determine the dose level of the 6th MAD cohort, and to assess safety and 
pharmacodynamics. As of the interim analysis, TAK-681 was well-tolerated and dose-dependent 
. The absorption of TAK-681 following SC 
dosing was slow, with absorption half-life ranging from 12.7 hours to 30.7 hours. The apparent 
clearance and volume of distribution were 0.105 L/hours and 14.3 L, respectively. The mean 
elimination half-life of TAK-681 ranged from 89.8 hours to 104 hours (ie, 3.7 days to 4.3 days) 
across dose levels. TAK-681 PK properties were observed to be linear and time-independent. 
Using a noncompartmental analysis, the area under the concentration-time curve from time zero 
to infinity of TAK-681 after multiple doses increased in a dose-proportional manner from 
0.2 mg/kg to 1 mg/kg. Based on these results, a dose of 4 mg/kg SHP681 (or placebo) every 
2 weeks over a 6-week period (3 doses) was nominated for the 6th MAD cohort. 
During dose escalation, protocol defined dose levels may be reduced, repeated, discontinued, or 
an intermediate increase may be added depending on the outcome of the blinded safety data 
review between dose escalations. 
3.1.2
Screening and Treatment Period
SAD (Part 1)
The SAD portion of the study will consist of a screening period of up to 28 days and one 
treatment period of 29 days. A total of 8 overnight stays are required for the SAD portion of the 
study.
The first dose will occur within 28 days of screening. Subjects will be admitted to the clinical 
research center (CRC) on Day -1 and randomized to SHP681 or placebo on Day -1 or the 
morning of Day 1 as indicated in Figure 1. Subjects will not participate in more than 1 treatment 
cohort.
Safety and tolerability will be assessed by treatment-emergent AEs (TEAEs), vital signs, 
electrocardiogram (ECG) findings, and clinical laboratory evaluations.
Blood samples for pharmacokinetic analysis of SHP681 will be collected through 672 hours post 
dose in each dosing period. The last study visit is scheduled at Day 29 and will include final 
safety assessments; there will be no further follow up. Additionally, blood draws for 
determination of anti-drug antibodies (ADAs) and neutralizing antidrug antibody (nADA) will be 
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The Study Completion Date is defined as the date the LAST subject, completes their final 
protocol-defined assessments.
Please note that this includes the last visit or contact, whichever is later. The Study Completion 
Date is used to ascertain timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at 1 CRC in the United States.
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4. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below. 
Subjects cannot be randomized before all inclusion criteria (including test results) are confirmed.
1. Ability to voluntarily provide written, signed, and dated informed consent to participate 
in the study.
2. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.
3. Age 18-50 inclusive at the time of consent. The date of signature of the informed consent 
is defined as the beginning of the screening period. This inclusion criterion will only be 
assessed at the first screening visit.
4. Male, or non-pregnant, non-lactating female who agrees to comply with any applicable 
contraceptive requirements of the protocol or females of non-childbearing potential.
5. Considered “healthy” by the investigator. Healthy status is defined by absence of 
evidence of any active or chronic disease or condition based on a detailed medical and 
surgical history, a complete physical examination including vital signs, 12-lead ECG, 
hematology, blood chemistry, and urinalysis.
6. Body mass index between 18.0 kg/m² and 30.0 kg/m² inclusive with a body weight 
50-100 kg (110-220 lbs). This inclusion criterion will only be assessed at the first 
screening visit.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. History of any hematological, hepatic, respiratory, cardiovascular, renal, neurological or 
psychiatric disease, gall bladder removal, or current or recurrent disease that could affect 
the action, absorption, or disposition of the investigational product, or clinical or 
laboratory assessments.
2. Current or relevant history of physical or psychiatric illness, any medical disorder that 
may require treatment or render the subject unlikely to fully complete the study, or any 
condition that presents undue risk from the investigational product or procedures.
3. Known or suspected intolerance or hypersensitivity to the investigational product(s), 
closely- related compounds, or any of the stated ingredients.
4. Significant illness, as judged by the investigator, within 2 weeks of the first dose of 
investigational product.
5. Known history of alcohol or other substance abuse within the last year.
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6. Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to 
receiving the first dose of investigational product.
7. Within 30 days prior to the first dose of investigational product:
a.
Have used an investigational product (if elimination half-life is <6 days, otherwise 
5 half-lives).
b. Have been enrolled in a clinical study.
c.
Have had any substantial changes in eating habits, as assessed by the investigator.
8. Use of DPP-4 inhibitors within 30 days or 5 half-lives, whichever is greater, prior to 
administration of the investigational product.
9. Confirmed systolic blood pressure >139mmHg or <89mmHg, and diastolic blood 
pressure >89 mmHg or <49 mmHg.
10. Twelve-lead ECG demonstrating QTcF >450 msec at screening. If QTcF exceeds 
450 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF 
values should be used to determine the subject’s eligibility.
11. Positive screen for alcohol or illicit drugs at screening or Day -1.
12. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. 
Female subjects who consume more than 14 units of alcohol per week or 2 units per day. 
(1 alcohol unit=1 beer or 1 wine (5 oz/150 mL) or 1 liquor (1.5 oz/40 mL) or 0.75 oz 
alcohol).
13. Positive HIV, HBsAg, or HCV antibody screen.
14. Use of tobacco in any form (eg, smoking or chewing) or other nicotine-containing 
products in any form (eg, gum, patch). Ex-users must report that they have stopped using 
tobacco for at least 30 days prior to receiving the first dose of investigational product.
15. Routine consumption of more than 2 units of caffeine per day or subjects who experience 
headaches associated with caffeine withdrawal. (1 caffeine unit is contained in the 
following items: one 6 oz (180 mL) cup of coffee, two 12 oz (360 mL) cans of cola, one 
12 oz cup of tea, three 1 oz (85 g) chocolate bars. Decaffeinated coffee, tea, or cola are 
not considered to contain caffeine).
16. Prior screen failure (unless Sponsor approval is given), randomization, participation, or 
enrollment in this study or prior exposure to any GLP-2 analogs
17. Unresected GI polyp, known polyposis condition, or premalignant changes in the GI 
tract.
18. Any history of malignancy in the GI tract or treatment for any other malignancy in the 
previous 5 years.
19. Current use of any medication (including over-the-counter, herbal, or homeopathic 
preparations; with the exception of hormonal replacement therapy or hormonal 
contraceptives and occasional use of ibuprofen or acetaminophen and pre-approved 
medication for sedation or other medications required during or after the endoscopy). 
Current use is defined as use within 14 days of the first dose of investigational product.
20. Findings of subclinical hepatobiliary disease, such as gallstones, on abdominal ultrasound 
at screening as determined by the Investigator in consultation with the Medical Monitor.
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4.3
Restrictions
1. Subjects should refrain from taking DPP4 inhibitors through the course of the study.
2. Subjects should refrain from strenuous physical exercise 48 hours prior to admission to 
the CRC and during the in-house stays at the CRC.
3. Subjects should refrain from alcohol 48 hours prior to admission to the CRC and during 
the in-house stay at the CRC.
4. Subjects should refrain from use of tobacco or any products containing nicotine within 
30 days of Day 1 of the first treatment period through the completion of the last treatment 
period.
5. Subjects should refrain from taking or regularly using any medication (including over-the 
counter multivitamin, herbal, or homeopathic preparations) with the exception of those 
listed in Section 5.2 from 14 days prior to receiving the first dose of the investigational 
product through the completion of the discharge assessments and procedures.
6. Subjects should refrain from foods or beverages containing caffeine/xanthine 48 hours 
prior to admission to the CRC and during the in-house stay at the CRC.
7. Subjects will be required to follow standardized meal schedules and eat the meals 
provided by the site while housed in the CRC. No outside food or beverages (including 
gum, mints, etc.) will be permitted. Menus will be identical for all subjects at the CRC. 
Subjects are not required to complete the entire meal but must meet their individual 
nutritional requirements to maintain stable weight. Copies of the menus will be provided 
to the sponsor for approval prior to the start of the study. 
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of childbearing potential should be using an acceptable form of 
contraception. Females of childbearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of 
investigational product. If hormonal contraceptives are used, they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually
active must agree to use acceptable contraception, as defined below, if they become sexually 
active during the period of the study and 30 days following the last dose of investigational 
product.
Female subjects should be either:

Medically confirmed postmenopausal surgically sterile (having undergone one of the 
following surgical acts: hysterectomy, bilateral tubal ligation, bilateral oophorectomy or 
bilateral salpingectomy) and at least 6 weeks post-sterilization, or

Females of childbearing potential with a negative serum beta-human chorionic gonadotropin 
(β-hCG) pregnancy test at screening and negative urine pregnancy test on Day -1. Females of 
childbearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
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Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the first dose of investigational product, plus condoms. Note: If subject 
becomes sexually active during the study, they should use one of the other acceptable 
methods noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.4.2
Male Contraception
Male subjects must be advised to use acceptable contraceptives throughout the study period 
and for 3 months following the last dose of investigational product. Male subjects must be 
advised not to donate sperm during the course of the study and within 3 months of the last dose 
of investigational product. The acceptable method of contraception for male subjects is a 
double-barrier method (eg, condom with spermicidal gel or foam).
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the early withdrawal 
evaluations listed in are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified follow-up. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for termination and date of stopping investigational product must be 
recorded in the case report form (CRF) and source documents.
Randomized subjects who discontinue from the study may be replaced at the sponsor’s 
discretion.
4.5.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the case report form (CRF). If a subject is withdrawn for more than 
1 reason, each reason should be documented in the source document and the most clinically 
relevant reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol deviation/violations
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
Withdrawal by subject

Lost to follow-up

Other (Note: If “Other” is selected, then the specific reason will need to be recorded in the 
CRF)
4.5.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any timepoint prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
4.5.3
Stopping Criteria for Dose Escalation
Dose escalation will not continue to the next planned dose/cohort if any of the following criteria 
are met:

A serious adverse event (SAE) related to active drug (according to Investigator assessment) 
occurs in 1 or more subjects receiving active drug. No further subjects will be enrolled or 
dosed until further evaluation of the available data is made by the medical monitor and 
investigator to determine whether to stop or proceed with the study. Following a safety 
review of the event, study enrollment or dosing of currently enrolled subjects may be 
restarted if the medical monitor and the investigator determine that it is safe to proceed with 
the study.

Two or more subjects experience a treatment emergent adverse event (TEAE) of National 
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0) 
Grade 3 or higher in the same system organ class (SOC).

If 2 or more subjects experience a treatment emergent adverse event (TEAE) of at least 
moderate severity (such as National Cancer Institute [NCI] Common Terminology Criteria 
for Adverse Events [CTCAE v5.0] Grade 3 or higher) in the same system organ class (SOC).
Individual Stopping Criteria
Individual subjects should be discontinued if any of the following laboratory findings are 
observed:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 8 × upper limit of 
normal (ULN)

AST or ALT > 5 × ULN for 2 weeks;

AST or ALT > 3 × ULN and either total bilirubin > 2 × ULN or international normalized 
ratio (INR) > 1.5;
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
AST or ALT > 3 × ULN with symptoms consistent with hepatic disease or injury 
(e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia >5%)

Any other drug related event occurs in subjects receiving active drug and is deemed to pose 
an unacceptable risk to subjects by the investigator or medical monitor after further 
evaluation.

