A Phase 2a, Randomized, Placebo Controlled, Proof of Mechanism Study to Evaluate the Safety and Efficacy of AMG 557/MEDI5872 in Subjects With Primary Sjögren's Syndrome
Phase: PHASE2
Conditions: Primary Sjögren's Syndrome
Sponsor: MedImmune LLC



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PROTOCOL SYNOPSIS
TITLE
A Phase 2a, Randomized, Placebo-controlled, Proof of Mechanism Study to Evaluate the Safety and Efficacy of 
AMG 557/MEDI5872 in Subjects with Primary Sjogren’s Syndrome
HYPOTHESES
The primary hypothesis is that subjects with primary Sjogren’s syndrome (pSS) treated with 
AMG 557/MEDI5872 will have improvement in objective measures of disease activity.
The secondary hypotheses are that AMG 557/MEDI5872 will lead to a decrease in biomarkers (peripheral blood 
and minor salivary gland tissue), reflecting the activity of the inducible T-cell costimulator (ICOS):B7-related 
protein-1 (B7RP-1) pathway in subjects with pSS; that AMG 557/MEDI5872 will have an acceptable safety 
profile in subjects with pSS; and that subjects with pSS treated with AMG 557/MEDI5872 will have 
improvement in subjective measures of disease activity.
OBJECTIVES
The primary objective is to evaluate the effect of AMG 557/MEDI5872 compared to placebo in reducing 
objective measures of overall disease activity in subjects with pSS.
The secondary objectives are:
•
To evaluate the effect of AMG 557/MEDI5872 compared to placebo on peripheral blood and salivary gland 
biomarkers in subjects with pSS.
•
To evaluate the safety and tolerability of multiple subcutaneous (SC) doses of AMG 557/MEDI5872 in 
subjects with pSS.
•
To evaluate the effect of AMG 557/MEDI5872 compared to placebo in reducing objective and subjective 
measures of overall disease activity.
The exploratory objectives are:
•
To evaluate the effect of AMG 557/MEDI5872 compared to placebo on individual clinical and laboratory 
components of pSS.
•
To evaluate the effect of AMG 557/MEDI5872 compared to placebo on specific subjective symptoms of 
pSS.
•
To evaluate the pharmacokinetics, immunogenicity, and pharmacodynamics (PD) of AMG 557/MEDI5872.
STUDY ENDPOINTS
The primary endpoint of the study is the change in the European League Against Rheumatism Sjogren’s 
Syndrome Disease Activity Index (ESSDAI) score from baseline to Day 99.
The secondary endpoints of the study are:
•
Biomarkers:
◦
Outcomes in peripheral blood
◦
Change in plasma cell (PC) levels (including plasma blast [PB] levels) from baseline to Day 99
◦
Change in T follicular helper (TFH) levels from baseline to Day 99
◦
Outcomes in minor salivary gland tissue
◦
Change in PC levels from baseline to Day 99
◦
Change in TFH levels from baseline to Day 99
◦
Focus score
◦
Change in focus score from baseline to Day 99
•
Safety and tolerability of multiple SC doses of AMG 557/MEDI5872 as measured by the incidence of 
treatment-emergent adverse events, treatment-emergent serious adverse events, adverse events of special 
interest, and laboratory abnormalities
•
Change in European League Against Rheumatism Sjogren’s Syndrome Patient Reported Index (ESSPRI)
score from baseline to Day 99

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•
ESSDAI[3] and ESSDAI[4] response, defined as a decrease of at least 3[4] points from baseline in the 
ESSDAI at Day 99 without premature discontinuation of investigational product and without receiving 
prohibited concomitant medications
The exploratory endpoints of the study are:
•
Biomarkers:
◦
Outcomes in peripheral blood
◦
Change in PB levels from baseline to Day 99
◦
Change from baseline in PC gene signature at Day 99
◦
Change from baseline in TFH gene signature at Day 99
◦
Outcomes in minor salivary gland tissue
◦
Change in PB levels from baseline to Day 99
◦
Change from baseline in PC gene signature at Day 99
◦
Change from baseline in TFH gene signature at Day 99
•
All of the secondary and biomarker exploratory endpoints (except for outcomes in minor salivary gland 
tissue) may be assessed at other time points
•
ESSPRI response, defined as a decrease of at least 1 point or ≥ 15% from baseline in the ESSPRI at Day 99 
without premature discontinuation of investigational product and without receiving prohibited concomitant 
medications
•
Primary Sjogren’s syndrome symptoms as measured by the Profile of Fatigue and Discomfort-Sicca 
Symptoms Inventory-Short Form
•
Health status as measured by the Short Form-36 version 2 Health Survey (acute recall)
•
Patient Global Impression of Severity
•
Patient Global Impression of Change
•
Subject Global Assessment of Disease Activity
•
Physician Global Assessment of Disease Activity
•
Pharmacokinetic/immunogenicity/PD profile of AMG 557/MEDI5872
•
Change in individual clinical and laboratory components of pSS at Day 99 and Day 197:
◦
Salivary gland dysfunction: change from baseline in unstimulated or stimulated whole salivary flow
◦
Lachrymal gland dysfunction: change from baseline in Schirmer’s or change from baseline in van 
Bijsterveld score 
◦
Change from baseline in autoantibodies (SS-A, SS-B)
◦
Change in levels of markers of inflammation from baseline (hypergammaglobulinemia, beta-2
microglobulin, erythrocyte sedimentation rate, C-reactive protein)
◦
Change in levels of immunoglobulin G and immunoglobulin M rheumatoid factor from baseline
STUDY DESIGN
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the clinical and biologic efficacy, as well as the safety of multiple SC doses of AMG 557/MEDI5872 in adult 
subjects with pSS. The study will be conducted at approximately 15sites in Europe and North America. A total 
of approximately 42 subjects will be randomized in a 1:1 ratio to receive a fixed SC dose of 210 mg 
AMG 557/MEDI5872 (n = 21) or placebo (n = 21) every week (QW) for 3 weeks (Days 1 to 15) and then every 
2 weeks (Q2W) for 9 weeks (Days 29 to 85). Beginning on Day 99, all subjects (n = 42) will receive a fixed SC 
dose of 210 mg AMG 557/MEDI5872 QW (Days 99 to 113) and Q2W (Days 127 to 183) for an additional 
12 weeks.
On Day 106, subjects who had received placebo will receive a blinded dose of AMG 557/MEDI5872, and 
subjects who received AMG 557/MEDI5872 will receive a blinded dose of placebo (as these subjects would 
have already achieved steady-state levels of AMG 557/MEDI5872).
Randomization will be stratified by screening cellular immunophenotyping abnormalities (elevated TFH or 
elevated PB/PC vs normal values for both parameters).

