Clinical trial NCT01771809
Conditions: Ulcerative Colitis
Keywords: Anti-TNF Refractory Active Ulcerative Colitis Immunosuppressant Refractory
Sponsor: Shire
Start date: 2013-03-18; Completion date: 2017-12-13
Enrollment: 330 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Subjects with Ulcerative Colitis who have completed an induction study with PF-00547659 will receive an additional 144 weeks of open-label treatment to evaluate the long-term safety of the drug.

Detailed description:

Arms: arm 1: Participants will receive 75 milligrams (mg) of SHP647 subcutaneous (SC) injection every 4 weeks for 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. During the first 72 weeks, a one time dose escalation to 225 mg of SHP647 SC injection every 4 weeks is allowed after 8 weeks of the study for participants who experience clinical deterioration or unacceptably low level of response to the investigational product. The decision to escalate will be guided by the response and relapse criteria tempered by clinical judgment. Following the first 72 weeks, participants will receive 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen. arm 2: Participants will receive 225 mg of SHP647 SC injection every 4 weeks for 72 weeks followed by 75 mg of SHP647 SC injection every 4 weeks for an additional 72 weeks in the anterolateral right/left thigh or the deltoid area or the abdomen.
Interventions: intervention 1: 75mg SHP647 (PF-00547659) intervention 2: 225mg SHP647 (PF-00547659)
Intervention descriptions: intervention 1: 75 mg sterile liquid injected subcutaneously every 4 weeks. intervention 2: 225 mg sterile liquid injected subcutaneously every 4 weeks.

Protocol documents:
Prot_000.pdf: 
CLINICAL PROTOCOL
A MULTICENTER OPEN-LABEL EXTENSION STUDY TO ASSESS LONG-TERM 
SAFETY OF PF-00547659 IN SUBJECTS WITH ULCERATIVE COLITIS
(TURANDOT II)
Compound:
PF-00547659*
Compound Name:
N/A
US IND Number:
100,222
European Clinical Trial Database 
(EudraCT) Number:
2012-002031-28
Protocol Number:
A7281010
Phase:
2
Principal/Coordinating Investigator:
Walter Reinisch, MD
Protocol History:
Original Protocol: 26 Jun 2012
Amendment 5: 14 Nov 2016
Amendment 4: 04 Dec 2015
Amendment 3:  24 Feb 2015
Amendment 2: 21 Mar 2013
Amendment 1: 04 Mar 2013
*Sponsorship of this study is transferred to Shire. The compound name has been modified from 
PF-00547659 to SHP647 (MAdCAM) or SHP647. PF-00547659 and SHP647 (MAdCAM) refer 
to the same compound and are interchangeable wherever they appear.
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


2 
P R O T O C O L SI G N A T U R E P A G E 
S p o ns or's ( S hir e) A p pr o v al 
Si g n at ur e: 
Pr a b h a k ar Vis w a n at h a n, M D, P h D 
 
I n v esti g at or's A c k n o wl e d g e m e nt 
I ha ve rea d t his pr ot o c ol f or S hir e St u d y A 7 2 8 1 0 I 0. 
Title: A M ulti c e nt er, O p e n-l a b el E xt e nsi o n Sttt d y t o Ass ess L o n g-t er m S af et y of P F- 0 0 5 4 7 6 5 9 
i n S u bj e cts wit h Ul c er ati v e C olitis ( T U R A N D O T II) 
I ha ve f ull y dis c uss e d t h e o bj e cti v e(s) of t his st u d y a n d t h e c o nt e nts of t his pr ot o c ol wit h t h e 
s p o ns or's r e pr es e nt ati v e. 
I u n d erst a n d t h at t h e i nf or m ati o n i n t his pr ot o c ol is c o nfi d e nti al a n d s h o ul d n ot be discl ose d, 
ot h er t h a n t o t h os e dir e ctl y i n v ol v e d i n t h e e x e c uti o n or t h e s ci e ntifi c/ et hi c al r e vi e w of t he st u d y, 
wit h o ut writt e n a ut h ori z ati o n fr o m t h e s p o ns or. It is, h o w e v er, p er missi bl e t o pr o vi d e t h e 
i nf or m ati o n c o nt ai n e d h er ei n t o a s u bj e ct i n or d er t o o bt ai n t h eir c o ns e nt t o p arti ci p at e. 
I a gr e e t o c o n d u ct t his st u d y a c c or di n g t o t his pr ot o c ol a n d t o c o m pl y wit h its r e q uir e m e nts, 
s u bj e ct t o et hi c al a n d s af et y c o nsi d er ati o ns a n d g ui d eli n es, a n d t o c o n d u ct t h e st u d y i n 
a c c or d a n c e wit h I nt er n ati o n al C o nf er e n c e o n H ar m o nis ati o n g ui d eli n es o n G o o d Cli ni c al 
Pr a cti c e a n d wit h t h e a p pli c a bl e r e g ul at or y r e q uir e m e nts. 
, 
\ 
I u n d erst a n d t h at fail ure t o c o m pl y wit h t h e r e q uir e m e nts of t h e pr ot o c ol m a y lea d t o t h e 
t er mi n ati o n of m y p arti ci p ati o n as a n i n v esti g at or f or t his st u d y. 
I u n d erst a n d t h at t h e s p o ns or m a y d e ci d e t o s us p e n d or pr e m at ur el y t er mi n at e t h e st u d y at a n y 
ti m e f or w h at e v er reas o n; s u c h a d e cisi o n will be c o m m u ni c at e d t o me i n writi n g. C o n v ers el y, 
s h o ul d I d e ci d e t o wit h dr a w fr o m e x e c uti o n oft h e st u d y I will c o m m u ni c at e m y i nt e nti o n 
i m m e di at el y i n writi n g t o t h e s p o ns or. 
I n v esti g at or N a m e a n d A d dr ess: 
( please ha n d pri nt or t y pe) 
Si g n at ur e: ----------------------------- D at e: 
S hire
C O N FI D E N TI A L
P a ge 2
P F -0 0 5 4 7 6 5 9/ S H P 6 4 7
A 7 2 8 1 0 1 0 Pr ot oc ol A m e n d me nt 5
1 4 N o ve m ber 2 0 1 6
P P D
P P D
P P D


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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
5
Amendment Date
14 November 2016
Global/Country/Site Specific
Global
Description of Change and Rationale
Section(s) Affected by Change
Added Principal/Coordinating Investigator name;
Listed prior protocol amendments
Cover page
Added footnote indicating that sponsorship of study was transferred to 
Shire and that the compound name has been modified from 
PF-00547659 to SHP647 (MAdCAM).
Cover page
Updated confidentiality statement with standard Shire language.
Cover page
Updated header to include Shire compound name.
Cover page
Updated footer from “Pfizer Confidential” to “Shire Confidential”.
Cover page
Inserted Protocol Signature page updated with Medical Monitor name 
consistent with Shire’s Standard Operating Procedure (SOP) for 
protocols 
Protocol Signature Page
Inserted Emergency Contact page updated with Medical Monitor name 
and contact information consistent with Shire’s SOP for protocols
Emergency Contact Page
Inserted Product Quality Complaint page consistent with Shire’s SOP 
for protocols
Product Quality Complaint Page
Updated Sponsor from Pfizer to Shire
Globally
Updated footnote for clarity
Schedule of Activities
Updated languge citing investigator’s brochure as the most current 
source of overall risk/benefit assessment of PF 00547659/SHP647.
Section 1.2.6. Risk Benefit
Removed text describing the details of the contact card as Shire does not 
provide a help desk contact.
Section 4.3 Sponsor Qualified 
Medical Personnel
Clarified text describing packaging.
Section 5.2.1 Formulation and 
Packaging
Updated text to be consistent with Shire’s standard processes for drug 
storage and temperature monitoring of storage facility.
Section 5.3 Drug Storage and Drug 
Accountability
Updated text to be consistent with Shire’s standard processes for 
reporting and follow-up of pregnancies of female study participants or 
partners of male study participants.
Section 8.10 Exposure During 
Pregnancy
Updated text to be consistent with Shire’s standard processes for 
reporting and follow-up of serious adverse events.
Section 8.14.1 Serious Adverse 
Event Reporting Requirements
Updated text to be consistent with Shire’s standard timeline for posting 
clinical study report synopses in which identifying patient information 
has been redacted.
Section 15.1 Communication of 
Results by Shire 


S hire
C O N FI D E N TI A L
P a ge 4
P F -0 0 5 4 7 6 5 9/ S H P 6 4 7
A 7 2 8 1 0 1 0 Pr ot oc ol A m e n d me nt 5
1 4 N o ve m ber 2 0 1 6
E M E R G E N C Y C O N T A C T I N F O R M A TI O N
I n t he e ve nt of a seri o us a d verse e ve nt ( S A E), t he i n vesti gat or m ust fa x or e- mail t he S hire 
Cli nical St u d y  A d verse E ve nt F or m f or Seri o us A d verse E ve nts ( S A Es) a n d N o n-seri o us AEs as 
Re q uire d b y Pr ot o c ol wit hi n 2 4 h o urs t o S hire Gl o bal Dr u g Safet y . A p plica ble fa x n u m bers a n d 
e-mail a d dress ca n be f o u n d o n t he f or m (se nt u n der se parate c o ver). A c o p y  of t his f or m m ust 
als o be se nt t o t he c o ntract researc h or ga nizati o n ( C R O)/ S hire me dical m o nit or b y fa x or e -mail 
usi n g t he d etails bel o w.
, M D, P h D, 
 
E mail:  
Fa x:  
F or pr ot oc ol - or s afet y -rel ate d iss ues d uri n g n or m al b usi ness h o urs ( 8 a m t o 5 p m, E aster n 
St a n d ar d Ti me) , t he i n vesti g ator m ust c o nt act t he S hire me dic al m o nit or:
, M D, P h D, 
P h o ne: 
M o bile: 
E mail:  
Fa x:  
, M D, 
Office P h o ne: 
M o bile: 
E mail: 
Fa x: 
F or pr ot oc ol - or s afet y -rel ate d iss ues o utsi de of n or m al b usi ness h o urs , t he i n vesti g at or 
m ust c o nt act t he Me dic al m o nit or:
P P D
, M D, P h D, 
 
M o bile: 
E mail:  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


S hire
C O N FI D E N TI A L
P a ge 5
P F -0 0 5 4 7 6 5 9/ S H P 6 4 7
A 7 2 8 1 0 1 0 Pr ot oc ol A m e n d me nt 5
1 4 N o ve m ber 2 0 1 6
P P D
, M D, 
Office P h o ne: 
M o bile: 
E mail: 
Fa x: 
P P D
P P D
P P D
P P D
P P D


S hire
C O N FI D E N TI A L
P a ge 6
P F -0 0 5 4 7 6 5 9/ S H P 6 4 7
A 7 2 8 1 0 1 0 Pr ot oc ol A m e n d me nt 5
1 4 N o ve m ber 2 0 1 6
P R O D U C T Q U A LI T Y C O M P L AI N T S
I n vesti gat ors are re q uire d t o re p ort i n vesti gati o nal pr o d uct q ualit y c o m plai nts t o S hire wit hi n 
2 4 h o urs. T his i ncl u des a n y  i nsta nces w herei n t he q ualit y or perf or ma nce of a S hire pr o d uct 
( mar kete d or i n vesti gati o nal) d oes n ot meet e x pectati o ns (e g, i na de q uate or fa ult y  cl os ure, 
pr o d uct c o nta mi nati o n) or t hat t he pr o d uct di d n ot meet t he s pecificati o ns defi ne d i n t he 
a p plicati o n f or t he pr o d uct (e g, wr o n g pr o d uct s uc h t hat t he la bel a n d c o nte nts are differe nt 
pr o d ucts). F or i nst r ucti o ns o n re p orti n g A Es relate d t o pr o d uct c o m plai nts, see Secti o n 8 .
Please use t he i nf or mati o n bel o w as a p plica ble t o re p ort t he Pr o d uct Q ualit y C o m plai nt:
Ori gi n of Pr o d uct Q u alit y C o m pl ai nt
E- m ail A d dress
N ort h a n d S o ut h A merica
E ur o p ea n U ni o n a n d Rest of W orl d
P P D
Tele p h o ne n u m bers ( pr o vi de d f or refere nce if nee de d):
S hire, Le xi n gt o n, M A ( U S A)
P P D
P P D


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Summary of Changes From Prior Versions
Document
Version Date
Summary of Changes
Amendment 4
04 December 2015

Revised Risk Benefit Section 1.2.6 to reflect current 
available biologic treatment for subjects with 
inflammatory bowel disease.

Changed the 24-month follow-up period to a 6 month 
follow-up period.  Specific changes include: 

Removing Study Weeks 148, 152, 160 and 164.  
Visits at study Weeks 156 and 168 remained and 
collection of blood samples for PK and ADA and Nab 
have been added to Week 156 visit.

Removing the 18 month telephone follow-up.  
Specific protocol sections affected by the change 
include: 

Protocol Summary, Schedule of Activities, 
Section 3.0, Section 3.1, Section 3.2, Section 6.3, 
Section 6.4.1, Section 7.1, and Section 7.3.

Updated Section 8 of the Protocol to be consistent with 
current Pfizer standards.
Amendment #3
24 February 2015

Addition of a Open Label Treatment Period 2 in which 
subjects will receive 75 mg PF-00547659 for an additional 
18 months.  Specific protocol sections changed to support 
this addition include:

Protocol Summary, Schedule of Activities, 
Section 1.2.3.1, Section 3.1, Section 3.2, Section 3.3, 
Section 5.1, Section 5.2.3, Section 6.2.19, Section 
6.2.20, Section 6.3, Section 6.4, Section 7.2, 
Section 7.2.1, Section 7.2.2.1, Section 7.2.2.2, 
Section 7.2.3, Section 7.2.4, Section 7.2.5 and 
Section 7.3.

Changed language pertaining to the feeder study to 
A7281009 study. Specific protocol sections affected by the 
change include:

Protocol Summary, Section 3.0, Section 3.4. 4.1 and 
Section 6.1.

Removed language “Study drug will be stopped for 
discontinued Non-Responders who will then enter the 
follow-up period” from the Protocol Summary and 
Section 2.2.3.1 Efficacy.

Updated Protocol throughout to be consistent with current 
Pfizer standards, which include Section 5.1, Section 5.2.4 
(now Section 8.4), Section 5.4, Section 5.5, Section 6.4, 
Section 7.1, and Section 15.1.

Specific changes include: 

Legal representative revised to acceptable 


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PF-00547659/SHP647
A7281010 Protocol Amendment 5
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representative.

Medication Errors moved from Section 5.2.4 
to Section 8.4.

Medication(s) changed to Treatment(s).

Addition of Withdraw Consent and Lost to 
Follow-up language.

Pregnancy testing regarding cases of a 
positive result.

Removed all language pertaining to Dose Escalation as 
results from A7281009 study did not show additional 
benefit 225 mg dose. Specific sections affected include the 
following:

Protocol Summary, Section 3.1, Section 5.6, 
Section 6.2.2, Section 6.2.4, Section 6.2.6, 
Section 6.2.8, Section 6.2.10, Section 6.2.12, 
Section 6.2.14 and Section 6.2.16.

Removed Figure 1 Study Schematic due to removal of 
Dose Escalation from study design.

Additional language added in Section 3.1 regarding 
guidance on Dose Interruption.

In Section 5.5.5 Oral Corticosteroid Rescue Therapy 
changed one additional course of oral corticosteroid rescue 
therapy to three additional course of oral corticosteroid
rescue therapy.

Section 7.2.2.1 Complete Physical Examination clarified 
that the external genitalia examination is optional.

In sections 7.4.1.2., 7.4.1.3.9., and 7.4.1.4 included 
clarification regarding the term baseline.

Added clarification regarding definition of immediately in 
Section 7.5.3 Subjectr Stool Diary.
Amendment #2
21 March 2013

Introduction of the feeder study throughout the protocol.

Updated Protocol Summary.

Updated Rationale for Discontinuing Immunosuppressive 
Therapy Section 1.2.2.

Updated Section 2.2.3.3 to clarify specimen collection.

Updated Approximate Number of Subjects Section 3.4.

Updated Inclusion Criteria 1 and 3 Section 4.1.

Added Sponsor Qualified Medical Personnel Section 4.3.

Removed Antidiarrheal language from Sections 5.5.1 and 


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5.5.3.

Blood Sample from RNA removed from Visit 2, Section 6.

Soluble MAdCAM testing removed from Visit 2 
Section 6.

JC virus DNA testing removed from Visits 2-6, 8-12, 14-
18 and 20-24 Section 6.

JC virus antibody testing added to Vists 7, 13, 19, 25 and 
Early Withdrawal Section 6.

Updated Early Withdrawal Section 6.4.

Added footnote e to Laboratory Assessments Table 3 to 
include creatinine clearance calculation by central lab 
(C&G method).

Added JC Virus Antibody to Table 3.

Clarified JC virus sampling Section 7.4.1.6.

Updated Optional Endoscopic Biopsy Substudy Section 
7.5.2.

Updated SCCAI Section 7.5.6.

Updated Exploratory Biomarkers Section 7.7.3.

Revised Adverse Event Reporting Section 8.2 to align 
with current protocol template

Updated Section 8.12.2 to clarify halting treatment with 
study medication for unexplained neurological signs or 
symptoms and undergoing further neurological evaluation.

Removed Pop-PK and PK/PD modeling references from 
Sections 9.3 and 9.4.

Updated Plasma to Serum in Section 9.4.

Removed the statement Subjects with a positive antibody 
status at any time during the study will be defined as 
having an overall positive antibody status while subjects 
with a negative antibody status throughout the study will 
be defined as having an overall negative antibody status 
from Section 9.5.

Minor administrative changes/corrections
Amendment #1
04 March 2013

Updated withdrawal criteria as defined for Week 16 
Section 6.2.4.


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
Revised language for Early Withdrawal Section 6.4.
Original Protocol
26 June 2012
N/A
This amendment incorporates all revisions to date, including amendments made at the request of 
country health authorities, institutional review boards/ethics committees (IRBs/ECs).


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Abbreviations
This is a list of abbreviations that may or may not be used in the protocol.
Abbreviation
Term
5-ASA
5-aminosalicylic acid derivative
6-MP
6-mercaptopurine
9-HPT
9-Hole Peg Test
ADA
anti-drug antibodies 
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AZA
Azathioprine
BUN
blood urea nitrogen
BNP
B-type Natriuretic Peptide
CD
Crohn’s Disease
CD4
Cluster of differentiation; glycoprotein on T-cell surface
CDS
Core data sheet
CNS
Central nervous system
CPK
Creatinine phosphokinase
CRF
case report form
CRP
C-reactive protein
CSR
Clinical study report
CTA
Clinical trial application
cTnI
Cardiac Troponin I
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram
EDP
Exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
EOS
end of study
EudraCT
European Clinical Trial Database
FDA
Food and Drug Administration (US)
FS
Feeder Study
GCP
Good Clinical Practice
GDH
Glutamate Dehydrogenase
GI
Gastrointestinal
HEENT
head, eyes, ears, nose, and throat 
hs-CRP
high-sensitivity C-reactive protein
IBD
inflammatory bowel disease
ICD
informed consent document
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IHC
Immunohistochemistry


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This is a list of abbreviations that may or may not be used in the protocol.
Abbreviation
Term
IND
investigational new drug application
IRB
institutional review board
LSLV
Last subject last visit
MTX
Methotrexate
MS
Multiple Sclerosis
MSFC
Multiple Sclerosis Functional Composite
MSNQ
Multiple Sclerosis Neuropsychological Questionnaire
Nab
Neutralizing antibody
NT-proBNP
N-terminal B-type Natriuretic Peptide
OL/OLE
open-label/open-label extension
PCR
Polymerase Chain Reaction
PD
pharmacodynamic(s)
PhRMA
Pharmaceutical Research and Manufacturers of America
PK
Pharmacokinetic(s)
PML
Progressive Multifocal Leukoencephalopathy
POC
proof-of-concept
PRO
Patient Reported Outcome
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous, subcutaneously
SCCAI
Simple clinical colitis activity index
SDMT
Symbol Digit Modality Test
SOA
Schedules of Activities
TNF
tumor necrosis factor
T25FW
Timed 25-Foot Walk 
UC
Ulcerative colitis
US
United States
ULN
upper limit of normal
WOCBP
women of childbearing potential
WONCBP
women of non-childbearing potential


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PROTOCOL SUMMARY
PF-00547659 is a fully human IgG2қ anti-MAdCAM-1 monoclonal antibody that binds to human 
MAdCAM to reduce lymphocyte homing to the gut and GI inflammation and is under 
development for the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC).
PF-00547659 has been shown to block the MAdCAM pathway which decreases leukocyte 
homing to gut by inhibiting the key interactions between MAdCAM and the 47+integrin 
expressed on lymphocytes. Although the selectively targeting of the MAdCAM receptors is a 
novel approach, the basic interference of lymphocyte homing by preventing the binding of these 
47+ lymphocytes to the MAdCAM receptor and the resultant efficacy in UC is well 
established. The main differentiation being that PF-00547659 blocks the interaction of 47+ 
lymphocytes to the MAdCAM receptor by selectively binding to the receptor. Principal sites of 
the MAdCAM expression on normal tissue includes intestine, pancreas, stomach, esophagus, 
spleen and to a lesser extent lung, liver, and bladder but not in the central nervous system 
(CNS).1 PF-00547659 also does not bind to VCAM and is therefore not expected to be effective 
for the treatment of Multiple Sclerosis or affect lymphocyte homing or surveillance in the CNS.
Subjects who participate in this study will have completed the A7281009 Study.
Objectives:
Primary Objective

The primary objective of this study is to monitor the safety and tolerability of 
PF-00547659 during long-term treatment.  
Secondary Objective

The secondary objective is to assess pharmacokinetics and immunogenicity of 
PF-00547659. 
Exploratory Objectives

Exploratory objectives include an assessment of the durability of response with long-term 
treatment with PF-00547659 based upon Clinical Remission and Clinical Response based 
upon the Mayo Score performed at Week 16 in Clinical Responders from study 
A7281009.

Explore relationships between PK of PF-00547659, PD and clinical endpoints.


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Endpoints:
Primary Endpoint

Safety

Frequency of on-treatment adverse events (AEs), AEs leading to withdrawal, and SAEs.
Secondary Endpoints

Immunogenicity

Frequency of the development of anti-drug antibodies (ADAs) and neutralizing 
antibodies (Nabs). 

Pharmacokinetics

Serum trough concentrations of PF-00547659 via listings and plots.
Mucosal Healing 

Proportion of subjects with mucosal healing at Week 16 (defined as absolute Mayo 
subscore for endoscopy of 0 or 1).
Exploratory Efficacy Endpoints

Assessment of the durability of response based upon Clinical Remission and Clinical 
Response based upon Total Mayo score assessed at Week 16 [28 weeks from initial dose] 
in subjects with a Clinical Response in study A7281009.

Non-Responders from study A7281009 will also be assessed at Week 16 for Clinical 
Remission and Clinical Response. 

Assessment of Clinical Remission and Clinical Response based upon the partial Mayo 
Score in all subjects at Week 40, Week 92 and Week 144.

Simple Clinical Colitis Activity Index (SCCAI) will be assessed at monthly visits.

Partial and Mayo subscores will also be assessed.
Exploratory Pharmacodynamic Endpoints

Blood samples will be collected prior to dosing at baseline and every 4 weeks to 
Week 24, Week 32 and Week 72 to measure hsCRP. Also, stool samples will be 
collected at the time points noted above to measure fecal calprotectin. 


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Exploratory Biomarkers (Blood/stool)

Soluble MAdCAM in blood may be assessed at baseline and Week 16.

Gene expression profiling (mRNA) in blood and protein associated with UC, 
inflammation and mechanism of drug activity may be assessed at baseline, Week 16 and 
Week 72.

Analyses relevant to the understanding and treatment of UC may be conducted on the 
portion of stool samples remaining after calprotectin analysis. 

Optional Exploratory Endoscopic Substudy:

Endoscopic biopsies at Week 16 for immunohistochemistry (IHC) that may include 
different subsets of lymphocytes, hematopoietic cells and/or protein biomarkers and 
assessment of RNA transcripts associated with UC, inflammation and mechanism of drug 
activity (all sites).

Effect of PF-00547659 on mucosal healing (all sites).

Change in biomarkers in endoscopic biopsy specimens (at selected centers).
Study Design:
This is a multi-center Phase 2, open-label, safety extension study for the A7281009 study which 
evaluates PF-00547659 in subjects with moderate to severe ulcerative colitis. Subjects eligible 
for this study will have completed the 12-week double-blind induction period in study A7281009
and must have discontinued immunosuppressant therapy. They will then enter into the Active 
Treatment period which consists of two consecutive 18 month periods. The first active period is 
called Open Label Treatment Period 1 (Weeks 0-72). All subjects will be randomly assigned to 
receive either 75 mg or 225 mg subcutaneously every 4 weeks without unblinding treatment 
assignment from the A7281009 study, and without regard to responder status in that study.
After completion of Open Label Treatment Period 1, all subjects will be permitted to continue in 
Open Label Treatment Period 2 (Weeks 76-144) and will receive the 75 mg dose on a every four 
weeks basis for a further 18 months.
Subjects entering this study will be given assigned treatment at the baseline visit and then every 
4 weeks through Week 144.  After the active treatment period, the subjects will enter a 6-month 
follow-up period including 2 visits 3 months apart.  At the last onsite visit (Week 168), subjects 
will undergo an End of Study visit.
In some cases, due to Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval, regulatory-specific, or other administrative delays, a subject may rollover into this 
study after the 12-week induction period but no later than the first follow-up visit of the 
A7281009 study with sponsor approval.


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A7281010 Protocol Amendment 5
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Dosing
The Active Treatment Period will be comprised of Open Label Treatment Period 1 and Open 
Label Treatment Period 2.  During Open Label Treatment Period 1 treatment of 75 mg or 225 mg 
SC, will be administered at baseline and then every 4 weeks through Week 72 (Visit 19). Once 
the Open Label Treatment Period 1 has been completed, subjects may continue for Open Label 
Treatment Period 2 and will be assigned to the 75 mg dose.
After the active treatment period, the subjects will enter a 6-month follow-up period.  At 
Week 168, subjects will undergo the Final Onsite Study Visit (see Section 6.3.2).
Dose Interruption
In the event of unforeseen circumstances or life events a dose may be delayed or missed up to a 
period of one month. If dosing cannot be resumed, the subject should discontinue active 
treatment and will then undergo the Early Withdrawal procedures (Section 6.4) and enter a 
6 month follow-up period which includes 2 follow-up visits each separated by 3 months.  If the 
subject has a dose held and the reason resolves within a one month period, the subject should be 
dosed as soon as possible after resolution and the original study schedule should be maintained.
Early Withdrawal from OLE Treatment
Subjects may withdraw from active treatment for a variety of reasons including: serious adverse 
event, loss of response or withdrawal of consent among others.  Subjects may be discontinued 
from treatment if they fail to respond.  In such cases, study drug will be withdrawn, the subject 
will complete early withdrawal procedures (see Section 6.4), and then enter the 6-month 
follow-up period beginning with Visit 38 (Week 156).  
Study Treatments:
Doses of PF-00547659 will be evaluated in subjects with UC.  Doses will be administered 
following the completion of study procedures at baseline (results of laboratory evaluations for 
samples collected at Week 12 of A7281009 are not required prior to dosing) and then every 
4 weeks (7 Days of the Projected Visit Date) through Week 144.  Subjects will have study 
medication administered subcutaneously in the anterolateral right or left thigh(s). Alternatively, 
the study drug may be injected into the deltoid area or the abdomen. Subjects assigned to receive 
75 mg will get a single injection, while those assigned to receive 225 mg will get 3 injections. 
Location of the study drug administration should be noted in the source documentation. If there 
are clinical reasons why multiple injections cannot be administered in the same leg, the drug may 
be administered in two (2) of these locations. Location of the study drug administration should 
be noted in the source documentation.
Injection site and allergic reaction monitoring should be completed by a member of the study 
staff and observed for a period of at least 30-60 minutes (but the total duration should be 
determined at the discretion of the investigator). 


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A7281010 Protocol Amendment 5
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Statistical Analysis:
Sample Size Determination
All eligible subjects, based on inclusion/exclusion criteria, from the feeder study may be 
enrolled.  It is estimated that approximately 90% of the subjects (about 270 subjects) from study 
A7281009 are likely to enroll into this open label extension study A7281010.  The sample size is 
chosen based on clinical outcome of the feeder study rather than statistical consideration.  
Safety Analysis
Safety data may be reviewed and summarized on an ongoing basis as needed during the study 
since this is an open-label study.  A set of safety summary tables will be produced to evaluate 
potential risks associated with the safety and tolerability of administering the study medication.  
All clinical AEs, SAEs, on-treatment AEs, as well as discontinuations due to AEs will be 
summarized with frequency and percentage. Continuous outcomes (eg, vitals, safety lab 
parameters, etc) will be summarized using n, mean, median, standard deviation etc.  Change 
from baseline on selected safety endpoints may be additionally summarized.  Subject listings 
may also be produced for these safety endpoints.
The safety endpoints will be listed and summarized in accordance with Shire Data Standards.  
Detailed methodologies of these analyses will be described in the SAP.
Interim Analysis
Two interim analyses (IAs) may be performed for this study when 50% of subjects from the 
Phase 2 study (A7281009) have been enrolled in this study (A7281010), and the last subject 
from the Phase 2 study (A7281009) has been enrolled in this study (A7281010). The purpose of 
the IAs is to provide additional data on the durability of response, remission, and safety from 
A7281009 to facilitate the decision-making process of initiating future studies. Summary 
statistics for safety, efficacy as well as subject demographics will be provided at IA. Detailed 
analysis will be described in the SAP. 
Additional interim analyses may also be performed when it is deemed necessary to evaluate 
safety and efficacy during the trial. 
Pharmacokinetic Analysis
Blood samples will be collected prior to dosing for analysis of plasma trough concentrations of 
PF-00547659.  Plasma concentration data obtained from all subjects in this study will be 
tabulated and plotted to assess average steady state concentrations following repeat subcutaneous 
(SC) dosing of PF-00547659.  As subjects enrolled in this study will have previously been 
followed in a separate protocol where more PK sampling may have been performed, the trough 
PK data collected from this study may be combined with data from the previous study into a 
single database.  


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PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
Exploratory Efficacy Analysis
Descriptive statistics will be provided for the exploratory efficacy analysis. The binary 
endpoints such as clinical remission, clinical response will be summarized with frequency and 
percentage by time point; and the continuous variables will be summarized with n, mean, 
median, standard deviation etc. These summaries may be provided by the strata of responder
status at entry based on the feeder study. 
All subjects who have received at least one dose of planned investigational product in the open 
label extension study will be included into the exploraty efficacy analysis. Detailed 
methodologies of these analyses will be described in the SAP.
Exploratory Pharmacodynamic Analysis
Fecal calprotectin, hsCRP and exploratory biomarkers will be listed and summarized by visit, 
and change from baseline for these endpoints will also be summarized at specific time points as 
reported in the Schedule of Activities (SOA). 
Appropriate regression models may be used to look at association between these endpoints and 
any covariates of clinical interests. 
Data Monitoring Committee
An external Data Monitoring Committee will be in place to review the safety of subjects on an 
ongoing basis and to adjudicate any subjects with unexplained neurological or cardiac findings.  
Membership of this committee shall include at least one neurologist with expertise in Progressive 
Multifocal Leukencephalopahty (PML) and one cardiologist with expertise in heart failure and/or 
myocarditis. Work-up of such suspected PML cases will include a neurology consultation as 
well as an MRI scan, and a lumbar puncture, if clinically indicated.  Additional procedures may 
be deemed necessary.  Given the lack of therapeutic options for subjects who have failed at least 
1 conventional therapy, PF-00547659 with its distinct mechanism of action and known safety 
profile appears to have a favorable Risk-Benefit profile.  
Additional cardiac monitoring will be implemented in this study.  Serum samples for CPK (with 
reflex isoenzymes), troponin I and NT-proBNP will be drawn with the safety labs.  Elevation of 
cardiac troponin I (cTnI) >0.05 ng/mL or CPK with MB should prompt a cardiology consult.  
Any subject who experiences an initial on-study elevation of NTproBNP to >300 pg/mL shall 
have an echocardiogram and cardiology consult. All subjects who have had an echocardiogram, 
in whom the NTproBNP remains >124 pg/mL at the Week 144 visit, shall have a repeat 
echocardiogram and cardiology consultation ordered no later than the following visit. All cases 
of on-study elevation of NTproBNP to >300 pg/mL, elevation in cardiac troponin I (cTnI) or 
CK/MB or new electrocardiogram (ECG) changes will be reviewed by the DMC.
The DMC will be responsible for ongoing monitoring of safety of subjects in the study according 
to the Charter.  The recommendations made by the DMC to alter the conduct of the study or 
amend the protocol will be forwarded to Shire for final decision.  Shire will notify investigative 
sites and regulatory authorities as appropriate.