Dosing will be discontinued in an individual subject if that subject has a laboratory 
abnormality or TEAE of CTCAE v5.0 Grade 3 or higher that is considered possibly related to 
study drug by the investigator.
Should any of the apparent stopping criteria be met, the data under examination will be 
unblinded to ensure the criteria have been met with respect to those subjects receiving active 
drug. The Shire Medical Monitor and/or principal investigator can request unblinding of the data 
at any time in order to further evaluate a possible safety concern for an individual subject or 
entire cohort.
In case one of these dose-limiting events occurs, it will be assumed that the minimum intolerable 
single dose or multiple doses has been reached. Further once-weekly dosing will be at a dose, 
determined by the Shire Medical Monitor and the principal investigator, below the minimum 
intolerable once-weekly dose and when needed in consultation with the Shire Safety Officer.
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5. PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy as appropriate) received within 30 days 
(or pharmacokinetic equivalent of 5 half-lives, whichever is longer) of the date of first dose of 
investigational product. Prior treatment information must be recorded on the appropriate source 
documentation.
5.2
Concomitant Treatment
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the last study visit (or last contact with the subject, whichever comes 
first), inclusive. Concomitant treatment information must be recorded on the appropriate source 
documentation.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications listed below) 
during the course of the study. Any medication which is considered necessary for the subject’s 
safety and well-being may be given at the discretion of the investigator. The administration of all 
medications (including investigational products) must be listed on the appropriate source 
documentation.
Medications permitted during the study are listed below:

Hormonal contraceptives for females of childbearing potential administered according to the 
package insert (see Section 4.4.1)

Hormone replacement therapy

Occasional use of ibuprofen or acetaminophen
5.2.2
Prohibited Treatment
Refer to Section 4.3 on restrictions for prohibited treatment.
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6. INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP681 which will be provided in vials.
The reference/comparator product is a placebo which will be provided in vials. Additional 
information related to SHP681, including preparation and administration, is provided in the 
current SHP681 investigator brochure, and in an investigational product preparation and 
administration manual that will be provided.
6.1.1
Blinding the Treatment Assignment
This is a randomized, double-blind, placebo-controlled study. The actual treatment given to 
individual subjects is determined by a randomization schedule. The associated treatment 
assignments giving details of individual subject treatment are in the form of vendor 
randomization schedule held at the investigational site which will be provided by the biostatistics 
vendor.
The randomization code will be sent to the unblinded dispenser at the site in a password 
protected file. This code will be opened by the unblinded dispenser and will be kept in a sealed 
envelope under locked conditions.
The investigator should assign the responsibility of unblinded dispenser to a person who will not 
participate in the evaluation of any study subject. This permits all other participants to remain 
blinded. A member of the staff of the CRU or clinical pharmacy should fulfill this role and 
should be fully trained in the relevant aspects of the study. His/her role should be documented on 
the site’s delegation of authority log. The unblinded dispenser may not administer the 
investigational product to study subjects. The unblinded dispenser must give the investigational 
product to the investigator or designee for administration. The unblinded dispenser will draw up 
the dose into a syringe and apply a colored wrap to the dosing syringe(s) to ensure blinding, as 
the active investigational product has a yellow-brown tinge compared to the placebo. The 
unblinded dispenser may not administer the investigational product to study subjects. Contact 
between the unblinded dispenser and study subjects should be kept to a minimum. The 
investigator, study coordinator, and any study participants other than the unblinded dispenser 
must not be allowed to know the investigational product assigned to any study subject and must 
not be allowed to see the randomization doe, investigational product containers, or treatment 
records. For emergency circumstances, please see Section 6.2.3.
Aside from unblinding for the interim analysis, the treatment assignment must not be broken 
during the study except in emergency situations where the identification of the investigational 
product is required for further treatment of the subject(s) or to assess any safety, tolerability, or 
pharmacokinetic questions based on the safety review.
Treatment assignments in the SAD cohorts and the first 3 MAD cohorts will be unblinded for an 
interim analysis after the last subject in the 3rd MAD cohort completes the Day 39 assessments.
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Each vial of SHP681 and placebo will be assigned a unique packaging identification number. 
When a vial of SHP681 or placebo is assigned to a subject, the packaging identification number 
will be recorded in the drug accountability records. Each subject will be assigned a specific vial 
or multiple vials of investigational product.
6.2
Administration of Investigational Product(s)
6.2.1
Allocation of Subjects to Treatment
This is a randomized, double-blind, placebo-controlled study.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. This will be a 4-digit number starting at 
0001.
The actual treatment given to individual subjects is determined by a randomization schedule. The 
randomization number represents a unique number representing study portion (SAD/MAD) as 
well as cohort and corresponds to investigational product allocated to the subject. This 
randomization number will be assigned prior to dosing after eligibility has been determined.
For the SAD portion Cohort 1, this unique 4-digit randomization number will be assigned as 
follows:
Cohort
Patient/Order of Randomization
Randomization #
Cohort 1
First Patient Randomized in the First SAD Cohort
1101
Cohort 1
Second Patient Randomized in the First SAD Cohort
1102
Cohort 1
Third Patient Randomized in the First SAD Cohort
1103
Cohort 1
X Patient randomized in the First SAD Cohort 
110X
For the MAD portion Cohort 1, this unique 4-digit randomization number will be assigned as 
follows:
Cohort
Patient/Order of Randomization
Randomization #
Cohort 1
First Patient Randomized in the First MAD Cohort
2101
Cohort 1
Second Patient Randomized in the First MAD Cohort
2102
Cohort 1
Third Patient Randomized in the First MAD Cohort
2103
Cohort 1
X Patient randomized in the First MAD Cohort 
210X
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If a randomization number is allocated incorrectly the study monitor must be notified as soon as 
the error is discovered. Once a randomization number has been assigned, that number must not 
be used again if, for example, a subject is withdrawn from the study.
Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject.
6.2.2
Dosing
After satisfying all screening and entry criteria, SHP681or placebo will be administered in the 
abdomen to all subjects according to the following schedule:
SAD portion of the study
The plan is to enroll 30 subjects in 5 cohorts. Each cohort will include 6 subjects. Subjects will 
be randomized within each cohort such that 5 subjects receive SHP681 and 1 subject receives 
placebo. After a single administration on Day 1 of each treatment period of SHP681 or placebo 
in each cohort, if the dose is assessed as safe and tolerable during a dose escalation meeting, the 
next cohort will be administered a SC dose of SHP681 at the next higher dose level or placebo.
Dose escalation will proceed sequentially to assess the following SC doses of SHP681: 
0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. During dose escalation, protocol defined 
dose levels may be reduced, repeated, discontinued, or an intermediate increase may be added 
depending on the outcome of the blinded safety data review between dose escalations.
MAD portion of the study
The plan is to enroll 72 subjects within 6 MAD cohorts. Each cohort will include 12 subjects. 
Subjects will be randomized within each cohort such that 10 subjects receive SHP681 and 
2 subjects receive placebo. Subjects in the first 5 MAD cohorts will receive SHP681 (or placebo) 
once weekly for 5 weeks, on Day 1, 8, 15, 22 and 29. After the first cohort has been administered 
2 doses of SHP681 (or placebo) over 2 weeks and the dose is assessed as safe and tolerable 
during a dose escalation meeting, the next MAD cohort will commence. Dose escalation will 
proceed sequentially to include the following SC doses: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg,
2 mg/kg, and 4 mg/kg. Subjects in the 6th MAD cohorts will receive 4 mg/kg SHP681 (or 
placebo) once every 2 weeks, on Day 1, 15, and 29. 
During dose escalation, protocol defined dose levels may be reduced, repeated, discontinued, or 
an intermediate increase may be added depending on the outcome of the blinded safety data 
review between dose escalations.
6.2.3
Unblinding the Treatment Assignment
Treatment assignments in the SAD cohorts and the first 3 MAD cohorts will be unblinded for an 
interim analysis after the last subject in the 3rd MAD cohort completes the Day 39 assessments.
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Aside from unblinding for the interim analysis, the treatment assignment must not be broken 
during the study except in emergency situations where the identification of the investigational 
product is required for further treatment of the subject. The investigator should contact the 
medical monitor as soon as possible after the blind has been broken.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code and the reason for breaking the code are recorded on the source documents. Upon 
breaking the blind, the subject is withdrawn from the study, but should be followed up for safety
purposes. Any code-breaks that occur must be reported to the sponsor and contract research 
organization (CRO). Code-break information is held by the unblinded dispenser at the site.
6.2.4
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product is labeled with a minimum of the protocol number, medication 
identification number, dosage form (including product name and quantity in pack), directions for 
use, storage conditions, batch number, and/or packaging reference, the statements "For clinical 
trial use only," and/or "CAUTION: New Drug - Limited by Federal (or US) Law to 
Investigational Use," and "Keep out of reach of children," and the sponsor's name and address.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and date of dispensation.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.
6.2.5
Packaging
One vial of investigational product is packaged in one labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.2.6
Storage
The investigator has overall responsibility for ensuring that investigational product is 
stored in a secure, limited-access location. Limited responsibility may be delegated to 
the pharmacy or member of the study team, but this delegation must be documented. 
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Investigational products are distributed by the unblinded dispenser or nominated member 
of the study team.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is 
responsible for ensuring that the temperature is monitored throughout the duration of the study 
and that records are maintained; the temperature should be monitored continuously by using 
either an in-house system, a mechanical recording device such as a calibrated chart recorder, or 
by manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects.
The investigator or designee will acknowledge receipt of the investigational product, 
documenting shipment content and condition. Accurate records of all investigational product 
dispensed, used, returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
medications will be documented on the CRFs and/or other investigational product record. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national laws 
must be adhered to for the transfer.
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With the written agreement of the sponsor, at the end of the study all unused stock, and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed, when and how, must be obtained 
with copies provided to the sponsor. Destruction of investigational products must be in 
accordance with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.4
Subject Compliance
Compliance must be assessed by observation of dosing by the investigator or designee. The 
investigator/nominated person will record details on the drug accountability log(s) and/or source 
documents. In addition, details of the dosing time (time and date) will be captured in the 
appropriate CRF.
6.5
Retention of Bioavailability and Bioequivalence Testing Samples
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7. STUDY PROCEDURES
7.1
Study Schedule
See the Study Schedules for study procedures to be followed in the study.
The following “priority order” will be in effect when more than 1 procedure or assessment is 
required at a particular timepoint.

Spontaneous or solicited adverse event (AE) reporting

Vital signs

Electrocardiogram (ECG)