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Investigational product (210 mg AMG 557/MEDI5872 or placebo) will be administered by SC injections in the 
anterior abdomen on each dosing day. Two 1.5 mL SC injections are required to deliver the investigational 
product. The injections should be administered at a distance of at least 2 cm apart and within 1 minute.
Screening visit(s) will be performed within 28 days prior to dosing, or at the discretion of the medical monitor, 
after signing the informed consent form. Screening assessments can be performed over multiple visits if 
necessary. Subjects will receive investigational product on Days 1, 8, 15, 29, 43, 57, 71, 85, 99, 106, 113, 127, 
141, 155, 169, and 183 during the active treatment period. Subjects will return to the study site on Days 197, 
225, 253, and 296 during the safety follow-up period.
Subjects will be in this study for approximately 46 weeks, which includes a screening period of up to 28 days 
and a safety follow-up period of 113 days.
TARGET SUBJECT POPULATION
The study population is representative of the subset of SS subjects with pSS who have more systemic 
inflammation and, in general, would be considered for treatment with biologic therapies. Existing data from the 
literature strongly suggest that this is also the subset of subjects where abnormalities related to B7RP-1-ICOS 
activation are more pronounced. Based on the gender distribution of pSS, it is anticipated that a predominantly 
(> 80%) female population will be recruited. Vulnerable populations will not be included in this study.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Subjects will receive a fixed SC dose of 210 mg AMG 557/MEDI5872 (n = 21) or placebo (n = 21) QW for 
3 weeks (Days 1 to 15) and then Q2W for 9 weeks (Days 29 to 85) as follows:
•
Fixed SC dose (two 1.5 mL SC injections in the anterior abdomen, administered at a distance of at least 
2 cm apart and within 1 minute) on Days 1, 8, 15, 29, 43, 57, 71, and 85.
Beginning on Day 99, all subjects (n = 42) will receive a fixed SC dose of 210 mg AMG 557/MEDI5872 QW 
(Days 99 to 113) and Q2W (Days 127 to 183) for an additional 12 weeks as follows:
•
Fixed SC dose (two 1.5 mL SC injections in the anterior abdomen, administered at a distance of at least 2 
cm apart and within 1 minute) on Days 99, 106, 113, 127, 141, 155, 169, and 183.
On Day 106, subjects who had received placebo will receive a blinded dose of AMG 557/MEDI5872, and 
subjects who received AMG 557/MEDI5872 will receive a blinded dose of placebo (as these subjects would 
have already achieved steady-state levels of AMG 557/MEDI5872).
STATISTICAL ANALYSIS PLAN
The planned sample size of 42 subjects (21 subjects per arm) will provide 80% power to detect a difference in 
mean change in ESSDAI of 4 (assumed standard deviation of 5) between two randomized groups at a two-sided 
0.1 level of statistical significance by using a two sample t-test. This sample size also provides about 80% power 
to detect 30% relative reduction in PC from tissue under assumption of coefficient of variation (CV) of 0.5. It 
should be noted that a smaller CV has been observed in blood from a previous study by Amgen (Study 
20060169), which could result in higher statistical power. The sample size was calculated by using nQuery 
Advisor 7.0.
Changes in ESSDAI score from baseline to Day 99 will be compared between AMG 557/MEDI5872 group and 
placebo group using an analysis of covariance adjusting for ESSDAI score at baseline, randomization stratum,
and treatment group. The analysis will be conducted using the intent-to-treat Population. The significance of 
treatment effect will be tested by using a two-sided test at significance level α of 0.1.

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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................2
LIST OF ABBREVIATIONS........................................................................................10
1
INTRODUCTION ..............................................................................................13
1.1
Disease Background..................................................................................13
1.2
AMG 557/MEDI5872 Background ...........................................................14
1.3
Summary of Nonclinical Experience .........................................................14
1.4
Summary of Clinical Experience...............................................................17
1.5
Rationale for Conducting the Study...........................................................20
1.6
Research Hypotheses ................................................................................20
1.6.1Primary Hypothesis...........................................................................20
1.6.2Secondary Hypotheses.......................................................................21
2
OBJECTIVES.....................................................................................................21
2.1
Objectives.................................................................................................21
2.1.1Primary Objective .............................................................................21
2.1.2Secondary Objectives........................................................................21
2.1.3Exploratory Objectives......................................................................21
2.2
Study Endpoints........................................................................................21
2.2.1Primary Endpoint ..............................................................................21
2.2.2Secondary Endpoint(s) ......................................................................22
2.2.3Exploratory Endpoint(s) ....................................................................22
3
STUDY DESIGN................................................................................................23
3.1
Description of the Study............................................................................23
3.1.1Overview...........................................................................................23
3.1.2Treatment Regimen...........................................................................25
3.2
Study Design and Dose Rationale .............................................................26
3.2.1Dose Rationale ..................................................................................26
3.2.2Rationale for Study Population..........................................................27
3.2.3Rationale for Endpoints.....................................................................27
4
MATERIALS AND METHODS.........................................................................28
4.1
Subjects ....................................................................................................28
4.1.1Number of Subjects...........................................................................28
4.1.2Inclusion Criteria...............................................................................28
4.1.3Exclusion Criteria..............................................................................30
4.1.4Subject Enrollment and Randomization.............................................32
4.1.5Withdrawal from the Study................................................................32
4.1.6Discontinuation of Investigational Product ........................................33
4.1.7Replacement of Subjects ...................................................................34