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Page 19
PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
Table 1.
Schedule of Activities Open Label Treatment Period 1
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
Protocol Activity
Open-label Treatment Period 1
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Study Week
0/Day 1
Baselinea
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Visit Window
7 Days
7 Days based on Baseline Visit
Enrollment Procedures
Informed Consent
X
Eligibility Assessment
X
Determine 
Responder/Non-Responder 
Statusr
X
Open-Label Treatment 
Assignment
X
Medical Procedures
Vital Signs
Blood pressure, pulse, 
respirations 
a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Temperature 
[°C-or °F]
a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight (lbs or kg) without 
shoes
a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height (in or cm) without 
shoes
X
Complete Physical Exam 
b
X
X
X
X
Targeted Physical Exam 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG (12-lead)
b
X
X
X
X
X
X
X
X
X
Laboratory Assessments
      Clinical Laboratory Evaluations 
Blood chemistry (to include 
cTn1 and NTproBNP), 
hematology, 
urinalysise
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy testf
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Flexible Sigmoidoscopy or 
Colonoscopy (if 
recommended)g
b
X
X
-----------------------------------------
X


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PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
Protocol Activity
Open-label Treatment Period 1
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Study Week
0/Day 1
Baselinea
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Visit Window
7 Days
7 Days based on Baseline Visit
Optional Endoscopic tissue 
biopsyh
b
X
Laboratory Pharmacodynamics
hs CRP
b
X
X
X
X
X
X
X
X
Soluble MAdCAM
b
X
Stool sample for fecal 
calprotectin
b
X
X
X
X
X
X 
X
X
Stool sample for enteric 
pathogensi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood gene expression 
profiling (mRNA) and 
proteins
b
X
X
Pharmacokinetics
PK blood sample collectionj
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA and Nab
b
X
X
X
X
X
X
Disease Activity Analysis
Stool Diary datas
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total Mayo Scoreu
b
X
X
--------------------------------------
X
SCCAI
b
X
X
X
X
X
X
X
X
Partial Mayo Scoreu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Procedures
Study Drug
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confrontational Visual 
Fieldsk
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Timed 25-foot walk 
(T25-FW)l
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
9-hole peg test (9-HPT)m
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Symbol Digit Modality Test 
(SDMT)n
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MSNQo
b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense stool specimen 
container and bagt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
JC virus DNA sample takenp
b
X
X
X
JC virus antibody testing
b
X
X
X
AE Assessment
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X


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Page 21
PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
Protocol Activity
Open-label Treatment Period 1
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Study Week
0/Day 1
Baselinea
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Visit Window
7 Days
7 Days based on Baseline Visit
Concomitant treatments
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Abbreviations: 9-HPT=nine hole peg test; ADA=anti-drug antibodies; AE=adverse event; cTnI=cardiac troponin I; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; eCRF=electronic case report form; EOS=end of study; GDH=glutamate dehydrogenase; 
hsCRP=high-sensitivity C-reactive protein; ICD=informed consent document; IS=immunosuppressants; MAdCAM=mucosal addressin cell adhesion molecule; 
MSFC=Multiple Sclerosis Functional Composite; MSNQ=Multiple Sclerosis Neuropsychological Questionnaire; Nab=neutralizing antibody; NT-
proBNP=N-terminal B-type Natriuretic Peptide; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; SCCAI= Simple Clinical Colitis 
Activity Index; SDMT=Symbol Digit Modality Test; T25FW=timed 25-foot walk; UC=Ulcerative Colitis
a.
Baseline (Day 1, Visit 1) procedures will correspond with the procedures conducted at the Week 12 (Day 84) or final visit in study A7281009.  Data 
transferred from study A7281009 and recorded on the appropriate eCRF will be captured after the ICD is signed.  The ICD for this study must be signed and 
dated before protocol-related procedures are performed.  All baseline assessments and procedures must be completed prior to administration of the open 
label investigational product.
b.
Responder/nonresponder analysis will be determined at the Week 12 (Day 84) or final visit of study A7281009.  This determination will be made based on 
the Total Mayo score.
c.
Vital signs (single sitting blood pressure [BP], pulse rate, and respirations [measured after 5 minute rest], temperature (oral or tympanic [ºC or ºF]), and 
weight (lbs or kg; measured without shoes) do not need to be repeated; however, the information must be entered into the eCRF.  Source documentation 
supporting this data previously obtained at the Week 12 (Day 84) or final visit of the study A7281009 must be available in the subject’s record for this study.
d.
Baseline evaluations/assessments that were previously obtained at the Week 12 (Day 84) or final visit of study A7281009 do not need to be repeated, nor any 
information entered into the eCRF.  Source documentation supporting this data previously obtained at the Week 12 (Day 84) or final visit of the study 
A7281009 must be available in the subject’s record for this study.  Adverse events (AEs) and concomitant treatment(s) that are continuing from study 
A7281009 will be recorded on the source documents and the respective AE and CM eCRFs at the baseline visit.  Note:  No blood or urine samples will be 
collected for the baseline visit of this study unless there is a need to repeat a safety laboratory test or tests.
e.
To include NT-proBNP and troponin I levels for additional cardiac monitoring. ECHO and cardiology consult will be performed locally only under specified 
conditions. These conditions are:

At baseline visit: if NTproBNP value is >300 pg/mL if no prior ECHO.

At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is >300 pg/mL.

At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the NTproBNP is >124 pg/mL or if there has been no prior 
ECHO, and the NTproBNP is >300 pg/mL.

At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300 pg/mL.
f.
For women of childbearing potential only.  A negative urine pregnancy test result is required beginning at baseline before investigational product 
administration, and at all subsequent visits during the open-label treatment period, the follow-up visit, and at early withdrawal (if necessary).
g.
Flexible sigmoidoscopy or Colonoscopy if recommended. Colonoscopy will be performed at Visits 11-19 for subjects undergoing routine cancer 
surveillance.


Shire
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Page 22
PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
h.
Eligible subjects will be asked if they would like to continue participation in an optional endoscopic substudy that will characterize the effect of 
PF-00547659 on mucosal healing and tissue biology. Participation in this part of the study will not affect participation in the main study (see Section 7.4.2).
i.
The detection of C. difficile by toxigenic stool culture [stool culture followed by detection of toxin] is considered the gold standard for the diagnosis of the 
colonization or infection with pathogenic C. difficile.  Comparable sensitivity may be achieved by direct testing of stool via point of use rapid membrane 
enzyme immunoassay card for both C. difficile toxin A and B and glutamate dehydrogenase (GDH) antigen on a card.  Use of the card for point of care 
screening is encouraged where permitted by local regulation.  Molecular techniques such as PCR for detection of toxin RNA are also acceptable alternatives. 
Refer to the lab manual for further guidance and instruction for C. difficile testing. This test will be mandatory for subjects who experience a disease flare 
and/or dose de-escalate.
j.
PK samples will be collected before dosing at visits where study drug will be administered.
k.
As part of the complete physical examination and targeted physical examination.  A confrontation visual field test will be performed to measure overall field 
of vision as a basic screening tool.
l.
The timed 25-foot time walk (T25-FW) test is part of the neurologic assessment and measures quantitative mobility and leg function.
m. The nine-hole peg test (9-HPT) is part of the neurologic assessment and measures upper extremity function.
n.
The Symbol Digit Modality Test (SDMT) is part of the neurologic assessment and assesses cognitive functioning over time and in response to treatment.  To 
help score the test, subjects must enter level of education completed onto the Social Status CRF page.
o.
The patient-MSNQ (Multiple Sclerosis Neuropsychological Questionnaire) is part of the neurologic assessment and assesses cognitive functioning over time.
p.
Samples may be stored and batched for analysis. At a minimum, baseline and end-of-study sample will be tested.
q.
Responder analysis will be determined at Week 12 of study A7281009. This determination will be made based on the Total Mayo Score.
r.
The subject stool diary to collect stool frequency and rectal bleeding will be collected via paper diary. Subjects will be required to enter diary data for 3 days 
immediately preceding the flexible sigmoidoscopy visit prior to Week 16. Should any subject be required to perform bowel preparation prior to the flexible 
sigmoidoscopy at Week 16, the subject should be instructed to complete the diary 1 day prior to initiating bowel preparation. Diaries to be completed by the 
subject will be distributed during the baseline visit [Week 12 of study A7281009 (for collection at the flexible sigmoidoscopy visit prior to Week 16)].
s.
At Visits 7 and 9-17, dispense stool specimen container and bag to subjects who have had a disease flare only.
t.
A Total Mayo Score will be calculated for subjects undergoing routine cancer surveillance at Visits 11-19. A Partial Mayo Score will be calculated for all 
other subjects at these visits.
u.
Does not include endoscopic biopsies performed at selected centers (see Section 7.4.2). However, mucosal healing may be assessed.


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Page 23
PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
SCHEDULE OF ACTIVITIES: Open Label Treatment Period 2 and Follow-Up Period
Protocol Activity
Open Label Treatment Period 2
Follow up
Early 
withdr
awal
EOS
Study Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Study Week
76
80
84
88
92
96
100
104
108
112
116
120
124
128
132
136
140
144
156
168
Visit Window
7 Days based on Baseline Visit
Enrollment Procedures
Amendment Informed Consent
X
Open-Label 75 mg Treatment 
Assignment
X
Medical Procedures
Vital Signs
Blood pressure, pulse,  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight (lbs or kg) without 
shoes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Targeted Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG (12-lead)0
X
X
X
X
X
X
X
X
Laboratory Assessments
      Clinical Laboratory Evaluations 
Blood chemistry (to include 
troponin I and NTproBNP), 
hematology, 
urinalysisb
X
X
X
X
X
X
X
X
Urine Pregnancy testc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Pharmacodynamics
Stool sample for enteric 
pathogensd
      X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Pharmacokinetics
PK blood sample collectione
X
X
ADA and Nab
X
X
Disease Activity Analysis
Stool Diary data
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCCAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Partial Mayo Score
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confrontational Visual Fields
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Timed 25-foot walk (T25-FW)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
9-hole peg test (9-HPT)g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Shire
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PF-00547659/SHP647
A7281010 Protocol Amendment 5
14 November 2016
Protocol Activity
Open Label Treatment Period 2
Follow up
Early 
withdr
awal
EOS
Study Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
Study Week
76
80
84
88
92
96
100
104
108
112
116
120
124
128
132
136
140
144
156
168
Visit Window
7 Days based on Baseline Visit
Symbol Digit Modality Test 
(SDMT)h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MSNQi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
JC virus DNA sample taken
X
X
X
X
X
JC virus antibody testing
X
X
X
X
X
AE Assessment
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
Concomitant treatments
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X
End of Study CRFj
X
X
Abbreviations: 9-HPT=nine hole peg test; ADA=anti-drug antibodies; AE=adverse event; cTnI=cardiac troponin I; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; eCRF=electronic case report form; EOS=end of study; GDH=glutamate dehydrogenase; 
hsCRP=high-sensitivity C-reactive protein; ICD=informed consent document; IS=immunosuppressants; MAdCAM=mucosal addressin cell adhesion molecule; 
MSFC=Multiple Sclerosis Functional Composite; MSNQ=Multiple Sclerosis Neuropsychological Questionnaire; Nab=neutralizing antibody; NT-
proBNP=N-terminal B-type Natriuretic Peptide; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; SCCAI= Simple Clinical Colitis 
Activity Index; SDMT=Symbol Digit Modality Test; T25FW=timed 25-foot walk; UC=Ulcerative Colitis
a.
A single ECG will be collected starting at Week 84, every 12 weeks and at EOS (Week 168).
b.
To include NT-proBNP and cTn1 levels for additional cardiac monitoring. ECHO and cardiology consult will be performed locally only under specified 
conditions.  These conditions are:

At baseline visit: if NTproBNP value is >300 pg/mL if no prior ECHO. 

At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is >300 pg/mL.

At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the NTproBNP is >124 pg/mL or if there has been no prior ECHO, 
and the NTproBNP is >300 pg/mL.

At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300 pg/mL.
c.
For women of childbearing potential only.  A negative urine pregnancy test result is required beginning at baseline before investigational product 
administration, and at all subsequent visits during the open-label treatment period, the follow-up visit, and at early withdrawal (if necessary).
d.
A stool sample for enteric pathogens will only be collected if subject is symptomatic. 
e.
A serum sample for PK analysis will be collected only at the first Follow-up visit (Week 156) and/or Early withdrawal visit.
f.
The timed 25-foot time walk (T25-FW) test is part of the neurologic assessment and measures quantitative mobility and leg function.
g.
The nine-hole peg test (9-HPT) is part of the neurologic assessment and measures upper extremity function.
h.
The Symbol Digit Modality Test (SDMT) is part of the neurologic assessment and assesses cognitive functioning over time and in response to treatment.  To 
help score the test, subjects must enter level of education completed onto the Social Status CRF page.
i.
The patient-MSNQ (Multiple Sclerosis Neuropsychological Questionnaire) is part of the neurologic assessment and assesses cognitive functioning over time.


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j.
Complete End of Study CRF when subjects withdraw from the study at Early withdrawal visit or when the subject completes participation in the study 
(Week 168).  


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TABLE OF CONTENTS
TABLE OF CONTENTS...............................................................................................................26
LIST OF TABLES.........................................................................................................................30
APPENDICES ...............................................................................................................................31
1. INTRODUCTION .....................................................................................................................32
1.1. Indication ..........................................................................................................................32
1.2. Background and Rationale................................................................................................32
1.2.1. Study Rationale........................................................................................................33
1.2.2. Rationale for Discontinuing Immunosuppressive Therapy .....................................33
1.2.3. Dose Selection Rationale.........................................................................................34
1.2.3.1. Active Treatment Period.................................................................................35
1.2.4. Safety Data...............................................................................................................35
1.2.4.1. Non-Clinical Safety ........................................................................................35
1.2.5. Anticipated Risks.....................................................................................................36
1.2.6. Risk Benefit .............................................................................................................37
2. STUDY OBJECTIVES AND ENDPOINTS.............................................................................38
2.1. Objectives .........................................................................................................................38
2.1.1. Primary Objective....................................................................................................38
2.1.2. Secondary Objective................................................................................................38
2.1.3. Exploratory Objectives ............................................................................................38
2.2. Endpoints ..........................................................................................................................38
2.2.1. Primary Endpoints ...................................................................................................38
2.2.1.1. Safety ..............................................................................................................38
2.2.2. Secondary Endpoints ...............................................................................................38
2.2.2.1. Immunogenicity..............................................................................................38
2.2.2.2. Pharmacokinetics............................................................................................39
2.2.2.3. Mucosal Healing.............................................................................................39
2.2.3. Exploratory Efficacy Endpoint ................................................................................39
2.2.3.1. Efficacy...........................................................................................................39
2.2.3.2. Exploratory Pharmacodynamic Endpoints .....................................................39
2.2.3.3. Exploratory Biomarkers (Blood/Stool):..........................................................39
3. STUDY DESIGN.......................................................................................................................40
3.1. Dosing...............................................................................................................................40
3.2. Approximate Duration of Subject Participation ...............................................................41
3.3. Approximate Duration of Study........................................................................................41
3.4. Approximate Number of Subjects ....................................................................................41
4. SUBJECT SELECTION............................................................................................................41


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4.1. Inclusion Criteria ..............................................................................................................41
4.2. Exclusion Criteria .............................................................................................................43
4.3. Sponsor Qualified Medical Personnel ..............................................................................43
5. STUDY TREATMENTS...........................................................................................................43
5.1. Allocation to Treatment....................................................................................................43
5.2. Drug Supplies....................................................................................................................44
5.2.1. Formulation and Packaging .....................................................................................44
5.2.2. Preparation and Dispensing .....................................................................................44
5.2.3. Administration .........................................................................................................44
5.2.4. Compliance ..............................................................................................................45
5.3. Drug Storage and Drug Accountability ............................................................................45
5.4. Prior Treatment(s).............................................................................................................45
5.5. Concomitant Treatment(s) ................................................................................................46
5.5.1. Steroids Taken During This Study...........................................................................46
5.5.2. Prohibited During This Study..................................................................................46
5.5.3. Permitted During This Study...................................................................................46
5.5.4. Tapering of Corticosteroids .....................................................................................46
5.5.5. Oral Corticosteroid Rescue Therapy........................................................................47
5.6. Permitted During Follow-up.............................................................................................47
6. STUDY PROCEDURES ...........................................................................................................47
6.1. Visit 1, Baseline................................................................................................................47
6.2. Study Period......................................................................................................................49
6.2.1. Visit 2, Week 4 (7 Days of the Projected Visit Date)............................................49
6.2.2. Visit 3, Week 8 (7 Days of the Projected Visit Date)............................................51
6.2.3. Visit 4, Week 12 (7 Days of the Projected Visit Date)..........................................52
6.2.4. Visit 5, Week 16 (7 Days of the Projected Visit Date)..........................................53
6.2.5. Visit 6, Week 20 (7 Days of the Projected Visit Date)..........................................54
6.2.6. Visit 7, Week 24 (7 Days of the Projected Visit Date)..........................................56
6.2.7. Visit 8, Week 28 (7 Days of the Projected Visit Date)..........................................57
6.2.8. Visit 9, Week 32 (7 Days of the Projected Visit Date)..........................................58
6.2.9. Visit 10, Week 36 (7 Days of the Projected Visit Date)........................................59
6.2.10. Visit 11, Week 40 (7 Days of the Projected Visit Date)......................................60
6.2.11. Visit 12, Week 44 (7 Days of the Projected Visit Date)......................................62
6.2.12. Visit 13, Week 48 (7 Days of the Projected Visit Date)......................................63
6.2.13. Visit 14, Week 52 (7 Days of the Projected Visit Date)......................................65
6.2.14. Visit 15, Week 56 (7 Days of the Projected Visit Date)......................................66
6.2.15. Visit 16, Week 60 (7 Days of the Projected Visit Date)......................................67


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6.2.16. Visit 17, Week 64 (7 Days of the Projected Visit Date)......................................68
6.2.17. Visit 18, Week 68 (7 Days of the Projected Visit Date)......................................70
6.2.18. Visit 19, Week 72 (7 Days of the Projected Visit Date)......................................71
6.2.19. Visits 20 - 36, Weeks 76 – 140 (7 Days of the Projected Visit Date) .................72
6.2.20. Visit 37 Week 144 (7 Days of the Projected Visit Date).....................................73
6.3. Follow-Up.........................................................................................................................75
6.3.1. Visit 38, Week 156 (7 Days of the Projected Visit Date)......................................75
6.3.2. Final Onsite StudyVisit: Visit 39, Week 168/End of Study (EOS) (7 Days 
of the Projected Visit Date)....................................................................................75
6.4. Early Withdrawal..............................................................................................................76
6.4.1. Post-Withdrawal Visit..............................................................................................78
7. ASSESSMENTS........................................................................................................................78
7.1. Pregnancy Testing.............................................................................................................78
7.2. Safety ................................................................................................................................79
7.2.1. Vital Signs, Height, and Weight ..............................................................................79
7.2.2. Physical Exam..........................................................................................................79
7.2.2.1. Complete Physical Exam................................................................................79
7.2.2.2. Targeted Physical Exam .................................................................................80
7.2.3. Electrocardiogram....................................................................................................80
7.2.4. Transthoracic Echocardiogram (ECHO) and Cardiology Consult (if 
applicable)..............................................................................................................80
7.2.5. Laboratory Tests ......................................................................................................81
7.3. Special Safety Assessments..............................................................................................82
7.3.1. Neurological Assessments .......................................................................................83
7.3.1.1. Confrontational Visual Fields (to be performed as part of the complete 
and Targeted Physical examinations).....................................................83
7.3.1.2. Timed 25-Foot Walk.......................................................................................84
7.3.1.3. 9-Hole Peg Test (9-HPT)................................................................................84
7.3.1.4. Symbol Digit Modality Test (SDMT).............................................................85
7.3.1.5. Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) ...................85
7.3.1.6. JC Virus ..........................................................................................................86
7.3.2. C. Difficile................................................................................................................86
7.4. Diagnostic and Efficacy Assessments ..............................................................................87
7.4.1. Flexible Sigmoidoscopy or Colonoscopy (if preferred) ..........................................87
7.4.2. Optional Endoscopic Biopsy Substudy....................................................................87
7.4.3. Subject Stool Diary..................................................................................................89
7.4.4. Mayo Score..............................................................................................................89
7.4.5. Partial Mayo Score...................................................................................................90


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7.4.6. Simple Clinical Colitis Activity Index (SCCAI) .....................................................90
7.5. Pharmacokinetics..............................................................................................................90
7.5.1. Serum Samples for Analysis of PF-00547659.........................................................90
7.5.1.1. Shipment of Serum Samples for Analysis of PF-0547659.............................90
7.6. Pharmacodynamics ...........................................................................................................91
7.6.1. hs CRP .....................................................................................................................91
7.6.1.1. Shipment of Samples for Analysis of hs CRP ................................................91
7.6.2. Fecal Calprotectin....................................................................................................91
7.6.2.1. Shipment of Fecal Samples for Analysis Fecal Calprotectin..........................91
7.6.3. Exploratory Biomarkers (Blood/Stool):...................................................................91
7.6.3.1. Shipment of Samples for Analysis of Exploratory Biomarkers......................91
7.7. Immunogenicity................................................................................................................92
7.7.1. Serum Samples for Anti-drug Antibodies................................................................92
7.7.1.1. Shipment of Serum Samples for Analysis of Anti-drug Antibodies...............92
7.8. Procedure for Serum Collection........................................................................................92
8. ADVERSE EVENT REPORTING............................................................................................92
8.1. Adverse Events .................................................................................................................92
8.2. Reporting Period...............................................................................................................93
8.3. Definition of an Adverse Event ........................................................................................93
8.4. Medication Errors .............................................................................................................94
8.5. Abnormal Test Findings ...................................................................................................94
8.6. Serious Adverse Events ....................................................................................................95
8.6.1. Protocol-Specified Serious Adverse Events ............................................................95
8.6.2. Potential Cases of Drug-Induced Liver Injury.........................................................95
8.7. Hospitalization..................................................................................................................96
8.8. Severity Assessment .........................................................................................................98
8.9. Causality Assessment........................................................................................................98
8.10. Exposure During Pregnancy ...........................................................................................98
8.11. Occupational Exposure...................................................................................................99
8.12. Withdrawal Due to Adverse Events (See also the Section 6.4 on Early 
Withdrawal)..............................................................................................................99
8.13. Eliciting Adverse Event Information..............................................................................99
8.14. Reporting Requirements .................................................................................................99
8.14.1. Serious Adverse Event Reporting Requirements.................................................100
8.14.2. Protocol Specific Medically Important Events....................................................100
8.14.3. Non-Serious Adverse Event Reporting Requirements ........................................101
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities ...........................101
9. DATA ANALYSIS/STATISTICAL METHODS...................................................................101


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9.1. Sample Size Determination.............................................................................................101
9.2. Exploratory Efficacy Analysis........................................................................................101
9.3. Exploratory Pharmacodynamic Analysis........................................................................101
9.4. Pharmacokinetic Analysis...............................................................................................102
9.5. Safety Analysis ...............................................................................................................102
9.6. Interim Analysis..............................................................................................................102
9.7. Data Monitoring Committee...........................................................................................103
10. QUALITY CONTROL AND QUALITY ASSURANCE.....................................................103
11. DATA HANDLING AND RECORD KEEPING .................................................................104
11.1. Case Report Forms/Electronic Data Record.................................................................104
11.2. Record Retention ..........................................................................................................104
12. ETHICS..................................................................................................................................105
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)....................105
12.2. Ethical Conduct of this Study.......................................................................................105
12.3. Subject Information and Consent..................................................................................105
12.4. Subject Recruitment......................................................................................................106
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP...........106
13. DEFINITION OF END OF TRIAL.......................................................................................106
13.1. End of Trial in a Member State.....................................................................................106
13.2. End of Trial in all Participating Countries....................................................................106
14. SPONSOR DISCONTINUATION CRITERIA ....................................................................106
15. PUBLICATION OF STUDY RESULTS..............................................................................106
15.1. Communication of Results by Shire .............................................................................107
15.2. Publications by Investigators ........................................................................................107
16. REFERENCES ......................................................................................................................109
LIST OF TABLES
Table 1.
Schedule of Activities Open Label Treatment Period 1................................19
Table 2.
Total Mayo Score ..........................................................................................39
Table 3.
Laboratory Tests............................................................................................82


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APPENDICES
Appendix 1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity*............110
Appendix 2. Simple Clinical Colitis Activity Index (SCCAI) ..............................................111
Appendix 3. Sample Subject Stool Diary ..............................................................................112
Appendix 4. Confrontational Visual Fields ...........................................................................113
Appendix 5. Timed Ambulation 25 Foot Test.......................................................................114
Appendix 6. 9-Hole Peg Test Administration........................................................................115
Appendix 7. Symbol Digit Modality Test..............................................................................116
Appendix 8. MSNQ - Patient.................................................................................................119


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1. INTRODUCTION
Ulcerative Colitis (UC) is a chronic, relapsing disease marked by ulceration and inflammation of 
the colonic mucosa and submucosa. Initially it usually involves the rectum but may extend 
proximally to involve a portion of or the entire colon. In the early stages hemorrhagic and 
erythematous tissue is observed, progressing to mucosal ulceration with purulent exudates in 
severe cases. The ulceration pattern is continuous and may extend the entire length of the colon.
Perforation of the bowel wall causing ileus and peritonitis can occur with transmural extension of 
the ulceration. Bloody diarrhea with or without mucus and lower abdominal pain with periods of 
remission and exacerbation are the most common symptoms.
The incidence of UC in the United States (US) is 10-12 cases per 100,000 person years. It 
occurs more frequently in Caucasians and affects 30% more females than males. Although UC 
can occur at any age, the incidence peaks between 15 to 25 years and 55 to 65 years.2 UC is a 
lifelong condition with a serious effect on the quality of life. Current treatment primarily consists 
of symptomatic management with dietary modifications, 5-aminosalicylic acid (5-ASA), opiates 
such as loperamide, systemic corticosteroids, immunosuppressive agents (azathioprine/6-
mercaptopurine, cyclosporine), and most recently anti-tumor necrosis factor (TNF) agents. 
However, despite recent advances, effective pharmacological treatment is needed which will 
induce and maintain remission.
While colectomy cures the disease and removes the possibility of colon cancer, the long-term
postoperative course may require adjustment to an ileostomy, ileoanal anastomosis, or
management of the chronic inflammation of an ileoanal pouch (pouchitis). A significant number 
of patients are refractory or unresponsive to conventional medical therapy, in addition to those 
patients who need more effective and tolerable therapy to maintain remissions and avoid surgery.
1.1. Indication
PF-00547659, also referred to as SHP647 (MAdCAM) or SHP647, is a fully human IgG2қ
anti-MAdCAM-1 monoclonal antibody, which is being developed by Shire as a treatment for the 
induction and maintenance of remission of Crohn’s disease (CD) and Ulcerative Colitis (UC).
1.2. Background and Rationale
PF-00547659 is a fully human IgG2қ anti-MAdCAM-1 monoclonal antibody that binds to 
MAdCAM with high affinity and selectivity to reduce lymphocyte homing to the gut and GI 
inflammation.
The selectivity of lymphocyte homing to specialized lymphoid tissue and mucosal sites of the 
gastrointestinal tract is determined by the endothelial expression of the mucosal addressin cell 
adhesion molecule (MAdCAM). MAdCAM is a member of the immunoglobulin super family of 
cell adhesion molecules and is mostly expressed on the cell surface of high endothelial venules 
of organized intestinal lymphoid tissue such as Peyer’s patches and mesenteric lymph nodes.3
MAdCAM plays a role in gut immune surveillance, and also appears to facilitate excessive 
lymphocyte infiltration under conditions of chronic gastrointestinal inflammation.  The 47
+
integrin is the recognized ligand for MAdCAM and expression of this ligand on populations of 
CD4+ and CD8+ T cells that distinguishes them as unique gut homing lymphocytes.


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PF-00547659 is an anti-MAdCAM monoclonal antibody with high affinity and selectivity that 
prevents the binding of α4β7+ lymphocytes to MAdCAM expressing sites in the high endothelial 
venules of the gastrointestinal tract.
1.2.1. Study Rationale
The rationale for conducting this open-label extension (OLE) study is primarily to evaluate 
long-term safety of PF-00547659. This protocol also provides the opportunity for continued 
treatment for subjects who completed study A7281009. 
1.2.2. Rationale for Discontinuing Immunosuppressive Therapy
The greatest concern for the safety of subjects receiving therapy that acts on the integrin/CAM 
axis of lymphocyte trafficking is the risk of progressive multifocal leukoencephalopathy (PML). 
This risk was first identified in subjects treated with natalizumab, an agent that targets the 4 
integrin on lymphocytes and is used to treat subjects with Multiple Sclerosis (MS) or Crohn’s 
disease. 
As of January 2012, three risk factors associated with increased risk of PML have been 
identified: prolonged use of natalizumab (2-4 years), JC virus seropositivity, and prior therapy 
with immunosuppressant agents. While no data have been presented for subjects who are JC 
virus seronegative, the PML incidence in JC virus seropositive subjects is shown in the table 
below:
Estimated PML Incidence Stratified by Risk Factor2
Anti-JCV Antibody Positive*
Anti-JCV Antibody Positive*
Tysabri Exposure† No Prior Immunosuppressant Use Prior Immunosuppressant Use
1-24 months
<1/1,000
2/1,000
25-48 months
4/1,000
11/1,000
Notes: Based on postmarketing PML data and Tysabri use data as of September 1, 2011.
†Data beyond 4 years of treatment are limited.
* Risk in anti-JCV antibody positive patients was estimated based on the assumptions that 18% of Tysabri-treated 
MS patients have a history of prior immunosuppressant treatment and that 55% of Tysabri-treated MS patients are 
anti-JCV antibody positive.
* The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically 
and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific 
antibodies with a false negative rate of 3%.
The maximum duration of study drug treatment anticipated at present is 3 months for subjects 
who receive active drug in study A7281009 plus 18 months for those who choose to enter this 
open label extension study, A7281010, for a total of 21 months. Subjects receiving Tysabri who 
had prior immunosuppressant therapy would be expected to have a PML risk of 0.2% if they 
were seropositive for JC virus, while the risk in seronegative individuals is not known.
The causative infectious agent of PML is the JC virus, a polyoma virus that is asymptomatically 
present in the majority of adults in whom the prevalence of seropositivity increases with age. 


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The mechanism of increased risk for PML in subjects treated with natalizumab is not known, but 
may involve reduced immune surveillance of the central nervous system. The JC virus appears 
to cause PML only in subjects with significant immune compromise, such as that associated with 
HIV infection, transplant-associated immunosuppression or treated leukemia.
In order to minimize the potential risk of excessive immunosuppression in study subjects, it is 
important to discontinue immunosuppressant therapy. Subjects entering this OLE study, 
regardless of disease activity, will have discontinued all immunosuppressant therapy. Subjects 
entering this trial will have received 3 doses of investigational therapy, but 25% of those subjects 
will have received placebo in study A7281009. Since immunosuppressants were withdrawn
during the previous study, there may be an increased risk of disease exacerbation in subjects who 
have not received any treatment with PF-00547659. Subjects will therefore be allowed to treat 
any disease exacerbations with oral corticosteroids for 6 months in clinically appropriate doses 
and durations. Immunosuppressants are not allowed in this study. 
1.2.3. Dose Selection Rationale
Study A7281001, a single and multiple dose study in Ulcerative Colitis (UC) was conducted 
with multiple IV and 3 subcutaneous (SC) doses in 60 subjects including: Single dose from 
0.03-10.0 mg/kg IV; Multiple dose 0.1-3.0 mg/kg IV; Single dose 3.0 mg/kg SC; Multiple dose 
0.3 and 1.0 mg/kg SC.  Results of the study indicate that PF-00547659 was well-tolerated with 
adverse reaction rates similar to placebo.  Approximately half of the subjects received 
background azathioprine.  There was no pattern of adverse events suggestive of increased risk of 
opportunistic infections or CNS effects.  SAEs and adverse events (AEs) leading to withdrawal 
were due to exacerbations of the underlying UC unrelated to dose or treatment assignment.  
There was no evidence of adverse effects on laboratory parameters, electrocardiogram (ECG), 
vital signs, or neurological function. 
Preliminary efficacy findings (Mayo Score) in the Study A7281001 were promising with higher 
response and remission rate for PF-00547659 as compared to Placebo; however, no 
dose-response relationship was observed in part due to the small sample size limitations. Results 
of biomarker assays (fecal calprotectin) supported the clinical findings of this study. 
PF-00547659 exhibited nonlinear pharmacokinetics (PK) with higher clearance at lower doses. 
The PK profile can be described using a mathematic model which depicts drug-binding to 
MAdCAM causing nonlinear clearance of PF-00547659, also called target-mediated drug 
disposition (TMDD) model. Availability of pharmacokinetic data covering a wide range of 
doses, made possible the development of a TMDD. A population PK model adequately 
described the nonlinear PK of PF-00547659 in A7281001. 
The two doses from study A7281009, considered most likely to be effective, 75 and 225 mg SC 
every 4 weeks, have been selected as the starting doses in this study.  It is predicted that 75 mg 
SC every 4 weeks will provide >98% MAdCAM suppression in >90% of subjects over a 4-week 
interval.  Escalation from 75 mg to 225 mg SC every 4 weeks will be allowed, at the 
Investigator’s discretion, for subjects that experience a relapse or who have had no response by 
Week 8.  A 225 mg SC dose is expected to provide >99% MAdCAM suppression in >90% of the 
population at the end of a 4-week interval.