Physical examination


Blood sampling for ADA and nADA

Pharmacokinetic blood sampling

Clinical laboratory tests

Pregnancy testing
NOTE: Blood sampling for PK evaluation must be performed at the precise protocol-scheduled 
time. Actual sampling time(s) must be accurately recorded in the source document and 
appropriate CRF. Pharmacokinetic blood collection must not deviate from the nominal collection 
time set forth in the protocol by more than ±5 minutes from samples drawn within 4 hours after 
the first dose or by more than ±15 minutes for samples drawn between 4 hours and 24 hours after 
the first dose. Samples drawn beyond study day 2 cannot deviate by more than 10% of the 
specified time from the first dose.
7.1.1
Screening Period
For both SAD and MAD part of the study, screening procedures must be completed within 
28 days prior to receiving the first dose of investigational product. All screening assessments and 
procedures are to be performed by the principal investigator or a qualified designee. See the 
Study Schedules for a complete list of screening procedures to be performed.
Written, signed, and dated informed consent from each subject prior to the performance of any 
study-related procedures must be obtained by the principal investigator or a designee. A copy of 
the signed informed consent must be given to the subject and/or subject’s parent/LAR for their 
records.
7.1.1.1
Screening Failure
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized and/or enrolled or 
administered investigational product(s).
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Subjects who fail to meet all inclusion/exclusion criteria will not be permitted to be rescreened 
for the study at any point.
Eligible subjects who meet all inclusion/exclusion criteria but are unable to participate in the 
study due to scheduling conflicts/timing may be rescreened based on investigator discretion and 
sponsor approval should their availability to participate fall outside the screening window. In 
these cases, a new subject number must be assigned for each subject who is rescreened and a 
new informed consent form must be signed.
7.1.2
Treatment Period
SAD (Part 1)
7.1.2.1
Admission to the CRC (Day -1)
Following the screening visit, eligible subjects will return to the CRC on Day -1 of the study. See
the Study Schedules for a list of procedures and assessments to be completed upon admission to 
the CRC. Subjects who successfully complete the pre-admission procedures and assessments will 
be admitted to the CRC on Day -1 and randomized and assigned a randomization number on Day
-1 or Day 1 as described in Section 6.2.1.
7.1.2.2
Treatment Period (Day 1 through Day 29)
Subjects will be admitted to the CRC after eligibility is confirmed on Day -1. Subjects will be 
confined at the CRC from Day -1 until after completion of the assessments on Day 8 as indicated 
in the Study Schedules. SHP681 or placebo will be administered on Day 1 of the treatment 
period for each cohort. On Day 8 subjects will be discharged from the CRC. From Day 11 to 
Day 29 the subjects will be back at the CRC for outpatient visits to complete the study 
procedures, safety and pharmacokinetic assessments as indicated in the Study Schedules.
MAD (Part 2)
7.1.2.3
Admission to the CRC (Day -1)
Following the screening visit, eligible subjects will return to the CRC on Day -1 of the study. 
See the Study Schedules for a list of procedures and assessments to be completed upon 
admission to the CRC. Subjects who successfully complete the pre-admission procedures and 
assessments will be admitted to the CRC on Day -1 and randomized and assigned a 
randomization number on Day -1 or Day 1 as described in Section 6.2.1.
7.1.2.4
MAD Cohorts 1-5 Treatment Period (Day 1 through Day 57)
Eligible subjects will be confined to the CRC from the morning of Day -1 until completion 
of all procedures and assessments on Day 4. SHP681 or placebo will be administered on 
Day 1 of the treatment period for each cohort. On Day 4 subjects will be discharged from the 
CRC. They will then be readmitted in the CRC on Day 7, Day 14, Day 21 and Day 28 and 
discharged from the CRC respectively on Day 10, Day 18, Day 24 and Day 36 after completion 
of the assessments as indicated in the Study Schedules. From Day 39 to Day 57 the subjects will 
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return to the CRC for outpatient visits to complete the study procedures, safety and 
pharmacokinetic assessments as indicated in the Study Schedules.
7.1.2.5
MAD Cohort 6 Treatment Period (Day 1 through Day 57)
Eligible subjects will be confined to the CRC from the morning of Day -1 until completion of all 
procedures and assessments on Day 4. SHP681 or placebo will be administered on Day 1 of the 
treatment period for each cohort. On Day 4 subjects will be discharged from the CRC. They will 
then be readmitted in the CRC on Day 14 and Day 28 and discharged from the CRC, 
respectively, on Day 18 and Day 36 after completion of the assessments as indicated in the 
Study Schedules. From Day 39 to Day 57 the subjects will return to the CRC for outpatient visits 
to complete the study procedures, safety and pharmacokinetic assessments as indicated in the 
Study Schedules.
7.1.3
Follow-up Period
There will be no further follow up.
7.1.4
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics such as date of birth, sex, weight, height and body mass index will 
be collected according to the Study Schedules.
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is 
that the investigator will ensure that every effort is made to perform all assessments at the 
precise protocol-scheduled time. Any safety assessment that deviates from the scheduled 
assessment time set forth in the protocol by more than ±15 minutes will be considered a protocol 
deviation.
An AE is any unfavorable and unintended sign, ie, any clinically significant worsening from 
baseline of an abnormal laboratory finding, symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH Guidance E2A 1995). Treatment emergent AEs (TEAEs) are 
adverse events that occur after initiation of either the investigational product or placebo (see 
Section 8 for more information).
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7.2.2.1
Medical and Medication History
A complete medical and medication history, as well as demographic information, will 
be performed at the screening visit/timepoints described in the Study Schedules by a 
qualified licensed physician, physician’s assistant, nurse practitioner, or a delegated study 
coordinator/assistant. The medical history will be reviewed and recorded, including:

Date of birth

Sex

Race and ethnicity

Recent ingestion of medication (30 days prior to entering the screening period)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases

Smoking habits
7.2.2.2
Physical Examination (Including Height and Weight)
Complete or abbreviated physical examinations will be performed as specified at the time points 
described in the Study Schedules by a qualified licensed physician, physician’s assistant, or nurse
practitioner.
The complete physical examinations will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys)
Abnormalities identified at the screening visit will be documented in the subject’s source 
documents and on the medical history CRF. Changes after the screening visit that are considered 
clinically significant by the investigator will be captured as AEs on the AE CRF page.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
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Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.)
7.2.2.4
Vital Signs
Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in the Study Schedules of this 
protocol. Additional blood pressure and pulse rate measurements may be performed, as 
determined by the investigator, in order to ensure appropriate monitoring of subject safety and 
accurate recording of vital sign measurements. Any changes from baseline which are deemed 
clinically significant by the investigator are to be recorded as an AE.
The same method for obtaining blood pressure measurement (auscultatory or oscillometric) 
should be used throughout the study for all subjects (and documented). In addition, the 
conditions of vital sign measurements should be controlled and as consistent as possible during 
the study, in order to minimize external variability of the readings. It is advised that 
measurements be collected at a comfortable room temperature with little to no background noise, 
using the same (appropriately sized) cuff placed at the same location of the same arm during the 
study.
The bladder deflation rate should be deflated (calibrated for oscillometric method or manually by 
auscultatory method) at a rate of 2-3 mmHg/s (and the first and last audible sounds recorded as 
systolic and diastolic pressure) after at least 5 minutes of rest in the assumed position.
The cuff should have a bladder length that is 80% and a width that is at least 40% of arm 
circumference (a length-to-width ratio of 2:1).
The subject should be asked to remove all clothing that covers the location of cuff placement. 
The subject should not have exercised or consumed caffeine, alcohol, or nicotine within 
30 minutes of collection. The subject should be instructed to relax as much as possible for at 
least 5 minutes prior to collection. The subject should remain quiet during this time and through 
the measurement.
The subject should be sitting comfortably, with the legs uncrossed. The arm should be supported 
with a pillow, such that the middle of the cuff on the upper arm is at the level of the right atrium 
(approximately halfway between the bed and the level of the sternum).
At the screening visit, blood pressure should be compared between both arms. If, after a single 
measurement is taken, there is a difference between arms in either systolic or diastolic blood 
pressure of >10 mmHg, the site will perform triplicate BP measurements in each arm to 
determine the arm with the higher BP. The arm with the higher BP (based on the average of the 
3 BP measurements for each arm) should be used for inclusion at screening, and the last of the 
3 measurements recorded in the eCRF as the screening BP. The same (right or left) arm with the 
higher blood pressure will be used throughout the study.
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One reading (seated systolic blood pressure/diastolic blood pressure-pulse) should be taken. The 
use of automated devices for measuring pulse rate is acceptable, although, when done manually, 
pulse rate will be measured in the brachial/radial artery for at least 30 seconds. When the timing 
of these measurements coincides with a blood collection, blood pressure and pulse rate should be 
obtained prior to the nominal time of the blood collection.
Body Temperature
Oral temperature should be taken by placing a digital thermometer under the tongue for at least 
30 seconds and the temperature reported in degrees Celsius. Tympanic temperature may also be 
used.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed:
Biochemistry
Blood samples (8.5 mL) for serum biochemistry will be collected into a gel separator tube at the 
timepoints described in the Study Schedules. The following parameters will be assessed:
Sodium
Potassium
Phosphorus
Total protein
-hCGa
Glucose
Blood urea nitrogen
Total CO2 (Bicarbonate)
Albumin
Creatinine
Aspartate transaminase
Amylase
Lipase
Calcium
Alanine transaminase
Chloride
Gamma glutamyl transferase
Thyroid stimulating hormone (TSH)
Free T3b
T3b
Thyroxine-binding Globulinb
T4b
Alkaline phosphatase
Uric acid
Total bilirubin
-hCG = beta-human chorionic gonadotropin
a Females only
b These parameters will only be calculated on Day 1, Day 8, and Day 15 for the SAD portion of the study. An additional 3.5 mL 
of blood will be collected from each subject on Days 1 and 8 for the assessment of TBG. T3, T4, and Free T3 will be assessed 
from the 8.5 mL collected for the biochemistry. On Day 15, an additional 7 mL of blood will be collected from each subject for 
the assessment of T3, T4, Free T3, and TBG
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Hematology
Blood samples (4 mL) for hematology will be collected into an EDTA 
(ethylenediaminetetraacetic acid) tube at the timepoints described in the Study Schedules. The 
following parameters will be assessed:
Hemoglobin
Total neutrophils (absolute) 
Hematocrit
Eosinophils (absolute)
Red blood cells
Monocytes (absolute) 
Platelet count Basophils (absolute) 
White blood cell count; total and differential Lymphocytes (absolute)
Urinalysis
A urine sample for urinalysis will be collected at the timepoints described in the 
Study Schedules. The following parameters will be assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.
7.2.2.6
Pregnancy Test
For all female subjects (regardless of reproductive potential status), a serum pregnancy test is 
performed at the screening visit, while urine pregnancy test will be performed at subsequent 
scheduled timepoints as indicated in the Study Schedules if pregnancy is suspected; or on 
withdrawal of the subject from the study.
7.2.2.7
Drug and Alcohol Screen
A urine screen for drugs of abuse and alcohol breath test will be performed at the timepoints 
described in the Study Schedules. Additional drug and alcohol screens may be performed at the 
investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine.
Results of urine drug and alcohol screens will be reviewed and verified by the study monitor but 
will not be collected in the CRF database.
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Any positive result for drugs of abuse or alcohol at screening or on Day -1 will exclude the 
subject from further participation in the study. If during the study, the subject becomes positive 
for drugs of abuse (except ethanol <0.08 mg/dl or cannabinoids), the subject will be withdrawn 
from the study.
7.2.2.8
Serology Screen
At the screening visit, a blood sample of approximately 8.5 mL will be drawn into a serum 
separator tube to test for the presence of HIV, HBsAg, and HCV antibody.
The test results must be confirmed negative prior to enrollment in the study. If a test result 
is positive, the subject will be excluded from entering the study. Results of the virology
screen will be reviewed and verified by the study monitor but will not be collected in the CRF 
database.
7.2.2.9
Electrocardiogram
Twelve-lead ECGs will be performed at the times specified in the Study Schedules. All ECGs 
will be performed using the equipment supplied by the CRC.
The following parameters will be recorded on the appropriate CRF page: heart rate, PR, 
RR, QRS, and QT intervals. The QTcB and QTcF will be derived from the data in the 
database. The investigator’s assessment of the ECG tracing as normal or abnormal must 
be documented, and if abnormal, his/her determination of whether the abnormality is 
clinically significant or not will be documented on the tracing and recorded in the source 
documentation.
The subject should be asked to remove all clothing that covers the location of lead placement. 
The subject should not have exercised or consumed caffeine, alcohol, or nicotine within 
30 minutes prior to collection. The subject must be resting in the supine position for at least 
5 minutes prior to collecting the ECG.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.
Triplicate recording, including a 10-second rhythm strip, will be obtained approximately 
2-4 minutes apart for all assessments excluding the screening visit (wherein a single ECG 
assessment is required). Each ECG parameter obtained with the 3 assessments will be recorded 
in the CRF. The average of the triplicate ECG measurements collected at each nominal timepoint 
will be used for analysis. The 3 recordings should be immediately assessed as valid recordings 
and if not valid, they should be repeated in order to obtain a total of 3 valid recordings. Invalid 
recordings will not be entered in the CRF.
When triplicate ECGs are obtained: The average of the triplicate ECG measurements collected 
predose on Day 1 will serve as the subject’s baseline ECG.
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To ensure safety of the subjects, a qualified individual at the investigational site will make 
comparisons to baseline measurements.
If the QTcF interval (calculated online on site) is increased by >45 msec from the baseline, or an 
absolute QTcF value is >500 msec for any scheduled ECG, then 2 additional ECGs will be 
collected, approximately 2-4 minutes apart, to confirm the original measurement. 
If either of the QTcF values from these repeated ECGs remains above the threshold value 
(>45 msec increase from the baseline; or >500 msec), then a single ECG must be repeated at 
least hourly until QTcF values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement. When triplicate ECGs are collected, the mean of the triplicate
measurements should be used to trigger the decision to collect follow-up ECGs.
If QTcF values remain above 500 msec (or >45 msec from the baseline) for >4 hours (or sooner 
at the discretion of the investigator) or QTcF intervals get progressively longer, the subject 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
intervals do not return to <500 msec (or to <45 msec above the baseline) after 8 hours of 
monitoring (or sooner at the discretion of the investigator). If a machine-read QTcF/QTcB value 
is prolonged, as defined above, repeat measurements may not be necessary if a qualified 
physician’s interpretation determines that the QTcF/QTcB values are in the acceptable range.
7.2.2.10
Abdominal Ultrasound
An abdominal ultrasound will be performed at the times specified in the Study Schedules.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory(ies) for this study will be maintained in the 
investigator’s files at the/each site and in the Trial Master File at the sponsor. A laboratory 
manual fully describing the schedule and method of sample handling will be provided to the site. 
Actual pharmacokinetic blood sample collection times versus time of dosing will be monitored. 
The sponsor’s expectation is that the investigator will ensure that every effort is made to collect 
all pharmacokinetic blood samples at the precise protocol scheduled time but must record the 
actual clock time (AM/PM or 24-hr) of the sample collection. Pharmacokinetic blood collection 
must not deviate from the nominal collection time set forth in the protocol by more than 
±5 minutes for samples drawn within 4 hours after the first dose or by more than ±15 minutes for 
samples drawn between 4 hours to 24 hours after the first dose. Samples drawn beyond study day 
2 cannot deviate by more than ±10% of the specified time from the first dose. Samples drawn 
outside these parameters will be considered a protocol deviation.
7.2.3.1
Blood Sample Collection and Handling Procedures
Blood samples will be collected at the time specified in the Study Schedules to measure plasma 
concentrations of SHP681.
A full description of the PK blood collection, handling, storage, and shipping can be found in the 
laboratory manual.
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Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the CRC. The labels will contain the following information:

Study number (SHP681-101)

Subject identifier

Treatment Dose and portion of the study (SAD or MAD)

Period

Nominal day (Day 1, Day 2, etc.)