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4.1.8Withdrawal of Informed Consent for Data and Biological Samples ...34
4.2
Schedule of Study Procedures...................................................................35
4.2.1Enrollment/Screening Period.............................................................35
4.2.2Active Treatment Period....................................................................36
4.2.3Follow-up Period...............................................................................40
4.3
Description of Study Procedures ...............................................................41
4.3.1Efficacy.............................................................................................41
4.3.1.1
European League Against Rheumatism Sjogren’s Syndrome 
Disease Activity Index .......................................41
4.3.2Patient-reported Outcomes ................................................................42
4.3.2.1
Subject Global Assessment of Disease Activity................43
4.3.2.2
Short-form 36 Version 2...................................................43
4.3.2.3
Profile of Fatigue and Discomfort-Sicca Symptoms 
Inventory-Short Form.........................................43
4.3.2.4
European League Against Rheumatism Sjogren’s Syndrome 
Patient Reported Index.......................................44
4.3.2.5
Patient Global Impression of Change ...............................44
4.3.2.6
Patient Global Impression of Severity ..............................44
4.3.3Medical History and Physical Examination, Electrocardiogram, 
Weight, and Vital Signs....................................................44
4.3.3.1
Medical History ...............................................................44
4.3.3.2
Physical Examination, Height, and Weight.......................44
4.3.3.3
Vital Signs .......................................................................45
4.3.3.4
Electrocardiogram............................................................45
4.3.4Chest Radiograph..............................................................................45
4.3.5Clinical Laboratory Tests ..................................................................46
4.3.6Pharmacokinetic Evaluation and Methods .........................................48
4.3.7Immunogenicity Evaluation and Methods..........................................48
4.3.8Biomarker Evaluation and Methods...................................................48
4.3.8.1
Biopsy of Salivary Gland .................................................48
4.3.8.2
Immunophenotyping Assay..............................................49
4.3.8.3
PAXgene Ribonucleic Acid..............................................49
4.3.8.4
Cell Pellet for Deoxyribonucleic Acid Methylation ..........49
4.3.8.5
Exploratory Biomarker Sample ........................................50
4.3.8.6
Optional Biomarker Repository Samples..........................50
4.3.9Disease Evaluation and Methods .......................................................51
4.3.9.1
Training………................................................................51
4.3.9.2
Sjogren’s Classification Worksheet..................................51
4.3.9.3
Physician Global Assessment of Disease Activity ............52

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4.3.9.4
28-joint Count..................................................................52
4.3.9.5
Oral Evaluation................................................................52
4.3.9.6
Ophthalmological Evaluation...........................................53
4.3.10Estimate of Volume of Blood to Be Collected .................................53
4.4
Study Suspension or Termination..............................................................54
4.5
Investigational Products............................................................................55
4.5.1Identity of Investigational Product(s).................................................55
4.5.1.1
Investigational Product Dose Preparation .........................56
4.5.1.2
Investigational Product Inspection....................................56
4.5.1.3
Investigational Product Thawing Instructions...................56
4.5.1.4
Dose Preparation Steps.....................................................58
4.5.1.5
Treatment Administration ................................................59
4.5.1.6
Monitoring of Dose Administration..................................59
4.5.1.7
Reporting Product Complaints .........................................60
4.5.2Labeling.............................................................................................60
4.5.3Storage............. .................................................................................60
4.5.4Treatment Compliance ......................................................................61
4.5.5Accountability...................................................................................61
4.6
Treatment Assignment and Blinding .........................................................61
4.6.1Methods for Assigning Treatment Groups .........................................61
4.6.2Methods for Ensuring Blinding..........................................................62
4.6.3Methods for Unblinding ....................................................................62
4.6.3.1
Unblinding in the Event of a Medical Emergency.............62
4.6.3.2
Unblinding for the Primary Analyses ...............................62
4.7
Restrictions During the Study and Concomitant Treatment(s) ...................63
4.7.1Permitted Concomitant Medications..................................................63
4.7.2Prohibited Concomitant Medications.................................................63
4.8
Statistical Evaluation.................................................................................64
4.8.1General Considerations .....................................................................64
4.8.2Sample Size and Power Calculations .................................................65
4.8.3Efficacy.............................................................................................65
4.8.3.1
Primary Analysis..............................................................65
4.8.3.2
Secondary Analyses .........................................................65
4.8.3.3
Exploratory Analyses.......................................................66
4.8.4Safety........... .....................................................................................66
4.8.4.1
Analysis of Adverse Events..............................................66
4.8.4.2
Analysis of Clinical Laboratory Parameters......................66
4.8.4.3
Other Safety and Tolerability Endpoints...........................66

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4.8.5Patient-Reported Outcomes...............................................................67
4.8.5.1
Analysis of ESSPRI .........................................................67
4.8.5.2
Analysis of PROFAD-SSI-SF ..........................................67
4.8.5.3
Analysis of SF-36v2.........................................................67
4.8.5.4
Analysis of Subject Global Assessment of Disease 
Activity..............................................................68
4.8.5.5
Patient Global Impression of Severity ..............................68
4.8.5.6
Patient Global Impression of Change ...............................68
4.8.6Analysis of Immunogenicity/Pharmacokinetics .................................68
4.8.7Planned Analyses ..............................................................................68
5
ASSESSMENT OF SAFETY..............................................................................68
5.1
Definition of Adverse Events ....................................................................68
5.2
Definition of Serious Adverse Events........................................................69
5.3
Definition of Adverse Events of Special Interest .......................................70
5.4
Recording of Adverse Events....................................................................70
5.4.1Time Period for Collection of Adverse Events...................................70
5.4.2Follow-up of Unresolved Adverse Events..........................................71
5.5
Reporting of Serious Adverse Events ........................................................71
5.6
Other Events Requiring Immediate Reporting ...........................................72
5.6.1Overdose............. ..............................................................................72
5.6.2Hepatic Function Abnormality ..........................................................72
5.6.3Pregnancy..........................................................................................73
5.6.4Adverse Events of Special Interest.....................................................73
6
STUDY AND DATA MANAGEMENT .............................................................74
6.1
Training of Study Site Personnel...............................................................74
6.2
Monitoring of the Study............................................................................74
6.2.1Source Data.......................................................................................75
6.2.2Study Agreements .............................................................................75
6.2.3Archiving of Study Documents..........................................................75
6.3
Study Timetable and End of Study............................................................75
6.4
Data Management .....................................................................................75
6.5
Medical Monitor Coverage........................................................................76
7
ETHICAL AND REGULATORY REQUIREMENTS........................................76
7.1
Ethical Conduct of the Study.....................................................................76
7.2
Subject Data Protection.............................................................................76
7.3
Ethics and Regulatory Review...................................................................77
7.4
Informed Consent......................................................................................77
7.5
Changes to the Protocol and Informed Consent Form................................78