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1.2.3.1. Active Treatment Period
The Active Treatment Period will be comprised of an Open Label Treatment Period 1 
(Weeks 0-72) and an Open Label Treatment Period 2 (Weeks 76-144). During the Open Label 
Treatment Period 1 subjects will be randomized to 75 mg or 225 mg SC starting at baseline and 
then every 4 weeks through Week 72 (Visit 19). After completion of the Open Label Treatment
Period 1 randomized subjects will be permitted to continue to receive treatment in an Open Label 
Treatment Period 2 for a further 72 weeks (18 months) at a dose of 75 mg every 4 weeks through 
Week 144. This dose was selected based upon the results of the A7281009 study that indicated 
no additional benefit associated with the 225 mg dose.
1.2.4. Safety Data
1.2.4.1. Non-Clinical Safety
Non-clinical pharmacology data indicate that blockade of the MAdCAM pathway decreases 
leukocyte homing to the gut by inhibiting the key interaction between MAdCAM and the 47
integrin expressed on lymphocytes.  PF-00547659 binds to recombinant human MAdCAM with 
a KD of 16.1 pM, and was shown to inhibit the adhesion of 47 expressing cells (human JY, 
B-cell line) to human and cynomolgus MAdCAM.  PF-00547659 does not bind to the closely 
related VCAM adhesion molecule, or Fcreceptor, and does not stimulate the in vitro release of 
pro-inflammatory cytokines from human whole blood.  When administered to cynomolgus 
monkeys, PF-00547659 caused a dose-dependent increase in blood levels of 7
+ central memory 
T cells with concurrent increases in CD4
+ 7
+ effector and naïve cells, by presumably reducing 
MAdCAM-mediated lymphocyte homing to the gut.
Repeat-dose toxicity studies, dosing once every 10 days, were conducted with PF-00547659 in 
cynomolgus monkeys for up to 6 months. In all studies, the drug was generally well-tolerated at 
doses up to 100 mg/kg. The exception was one high dose female receiving 100 mg/kg in the 
1-month IV study that became moribund starting on study Day 15 in the period between the 
second and third doses. This animal’s clinical condition required euthanasia, and at post-mortem 
this animal was diagnosed with myocardial inflammation of unknown etiology resulting in heart 
failure. A recent expert diagnostic opinion on this animal suggested that myocarditis was a 
component of Systemic Inflammatory Response Syndrome (SIRS), triggered by ulcerative 
gingivitis, and not a primary myocardial inflammation. Ultimately, it was unknown whether 
inflammation in the heart in this single animal was related to the pharmacological activity of 
PF-00547659 or was the result of spontaneous disease. It is notable that myocardial 
inflammation in this animal was an isolated occurrence and did not occur in any other animal in 
this study, nor in the subsequent 1-month SC or 6-month SC and IV repeat-dose studies at doses 
up to 100 mg/kg. Other notable findings in repeat-dose toxicology studies included sporadic 
local or systemic hypersensitivity reactions such as anaphylaxis (1 animal,10 mg/kg, 1-month IV 
study), nonadverse self-limiting skin rash/injection site reactions (sporadic at doses of 10 mg/kg 
and greater across studies), and glomerulonephropathy (2 animals receiving 100 mg/kg SC in the 
6-month studies). Hypersensitivity reactions were not unexpected in nonhuman primates 
receiving repeated large doses of foreign (ie, human) protein. For detailed summaries of the 
findings in the toxicology studies, please refer to Section 5.3 of the Investigator’s Brochure.


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1.2.5. Anticipated Risks
A total of 60 subjects have received single doses up to 10 mg/kg (24 subjects) or 3 doses of up to 
3 mg/kg (36 subjects) of PF-00547659 or placebo (20 subjects) in the Phase I clinical study 
(A7281001) with adverse events comparable to placebo.  The majority of withdrawals due to 
AEs or SAEs were related to lack of efficacy particularly with single or subtherapeutic doses.
Since April 2011, study drug has been under investigation for the treatment of patients with 
moderate to severe Crohn’s disease. As of 31 March 2012, 31 subjects have entered the 
induction study, 11 have entered the open label extension study and 148 monthly doses of study 
drug have been administered. 3 subjects experienced a single episode of injection site pain or 
burning (2% of injections). 
During the CD induction study (OPERA, A7281006) three subjects reported Serious Adverse 
Events (SAEs): 2 small bowel obstructions, 1 with ileus, and one subject had electrolyte 
abnormalities that required hospitalization. None of these was considered related to study drug. 
Seven subjects reported nonserious adverse events related to study drug; none of these events 
occurred in more than one subject. 18 subjects reported unrelated adverse events; 3 reported 
mild to moderate nausea and vomiting, and 2 each reported blurred vision, fever, elevated 
neutrophil count, flatulence, and frequent bowel movements.
In the CD Open Label Extension study (OPERA 2, A7281007) 3 subjects reported 6 SAEs, none 
related to study drug: worsening Crohn’s disease, viral gastroenteritis, rectal hemorrhage, viral 
upper respiratory tract infection, tooth abscess and a urinary tract infection. One subject reported 
a SAE related to study drug: a left hydrocele with cellulitis that resolved without treatment. 
7 subjects reported nonserious AEs related to study drug. 2 subjects reported vomiting, while the 
other AEs were reported only by one subject. 6 subjects reported unrelated AEs. 3 reported 
arthralgia, and 2 (the same 2 as in OPERA) reported blurred vision. All other AEs were reported 
only by single subjects.
The mechanism of action of PF-00547659, an anti-MAdCAM receptor antibody, is distinct from 
natalizumab in that it does not directly bind to 47+ T-lymphocytes.  It prevents the binding of 
47 + T-lymphocytes to the MAdCAM receptor but does not affect binding to ICAM or 
VCAM.  Therefore, it is not expected to affect CNS lymphocyte surveillance.  However, since 
the drug is early in development and due to some overlap of the mechanisms, additional 
prudence is warranted.
In addition to routine safety, additional surveillance will be in place to look for potential cases of 
Progressive Multifocal Leukoencephalopathy (PML) as a precaution due to the increased risk 
seen with natalizumab.4 Subjects with unexplained neurological changes, new onset seizures, 
sensory or motor neuropathy, cognitive or behavior changes observed during the treatment 
period will undergo neurologic evaluation and if appropriate discontinue treatment and enter the 
follow-up period. Samples for JC virus testing will be taken every 6 months throughout the 
study until the final onsite visit.
The following neurological assessments will be performed monthly throughout the Open Label 
Treatment Period 1 and the Open Label Treatment Period 2:


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
Confrontational Visual Fields will be performed as part of the physical exam.

Timed 25-Foot Walk (T25FW).

9-Hole Peg Test (9-HPT).

Symbol Digit Modality Test (SDMT-written).

Patient-Multiple Sclerosis Neuropsychological Questionnaire (MSNQ). (Does not trigger 
a neurology consult (refer to Special Safety Assessments Section 7.3).
1.2.6. Risk Benefit
The subjects that roll-over into this study from A7281009 will have completed Week 12 
(Day 84). These subjects have failed at least 1 conventional therapy.  This open-label extension 
study will provide additional treatment for these subjects with limited therapeutic options. 
Beyond anti-TNFs, patients with inflammatory bowel disease have limited options for biologic 
therapy.  One agent, approved for Crohn’s disease only in the US is natalizumab, which has a 
0.1% (1:1000) incidence of progressive multifocal leukoencephalopathy (PML)5 which makes it 
unacceptable to most subjects with Crohn’s disease and their physicians.  
PF-00547659, an anti-MAdCAM monoclonal antibody under investigation for the treatment of 
both CD and UC, provides a novel mechanism of action that is distinct from natalizumab. There 
is no interference with central nervous system lymphocyte surveillance since the drug binds to 
the MAdCAM receptor which is primarily located to venules of the GI tract and to a lesser extent 
lung, liver and spleen but is not present in the central nervous system. Natalizumab binds to the 
47+ and 41+ lymphocytes and prevents their binding to MAdCAM in the GI tract.  
Therefore, for subjects with ulcerative colitis the efficacy may be similar.  However, natalizumab 
also prevents these lymphocytes from binding to VCAM6 in the choroid plexus which is 
responsible for its efficacy in Multiple Sclerosis.  
PF-00547659 demonstrated a favorable safety profile in the Phase 1 single and multiple dose 
study conducted in subjects with ulcerative colitis.  However, due to the limited safety database, 
additional precautions will be taken to ensure the safety of subjects.  Subjects will not be allowed 
long-term co-administration with immunosuppressives since IS use has been associated with 
increased risk of PML in MS patients taking Tysabri. However, the type of IS used is quite 
different from those used in IBD and it is not known whether or not inflammatory CNS disease 
makes patients more prone to PML.  Since subjects may have stopped immunosuppressives 
shortly before entering into this study, they may be at increased risk for exacerbation or flare of 
their ulcerative colitis, especially subjects who enroll from the placebo-treatment arm of study 
A7281009.
Monitoring of subjects will include standardized focused neurological assessments, and JC virus 
testing throughout the study and follow-up period.  Any new unexplained neurological finding 
will trigger an immediate neurologic consultation with appropriate actions. Samples for JC virus 
testing will be taken every 6 months throughout the study until the final onsite visit. In addition, 


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an external Data Monitoring Committee will be in place to adjudicate any subjects with 
unexplained neurological findings.  
Given the lack of therapeutic options for subjects who have failed at least 1 conventional 
therapy, PF-00547659 with its distinct mechanism of action and known safety profile appears to 
have a favorable Risk-Benefit profile.  The added precautions regarding Progressive Multifocal 
Leukoencephalopathy (PML) are probably unnecessary but will serve to increase the confidence 
in PF-00547659 in future development. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

The primary objective of this study is to monitor the safety and tolerability of 
PF-00547659 during long-term treatment.
2.1.2. Secondary Objective

The secondary objective is to assess pharmacokinetics and immunogenicity of 
PF-00547659.
2.1.3. Exploratory Objectives

Exploratory objectives include an assessment of the durability of response with long term 
treatment with PF-00547659 based upon Clinical Remission and Clinical Response based 
upon the Mayo Score performed at Week 16 in Clinical Responders from study 
A7281009.

Explore relationships between PK of PF-00547659, PD and clinical endpoints.
2.2. Endpoints
2.2.1. Primary Endpoints 
2.2.1.1. Safety

Frequency of on-treatment AEs, AEs leading to withdrawal, and SAEs.
2.2.2. Secondary Endpoints
2.2.2.1. Immunogenicity

Frequency of the development of anti-drug antibodies (ADAs) and neutralizing 
antibodies (Nabs). 


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2.2.2.2. Pharmacokinetics

Serum trough concentrations of PF-00547659 via listings and plots.
2.2.2.3. Mucosal Healing

Proportion of subjects with mucosal healing at Week 16 (defined as absolute Mayo 
subscore for endoscopy of 0 or 1).
2.2.3. Exploratory Efficacy Endpoint
2.2.3.1. Efficacy

Assessment of the durability of response based upon Clinical Remission and Clinical 
Response based upon Total Mayo score assessed at Week 16 (28 weeks from initial dose)
in subjects with a Clinical Response in study A7281009.

Non-Responders from study A7281009 will also be assessed at Week 16 for Clinical 
Remission and Clinical Response.

Assessment of Clinical Remission and Clinical Response based upon the partial Mayo 
Score in all subjects at Week 40, Week 92 and Week 144.

Simple Clinical Colitis Activity Index (SCCAI) will be assessed at monthly visits.

Partial and Mayo subscores will also be assessed.
Table 2.
Total Mayo Score
Clinical 
Remission
Total Mayo Score of 2 points or lower with no individual subscore exceeding 1 point and 
rectal bleed subscore of 0 or 1.
Clinical 
Response
A decrease from baseline in Total Mayo Score by at least 3 points and at least 30% 
decrease in subscore for rectal bleeding of at least 1 point or absolute subscore of 0 or 1.
Relapse
In a subject who was previously in Clinical Remission, an increase in the Partial Mayo 
Score to >4 without evidence of enteric infection. 
2.2.3.2. Exploratory Pharmacodynamic Endpoints

Blood samples will be collected prior to dosing at baseline and every 4 weeks to 
Week 24, Week 32 and Week 72 to measure hsCRP. Also, stool samples will be 
collected at the same time points to measure fecal calprotectin.
2.2.3.3. Exploratory Biomarkers (Blood/Stool):

Soluble MAdCAM in blood may be assessed at baseline and Week 16

Gene expression profiling (mRNA) in blood and protein associated with UC, 
inflammation and mechanism of drug activity may be assessed at baseline, Week 16 and 
Week 72


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
Analyses relevant to the understanding and treatment of UC may be conducted on the 
portion of stool samples remaining after calprotectin analysis. 

Optional Exploratory Endoscopic Substudy:

Endoscopic biopsies at Week 16 for immunohistochemistry (IHC) that may include 
different subsets of lymphocytes, hematopoietic cells and/or protein biomarkers and 
assessment of RNA transcripts associated with UC, inflammation and mechanism of drug 
activity (all sites).

Effect of PF-00547659 on mucosal healing (all sites).

Change in biomarkers in endoscopic biopsy specimens (at selected centers).
3. STUDY DESIGN
This is a multi-center Phase 2, open-label, safety extension study for the A7281009 study which 
evaluates PF-00547659 in subjects with moderate to severe ulcerative colitis. Subjects eligible 
for this study will have completed the 12-week double-blind induction period in study A7281009
and must have discontinued immunosuppressant therapy. They will then enter into the Active 
Treatment period which consists of two consecutive 18 month periods. The first active period is 
called Open Label Treatment Period 1 (Weeks 0-72). All subjects will be randomly assigned to 
receive either 75 mg or 225 mg subcutaneously every 4 weeks without unblinding treatment 
assignment from the A7281009study, and without regard to responder status in that study. 
After completion of Open Label Treatment Period 1, all subjects will be permitted to continue in 
Open Label Treatment Period 2 (Weeks 76-144) and will receive the 75 mg dose every four 
weeks for a further 18 months. 
After the active treatment period, the subjects will enter a 6-month follow-up period including 
2 visits 3 months apart.  At the last onsite visit (Week 168), subjects will undergo an End of 
Study visit.
In some cases, due to Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval, regulatory-specific, or other administrative delays, a subject may rollover into this 
study after the 12-week induction period but no later than the first follow-up visit of Study 
A7281009 with sponsor approval.
3.1. Dosing
The Active Treatment Period will be comprised of Open Label Treatment Period 1 and Open 
Label Treatment Period 2. During the Open Label Treatment Period 1, 75 mg or 225 mg SC, 
will be administered at baseline and then every 4 weeks through Week 72 (Visit 19).  Once the 
Open Label Treatment Period 1 has been completed, subjects may continue for Open Label 
Treatment Period 2 and will be assigned to the 75 mg dose.
After the active treatment period, the subjects will enter a 6-month follow-up period.  At 
Week 168, subjects will undergo the Final Onsite Study Visit (see Section 6.3.2).


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Dose Interruption
In the event of unforeseen circumstances or life events a dose may be delayed or missed up to a 
period of one month. If dosing cannot be resumed, the subject should discontinue active 
treatment and will then undergo the Early Withdrawal procedures (Section 6.4) and enter a 
6-month follow-up period which includes 2 follow-up visits separated by 3 months. If the 
subject has a dose held and the reason resolves within a one month period, the subject should be 
dosed as soon as possible after resolution and the original study schedule should be maintained.
Early Withdrawal from OLE Treatment
Subjects may withdraw from active treatment for a variety of reasons including: serious adverse 
events, loss of response or widrawal of consent among others. Subjects will be discontinued 
from treatment, if they fail to respond. Investigational product will be withdrawn, the subject 
will complete early withdrawal procedures (see Section 6.4), and then enter the 6-month 
follow-up period beginning with Visit 38 (Week 156).
3.2. Approximate Duration of Subject Participation
Subjects will actively participate in this study for up to 43 months.  This includes a 37 month 
treatment period and a 6 month follow-up period.  Dosing of eligible subjects will begin at the 
baseline visit and continue every 4 weeks through Week 144. Subjects will return to the study 
site for visits every 4 weeks from their baseline visit (Week 0) through the treatment and 
follow-up periods until Visit 39 [Week 168 (End of Study visit)] unless they withdraw early.
3.3. Approximate Duration of Study
This study will be clinically complete in approximately 78 months.
3.4. Approximate Number of Subjects
All eligible subjects, based on inclusion/exclusion criteria, from the A7281009 study may be 
enrolled. 
Approximately 331 subjects (estimated as 90% of the subjects in A7281009) are anticipated to 
be eligible for this study at Week 12 of study A7281009 at approximately 100 sites worldwide. 
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before subjects are included in this study.


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Subjects must meet all of the following inclusion criteria to be eligible for enrollment into this
study:
1. Subjects previously enrolled in study A7281009 who have completed the blinded 84-day 
(12-week) induction period.
2. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or a legally acceptable representative) has been informed of all pertinent aspects 
of the study.
3. Male and/or female subjects between the ages of 18 and 66 years at the time of 
informed consent if they were previously enrolled in study A7281009.
4. All women of childbearing potential (WOCBP) as determined during the feeder study
(data must be available as source documents for this study) must have a negative urine 
pregnancy test result at the Baseline visit and throughout the duration of this study 
(defined as the time of the signing of the ICD through the end of this study).
5. Male and female subjects of childbearing potential must agree to use a highly effective 
method of contraception throughout the duration of the study (defined as the time of the 
signing of the ICD through the conclusion of onsite subject participation or for 
approximately 6 months from the last dose of investigational product for any subject who 
discontinues early from the study). A subject is of childbearing potential if, in the 
opinion of the investigator, he/she is biologically capable of having children and is 
sexually active.

Women of childbearing potential (WOCBP) must have a negative urine pregnancy 
test result at baseline. WOCBP are defined as women who are biologically capable 
of becoming pregnant, including women who are using contraceptives or whose 
sexual partners are either sterile or using contraceptives.

Women of non-childbearing potential (WONCBP) do not require a urine pregnancy 
test and must meet at least one of the following criteria:

Have undergone hysterectomy or bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Are medically confirmed to be post-menopausal (cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause). 
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.


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4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in this study:
1. Subjects that have completed Day 84 (Week-12) of study A7281009 but have 
experienced serious event(s) related to the investigational product, an unstable medical 
condition, or any other reason, in the opinion of the investigator, would preclude entry or 
participation in this study.
2. Subjects who are taking any dose of AZA, 6-MP or MTX.
3. Pregnant or breastfeeding women.
4. Males and females of childbearing potential not using highly effective contraception or 
not agreeing to continue highly effective contraception through the conclusion of onsite 
subject participation or for approximately 6 months from the last dose of investigational 
product for any subject who discontinues early from the study).
5. Evidence of right or left heart failure based on echocardiographic assessments conducted 
as part of a prior study of PF-00547659.
6. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate entry into this study.
7. Received any prohibited treatment during the feeder study that, in the opinion of the 
investigator, compromised the safety or efficacy of this study.
8. Planned live (attenuated) vaccination during the course of the study.
9. Planned major elective medical or surgical procedure during the course of this study.
10. Participation in other interventional studies during participation in this study.
11. The inability to complete any of the five neurological assessments without a clear 
explanation (eg, broken leg, sprained wrist, etc).
4.3. Sponsor Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the study
is documented in the study contact list located in the coordinator’s manual.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This is an open-label study and the investigator’s knowledge of the treatment should not 
influence the decision to enroll a particular subject or affect the order in which subjects are 
enrolled. All subjects will be assigned either 75 mg or 225 mg of the investigational product 


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upon study entry for the first 18 month treatment period. The allocation ratio to treatment will be 
1:1. Subsequently all subjects will be assigned to the 75 mg dose for an additional 18 month 
treatment period.
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Investigational product is packaged in the followed labeled containers: Active PF-00547659
Injection, approximately 75 mg/mL will be presented as a ready to use sterile solution in a vial.
5.2.2. Preparation and Dispensing
A pharmacist or other qualified person (eg, registered nurse with previous experience in drug 
preparation and withdrawing solution from sterile vials via a syringe) at the Clinical Site, will 
prepare each dose of investigational product according to the Dosing an Administration 
Instructions (DAI), supplied under a separate cover.
5.2.3. Administration
Doses of PF-00547659 (75 mg SC [and 225 mg SC, if required]) will be evaluated in subjects 
with UC.  Doses will be administered following the completion of study procedures at baseline 
(results of laboratory evaluations for samples collected at Week 12 of A7281009 are not required 
prior to dosing) and then every 4 weeks (7 Days of the Projected Visit Date) through Week 144.  
Subjects will have study medication administered subcutaneously in the anterolateral right or left 
thigh(s). Alternatively, the study drug may be injected into the deltoid area, or the abdomen. If 
there are clinical reasons why multiple injections cannot be administered in the same leg, the 
drug may be administered in two (2) of these locations. Location of the study drug 
administration should be noted in the source documentation.
Drug product will be administered according to Dosage and Administration Instructions (DAI) 
provided under separate cover as a 75 mg/ml solution at a maximum of 1.0 mL per injection.  
The administration format for a given dose for the Open Label Treatment Period 1 described in 
the followingtable:
Dose
75 mg
225 mg
Administration
1 injection of 1.0 mL
3 injections of 1.0 mL
The administration format for a given dose for the Open Label Treatment Period 2 is described in 
the below table:
Dose
75 mg
Administration
1 injection of 1.0 mL


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Injection site and allergic reaction monitoring should be completed by a member of the study 
staff and observed for a period of at least 30-60 minutes (but the total duration should be 
determined at the discretion of the investigator).
Investigator directed delays in dosing due to abnormal labs or AEs should be discussed with the 
sponsor to determine whether the subject should remain in the study.
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is dispensed by qualified staff members.
5.2.4. Compliance
All doses of the investigational product will be administered under the supervision of 
investigator site personnel and recorded on source documents and CRFs.
5.3. Drug Storage and Drug Accountability
Storage conditions stated in the SRSD (ie, Investigator Brochure [IB], Core Data Sheet [CDS], 
United States Package Insert [USPI], Summary of Product Characteristics [SPC], or Local 
Product Document [LPD]) may be superseded by the label storage.
Investigators and site staff are reminded to ensure that thermometers are working correctly as 
required for proper storage of investigational products.  These include thermometers for both the 
room storage and refrigerator storage.  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.
All investigational product is stored in refrigerated temperatures (2-8C) and in accordance with 
applicable regulatory requirements.   
Unless otherwise authorized by Shire, all unallocated or drug supplies unused by the subjects 
must be returned to Shire or its appointed agent (eg, CRO) at the end of the clinical trial.  If Shire
authorizes destruction at the study site, the investigator must ensure that the materials are 
destroyed in compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Shire.  Destruction must be adequately documented.
5.4. Prior Treatment(s)
Medication data from the A7281009 study may be used as data for this study, but these data must 
be included in the subject file and source documentation for this study as well. The start date, 
stop date, indication, total daily dose, route, and unit of all concomitant treatments including 
vitamins, herbals, and dietary supplements must be recorded on the appropriate CRF. 


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5.5. Concomitant Treatment(s)
Subjects will abstain from all concomitant treatments as described in the Exclusion Criteria
section of this protocol.  Medications taken after the first dose of study medication will be 
documented as concomitant treatments.
The start date, stop date, and indication for all concomitant treatments received will be recorded 
on the CRF.  The start date, stop date and indication for all non-drug therapies received will be 
recorded on the CRF.  
The start date, stop date and indication for all other concomitant treatments and/or therapies 
given because of an AE, from the first dose until the last scheduled onsite visit will be recorded 
on the CRF.  
5.5.1. Steroids Taken During This Study
Any steroids taken during this study will be recorded on a separate CRF page. The CRF page 
will capture start and stop dates, total daily dose and unit.
5.5.2. Prohibited During This Study

Any live (attenuated) vaccines.

Use of AZA, 6-MP or MTX.

Any investigational or marketed biologic immunosuppressive drugs.

Bismuth subsalicylate products. Concomitant use of mesalamine with bismuth 
subsalicylate can lead to salicylate over dosage.
5.5.3. Permitted During This Study

Mesalamine and related 5-ASA compounds.

Oral steroids through the Week 24 visit.

Stable doses of statins.

Any drugs or classes of drugs not listed in the Prohibited During This Study 
(Section 5.5.2).
5.5.4. Tapering of Corticosteroids
Steroids should be tapered slowly per local guidelines in all subjects entering the OLE in 
remission or with a clinically significant response.  Subjects who have not achieved a clinical 
response in the induction study, should begin tapering when they achieve remission or a 
clinically significant response and should be off steroids if possible by Week 40 (Week 16 + 
24 Weeks).  Subjects unable to taper should be considered treatment failures. 


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5.5.5. Oral Corticosteroid Rescue Therapy
Oral corticosteroids (max of 1 mg/kg) may be administered for rescue but the subjects should be 
tapered off steroids within 12 weeks. Similarly budesonide up to 9 mg may be used. Typically 
9 mg of budesonide is given over 8 weeks and then reduced to 6 mg for 2 weeks and then 3 mg 
for 2 weeks and then stopped.
Alternate tapering regimens may be used as long as the duration for an individual rescue 
treatment does not exceed 12 weeks. 
Subjects unable to taper or who relapse within 2 months should be considered treatment failures 
and should withdraw from active treatment and enter the follow-up phase. Similarly, if subjects 
require IV steroids, they will be considered treatment failures. 
Beyond 2 months, three additional course of oral corticosteroid rescue therapy as described 
above will be allowed. 
5.6. Permitted During Follow-up
Subjects may receive IV steroids and other previously prohibited rescue therapies during the 
follow-up period. Within 6 months of the last dose of investigational product, other 
immunosuppressants should be used with caution since the investigational product will still be 
present for up to 6 months from the last dose. Biologic therapies should not be started without 
discussion with the sponsor.  
6. STUDY PROCEDURES
Refer to the Schedule of Activity (SOA) for a detailed list of study procedures as they should be 
conducted at each respective visit.
6.1. Visit 1, Baseline
Visit 1, Baseline for this study refers to the Week-12 visit date of the A7281009 study. 
Therefore, Week 12 visit date of the A7281009 study = Visit 1, Baseline of A7281010.
Most evaluations/assessments obtained at the Week-12 visits of the A7281009 study, will serve 
as baseline evaluations in this extension study and will not need to be repeated or entered into the 
eCRFs.  No blood or urine samples will be collected for the baseline visit of this study unless 
there is a need to repeat a safety laboratory test or tests.  Source documentation supporting data 
from evaluations/assessments from the previous studies may be used as data for the Baseline 
visit in this study, but this data must be included in the subject file and source documentation for 
this study.
The ICD for this study must be signed and dated before protocol-related procedures are 
performed.  Data transferred from the feeder study and recorded on the appropriate CRF will be 
captured after the ICD is signed.  All baseline procedures and tests that must be completed at this 
visit must be completed prior to administration of the open-label investigational product.
The following procedures will be performed at the Baseline visit of this study:


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
Informed consent: to participate in the study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria. This study begins with the signing and dating 
of the ICD.

Eligibility Assessment.

Responder/Non-responder determination for subjects entering from study A7281009 –
Responder/Non-Responder analysis will be determined at the final visit (Week 12) of 
study A7281009. This determination will be made based on the Total Mayo score.

Open-Label Treatment assignment.

Height (in or cm) (measured without shoes) (see Section 7.2.1) will also be measured.

Drug dispensing: administer SC PF-00547659 to subject as described in the Study Drug 
and Administration (Section 5.2.2, 5.2.3 and SOA).  After all eligibility criteria have
been confirmed and other baseline procedures and tests are completed. Observe for 
injection site and allergic reactions for a period of at least 30-60 minutes (but total 
duration should be determined at the discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Dispense paper stool diaries (See Section 7.4.3, Appendix 3 and the SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA). AEs that are 
continuing from the previous study will be recorded on the source documents and the AE 
CRF at the baseline visit for this study.

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA). Concomitant treatment(s) 
continuing from the previous study will be recorded on the source documents and the 
appropriate CM CRF at the baseline visit for this study.  

Vital signs and temperature: single sitting blood pressure (BP), pulse rate, and 
respirations (measured after 5 minute rest), temperature (oral or tympanic [C or F]) and 
weight (lbs or kg) (measured without shoes) will be conducted at the Week 12 visit in 
study A7281009, therefore, do not need to be repeated.  However, this information must
be entered into the eCRF and the source documents supporting this data must be available 
in the subject’s record for this study.
The following data will be transferred from the Day 84 (Week 12) visit of Study A7281009:

Complete physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.1).


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
Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and the SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, echocardiogram (ECHO) and 
cardiology consult prior to Visit 2 unless there has already been an ECHO and cardiology 
consult for NTproBNP >300 pg/mL during the prior study of PF-00547659.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Peripheral blood gene expression profiling (mRNA) and proteins associated with UC, 
inflammation and mechanism of drug activity (see Section 7.4 and SOA).

Optional endoscopicbiopsy to assess RNA transcripts and proteins associated with UC, 
inflammation and mechanism of drug activity (see Section 7.4.2 and the SOA).

Flexible sigmoidoscopy or colonoscopy (if preferred).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy results, 
stool frequency, rectal bleeding, and physician’s global assessment) (see Section 7.4, 
Appendix 1, and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Laboratory Pharmacodynamics: hsCRP, Soluble MAdCAM, and stool sample for fecal 
calprotectin (see SOA and Section 7.6).

Pharmacokinetics: PF-00547659 and ADAs (see SOA and Section 7).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus deoxyribonucleic acid (DNA) testing (see Section 7.3.1.6 and SOA).

JC virus Antibody testing (see Section 7.3.1.6 and SOA).
6.2. Study Period
6.2.1. Visit 2, Week 4 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).


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
Review ECHO/Cardiology consult if applicable (see Section 7.2.4 and SOA).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and the SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 3 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Study Drug and Administration (Section 5.2.2 and 5.2.3). Observe for 
injection site and allergic reactions for a period of at least 30-60 minutes (but total 
duration should be determined at the discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Pharmacokinetics: PF-00547659 (see SOA, Section 7.5).

Laboratory Pharmacodynamics: hsCRP, and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  


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6.2.2. Visit 3, Week 8 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration.  Disease activity should also be reviewed to 
establish each subject’s response and relapse status.
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis. (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 4 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Pharmacokinetics: PF-00547659, ADAs and Nabs (see Section 7 and SOA).

Urine pregnancy test (see Section 7.2.5 and Table 3).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.3, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.3, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).


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
Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.3. Visit 4, Week 12 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4 and SOA)

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 5 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).


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
Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.4. Visit 5, Week 16 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration.  Disease activity should also be reviewed to 
establish each subject’s relapse status and/or treatment failure.
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 6 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL. 

Urine pregnancy test (see Section 7.2.5 and Table 3).


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
Flexible sigmoidoscopy or colonoscopy (if preferred).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Laboratory Pharmacodynamics: hsCRP, Soluble MAdCAM, and stool sample for fecal 
calprotectin (see SOA and Section 7.6).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy results, 
stool frequency, rectal bleeding, and physician’s global assessment) (see Section 7.4, 
Appendix 1 and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Optional endoscopic biopsy to assess RNA transcripts and proteins associated with UC, 
inflammation and mechanism of drug activity (see Section 7.4 and the SOA).

Peripheral blood gene expression profiling (mRNA) and proteins associated with UC, 
inflammation and mechanism of drug activity (see Section 7.4 and the SOA).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.5. Visit 6, Week 20 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).


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
Review ECHO/Cardiology Consult if applicable (see Section 7.2.4 and SOA).

Complete physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.1).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 7 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  


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6.2.6. Visit 7, Week 24 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration. Disease activity should also be reviewed to 
establish each subject’s relapse status and/or treatment failure.  
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 8 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).


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
Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample (see Section 7.3.1.6).

JC virus Antibody testing (see Section 7.3.1.6).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.7. Visit 8, Week 28 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 9 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA and Section 7.5).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).


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
Collect stool sample for enteric pathogens (see Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.8. Visit 9, Week 32 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK and PD biomarkers must be collected prior to
investigational product administration. Disease activity should also be reviewed to establish 
each subject’s relapse status and/or treatment failure.  
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 10 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.


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
Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had 
adisease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.9. Visit 10, Week 36 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).


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
Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 11 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.10. Visit 11, Week 40 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration. Disease activity should also be documented to 
establish each subject’s relapse status and/or treatment failure. 
From this visit through Visit 19 (Week 72), any subject who has a routine screening colonoscopy 
should have a Total Mayo Score documented at the first visit after the procedure. All other visits 
for which no colonoscopy is performed should have a Partial Mayo Score documented. 