Nominal time

Matrix identifier (plasma for PK)

Split (primary or backup or aliquot 1 or aliquot 2)
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples
All pharmacokinetic samples should be placed in a cryo-box, double-bagged to contain leaks and 
packed with a sufficient quantity of dry ice to ensure that they remain frozen for at least 72 hours 
to allow for delays in shipment. All applicable shipping regulations must be followed. Shipments 
should be scheduled so that no samples arrive on the weekend and should be shipped 
Monday-Wednesday only. Samples should be transported to ensure that they arrive at the 
bioanalytical laboratory between the hours of 9:00 AM and 4:00 PM. The recipient and primary 
Shire contact must be notified by telephone or e-mail when the samples are shipped, and they 
must be provided with the shipment tracking number.
Full directions for shipment of all PK samples, (along with the corresponding documentation) 
can be found in the laboratory manual provided under separate cover.
Pharmacokinetic samples will be stored nominally at -70° C prior to and after analysis at the 
laboratory performing the assay until sample disposal is authorized by Shire.
7.2.3.3
Plasma Drug Assay Methodology
Plasma sample analysis will be performed according to the relevant Standard Operating 
Procedures at the contract bioanalytical lab.
Plasma concentrations will be measured using the most current validated bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate. Raw data will be stored in the archive 
of the designated bioanalytical contract laboratory.
7.2.4
Pharmacodynamic Assessments
Not applicable.
7.2.5
Pharmacogenomic Assessments
Not applicable.
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7.2.7
Volume of Blood to be Drawn from Each Subject
Table 12
Volume of Blood to be Drawn from Each Subject
SAD (Part 1 of the study)
Assessment
Sample Volume (mL)
Number of
Samples
Total Volume (mL)
Pharmacokinetic samplesa
7
14
98
ADA and nADA samples
6
2
12
HBsAg, HIV, HCV
8.5
1
8.5
Safety
Biochemistry and 
-hCGb
8.5
6
51
Hematology
4
6
24
Thyroid Panelc
3.5
4
14
Total mL
207.5
MAD Cohorts 1-5 (Part 2 of the study)
Pharmacokinetic samplesa
7
22
154
ADA and nADA samples
6
7
42
HBsAg, HIV, HCV
8.5
1
8.5
Safety
Biochemistry and 
-hCGb
8.5
13
110.5
Hematology
4
13
52
6
3
18
Total mL
385
MAD Cohort 6 (Part 2 of the study)
Pharmacokinetic samplesa
7
20
140
ADA and nADA samples
6
7
42
HBsAg, HIV, HCV
8.5
1
8.5
Safety
Biochemistry and 
-hCGb
8.5
13
110.5
Hematology
4
13
52
6
3
18
Total mL
371
-hCG=beta-human chorionic gonadotropin; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus
a If a catheter is used, the first mL is to be discarded; then take 6 mL into appropriate tube for pharmacokinetic sample. A total of
7 mL of blood drawn has been used in determination of sample volume.
b -hCG testing for females only.
c Thyroid Panels consist of T3, T4, Free T3, TSH, and Thyroxine-binding globulin (TBG); on Day 1 and Day 8, one 3.5 mL tube 
will be collected. On Day 15, two 3.5 mL tubes will be collected.
During this study, it is expected that approximately 207.5 mL of blood in the SAD portion of the 
study, and approximately 385 mL of blood in the MAD part will be drawn from the subjects, 
regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 207.5 mL and 385 mL for the SAD subjects and MAD subjects, 
respectively. When more than 1 blood assessment is to be done at the timepoint/period, if they 
require the same type of tube, the assessments may be combined.
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8. ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign, (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic
intervention. The event interferes with usual activities of daily living,
causing discomfort but poses no significant or permanent risk of harm to the 
research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
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8.1.2
Relationship Categorization
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.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, a 
shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
treatment or after the end of treatment with the investigational product, and the range of variation 
of the respective parameter within its reference range, must be taken into consideration.
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If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.5
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until last visit (or 
last contact with the subject) stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Safety Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical 
monitor using the details specified in the emergency contact information section of the protocol. 
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 1 year post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine -hCG 
test or ultrasound result will determine the pregnancy onset date.
8.1.6
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 as described 
in Section 8.2. 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.
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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 – Intentional or unintentional intake of a dose of investigational product 
higher than the protocol-prescribed dose

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/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. Violation of storage or refrigeration requirements for the 
investigational product is considered a reportable medication error and as such must be reported 
to the sponsor.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the Investigator’s Brochure which the 
sponsor has provided under separate cover to all investigators. However, this is the first clinical 
experience with SHP681 in humans. While major AEs are not anticipated, the investigator 
should proceed with caution. Equipment, supplies, and properly skilled medical personnel should 
be immediately available for emergency use in the event of an unexpected reaction. Subjects 
must be carefully selected and monitored closely.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Safety Department and the CRO/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 (see Section 8.1.6) unless they result in an SAE.
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The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department.
A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs Required by the 
Protocol Form (and any applicable follow-up reports) must also be sent to the CRO/Shire 
medical monitor using the details specified in the emergency contact information section of the 
protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.
Note: Hospitalizations that are the result of elective or previously scheduled surgery for
pre-existing conditions and have not worsened after initiation of treatment should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 and may require medical or 
surgical intervention to prevent 1 of the 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 inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the CRO/Shire 
medical monitor within 24 hours of the first awareness of the event.
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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor is responsible for notifying the relevant regulatory authorities of related, unexpected 
SAEs.
In addition the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP681 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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9. DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within a reasonable window of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product blood 
concentrations, antibodies to SHP681, 
 
, treatment allocation, and investigational product preparation/accountability data, 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the PK and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
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Descriptive analysis will be performed to evaluate PK endpoints and safety endpoints. All 
analyses/summaries will be based on observed data, with missing data handling rules specified in 
Section 9.8.1 or the SAP.
Continuous endpoints will be summarized with the number of subjects (n), mean, standard 
deviation (SD), median, minimum and maximum value. As appropriate, raw (actual) values, 
changes from baseline, and percent changes from baseline will be summarized at each scheduled 
timepoint. Baseline is defined as the last non-missing value observed prior to dosing with 
SHP681 or placebo. Additional summary statistics will be provided for PK endpoints and are 
indicated in Section 9.8.1.
Categorical endpoints will be summarized, displaying counts and percentages. Summaries will 
include, where applicable: number and percentage of subjects with an outcome measure and shift 
tables (categorical change from baseline). Summaries will be presented by dose cohort and for 
the placebo group, and, if appropriate, by scheduled timepoint.
All data, including derived data, will be presented in subject data listings.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
The pharmacokinetic analysis will be conducted using Phoenix WinNonlin version 6.2 or higher 
(Pharsight Corporation, Mountain View, California, USA). The statistical analyses will be 
performed using SAS® (SAS Institute, Cary, NC 27513).
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
To support an initiation of the MAD phase and confirm the dosing interval, an interim data 
analysis will be required. Blinded plasma data obtained after dosing in Cohort 1, Cohort 2, and 
part of Cohort 3 in the SAD portion will be evaluated and justified for this purpose.
An interim analysis will be performed after the last patient from the 3rd MAD cohort has 
completed the Day 39 visit, to determine the dose level of the 6th MAD cohort, and to assess any 
safety, tolerability, or pharmacokinetic questions based on the safety review. The data for this 
analysis will be source data verified and cleaned according to the Interim Snapshot Plan. This 
analysis will unblind all completed SAD cohorts and the first 3 MAD cohorts for the Sponsor 
and external statistical groups. MAD cohorts 4, 5 and 6 will not be unblinded to any parties due 
to this interim analysis.
No adaptive design or data monitoring committee (DMC) is planned.
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9.6
Sample Size Calculation and Power Considerations
SAD (Part 1)
It is planned that dose escalation will proceed for up to 5 dose levels. Each cohort will 
include 5 subjects treated with SHP681 and 1 subject treated with placebo for a planned total of 
30 subjects. However, if dose levels are repeated, modified, or not conducted or if additional 
dose levels are studied, the total number of subjects may change. The number of subjects is 
expected to provide reasonable information on initial testing of SHP681 for safety and PK while 
exposing as few subjects as possible to investigational drug materials. The number of subjects in 
this study is not based on statistical hypothesis testing and power considerations as this is the first 
in human study. The statistical analyses are primarily descriptive, and no hypothesis testing is 
specified for this portion.
MAD (Part 2)
It is planned that the MAD portion of the study will include 6 cohorts. Each cohort will 
include 10 subjects treated with SHP681 and 2 subjects treated with placebo for a planned total 
of 72 subjects. The number of subjects is expected to provide reasonable information on initial 
testing of SHP681 for safety and PK while exposing as few subjects as possible to 
investigational drug materials. The number of subjects in this study is not based on statistical 
power considerations as this is the first time in human study. The statistical analyses are 
primarily descriptive, and no hypothesis testing is specified in the study.
9.7
Study Population
Subject populations are separately defined to analyze the data in the SAD portion and the MAD 
portion of the study:
SAD

The safety analysis set includes subjects who have received at least 1 dose of SHP681 
or placebo in the SAD portion.

The PK analysis set consists of subjects who have received at least 1 dose of SHP681 
and have at least 1 evaluable post-dose PK concentration value in the SAD portion.
MAD

The safety analysis set includes subjects who have received at least 1 dose of 
SHP681or placebo in the MAD portion.
The PK analysis set consists of subjects who have received at least 1 dose of SHP681 and have at 
least 1 evaluable post-dose PK concentration value in the MAD portion.
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9.8
Pharmacokinetic Analyses
9.8.1
Pharmacokinetic Analysis
The PK analysis will be based on the PK analysis set.
Pharmacokinetic parameters will be calculated from plasma SHP681 concentration-time data 
using non-compartmental methods and all calculations will be based on actual sampling times. 
Pharmacokinetic parameters will include, but not be limited to, the following:
SAD 

Cmax
Maximum concentration occurring at tmax 

tlast
Time of the last measurable concentration

tmax
Time of maximum observed concentration sampled during a dosing interval

AUC0-last
Area under the curve from the time of dosing to the last measurable concentration

AUC0-∞
Area under the curve extrapolated to infinity

t1/2
Terminal half-life

z
First order rate constant associated with the terminal (log-linear) portion of the 
curve

CL/F
Apparent total body clearance for extravascular administration divided by the 
fraction of dose absorbed calculated as dose divided by AUC0-∞. 