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7.6
Audits and Inspections ..............................................................................78
8
REFERENCES ...................................................................................................80
9
CHANGES TO THE PROTOCOL......................................................................84
LIST OF IN-TEXT TABLES
Table 3.1.2-1
Investigational Product Dose and Treatment Regimen ......................25
Table 4.1.2-1
Highly Effective Methods of Contraception......................................30
Table 4.2.1-1
Schedule of Screening Procedures ....................................................35
Table 4.2.2-1
Schedule of Study Procedures...........................................................37
Table 4.2.3-1
Schedule of Follow-up Procedures....................................................40
Table 4.3.10-1
Estimate of Blood Volume to be Collected........................................53
Table 4.5.1-1
Identification of Investigational Products..........................................55
Table 4.5.1.3-1
Allowable Time and Temperatures for Investigational Product 
Thawing ...........................................................................................57
Table 4.5.1.4-1
Preparation of Investigational Product Dose......................................59
Table 4.5.3-1
Storage of Investigational Product ....................................................61
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................25
LIST OF APPENDICES
Appendix 1
Signatures.........................................................................................92
Appendix 2
Additional Safety Guidance ..............................................................96
Appendix 3
American European Consensus Group Criteria .................................98
Appendix 4
European League Against Rheumatism Sjogren’s Syndrome Disease 
Activity Index...................................................................................99
Appendix 5
Subject Global Assessment of Disease Activity ..............................103
Appendix 6
Short-form 36 Version 2 .................................................................104
Appendix 7
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory-Short 
Form...............................................................................................110
Appendix 8
European League Against Rheumatism Sjogren’s Syndrome Patient 
Reported Index ...............................................................................115
Appendix 9
Patient Global Impression of Change ..............................................116
Appendix 10
Patient Global Impression of Severity.............................................117
Appendix 11
Guidance for Abnormal Liver Function Tests Management ............118

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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
AE
adverse event
AECG
American-European Consensus Group
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC0-14
area under the curve from Days 0 to 14
B7RP-1
B7-related protein-1
Cmax
observed maximum concentration
CI
confidence interval
CRP
C-reactive protein
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events 
CV
coefficient of variation
DNA
deoxyribonucleic acid
EBAP
exploratory biomarker analysis plan
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOS
End of Study
ESR
erythrocyte sedimentation rate
ESSDAI
European League Against Rheumatism Sjogren’s Syndrome Disease Activity 
Index
ESSPRI
European League Against Rheumatism Sjogren’s Syndrome Patient Reported 
Index
EU
European Union
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICOS
inducible T-cell costimulator
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
IgM
immunoglobulin M
IGRA
interferon-gamma release assay
IL
interleukin

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Abbreviation or 
Specialized Term
Definition
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IVRS/IWRS
interactive voice/web response system
KLH
keyhole limpet hemocyanin
Km
Michaelis-Menten constant
LA
lupus arthritis
MCP
metacarpophalangeal
MCS
mental component score
MDGA
Physician Global Assessment of Disease Activity
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect-level
NSAID
nonsteroidal anti-inflammatory drug
PB
plasma blast
PC
plasma cell
PCS
physical component score
PD
pharmacodynamics
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PIP
proximal interphalangeal
PK
pharmacokinetic(s)
PRO
patient-reported outcome
PROFAD-SSI-SF
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory-Short Form
pSS
primary Sjogren’s syndrome
Q2W
every 2 weeks
QW
every week
RF
rheumatoid factor
RNA
ribonucleic acid
SAE
serious adverse event
SC
subcutaneous
SF-36v2
Short Form-36 version 2
SGA
Subject Global Assessment of Disease Activity
SID
subject identification
SLE
systemic lupus erythematosus
SS
Sjogren’s syndrome
sSS
secondary Sjogren’s syndrome
TB
tuberculosis
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event

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Abbreviation or 
Specialized Term
Definition
TFH
T follicular helper
tmax
time to maximum concentration
ULN
upper limit of normal
US FDA
United Stated Food and Drug Administration
Vmax
maximum metabolic rate

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1
INTRODUCTION
1.1
Disease Background
Sjogren’s syndrome (SS) is an autoimmune disease characterized by chronic inflammation 
involving the exocrine glands. Salivary and lacrimal glands are predominantly affected 
leading to dry mouth and dry eyes (sicca symptoms) but other exocrine organs are also 
frequently involved. It the second most common rheumatic autoimmune disease and 
predominantly affects women, with a female to male ratio of 9:1. The annual incidence rate 
has been estimated to be between 0.11 to 0.53 cases per 10,000 adults (Alamanos et al, 2006; 
Pillemer et al, 2001; Plesivcnik Novljan et al, 2004; Yu et al, 2013) and the annual 
prevalence rate has been estimated to be between 2 to 330 cases per 10,000 adults 
(Alamanos et al, 2006; Birlik et al, 2009; Goransson et al, 2011; Miyasaka, 1995; 
Thomas et al, 1998; Tomsic et al, 1999; Trontzas and Andrianakos, 2005; Zhang et al, 1995).
Sjogren’s syndrome may occur alone (pSS), or may coexist with other systemic connective 
tissue disorders (secondary Sjogren’s syndrome [sSS]). In about 20% to 25% of patients,
systemic manifestations, such as arthritis, vasculitis, lung disease, peripheral or central 
neuropathy, and autonomic nervous system dysfunction accompany glandular involvement. 
Certain laboratory abnormalities, such as cryoglobulinemia, low complement levels, and 
markers of increased B-lymphocyte activation (increased levels of autoantibodies and 
hypergammaglobulinemia) are also more common in patients with systemic manifestations 
and can be used to identify this subpopulation. Patients with systemic manifestations are at 
higher risk of lymphoma, the incidence of which is increased 4- to 14-fold in SS. The 
treatment of sicca symptoms is mainly symptomatic. The management of extraglandular 
manifestations is unsatisfactory and is based on treatment of similar manifestations in other 
autoimmune diseases (Ramos-Casals et al, 2010).
The cause and pathogenesis of SS is still largely unknown. Key events include epithelial cell 
activation and a protracted inflammatory response with features of autoimmunity. B7-related 
protein-1 (B7RP-1) is the sole ligand for inducible T-cell costimulator (ICOS). The 
interaction between ICOS and B7RP-1 plays a significant role in T-cell cytokine production 
and differentiation into T follicular helper (TFH) cells, effector memory T cells and T-helper 
17 cells (Yoshinaga et al, 1999; Coyle et al, 2000; McAdam et al, 2001; Paulos et al, 2010; 
Crotty, 2011; Deenick and Ma, 2011). T follicular helper cells are CD4+ T cells specialized 
in providing help to B cells (Crotty, 2011, Deenick and Ma, 2011). Inducible T-cell 
costimulator expression on TFH cells is critical for optimal B-cell differentiation and 
immunoglobulin (Ig) isotype switching (Yoshinaga et al, 1999; Coyle et al, 2000, 
McAdam et al, 2001, Paulos et al, 2010). Inducible T-cell costimulator-null patients have a 