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The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Complete physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.1).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 12 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).


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
Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA). 
6.2.11. Visit 12, Week 44 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 13 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).


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
Collect stool sample for enteric pathogens (See Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.12. Visit 13, Week 48 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration. Disease activity should also be documented to 
establish each subject’s relapse status and/or treatment failure.
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 14 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.


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
Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample (see Section 7.3.1.6).

JC virus Antibody testing (see Section 7.3.1.6).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  


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6.2.13. Visit 14, Week 52 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 15 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (See Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).


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
Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.14. Visit 15, Week 56 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK and PD biomarkers must be collected prior to
investigational product administration. Disease activity should also be documented to establish 
each subject’s relapse status and/or treatment failure.  
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 16 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 


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Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a  
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA).  
6.2.15. Visit 16, Week 60 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Complete physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.1).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 17 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.


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
Urine pregnancy test (see Section 7.2.5 and Table 3).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment and/or therapies and medications: as described in the Concomitant 
Medications Sections (see Section 5.5 and the SOA). 
6.2.16. Visit 17, Week 64 (7 Days of the Projected Visit Date)
At this visit, the serum samples for PK, ADAs and Nabs, and PD biomarkers must be collected 
prior to investigational product administration. Disease activity should also be documented to 
establish each subject’s relapse status and/or treatment failure. 


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The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 18 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Collect stool sample for enteric pathogens (see Section 7.3.2).

Dispense labeled stool container and plastic bag to subject to subjects who have had a 
disease flare only.

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).


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
Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA). 
6.2.17. Visit 18, Week 68 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg) 
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 19 unless there has already been an ECHO and cardiology consult for 
NTproBNP >300 pg/mL.

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).

Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).


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
Collect stool sample for enteric pathogens (See Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Dispense labeled stool container and plastic bag to subject to provide a refrigerated or 
frozen stool specimen at the subsequent visit.

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).  
6.2.18. Visit 19, Week 72 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs and temperature: single sitting blood pressure, pulse rate, respiratory rate 
(after 5 minute rest), and temperature (oral or tympanic [C or F]); weight (lbs or kg)
(see Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Complete physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.1).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis. (see Section 7.2.5 and SOA).

Urine pregnancy test (see Section 7.2.5 and Table 3).

Laboratory Pharmacodynamics: hsCRP and stool sample for fecal calprotectin (see SOA
and Section 7.6).

Pharmacokinetics: PF-00547659 (see SOA, and Section 7.5).


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
Colonoscopy will be performed for subjects undergoing routine cancer surveillance (see 
Section 7.4.1 and SOA).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Calculation of total Mayo Score (includes flexible sigmoidoscopy or colonoscopy 
results, stool frequency, rectal bleeding, and physician’s global assessment) (see 
Section 7.4, Appendix 1, and SOA footnote t). Only for subjects undergoing 
routine cancer surveillance. Total Mayo Score should be calculated only for the 
first study visit following the surveillance colonoscopy.

Collect stool sample for enteric pathogens (See Section 7.3.2).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3). Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample (see Section 7.3.1.6).

JC virus Antibody testing (see Section 7.3.1.6).

Peripheral blood gene expression profiling (mRNA) and proteins associated with UC, 
inflammation and mechanism of drug activity (see Section 7.4 and SOA).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).  
6.2.19. Visits 20 - 36, Weeks 76 – 140 (7 Days of the Projected Visit Date)

Amended Informed Consent (Visit 20).

Vital signs: single sitting blood pressure, pulse rate; weight (lbs or kg) (see 
Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Single, standard 12-lead electrocardiogram only at Visits 22, 25, 28, 31 and 34 (see SOA
and Section 7.2.3).


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
Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis only at Visits 22, 25, 28, 31 and 34 (see SOA and Section 7.2.5).

Urine pregnancy test (see Section 7.2.5 and Table 3).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Collect stool sample for enteric pathogens only if symptomatic (See Section 7.3.2).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample only at Visits 26 and 32 (see Section 7.3.1.6).

JC virus Antibody testing only at Visits 26 and 32 (see Section 7.3.1.6).

Drug dispensing: complete 75 mg SC PF-00547659 assignment as described in the Study 
Drug and Administration at Visit 20. Administer the appropriate dose of SC 
PF-00547659 to subject as described in the Investigational Product Administration 
section of this protocol (see Sections 5.2.2 and 5.2.3).  Observe for injection site and 
allergic reactions for a period up to 30-60 minutes (but total duration should be 
determined at the discretion of the investigator). 

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).  
6.2.20. Visit 37 Week 144 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs: single sitting blood pressure, pulse rate; weight (lbs or kg) (see 
Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).


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
Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis. (see Section 7.2.5 and SOA).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 38; if NTproBNP >124 pg/mL, and subject has previously had an ECHO, 
order ECHO and cardiology consult prior to Visit 38. 

Urine pregnancy test (see Section 7.2.5 and Table 3).

Partial Mayo Score (see Section 7.4, Appendix 1 and SOA).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Collect stool sample for enteric pathogens only if symptomatic (See Section 7.3.2).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample (see Section 7.3.1.6).

JC virus Antibody testing (see Section 7.3.1.6).

Drug dispensing: administer the appropriate dose of SC PF-00547659 to subject as 
described in the Investigational Product Administration section of this protocol (see 
Sections 5.2.2 and 5.2.3).  Observe for injection site and allergic reactions for a 
period of at least 30-60 minutes (but total duration should be determined at the 
discretion of the investigator). 

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant Treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).  


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6.3. Follow-Up
6.3.1. Visit 38, Week 156 (7 Days of the Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs: single sitting blood pressure, pulse rate; weight (lbs or kg) (see 
Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659, ADAs and Nabs (see SOA and Section 7).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

Collect stool sample for enteric pathogens only if symptomatic (See Section 7.3.2).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).  
6.3.2. Final Onsite StudyVisit: Visit 39, Week 168/End of Study (EOS) (7 Days of the 
Projected Visit Date)
The following procedures will be performed at this visit:

Vital signs: single sitting blood pressure, pulse rate, weight (lbs or kg) (see 
Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5).


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
Urine pregnancy test (see Section 7.2.5 and Table 3).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA testing (see Section 7.3.1.6).

JC virus Antibody testing (see Section 7.3.1.6).

Collect stool sample for enteric pathogens only if symptomatic (See Section 7.3.2).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA).

End of Study CRF is completed when the subject completes participation in the study.
6.4. Early Withdrawal
Subjects may withdraw from this study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
administrative reasons. Subjects must be withdrawn if they develop any opportunistic infection, 
eg, PML. Subjects are encouraged to stay in the protocol unless disease symptoms become 
intolerable, as lack of response may be due to the pharmacokinetic/pharmacodynamic 
characteristics of the study drug.
Subjects who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures.  The only exception to this is when a 
subject specifically withdraws consent for any further contact.  Subjects should notify the 
investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible.  The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug only or also 
from study procedures and/or post treatment study follow-up.  
Additional reasons a subject may be withdrawn from active treatment include but are not limited 
to, AE, SAE, protocol violations, and failure to return for visits. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status.  This includes follow-up with persons authorized by the subject.  Lost to follow-
up is defined by the inability to reach the subject after a minimum of three documented phone 
calls, faxes, or emails as well as lack of response by subject to one registered mail letter.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use permissible local methods to obtain the date and cause of death.  


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The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If after all attempts, the 
subject remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the subject’s medical records. In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request the subject to return for a 
final visit, if applicable, and follow up with the subject regarding any unresolved AE(s).
Subjects who withdraw from this study due to an increase in disease symptoms may see their 
personal physician for treatment, which may include treatments prohibited during the study. 
Subjects that do withdraw from active treatment should complete the procedures for the early 
withdrawal visit listed below, and enter the 6 month follow up period of the protocol.
The following procedures will be performed at the Early Withdrawal Visit prior to Visit 37:

Vital signs: single sitting blood pressure, pulse rate, weight (lbs or kg) (see 
Section 7.2.1).

Review ECHO/Cardiology Consult if applicable (see Section 7.2.4).

Targeted physical examination: To include confrontational visual fields for neurologic 
assessment (see Section 7.2.2.2).

Single, standard 12-lead electrocardiogram (see Section 7.2.3).

Laboratory testing: blood chemistry to include cTnI and NTproBNP, hematology and 
urinalysis (see SOA and Section 7.2.5 and).
Note: if NTproBNP >300 pg/mL order repeat NTproBNP, ECHO and cardiology consult 
prior to Visit 20; if NTproBNP >124 pg/mL, and subject has previously had an ECHO, 
order ECHO and cardiology consult prior to Visit 20 

Urine pregnancy test (see Section 7.2.5 and Table 3).

Pharmacokinetics: PF-00547659, ADAs and NAbs (see Section 7 and SOA).

Complete SCCAI (see Section 7.4, Appendix 2, and SOA).

Collect stool sample for enteric pathogens only if symptomatic (See Section 7.3.2).

Complete Stool Diary (see Section 7.4, Appendix 3, and SOA).

Neurological Assessments: Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT), 
Symbol Digit Modality Test (SDMT), and Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) (see Section 7.3.1 and SOA).

JC virus DNA sample (see Section 7.3.1.6).


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
JC virus Antibody testing (see Section 7.3.1.6).

Monitoring of adverse events: as described in the Adverse Event, Serious Adverse Event 
Recording and Reporting Sections (see Section 8.14.1 and the SOA).

Concomitant treatment: as described in the Concomitant Treatments Sections (see 
Section 5.5 and the SOA). 

End of study CRF is completed when subjects withdraw from the study.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent.
6.4.1. Post-Withdrawal Visit
Results from study A7281001 indicated the elimination of PF-00547659 follows IgG2 
pharmacokinetics when dosed in the range selected from the current study. It has been 
determined that at 24 weeks after the last dose the majority of subjects are likely to have 
concentrations below the limit of quantification. Therefore, it is advised that subjects 
withdrawing from the study prior to Week 144 enter into the follow-up period with their first 
follow-up visit occurring 3 months after their last dose.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to perform 
the test.  In these cases the investigator will take all steps necessary to ensure the safety and well 
being of the subject.  When a protocol required test can not be performed the investigator will 
document the reason for this and any corrective and preventive actions which he/she has taken to 
ensure that normal processes are adhered to as soon as possible.  The study team will be 
informed of these incidents in a timely fashion.
7.1. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed before investigational product administration at the baseline visit 
and at the end of treatment visit.  A negative pregnancy result is required before the subject may 
receive the investigational product.  Pregnancy tests will also be done whenever one menstrual 
cycle is missed during the active treatment period (or when potential pregnancy is otherwise 
suspected), repeated at all visits, follow-up visit and early withdrawal to confirm the subject has 
not become pregnant during the study.  Pregnancy tests may also be repeated as per request of 
IRB/IECs or if required by local regulations.


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In the case of a positive confirmed pregnancy, the subject will be withdrawn from study 
medication, should complete the procedures for the early withdrawal visit and enter the 6 month 
follow-up period.
7.2. Safety
Average monthly blood sampling volume for a subject that completes all currently scheduled 
assessments through Week 168 is approximately 33 mL.  
7.2.1. Vital Signs, Height, and Weight
Vital signs (blood pressure, heart rate, respirations and oral or tympanic temperature (C or F) 
will be measured at every study visit up to Visit 19.  After Visit 19, vital signs (blood pressure 
and heart rate) will be measured at every study visit. Additional collection times, or changes to 
collection times of blood pressure and pulse rate will be permitted, as necessary, to ensure 
appropriate collection of safety data.
It is preferred that body temperature be collected using the tympanic or oral methods and that the 
same method be used consistently throughout this study.
Sitting blood pressure will be measured with the subject’s arm supported at the level of the heart, 
and recorded to the nearest mm Hg.  It is preferred that the same arm (preferably the dominant 
arm) will be used throughout this study.
The same size blood pressure cuff, which has been properly sized and calibrated, will be used to 
measure blood pressure each time.  The use of automated devices for measuring blood pressure 
(BP) and pulse rate are 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, all vital signs should be obtained prior to the nominal time of 
the blood collection.
Height (inches or centimeters) will be recorded at the Baseline visit only.  
Weight (lbs or kg) without shoes will be measured at each visit, and at Early Withdrawal (see 
STUDY PROCEDURES).
7.2.2. Physical Exam
7.2.2.1. Complete Physical Exam
Complete physical examinations will be performed at the Baseline visit, Weeks 20, 40, 60, and 
72, if required (see Table 1 and Section 6).  Complete physical examinations must be performed 
by the investigator, sub-investigator, or a qualified health professional per local guidelines.  
Complete physical examinations consist of assessments of general appearance; skin; head, eyes, 
ears, nose and throat (HEENT); heart; lungs; breast (optional); abdomen; external genitalia
(optional); extremities; neurologic function; back and lymph nodes.


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7.2.2.2. Targeted Physical Exam
Targeted physical examinations will be performed at Weeks 4, 8, 12, 16, 24, 28, 32, 36, 44, 48, 
52, 56, 64, and 68 during Open Label Treatment Period 1. Targeted physical examination will 
be performed at each visit during Open Label Treatment Period 2 until EOS (Week 168), and at 
Early Withdrawal. (see Table 1 and Section 6).  Targeted physical examinations must be 
performed by investigator, sub-investigator, or a qualified health professional per local 
guidelines and should include skin, heart, lung, confrontational visual fields (eyes) and abdomen. 
7.2.3. Electrocardiogram
Single 12-lead ECGs should be collected at the Baseline visit, every 8 weeks to Week 72. After 
Week 72, a single 12-lead ECG should be collected starting at Week 84, every 12 weeks to 
Week 144 and at Week 168 or Early Withdrawal (if required) (see Table 1 and Section 6).
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a sitting position.
The values of the ECG collected at the Baseline visit will serve as each subject’s baseline ECG
values.  When the timing of the measurements coincides with a blood collection, the ECG should 
be obtained prior to the nominal time of the blood collection, blood pressure and pulse rate. To 
ensure safety of the subjects, a qualified individual (eg, sub-investigator) at the investigator site 
will make comparisons to baseline measurements.
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.
7.2.4. Transthoracic Echocardiogram (ECHO) and Cardiology Consult (if applicable)
ECHO and cardiology consult will be performed locally only under specified conditions. These 
conditions are:

At baseline visit: if NTproBNP value is >300 pg/mL if no prior ECHO.

At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is 
>300 pg/mL.

At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the 
NTproBNP is >124 pg/mL or if there has been no prior ECHO, and the NTproBNP is 
>300 pg/mL.

At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300.
At a minimum, the ECHO must assess RV and LV function, determine LVEF and evaluate for 
diastolic dysfunction.
The cardiology consult should be focused on any evidence of myocarditis or right or left heart 
failure or any alternative explanations of the subject’s elevated NTproBNP. The cardiologist 


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should review the serial NTproBNP data available up to that point, and the ECHO, and provide a 
report that evaluates the etiology of the heart failure or myocarditis if present.
7.2.5. Laboratory Tests
As much as possible, only 1 local laboratory should be used by each investigator for all local 
laboratory tests. Laboratory certification and laboratory normal ranges must be provided to the 
sponsor for all laboratories used. A central laboratory will be used for the majority of the 
laboratory tests; however a local laboratory will be allowed for urgent test results if needed.
Laboratory tests are listed in detail in Table 1 and Section 6.
All laboratory tests with values that become abnormal to a clinically significant degree after 
investigational product administration must be repeated and the investigator must continue to 
follow up as medically indicated until values have returned to baseline or until the condition 
stabilizes. If laboratory values do not return to normal or baseline within a reasonable period, the 
etiology must be identified and the sponsor notified.


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Table 3.
Laboratory Tests
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and Creatininee
Glucose (fasting if possible)
Calcium
Sodium
Potassium
Chloride
AST, ALT
Total Bilirubin
Direct Bilirubina
Alkaline phosphatase
Uric acid
Albumin
Total protein
CPK
CPK fractionationb
NT-proBNPd
Troponin Id
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Microscopy c
hsCRPf
Transthoracic 
echocardiogram (ECHO)d
Urine pregnancy test
Stool sample for fecal 
calprotectinf
JC virus DNA testing
JC virus Serology (antibody)
ADAs
Soluble MAdCAM f
mRNA and proteins f
a. Only if Total Bilirubin is elevated.
b. Only if CPK  is elevated
c. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
d. ECHO and cardiology consult will be performed locally only under specified conditions. These conditions 
are:

At baseline visit if NTproBNP value is >300 pg/mL and no prior ECHO.

At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is >300 pg/mL.

At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the NTproBNP is 
>124 pg/mL or if there has been no prior ECHO, and the NTproBNP is >300 pg/mL.

At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300.
e. Creatinine Clearance determination by central lab using Cockcroft&Gault method.
f. After completion of the Week 72 visit, hsCRP, Soluble MAdCAM and stool sample for fecal calprotectin will 
no longer be collected for the Open Label Treatment Period 2.
7.3. Special Safety Assessments
As noted above (see Section 1.2.4.1) nonselective inhibitors of lymphocyte trafficking into 
tissue, such as natalizumab, have been associated with rare cases of Progressive Multifocal 
Leukoencephalopathy (PML). Because PF-00547659 acts only on the MAdCAM receptor, 
which is the mediator of lymphocyte trafficking into the gut, this agent should be much safer 
because it does not interact with VCAM, the mediator of lymphocyte trafficking into the CNS. It 
is hypothesized that natalizumab interferes with immune surveillance of the CNS, thus 
permitting opportunistic infections. However, the actual mechanism by which natalizumab 
therapy results in PML is unknown.
Since PF-00547659 is still in early development, in order to maximally protect study subjects 
from any potential neurologic risk, this study includes frequent neurologic assessments to detect 
the earliest possible changes in neurologic function. Any change in function detected by this 
assessment should trigger an immediate neurologic consultation to rule out PML.


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The tests selected for assessment were identified by expert consultation as the rarity of PML has 
prevented the establishment of clear-cut guidelines for its early detection. Since PML and 
Multiple Sclerosis (MS) are both white matter diseases, similar findings are expected. Therefore, 
many of the chosen tests are used frequently to assess MS subjects. 
Because none of these tests has been validated for this specific purpose, the investigator’s 
clinical judgment will be necessary in the interpretation of changes that will trigger an immediate 
formal neurological consultation to determine the cause of the change in neurological function 
and exclude PML. Such a consultation will typically include MRI and lumbar puncture.  
The following neurological assessments will be performed monthly throughout the Open Label 
Treatment Period 1 and Open Label Treatment Period 2:

Confrontational Visual Fields which will be performed as part of the physical exam.

Timed 25-Foot Walk.

9-Hole Peg Test (9-HPT).

Symbol Digit Modality Test (SDMT-written).

Patient-Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) (Does not trigger 
a neurology consult).
7.3.1. Neurological Assessments
These tests are rapid, simple to perform and may be performed by the study site staff after 
reading the simple instructions.  Additional training in these tests will be provided at the 
investigator meeting.
7.3.1.1. Confrontational Visual Fields (to be performed as part of the complete and 
Targeted Physical examinations)
Confrontation Visual Field Test (CVFT): The CVFT is a basic screening tool to measure the 
overall field of vision.  It is also useful for detecting blind spots and eye diseases.  Subjects will 
be asked to cover one eye while fixing their gaze on the examiner’s eyes.  This test should be 
administered by a qualified health professional trained in confrontational visual fields. The 
examiner will make finger movements, bringing his/her fingers into each quadrant of the visual 
field.  Subjects will be asked how many fingers they see without actually looking at them in 
order to test peripheral vision.  (See Appendix 4 for instructions).  
Any change in visual fields detected by this examination must trigger a formal visual field 
examination by an ophthalmologist.  If the visual field test is abnormal then a neurologic 
consultation to rule out PML must be initiated immediately.
Reference: http://vision.about.com/od/eyeexamination1/f/Confrontation_Fields.htm


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7.3.1.2. Timed 25-Foot Walk
Timed 25-Foot Walk (T25-FW): The T25-FW is a quantitative mobility and leg function test 
based on a timed 25 foot walk.  The subject is directed to walk to one end of a clearly marked 
25-foot straight course.  The subject is instructed to walk as quickly as possible, but safely.  The 
examiner uses a stopwatch to time how long it takes the subject to walk to the 25-foot mark.  The 
task is immediately administered again by having the subject walk back to the start of the 25-foot 
course.  Subjects may use assistive devices when doing this task.  The average time of the two 
trials is taken.  Total administration time should be approximately 1-5 minutes.  (see Appendix 5
for instructions).
Note: This test requires a stopwatch, a measuring tape (at least 25 feet long), and masking tape 
to mark the floor are needed.  
In a study of normal volunteers, the typical time to complete the 25 foot walk was 3-4 seconds, 
in contrast to patients with Multiple Sclerosis who took about twice as long.9 Arthritis and other 
orthopedic problems can also affect the time on the test. 
A 20% increase compared with baseline of the previous study is clinically significant and 
deterioration not explained by another clear reason should prompt a neurological 
consultation. Note the term baseline is not defined as the “baseline visit”. To further 
clarify “the baseline” value is the WORSE of the values determined at the screening visit 
and baseline visit of study A7281009.
Reference: http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-
measures/t25-fw/index.aspx
7.3.1.3. 9-Hole Peg Test (9-HPT)
9 Hole Peg Test: The 9-HPT is a brief, standardized test of upper limb function.  Both the 
dominant and non-dominant hands are tested (note: dominant hand is usually the hand that the 
patient uses to write).  The subject is seated at a table with a small, shallow container containing 
9 pegs and a wooden or plastic block with 9 empty holes.  On a start command when a stopwatch 
is started, the subject picks up the 9 pegs one peg at a time, and as quickly as possible, puts the 
pegs in the holes.  Once all the pegs are in the holes the patient removes them again as quickly as 
possible, one at a time, replacing them into the shallow container.  The total time to complete the 
task is recorded.  Two consecutive trials with the dominant hand are immediately followed by 
two consecutive trials with the non-dominant hand.  The average time for each hand is 
calculated.  Total administration time should be approximately 10 minutes or less. 
Note: this test requires a stopwatch.  
In a study of healthy volunteers, typical completion time was about 18 seconds, compared with 
Multiple Sclerosis patients who required 21-25 seconds.9 Performance of the test can also be 
affected by injuries and arthritis. 
A 20% increase compared with baseline of the previous study is clinically significant along 
with deterioration in performance that is not readily explained especially if within the MS 


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range should prompt a neurological consultation. Note the term baseline is not defined as 
the “baseline visit”. To further clarify “the baseline” value is the WORSE of the values 
determined at the screening visit and baseline visit of study A7281009.
Refer to (Appendix 6) for instructions.
Reference: http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-
measures/9-hpt/index.aspx
7.3.1.4. Symbol Digit Modality Test (SDMT)
Symbol Digit Modality Test (SDMT): The SDMT is a simple test used to screen for organic 
cerebral dysfunction.  It evaluates multiple domains, including attention, visual spanning and 
motor speed. The SDMT is brief, easy to administer, and has demonstrated sensitivity in 
detecting not only the presence of brain damage but also changes in cognitive functioning over 
time and in response to treatment.  The SDMT involves a simple substitution task such as in 
deciphering a code.  Using a reference key, the subject has 90 seconds to pair specific numbers 
with given geometric figures.  Subjects can give either written or verbal responses.  The written 
version is being used in this study. Time to administer is approximately 5 minutes.  
Results of the SDMT are compared against a normative table that indicates values for 
populations by age and educational level (12 years of school/high school graduate or less vs 
13 years of school/any college or more). Scores are ranked in terms of standard deviation, from 
+3.0 to -3.0 in 0.5 SD increments. When given a single time, a value that is -1 SD is considered 
low, -1.5 SD moderately low, and -2.0 SD very low. There has been no validation of change 
over time, but in a study of impaired patients (baseline no more than -1.5 SD) with Multiple 
Sclerosis with an ineffective treatment both the placebo and treated patients varied by 
4.8-5.2 points over 28 days.10 The minimum change to reflect 1 SD is 8 points. 
A deterioration 1 standard deviation on two consecutive visits compared to the baseline of 
the previous study and a drop in performance should be of concern and prompt a 
neurological consultation. Note the term baseline is not defined as the “baseline visit”. To 
further clarify “the baseline” value is the WORSE of the values determined at the 
screening visit and baseline visit of study A7281009.
Refer to Appendix 7 for instructions.
Reference: http://www.hogrefe.co.uk/?/test/show/272/ and Parmenter et al, 2007 article.11
7.3.1.5. Multiple Sclerosis Neuropsychological Questionnaire (MSNQ)
Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ): The MSNQ is a 
self-administered PRO questionnaire. It is designed as a quick test to identify possible 
neuropsychological impairment, originally in subjects with Multiple Sclerosis.  The MSNQ has 
15 questions, and subjects rate the frequency and severity of symptoms associated with 
neuropsychological impairment.  There are 2 MSNQ; one for patients and one for a close family 
member or friend. Both forms are reliable and valid. However, only the patient form will be 
used in this study. 


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The MSNQ is a sensitive test for detection of neurocognitive abnormalities in patients with MS.  
The test covers several different cognitive domains (attention, memory, language) and integrates 
them into a single value. Patients with MS scored significantly higher than normal controls on 
the self-reported values. 
Self-report (mean+/-sd)
MS
27.4+/-11.9
Normal
16.0+/-6.2
For self-reported results, a cut-off of 24 correctly identified cognitive impairment 68% of the 
time (sensitivity 0.83, specificity 0.6).
Experience with this test is generally limited to subjects with multiple sclerosis. Based on 
early experience with Crohn’s Disease subjects, variability between repeat tests appears 
excessive and results are being evaluated for information only.
Refer to Appendix 8 for instructions.
7.3.1.6. JC Virus
Samples for JC virus antibody will be taken every 6 months throughout the study until the final 
onsite visit. At a minimum, the final samples will be tested. The samples may be stored with the 
central shipper until an appropriate analysis plan is determined.
Samples for JC Virus DNA will be taken every 6 months throughout the study until the final 
onsite visit. At a minimum, the final samples may be tested. The shipment address and contact 
information for the lab will be provided to the Investigator as soon as this information will 
become available. The samples may be stored with the central shipper until an appropriate 
analysis plan is determined.
7.3.2. C. Difficile
Highly sensitive tests, with high negative predictive value, should be employed to exclude 
C. difficile infection in subjects with a flare of UC. The detection of C. difficile by toxigenic 
stool culture [stool culture followed by detection of toxin] is considered the gold standard for the 
diagnosis of the colonization or infection with pathogenic C. difficile. Comparable sensitivity 
may be achieved by direct testing of stool via point of use rapid membrane enzyme 
immunoassay card for both C. difficile toxin A and B and glutamate dehydrogenase (GDH) 
antigen on a card.  Use of the card for point of care is encouraged where permitted by local 
regulation.  Molecular techniques such as PCR for detection of toxin RNA are also acceptable 
alternatives. This test will be mandatory for subjects who experience a disease flare.
Refer to the lab manual for further guidance and instruction for C. difficile testing.


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7.4. Diagnostic and Efficacy Assessments
7.4.1. Flexible Sigmoidoscopy or Colonoscopy (if preferred)
A flexible sigmoidoscopy or colonoscopy must be performed at study Visit 5 (Week 16). 
Additionally, between Weeks 52 and 68, if routine colonoscopy for cancer surveillance is 
performed within the study a Total Mayo score should be obtained. Optional 
colonoscopies/flexible sigmoidoscopy performed between Weeks 40 and 72 will provide 
additional Total Mayo Score for exploratory analysis. If it is necessary a bowel prep should be 
conducted as per local routine.  The position of the endoscope at the post-treatment visit will be 
based on the length of the instrument at various levels of insertion as well as the morphological 
features of the intestine as seen during flexible sigmoidoscopy or colonoscopy at baseline.  The 
endoscopy report and any photographs and/or video recordings taken during the procedure per 
local custom should be filed in the patient’s chart.  The findings of the endoscopy component 
should be completed at the end of the procedure to document the endoscopic subscore in the 
event that the data is entered at a different location.
A copy of the endoscopy report and any photographs and/or video recordings taken during the 
procedure must be obtained and filed in the subject’s chart and must be available to the sponsor 
upon request.  The report and any photographs and/or video recordings taken during the 
procedure must be sufficient to complete the endoscopy component on the Mayo Scoring System 
CRF.  A request should also be made to obtain any biopsy samples that were taken during the 
procedure.
To ensure measurement consistency and validity of study efficacy assessments, video recordings 
of endoscopic procedures will be captured using a study-specific video capture kit and uploaded 
to a secure website for review by a central reader.
Scoring will be performed by the central reader at Week 16 of the study. Scores will be returned 
to the investigative sites in a timely manner. Site personnel will be trained on the video capture 
equipment suppliedby the central reading CRO and instructed on how to upload the video 
recording data. 
Precautions will be taken to ensure confidentiality. The central reader will remain blinded to the 
study as no information regarding disease history or treatments is to be communicated from the 
sites.
7.4.2. Optional Endoscopic Biopsy Substudy
Only for subjects who consent during flexible sigmoidoscopy or colonoscopy (whichever 
preferred). The analysis may include the following:
mRNA (all sites):
The largest standard forceps should be used to obtain biopsies.  Biopsies should be taken 
one-at-a-time, and each should be immediately placed into a separate sample collection tube.  
The biopsy collection tube will contain an RNA stabilizing liquid.  For RNA biopsies should be 
taken from abnormally lesional mucosa, and biopsies from non lesionsal mucosa.  The biopsy 


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must be completely submerged in the liquid. Labels should clearly specify whether the biopsy is 
from a lesional or non-lesional area.  Frankly ulcerated areas should be avoided.  Shire and the 
central laboratory vendor will provide sites with instructions and supplies for the collection, 
processing, and shipment of biopsy samples.
Assessment of Histology (all sites):
These biopsies are being collected for the purposes of assessing the effectiveness of drug in 
decreasing inflammatory cell infiltration at the site of disease. Histological and protein 
assessment may include different subsets of lymphocytes, hematopoietic cells and/or protein 
biomarkers and will be performed on formalin fixed tissue.  The largest standard forceps should 
be used to obtain biopsies.  Biopsies should be taken one-at-a-time. Biopsies from lesional tissue 
should be placed in the container provided (which contains formalin).  Additionally, biopsies 
from non-lesional mucosa should be placed in the separate contained (also containing formalin.  
Labels should clearly specify whether the biopsies are from inflamed or normal appearing 
mucosa.  Frankly ulcerated areas should be avoided.  Shire and the central laboratory vendor will 
provide sites with instructions and supplies for the collection, processing, and shipment of biopsy 
samples.
Mucosal Healing (all sites):
Subjects may undergo endoscopy to evaluate mucosal healing by visualization.  Data may be 
combined with the data from the other MAdCAM IBD studies. Endoscopic scoring will be 
performed using the Mayo-Score. The procedures may also be recorded on CD-ROMs.
Tissue Biology (SELECTED SITES):
The objective of this study is to explore the effect of PF-00547659 on endoscopic tissue. 
Approximately 40 subjects are needed for meaningful data. Data may be combined with the data 
from the other MAdCAM IBD studies.
The analysis may include the following:

T and B lymphocytes to be isolated from LMPC’s (obtained from intestinal biopsies) and 
subsequently subjected to FACS analysis that may include using antibodies against B7, 
CD45 RO, CD27, CCR6, CCR9, CD3 and CD19/CD10.

Histologic disease activity.

Immunohistochemistry (IHC) that may include different subsets of lymphocytes, 
hematopoietic cells and/or protein biomarkers.

mRNA transcripts.
Additional information may be provided in the laboratory manual under separate cover.


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Individual subjects may also elect to participate or not in this portion of the study without 
affecting their overall eligibility for the study.  
7.4.3. Subject Stool Diary
Subjects will use a paper diary in order to record on a daily basis the following information 
during the study:

‘Normal’ number of stools per day (when not having a flare).  

Number of times need to visit the toilet to have a bowel movement (per day).

Presence of blood in the stools (if any).

Description of blood in the stools (if any).
Patients will be required to enter diary data for the 3 days immediately preceding the flexible
sigmoidoscopy visit prior to the Week 16 visit. Note: The term “immediately” indicates a 
preference and is not considered a requirement. To calculate the Mayo Score data, 3 consecutive 
days preceding the flexible sigmoidoscopy or colonoscopy may be used. Should any patient be
required to perform bowel preparation prior to the flexible sigmoidoscopy at Week 16, the 
patient should be instructed to complete the diary one day prior to initiating bowel preparation. 
Note: If a bowel preparation is needed data for 3 consecutive days up to one day prior to the 
bowel preparation may be used to calculate the Mayo Score. Diaries to be completed by the 
patients will be distributed during the baseline visit [Week 12 of study A7281009 (for collection 
at the flexible sigmoidoscopy visit prior to Week 16)] (See Appendix 3).
7.4.4. Mayo Score
The Mayo score is a tool designed to measure disease activity for UC.  The Mayo scoring system 
ranges from 0 to 12 points and consists of 4 subscores, each graded 0 to 3 with the higher score 
indicating more severe disease activity (see Appendix 1).