Vz/F
Apparent volume of distribution following extravascular administration divided 
by the fraction of dose absorbed calculated as CL/F divided by z. 
MAD 
Post first dose

AUC0-24
Area under the curve from the time of dosing to the 24 hours post first dose

Cmax,24
Maximum concentration occurring during 24 hours after first dose 

tmax,24
Time of maximum observed concentration during 24 hours after first dose 
Between the first dose and last dose

Ctrough
Observed concentration at the end of each dosing interval 
(immediately before next dose for the first 5 cohorts and immediately before 
2nd and 3rd dose of the 6th MAD cohort)
Post last dose

Cmax
Maximum concentration during the dosing interval occurring at tmax
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
Tlast
Time of the last measurable concentration

tmax
Time of maximum observed concentration during the dosing interval 

AUCtau
Area under the curve for the defined interval between doses (only calculated if 
interpretable)

AUC0-last
Area under the curve from the time of dosing to the last measurable concentration 
post last dose 

AUC0-∞
Area under the curve (post last dose) extrapolated to infinity, calculated using the 
observed value of the last non-zero concentrations (only calculated if 
interpretable)

t1/2
Terminal half-life 

z
First order rate constant associated with the terminal (log-linear) portion of the 
curve 

CL/F
Apparent total body clearance following extravascular administration divided by 
the fraction of dose absorbed calculated as dose divided by AUCtau

Vz/F
Apparent volume of distribution following extravascular administration divided 
by the fraction of dose absorbed calculated as CL/F divided by z
9.8.1.1
Statistical Analysis of Pharmacokinetic Parameters
The pharmacokinetic analysis will be conducted by the pharmacokinetics CRO.
The applicable analysis conventions will be detailed in the statistical analysis plan, including the 
minimum number of quantifiable postdose concentrations to be used to derive AUC, handling 
rules of concentration values below the assay quantitation limit (BLQ), handling of potential 
anomalous predose concentration values, etc. Subjects randomized to SHP681 but excluded from 
the PK analysis set will be listed by subject and reason(s) leading to exclusion.
SAD
The PK analysis will be based on the PK analysis set for the SAD portion.
Individual subject’s raw concentrations of SHP681and actual sampling time will be listed by 
nominal sampling timepoint. Individual subject’s PK parameters will be listed by dose cohort, 
along with the number of timepoints of the terminal log-linear phase used to estimate the 
terminal rate constant and percentage of extrapolated AUC.
Raw concentrations for each nominal sampling timepoint and PK parameters except tmax and tlast 
will be summarized by dose cohort with descriptive statistics such as number of subjects, 
geometric mean, median, arithmetic mean, standard, deviation, coefficient of variation, and 
geometric coefficient of variation, minimum and maximum. The other parameters, tmax and tlast, 
will be summarized by median, minimum and maximum grouped by dose cohort.
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Individual subject’s concentration-time curves will be presented in linear/linear and log/linear 
scale using lattice plots, with one panel for each subject grouped by dose cohort. Figures 
showing the mean (with ±SD as error bar) as well as the median (with 25th to 75th quantiles as 
error bar) concentration time profiles will be presented in linear/linear and log/linear scale using 
lattice plots, with one panel for each dose cohort. Mean and median concentration time profiles 
for all dose cohorts will be also visualized in one plot.
MAD
The PK analysis will be based on the PK analysis set for the MAD portion.
Individual raw concentration data and actual sampling time will be listed by nominal sampling 
timepoint. Individual subject’s PK parameters derived post the first dose and repeat doses 
(ie, after the last dose) will be listed by dose cohort, along with the number of timepoints of the 
terminal log-linear phase used to estimate the terminal rate constant and percentage of 
extrapolated AUC if applicable.
Raw concentrations for each nominal sampling timepoint and PK parameters post the first dose 
and repeat doses, except tmax,24, tmax and tlast, will be summarized by dose cohort with descriptive 
statistics such as number of subjects, geometric mean, median, arithmetic mean, standard, 
deviation, coefficient of variation, and geometric coefficient of variation, minimum and 
maximum where tmax,24, tmax and tlast will be summarized by median, minimum and maximum 
grouped by dose cohort.
Individual subject’s concentration-time profile up to 24 hours after the first dose will be 
visualized with correspondingly superimposed concentration-time profile up to 24 hours 
following the 5th dose in linear/linear and log/linear scale using lattice plots, with one panel for 
each subject grouped by dose cohort.
Individual concentration-time curves following after the last dose will be presented in 
linear/linear and log/linear scale using lattice plots, with one panel for each subject grouped by
dose cohort. Mean (with ±SD as error bar) as well as the median (with 25th to 75th quantiles as 
error bar) concentration time profiles will be presented in linear/linear and log/linear scale using 
lattice plots, with one panel for each dose cohort. Mean and median concentration time profiles 
for all dose cohorts will be superimposed in one plot.
9.9
Safety Analyses
For each portion, statistical analysis of safety data will be based on the safety analysis data set for 
the portion. Descriptive analysis, as described in Section 9.4 will be performed to evaluate all 
safety endpoints.
Safety data will be listed by subject and summarized for each dose cohort of SHP681 and a 
pooled placebo group of all subjects who were administered placebo, using descriptive statistics. 
Continuous variables will be summarized by sample size, mean, standard deviation, median, 
minimum and maximum. Categorical variables will be summarized by number of subjects and 
the percent of subjects in each category.
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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, and local ethical 
and legal requirements.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
inter/national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Indemnity/Liability and Insurance
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the investigator as necessary.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.
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10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
Agreement with the final clinical study report is documented by the signed and dated signature of 
the principal investigator, in compliance with Directive 2001/83/EC as amended by Directive 
2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
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Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the coordinating principal investigator, according to national provisions, and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the sponsor and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports. 
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
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10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the clinical trial agreement. Prior to 
implementing changes in the study, the sponsor and the IRB/EC must approve any revisions of 
all informed consent documents and amendments to the protocol unless there is a subject safety 
issue.
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or investigator, or, for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’ 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP681; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee. The purpose 
of the publication steering committee is to act as a non-commercial body that advises or decides 
on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
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SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11. REFERENCES
Amiot, A., Messing, B., Corcos, O., Panis, Y.and Joly, F. 2013. Determinants of home parenteral 
nutrition dependence and survival of 268 patients with non-malignant short bowel 
syndrome. Clinical Nutrition, 32, 368-374.
Bakker, H., Bozzetti, F., Staun, M., Leon-Sanz, M., Hebuterne, X., Pertkiewicz, M., Shaffer, 
J.and Thul, P. 1999. Home parenteral nutrition in adults: a european multicentre survey in 
1997. ESPEN-Home Artificial Nutrition Working Group. Clin Nutr, 18, 135-40.
Dudrick, S. J., Latifi, R.and Fosnocht, D. E. 1991. Management of the short-bowel syndrome. 
Surg Clin North Am, 71, 625-43.
Goulet, O., Baglin-Gobet, S., Talbotec, C., Fourcade, L., Colomb, V., Sauvat, F., Jais, J.-P., 
Michel, J.-L., Jan, D.and Ricour, C. 2005. Outcome and Long-Term Growth After 
Extensive Small Bowel Resection in the Neonatal Period: A Survey of 87 Children. 
European Journal of Pediatric Surgery, 15, 95-101.
Guarino, A.and De Marco, G. 2003. Natural History of Intestinal Failure, Investigated Through a 
National Network-Based Approach. Journal of Pediatric Gastroenterology and Nutrition,
37, 136-141.
Jeppesen, P. B.and Mortensen, P. B. 2000. Intestinal failure defined by measurements of 
intestinal energy and wet weight absorption. Gut, 46, 701-6.
Kelly, D. G., Tappenden, K. A.and Winkler, M. F. 2014. Short Bowel Syndrome: Highlights of 
Patient Management, Quality of Life, and Survival. Journal of Parenteral and Enteral 
Nutrition, 38, 427-437.
Messing, B., Crenn, P., Beau, P., Boutron-Ruault, M. C., Rambaud, J. C.and Matuchansky, C. 
1999. Long-term survival and parenteral nutrition dependence in adult patients with the 
short bowel syndrome. Gastroenterology, 117, 1043-50.
Mughal, M.and Irving, M. 1986. Home parenteral nutrition in the United Kingdom and Ireland. 
Lancet, The, 2, 383-7.
Nightingale, J.and Woodward, J. M. 2006. Guidelines for management of patients with a short 
bowel. Gut, 55 Suppl 4, iv1-12.
Nightingale, J. M. 1999. Management of patients with a short bowel. Nutrition, 15, 633-7.
O' Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B.and Shaffer, 
J. 2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Pironi, L., Arends, J., Bozzetti, F., Cuerda, C., Gillanders, L., Jeppesen, P. B., Joly, F., Kelly, D., 
Lal, S., Staun, M., Szczepanek, K., Van Gossum, A., Wanten, G.and Schneider, S. M. 
2016. ESPEN guidelines on chronic intestinal failure in adults. Clin Nutr, 35, 247-307.
Rombeau, J. L.and Rolandelli, R. H. 1987. Enteral and parenteral nutrition in patients with 
enteric fistulas and short bowel syndrome. Surg Clin North Am, 67, 551-71.
Shanbhogue, L. K.and Molenaar, J. C. 1994. Short bowel syndrome: metabolic and surgical 
management. Br J Surg, 81, 486-99.
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SHP681-101 Protocol Amendment 4
GLP-2 analog-Fc fusion
19 Nov 2019
Vanderhoof, J. A.and Langnas, A. N. 1997. Short-bowel syndrome in children and adults. 
Gastroenterology, 113, 1767-78.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T.and Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
Wilmore, D. W., Byrne, T. A.and Persinger, R. L. 1997. Short bowel syndrome: New therapeutic 
approaches. Current Problems in Surgery, 34, 389,391-444.
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12.
APPENDICES
Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
29 Oct 2018
Global
Amendment 1
11 Feb 2019
Global
Amendment 2
10 May 2019
Global
Amendment 3
08 Oct 2019
Global
Amendment 4
19 Nov 2019
Global
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
TAK-681 (Glucagon-like peptide-2 (GLP-2) analog-Fc fusion protein) 
PHASE 1 
A Randomized, Double-blind, Placebo-controlled, Phase 1 Study to Assess the 
Safety, Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and 
Multiple Doses of TAK-681 (GLP-2 analog-Fc fusion) in Healthy Adult Subjects 
PROTOCOL IDENTIFIER: TAK-681-101 
Study Sponsor(s): 
Shire Human Genetic Therapies, 
Inc. (Shire) 
300 Shire Way, Lexington, MA 
02421 USA 
Author: 
Protocol: 
19 Nov 2019, Amendment 4 
SAP Version #: 
2.0 
SAP Date: 
29 Jan 2020 
Status: 
 Final 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-681-101 
29 Jan 2020 
 
REVISION HISTORY 
 
Version  
Issue Date 
Summary of Changes 
1.0 
11 Jun 2019 
New Document 
2.0 
29 Jan 2020 
Update based on Protocol Amendments 3 and 4 
 
Minor editorial changes and corrections to 
typographical errors 
 
 
 