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significant reduction in B cells and TFH and a significant decrease in serum immunoglobulin 
G (IgG) levels (Grimbacher et al, 2003; Bossaller et al, 2006; Warnatz et al, 2006;
Takahashi et al, 2009), which suggests, by inference, that targeting the ICOS and B7RP-1 
interaction may lead to the reduction in antibody production, including autoantibodies.
Subjects with pSS have elevated ICOS and elevated percentages of TFH cells in the blood 
(Hutloff et al, 2004; Simpson et al, 2010; Li et al, 2012; Ma et al, 2012; Szabo et al, 2013). 
The frequency of TFH cells in the blood correlates with various markers of disease activity, 
such as anti-SS-A and anti-SS-B autoantibody levels and the presence of extraglandular 
manifestations. Higher focus scores on labial salivary gland biopsies correlate with TFH cells 
(defined by CD4+CXCR5+ICOS+PD-1+; Szabo et al, 2013), whereas the European League 
Against Rheumatism Sjogren’s Syndrome Disease Activity Index (ESSDAI) correlates with 
CD4+CXCR5+CCR6+TFH (Li et al, 2012). In addition, in systemic lupus erythematosus 
(SLE), which shares many immune abnormalities with SS, ICOS+ T cells co-localize with 
B cells in SLE nephritis lesions (Hutloff et al, 2004; Liarski et al, 2014); this suggests that 
ICOS+ T cells may not be only dysregulated in the central lymphoid compartment but also in 
the inflamed tissues, such as the salivary gland in SS.
Based on the role of the ICOS:B7RP-1 pathway in several key steps in the 
immunopathogenesis of SS, we propose that blocking B7RP-1 will lead to an improvement 
in blood and tissue markers of T- and B-cell activation with eventual clinical benefit.
1.2
AMG 557/MEDI5872 Background
AMG 557/MEDI5872 is briefly described below. Refer to the current Investigator’s 
Brochure (IB) for details.
AMG 557/MEDI5872 is a fully human immunoglobulin G2 monoclonal antibody that binds 
an epitope in the first Ig-like domain of B7RP-1 and inhibits its interaction with the ICOS 
receptor expressed by activated T cells. AMG 557/MEDI5872 has potential relevance in a 
number of autoimmune diseases including SLE and pSS and is being developed in 
partnership between Amgen and MedImmune.
1.3
Summary of Nonclinical Experience
Cynomolgus monkeys were selected as the nonclinical toxicology species because the 
in vitro potency of AMG 557/MEDI5872 was similar in cynomolgus monkeys and humans. 
Additionally, AMG 557/MEDI5872 does not cross react with rat or murine B7RP-1. 
Repeat-dose studies with weekly administration of AMG 557/MEDI5872 (1 to 300 mg/kg) 
included a 15-day subcutaneous (SC) repeat-dose study, a 6-week intravenous (IV) and 

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SC repeat-dose study, and a 3-month and 6-month SC repeat-dose study. In addition, a 
single-dose safety pharmacology study evaluating cardiovascular, respiratory, and central 
nervous system effects was conducted in cynomolgus monkeys.
Results of a safety pharmacology study with AMG 557/MEDI5872 were unremarkable. No 
adverse toxicologic effects have been observed in repeat-dose studies with 
AMG 557/MEDI5872 at weekly doses of ! 300 mg/kg IV or 30 mg/kg SC for 15 days, 
! 10 mg/kg IV for 6 weeks, or ! 5 mg/kg SC for 3 months in cynomolgus monkeys. In a 
6-week repeat-dose study, doses of 75 and 300 mg/kg IV were associated with toxicologic 
effects that included clinical manifestations that required the euthanasia of 1 male and 
1 female in the 300 mg/kg IV group. Slight to marked chronic periarteritis was observed in
various organs of 1 male and 1 female given 300 mg/kg/dose IV and in the cervix of 1 female 
given 75 mg/kg/dose IV necropsied at the termination of dosing. The chronic periarteritis 
was characterized by perivascular inflammation with occasional increased intimal cellularity 
and rarely medial hypertrophy in various organs (gastrointestinal tract, pancreas, kidney, 
gallbladder, heart, tongue, urinary bladder, ureter, uterus, cervix, vagina, and seminal 
vesicles). This periarteritis was rarely observed in animals administered 300 mg/kg 
AMG 557/MEDI5872 by SC injection (only occurring in the gallbladder of 1 male). The 
anatomic pathology findings of decreased germinal centers in lymphoid tissues were 
considered to be related to the expected pharmacology of ICOS/B7RP-1 blockade. Similar 
histopathologic changes were not observed in the earlier dose range-finding study where 
weekly IV (1 to 300 mg/kg) or SC (30 mg/kg) doses of AMG 557/MEDI5872 were 
administered for 15 days.
The test article-related findings in the 3-month study included chronic periarteritis 
characterized by increased intimal cellularity in the seminal vesicle in 1 male given 
25 mg/kg/dose. This lesion affected a majority of vessels and was characterized 
microscopically by hypertrophy of the endothelial cells with accumulated cells in the intima. 
The chronic periarteritis with increased intimal cellularity in the seminal vesicle was 
considered an adverse finding. Other test article-related findings included an increased 
incidence of decreased germinal centers in the spleen and mesenteric lymph node of animals 
given 25 or 90 mg/kg/dose, an increased incidence of decreased germinal centers in the 
mandibular lymph node of animals given 90 mg/kg/dose, and an increased incidence of 
lymphocyte depletion in the thymus of males given 90 mg/kg/dose; these findings were 
considered to be related to the expected pharmacology of AMG 557/MEDI5872. 
Microscopic changes seen in the lymphoid organs appeared reversible because they were not 
noted at the end-of-recovery-phase necropsy. In addition, no vascular lesions were seen in 
any organ, including the seminal vesicles, suggesting that if any lesions had been present, 