Stool frequency (Subscore 0-3).

Rectal bleeding (Subscore 0-3).

Findings on flexible sigmoidoscopy (Subscore 0-3).

Physician’s global assessment (Subscore 0-3).
Calculation of the Mayo score requires an assessment of the subject’s stool frequency and any 
amount of blood in the stool. The Mayo score at baseline and Week 16 visit will be calculated 
based on the subject’s diary data recorded over the 3 prior consecutive days.
The Mayo endoscopic subscore will be assessed by the mucosal appearance during the flexible 
sigmoidoscopy or colonoscopy based on the scoring system provided in the protocol 
(Appendix 1). The endoscopic appearance will be read by both the investigator and central 


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reader. Centrally read endoscopic subscores will be used for both eligibility and efficacy 
analyses.
The physician’s global assessment (PGA) acknowledges the other three criteria, the subject’s 
abdominal discomfort and sense of general well-being. In addition, the investigator should 
consider other observations (ie, physical findings) and subject’s performance status when making 
the PGA assessment. It is preferred that the same physician performs all such assessments for a 
given subject throughout the study.
7.4.5. Partial Mayo Score
A partial Mayo score (Mayo score without the endoscopic subscore) will be assessed prior to the 
administration of the investigational product and at the specified study visits in the SOA.
7.4.6. Simple Clinical Colitis Activity Index (SCCAI)
The SCCAI measures disease activity as defined by both subjects and examiners and includes the 
following 13 items: general well-being, abdominal pain, bowel frequency, stool consistency, 
bleeding, anorexia, nausea or vomiting, abdominal tenderness, extra intestinal complications 
(eye, mouth, joint, skin), temperature, sigmoidoscopic assessment, nocturnal bowel movements, 
and urgency of defecation.7 Scores range from 0 to 19 points, and scores <2.5 have been shown 
to correlate with Patient-Defined Remission, and a decrease of >1.5 points from baseline 
correlates with Patient-Defined Significant Improvement.8  SCCAI will be administered by study 
site personnel and will reflect a subject’s self-assessment of the prior 24-hour period. Scores will 
be obtained prior to the first dose of study treatment at baseline. Subsequent SCCAI assessments 
will occur throughout the treatment period prior to the performance of any other study 
procedures (See Appendix 2).
7.5. Pharmacokinetics
7.5.1. Serum Samples for Analysis of PF-00547659
Blood samples for the assessment of PF-00547659 will be collected and analyzed at the specified
time points for the duration of the study at protocol-specified times (See Schedule of Activities).
Samples will be analyzed for PF-00547659 using a validated assay. Follow Section 7.7 for 
serum harvest procedure.
Samples will be analyzed using a validated analytical method in compliance with Shire standard 
operating procedures.
Collection tube labels must include the following preprinted information: protocol number, 
subject number, treatment period, study day, and nominal time of sample withdrawal as well as 
the test identification ‘PF-00547659/serum’.
7.5.1.1. Shipment of Serum Samples for Analysis of PF-0547659
The shipment address and contact information for the lab will be provided to the Investigator site 
prior to initiation of the trial.


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7.6. Pharmacodynamics
7.6.1. hs CRP 
Highly sensitive C reactive protein (hs CRP) is a highly sensitive inflammation biomarker.  hs 
CRP will be measured through regularly scheduled safety laboratory serum samples as specified 
in the Table 1 and Section 6.
7.6.1.1. Shipment of Samples for Analysis of hs CRP
The shipment address and contact information for the lab will be provided to the Investigator site 
prior to initiation of the trial.
7.6.2. Fecal Calprotectin
Fecal calprotectin (a neutrophil degradation product) is a second inflammation biomarker that 
will be analyzed.  Stool samples for fecal calprotectin measurements will be obtained through 
stool samples collected at baseline through Week 24, Week 32, and Week 72 as specified in 
Table 1 and Section 6.  Stool samples for fecal calprotectin should be collected at the specified 
study visit. Labeled stool containers and plastic bags will be provided to the subjects at the 
preceding visit so they can bring the stool specimen with them at that visit. While it is preferred 
to provide a fresh specimen, it will not interfere with testing if the stool is refrigerated or frozen. 
If the subject fails to bring in the stool specimen, they should stay at the site and provide it the 
day of the visit if at all possible or at the earliest possible time.
Note: Fecal calprotectin will be collected from subjects who were previously in study A7281009 
only.
7.6.2.1. Shipment of Fecal Samples for Analysis Fecal Calprotectin
The shipment address and contact information for the lab will be provided to the Investigator site 
prior to initiation of the trial.
7.6.3. Exploratory Biomarkers (Blood/Stool):

Soluble MAdCAM in blood may be assessed at baseline and Week 16.

Gene expression profiling (mRNA) in blood and protein associated with UC, 
inflammation and mechanism of drug activity may be assessed at baseline, Week 16 
and Week 72.

Analyses relevant to the understanding and treatment of UC may be conducted on the 
portion of stool samples remaining after calprotectin analysis. 
7.6.3.1. Shipment of Samples for Analysis of Exploratory Biomarkers
The shipment address and contact information for the lab will be provided to the Investigator site 
prior to initiation of the trial.


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7.7. Immunogenicity
7.7.1. Serum Samples for Anti-drug Antibodies
During all trial sessions, blood samples (2 mL) to provide a minimum of 1 mL of serum for the 
analysis of anti-PF-00547659 antibodies will be collected at the time points specified in the 
Table 1 and Section 6.  
Samples will be analyzed using a validated analytical method in compliance with Shire standard 
operating procedures.  A positive ADA sample will be further tested for neutralizing antibodies.
Collection tube labels must include the following preprinted information: protocol number, 
subject number, treatment period, study day, and nominal time of sample withdrawal as well as 
the test identification ‘ADA/serum’.
7.7.1.1. Shipment of Serum Samples for Analysis of Anti-drug Antibodies
The shipment address and contact information for the lab will be provided to the Investigator site 
prior to initiation of the trial.
7.8. Procedure for Serum Collection
During all trial periods, blood samples will be collected into appropriately labeled vacuum tubes 
containing no additive glass tube (the silicone coated plastic tube is acceptable if 
non-additive glass red top tube is not available) at times specified in the protocol.  A serum 
separator tube should not be used.
Blood samples will be allowed to clot at room temperature (18C-25C) for at least 
30 minutes for a complete clot.  Place the clotted samples into an ice/bath for approximately 
10 minutes prior to the centrifugation.  Serum will be separated from the whole blood within 
approximately 40 minutes of collection.  Specimen should be centrifuged at 1000 to 1200 x g for 
approximately 10 to 15 minutes in an ambient centrifuge (refrigerated centrifuge is acceptable if 
it’s available) to harvest the serum.  After centrifugation, the upper serum layer is carefully 
transferred with a disposable pipette into a labeled screw capped plastic storage tube.  Sample 
should be re centrifuged immediately if red blood cells are inadvertently drawn into the serum.  
Serum samples will be frozen in an upright position at approximately -20°C or colder within 
60 minutes of sample collection.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections.
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a SAE
requiring immediate notification to Shire or its designated representative.  For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of the AE.  The 
investigator is required to assess causality.  Follow-up by the investigator may be required until 


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the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and Shire
concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any nonserious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To assist in 
the determination of case seriousness further information may be requested from the investigator 
to provide clarity and understanding of the event in the context of the clinical trial.
8.2. Reporting Period
For SAEs, the active reporting period to Shire or its designated representative begins from the 
time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving 
investigational product, through and including the End of Study visit.  SAEs occurring to a 
subject after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have 
at least a reasonable possibility of being related to investigational product are to be reported to 
the Sponsor.

AEs (serious and non-serious) should be recorded on the CRF from the time the subject 
has taken at least 1 dose of investigational product through the subject’s last visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;


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
Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure
8.4. Medication Errors
Medication error may result, in this study, from the administration of the wrong product, to the
wrong subject, at the wrong time, per the wrong route, wrong administration location, or at the 
wrong dosage strength, due to human error.  Medication errors include overdose (accidental or 
intentional).  Such medication errors occurring to a study participant are to be captured on the 
medication error case report form (CRF) which is a specific version of the adverse event (AE) 
page, and on the SAE form when appropriate. In the event of medication dosing error, the 
sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the investigator, 
the medication error is captured on the medication error version of the adverse event (AE) page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, and/or

Test result leads to a change in study dosing or discontinuation from this study, 
significant additional concomitant drug treatment, or other therapy, and/or


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
Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not
constitute an adverse event.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity(substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

Medical and scientific judgment is exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization.  However, if it is determined that 
the event may jeopardize the subject or may require intervention to prevent one of the 
other adverse event outcomes, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study. All SAEs will be reported by the investigator 
as described in previous sections and will be handled as SAEs in the safety database (see the 
section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered important 
medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values:


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
Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of normal 
(X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition mentioned 
above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 X ULN or if the 
value reaches 3 X ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, total 
bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/
international normalized ratio (INR) and alkaline phosphatase.  A detailed history, including 
relevant information, such as review of ethanol, acetaminophen, recreational drug and 
supplement consumption, family history, occupational exposure, sexual history, travel history, 
history of contact with a jaundiced person , surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected.  Further testing for acute hepatitis A, B, or C 
infection and liver imaging (eg, biliary tract) may be warranted.  
All cases confirmed on repeat testing as meeting the laboratory criteria, defined above with no 
other cause for liver function test (LFT) abnormalities identified at the time should be considered 
potential Hy’s Law cases irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal LFTs.  Such potential Hy’s Law cases should 
be reported as serious adverse events.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric wing 
to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis 
unit). An emergency room visit does not necessarily constitute a hospitalization; however, the 
event leading to the emergency room visit should be assessed for medical importance.


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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (eg, for work-up 
of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.

Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as an AE, and 
the resulting appendectomy should be recorded as treatment of the AE.


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8.8. Severity Assessment
If required on the adverse event case report forms, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the serious adverse reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an adverse event; 
generally the facts (evidence) or arguments to suggest a causal relationship should be provided.  
If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor (see the Section on Reporting Requirements). If the investigator's 
causality assessment is "unknown but not related to investigational product", this should be 
clearly documented on study records.  
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse event 
reporting requirements, if applicable.
8.10. Exposure During Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to Shire Global Drug Safety 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.


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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 30 calendar days postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol. 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 Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 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.
8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person (whether a 
healthcare professional or otherwise) gets in unplanned direct contact with the product, which 
may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the investigator’s 
awareness, using the SAE report form, regardless of whether there is an associated AE/SAE.  
Since the information does not pertain to a subject enrolled in the study, the information is not 
reported on a CRF: however, a copy of the completed SAE report form is maintained in the 
investigator site file.
8.12. Withdrawal Due to Adverse Events (See also the Section 6.4 on Early Withdrawal)
Withdrawal due to adverse events should be distinguished from withdrawal due to other causes, 
according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page.
When a subject withdraws because of a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be questioned 
about adverse events.
8.14. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
All initial and follow-up SAE reports must be reported by the investigator to Shire Global Drug 
Safety and the CRO/Shire medical monitor within 24 hours of the first awareness of the event. 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 Shire Global Drug 
Safety within 24 hours of the first awareness of the event.
In particular, if the serious adverse event is fatal or life-threatening, notification to Shire must be 
made immediately, irrespective of the extent of available adverse event information.  This 
timeframe also applies to additional new information (follow-up) on previously forwarded 
serious adverse event reports as well as to the initial and follow-up reporting of exposure during 
pregnancy exposure via breastfeeding and occupational exposure cases.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol and verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested) and fax or e-mail the form to Shire 
Global Drug Safety. A copy of the Shire Clinical Study Adverse Event Form for Serious Adverse 
Events (SAEs) and Non-serious AEs as Required by Protocol (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.
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), 
the investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information to 
Shire in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Shire to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for serious adverse events is more detailed than 
that captured on the adverse event case report form.  In general, this will include a description of 
the adverse event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of the 
event, such as concomitant medications, vaccines, and/or illnesses must be provided.  In the case 
of a subject death, a summary of available autopsy findings must be submitted as soon as 
possible to Shire or its designated representative.
8.14.2. Protocol Specific Medically Important Events
Any unexplained change in neurological status or abnormalities in the neurological assessments 
should prompt a neurological consult and if appropriate, be reported as an adverse event or 
medically important event. Events that already meet SAE criteria (eg, seizure, stroke) should be 
reported immediately (See Section 8.6). If clinically indicated, an MRI scan and possibly a 
lumbar puncture for JC virus DNA should be performed to rule out PML or other causes of the 
neurological findings.  All cases will be reviewed and adjudicated by the DMC.


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In case of unexplained neurological signs or symptoms consistent with PML, treatment with PF-
00547659 should be halted and further neurological evaluation is required.
8.14.3. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be noted 
that the form for collection of serious adverse event information is not the same as the adverse 
event CRF.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same adverse event term should be used on both forms.  Adverse 
events should be reported using concise medical terminology on the CRFs as well as on the form 
for collection of serious adverse event information.
8.14.4. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan, which will be maintained by the sponsor.  This 
document may modify the plans outlined in the protocol; however, any major modifications of 
the primary endpoint definition and/or its analysis will also be reflected in a protocol 
amendment.
9.1. Sample Size Determination
All eligible subjects, based on inclusion/exclusion criteria, from the A7281009 study may be 
enrolled.  It is estimated that approximately 90% of the subjects (about 331 subjects) from study 
A7281009 are likely to enroll into this open label extension study A7281010.  The sample size is 
chosen based on clinical outcome of study A7281009 rather than statistical consideration.  
9.2. Exploratory Efficacy Analysis
Descriptive statistics will be provided for the exploratory efficacy analysis. The binary 
endpoints such as clinical remission, clinical response will be summarized with frequency and 
percentage by time point; and the continuous variables will be summarized with n, mean, 
median, standard deviation etc. These summaries may be provided by the strata of responding 
status at entry based on the feeder study. 
All subjects who have received at least one dose of planned investigational product in the open 
lable extension study will be included into the exploraty efficacy analysis. Detailed 
methodologies of these analyses will be described in the SAP.
9.3. Exploratory Pharmacodynamic Analysis
Fecal calprotectin, hsCRP and exploratory biomarkers will be listed and summarized by visit, 
and change from baseline for these endpoints will also be summarized at specific time points as 
reported in the SOA. 


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Appropriate regression models may be used to look at association between these endpoints and 
any covariates of clinical interests. 
Data from the substudy may be combined with biopsy data from other ongoing MAdCAM 
studies for analysis.
9.4. Pharmacokinetic Analysis
Blood samples will be collected prior to dosing for analysis of plasma trough concentrations of 
PF-00547659.  Serum concentration data obtained from all subjects in this study will be 
tabulated and plotted to assess average steady state concentrations following repeat SC dosing of 
PF-00547659.  As subjects enrolled in this study will have previously been followed in a 
separate protocol (the feeder study) where more PK sampling may have been performed, the 
trough PK data collected from this study may be combined with data from the previous study 
(the A7281009 study) into a single database. 
Presence of anti-PF-00574659 antibodies will be listed and summarized by time post dose for 
each dose. 
In subjects with a positive ADA, presence of neutralizing antibodies may be listed and 
summarized by time post dose for each dose.
9.5. Safety Analysis
Safety data may be reviewed and summarized on an ongoing basis as needed during the study 
since this is an open-label study.  A set of safety summary tables will be produced to evaluate 
potential risks associated with the safety and tolerability of administering the study medication. 
All clinical AEs, SAEs, on-treatment AEs, as well as discontinuations due to AEs will be 
summarized with frequency and percentage.  Continuous outcomes (eg, vitals, safety lab 
parameters, etc) will be summarized using n, mean, median, standard deviation etc.  Change 
from baseline on selected safety endpoints may be additionally summarized.  Subject listings 
may also be produced for these safety endpoints.
The safety endpoints will be listed and summarized in accordance with Shire Data Standards.  
Detailed methodologies of these analyses will be described in the SAP.
9.6. Interim Analysis
Two interim analyses (IAs) may be performed for this study when 50% of subjects from the 
Phase 2 study (A7281009) have been enrolled in this study (A7281010), and the last subject 
from the Phase 2 study (A7281009) has been enrolled in this study (A7281010).  The purpose of 
the IAs is to provide additional data on the durability of response, remission, and safety from 
A7281009 to facilitate the decision-making process of initiating future studies.  Summary 
statistics for safety, efficacy as well as subject demographics will be provided at IA.  Detailed 
analysis will be described in the SAP. 
Additional interim analyses may also be performed when it is deemed necessary to evaluate 
safety and efficacy during the trial.


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9.7. Data Monitoring Committee 
An external Data Monitoring Committee will be in place to review the safety of subjects on an 
ongoing basis and to adjudicate any subjects with unexplained neurological or cardiac findings.  
Membership of this committee shall include at least one neurologist with expertise in PML and 
one cardiologist with expertise in heart failure and/or myocarditis. Work-up of such suspected 
PML cases will include a neurology consultation as well as an MRI scan, and a lumbar puncture, 
if clinically indicated.  Additional procedures may be deemed necessary.  Given the lack of 
therapeutic options for subjects who have failed at least 1 conventional therapy, PF-00547659 
with its distinct mechanism of action and known safety profile appears to have a favorable 
Risk-Benefit profile.  The added precautions regarding PML are probably unnecessary but will 
serve to increase the confidence in PF-00547659 for future development.
Additional cardiac monitoring will be implemented in this study.  Serum samples for CPK (with 
reflex isoenzymes), troponin I and NT-proBNP will be drawn with the safety labs.  Elevation of 
troponin I >0.05 ng/mL or CPK with MB or should prompt a cardiology consult.  Any subject 
who experiences an initial on-study elevation of NTproBNP to >300 pg/mL shall have an 
echocardiogram and cardiology consult. All subjects who have had an echocardiogram, in 
whom the NTproBNP remains >124 pg/mL at the 144 week visit, shall have a repeat 
echocardiogram and cardiology consultation ordered no later than the following visit. All cases 
of on-study elevation of NTproBNP to >300 pg/mL, elevation in cardiac troponin I (cTnI) or 
CK/MB or new ECG changes will be reviewed by the DMC.
The DMC will be responsible for ongoing monitoring of safety of subjects in the study according 
to the Charter.  The recommendations made by the DMC to alter the conduct of the study or 
amend the protocol will be forwarded to Shire for final decision.  Shire will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of safety 
data that are not endpoints, to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Shire or its agent will conduct periodic monitoring visits to ensure that the 
protocol and GCPs are being followed.  The monitors may review source documents to confirm 
that the data recorded on CRFs is accurate.  The investigator and institution will allow Shire
monitors or its agents and appropriate regulatory authorities direct access to source documents to 
perform this verification.
The study site may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), and/or to quality assurance audits performed by Shire, or companies 
working with or on behalf of Shire, and/or to inspection by appropriate regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term case report form (CRF) should be understood to refer to either 
a paper form or an electronic data record or both, depending on the data collection method used 
in this study.
A CRF is required and should be completed for each included subject.  The completed original 
CRFs are the sole property of Shire and should not be made available in any form to third 
parties, except for authorized representatives of Shire or appropriate regulatory authorities, 
without written permission from Shire.
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring and available when required.  The CRFs must be signed by 
the investigator or by an authorized staff member to attest that the data contained on the CRFs is 
true. Any corrections to entries made in the CRFs, source documents must be dated, initialed 
and explained (if necessary) and should not obscure the original entry.
In most cases, the source documents are the hospital's or the physician's subject chart.  In these 
cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these cases, 
a document should be available at the investigator’s site as well as at Shire and clearly identify 
those data that will be recorded in the CRF, and for which the CRF will stand as the source 
document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Shire, the investigator agrees 
to keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, CRFs and hospital records), all original signed informed consent documents, copies 
of all CRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (eg, letters, meeting 
minutes, telephone calls reports).  The records should be retained by the investigator according to 
ICH, local regulations, or as specified in the Clinical Study Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Shire should be prospectively notified.  The study 
records must be transferred to a designee acceptable to Shire, such as another investigator, 
another institution, or to an independent third party arranged by Shire. Investigator records must 
be kept for a minimum of 15 years after completion or discontinuation of the study or for longer 
if required by applicable local regulations.
The investigator must obtain Shire's written permission before disposing of any records, even if 
retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Shire.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/IEC and Shire in writing immediately after the 
implementation.
12.2. Ethical Conduct of this Study
This study will be conducted in accordance with legal and regulatory requirements, as well as the 
general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), 
Guidelines for Good Clinical Practice (International Conference on Harmonization 1996), and 
the Declaration of Helsinki (World Medical Association 1996 and 2008).
In addition, this study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.
Subject names, address, birth date and other identifiable data will be replaced by anumerical 
code consisting of a numbering system provided by Shire in order to de-identify the trial subject.
In case of data transfer, Shire will maintain high standards of confidentiality and protection of 
subject personal data.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent document(s) used during the informed consent process must be reviewed 
by the sponsor, approved by the IRB/IEC, and available for inspection.
The investigator must ensure that each study subject, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of this study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each subject or the subject's legally acceptable representative before any 


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study-specific activity is performed. The investigator will retain the original of each subject's 
signed consent document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.  
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, Shire should be informed immediately.
In addition, the investigator will inform Shire immediately of any urgent safety measures taken 
by the investigator to protect the study subjects against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed this study as stated in the 
regulatory application (ie, Clinical Study Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by a 
Member State is not a reason for premature termination but is considered a normal conclusion to 
this study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of Shire.  In addition, Shire
retains the right to discontinue development of PF-00547659 at any time.
If a study is prematurely terminated or discontinued, Shire will promptly notify the investigator.  
After notification, the investigator must contact all participating subjects and the hospital 
pharmacy (if applicable) within 28 days.  As directed by Shire, all study materials must be 
collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
Publication of study results is discussed in the Clinical Study Agreement.


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15.1. Communication of Results by Shire
Shire fulfils its commitment to publicly disclose clinical trial results through posting the results 
of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials Database 
(EudracCT), and/or www.shire.com and other public registries in accordance with applicable 
local laws/regulations.
In all cases, study results are reported by Shire in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study or the country in which the study 
was conducted.
www.clinicaltrials.gov
Shire posts clinical trial US Basic Results on www.clinicaltrials.gov for Shire-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Shire
product regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary Completion Date is defined as the date that the final subject was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical study concluded according to the pre-specified protocol or was terminated.
EudraCT
Shire posts EU Basic Results on EudraCT for all Shire-sponsored interventional studies that are 
in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year of the 
primary completion date for studies in adult populations or within 6 months of the primary 
completion date for studies in pediatric populations.
www.shiretrials.com
Shire posts Public Disclosure Synopses (clinical study report synopses in which any data that 
could be used to identify individual patients has been removed) on www.shire.com for Shire-
sponsored interventional studies after primary publication or after 18 months of last subject last 
visit.
15.2. Publications by Investigators
Shire has no objection to publication by Investigator of any information collected or generated 
by Investigator, whether or not the results are favorable to the Investigational Drug. However, to 
ensure against inadvertent disclosure of Confidential Information or unprotected Inventions, 
Investigator will provide Shire an opportunity to review any proposed publication or other type 
of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Shire at 


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least 30 days before they are submitted for publication or otherwise disclosed. If any patent 
action is required to protect intellectual property rights, Investigator agrees to delay the 
disclosure for a period not to exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If this Study is part of a multi-centre study, the investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been submitted 
for publication within 12 months of completion or termination of this Study at all participating 
sites, Investigator is free to publish separately, subject to the other requirements of this Section.
For all publications relating to this Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between Shire
and the institution.  In this section entitled Publications by Investigators, the defined terms shall 
have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Steffen BJ, Breir G, Butcher EC, et al. ICAM-1, VCAM-1, and MAdCAM-1 Are Expressed 
on Choroid Plexus but Not Endothelium and Mediate Binding of Lymphocytes in Vitro. 
Amer J Path 1996;148:1819-1838.
2.
Available at http://www.fda.gov/DrugSafety/ucm288186.htm.Accessed 31 Jan 2013.
3.
Shyjan AM, Bertagnolli M, Kenney CJ, Briskin MJ. Human mucosal addressin cell 
adhesion molecule-1 (MAdCAM-1) demonstrates structural and functional similarities to 
the alpha 4 beta 7-integrin binding domains of murine MAdCAM-1, but extreme 
divergence of mucin-like sequences, J Immunol. 1996;156(8):2851-7.
4.
Major, EO. (2010).Progressive Multifocal Leukoencephalopathy in Subjects on 
Immunodulatory Therapies. Annual Review of Medicine, 6135-47. 
5.
Warneke C, Menge T, Hartung H-P et al. Natalizumab and Progressive Multifocal 
Leukoencephalopathy What are the causal factors and can it be avoided? Arch Neurol 2010; 
67:923-930.
6.
Stuve, O et al. (2006). Immune Surveillance in Multiple Sclerosis Subjects Treated with 
Natalizumab. Annuals of Neurology, 59 (5) 743-747.
7.
D’Haens et al., 2007; Walmsely et al, 1998.
8.
Higgins, et al., 2005; D’Haens et al., 2007.
9.
Rosti-Otajarvi E, Hamalainen P, Koivisto K, Hokkanen L. The reliability of the MSFC and 
its components. Acta Neurol Scand 2008: 117: 421–427.
10.
Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RHB. 
The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized 
controlled trial. J Neurol (2009) 256:1095–1102.
11.
Parmenter BA et al. (2007) Screening for cognitive impairment in multiple sclerosis using 
the Symbol Digit Modalities Test. Mult Scler 13: 52–57.
12.
Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as Induction and Maintenance 
Therapy for Ulcerative Colitis. New Engl J Med 2013;369:699-710.
13.
Clifford D, McAuliffe M, Stephens K, et al. Risk Assessment and Minimization for 
Progressive Multifocal Leukoencephalopathy (PML RAMP): A Program to Assess for 
Potential Early Signs and Symptoms of PML during Clinical Development of 
Vedolizumab. Am J Gastroenterol. 2013;108(Supplement 1):S502.


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Appendix 1. Mayo Scoring System for Assessment of Ulcerative Colitis Activity*
Stool frequency†:
0 = Normal no. of stools for this subject
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleeding‡:
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy:
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessment§:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
*
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  Data are from 
Schroeder et al.
†
Each subject serves as his or her own control to establish the degree of abnormality of the stool frequency.
‡
The daily bleeding score represents the most severe bleeding of the day.
§
The physician’s global assessment acknowledges the three other criteria, the subject’s daily recollection of 
abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the 
subject’s performance status.


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Appendix 2. Simple Clinical Colitis Activity Index (SCCAI)


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Appendix 3. Sample Subject Stool Diary
SUBJECT STOOL DIARY
What is your normal number of stools per day 
(when not having a flare)?
_______
QUESTIONS
ANSWERS
Date (dd/MMM/yyyy)
(eg,: 10 Aug 2010)
___ - ____ - _____
How many times did you need to go to the toilet 
to have a bowel movement? 
_______
Was there any blood present in your stool at any 
of these times?
[ ] Yes            [ ] No
How would you describe the blood in your 
stools? (Please cross one box only) 
[ ]  No blood seen
[ ]  Streaks of blood with stool less than half the time
[ ]  Obvious blood with stool most of the time
[ ]  Blood alone passes


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Appendix 4. Confrontational Visual Fields
To begin the test, you will be asked to cover one eye, fixing your gaze on the examiner's eyes.  
The examiner will then conduct finger movements, bringing his or her hands into your visual 
field from the sides.  Because your vision is divided into four quadrants in your brain, the 
examiner will hold up fingers in each quadrant.  You will say how many fingers you see without 
actually looking at them, thus testing your peripheral, or side, vision. 
Source: http://vision.about.com/od/eyeexamination1/f/Confrontation_Fields.htm


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Appendix 5. Timed Ambulation 25 Foot Test
Subjects will walk a predefined straight 25-foot course as quickly as possible.  The location of 
the course should remain constant.  It should be made clear to the subjects that they should walk 
as quickly as possible and that they will be timed.  Stopwatch timing will begin as soon as the 
subject indicates that they are ready to go and fully cross the start line.  Timing will stop once the 
subject fully steps over the finish line.
Reference: Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring 
Manual.  National Multiple Sclerosis Society, October 2001.


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Appendix 6. 9-Hole Peg Test Administration
Pegboard is centered in front of subject with pegs placed in the container next to the board on the 
same side as the hand being tested.  The dominant hand is tested first.  The following instructions 
are given to the subject as the examiner briefly demonstrates the test:
“Pick up the pegs one at a time, using your dominant hand only, and put them into the holes in 
any order until all of the holes are filled.  Then remove pegs one at a time, and return them to the 
container.  Stabilize the board with your other hand.  This is a practice test.  See how fast you 
can put all the pegs in and take them out again.  Are you ready? Go.”
After the subject completes the practice trial, the examiner says, “This will be the actual test.  
The Instructions are the same.  Work as quickly as you can.  Are you ready? Go!
[During the test] The examiner says, “faster.”
The stopwatch is started by the examiner as soon as the subject touches the first peg, and is 
stopped when the last peg hits the container.  The container is next placed on the opposite side of 
the pegboard and the other hand is tested.
Other considerations:
1. It is acceptable to switch the position of the box to accommodate the patient.
2. Record time for each trial in total seconds.  There are two trials per hand.
3. Maximum time of 5 minutes (300 seconds) to complete one trial.
4. For subjects with upper extremity tremors or truncal ataxias, stabilization of elbows on 
the table surface may be used.
The Rolyan 9-Hole Peg Test container cover (manufactured by Smith and Nephew, Inc), can be 
used to store pegs during administration of the test; however, a towel, felt cloth or the Dycem 
Mat under the container to keep dropped pegs from rolling away on the floor may be helpful.  
Please calculate the total score in seconds.  Test is administered using the dominant and 
nondominant hands.
Reference: Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring 
Manual.  National Multiple Sclerosis Society, October 2001.


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Appendix 7. Symbol Digit Modality Test
Administering the Written Version of the SDMT
This version of the test may be either group or individually administered.  The test form is 
handed to the examinee(s) and the following instructions are read aloud by the examiner 
(examiner reads only the boldface words):

Please look at these boxes at the top of the page.  You can see that each box in the upper 
row has a little mark in it.  Now look at the boxes under the marks has a number.  Each of 
the marks in the top row is different, and under each mark in the bottom row is a different 
number.

Now look at the next line of boxes (examiner points to line of boxes) just under the top 
two rows.  Notice that the boxes on the top have marks, but the boxes underneath are 
empty.  You are to fill each empty box with the number that should go there according to 
the way they are paired in the key at the top of the page.  For example, if you look at the 
first mark, and then look up at the key, you will see that the number 1 goes in the first 
empty box.  So write the number 1 in the first box.  Now, what number should you put in 
the second box? (Number 5) That’s right.  So write the number 5 in the second box.  
What number goes in the third box? (Number 2) Two, right.  That is the idea.  You are to 
fill each of the empty boxes with the numbers that should go in them according to the 
key.  Now for practice, fill in the rest of the boxes until you come to the double line.  
When you come to the double line, stop.
The examiner should check to see that each examinee understands the task.  Any errors made in 
the first 10 practice responses should be immediately pointed out by the examiner and corrected 
by the examinee.  If an examinee has not understood the nature of the task, the instructions are 
repeated with further examples until the nature of the test is clearly understood.  The examiner 
then continues with the following instructions:

Now when I say “Go!” write in the numbers just like you have been doing as fast as you 
can until I say “Stop!”  When you come to the end of the first line, go quickly to the next 
line without stopping, and so on.  If you make a mistake, do not erase, just write the 
correct answer over your mistake.  I repeat, DO NOT ERASE as you will waste time.  
Just write the correct answer over your mistake.  Do not skip any boxes and work as 
quickly as you can.  Ready? Go!
Exactly 90 seconds from starting, the examiner says:

Stop!


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Reference: Symbol Digit Modalities Test Manual (Aaron Smith, Ph.D. University of Michigan). 
Western Psychological Services, March 2010.