 
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Statistical Analysis Plan v2.0 
Protocol Number: TAK-681-101 
29 Jan 2020 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - AUTHORS .....................2 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - APPROVAL ...................3 
REVISION HISTORY ......................................................................................................4 
TABLE OF CONTENTS ..................................................................................................5 
ABBREVIATIONS ............................................................................................................8 
1. 
INTRODUCTION..................................................................................................9 
2. 
OBJECTIVES AND ENDPOINTS ......................................................................9 
2.1 
Objectives ............................................................................................................9 
2.1.1 Primary Objective ........................................................................................9 
2.1.2 Secondary Objective ....................................................................................9 
2.1.3 Exploratory Objective ..................................................................................9 
2.2 
Endpoints ............................................................................................................9 
2.2.1 Safety Endpoints ..........................................................................................9 
2.2.2 Pharmacokinetic Endpoints .........................................................................9 
2.2.3 Exploratory Endpoints ...............................................................................10 
3. 
STUDY DESIGN ..................................................................................................10 
3.1 
General Description ..........................................................................................10 
3.2 
Randomization ..................................................................................................12 
3.3 
Blinding .............................................................................................................13 
3.4 
Sample Size and Power Considerations ............................................................13 
4. 
STATISTICAL ANALYSIS SETS .....................................................................13 
4.1 
Safety Analysis Set ...........................................................................................13 
4.2 
Pharmacokinetic Analysis Set ...........................................................................14 
5. 
STUDY SUBJECTS .............................................................................................14 
5.1 
Disposition of Subjects .....................................................................................14 
5.2 
Demographic and Other Baseline Characteristics.............................................14 
5.3 
Medical History .................................................................................................15 
5.4 
Prior Medications ..............................................................................................15 
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5.5 
Concomitant Medications .................................................................................15 
5.6 
Exposure to Investigational Product .................................................................15 
5.7 
Measurements of Treatment Compliance .........................................................15 
5.8 
Protocol Deviations ...........................................................................................16 
6. 
PHARMACODYNAMIC ANALYSIS...............................................................16 
7. 
SAFETY ANALYSIS...........................................................................................16 
7.1 
Adverse Events..................................................................................................16 
7.1.1 Adverse Events of Special Interest ............................................................17 
7.2 
Clinical Laboratory Data ...................................................................................17 
7.3 
Vital Signs .........................................................................................................18 
7.4 
Electrocardiogram .............................................................................................18 
7.5 
Immunogenicity ................................................................................................19 
7.6 
Ultrasound .........................................................................................................19 
8. 
PHARMACOKINETIC ANALYSIS .................................................................19 
8.1 
Drug Concentration ...........................................................................................20 
8.2 
Single Ascending Dose .....................................................................................20 
8.3 
Multiple Ascending Dose ..................................................................................20 
8.4 
Handling Below Limit of Quantitation (BLQ) Values .....................................21 
8.5 
Pharmacokinetic Parameters .............................................................................22 
8.6 
Statistical Analysis of Pharmacokinetic Data ...................................................25 
8.7 
Assessment of Immunogenicity on Pharmacokinetic Parameters ....................25 
9. 
EXPLORATORY PHARMACODYNAMIC ANALYSES .............................26 
10. 
INTERIM ANALYSIS/DATA MONITORING COMMITTEE ....................26 
11. 
DATA HANDLING CONVENTIONS ..............................................................27 
11.1 
General Data Reporting Conventions ...............................................................27 
11.2 
Definition of Baseline .......................................................................................27 
11.3 
Repeated or Unscheduled Assessments of Safety Parameters ..........................27 
11.4 
Handling of Missing, Unused, and Spurious Data ............................................27 
11.4.1 Missing Date of Investigational Product....................................................27 
11.4.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..............................................................................28 
11.4.2.1 Incomplete Start Date ..................................................................28 
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Statistical Analysis Plan v2.0 
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11.4.2.2 Incomplete Stop Date ..................................................................28 
11.4.3 Missing Date Information for Adverse Events ..........................................29 
11.4.3.1 Incomplete Start Date ..................................................................30 
11.4.3.2 Incomplete Stop Date ..................................................................30 
11.4.4 Missing Severity Assessment for Adverse Events.....................................30 
11.4.5 Missing Relationship to Investigational Product for Adverse Events .......30 
11.4.6 Character Values of Clinical Laboratory Variables ...................................30 
12. 
ANALYSIS SOFTWARE ...................................................................................30 
13. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................31 
14. 
REFERENCES .....................................................................................................31 
15. 
APPENDICES ......................................................................................................31 
15.1 
Schedule of Activities .......................................................................................31 
15.2 
Potential Clinical Importance (PCI) Criteria for Laboratory, Vital Signs 
and ECGs in Individual Healthy Subjects .........................................................32 
 
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Statistical Analysis Plan v2.0 
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ABBREVIATIONS 
AE 
adverse event 
ADA 
anti-drug antibody 
ATC 
anatomical therapeutic chemical 
AUC 
area under the plasma concentration-time curve 
AUCextra 
area under the plasma concentration-time curve extrapolated from time t 
to infinity as a percentage of AUC0-∞ 
AUC0- 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-last 
area under the plasma concentration-time curve from time zero to the last 
sampling time at which the concentration is at or above LLOQ 
AUCo-τ 
area under the curve for the defined dose interval tau 
BLQ 
below limit of quantitation 
Cmax 
maximum observed concentration 
CL/F 
apparent total body clearance 
CLss 
apparent total body clearance at steady-state 
Ctrough 
observed concentration at the end of 1st, 2nd, 3rd, 4th, and 5th dosing 
interval (immediately before next dose) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
λz  
first order rate constant, lambda_z 
LLOQ 
lower limit of quantitation 
MAD 
multiple ascending dose 
NCA 
noncompartmental analysis 
PCI 
potentially clinically important  
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
SAD 
single ascending dose 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation  
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
t1/2 
apparent terminal half-life  
tlast 
time of the last measurable concentration 
Vz/F 
apparent volume of distribution  
Vss 
apparent volume of distribution at steady state  
 
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Statistical Analysis Plan v2.0 
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1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety, tolerability, pharmacokinetic (PK), and pharmacodynamic 
(PD) data as described in the study protocol amendment 4 dated 19 Nov 2019. 
Specifications for tables, figures, and listings are contained in a separate document.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
The primary objective of this study is to assess the safety and tolerability of single and 
multiple, ascending, subcutaneous (SC) doses of TAK-681 (referred as SHP681 in the 
study protocol) in healthy adult subjects. 
2.1.2 Secondary Objective 
The secondary objective of this study is to characterize the PK of TAK-681 following 
single and multiple, ascending SC doses in healthy adult subjects. 
2.1.3 Exploratory Objective 
2.2 
Endpoints 
2.2.1 Safety Endpoints 
For both the single ascending dose (SAD) and MAD portions, the safety and tolerability 
of escalating SC doses of TAK-681 will be evaluated by examining for each cohort: 
number, severity, seriousness and causality of all treatment-emergent adverse events 
(TEAEs), including injection site and hypersensitivity reactions, changes in vital signs, 
electrocardiograms (ECGs), abdominal ultrasounds, and clinical laboratory results 
(hematology, chemistry, and urinalysis) from baseline to post-baseline timepoints, 
incidence of anti-drug antibodies (ADA) to TAK-681. 
2.2.2 Pharmacokinetic Endpoints 
Pharmacokinetic parameters, including exposure parameters, will be calculated for 
individual subjects using plasma TAK-681 concentration-time data and 
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noncompartmental analysis (NCA) for both SAD and MAD parts. All calculations will be 
based on actual sampling times. Effect of ADA on PK will be evaluated. 
2.2.3 Exploratory Endpoints 
3. 
STUDY DESIGN 
3.1 
General Description 
This study is a randomized, double-blind, placebo-controlled, Phase 1 study to assess the 
safety and tolerability, and PK of TAK-681 following single and multiple, ascending, SC 
doses in healthy adult subjects. This study will be conducted at a single center and 5 dose 
levels are planned for both the SAD and MAD parts of this study. A total of 102 subjects 
(30 for the SAD portion and 72 subjects for the MAD portion) are planned to be enrolled 
for this study. 
In the SAD, dose escalation will proceed sequentially to assess the following single SC 
doses of TAK-681: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg.  
In the MAD, dose escalation for the first 5 cohorts will proceed sequentially to include 
the following SC doses: 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. Each 
cohort will receive TAK-681 (or placebo) once weekly for 5 weeks.  
A 6th MAD cohort will receive 4 mg/kg TAK-681 (or placebo) every 2 weeks over a 6-
week period (3 doses). The dose level of the last MAD cohort was determined based on 
the results of an interim analysis of the first 3 MAD cohorts.  
During dose escalation, protocol defined dose levels may be reduced, repeated, 
discontinued, or an intermediate increase may be added depending on the outcome of the 
blinded safety data review between dose escalations. 
The study design is shown in the study schema in Figure 1 and  
 
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Statistical Analysis Plan v2.0 
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Figure 2. 
Figure 1  
Study Design Flow Chart for the SAD portion 
 
 
 
 
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Statistical Analysis Plan v2.0 
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Figure 2  
Study Design Flow Chart for the MAD portion 
 
 
 
3.2 
Randomization 
The plan is to enroll in the SAD portion of the study 30 subjects in 5 cohorts. Each cohort 
will include 6 subjects. Subjects will be randomized within each cohort such that 5 
subjects receive TAK-681 and 1 subject receives placebo.  
The MAD portion of this study may initiate upon completion of a PK and safety data 
review of SAD Cohort 1, SAD Cohort 2, and partial data from SAD Cohort 3. The plan is 
to enroll 72 subjects within 6 MAD cohorts. Each cohort will include 12 subjects. 
Subjects will be randomized within each cohort such that 10 subjects receive TAK-681 
and 2 subjects receive placebo. 
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3.3 
Blinding 
This is a randomized, double-blind, placebo-controlled study. 
3.4 
Sample Size and Power Considerations 
SAD (Part 1) 
It is planned that dose escalation will proceed for up to 5 dose levels. Each cohort will 
include 5 subjects treated with TAK-681 and 1 subject treated with placebo for a planned 
total of 30 subjects. However, if dose levels are repeated, modified, or not conducted or if 
additional dose levels are studied, the total number of subjects may change. The number 
of subjects is expected to provide reasonable information on initial testing of TAK-681 
for safety and PK while exposing as few subjects as possible to investigational drug 
materials. The number of subjects in this study is not based on statistical hypothesis 
testing and power considerations as this is the first in human study. The statistical 
analyses are primarily descriptive, and no hypothesis testing is specified for this portion. 
MAD (Part 2) 
It is planned that the MAD portion of the study will include 6 cohorts. Each cohort will 
include 10 subjects treated with TAK-681 and 2 subjects treated with placebo for a 
planned total of 72 subjects. The number of subjects is expected to provide reasonable 
information on initial testing of TAK-681 for safety and PK while exposing as few 
subjects as possible to investigational drug materials. The number of subjects in this 
study is not based on statistical power considerations as this is the first in human study. 
The statistical analyses are primarily descriptive, and no hypothesis testing is specified in 
the study. 
4. 
STATISTICAL ANALYSIS SETS 
Subject populations are separately defined to analyze the data in the SAD portion and the 
MAD portion of the study. 
4.1 
Safety Analysis Set   
The Safety Analysis Set includes subjects who have received at least 1 dose of TAK-681 
or placebo. Analysis will be performed according to the treatment actually received 
regardless of the randomized treatment. 
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4.2 
Pharmacokinetic Analysis Set  
The PK Analysis Set consists of subjects who have received at least 1 dose of TAK-681 
and have at least 1 post-dose PK concentration value which was evaluable and 
interpretable. 
Examples of situations that may exclude a subject from the PK analysis set include, but 
may not be limited to: 
• Sample processing errors that lead to inaccurate bioanalytical results 
• Inaccurate dosing on the day of PK sampling.  
In the case of an important protocol deviation, PK data collected during the affected 
treatment will be excluded from the study results. 
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects in the Safety and PK Analysis Sets will be summarized by a 
pooled placebo group (Safety Analysis Set only), each dose cohort of TAK-681, and 
TAK-681 overall. 
The number and percentage of subjects who completed and prematurely discontinued 
will be presented for a pooled placebo group, each dose cohort of TAK-681, and TAK-
681 overall for the Safety Analysis Set. Reasons for premature discontinuation as 
recorded on the study completion/termination page of the electronic case report form 
(eCRF) will be similarly summarized (number and percentage) and listed as well. 
5.2 
Demographic and Other Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by a 
pooled placebo group, each dose cohort of TAK-681, and TAK-681 overall for the Safety 
Analysis Set. 
The following demographic characteristics will be summarized in the following order in 
the tables: age (years), sex, ethnicity, race, weight (kg), height (cm), and body mass index 
(kg/m2).  
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5.3 
Medical History 
Medical history will be collected at the Screening Visit and will be coded using MedDRA 
Version 22.0 or newer. A listing will be provided using the Safety Analysis Set. 
5.4 
Prior Medications  
Prior medications will be coded using the WHO Drug Dictionary Global (Enhanced 
w/WHO Herbal Dictionary) Version March2019 or newer.  
Prior medication is defined as any medication with the start date and end date prior to the 
date of the first dose of investigational product.  
All prior medications will be listed for the Safety Analysis Set. 
5.5 
Concomitant Medications  
Concomitant medications will be coded using the WHO Drug Dictionary Global 
(Enhanced w/WHO Herbal Dictionary) Version March2019 or newer.  
Concomitant medication is defined as any medication with a start date prior to the date of 
the first dose of investigational product and continuing after the first dose of 
investigational product or with a start date on or after the date of the first dose of 
investigational product. 
Concomitant medication usage will be summarized by the number and proportion of 
subjects receiving each medication by therapeutic class (Anatomical Therapeutic 
Chemical [ATC] Level 1) and preferred term (PT) for the Safety Analysis Set.  
All concomitant medications will be listed for the Safety Analysis Set. 
5.6 
Exposure to Investigational Product 
A listing will be created by subject number and study day giving the date and time of 
dose administration. 
5.7 
Measurements of Treatment Compliance  
Compliance will be assessed by observation of dosing by the investigator or designee. No 
listing or summary of compliance will be presented. 
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5.8 
Protocol Deviations 
Protocol deviations will be recorded by the site separately from the clinical database. 
Protocol deviations, including a classification of minor or major, will be listed for the 
Safety Analysis Set. 
6. 
PHARMACODYNAMIC ANALYSIS 
7. 
SAFETY ANALYSIS  
The safety summary will be performed using the Safety Analysis Set. Safety variables 
include AEs, clinical laboratory variables, vital signs, and ECG variables. For each safety 
variable, the last value collected before the first dose of investigational product, including 
unscheduled when applicable, will be used as baseline for all analyses of that safety 
variable.  
All safety analyses will be conducted according to the treatment the subject actually 
received. 
7.1 
Adverse Events  
Adverse events will be coded using MedDRA Version 22.0 or newer. 
An AE (classified by PT) that occurs during the Double-blind Evaluation Phase will be 
considered a TEAE if it has a start date on or after the first dose of double-blind 
investigational product or placebo.  
An overall summary of the number of subjects with TEAEs as well as the number of 
events will be presented, including the number and percentage of subjects with any 
TEAEs, serious TEAEs, TEAEs related to investigational product and TEAEs leading to 
discontinuation. 
 