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they also had resolved. Immunohistochemical evaluation of the arterial lesions from animals 
treated for 6 weeks or 3 months with AMG 557/MEDI5872 compared with controls showed 
that these lesions had increased granular deposits of cynomolgus monkey (IgG and 
immunoglublin M [IgM]) or human (AMG 557/MEDI5872) Igs consistent with immune 
complex deposition, suggesting this as an etiology for the lesion. Many of these immune 
complexes contained AMG 557/MEDI5872 and cynomolgus monkey Igs that supported 
anti-AMG 557/MEDI5872 antibodies and suggested that these may have been a contributing 
or inciting factor for the lesion.
In the 6-month repeat-dose study, male and female cynomolgus monkeys were administered 
AMG 557/MEDI5872 at a dose level of 0, 5, 25, or 90 mg/kg via SC injection once weekly 
for 6 months. A decrease in the size/number of germinal centers were noted in the spleen of 
some animals at ≥ 25 mg/kg/dose, which is an anticipated pharmacological effect of 
AMG 557/MEDI5872; the changes in the spleen were not present or had partially reversed 
following the 4-month (16-week) treatment-free phase. Macroscopic findings at the SC 
injection site that correlated with microscopic findings of subacute inflammation were 
observed at all doses, and were not present or were partially reversed following the 4-month 
(16-week) treatment-free phase. Due to the mild severity of the findings, none of the effects 
in the study noted were considered adverse, and the no-observed-adverse-effect-level 
(NOAEL) was determined to be the highest dose, 90 mg/kg. The 90 mg/kg dose level 
corresponds to mean observed maximum concentration (Cmax) and area under the curve from 
Days 0 to 168 values of 1,930 μg/mL and 279,000 μg·hour/mL, respectively. The NOAEL 
established in the chronic 6-month study of 90 mg/kg is higher than previous studies where 
the NOAEL was determined based on toxicities that are caused by the development of 
neutralizing antibodies to AMG 557/MEDI5872 in the cynomolgus monkey. The NOAEL of 
90 mg/kg following 6 months of treatment with AMG 557/MEDI5872 is appropriate for 
determining safety margins in patients. Anti-AMG 557/MEDI5872 antibodies will continue 
to be monitored in the clinical studies. Results of the histopathology data further support that 
the chronic periarteritis observed in the prior 6-week and 3-month studies were most likely 
caused by anti-AMG 557/MEDI5872 antibodies; anti-AMG 557/MEDI5872 antibodies were 
observed only at a low incidence in the 6-month study when AMG 557/MEDI5872 was 
administered by the SC route.
Pharmacokinetic (PK) data were obtained from 2 cynomolgus monkey studies after 
single-dose IV and single-dose SC administration of 0.1 to 10 mg/kg AMG 557/MEDI5872. 
AMG 557/MEDI5872 exhibited a greater than dose-proportional increase in exposure in the 
0.1 to 1 mg/kg IV and 0.1 to 10 mg/kg SC dose range, and an approximately 
dose-proportional increase in the 1 to 10 mg/kg IV dose range.

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Multiple-dose toxicokinetic data were obtained from 4 cynomolgus monkey studies after 
once weekly, multiple-dose IV or SC administration for 15 days, 6 weeks, 13 weeks, or 
6 months (1 to 300 mg/kg). After multiple IV or SC administrations, the exposure increased 
approximately dose proportionally after the first dose and the last dose. No notable sex-based 
differences in toxicokinetics were observed. Moderate accumulation was observed after IV 
and SC dosing under the various aforementioned multiple dosing schedules with 
accumulation ratios ranging from 1.35 to 2.82.
A total of 77 of 158 monkeys (48.7%) treated with single or multiple doses of 
AMG 557/MEDI5872 tested positive for anti-AMG 557/MEDI5872 antibodies. The presence 
of anti-AMG 557/MEDI5872 antibodies was associated with a general decrease in exposure 
of AMG 557/MEDI5872 in the systemic circulation.
Additional details regarding the nonclinical experience of AMG 557/MEDI5872 are provided
in the IB.
1.4
Summary of Clinical Experience
AMG 557/MEDI5872 has been or is being investigated in 5 Amgen-sponsored clinical 
studies in subjects with mild, stable SLE, subacute cutaneous lupus erythematosus, lupus 
arthritis (LA), and moderate to severe psoriasis. Two studies (Studies 20060132 and 
20060169) in subjects with SLE have been completed. Two studies (Studies 20110105 and 
20100037) in subjects with moderate to severe psoriasis and subacute cutaneous lupus
erythematosus, respectively, have been prematurely terminated due to slow enrollment. One 
study (Study 20101103) in subjects with SLE with active LA is ongoing.
Study 20060132 was a randomized, single-dose, placebo-controlled, double-blind, 
dose-escalation study that evaluated the safety, tolerability, PK, and pharmacodynamics (PD)
of AMG 557/MEDI5872 in subjects with SLE (n = 57). Subjects were randomized to receive 
1.8, 6, 18, 60, 140, or 210 mg SC, or 18 mg IV AMG 557/MEDI5872 or placebo, with dose 
escalation occurring after consideration of the safety results seen at lower doses. Subjects 
were also immunized with keyhole limpet hemocyanin (KLH) on Days 2 and 29 (60 mg SC 
cohort), Days 8 and 36 (140 mg SC and 6 subjects in the 210 mg SC), and Days 15 and 43 
(2 subjects in the 210 mg SC cohort) to assess the impact of AMG 557/MEDI5872 on the 
anti-KLH IgM and IgG responses. After a single administration of AMG 557/MEDI5872, 
serum concentrations exhibited nonlinear PK behavior. Serum AMG 557/MEDI5872
exposure, as measured by area under the curve at last time point and Cmax, increased greater 
than dose proportionally across the dose range of 1.8 to 140 mg SC. However, an 
approximate dose-proportional increase in exposure was observed in the range of 140 to 