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Adult Norms for Mean Written SDMT Scores by Age Group and Level of Education1
Age Range
Deviation Unitsa
18-24
25-34
35-44
45-54
55-64
65 or more
12 Years or Less of Educationb
-3.0 SD
29
29
27
19
19
6
-2.5 SD
34
33
31
23
23
11
-2.0 SD
38
37
35
28
27
15
-1.5 SD
42
41
39
33
31
20
-1.0 SD
46
45
43
38
35
24
-0.5 SD
50
49
47
42
39
29
0.0 SD
54
53
52
47
43
33
+0.5 SD
59
57
56
52
47
38
+1.0 SD
63
61
60
57
51
42
+1.5 SD
67
65
64
62
55
47
+2.0 SD
71
69
68
66
59
51
+2.5 SD
75
73
72
71
63
56
+3.0 SD
79
77
76
76
67
60
Age Range
Deviation Unitsa
18-24
25-34
35-44
45-54
55-64
65 or more
13 Years or More of Educationc
-3.0 SD
31
30
21
27
23
10
-2.5 SD
37
35
26
31
27
15
-2.0 SD
42
40
32
35
31
21
-1.5 SD
47
44
37
40
35
27
-1.0 SD
52
49
43
44
39
32
-0.5 SD
57
53
49
48
43
38
0.0 SD
62
58
54
52
48
44
+0.5 SD
67
62
60
57
52
49
+1.0 SD
72
67
65
61
56
55
+1.5 SD
77
71
71
65
60
60
+2.0 SD
82
76
77
69
64
66
+2.5 SD
87
80
82
73
68
72
+3.0 SD
92
85
88
78
73
77
a. SD = standard deviation from the mean
b. n = 477
c. n = 830
                                                
1 Smith A. Symbol Digit Modalities Test Manual. Western Psychological Services, Los Angeles. 1982.


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Appendix 8. MSNQ - Patient

SAP_001.pdf: 
Protocol A7281010 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
A7281010 
Protocol Title: 
 
A 
MULTICENTER 
OPEN-LABEL 
EXTENSION 
STUDY TO ASSESS LONG-TERM SAFETY OF PF-
00547659 IN SUBJECTS WITH ULCERATIVE 
COLITIS 
(TURANDOT II) 
 
Drug: 
SHP647 (MAdCAM) (previously PF-00547659) 
Sponsor:  
Shire Human Genetic Therapies Inc. 
300 Shire Way  
Lexington, MA 02421 USA 
Version No. and Date 
Version 3.1, 02 February 2018 
 
 
Version 
No: 
Document History 
Description of Update 
Author(s) 
Effective 
Date 
3.0 
Update statistical analysis plan received from Pfizer to 
Shire standards.   
 
22 September 
2017 
3.1 
Changed the exposure summaries to include data only 
from 1010 and added by dose summaries. 
Added 1009 medications as prior medications 
Updated PCI criteria for weight 
Removed 
Changes 
from 
baseline 
analysis 
of 
Geometric mean and added 90% CI for percent 
change from baseline geometric mean analysis 
Added clarification on imputation of missing start 
dates  
Addition of new outputs and removal of redundant 
outputs 
Minor editorial updates throughout 
 
02 
February 
2018 
 
PPD
PPD


Protocol A7281010 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF TABLES ...................................................................................................................... 5 
ABBREVIATIONS .................................................................................................................... 5 
1. INTRODUCTION .................................................................................................................. 8 
2. STUDY DESIGN ................................................................................................................... 9 
2.1. General Study Design .......................................................................................................... 9 
2.2. Randomization ..................................................................................................................... 9 
2.3. Blinding ............................................................................................................................... 9 
2.4. Schedule of Assessments ..................................................................................................... 9 
2.5. Determination of Sample Size ........................................................................................... 18 
2.6. Multiplicity Adjustments for Type I Error Control ........................................................... 18 
3. OBJECTIVES ....................................................................................................................... 19 
3.1. Primary Objective .............................................................................................................. 19 
3.2. Secondary Objectives ........................................................................................................ 19 
3.3. Exploratory Objectives ...................................................................................................... 19 
4. SUBJECT POPULATION SETS ......................................................................................... 20 
4.1. Open Label Treatment Period 1 (Week 0-72) ................................................................... 20 
4.1.1. Enrolled Subjects ..................................................................................................... 20 
4.1.2. Safety Analysis Set .................................................................................................. 20 
4.1.3. Pharmacokinetic (PK) Set ........................................................................................ 20 
4.1.4. Pharmacodynamic (PD) Set ..................................................................................... 20 
5. SUBJECT DISPOSITION .................................................................................................... 21 
6. PROTOCOL DEVIATIONS ................................................................................................ 22 
7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................... 23 
8. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ..................................... 24 
8.1. Exposure to Investigational Product .................................................................................. 24 
8.2. Measurement of Treatment Compliance ........................................................................... 24 
9. PRIOR AND CONCOMITANT MEDICATION ................................................................ 25 
10. EFFICACY ANALYSES ................................................................................................... 26 


Protocol A7281010 
 
 
 
10.1. Primary Efficacy Endpoint(s) and Analysis .................................................................... 26 
10.2. Secondary Efficacy Endpoint(s) and Analysis ................................................................ 26 
10.3. Exploratory Efficacy Endpoint(s) and Analyses ............................................................. 26 
11. SAFETY ANALYSES ....................................................................................................... 29 
11.1. Adverse Events ................................................................................................................ 29 
11.2. Clinical Laboratory Variables.......................................................................................... 30 
11.3. Vital Signs ....................................................................................................................... 34 
11.4. Electrocardiogram (ECG) and Echocardiogram (ECHO) ............................................... 35 
11.5. Immunogenicity ............................................................................................................... 36 
11.6. Physical Examination ...................................................................................................... 36 
11.7. Enteric Pathogen .............................................................................................................. 36 
11.8. Other Safety Variables ..................................................................................................... 36 
11.8.1. Neurological Assessments ..................................................................................... 36 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 38 
12.1. Pharmacokinetics Population and Pharmacodynamic Population, .................................. 38 
12.2. Pharmacokinetic Methods ............................................................................................... 38 
12.2.1. Concentration Data ................................................................................................ 38 
12.2.2. Handling BLQ Values ............................................................................................ 38 
12.2.3. Pharmacokinetic Parameters .................................................................................. 38 
12.3. Statistical Analysis of Pharmacokinetic Data .................................................................. 39 
12.4. Pharmacodynamic Methods............................................................................................. 39 
12.5. Statistical Analysis of Pharmacodynamic Data ............................................................... 39 
13. OTHER ANALYSES ......................................................................................................... 40 
14. INTERIM ANALYSIS ....................................................................................................... 41 
14.1. Interim Analyses .............................................................................................................. 41 
14.2. Data Monitoring Committee ............................................................................................ 41 
15. COMPUTER METHODS .................................................................................................. 42 
16. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 43 
17. DATA HANDLING CONVENTIONS .............................................................................. 44 
17.1. General Data Reporting Conventions .............................................................................. 44 
17.2. Derived Efficacy Endpoints ............................................................................................. 44 
17.2.1. Imputation Method ................................................................................................. 44 
17.2.2. Total Mayo Score ................................................................................................... 44 
17.2.3. Partial Mayo Score ................................................................................................. 44 


Protocol A7281010 
 
 
 
17.2.4. Simple Clinical Colitis Activity Index ................................................................... 44 
17.3. Repeated or Unscheduled Assessments of Safety Parameters ........................................ 45 
17.4. Missing Date of Investigational Product ......................................................................... 45 
17.5. Missing Date Information for Prior or Concomitant Medications .................................. 45 
17.5.1. Incomplete Start Date ............................................................................................. 45 
17.5.2. Incomplete Stop Date ............................................................................................. 46 
17.6. Missing Date Information for Adverse Events ................................................................ 47 
17.6.1. Incomplete Start Date ............................................................................................. 47 
17.6.2. Incomplete Stop Date ............................................................................................. 47 
17.7. Missing Severity Assessment for Adverse Events .......................................................... 47 
17.8. Missing Relationship to Investigation Product for Adverse Events ................................ 47 
17.9. Character Values of Clinical Laboratory Variables ......................................................... 47 
18. REFERENCES ................................................................................................................... 48 
19. APPENDICES .................................................................................................................... 49 
19.1. Data Derivation Details ................................................................................................... 49 
19.1.1. Definitions and Use of Visit Windows in Reporting ............................................. 49 
19.1.2. Mayo Scoring System for Assessment of Ulcerative Colitis Activity ................... 51 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .......................... 53 


Protocol A7281010 
 
 
 
LIST OF TABLES 
Table 1a:  Schedule of Activities: Open Label Treatment Period 1 ....................................... 10 
Table 1b:  Schedule of Activities: Open Label Treatment Period 2 and Follow-Up 
Period ..................................................................................................................... 15 
Table 2:  
Total Mayo Score................................................................................................... 27 
Table 3:  
Partial Mayo Score................................................................................................. 27 
Table 4:  
Simple Clinical Colitis Activity Index................................................................... 28 
Table 5:  
Criteria for Potentially Clinically Important Laboratory Tests ............................. 31 
Table 6:  
Criteria for Potentially Clinically Significant Vital Signs ..................................... 35 
Table 7:  
Criteria for Potentially Clinically Important ECG Values..................................... 36 


Protocol A7281010 
 
 
 
ABBREVIATIONS 
 
9-HPT 
9-Hole Peg Test 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALQ 
Above the limit of quantification 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic class 
BLQ 
Below the limit of quantification 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
BP 
Blood Pressure 
CI 
Confidence interval 
CPK 
Creatinine phosphokinase 
CRP 
C-reactive protein 
CTn1 
Cardiac troponin I 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
FAS 
Full Analysis Set 
FoTA 
Final-on-treatment assessment 
hsCRP 
High-sensitivity C-reactive protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSNQ 
Multiple Sclerosis Neuropsychological Questionnaire 
Nabs 
Neutralizing antibodies 
NT-proBNP 
N-terminal B-type Natriuretic Peptide 
PCI 
Potentially clinically important 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred term 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 


Protocol A7281010 
 
 
 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SCCAI 
Simple clinical colitis activity index 
SD 
Standard deviation 
SDMT 
Symbol digit modality test 
SOC 
System organ class 
TEAE   
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
WHO 
World Health Organization 


Protocol A7281010 
 
 
 
1. Introduction 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety, efficacy, tolerability, pharmacokinetic/pharmacodynamic data as 
described in the final study protocol version dated 14 November 2016 incorporating most 
recent amendment 5. Specifications for tables, figures, and listings are contained in a separate 
document. Statistical analysis plans for pharmacokinetic/pharmacodynamic data are prepared 
separately and included as appendices to the SAP, as appropriate.   
 


Protocol A7281010 
 
 
 
2. STUDY DESIGN  
2.1. General Study Design 
This is a multi-center Phase 2, open-label, safety extension study for the A7281009 study, 
which evaluated SHP647 in subjects with moderate to severe ulcerative colitis. Subjects 
eligible for this study will have completed the 12-week double-blind induction period in study 
A7281009 and must have discontinued immunosuppressant therapy. They will then enter into 
the Active Treatment period which consists of two consecutive 18 month periods. The first 
active period is called Open Label Treatment Period 1 (Weeks 0-72). All subjects will be 
randomly assigned to receive either 75 mg or 225 mg subcutaneously every 4 weeks without 
unblinding treatment assignment from the A7281009 study, and without regard to responder 
status in that study. 
After completion of Open Label Treatment Period 1, all subjects will be permitted to continue 
in Open Label Treatment Period 2 (Weeks 76-144) and will receive the 75 mg dose every four 
weeks for a further 18 months. 
After the active treatment period, the subjects will enter a 6 month follow up period including 
2 visits 3 months apart.  At the last onsite visit (Week 168), subjects will undergo an End of 
Study visit. 
Eligible subjects will be asked if they would like to continue participation in an optional 
endoscopic substudy that will characterize the effect of SHP647 on mucosal healing and 
tissue biology. Participation in this part of the study will not affect participation in the main 
study. Approximately 40 subjects are needed for meaningful data. Data may be combined 
with the data from the other MAdCAM IBD studies. Details of the substudy analysis will not 
be included in this SAP and will be captured in an independent SAP. 
2.2. Randomization 
This is an open-label study and the investigator’s knowledge of the treatment should not 
influence the decision to enroll a particular subject or affect the order in which subjects are 
enrolled. All subjects will be assigned either 75 mg or 225 mg of the investigational product 
upon study entry for the first 18 month treatment period. The allocation ratio to treatment will 
be 1:1. Subsequently all subjects will be assigned to the 75 mg dose for an additional 18 
month treatment period. 
2.3. Blinding 
This is an open-label study so blinding is not applicable. 
2.4. Schedule of Assessments  
 
 


Protocol A7281010 
 
Table 1a:  Schedule of Activities: Open Label Treatment Period 1 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures (Section 6 
of protocol) and Assessments (Section 7 of protocol) for detailed information on each procedure and assessment required for 
compliance with the protocol. 
Protocol Activity 
Open-label Treatment Period 1 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 19 
Study Week 
0/Day 1 
Baselinea 
 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 72 
Visit Window 
7 Days 
7 Days based on Baseline Visit 
Enrollment Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine 
Responder/Non-Responder 
Statusr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Open-Label Treatment 
Assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Procedures 
Vital Signs 
Blood pressure, pulse, 
respirations  
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Temperature  
[°C-or °F] 
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Weight (lbs or kg) without 
shoes 
a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Height (in or cm) without 
shoes 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam  
b 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Targeted Physical Exam  
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
ECG (12-lead) 
b 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 


Protocol A7281010 
 
Protocol Activity 
Open-label Treatment Period 1 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 19 
Study Week 
0/Day 1 
Baselinea 
 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 72 
Visit Window 
7 Days 
7 Days based on Baseline Visit 
Laboratory Assessments 
     Clinical Laboratory Evaluations  
Blood chemistry (to include 
cTn1 and NTproBNP), 
hematology,  
urinalysise 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Urine Pregnancy testf 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Flexible Sigmoidoscopy or 
Colonoscopy (if 
recommended)g 
b 
 
 
 
X 
 
 
 
 
 
X 
----------------------------------------- 
X 
Optional Endoscopic tissue 
biopsyh 
b 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Pharmacodynamics 
hs CRP 
b 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
Soluble MAdCAM 
b 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool sample for fecal 
calprotectin 
b 
X 
X 
X 
X 
X 
X  
 
X 
 
 
 
 
 
 
 
 
 
X 
Stool sample for enteric 
pathogensi 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Blood gene expression 
profiling (mRNA) and 
proteins 
b 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetics 
PK blood sample collectionj 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
ADA and Nab 
b 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Disease Activity Analysis 
Stool Diary datas 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 


Protocol A7281010 
 
Protocol Activity 
Open-label Treatment Period 1 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 19 
Study Week 
0/Day 1 
Baselinea 
 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
60 
64 
68 72 
Visit Window 
7 Days 
7 Days based on Baseline Visit 
Total Mayo Scoreu  
b 
 
 
 
X 
 
 
 
 
 
X 
-------------------------------------- 
X 
SCCAI 
b 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Partial Mayo Scoreu 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Trial Treatment Procedures 
Study Drug 
Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Confrontational Visual 
Fieldsk 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Timed 25-foot walk 
(T25-FW)l 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
9-hole peg test (9-HPT)m 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Symbol Digit Modality Test 
(SDMT)n 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
MSNQo 
b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
Dispense stool specimen 
container and bagt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
JC virus DNA sample takenp 
b 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
JC virus antibody testing 
b 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
AE Assessment 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant treatments 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Abbreviations: 9-HPT=nine hole peg test; ADA=anti-drug antibodies; AE=adverse event; cTnI=cardiac troponin I; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; eCRF=electronic case report form; EOS=end of study; GDH=glutamate dehydrogenase; 
hsCRP=high-sensitivity C-reactive protein; ICD=informed consent document; IS=immunosuppressants; MAdCAM=mucosal addressin cell adhesion molecule; 


Protocol A7281010 
 
MSFC=Multiple Sclerosis Functional Composite; MSNQ=Multiple Sclerosis Neuropsychological Questionnaire; Nab=neutralizing antibody; NT-
proBNP=N-terminal B-type Natriuretic Peptide; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; SCCAI= Simple Clinical Colitis 
Activity Index; SDMT=Symbol Digit Modality Test; T25FW=timed 25-foot walk; UC=Ulcerative Colitis 
a. 
Baseline (Day 1, Visit 1) procedures will correspond with the procedures conducted at the Week 12 (Day 84) or final visit in study A7281009.  Data 
transferred from study A7281009 and recorded on the appropriate eCRF will be captured after the ICD is signed.  The ICD for this study must be signed and 
dated before protocol-related procedures are performed.  All baseline assessments and procedures must be completed prior to administration of the open 
label investigational product. 
b. Responder/nonresponder analysis will be determined at the Week 12 (Day 84) or final visit of study A7281009.  This determination will be made based on 
the Total Mayo score. 
c. 
Vital signs (single sitting blood pressure [BP], pulse rate, and respirations [measured after 5 minute rest], temperature (oral or tympanic [ºC or ºF]), and 
weight (lbs or kg; measured without shoes) do not need to be repeated; however, the information must be entered into the eCRF.  Source documentation 
supporting this data previously obtained at the Week 12 (Day 84) or final visit of the study A7281009 must be available in the subject’s record for this study.  
d. Baseline evaluations/assessments that were previously obtained at the Week 12 (Day 84) or final visit of study A7281009 do not need to be repeated, nor any 
information entered into the eCRF.  Source documentation supporting this data previously obtained at the Week 12 (Day 84) or final visit of the study 
A7281009 must be available in the subject’s record for this study.  Adverse events (AEs) and concomitant treatment(s) that are continuing from study 
A7281009 will be recorded on the source documents and the respective AE and CM eCRFs at the baseline visit.  Note:  No blood or urine samples will be 
collected for the baseline visit of this study unless there is a need to repeat a safety laboratory test or tests. 
e. 
To include NT-proBNP and troponin I levels for additional cardiac monitoring. ECHO and cardiology consult will be performed locally only under specified 
conditions.  These conditions are: 
 
At baseline visit: if NTproBNP value is >300 pg/mL if no prior ECHO.  
 
At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is >300 pg/mL. 
 
At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the NTproBNP is >124 pg/mL or if there has been no prior 
ECHO, and the NTproBNP is >300 pg/mL. 
 
At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300 pg/mL. 
f. 
For women of childbearing potential only.  A negative urine pregnancy test result is required beginning at baseline before investigational product 
administration, and at all subsequent visits during the open-label treatment period, the follow-up visit, and at early withdrawal (if necessary). 
g. Flexible sigmoidoscopy or Colonoscopy if recommended.  Colonoscopy will be performed at Visits 11-19 for subjects undergoing routine cancer 
surveillance. 
h. Eligible subjects will be asked if they would like to continue participation in an optional endoscopic substudy that will characterize the effect of 
PF-00547659 on mucosal healing and tissue biology.  Participation in this part of the study will not affect participation in the main study (see Section 7.4.2 
of protocol). 
i. 
The detection of C. difficile by toxigenic stool culture [stool culture followed by detection of toxin] is considered the gold standard for the diagnosis of the 
colonization or infection with pathogenic C. difficile.  Comparable sensitivity may be achieved by direct testing of stool via point of use rapid membrane 
enzyme immunoassay card for both C. difficile toxin A and B and glutamate dehydrogenase (GDH) antigen on a card.  Use of the card for point of care 
screening is encouraged where permitted by local regulation.  Molecular techniques such as PCR for detection of toxin RNA are also acceptable alternatives. 
Refer to the lab manual for further guidance and instruction for C. difficile testing.  This test will be mandatory for subjects who experience a disease flare 
and/or dose de-escalate. 
j. 
PK samples will be collected before dosing at visits where study drug will be administered. 
k. As part of the complete physical examination and targeted physical examination.  A confrontation visual field test will be performed to measure overall field 
of vision as a basic screening tool. 


Protocol A7281010 
 
l. 
The timed 25-foot time walk (T25-FW) test is part of the neurologic assessment and measures quantitative mobility and leg function. 
m. The nine-hole peg test (9-HPT) is part of the neurologic assessment and measures upper extremity function. 
n. The Symbol Digit Modality Test (SDMT) is part of the neurologic assessment and assesses cognitive functioning over time and in response to treatment.  To 
help score the test, subjects must enter level of education completed onto the Social Status CRF page. 
o. The patient-MSNQ (Multiple Sclerosis Neuropsychological Questionnaire) is part of the neurologic assessment and assesses cognitive functioning over time. 
p. Samples may be stored and batched for analysis.  At a minimum, baseline and end-of-study sample will be tested. 
q. Responder analysis will be determined at Week 12 of study A7281009.  This determination will be made based on the Total Mayo Score. 
r. 
The subject stool diary to collect stool frequency and rectal bleeding will be collected via paper diary.  Subjects will be required to enter diary data for 3 days 
immediately preceding the flexible sigmoidoscopy visit prior to Week 16.  Should any subject be required to perform bowel preparation prior to the flexible 
sigmoidoscopy at Week 16, the subject should be instructed to complete the diary 1 day prior to initiating bowel preparation.  Diaries to be completed by the 
subject will be distributed during the baseline visit [Week 12 of study A7281009 (for collection at the flexible sigmoidoscopy visit prior to Week 16)]. 
s. 
At Visits 7 and 9-17, dispense stool specimen container and bag to subjects who have had a disease flare only. 
t. 
A Total Mayo Score will be calculated for subjects undergoing routine cancer surveillance at Visits 11-19.  A Partial Mayo Score will be calculated for all 
other subjects at these visits. 
u. Does not include endoscopic biopsies performed at selected centers (see Section 7.4.2 of protocol).  However, mucosal healing may be assessed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol A7281010 
 
Table 2b:  Schedule of Activities: Open Label Treatment Period 2 and Follow-Up Period 
Protocol Activity
Open Label Treatment Period 2 
Follow up 
Early 
withdr
awal 
 
EOS 
Study Visit
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
Study Week
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
156 
168 
Visit Window
7 Days based on Baseline Visit 
Enrollment Procedures 
Amendment Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Open-Label 75 mg Treatment 
Assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Procedures 
Vital Signs 
Blood pressure, pulse,   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight (lbs or kg) without 
shoes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead)0 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Laboratory Assessments 
     Clinical Laboratory Evaluations  
Blood chemistry (to include 
troponin I and NTproBNP), 
hematology,  
urinalysisb 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Urine Pregnancy testc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Pharmacodynamics 
Stool sample for enteric 
pathogensd 
     X-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X  
Pharmacokinetics 
PK blood sample collectione 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ADA and Nab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


Protocol A7281010 
 
Protocol Activity
Open Label Treatment Period 2 
Follow up 
Early 
withdr
awal 
 
EOS 
Study Visit
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
Study Week
76 
80 
84 
88 
92 
96 
100 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
156 
168 
Visit Window
7 Days based on Baseline Visit 
Disease Activity Analysis 
Stool Diary data 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
SCCAI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Partial Mayo Score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug 
Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Confrontational Visual Fields 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Timed 25-foot walk (T25-FW)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
9-hole peg test (9-HPT)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symbol Digit Modality Test 
(SDMT)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MSNQi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
JC virus DNA sample taken 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
JC virus antibody testing 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
AE Assessment 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant treatments 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
End of Study CRFj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: 9-HPT=nine hole peg test; ADA=anti-drug antibodies; AE=adverse event; cTnI=cardiac troponin I; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; ECHO=echocardiogram; eCRF=electronic case report form; EOS=end of study; GDH=glutamate dehydrogenase; 
hsCRP=high-sensitivity C-reactive protein; ICD=informed consent document; IS=immunosuppressants; MAdCAM=mucosal addressin cell adhesion molecule; 
MSFC=Multiple Sclerosis Functional Composite; MSNQ=Multiple Sclerosis Neuropsychological Questionnaire; Nab=neutralizing antibody; NT-


Protocol A7281010 
 
proBNP=N-terminal B-type Natriuretic Peptide; PCR=polymerase chain reaction; PD=pharmacodynamic; PK=pharmacokinetic; SCCAI= Simple Clinical Colitis 
Activity Index; SDMT=Symbol Digit Modality Test; T25FW=timed 25-foot walk; UC=Ulcerative Colitis 
a. 
A single ECG will be collected starting at Week 84, every 12 weeks and at EOS (Week 168). 
b. To include NT-proBNP and cTn1 levels for additional cardiac monitoring. ECHO and cardiology consult will be performed locally only under specified 
conditions.  These conditions are: 
 
At baseline visit: if NTproBNP value is >300 pg/mL if no prior ECHO.  
 
At the on-treatment visits up to Week 144: If no prior ECHO, the first time NTproBNP is >300 pg/mL. 
 
At the Week 144 or early withdrawal visit: If there has been any prior ECHO AND the NTproBNP is >124 pg/mL or if there has been no prior ECHO, 
and the NTproBNP is >300 pg/mL. 
 
At the post-week 144 visits: if there has been no prior ECHO and NTproBNP is >300 pg/mL. 
c. 
For women of childbearing potential only.  A negative urine pregnancy test result is required beginning at baseline before investigational product 
administration, and at all subsequent visits during the open-label treatment period, the follow-up visit, and at early withdrawal (if necessary). 
d. A stool sample for enteric pathogens will only be collected if subject is symptomatic.  
e. 
A serum sample for PK analysis will be collected only at the first Follow-up visit (Week 156) and/or Early withdrawal visit. 
f. 
The timed 25-foot time walk (T25-FW) test is part of the neurologic assessment and measures quantitative mobility and leg function. 
g. The nine-hole peg test (9-HPT) is part of the neurologic assessment and measures upper extremity function. 
h. The Symbol Digit Modality Test (SDMT) is part of the neurologic assessment and assesses cognitive functioning over time and in response to treatment.  To 
help score the test, subjects must enter level of education completed onto the Social Status CRF page. 
i. 
The patient-MSNQ (Multiple Sclerosis Neuropsychological Questionnaire) is part of the neurologic assessment and assesses cognitive functioning over time. 
j. 
Complete End of Study CRF when subjects withdraw from the study at Early withdrawal visit or when the subject completes participation in the study 
(Week 168).   
 


Protocol A7281010 
 
2.5. Determination of Sample Size 
Statistical hypothesis is not applicable to this study and there are no statistical decision rules 
for this study. 
All eligible subjects, based on inclusion/exclusion criteria, from the A7281009 study may be 
enrolled. It is estimated that approximately 90% of the subjects (about 270 subjects) from 
study A7281009 are likely to enroll into this open label extension study A7281010. The 
sample size is chosen based on clinical outcome of study A7281009 rather than statistical 
consideration. 
 
2.6. Multiplicity Adjustments for Type I Error Control 
Adjusting for multiplicity is not applicable, there are no statistical hypotheses being tested.  
 
 
 
 
 
 
 
 
 
 
 
 


Protocol A7281010 
 
3. OBJECTIVES 
3.1. Primary Objective 
 The primary objective of this study is to monitor the safety and tolerability of SHP647 
during long-term treatment. 
3.2. Secondary Objectives 
 The secondary objective is to assess pharmacokinetics and immunogenicity of 
SHP647. 
3.3. Exploratory Objectives 
 Exploratory objectives include an assessment of the durability of response with long 
term treatment with SHP647 based upon Clinical Remission and Clinical Response 
based upon the Mayo Score performed at Week 16 in Clinical Responders from study 
A7281009. 
 
 Explore relationships between PK of SHP647, PD and clinical endpoints. 


Protocol A7281010 
 
4. SUBJECT POPULATION SETS 
4.1. Open Label Treatment Period 1 (Week 0-72) 
4.1.1. Enrolled Subjects  
 Enrolled subjects consists of all subjects for whom some study procedures have begun. 
4.1.2. Safety Analysis Set 
The Safety Set will consist of all enrolled subjects who have taken at least 1 dose of 
investigational product. 
4.1.3. Pharmacokinetic (PK) Set 
The PK population is defined as all subjects who received at least 1 dose of investigational 
product and for whom at least 1 postdose PK sample was collected.  
4.1.4. Pharmacodynamic (PD) Set 
The PD population is defined as all subjects who received at least 1 dose of investigational 
product and for whom at least 1 postdose PD sample was collected  
 


Protocol A7281010 
 
5. SUBJECT DISPOSITION 
The number of subjects included in each subject set will be summarized by the following 
treatment groups:  
 SH647 75mg no escalation - this comprises all data for patients who receive 75mg 
throughout the Open Label Treatment Period 1.  
 SHP647 75->225 mg – this comprises all data for patients who (prior to protocol 
amendment 3) up-titrated from 75 mg to 225 mg in Open Label Treatment Period 1.  
 SHP647 75 mg overall – this comprises all patients who were randomized to 75 mg in 
Open Label Treatment Period 1. 
 SHP647 225mg – this comprises all patients who were randomized to 225 mg in Open 
Label Treatment Period 1. 
 SHP647 all doses – this comprises all patients. 
A subject disposition table will be provided.  The subject disposition table will include the 
number and percentage of subjects included in each subject set. It will also include number 
and percentage of subjects enrolled, randomized, treated, entering Open Label Treatment 
Period 1,Open Label Treatment Period 2, follow up period, discontinuing from the study, 
discontinuing from Open Label Treatment Period 1,Open Label Treatment Period 2, follow 
up period  and discontinuing from the treatment. A detailed summary of the primary reasons 
for discontinuation from the study and discontinuation from treatment will be presented by 
treatment group. The percentages will use the number of subjects in the safety analysis set as 
the denominator and will be presented by the treatment groups defined above.  The subject 
disposition table will be based on the enrolled set. 
All subjects who prematurely discontinued during the study will be listed. 
The number of subjects enrolled, randomized and completed will be tabulated by site and 
country.  In addition, the duration of enrollment, in days, will be summarized for each site, 
country, and overall.  Duration of enrollment will be calculated as (last date of contact for any 
subject at that site - the first date of screening or enrollment for any subject at that site + 1). 


Protocol A7281010 
 
6. PROTOCOL DEVIATIONS 
Different protocol deviations may have a different impact on the analyses.  A full list of 
protocol deviations will be compiled and reviewed by the Clinician and the Statistician to 
identify key and non-key deviations prior to database release.   
Protocol deviations will be listed. In addition, a listing of key deviations will be provided. 
 


Protocol A7281010 
 
7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The demographic table will include the summary of age, sex, ethnicity, race, weight, height, 
body mass index, anti-TNF use (naïve or experienced), smoking history classification and 
time since diagnosis of Ulcerative Colitis. All information will come from the A7281010 
eCRF page with the exception of anti-TNF use and smoking history which will be taken from 
the A7281009 demographic page, and time since diagnosis of Ulcerative Colitis which will be 
re-derived as defined below. The demographic table will be presented by the treatment groups 
defined in Section 5 and also further presented by clinical response status from A7281009.  
Time since diagnosis of Ulcerative Colitis = ([Date of Visit 1 {in 1010} - Date of Diagnosis 
{from 1009}]+1)/365.25. 
The baseline characteristics table will include the summary of clinical response, remission and 
mucosal healing status collected at A7281009 week 12.  This table will be presented by the 
treatment groups defined in Section 5 and will be based on the safety analysis set. 
Categorical variables will be summarized by the number of subjects in each category and the 
percentage of subjects out of the total in the respective analysis set; continuous variables will 
be described using summary statistics (n, mean, standard deviation, minimum, median, and 
maximum). 
Height and weight at baseline will be used to calculate BMI using the formula below: 
 
 
 
BMI =
 
A listing will be created to show all the demographics and baseline characteristics for each 
subject in the Safety population. 
Medical history, collected at the baseline visit, will be presented by system order class and 
preferred term using MedDRA version 19.1 and will be listed. In addition, the medical history 
collected at the screening visit of A7281009 will be presented based on the A7281010 safety 
analysis set. The data from A7281009 were coded to MedDRA version 18.1 and will be re-
coded for this summary. Drug allergies will also be listed.  
 
 
2
[m])
 
(height
[kg]
 
weight


Protocol A7281010 
 
8. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1. Exposure to Investigational Product  
The Active Treatment Period will be comprised of Open Label Treatment Period 1 and Open 
Label Treatment Period 2. During the Open Label Treatment Period 1, 75 mg or 225 mg 
subcutaneous (SC), will be administered at baseline and then every 4 weeks through Week 72 
(Visit 19). Once the Open Label Treatment Period 1 has been completed, subjects may 
continue for Open Label Treatment Period 2 and will be assigned to the 75 mg dose. 
 Exposure to the investigational product for the safety analysis set will be summarized 
in terms of treatment duration, which is calculated as the number of days from the 
date of first dose of investigational product taken in A7281010 to the date of the last 
dose investigational product taken in A7281010, inclusively. In addition, the number 
of injections of investigational product will be summarized both continuously and 
categorically (6, 12, 18, 24, 30, 36 injections received). Number of injections received 
for 75mg and 225 mg doses respectively will be presented as well. Descriptive 
statistics will be presented by treatment group defined in Section 5. 
8.2. Measurement of Treatment Compliance 
Investigational product dosing compliance for a specified period is defined as the total 
number of injections actually administered during that period divided by the number of 
injections planned to be administered during the same period multiplied by 100. Compliance 
will be summarized by treatment group/Open Label Treatment Period. 
Compliance during the treatment period 1 and 2 and overall will be calculated for each subject 
using the formula:  
Compliance = (# injections actually administrated / # injections planned) * 100 
The definition of number of injections planned will be the injection schedule following the 
protocol (baseline to week 72, every 4 weeks for Open Label Treatment Period 1, week 76 to 
week 144, every 4 weeks for Open Label Treatment Period 2 and baseline to week 144, every 
4 weeks for the overall compliance).  For early withdrawal, it will be all the scheduled 
injections before the withdrawn dates. 