The number and percentage of subjects reporting TEAEs, as well as the number of events 
(where applicable), in each treatment group and TAK-681 overall will be tabulated by 
system organ class (SOC) and PT; by SOC, PT, and severity. TEAEs considered related 
to investigational product will also be summarized by SOC and PT. If more than 1 AE 
occurs with the same PT and the same severity for the same subject, then the subject will 
be counted only once for that PT and that severity for the summarization by severity. 
Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC 
by descending incidence. 
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Serious TEAEs, TEAEs leading to discontinuation of investigational product will be 
summarized by SOC, PT, and treatment group and listed. Serious TEAEs leading to death 
will be listed.  
7.1.1 
Adverse Events of Special Interest  
Separate summaries will be provided for the TEAEs of injection site reactions as 
identified in the eCRF.  
7.2 
Clinical Laboratory Data 
Descriptive statistics for clinical laboratory values and changes from baseline at each 
assessment timepoint as well as shift tables from baseline to each visit for quantitative 
variables will be presented by treatment group for the following clinical laboratory 
variables: 
Hematology 
Hemoglobin, hematocrit, red blood cells, platelet count, white blood 
cell count – total and differential, total neutrophils (absolute), 
eosinophils (absolute), monocytes (absolute), basophils (absolute), 
lymphocytes (absolute) 
Biochemistry 
Sodium, potassium, glucose, blood urea nitrogen, creatinine, amylase, 
calcium, chloride, thyroid stimulating hormone, uric acid, phosphorus, 
total protein, total CO2 (bicarbonate), albumin, aspartate transaminase, 
lipase, alanine transaminase, gamma glutamyl transferase, alkaline 
phosphatase, total bilirubin 
Urinalysis 
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte 
esterase, specific gravity, erythrocytes, leukocytes, casts, bacteria 
Clinical laboratory test values/changes are potentially clinically important (PCI) if they 
meet either the low or high PCI criteria listed in Appendix 15.2 Table 1. The number and 
percentage of subjects with post-baseline PCI values will be tabulated by treatment 
group. The percentages will be calculated relative to the number of subjects with 
available baseline values and at least 1 post-baseline assessment. The numerator is the 
total number of subjects with at least 1 post-baseline PCI value. A supportive listing of 
subjects with PCI values will be provided.  
All laboratory data will be listed for the Safety Analysis Set. 
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7.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, pulse rate, 
temperature, and body weight) and their changes from baseline at each post-baseline visit 
and at the end of study will be presented by treatment group. 
Vital sign values will be considered PCI if they meet both the observed value criteria and 
the change from baseline criteria listed in Appendix 15.2 Table 2. The number and 
percentage of subjects with PCI post-baseline values will be tabulated by treatment 
group. The percentages will be calculated relative to the number of subjects with baseline 
and at least 1 post-baseline assessment. The numerator is the total number of subjects 
with at least 1 PCI post-baseline vital sign value. A supportive listing of subjects with 
PCI values will be provided.  
All vital signs data will be listed for the Safety Analysis Set. 
7.4 
Electrocardiogram 
The average (for continuous data) or worst assessment (for interpretation) from the 
triplicate ECG measurements collected at each nominal timepoint will be used for 
analysis. Descriptive statistics for ECG variables (heart rate, PR, RR, QRS, and QT 
intervals) and their changes from baseline at each assessment timepoint will be presented 
by treatment group. QTc interval will be calculated using both Bazett 
(QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not 
available, QTc will not be calculated. Electrocardiogram interpretation will be summarized 
by visit. A shift table from baseline to each visit for qualitative ECG results will be presented.  
Electrocardiogram variable values will be considered PCI if they meet or exceed the 
upper limit values listed in Appendix 15.2 Table 3. The number and percentage of 
subjects with post-baseline PCI values will be tabulated by treatment group. The 
percentages will be calculated relative to the number of subjects with available non-PCI 
baseline and at least 1 post-baseline assessment. The numerator is the total number of 
subjects with at least 1 PCI post-baseline ECG value. A listing of all subjects with PCI 
value will be provided. 
All ECG data will be listed for the Safety Analysis Set. 
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7.5 
Immunogenicity 
SAD (Part1) 
Blood draws (6 ml in K2EDTA tubes for each applicable timepoint) for determination of 
ADAs will be collected prior to dose on Day 1 and at 672 hours post-dose. Subjects with 
detectable ADAs in their plasma might require additional visits and blood collection for 
follow-up assessments of antibody titers up to a year post-dose. 
MAD (Part 2) 
Blood draws for determination of ADAs will be collected (6 mL in K2EDTA tubes for 
each applicable timepoint) prior to each dose, 7 days after the last dose (Day 36), and 28 
days after the last dose (Day 57) in each cohort. Subjects with detectable ADAs in their 
plasma on Day 57 might require additional visits and blood collection for follow-up 
assessments of antibody titers up to a year post-dose. 
Immunogenicity in each dose cohort will be analyzed by number and percent of subjects 
testing positive for ADA by predose and post-dose study visits. Overall, a subject will be 
categorized as ADA positive if at least one confirmatory positive result at any timepoint 
is reported, otherwise ADA negative if all results negative. 
Immunogenicity data will be listed for the Safety Analysis Set.  
7.6 
Ultrasound 
The results of abdominal ultrasound tests for MAD Cohort 6 will be listed. 
8. 
PHARMACOKINETIC ANALYSIS  
The PK analysis will be based on the PK analysis set (Section 4.2). 
Pharmacokinetic parameters will be calculated from plasma TAK-681 concentration-time 
data using noncompartmental methods and all calculations will be based on actual 
sampling times.  
The PK analysis of parameter estimates will be conducted by a contract research 
organization for the Clinical Pharmacology and Pharmacokinetics Department of Shire 
using Phoenix WinNonlin Version 8.0 or higher (Certara, L.P., Princeton, New Jersey, 
USA). 
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8.1 
Drug Concentration 
The plasma sample analysis for specified analyte concentrations will be performed 
according to the relevant Standard Operating Procedures at the contract bioanalytical lab. 
Plasma concentrations will be measured using the most current validated bioanalytical 
method.  
In addition, selected plasma samples may be used to investigate incurred sample 
reproducibility (full details will be described in the bioanalytical study plan). The 
presence of other metabolites or artifacts may be monitored or quantified as appropriate. 
All TAK-681 PK concentration data will be summarized by part, cohort, and/or 
scheduled timepoint, as appropriate. Repeated and unscheduled measurements are 
included in the listings but not used for statistical analysis or summary tables, unless the 
repeated measurement was performed due to unreliable values/technical reasons, e.g., 
clotted samples. 
8.2 
Single Ascending Dose  
The PK analysis will be based on the PK analysis set for Part 1 SAD. 
Individual subject’s raw concentrations of TAK-681 and actual sampling time will be 
listed by nominal sampling timepoint and summarized by dose cohort with descriptive 
statistics such as number of subjects, arithmetic mean, standard deviation (SD), 
coefficient of variation, minimum, median, maximum, geometric mean, and geometric 
coefficient of variation.  
Individual subject’s concentration-time curves will be presented in linear/linear and 
log/linear scale using lattice plots, with one panel for each subject grouped by dose 
cohort. Figures showing the mean (with ±SD as error bar) as well as the median (with 
25th to 75th quantiles as error bar) concentration time profiles will be presented in 
linear/linear and log/linear scale using lattice plots, with one panel for each dose cohort. 
Mean (±SD) concentrations after first dose and just prior to next dose (Ctrough) will be 
summarized by each cohort and presented in a single figure containing all cohorts 
(without SD) for a visual assessment of attainment of steady-state. 
8.3 
Multiple Ascending Dose 
The PK analysis will be based on the PK analysis set for Part 2 MAD. 
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Individual raw concentration data and actual sampling time will be listed by nominal 
sampling timepoint.  
Raw concentrations for each nominal sampling timepoint for post first dose, between first 
and last dose, and post last dose will be summarized by dose cohort with descriptive 
statistics such as number of subjects, arithmetic mean, SD, coefficient of variation, 
minimum, median, maximum, geometric mean, and geometric coefficient of variation.  
Individual subject’s Day 1 concentration-time profile up to 24 hours after the first dose 
will be visualized with correspondingly superimposed concentration-time profile up to 
24 hours following the last dose in linear/linear and log/linear scale using lattice plots, 
with one panel for each subject grouped by dose cohort. 
Mean (±SD) concentrations after first dose and just prior to next dose (Ctrough) will be 
summarized by each cohort and presented in a single figure containing all cohorts 
(without SD) for a visual assessment of attainment of steady-state. 
Individual concentration-time curves following the last dose will be presented in 
linear/linear and log/linear scale using lattice plots, with one panel for each subject 
grouped by dose cohort. Mean (with ±SD as error bar) as well as the median (with 25th 
to 75th quantiles as error bar) concentration time profiles will be presented in 
linear/linear and log/linear scale using lattice plots, with one panel for each dose cohort. 
Mean and median concentration time profiles for all dose cohorts will be superimposed in 
one plot. 
8.4 
Handling Below Limit of Quantitation (BLQ) Values 
Values below the lower limit of quantitation (LLOQ) will be replaced as zero for 
descriptive statistics of PK concentrations.  
For the PK analysis, predose sample concentrations that are BLQ will be assigned a 
numerical value of zero for the calculation of area under the plasma concentration-time 
curve (AUC). Samples not collected will be identified as missing. Any anomalous 
concentration values observed at predose will be identified in the study report and used 
for the computation of PK parameters, even if the anomalous value is greater than 5% of 
the maximum observed concentration (Cmax). Plasma concentrations of BLQ before the 
last quantifiable data point will be taken as zero for calculating the AUC (i.e., embedded 
BLQ values will be set to zero). Plasma concentrations of BLQ after the last quantifiable 
data point will be set to ‘zero’ and will not be considered for the determination of 
lambda_z (λz).  
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8.5 
Pharmacokinetic Parameters 
The PK analysis will be based on the PK analysis set for each study part. 
Pharmacokinetic parameters will be evaluated and listed for all volunteers who provide 
sufficient concentration time data. Noncompartmental computation of PK parameters will 
be performed. 
Individual PK parameters will be calculated using unrounded actual sampling times (or 
using scheduled time if actual time is not available). The predose sample will be 
considered as if it had been taken simultaneously with the administration of study drug. 
Pharmacokinetic parameters will be calculated from plasma TAK-681 concentration-time 
data based on actual sampling times. Pharmacokinetic parameters will include the 
following: 
Part 1 SAD: 
AUC0- 
Area under the concentration-time curve in serum from time zero 
(predose) extrapolated to infinity, calculated by linear up/log down 
trapezoidal summation and extrapolated to infinity by addition of the 
last quantifiable concentration (Ct) divided by the terminal rate 
constant, λz [ie, AUC0-last + Ct/λz].  
AUC0-last 
Area under the plasma concentration-time curve from time zero to the 
last sampling time at which the concentration is at or above LLOQ, 
calculated according to the mixed log linear trapezoidal rule (i.e., 
linear up/log down). 
AUCextra 
AUC extrapolated from time tlast to infinity obtained by 
extrapolation (%). Equation: (1－ [AUC0-last / AUC0-∞]) × 100.  
Cmax 
Maximum observed concentration obtained directly from the 
concentration-time profile after a single dose.  
Cavg,0-24 
Average concentration from time zero to 24 hours postdose 
CL/F 
Apparent total body clearance for extravascular  
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administration divided by the fraction of dose absorbed calculated as 
dose divided by AUC0-∞.  
λz 
First order rate constant, lambda_z, associated with the terminal 
(log-linear) portion of the terminal data points of the curve. A 
minimum of 3 points will be included in the regression analysis. 
  