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210 mg SC. After single SC administration, the median time to maximum concentration 
(tmax) ranged from 3 to 7 days. Because of the nonlinear PK behavior, the bioavailability of 
AMG 557/MEDI5872 could not be assessed by comparison of SC and IV areas under the 
curves. However, based on simultaneous compartmental modeling of the available data, 
bioavailability after SC dosing was estimated to be 57%. Target occupancy results showed 
reversible and dose-related AMG 557/MEDI5872 coverage of B7RP-1 on circulating B cells. 
Flow cytometric data indicated a dose-related increase in mean total B7RP-1 and a dose-
related decrease in mean free B7RP-1 on peripheral B cells. No difference in either the 
anti-KLH IgG or IgM response was detected between the AMG 557/MEDI5872 and placebo 
groups. Single doses of AMG 557/MEDI5872 up to 210 mg SC and 18 mg IV were 
reasonably tolerated. No deaths were reported, and no subjects withdrew from the study or 
investigational product due to an adverse event (AE).
Study 20060169 was a randomized, double-blind, placebo-controlled, ascending, 
multiple-dose study that evaluated the safety, tolerability, PK, and PD of 
AMG 557/MEDI5872 in subjects with SLE (n = 58). Subjects were randomized to receive 6, 
18, 30, 45, 70, 140, or 210 mg SC AMG 557/MEDI5872 or placebo, administered every 
2 weeks (Q2W) for 7 doses. Subjects were also immunized with KLH on Days 57 and 85 to 
assess the impact of AMG 557/MEDI5872 on the anti-KLH IgG responses.
AMG 557/MEDI5872 exposure, as measured by area under the curve from Days 0 to 
14 (AUC0-14) and Cmax after the first and seventh doses, increased greater than dose
proportionally across the dose range of 6 to 70 mg SC. However, an approximate 
dose-proportional increase in exposure was observed in the dose range of 70 to 210 mg SC. 
Median tmax ranged from 4 to 7.6 days. Moderate accumulation was observed after 7 doses of 
AMG 557/MEDI5872 at 6 to 210 mg SC, with median accumulation ratios for AUC0-14 
ranging from 1.94 to 4.41. Based on trough values, steady state appeared to be reached 
during this time period in all SC dose groups. Target occupancy results showed reversible 
and dose-related AMG 557/MEDI5872 coverage of B7RP-1 on circulating B cells. Flow 
cytometric data indicated a dose-related increase in mean total B7RP-1 and a dose-related 
decrease in mean free B7RP-1 on peripheral B cells. A significant reduction in the anti-KLH 
IgG response was observed in the AMG 557/MEDI5872 group compared with the placebo 
group (p = 0.0044). Although KLH is considered a neoantigen, 9 of the 56 subjects were 
found to have detectable levels of anti-KLH IgG antibodies prior to the first immunization in 
the study. To ensure a more appropriate comparison between groups that were homogenously 
naive to the administered antigen (and associated epitopes), a post-hoc analysis was 
conducted in which data from these subjects were censored. A clearer dose response was
observed along with reduced variability in the data. The inhibition of the primary response 
(between Days 57 and 85) was more readily achieved compared with the secondary response,

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with all the dose levels showing decreases in anti-KLH IgG responses relative to placebo. In 
the secondary response following the Day 85 immunization, greater degrees of inhibition of 
the anti-KLH antibody responses were observed with increasing dose levels. The 140 and 
210 mg dose levels appeared to have comparable effects, separable from the lower dose 
levels. Unlike the decreases observed with AMG 557/MEDI5872 administration on 
anti-KLH IgG responses, no decreases were seen on anti-KLH IgM responses. This lack of 
impact of ICOS blockade on the antigen-specific IgM response is consistent with the human 
and mouse genetic studies and in studies of pharmacologic blockade in mice 
(Metz et al, 2009; Bossaller et al, 2006; Grimbacher et al, 2003; Takahashi et al, 2009;
Yusuf et al, 2014). Multiple doses of AMG 557/MEDI5872 up to 210 mg SC were 
reasonably tolerated. No deaths were reported. Five subjects who received 
AMG 557/MEDI5872 had serious adverse events (SAEs; cellulitis, respiratory failure, 
tachycardia, uterine leiomyoma, and viral cardiomyopathy) and 2 subjects who received 
placebo had SAEs (chest pain and cholecystitis). All SAEs occurred in a single subject each 
and all SAEs but one (respiratory failure) were considered to be not related to investigational 
product. One subject who had a related SAE of respiratory failure withdrew from the study.
Study 20110105 was a randomized, double-blind, placebo-controlled, multiple-dose study 
that evaluated the safety, tolerability, PK, and PD of AMG 557/MEDI5872 in subjects with 
moderate to severe psoriasis (n = 6). Subjects were randomized to receive 105 or 210 mg SC 
AMG 557/MEDI5872 or placebo on Days 1, 8, 15, 29, 43, 57, and 71. The study was 
prematurely terminated by Amgen because of slow enrollment; 6 out of 10 planned subjects 
had been enrolled (4 subjects had received AMG 557/MEDI5872 and 2 subjects received 
placebo), 5 had completed the study and 1 had withdrawn from the study. After 
administration of 210 mg SC on Days 1, 8, 15, 29, 43, 57, and 71 in 4 subjects, steady-state 
concentrations of AMG 557/MEDI5872 were reached on Day 15 (predose of the third dose). 
The mean trough concentrations on Days 43 and 57 were slightly low (24 to 26 μg/mL),
mainly because 1 subject had decreasing AMG 557/MEDI5872 concentrations due to the 
presence of anti-drug antibodies. Without these two time points, mean steady-state trough 
concentrations were 28 to 29 μg/mL. No deaths were reported. Two subjects who received 
AMG 557/MEDI5872 had 4 SAEs (cyst rupture and oedema peripheral in 1 subject; 
pulmonary embolism and deep vein thrombosis in 1 subject); however, none of these events 
were considered to be related to investigational product.
Study 20100037 was a randomized, double-blind, placebo-controlled, multiple-dose study 
that evaluated the safety, tolerability, PK, and PD of AMG 557/MEDI5872 in subjects with 
subacute cutaneous lupus erythematosus. In this study, subjects were to be randomized to 
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followed by 6 additional doses Q2W. The study was prematurely terminated by Amgen 
because of slow enrollment; 1 subject received placebo and completed the study.
Study 20101103 is a randomized, double-blind, placebo-controlled, multiple-dose, 
parallel-group study evaluating the safety, tolerability, PK, PD, and clinical effect of 
AMG 557/MEDI5872 in subjects with SLE with active LA. Subjects will be randomized to 
receive 210 mg SC QW for 3 weeks followed by 10 additional doses Q2W. The study is 
currently ongoing; approximately 40 subjects are planned to be enrolled in the study.
Additional details regarding the clinical experience of AMG 557/MEDI5872 are provided in 
the IB.
1.5
Rationale for Conducting the Study
There is an unmet medical need for disease-modifying therapies in SS. This is the first time 
the ICOS:B7RP-1 pathway will be targeted in subjects with pSS. Therefore, there may be no 
direct benefit to subjects participating in the study. However, based on the role of the 
ICOS:B7RP-1 pathway in several key steps in the immunopathogenesis of SS, blocking 
B7RP-1 may improve some underlying immunologic abnormalities, which may result in 
clinical benefit. Changes observed in the blood and tissue markers of T- and B-cell activation 
will contribute to generalizable knowledge.
There are no identified risks with AMG 557/MEDI5872. Potential risks with 
AMG 557/MEDI5872 include injection-site reactions. Important potential risks include 
anaphylaxis and serious allergic reactions, immune complex disease, bacterial, viral, and 
opportunistic infections, including progressive multifocal leukoencephalopathy, and 
malignancy. As with the administration of any foreign protein or biologic agent, subjects will 
be closely monitored for anaphylaxis and serious allergic reactions, as well as injection-site 
reactions. Immune complex disease, infections, and malignancies will also be monitored.
The results of this study will provide proof of mechanism of AMG 557/MEDI5872 in 
autoimmune diseases and will be informative for the design of larger Phase 2b studies.
A detailed assessment of benefit-risk is provided in the IB.
1.6
Research Hypotheses
1.6.1
Primary Hypothesis
The primary hypothesis is that subjects with pSS treated with AMG 557/MEDI5872 will 
have improvement in objective measures of disease activity.