Protocol A7281010 
 
9. PRIOR AND CONCOMITANT MEDICATION  
Version dated 01 December 2016 of the WHO Drug Dictionary will be used to classify prior 
and concomitant medications by preferred term name.   
Prior medication is defined as any medication with the start date prior to the date of the first 
dose of investigational product within A7281010. 
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 between the dates of the first and last doses of investigational 
product, inclusive.  Any medication with a start date after the date of the last dose of 
investigational product will not be considered a concomitant medication.  
All the medications from A7281009 study will be imported to A7281010 study. If the 
medication is discontinued at end of study A7281009 , it will be considered as Prior for study 
A7281010 whereas if medication is ongoing, then it will be considered as concomitant for 
study A7281010 
Both prior and concomitant medication usage will be summarized by the number and 
percentage of subjects in each treatment group receiving each medication within each 
preferred term for the safety analysis set.  Medications can be counted both as prior and 
concomitant medication.  Multiple medication usage by a subject in the same category will be 
counted only once. 
All prior and concomitant medication will be listed. 
Subjects in the follow up period will be characterized by additional biologic therapy (anti-
TNF 
(Adalimumab, 
Certolizumab, 
Certolizumab 
Pegol, 
Golimumab, 
Infliximab), 
Vedolizumab and Other Biologics (Ustekinumab)) and summarized by treatment group.  
Additional biological therapies will be listed.  


Protocol A7281010 
 
10. EFFICACY ANALYSES 
The safety analysis set will be used for all efficacy analyses.  No formal statistical analyses 
will be performed. Descriptive statistics will be provided for the exploratory efficacy analysis. 
The continuous variables will be summarized with n, mean, standard deviation, minimum, 
median and maximum by treatment and time point. The categorical endpoints will be 
summarized with frequency counts and percentages by treatment and time point. All 
summaries will be presented by A7281010 treatment group as defined in Section 5. 
10.1. Primary Efficacy Endpoint(s) and Analysis  
Not applicable 
10.2. Secondary Efficacy Endpoint(s) and Analysis  
The proportion of subjects with mucosal healing (defined as absolute Mayo subscore for 
endoscopy of 0 or 1), along with their corresponding 90% confidence intervals based on the 
Wilson score method, at Baseline and Week 16 will be listed and summarized by the 
treatment groups as defined in Section 5 and their treatment in the A7281009 study (Placebo 
vs. SHP647) and overall. These three tables will be presented based on centrally read Mayo 
subscores only. This will initially be based on the non-responder imputation method (please 
see Section 17.2.1).These summaries will be produced for all subjects, for subjects who were 
deemed to be clinical responders in A7281009 and for non-responders in A7281009. 
 
These three tables will be repeated based on the observed cases rather than the non-responder 
imputation method. 
 
Bar graphs with confidence intervals will also be presented for these summaries. 
10.3. Exploratory Efficacy Endpoint(s) and Analyses  
10.3.1 Total Mayo, Partial Mayo, SCCAI Clinical Response and Clinical Remission 
 
The proportion of subjects with Clinical Response at Baseline and at Week 16 (based on Total 
Mayo score and defined in Table 2, below and using the A7281009 baseline) will be 
presented in the same way as mucosal healing (defined in Section 10.2). 
 
The proportion of subjects with Clinical Remission at Baseline and at Week 16 (based on 
Total Mayo score and defined in Table 2, below) will be presented in the same way as 
mucosal healing (defined in Section 10.2). In addition, the proportion of patients with Clinical 
Remission at Baseline and Week 16 will also be presented by remission status in A7281009 
and imputation method. 
 
The proportion of subjects with Clinical Response based upon the partial Mayo Score (using 
the A7281009 baseline) along with the corresponding 90% Wilson confidence intervals will 
be summarized by the treatment groups defined in Section 5 and their treatment in the 


Protocol A7281010 
 
A7281009 study (Placebo vs. SHP647) and overall by monthly visits. This summary table 
will be produced for both the non-responder imputation method and the observed case. 
 
The proportion of subjects with Clinical Remission based upon the partial Mayo Score will be 
presented in the same way as the Clinical Response based on the partial Mayo score.  
 
The proportion of subjects with Clinical Response based upon SCCAI (using the A7281009 
baseline) along with the corresponding 90% Wilson confidence intervals will be summarized 
by the treatment groups defined in Section 5 and their treatment in the A7281009 study 
(Placebo vs. SHP647) and overall by monthly visits. This summary table will be produced for 
both the non-responder imputation method and the observed case. 
 
The proportion of subjects with Clinical Remission based upon the SCCAI will be presented 
in the same way as the Clinical Response based on the SCCAI. 
 
Definitions of remission, response and relapse for the Total Mayo, Partial Mayo, and SCCAI 
are given in Table 2, Table 3 and Table 4. 
 
In addition, the Total Mayo Score, Partial Mayo Score, individual Mayo Subscores, and 
SCCAI data at baseline from both A7281009 and A7281010 study and the change from 
baseline of A7281009 over time will be presented by their treatment groups in study 
A7281010 and A7281009 and overall. Total Mayo Score and endoscopic subscore will be 
summarized by source of sigmoidoscopy (Centrally or locally read) separately. In addition, 
categorical summary will also be provided for the subscores in Mayo scores.  
 
Table 2:  Total Mayo Score  
Clinical Remission 
Total Mayo Score of 2 points or lower with no individual 
subscore exceeding 1 point and rectal bleed subscore of 0 or 1. 
Clinical Response 
A decrease from baseline of at least 3 points in total Mayo 
score with at least a 30% change, accompanied by at least one 
point decrease or absolute score of 0 or 1 in rectal bleeding 
subscore 
 
Table 3:  Partial Mayo Score 
Clinical Remission 
Partial Mayo Score of 2 points or lower with no individual 
subscore exceeding 1 point and rectal bleed subscore of 0 or 1. 
Clinical Response 
A decrease from baseline of at least 2 points in partial Mayo 
score with at least a 30% change, accompanied by at least one 
point decrease or absolute score of 0 or 1 in rectal bleeding 
subscore 
 


Protocol A7281010 
 
Table 4:  Simple Clinical Colitis Activity Index 
Clinical Remission 
Total SCCAI score of <2 points 
Clinical Response 
Decrease in SCCAI score of 3 points 
 
10.3.2 Dose Escalation  
 
For the table for dose escalation only subjects with starting dose of 75mg will be included. 
Time to dose escalation in subjects for loss of response will be summarized using Kaplan 
estimates at 0-8, >8-12, >12-16 in 4 week intervals up to >72, together with their SE will be 
provided. The number and percentage of subjects who experienced dose escalation and 
censored (subjects who discontinued during the time period or don’t have further dosing data 
after the time period) at each 4 week interval will be presented. The associated Kaplan-Meier 
plot will be produced. 


Protocol A7281010 
 
11. SAFETY ANALYSES 
The safety analysis will be performed using the safety analysis set.  Safety variables include 
AEs, clinical laboratory variables, vital signs, and ECG variables, antibody testing, and 
neurologic assessments.  For each safety variable, the last available value on or before first 
study dosing date (Day 1) is defined as the baseline. A Final on-Treatment Assessment 
(FoTA) will be defined as the last observation recorded within the period in which the 
treatment is administered.  
11.1. Adverse Events  
Adverse events will be coded using Version 19.1 or newer of MedDRA. 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  
 
An AE (classified by preferred term) that occurs during the study will be considered a 
treatment-emergent AE (TEAE) if it has a start date and time on or after the first dose of 
investigational product or if it has a start date and time before the date and time of the first 
dose of investigational product, but increases in severity on or after the date and time of the 
first dose of investigational product. If more than 1 AE with the same preferred term is 
reported before the date and time of the first dose of investigational product, then the AE with 
the greatest severity will be used as the benchmark for comparison to the AEs occurring after 
dose of investigational product under the preferred term. For the purposes of summarizing by 
treatment period, an AE will be considered to be treatment emergent in Treatment Period 1 if 
it has a start date or increases in severity during open label Treatment Period 1;  an AE will be 
considered to be treatment emergent in Treatment Period 2 if it has a start date or increases in 
severity during open label Treatment Period 2; an AE will be considered to be treatment 
emergent in the Follow-up Period if it has a start date or increases in severity during the 
Follow-up Period. 
 
An overall summary of the number of subjects with TEAEs will be presented by treatment 
group, overall and for each of the periods that includes the number and percentage of subjects 
with: 
 Any TEAEs,  
 Any serious TEAEs, 
 Any TEAEs related to investigational product, 
 Any serious TEAEs related to investigational product, 
 Any TEAEs leading to discontinuation of investigational product,  
 Any severe TEAEs, 
 Any TEAE leading to death 
 
The number and percentage of subjects reporting TEAEs in each treatment group, overall and 
for each of the periods, will be tabulated in the following ways: 


Protocol A7281010 
 
 By system organ class (SOC) and preferred term (PT),  
 Common TEAEs ( 5% of subjects in   all doses group) by PT 
 By SOC, PT, and maximum severity, 
 TEAEs considered related to investigational product by SOC and PT.  
 Serious TEAEs by SOC and PT,  
 TEAEs leading to withdrawal of investigational product by SOC and PT 
If more than 1 AE occurs with the same preferred term for the same subject, then the subject 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarization by severity and by relationship to investigational product. 
All information about AEs collected on the eCRF will be listed alongside the treatment, 
preferred term, and SOC.  For injection site AEs, serious AEs, deaths, AEs related to 
investigational product, and TEAEs leading to study discontinuation, a separate listing will 
also be provided. 
An additional summary of AE’s and SAE’s by SOC and PT occurring after initiation of 
additional biologic therapy will be performed by additional biologic (anti-TNF (Infliximab, 
Adalimumab, Certolizumab, Certolizumab Pegol, Golimumab)vs. Vedolizumab vs. Other 
Biologics (Ustekinumab)) received in the follow-up period.  For this analysis subjects who 
have adverse events after the first dose of additional biologic therapy will be considered 
treatment emergent. 
Furthermore the following listings will be provided: listing of TEAEs of Myalgia, listing of 
Clostridium difficile infection adverse events, listing of Gastroenteritis adverse events, listing 
of injection site reactions and listing of Nasophrayngitis adverse events. 
11.2. Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point 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 cell (RBC) count, white blood cell 
(WBC) count, platelet count, total neutrophils (Abs), eosinophils(Abs), 
monocytes (Abs), basophils (Abs), lymphocytes (Abs) 
Biochemistry 
Blood urea nitrogen (BUN), creatinine, glucose, sodium, potassium, 
chloride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), creatine phosphokinase (CPK and CPK 
fractionation), bilirubin (total and direct), calcium, total protein, albumin, 
uric acid, NT-proBNP and Troponin I. 
Urinalysis 
Dipstick (pH, protein, glucose, ketones, blood, leukocyte esterase, and 
nitrites).  NOTE:  microscopic evaluation (RBCs, WBCs, crystals, casts, 
and bacteria) will be performed when indicated by the dipstick results. 


Protocol A7281010 
 
Other 
 JC virus DNA testing, JC virus Serology (antibody). 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 5:  
Criteria for Potentially Clinically Important 
Laboratory Tests.  The number and percentage of subjects with post-baseline PCI values will 
be tabulated by treatment group, overall and by Open Label Treatment Period.  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 post-baseline 
PCI values will be provided including the subject number, site, baseline, and post-baseline 
values.   
Table 5:  Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Age 
Range Gender 
Outlier Criteria 1 
Low 
High 
Hematology 
 
 
 
 
Eosinophils (%) 
All 
Male, 
Female 
NA  
>0.6x103 /uL 
Hemoglobin 
All 
Male, 
Female 
<9g/dL 
NA 
Neutrophils (%) 
All 
Male, 
Female 
<1.5x103/uL   
>8.0x103/uL  
Platelets 
All 
Male, 
Female 
<75.0x103/uL 
>500.0x103/uL  
Leukocytes (WBC)  
All 
Male, 
Female 
<3.0x103/uL  
>16.0x103/uL 
Lymphocytes 
All 
Male, 
Female 
<0.8xLLN 
>1.2xULN 
Monocytes 
All 
Male, 
Female 
<0.1x103/uL 
>1.1x103/uL 
Chemistry 
 
Albumin 
All 
Male, 
Female 
<3g/dL 
NA 
Alkaline Phosphatase 
All 
Male, 
Female 
 
>2.5 x ULN 
Alanine 
Aminotransferase 
(ALT) 
All 
Male, 
Female 
 
>2.5 x ULN 
Aspartate 
Aminotransferase 
(AST) 
All 
Male, 
Female 
 
>2.5 x ULN 
DILI Screen (ongoing 
safety monitoring) 
All 
Male, 
Female 
 
AST or ALT >3 x 
ULN and 
TBL >2 x ULN 


Protocol A7281010 
 
Table 5:  Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Age 
Range Gender 
Outlier Criteria 1 
Low 
High 
Total Bilirubin  
All 
Male, 
Female 
 
>1.5 x ULN 
Direct Bilirubin  
All 
Male, 
Female 

>1.5 x ULN 
Blood Urea Nitrogen 
(BUN) 
All 
Male, 
Female 
 
>2.5 x ULN 
Calcium 
All 
Male, 
Female 
< 8mg/dL 
>11.5mg/dL 
Chloride 
All 
Male, 
Female 
< 90mEq/L 
>115mEq/L 
Creatinine 
All 
Male, 
Female 
 
>1.5 x ULN 
Potassium 
All 
Male, 
Female 
< 3.5mEq/L 
>5.5mEq/L 
Total Protein 
All 
Male, 
Female 
< 5g/dL 
>9g/dL 
Glucose 
All 
Male, 
Female 
< 55mg/dL 
>160mg/dL 
Sodium 
All 
Male, 
Female 
< 130mEq/L 
>150mEq/L 
NT-proBNP 
All 
Male, 
Female 
 
>300 pg/mL 
Troponin I 
All 
Male, 
Female 
 
>0.03ug/L 
CK-MB 
All 
Male, 
Female 
 
≥25 U/L 
Uric acid, Serum 
All 
Males 
 
>10mg/dL 
Uric acid, Serum 
All 
Females  
>9mg/dL 
Creatinine 
phosphokinase (CPK) 
All 
Male, 
Female 
 
>2.5 x ULN 
Urinalysis 
Leukocyte esterase 
All 
Male, 
Female 
Present 
Present 
Protein 
All 
Male, 
Female 
NA 
> 2+ 
Glucose 
All 
Male, 
Female 
NA 
>1+ 
Blood 
All 
Male, 
Female 
NA 
>2+ 
NA=Not Applicable; LLN=Lower Limit of Normal; ULN=Upper Limit of Normal; Intl.=International. 
1 
If criteria in both directions are shown for a single parameter, then abnormalities in each direction 
are summarized separately. 


Protocol A7281010 
 
 
A separate listing of CPK data, of subjects with AE of Myalgia, defined as subjects with 
preferred term of Myalgia, will be presented.  
 
Hy’s law 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced liver 
injury (potential Hy’s Law cases). 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions: 
 Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT >=3 times the upper limit of normal (X 
ULN) concurrent with a total bilirubin >=2 X ULN with no evidence of hemolysis and an 
alkaline phosphatase <=2 X ULN or not available. 
 For subjects with preexisting ALT or AST or total bilirubin values above the upper limit 
of normal, the following threshold values should be used in the definition mentioned 
above: 
 For subjects with pre-existing AST or ALT baseline values above the normal range: 
AST or ALT >=2 times the baseline values and >=3 X ULN, or >=8 X ULN 
(whichever is smaller). 
Concurrent with 
 For subjects with pre-existing values of total bilirubin above the normal range: Total 
bilirubin increased by one time the upper limit of normal or >=3 times the upper limit 
of normal (whichever is smaller). 
Subjects potentially meeting Hy’s law will be listed.  


Protocol A7281010 
 
JC Virus 
JC virus antibody will be summarized at baseline of 1009 by treatment group.  A shift table 
from baseline of 1009 to the end of study at each visit will be presented by treatment group in 
study A7281010. 
Any subjects that have a seroconversion (change from negative to positive) or a 
seroconversion from the baseline of 1009 at any point in either the 1009 or 1010 study will be 
listed. 
JC virus antibody will be listed.  JC virus DNA will not be analyzed. 
11.3. Vital Signs 
Descriptive statistics for vital signs (e.g., 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 Table 6:  
Criteria 
for 
Potentially 
Clinically 
Significant Vital Signs.  The number and percentage of subjects with PCI post-baseline values 
will be tabulated by treatment group and  overall,.  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 post-baseline PCI values will be provided including the 
subject number, baseline, and post-baseline PCI values.   


Protocol A7281010 
 
Table 6:  Criteria for Potentially Clinically Significant Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Systolic blood pressure 
(mmHg) 
High 
180 
Increase of 20 
Low 
90 
Decrease of 20 
Diastolic blood pressure 
(mmHg) 
High 
105 
Increase of 15 
Low 
50 
Decrease of 15 
Pulse rate 
(beats per minute) 
High 
120 
Increase of 15 
Low 
50 
Decrease of 15 
Weight (kg) 
High 
- 
Increase of 10% 
Low 
- 
Decrease of 10% 
BMI (kg/m2) 
High 
- 
Increase of 10% 
Low 
<18 
Decrease of 10% 
a A post-baseline value is considered as a PCI value if its meets both criteria for observed value and change from baseline. 
11.4. Electrocardiogram (ECG) and Echocardiogram (ECHO) 
Descriptive statistics for ECG variables (e.g., heart rate, PR interval, RR interval, QRS 
interval, QT interval, and QTc interval (QTcB and QTcF) and their changes from baseline at 
each assessment time point will be presented by treatment group.  ECG 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 Table 7:  Criteria for Potentially Clinically Important ECG Values.  The 
number and percentage of subjects with post-baseline PCI values will be tabulated by 
treatment group and overall,.  The percentages will be calculated relative to the number of 
subjects with available 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 post-baseline PCI value will be provided including the subject number, site, baseline, 
and post-baseline PCI values. 
Echocardiogram data will be listed. 


Protocol A7281010 
 
Table 7:  Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
Higher Limit 
QRS Interval 
msec 
150 
PR Interval 
msec 
250 
QTcB Interval 
msec 
500 
QTcF Interval 
msec 
500 
11.5. Immunogenicity  
Presence of anti-PF-00574659 antibodies will be listed and summarized by visit for each 
treatment group.  
 
In subjects with a positive ADA, presence of neutralizing antibodies will be listed and 
summarized by visit for each treatment group. 
 
These endpoints will be analyzed for the safety analysis set. 
11.6.  Physical Examination 
Physical examination will be listed. 
11.7. Enteric Pathogen 
Enteric Pathogen data will be listed. 
11.8. Other Safety Variables 
11.8.1. Neurological Assessments 
As part of the safety evaluation, the following neurological assessments are performed for 
each subject. 
 Confrontational Visual Fields 
 Timed 25-Foot Walk 
 9-Hole Peg Test (9-HPT) 
 Symbol Digit Modality Test (SDMT) 
 Patient-Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) 
 
To provide more precise results about the measurement, programming derived scores will be 
used in the listing and summary instead of the CRF recorded scores for SDMT. The derived 
standard deviation (SD) will be based on the age (derived based on test date and date of birth), 
education level (from the 1009 Social Status CRF page) and test score reported and the norm 
table provided in the protocol Appendix 7. When the test score is not equal to any of the norm 
scores, the closet norm score will be used to define the SD. When two norm scores have equal 
distance to the test score, the lower one will be used. 
 


Protocol A7281010 
 
The neurological assessments will be summarized for the safety population by treatment 
group.  In addition, a summary of clinically significant on-treatment changes in neurological 
assessments will be presented by treatment group, overall, and period. Clinically significant 
worsening changes are defined as the following: 
 Symbol Digit Modality Test - 1 S.D. decrease or more on two consecutive visits, from 
the worst (smallest) case before first dosing; 
 9-hole Peg Test - 20% increase or more compared with the worst (greatest) case 
before first dosing; 
 Confrontational Visual Fields Test - change from NORMAL to ABNORMAL when 
compared to the worst case before first dosing;  
 25-Foot Walk Test - 20% increase or more compared with the worst (greatest) case 
before first dosing. 
 Patient-Multiple Sclerosis Neuropsychological Questionnaire - a 5-point increase or 
more compared with the worst (greatest) case before first dosing. 
Neurological assessments will be listed.  Separate listings for subjects with clinically 
significant on-treatment changes in neurological assessments will also be presented. 
 
 
 
 


Protocol A7281010 
 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES 
12.1. Pharmacokinetics Population and Pharmacodynamic Population, 
Please see Section 4. 
12.2. Pharmacokinetic Methods 
All of the pharmacokinetic analyses will be performed using the Pharmacokinetic Analysis 
Set. 
12.2.1. Concentration Data 
Blood samples will be collected prior to dosing for analysis of plasma trough concentrations 
of PF-00547659. Plasma concentrations at each nominal time post dose will be presented by 
treatment group and summarized using descriptive statistics which include n, mean, median, 
SD, coefficient of variation (CV), minimum and maximum. A listing of all concentrations 
will be provided along with scheduled and actual sampling times. A spaghetti plot of 
individual subject plasma-concentration against actual time post dose (separate plot for each 
treatment group). Mean concentrations against nominal time will be plotted for each treatment 
group. This plot will be presented on linear-linear and log-linear scales. These data will be 
analyzed for the PK population.  
 
Further details of the Population PK methodology will be described in the separate Population 
Modeling and Analysis Report.  
12.2.2. Handling BLQ Values 
For PK concentrations, in the listings, Concentrations below the limit of quantification 
(BLQ) values will be reported as “<LLQ”, where LLQ will be replaced with the value for the 
lower limit of quantification. 
 
For PD and biomarkers with concentrations outside the limit of quantification, in all data 
presentations (except listings), assayed values below the limit of quantification (BLQ) will be 
set to 10% less than the given assay lower limit for the specific biomarker. In addition, 
assayed values above the limit of quantification (ALQ) will be set to 10% more than the assay 
upper limit if applicable. In listings BLQ values will be reported as “<LLQ” and ULQ values 
will be reported as “>ULQ” where LLQ and ULQ will be replaced with the values for the 
lower and upper limits for qualification respectively. 
 
No missing values will be imputed. 
12.2.3. Pharmacokinetic Parameters 
Please see the separate Population Modeling and Analysis Report.  


Protocol A7281010 
 
12.3. Statistical Analysis of Pharmacokinetic Data 
Please see the separate Population Modeling and Analysis Report. 
12.4. Pharmacodynamic Methods 
All of the Pharmacodynamic analyses will be performed using the Pharmacodynamic 
Analysis Set. 
Pharmacodynamic parameters: Fecal calprotectin, hsCRP and Soluble MAdCAM will be 
summarized as specified below. 
12.5. Statistical Analysis of Pharmacodynamic Data 
Descriptive statistics (n, mean, SD, coefficient of variation, median, maximum, minimum, 
geometric mean, and coefficient of variation of geometric mean) for  fecal calprotectin, 
hsCRP and soluble MAdCAM will be presented by timepoint as indicated below,treatment 
groupand and their treatment in the A7281009 study and overall. Geometric mean percent 
change from baseline and 90% CIs for these endpoints will also be summarized. 
 hsCRP from blood samples will be summarized for the following timepoints: prior to 
dosing at baseline and every 4 weeks to Week 24, Week 32 and Week 72.  
 Fecal calprotectin from stool samples will be summarized at the same time points as 
for hsCRP. 
 Soluble MAdCAM in blood will be summarized for baseline and Week 16. 
The following figures will also be provided for the following endpoints: 
 hsCRP geometric mean over time with geometric mean SD. 
 hsCRP geometric mean percent change from baseline with geometric mean  SD. 
 Fecal calprotectin geometric mean over time with geometric mean SD. 
 Fecal calprotectin geometric mean percent change from baseline with geometric 
mean SD. 
Fecal calprotectin, hsCRP, and soluble MAdCAM will be listed. 
 


Protocol A7281010 
 
13. OTHER ANALYSES 
Not applicable 


Protocol A7281010 
 
14. INTERIM ANALYSIS 
14.1. Interim Analyses 
Two interim analyses (IAs) were planned to be performed for this study when 50% of subjects 
from the Phase 2 study (A7281009) had been enrolled in this study (A7281010), and the last 
subject from the Phase 2 study (A7281009) had been enrolled in this study (A7281010). In 
practice, two IAs occurred, one at the time of the topline report for the A7281009 study and 
one for an end of phase 2 meeting.  The purpose of the IAs was to provide additional data on 
the durability of response, remission, and safety from A7281009, to facilitate the decision-
making process of future studies.  
14.2. Data Monitoring Committee 
An external Data Monitoring Committee was placed to review the safety of subjects on an 
ongoing basis and to adjudicate any subjects with unexplained neurological or cardiac 
findings. Membership of this committee included a neurologist with expertise in PML and a 
cardiologist with expertise in heart failure and/or myocarditis. Work-up of suspected PML 
cases included a neurology consultation as well as an MRI scan, and a lumbar puncture, if 
clinically indicated. Given the lack of therapeutic options for subjects who have failed at least 
1 conventional therapy, SHP647 with its distinct mechanism of action and known safety 
profile appears to have a favorable Risk-Benefit profile. The added precautions regarding 
PML served to increase the confidence in SHP647 for future development. 
Additional cardiac monitoring was implemented in this study.  Serum samples for CPK (with 
reflex isoenzymes), troponin I and NT-proBNP were drawn with the safety labs.  Elevation of 
troponin I >0.05 ng/mL or CPK with MB prompted a cardiology consult.  Any subject who 
experienced an initial on-study elevation of NTproBNP to >300 pg/mL had an 
echocardiogram and cardiology consult.  All subjects who had an echocardiogram, in whom 
the NTproBNP remains >124 pg/mL at the 144 week visit, had a repeat echocardiogram and 
cardiology consultation ordered no later than the following visit.  All cases of on-study 
elevation of NTproBNP to >300 pg/mL, elevation in cardiac troponin I (cTnI) or CK/MB or 
new ECG changes was reviewed by the DMC. 
The DMC is responsible for ongoing monitoring of safety of subjects in the study according 
to the Charter.  The recommendations made by the DMC to alter the conduct of the study or 
amend the protocol was forwarded to Shire for final decision.  Shire will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data that are not endpoints, to regulatory authorities, as appropriate. 
 


Protocol A7281010 
 
15. COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   


Protocol A7281010 
 
16. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Dose escalation was removed in protocol amendment 3, SAP accommodates for subjects enrolled 
under prior to protocol amendment. 
Gene expression profiling (mRNA) and proteins will not be analyzed.  JC Virus DNA will not be 
analyzed. 


Protocol A7281010 
 
17. DATA HANDLING CONVENTIONS 
17.1. General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum, maximum.  Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in each category.  
Percentages will be presented to a single decimal place.  
17.2. Derived Efficacy Endpoints  
17.2.1. Imputation Method 
For analyses of binary endpoints in exploratory efficacy endpoints, the non-responder 
imputation method will be used for missing value imputation from drop out subjects. Subjects 
that have missing data which means it is not possible to determine their remission/clinical 
response/mucosal healing will be assigned as having no remission/no clinical response/no 
mucosal healing to the missing visits.   
17.2.2. Total Mayo Score 
Responder/Non-responder status will be determined at the final visit (Week 12) of study 
A7281009 and recorded at the baseline visit of A7281010, however, the responder/non-
responder status from the Week 12 visit of study A7281009 in the A7281009 analysis datasets 
will be used for this study. 
 
The determination of clinical response and clinical remission will be based on the total Mayo 
score. 
The calculation of total Mayo Score includes flexible sigmoidoscopy or colonoscopy results, 
stool frequency, rectal bleeding, and physician’s global assessment. See Appendix 19.1.2 
Mayo Scoring System for Assessment of Ulcerative Colitis Activity for how the stool 
frequency and rectal bleeding subscores are calculated Definitions of clinical response and 
remission by the Total Mayo score are located in Section 10.3. 
17.2.3. Partial Mayo Score 
Partial Mayo score is Mayo score without the endoscopic subscore. Therefore the calculation 
of the partial Mayo score includes stool frequency, rectal bleeding, and physician’s global 
assessment. Definitions of clinical response and remission by the Partial Mayo score are 
located in Section 10.3. 
17.2.4. Simple Clinical Colitis Activity Index 
The SCCAI measure disease activity and includes the following 13 items: general well-being, 
abdominal pain, bowel frequency, stool consistency, bleeding, anorexia, nausea or vomiting, 
abdominal tenderness, extra intestinal complications (eye, mouth, joint, skin), temperature, 
sigmoidoscopic assessment, nocturnal bowel movements, and urgency of defecation. The total 


Protocol A7281010 
 
SCCAI score is the sum of the all points collected in the eCRF. Definitions of clinical 
response and remission by the SCCAI score are located in Section 10.3. 
 
17.3. 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.  
17.4. Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject, all efforts 
should be made to obtain the date from the site.   
17.5. Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (ie, 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.     
17.5.1. 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. 
17.5.1.1. 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. 
17.5.1.2. Missing month only 
 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 


Protocol A7281010 
 
17.5.1.3. 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.  
17.5.2. 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.  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. 
17.5.2.1. 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. 
17.5.2.2. Missing month only 
 
The day will be treated as missing and both month and day will be replaced according 
to the above procedure. 
17.5.2.3. 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 


Protocol A7281010 
 
 
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. 
17.6. Missing Date Information for Adverse Events  
AEs with completely missing start dates will be considered Treatment emergent for period 1 
and start date will be imputed as the first dose date.  .  Incomplete stop dates may also be 
imputed when calculation of the duration of an AE is 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. 
17.6.1. Incomplete Start Date  
Follow same rules as in Section 17.5.1. 
17.6.2. Incomplete Stop Date  
When required per the protocol, follow the same rules as in Section 17.5.2.  
17.7. 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 the actual values will be used in data listings. 
17.8. Missing Relationship to Investigation 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 the actual values will be presented in data listings. 
17.9. 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 will be used in the statistical analysis.  However, the 
actual values as reported in the database will be presented in data listings. 


Protocol A7281010 
 
18. References 
No references to note 


Protocol A7281010 
 
19. Appendices 
19.1. Data Derivation Details 
19.1.1.  Definitions and Use of Visit Windows in Reporting 
Periods  
Visit 
Study Week 
Target Day 
Window 
Open-Label 
Treatment 
Period 1 
1 
Baseline 
1 
Rel_day<=1 
2 
Week 4 
29 
1<rel_day<=43 
3 
Week 8 
57 
43<rel_day<=71 
4 
Week 12 
85 
71<rel_day<=99 
5 
Week 16 
113 
99<rel_day<=127 
6 
Week 20 
141 
127<rel_day<=155 
7 
Week 24 
169 
155<rel_day<=183 
8 
Week 28 
197 
183<rel_day<=211 
9 
Week 32 
225 
211<rel_day<=239 
10 
Week 36 
253 
239<rel_day<=267 
11 
Week 40 
281 
267<rel_day<=295 
12 
Week 44 
309 
295<rel_day<=323 
13 
Week 48 
337 
323<rel_day<=351 
14 
Week 52 
365 
351<rel_day<=379 
15 
Week 56 
393 
379<rel_day<=407 
16 
Week 60 
421 
407<rel_day<=435 
17 
Week 64 
449 
435<rel_day<=463 
18 
Week 68 
477 
463<rel_day<=491 
19 
Week 72 
505 
491<rel_day<=519 
Open-Label 
20 
Week 76 
533 
519<rel_day<=547 


Protocol A7281010 
 
Treatment 
Period 2  
21 
Week 80 
561 
547<rel_day<=575 
22 
Week 84 
589 
575<rel_day<=603 
23 
Week 88 
617 
603<rel_day<=631 
24 
Week 92 
645 
631<rel_day<=659 
25 
Week 96 
673 
659<rel_day<=687 
26 
Week 100 
701 
687<rel_day<=715 
27 
Week 104 
729 
715<rel_day<=743 
28 
Week 108 
757 
743<rel_day<=771 
29 
Week 112 
785 
771<rel_day<=799 
30 
Week 116 
813 
799<rel_day<=827 
31 
Week 120 
841 
827<rel_day<=855 
32 
Week 124 
869 
855<rel_day<=883 
33 
Week 128 
897 
883<rel_day<=911 
34 
Week 132 
925 
911<rel_day<=939 
35 
Week 136 
953 
939<rel_day<=967 
36 
Week 140 
981 
967<rel_day<=995 
37 
 
Week 144 
1009 
 
995<rel_day<=1023 
 
3 Month 
Follow-up 
38 
Week of last dose 
+ 12 Weeks 
((Week of last 
dose + 12 
Weeks) x 7) + 1 
((Week of last dose + 12 
Weeks) 
x 
7) 
- 
13 
<rel_day<=((Week 
of 
last dose + 12 Weeks) x 
7) + 15 
6 Month 
Follow-up 
39 
Week of last dose 
+ 24 Weeks 
((Week of last 
dose + 24 
Weeks) x 7) + 1 
((Week of last dose + 24 
Weeks) 
x 
7) 
- 
13 
<rel_day<=((Week 
of 
last dose + 24 Weeks) x 
7) + 15 


Protocol A7281010 
 
 
Day 1= First study dosing date.  
Baseline is defined as the last available value on or before first study dosing date.  If two or 
more visits fall into the same window, keep the one closest to the Target Day.  If two visits 
are equal distant from the Target Day in absolute value, the visit with correct nominal label 
should be used.  For example, if two visits fall in the window for Week 4 visit with days 24 
and 32, the visit that was recorded as Week 4 visit should be used. 
19.1.2.  Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
The Mayo Score ranges from 0 to 12, with higher scores indicating more severe disease.  It 
consists of 4 subscores.  Each sub-score ranges from 0 to 3.  The 4 components of the Mayo 
Score are: 
Stool Frequency†: 
0 = Normal no. of stools for this patient. 
1 = 1 to 2 stools more than normal. 
2 = 3 to 4 stools more than normal. 
3 = 5 or more stools more than normal. 
Rectal Bleeding‡: 
0 = No blood seen. 
1 = Streaks of blood with stool less than half the time. 
2 = Obvious blood with stool most of the time. 
3 = Blood alone passes. 
Findings on Endoscopy: 
0 = Normal or inactive disease. 
1 = Mild disease (erythema, decreased vascular pattern, mild friability). 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions). 
3 = Severe disease (spontaneous bleeding, ulceration). 
Physician’s Global Assessment§: 
0 = Normal. 