t1/2 
Apparent terminal half-life calculated as ln2/λz. 
tlast 
Time of the last measurable concentration. 
tmax 
Minimum time to reach the Cmax concentration after a single dose. 
Vz/F 
Apparent volume of distribution following extravascular  
administration divided by the fraction of dose absorbed calculated as 
CL/F divided by λz. 
Part 2 MAD (Post first dose): 
Cavg,0-24 
Average concentration from time zero to 24 hours postdose 
MAD (Between first dose and last dose: 
Ctrough 
Observed concentration at the end of each dosing interval 
(immediately before next dose for the first 5 cohorts and immediately 
before 2nd and 3rd dose of the 6th MAD cohort) 
Part 2 MAD (Post last dose): 
AUC0- 
Area under the concentration-time curve in serum from time zero 
(predose) extrapolated to infinity, calculated by linear up/log down 
trapezoidal summation and extrapolated to infinity by addition of the 
last quantifiable concentration (Ct) divided by the terminal rate 
constant, λz [i.e., AUC0-last + Ct/λz]. 
Cavg,0-24 
Average concentration from time zero to 24 hours postdose 
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AUC0-last 
Area under the plasma concentration-time curve from time zero (for 
the last dose) to tlast, calculated according to the mixed log linear 
trapezoidal rule (i.e., linear up/log down). 
AUC0-tau 
Area under the concentration versus time curve over a dosing interval 
(tau). Only calculated if interpretable i.e., last sample timepoint for 
dose interval is present, and sample at tmax is present. 
Cmax 
Maximum observed concentration obtained directly from the 
concentration-time profile. 
CL/F 
Apparent total body clearance for extravascular  
administration divided by the fraction of dose absorbed calculated as 
dose divided by AUC0-tau. 
λz 
First order rate constant, lambda_z, associated with the terminal 
(log-linear) portion of the terminal data points of the curve. A 
minimum of 3 points will be included in the regression analysis. 
  
t1/2 
Apparent terminal half-life calculated as ln2/λz. 
tlast 
Time of the last measurable concentration. 
tmax 
Minimum time to reach the Cmax concentration. 
Vz/F 
Apparent volume of distribution following extravascular  
administration divided by the fraction of dose absorbed, calculated as 
CL/F divided by λz. 
No dose adjustment will be made for parameters that require dose for calculation. 
The following PK parameters will be calculated for diagnostic purposes and provided in a 
separate table for each study part, but will not be summarized: 
• The time interval (h) of the log-linear regression to determine λz (t½, Interval).  
• Number of data points (t½, N) included in the log-linear regression analysis to determine 
λz. 
• Goodness-of-fit statistic (Rsq_adj) for calculation of λz, if <0.800 then parameters using 
λz will be flagged for exclusion in summary tables. 
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• If AUCextra is > 20.0% then AUC0- will be flagged for exclusion in summary tables.  
 
Any anomalous concentration values observed at predose will be identified. Predose 
TAK-681 plasma concentrations that are greater than 5% of the maximum concentration 
of the individual’s profile will exclude that individual (concentrations and PK 
parameters) from the PK analysis set.  
Predose TAK-681 plasma concentrations below the level of quantitation (BLQ) and BLQ 
plasma values prior to quantifiable concentrations will be set to zero for both descriptive 
statistics estimations and PK concentration tables. If the actual time is missing (i.e. not 
recorded) then the scheduled sampling time will be used for the estimation of the PK 
parameters, unless otherwise warranted by the data. 
Individual subject’s PK parameters will be listed by part, dose cohort, and applicable 
dose (Part 2, MAD). Diagnostic parameters such as the number of timepoints of the 
terminal log-linear phase used to estimate the terminal rate constant and percentage of 
extrapolated AUC will be listed similarly. 
PK parameters will be summarized by part, dose cohort, and applicable dose (Part 2, 
MAD) with descriptive statistics such as number of subjects, arithmetic mean, SD, 
coefficient of variation, minimum, median, maximum, geometric mean, and geometric 
coefficient of variation.  The parameters, tmax and tlast, will be summarized by median, 
minimum, and maximum grouped by dose cohort. 
Pharmacokinetic parameters of AUC0-∞, AUC0-tau, AUC0-24, and Cmax will be presented in 
box plots by part when appropriate for each dose cohort. 
8.6 
Statistical Analysis of Pharmacokinetic Data 
The statistical analyses are primarily descriptive, and no hypothesis testing is specified 
for this portion. 
8.7 
Assessment of Immunogenicity on Pharmacokinetic Parameters 
Subjects that test positive for immunogenicity markers ADA will have PK parameters 
summarized by part and cohort using descriptive statistics. Only subjects with both 
immunogenicity and PK parameter data will be included. 
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9. 
EXPLORATORY PHARMACODYNAMIC ANALYSES 
10. 
INTERIM ANALYSIS/DATA MONITORING COMMITTEE  
To support an initiation of the MAD phase and confirm the dosing interval, an interim 
analysis will be required. Blinded plasma concentrations at nominal collection times 
obtained after dosing in Cohort 1, Cohort 2, and part of Cohort 3 in the SAD portion will 
be evaluated and justified for this purpose. To support additional development decisions, 
blinded plasma concentrations at nominal collection times obtained after SAD, and 3 
cohort MAD portions will be evaluated and justified for this purpose. All of this work 
will be done separately from the final NCA analyses and reported separately.   
An interim analysis will be performed after the last patient from the 3rd MAD cohort has 
completed the Day 39 visit, to determine the dose level of the 6th MAD cohort, and to 
assess any safety, tolerability, or PK questions based on the safety review. The data for 
this analysis will be source data verified and cleaned according to the Interim Snapshot 
Plan. This analysis will unblind all completed SAD cohorts and the first 3 MAD cohorts 
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for the Sponsor and external statistical groups. MAD cohorts 4, 5 and 6 will not be 
unblinded to any parties due to this interim analysis. 
No adaptive design or data monitoring committee is planned, all applicable data will be 
reviewed by the Clinician and Clinical PK (Sponsor). 
11. 
DATA HANDLING CONVENTIONS  
11.1 
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics: the 
number of subjects (n), mean, median, SD, minimum, and maximum. Categorical and 
count variables will be summarized by the number of subjects and the percent of subjects 
in each category. Additional summary statistics will be provided for PK endpoints and 
are indicated in Section 8. 
11.2 
Definition of Baseline  
Baseline is defined as the last non-missing value observed prior to dosing with TAK-681 
or placebo. 
11.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the 
results from the final assessment made prior to the start of investigational product will be 
used as baseline. If end-of-study assessments are repeated or unscheduled, the last 
post-baseline assessment will be used as the end of study assessment for generating 
descriptive statistics. However, all post-baseline assessments will be used for PCI value 
determination and all assessments will be presented in the data listings. 
11.4 
Handling of Missing, Unused, and Spurious Data  
Missing safety data will not be imputed.  
Missing PK concentrations will be handled as described in Section 8.4. 
11.4.1 Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the 
Safety Analysis Set, all efforts should be made to obtain the date from the investigator.  
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11.4.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or 
stop date will be imputed. When the start date and the stop date are both incomplete for a 
subject, impute the start date first. 
11.4.2.1 Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop 
date is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
11.4.2.1.1 
Missing Day and Month 
• 
If the year of the incomplete start date is the same as the year of the date of the first 
dose of investigational product, then the day and month of the date of the first dose 
of investigational product will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of the first dose 
of investigational product, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
11.4.2.1.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
11.4.2.1.3 
Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and year 
of the date of the first dose of investigational product, then the day of the date of the 
first dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the first dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the first dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the date of the first dose of investigational product 
or if both years are the same but the month is after the month of the date of the first 
dose of investigational product, then the first day of the month will be assigned to 
the missing day. 
11.4.2.2 Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the date of 
the last dose of investigational product is missing, then replace it with the last visit date. 
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If the imputed stop date is before the start date (imputed or non-imputed start date), then 
the imputed stop date will be equal to the start date. 
11.4.2.2.1 
Missing Day and Month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose 
of investigational product will be assigned to the missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose 
of investigational product, then 31 December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
11.4.2.2.2 
Missing Month Only 
• 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
11.4.2.2.3 
Missing Day Only 
• 
If the month and year of the incomplete stop date are the same as the month and year 
of the date of the last dose of investigational product, then the day of the date of the 
last dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational 
product or if both years are the same but the month is before the month of the date 
of the last dose of investigational product, then the last day of the month will be 
assigned to the missing day 
• 
If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
11.4.3 Missing Date Information for Adverse Events  
For AEs with partial start dates, non-missing date parts will be used to determine if the 
AE is treatment-emergent or not. If a determination cannot be made using the 
non-missing date parts as to when the AE occurred relative to study drug administration, 
e.g., AE start year and month are the same as the year and month of the first dose of 
investigational product, then the AE will be classified as treatment-emergent. 
 
To facilitate categorization of AEs as treatment emergent, imputation of dates can be 
used. For AEs, the default is to only impute incomplete (i.e., partially missing) start dates. 
Incomplete stop dates may also be imputed when calculation of the duration of an AE is 
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required per the protocol. If imputation of an incomplete stop date is required, and both 
the start date and the stop date are incomplete for a subject, impute the start date first. 
11.4.3.1 Incomplete Start Date  
[Follow the same rules as in Section 11.4.2.1] 
11.4.3.2 Incomplete Stop Date  
[Follow the same rules as in Section 11.4.2.2] 
11.4.4 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of 
investigational product, then a severity of “Mild” will be assigned. If the severity is 
missing for an AE starting on or after the date of the first dose of investigational product, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment 
will be used for incidence summaries, while both the actual and the imputed values will 
be used in data listings. 
11.4.5 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the 
date of the first dose of investigational product, a causality of “Related” will be assigned. 
The imputed values for relationship to double-blind investigational product will be used 
for incidence summaries, while both the actual and the imputed values will be presented 
in data listings. 
11.4.6 Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical 
analysis due to, for example, that a character string is reported for a numerical variable. 
The appropriately determined coded value, upon discussion and agreement with the study 
physician, will be used in the statistical analysis. However, the actual values as reported 
in the database will be presented in data listings. 
12. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.  
The PK analysis will be conducted using Phoenix WinNonlin Version 8.0 or higher 
(Certara, L.P., Princeton, New Jersey, USA). 
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13. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
. Pharmacokinetic parameter Cavg,0-24 was added to the following study portions:  SAD, 
MAD post first dose, and MAD post last dose. MAD post first dose parameters of AUC0-
24, Cmax, 24 and tmax, 24 were removed. Interim PK analysis results showed the MAD post 
first dose sampling scheme was insufficient to accurately characterize these parameters. 
Immunogenicity data for nADA will not be presented as the analysis was not performed 
for nADA. 
14. 
REFERENCES 
There are no references. 
15. 
APPENDICES  
15.1 
Schedule of Activities 
Refer to Tables 1-7 in the protocol. 
 
 
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