Protocol A7281010 
 
1 = Mild disease. 
2 = Moderate disease. 
3 = Severe disease. 
* The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  Each subscore 
ranges from 0 to 3. 
† Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency. 
‡ The daily bleeding score represents the most severe bleeding of the day. 
§ The physician’s global assessment acknowledges the three other criteria, the patient’s daily recollection of 
abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the 
patient’s performance status. 
If there are missing diary data, the average will be taken from the 3 most recently available 
days reported within 5 days prior to the study visit.  If there are less than 3 available days 
reported within 5 days prior to the study visit, the average will be taken from the limited 
available data unless there is no diary data reported within 5 days.  In this case, stool 
frequency and rectal bleeding subscores will be considered as missing.  If at least one of the 
4 Mayo subscores is missing, the total Mayo score will be considered as missing. 
 
 


Protocol A7281010 
 
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS 
Table 
Title 
Shire 
Std 
14.1.1.1 
Disposition by Treatment Group [All Enrolled Subjects] 
N 
14.1.1.2 
Enrollment Duration by Site and Country [All Enrolled Subjects] 
Y 
14.1.4.1.1 
Demographic Characteristics [Safety Analysis Set] 
Y 
14.1.4.1.2 
Demographic Characteristics in Responders [Safety Analysis Set] 
Y 
14.1.4.1.3 
Demographic Characteristics in Non-responders [Safety Analysis 
Set] 
Y 
14.1.4.2 
Baseline Characteristics by Treatment Group [Safety Analysis Set] 
Y 
14.1.4.3.1 
Medical History in Study A7281009 and A7281010 by System 
Organ Class, Preferred Term and Treatment Group [Safety Analysis 
Set] 
Y 
14.1.4.4 
Prior Medications by Treatment Group [Safety Analysis Set] 
Y 
14.1.4.5.1 
Concomitant Medications by Treatment Group [Safety Analysis 
Set] 
Y 
14.1.4.5.2 
Summary of Additional Biologic Therapies in the Follow-up 
Period[Safety Analysis Set] 
N 
14.2.2.1.1.1 
 Proportion of Subjects with Mucosal Healing by Timepoint  using 
Non-responder Imputation Method [Safety Analysis Set] 
N 
14.2.2.1.1.2 
Proportion of Subjects with Mucosal Healing by Timepoint for 
Responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set] 
N 
14.2.2.1.1.3 
Proportion of Subjects with Mucosal Healing  by Timepoint for 
Non-responders in Study A7281009 using Non-responder 
Imputation Method [Safety Analysis Set] 
N 
14.2.2.1.2.1 
Proportion of Subjects with Mucosal Healing by Timepoint using 
Observed Case [Safety Analysis Set] 
N 
14.2.2.1.2.2 
Proportion of Subjects with Mucosal Healing by Timepoint for 
Responders using Observed Case [Safety Analysis Set] 
N 
14.2.2.1.2.3 
Proportion of Subjects with Mucosal Healing  by Timepointfor 
Non-responders using Observed Case [Safety Analysis Set] 
N 
14.2.2.2.1.1 
Proportion of Subjects with Clinical Response  by Timepoint using 
Non-responder Imputation Method [Safety Analysis Set] 
N 
14.2.2.2.1.2 
Proportion of Subjects with Clinical Response  by Timepoint for 
Responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set] 
N 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.2.2.2.1.3 
Proportion of Subjects with Clinical Response  by Timepoint for 
Non-responders in Study A7281009 using Non-responder 
Imputation Method [Safety Analysis Set] 
N 
14.2.2.2.2.1 
Proportion of Subjects with  by Timepoint  using Observed Case 
[Safety Analysis Set] 
N 
14.2.2.2.2.2 
Proportion of Subjects with Clinical Response  by Timepoint for 
Responders using Observed Case[Safety Analysis Set] 
N 
14.2.2.2.2.3 
Proportion of Subjects with Clinical Response by Timepoint for 
Non-responders using Observed Case[Safety Analysis Set] 
N 
 
14.2.2.2.3.1 
Proportion of Subjects in Clinical Remission by Timepoint using 
Non-responder Imputation Method[Safety Analysis Set] 
N 
14.2.2.2.3.2 
Proportion of Subjects in Clinical Remission by Timepoint  for 
Responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set] 
N 
14.2.2.2.3.3 
Proportion of Subjects in Clinical Remission by Timepoint  for Non-
responders in Study A7281009 using Non-responder Imputation 
Method[Safety Analysis Set] 
N 
14.2.2.2.4.1 
Proportion of Subjects in Clinical Remission by Timepoint using 
Observed Case[Safety Analysis Set] 
N 
14.2.2.2.4.2 
Proportion of Subjects in Clinical by Timepoint for Responders 
using Observed Case[Safety Analysis Set] 
N 
14.2.2.2.4.3 
 
Proportion of Subjects in Clinical Remission by Timepoint for Non-
responders using Observed Case [Safety Analysis Set] 
N 
14.2.2.2.5.1 
Proportion of Subjects in Clinical Remission by Timepoint for those 
with Remission using Non-responder Imputation Method [Safety 
Analysis Set] 
N 
14.2.2.2.5.2 
Proportion of Subjects in Clinical Remission by Timepoint for those 
with No Remission using Non-responder Imputation 
Method[Safety Analysis Set] 
N 
14.2.2.2.6.1 
Proportion of Subjects in Clinical Remission by Timepoint for those 
with Remission using Observed Case [Safety Analysis Set] 
N 
14.2.2.2.6.2 
Proportion of Subjects in Clinical Remission by Timepoint for those 
with No Remission using Observed Case[Safety Analysis Set] 
N 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.2.2.3.1 
Proportion of Subjects with Clinical Response based on the Partial 
Mayo Score using Non-Responder Imputation Method[Safety 
Analysis Set] 
N 
14.2.2.3.2 
Proportion of Subjects with Clinical Response based on the Partial 
Mayo Score using Observed Case[Safety Analysis Set] 
N 
14.2.2.3.3 
Proportion of Subjects in Clinical Remission based on the Partial 
Mayo Score by Week using Non-Responder Imputation 
Method[Safety Analysis Set] 
N 
14.2.2.3.4 
Proportion of Subjects in Clinical Remission based on the Partial 
Mayo Score using Observed Case[Safety Analysis Set] 
N 
14.2.2.3.5 
Summary of Total Mayo Score, Partial Mayo Score and Subscores 
by Week [Safety Analysis Set] 
Y 
14.2.2.4.1 
Proportion of Subjects with Clinical Response based on Simple 
Clinical Colitis Activity Index (SCCAI) Score by Monthly Visits using 
Non-Responder Imputation Method[Safety Analysis Set] 
N 
14.2.2.4.2 
Proportion of Subjects with Clinical Response based on Simple 
Clinical Colitis Activity Index (SCCAI)Score by Monthly Visits using 
Observed Case[Safety Analysis Set] 
N 
14.2.2.4.3 
Proportion of Subjects in Clinical Remission based on Simple 
Clinical Colitis Activity Index (SCCAI) Score by Monthly Visits using 
Non-Responder Imputation Method[Safety Analysis Set] 
N 
14.2.2.4.4 
Proportion of Subjects in Clinical Remission based on the Simple 
Clinical Colitis Activity Index (SCCAI) Score by Monthly Visits using 
Observed Case [Safety Analysis Set] 
N 
14.2.2.4.5 
Summary of Simple Clinical Colitis Activity Index (SCCAI) at 
Monthly Visits [Safety Analysis Set] 
Y 
14.2.2.5.1 
Categorical summary of Mayo Subscore- Stool Frequency by Week 
[Safety Analysis Set] 
N 
14.2.2.5.2 
Categorical summary of Mayo Subscore- Rectal Bleeding by Week 
[Safety Analysis Set] 
N 
14.2.2.5.3 
Categorical summary of Mayo Subscore- Findings of 
Sigmoidoscopy by Week [Safety Analysis Set] 
N 
14.2.2.5.4 
Categorical summary of Mayo Subscore- Physician’s Global 
Assessment by Week [Safety Analysis Set] 
N 
14.2.2.6 
Summary of Time to Dose Escalation [Safety Analysis Set] 
N 
14.2.3.1 
Summary of Plasma Concentration (ng/mL) by Nominal Time and 
Treatment Group[Pharmacokinetic Set] 
Y 
14.2.3.2.1 
Summary of hsCRP (mg/dL) and Change from Baseline of hsCRP 
(mg/dL) by Week and Treatment Group [Pharmacodynamic Set] 
Y 
14.2.3.2.2 
Summary of Fecal Calprotectin and Change from Baseline of Fecal 
Calprotectin (ug/g) by Week and Treatment Group 
[Pharmacodynamic Set] 
Y 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.2.3.2.3 
Summary of Soluble MAdCAM and Change from Baseline of 
Soluble MAdCAM (pmol/L) by Week and Treatment Group 
[Pharmacodynamic Set] 
Y 
14.3.1.1.1 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group [Safety Analysis Set] 
Y 
14.3.1.1.2 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group in Treatment Period 1 [Safety Analysis Set] 
Y 
14.3.1.1.3 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group in Treatment Period 2 [Safety Analysis Set] 
Y 
14.3.1.1.4 
Overall Treatment-emergent Adverse Events (TEAEs) by Treatment 
Group in Follow-up Period [Safety Analysis Set] 
Y 
14.3.1.2.1 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group [Safety Analysis Set] 
Y 
14.3.1.2.2 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group in Treatment Period 1 
[Safety Analysis Set] 
Y 
14.3.1.2.3 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group in Treatment Period 2 
[Safety Analysis Set] 
Y 
14.3.1.2.4 
Treatment-emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group in Follow-up Period [Safety 
Analysis Set] 
Y 
14.3.1.2.5 
Treatment-emergent Adverse Events after Initiation of Additional 
Anti-TNF Biologic Therapy in the Follow-up period by System 
Organ Class, Preferred Term and Treatment Group [Safety Analysis 
Set] 
Y 
14.3.1.2.6 
Treatment-emergent Adverse Events after Initiation of Additional 
Vedolizumab Biologic Therapy in the Follow-up period by System 
Organ Class, Preferred Term and Treatment Group [Safety Analysis 
Set] 
Y 
14.3.1.2.7 
Treatment-emergent Adverse Events after Initiation of Additional 
Other Biologic Therapy in the Follow-up period by, System Organ 
Class, Preferred Term and Treatment Group [Safety Analysis Set] 
Y 
14.3.1.3.1 
Frequently Occurring (≥5%) Treatment-emergent Adverse Events 
by Preferred Term and Treatment Group [Safety Analysis Set] 
Y 
14.3.1.3.2 
Frequently Occurring (≥5%) Treatment-emergent Adverse Events 
by Preferred Term and Treatment Group in Treatment Period 1 
[Safety Analysis Set] 
Y 
14.3.1.3.3 
Frequently Occurring (≥5%) Treatment-emergent Adverse Events 
by Preferred Term and Treatment Group in Treatment Period 2 
[Safety Analysis Set] 
Y 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.3.1.3.4 
Frequently Occurring (≥5%) Treatment-emergent Adverse Events 
by Preferred Term and Treatment Group in Follow-up Period 
[Safety Analysis Set] 
Y 
14.3.2.1.1 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group [Safety 
Analysis Set] 
Y 
14.3.2.1.2 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group in 
Treatment Period 1 [Safety Analysis Set] 
Y 
14.3.2.1.3 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group in 
Treatment Period 2 [Safety Analysis Set] 
Y 
14.3.2.1.4 
Treatment-emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term and Treatment Group in 
Follow-up Period [Safety Analysis Set] 
 
14.3.2.2.1 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group [Safety Analysis Set] 
Y 
14.3.2.2.2 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
in Treatment Period 1 [Safety Analysis Set] 
Y 
14.3.2.2.3 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
in Treatment Period 2 [Safety Analysis Set] 
Y 
14.3.2.2.4 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and 
in Follow-up Period [Safety Analysis Set] 
 
14.3.3.2.1 
 
Treatment-emergent Adverse Events leading to Withdrawal  of 
Investigation Product by System Organ Class, Preferred Term and 
Treatment Group [Safety Analysis Set] 
Y 
14.3.3.2.2 
 
Treatment-emergent Adverse Events leading to Withdrawal of 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group in Treatment Period 1 [Safety Analysis Set]  
Y 
14.3.3.2.3 
 
Treatment-emergent Adverse Events leading to Withdrawal of 
Investigational Product by System Organ Class, Preferred Term and 
Treatment Group in  Treatment Period 2 [Safety Analysis Set 
Y 
14.3.3.4.1 
Serious Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group [Safety Analysis Set] 
Y 
14.3.3.4.2 
Serious Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group in Treatment Period 1 
[Safety Analysis Set] 
Y 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.3.3.4.3 
Serious Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group in Treatment Period 2 
[Safety Analysis Set] 
Y 
14.3.3.4.4 
Serious Treatment-emergent Adverse Events by System Organ 
Class, Preferred Term and Treatment Group in Follow-up Period 
[Safety Analysis Set] 
Y 
14.3.3.4.5 
Serious Treatment-emergent Adverse Events after Initiation of 
Additional Anti-TNF Biologic Therapy in the Follow-up period by, 
System Organ Class, Preferred Term and Treatment Group [Safety 
Analysis Set] 
Y 
14.3.3.4.6 
Serious Treatment-emergent Adverse Events after Initiation of 
Additional Vedolizumab Biologic Therapy in the Follow-up period 
by, System Organ Class, Preferred Term and Treatment Group 
[Safety Analysis Set] 
Y 
14.3.3.4.7 
Serious Treatment-emergent Adverse Events after Initiation of 
Additional Other Biologic Therapy in the Follow-up period by, 
System Organ Class, Preferred Term and Treatment Group [Safety 
Analysis Set] 
Y 
14.3.4.1 
Quantitative Clinical Laboratory Results by Treatment Group: 
Hematology [Safety Analysis Set] 
Y 
14.3.4.2 
Quantitative Clinical Laboratory Results by Treatment Group: 
Biochemistry [Safety Analysis Set] 
Y 
14.3.4.3 
Quantitative Clinical Laboratory Results by Treatment Group: 
Urinalysis [Safety Analysis Set] 
Y 
14.3.4.4 
Qualitative Clinical Laboratory Results Treatment Group: Urinalysis 
[Safety Analysis Set] 
Y 
14.3.4.5 
Shift from Baseline in Clinical Laboratory Results by Treatment 
Group: Hematology [Safety Analysis Set] 
Y 
14.3.4.6 
Shift from Baseline in Clinical Laboratory Results by Treatment 
Group: Biochemistry [Safety Analysis Set] 
Y 
14.3.4.7 
Shift from Baseline in Clinical Laboratory Results by Treatment 
Group: Urinalysis [Safety Analysis Set] 
Y 
14.3.4.8 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group: Hematology [Safety Analysis Set] 
Y 
14.3.4.9 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 1: Hematology [Safety 
Analysis Set 
Y 
14.3.4.10 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 2: Hematology [Safety 
Analysis Set] 
Y 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.3.4.11 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group: Biochemistry [Safety Analysis Set] 
Y 
14.3.4.12 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 1: Biochemistry [Safety 
Analysis Set] 
Y 
14.3.4.13 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 2: Biochemistry [Safety 
Analysis Set] 
Y 
14.3.4.14 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group: Urinalysis [Safety Analysis Set] 
Y 
14.3.4.15 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 1: Urinalysis [Safety Analysis 
Set] 
Y 
14.3.4.16 
Potentially Clinically Important (PCI) Laboratory Results by 
Treatment Group in Treatment Period 2: Urinalysis [Safety Analysis 
Set] 
Y 
14.3.4.17 
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Hematology 
Y 
14.3.4.18 
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Biochemistry 
Y 
14.3.4.19 
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Urinalysis 
Y 
14.3.4.20 
Categorical Summary of Baseline JC Virus Antibody[Safety Analysis 
Set] 
N 
14.3.4.21 
Shift from Baseline in JC Virus Antibody to End of Study[Safety 
Analysis Set] 
Y 
14.3.5.1 
Actual Values and Change from Baseline in Vital Signs by 
Treatment Group [Safety Analysis Set] 
Y 
14.3.5.2 
Potentially Clinically Important (PCI) Vital Signs Results by 
Timepoint and Treatment Group [Safety Analysis Set] 
Y 
14.3.6.1 
Actual Values and Change from Baseline in ECG by Treatment 
Group [Safety Analysis Set] 
Y 
14.3.6.2 
ECG Interpretation by Timepoint and Treatment Group [Safety 
Analysis Set]  
Y 
14.3.6.3 
Potentially Clinically Important (PCI) ECG Results by Timepoint and 
Treatment Group [Safety Analysis Set] 
Y 
14.3.6.6 
Shift from Baseline to Post-Baseline Timepoint in Qualitative ECG 
Results by Treatment Group [Safety Analysis Set] 
Y 
14.3.6.7 
Presence of Anti-drug Antibodies (ADA) by Timepoint[Safety 
Analysis Set] 
N 


Protocol A7281010 
 
Table 
Title 
Shire 
Std 
14.3.6.8 
Neutralising Antibodies Development in Subjects with Positive 
Anti-drug-Antibodies by Timepoint[Safety Analysis Set] 
N 
14.3.6.9 
Categorical summary of Confrontational Visual Fields by 
Timepoint[Safety Analysis Set] 
N 
14.3.6.10 
Summary of Timed 25-Foot Walk (sec) by Timepoint [Safety 
Analysis Set] 
Y 
14.3.6.11 
Summary of 9-Hole Peg Test by Timepoint [Safety Analysis Set] 
Y 
14.3.6.12 
Summary of Symbol Digit Modalities Test (SDMT) Scores by 
Timepoint[Safety Analysis Set] 
Y 
14.3.6.13 
Summary of Patient-Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) Total Score by Timepoint[Safety Analysis 
Set] 
Y 
14.3.6.14 
Summary of Clinically Significant On-Treatment Changes in 
Neurological Assessments[Safety Analysis Set] 
N 
14.3.8.1 
Investigational Product Exposure by Treatment Group [Safety 
Analysis Set] 
Y 
 
Figure 
Title 
14.2.2.1.1.1 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) using Non-responder Imputation Method 
[Safety Analysis Set] 
14.2.2.1.1.2 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) for Responders in Study A7281009 using Non-
responder Imputation Method [Safety Analysis Set] 
14.2.2.1.1.3 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) for Non-responders in Study A7281009 using 
Non-responder Imputation Method [Safety Analysis Set] 
14.2.2.1.2.1 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) using Observed Case[Safety Analysis Set]  
14.2.2.1.2.2 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) for Responders using Observed Case [Safety 
Analysis Set] 


Protocol A7281010 
 
Figure 
Title 
14.2.2.1.2.3 
Proportion of Subjects with Mucosal Healing at Baseline and Week 
16(Centrally read) for Non-responders using Observed Case 
[Safety Analysis Set] 
14.2.2.2.1.1 
Proportion of Subjects with Clinical Response at Baseline and 
Week 16 based on Total Mayo Score (Centrally read) using Non-
responder Imputation Method [Safety Analysis Set] 
14.2.2.2.1.2 
Proportion of Subjects with Clinical Response at Baseline and 
Week 16 based on Total Mayo Score (Centrally read) for 
Responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set] 
14.2.2.2.1.3 
Proportion of Subjects with Clinical Response at Baseline and 
Week 16 based on Total Mayo Score (Centrally read) for Non-
responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set] 
14.2.2.2.2.1 
Proportion of Subjects with Clinical Response at Week 16 based on 
the Total Mayo Score (Centrally read) using Observed Case [Safety 
Analysis Set]   
14.2.2.2.2.2 
Proportion of Subjects with Clinical Response at Week 16 based on 
the Total Mayo Score (Centrally read) for Responders using 
Observed Case [Safety Analysis Set]    
14.2.2.2.2.3 
Proportion of Subjects with Clinical Response at Week 16 based on 
the Total Mayo Score (Centrally read) for Non-responders using 
Observed Case [Safety Analysis Set]     
14.2.2.2.3.1 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on Total Mayo Score (Centrally read) using Non-
responder Imputation Method [Safety Analysis Set]     
14.2.2.2.3.2 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for Responders 
in Study A7281009 [Safety Analysis Set]     
14.2.2.2.3.3 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for Non-
responders in Study A7281009 using Non-responder Imputation 
Method [Safety Analysis Set]   
14.2.2.2.4.1 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) using Observed 
Case [Safety Analysis Set]    


Protocol A7281010 
 
Figure 
Title 
14.2.2.2.4.2 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for Responders 
using Observed Case [Safety Analysis Set]     
14.2.2.2.4.3 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for Non-
responders using Observed Case [Safety Analysis Set]  
14.2.2.2.5.1 
Proportion of Subjects in Clinical Remission at Baseline and  Week 
16 based on the Total Mayo Score (Centrally read) for those with 
Remission using Non-responder Imputation Method [Safety 
Analysis Set]   
14.2.2.2.5.2 
Proportion of Subjects in Clinical Remission at Baseline and  Week 
16 based on the Total Mayo Score (Centrally read)  for those with 
No Remission using Non-responder Imputation Method [Safety 
Analysis Set]    
14.2.2.2.6.1 
 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for those with 
Remission using Observed Case [Safety Analysis Set]     
14.2.2.2.6.2 
Proportion of Subjects in Clinical Remission at Baseline and Week 
16 based on the Total Mayo Score (Centrally read) for those with 
No Remission using Observed Case [Safety Analysis Set]     
14.2.2.3.1 
Proportion of Subjects with Clinical Response  based on the Partial 
Mayo Score using Non-responder Imputation Method [Safety 
Analysis Set]     
14.2.2.3.2 
Proportion of Subjects with Clinical Response based on the Partial 
Mayo Score Observed Case [Safety Analysis Set]     
14.2.2.3.3 
Proportion of Subjects in Clinical Remission based on the Partial 
Mayo Score using Non-Responder Imputation Method [Safety 
Analysis Set]    
14.2.2.3.4 
Proportion of Subjects in Clinical Remission based on the Partial 
Mayo Score using Observed Case [Safety Analysis Set]    
14.2.2.4.1 
 
Proportion of Subjects in Clinical Response  based on SCCAI Score 
by Monthly Visits using Non-responder Imputation Method [Safety 
Analysis Set]    


Protocol A7281010 
 
Figure 
Title 
14.2.2.4.2 
Proportion of Subjects in Clinical Response based on SCCAI Score 
by Monthly Visits using Observed Case [Safety Analysis Set]    
14.2.2.4.3 
Proportion of Subjects in Clinical Remission based on SCCAI Score 
by Monthly Visits using Non-Responder Imputation Method 
[Safety Analysis Set]    
14.2.2.4.4 
Proportion of Subjects in Clinical Remission based on SCCAI Score 
by Monthly Visits using Observed Case [Safety Analysis Set]    
14.2.2.5 
Kaplan-Meier curve for Time to Dose Escalation for Subjects 
Assigned to SHP647 75mg [Safety Analysis Set]    
14.2.3.1.1.1 
Individual Serum Concentration-Time Profile for SHP647(Linear 
Scale) [Pharmacokinetic Set]  
14.2.3.1.1.2 
Individual Serum Concentration-Time profile for SHP647 by ADA 
status(linear Scale) [Safety Analysis Set] 
14.2.3.1.1.3 
Individual Serum Concentration-Time profile for SHP647 by NAb 
status(Linear Scale) [Safety Analysis Set] 
14.2.3.1.2 
Individual Serum Concentration-Time Profile for SHP647(Log 
Scale) [Pharmacokinetic Set] 
14.2.3.1.3 
Mean Serum Concentration-Time Profile for SHP647 (Linear 
Scale)[Pharmacokinetic Set]  
14.2.3.1.4 
Mean Serum Concentration-Time Profile for SHP647 (Log 
Scale)[Pharmacokinetic Set]  
14.2.3.2.1 
hsCRP (mg/dL)  Geometric  Mean over Time [Pharmacodynamic 
Set] 
14.2.3.2.2 
hsCRP (mg/dL)  Geometric  Mean Percent Change From Baseline 
over Time [Pharmacodynamic Set] 
14.2.3.2.3 
Fecal Calprotectin (mg/dL) Geometric Mean over 
Time[Pharmacodynamic Set] 
14.2.3.2.4 
Fecal Calprotectin (mg/dL) Geometric Mean Percent Change from 
Baseline over Time[Pharmacodynamic Set] 
 
Listing 
Title 
Shire Std 


Protocol A7281010 
 
Listing 
Title 
Shire Std 
16.1.7 
Randomization Assignments [All Randomized Subjects] 
Y 
16.2.1.1 
Subject Disposition [All Enrolled Subjects] 
Y 
16.2.1.2 
Subjects Who Terminated from the Study [All Enrolled 
Subjects] 
Y 
16.2.1.3 
Subject Analysis Set Classification [All Enrolled Subjects] 
N 
16.2.2.1 
Deviations from Inclusion/Exclusion Criteria [All Enrolled 
Subjects] 
N 
16.2.2.2 
Listing of Protocol Deviations [All Enrolled Subjects] 
N 
16.2.4.1 
Subject Demographics [Safety Analysis Set] 
Y 
16.2.4.2 
Subject Baseline Characteristics [Safety Analysis Set] 
N 
16.2.4.3 
Medical History in Studies A7281009 and A7281010 [Safety 
Analysis Set] 
Y 
16.2.4.4 
Prior and Concomitant Medications [Safety Analysis Set] 
Y 
16.2.4.5 
Drug allergies [Safety Analysis Set]  
N 
16.2.4.6 
Additional Biological Therapy taken during Follow-up Period 
[Safety Analysis Set] 
N 
16.2.5.1 
Investigational Product Exposure [Safety Analysis Set] 
Y 
16.2.5.2 
Pharmacokinetic Blood Serum Draw Times and Concentration 
Data [Pharmacokinetic  Set] 
N 
16.2.5.3 
Pharmacodynamics Fecal Calprotectin Collection data 
[Pharmacodynamic  Set] 
N 
16.2.5.4 
Pharmacodynamics Serum hsCRP Collection data 
[Pharmacokinetic  Set] 
N 
16.2.5.5 
Pharmacodynamics Soluble MAdCAM data [Pharmacodynamic 
Set] 
N 
16.2.6.1 
Listing of Total Mayo Score, Mayo Subscores, Clinical 
Remission and Clinical Response-Centrally Read [Safety 
Analysis Set] 
N 
16.2.6.2 
Listing of Partial Mayo Score [Safety Analysis Set] 
N 
16.2.6.3 
Listing of Mayo Score –Endoscopy Subscore [Safety Analysis 
Set] 
N 
16.2.6.4 
Listing of Simple Clinical Colitis Activity Index (SCCAI) [Safety 
Analysis Set] 
N 


Protocol A7281010 
 
Listing 
Title 
Shire Std 
16.2.7.1.1 
Adverse Events-Including Injection Site AEs [Safety Analysis 
Set] 
Y 
16.2.7.1.2 
Adverse Events-Excluding Injection Site AEs [Safety Analysis 
Set] 
Y 
16.2.7.2.1 
Subjects Reporting Serious Treatment-Emergent Adverse 
Events [Safety Analysis Set] 
Y 
16.2.7.2.2 
Subjects Reporting Serious Treatment-Emergent Adverse 
Events Leading to Death [Safety Analysis Set] 
Y 
16.2.7.3 
Subjects Reporting TEAEs Leading to Withdrawal of 
Investigational Product [Safety Analysis Set] 
Y 
16.2.7.4 
Subjects Reporting Treatment-Emergent Adverse Events 
[Safety Analysis Set] 
Y 
16.2.7.5 
Subjects Reporting TEAEs Related to Investigational Product 
[Safety Analysis Set] 
Y 
16.2.7.6 
Subjects Reporting TEAEs of Myalgia [Safety Analysis Set] 
Y 
16.2.7.7 
Subjects Reporting TEAEs of Clostridium Difficile Infection 
[Safety Analysis Set] 
Y 
16.2.7.8 
Subjects Reporting TEAEs of  Gastroenteritis [Safety Analysis 
Set] 
Y 
16.2.7.9 
Subjects Reporting TEAEs of Nasophrayngitis [Safety Analysis 
Set] 
Y 
16.2.7.10 
Medication Error [Safety Analysis Set] 
Y 
16.2.7.11 
Subjects Reporting TEAEs of Injection site reactions [Safety 
Analysis Set] 
Y 
16.2.8.1.1.1 
Clinical Laboratory Sample Collection and Results for 
Pregnancy Screen [Safety Analysis Set] 
Y 
16.2.8.1.1.2 
Clinical Laboratory Sample Collection [Safety Analysis Set] 
Y 
16.2.8.1.2 
Clinical Laboratory Test Results [Safety Analysis Set] 
Y 
16.2.8.1.3 
Subjects with Potentially Clinically Important Laboratory Test 
Results [Safety Analysis Set] 
Y 
16.2.8.1.4 
Subjects That Meet the Hy’s Law Criteria [Safety Analysis Set] 
N 
16.2.8.1.5 
CK data for Subjects with Adverse Event of Myalgia [Safety 
Analysis Set] 
Y 
16.2.8.1.6 
JC Virus Antibody[Safety Analysis Set] 
N 


Protocol A7281010 
 
Listing 
Title 
Shire Std 
16.2.8.1.7 
Subjects with Seroconversion at any point during Studies 
A7281009 and A7281010 [Safety Analysis Set] 
N 
16.2.8.1.8 
Enteric Pathogens [Safety Analysis Set] 
N 
16.2.8.2.1 
Vital Signs [Safety Analysis Set] 
Y 
16.2.8.2.2 
Subjects with Potentially Clinically Important Vital Signs 
[Safety Analysis Set] 
Y 
16.2.8.3.1 
12-lead ECG Results and Interpretation by Central Reader 
[Safety Analysis Set] 
Y 
16.2.8.3.2 
Subjects with Potentially Clinically Important ECG Results 
[Safety Analysis Set] 
Y 
16.2.8.3.3 
Cardiac Function Evaluation-Echocardiogram [Safety Analysis 
Set] 
N 
16.2.8.4.1 
Anti-drug Antibodies Results [Safety Analysis Set] 
N 
16.2.8.4.2 
Presence of Neutralizing Antibody Development in Subjects 
with positive Anti-drug Antibodies [Safety Analysis Set] 
N 
16.2.8.5 
Physical Examination [Safety Analysis Set] 
N 
16.2.8.6.1 
Listing of Confrontational Visual Fields [Safety Analysis Set] 
N 
16.2.8.6.2 
Listing of Timed 25-foot Walk [Safety Analysis Set] 
N 
16.2.8.6.3 
Listing of 9-Hole Peg Test [Safety Analysis Set] 
N 
16.2.8.6.4 
Symbol Digit Modalities Test [Safety Analysis Set] 
N 
16.2.8.6.5 
Multiple Sclerosis Neuropsychological Questionnaire Results 
[Safety Analysis Set] 
N 
16.2.8.6.6 
Listing of Subjects with Clinically Significant On-Treatment 
Changes in Confrontational Visual Fields Test [Safety Analysis 
Set] 
N 
16.2.8.6.7 
Listing of Subjects with Clinically Significant On-Treatment 
Changes in 25-Foot Walk Test [Safety Analysis Set] 
N 
16.2.8.6.8 
Listing of Subjects with Clinically Significant On-Treatment 
Changes in 9-Hole Peg Test [Safety Analysis Set] 
N 
16.2.8.6.9 
Listing of Subjects with Clinically Significant On-Treatment 
Changes in Symbol Digit Modality Test (SDMT) [Safety Analysis 
Set] 
N 


Protocol A7281010 
 
Listing 
Title 
Shire Std 
16.2.8.6.10 
Listing of Subjects with Clinically Significant On-Treatment 
Changes in Multiple Sclerosis Neuropsychological 
Questionnaire (MSNQ) [Safety Analysis Set] 
N 
16.2.8.7 
Biopsy Sample [Safety Analysis Set] 
N 
16.2.8.8 
Colonoscopy Report [Safety Analysis Set] 
N