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1.6.2
Secondary Hypotheses
The secondary hypotheses are that:
1. AMG 557/MEDI5872 will lead to a decrease in biomarkers (peripheral blood and minor 
salivary gland tissue), reflecting the activity of the ICOS:B7RP-1 pathway in subjects 
with pSS.
2. AMG 557/MEDI5872 will have an acceptable safety profile in subjects with pSS.
3. Subjects with pSS treated with AMG 557/MEDI5872 will have improvement in 
subjective measures of disease activity.
2
OBJECTIVES
2.1
Objectives
2.1.1
Primary Objective
To evaluate the effect of AMG 557/MEDI5872 compared to placebo in reducing objective 
measures of overall disease activity in subjects with pSS.
2.1.2
Secondary Objectives
1. To evaluate the effect of AMG 557/MEDI5872 compared to placebo on peripheral blood 
and salivary gland biomarkers in subjects with pSS.
2. To evaluate the safety and tolerability of multiple SC doses of AMG 557/MEDI5872 in 
subjects with pSS.
3. To evaluate the effect of AMG 557/MEDI5872 compared to placebo in reducing 
objective and subjective measures of overall disease activity.
2.1.3
Exploratory Objectives
1. To evaluate the effect of AMG 557/MEDI5872 compared to placebo on individual 
clinical and laboratory components of pSS.
2. To evaluate the effect of AMG 557/MEDI5872 compared to placebo on specific 
subjective symptoms of pSS.
3. To evaluate the PK, immunogenicity, and PD of AMG 557/MEDI5872.
2.2
Study Endpoints
2.2.1
Primary Endpoint
The primary endpoint of the study is the change in the ESSDAI score from baseline to 
Day 99.

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2.2.2
Secondary Endpoint(s)
The secondary endpoints of the study are:
1. Biomarkers:
a.
Outcomes in peripheral blood
i.
Change in plasma cell (PC) levels (including plasma blast [PB] levels) from 
baseline to Day 99
ii. Change in TFH levels from baseline to Day 99
b. Outcomes in minor salivary gland tissue
i.
Change in PC levels from baseline to Day 99
ii. Change in TFH levels from baseline to Day 99
c.
Focus score
i.
Change in focus score from baseline to Day 99
2. Safety and tolerability of multiple SC doses of AMG 557/MEDI5872 as measured by the 
incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious 
adverse events (TESAEs), adverse events of special interest (AESIs), and laboratory 
abnormalities
3. Change in European League Against Rheumatism Sjogren’s Syndrome Patient Reported 
Index (ESSPRI) score from baseline to Day 99
4. ESSDAI[3] and ESSDAI[4] response, defined as a decrease of at least 3[4] points from 
baseline in the ESSDAI at Day 99 without premature discontinuation of investigational 
product and without receiving prohibited concomitant medications
2.2.3
Exploratory Endpoint(s)
The exploratory endpoints of the study are:
1. Biomarkers:
a.
Outcomes in peripheral blood
i.
Change in PB levels from baseline to Day 99
ii. Change from baseline in PC gene signature at Day 99
iii. Change from baseline in TFH gene signature at Day 99
b. Outcomes in minor salivary gland tissue
i.
Change in PB levels from baseline to Day 99
ii. Change from baseline in PC gene signature at Day 99
iii. Change from baseline in TFH gene signature at Day 99
2. All of the secondary and biomarker exploratory endpoints (except for outcomes in minor 
salivary gland tissue) may be assessed at other time points
3. ESSPRI response, defined as a decrease of at least 1 point or ≥ 15% from baseline in the 
ESSPRI at Day 99 without premature discontinuation of investigational product and 
without receiving prohibited concomitant medications

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4. Primary Sjogren’s syndrome symptoms as measured by the Profile of Fatigue and 
Discomfort-Sicca Symptoms Inventory-Short Form (PROFAD-SSI-SF)
5. Health status as measured by the Short Form-36 version 2 (SF-36v2) Health Survey 
(acute recall)
6. Patient Global Impression of Severity (PGI-S)
7. Patient Global Impression of Change (PGI-C)
8. Subject Global Assessment of Disease Activity (SGA)
9. Physician Global Assessment of Disease Activity (MDGA)
10. Pharmacokinetic/immunogenicity/PD profile of AMG 557/MEDI5872
11. Change in individual clinical and laboratory components of pSS at Day 99 and Day 197:
a.
Salivary gland dysfunction: change from baseline in unstimulated or stimulated whole 
salivary flow
b. Lachrymal gland dysfunction: change from baseline in Schirmer’s or change from 
baseline in van Bijsterveld score 
c.
Change from baseline in autoantibodies (SS-A, SS-B)
d. Change in levels of markers of inflammation from baseline 
(hypergammaglobulinemia, beta-2 microglobulin, erythrocyte sedimentation rate
[ESR], C-reactive protein [CRP])
e.
Change in levels of IgG and IgM rheumatoid factor (RF) from baseline
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the clinical and biologic efficacy, as well as the safety of multiple SC doses 
of AMG 557/MEDI5872 in adult subjects with pSS. 
The study will be conducted at approximately 15 sites in Europe and North America.
A total of 42 subjects will be randomized in a 1:1 ratio to receive a fixed SC dose of 210 mg 
AMG 557/MEDI5872 (n = 21) or placebo (n = 21) QW for 3 weeks (Days 1 to 15) and then 
Q2W for 9 weeks (Days 29 to 85). Beginning on Day 99, all subjects (n = 42) will receive a 
fixed SC dose of 210 mg AMG 557/MEDI5872 QW (Days 99 to 113) and Q2W (Days 127 
to 183) for an additional 12 weeks.
On Day 106, subjects who had received placebo will receive a blinded dose of 
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blinded dose of placebo (as these subjects would have already achieved steady-state levels of 
AMG 557/MEDI5872).
Randomization will be stratified by screening cellular immunophenotyping abnormalities 
(elevated TFH or elevated PB/PC vs normal values for both parameters).
Investigational product (210 mg AMG 557/MEDI5872 or placebo) will be administered by a 
qualified healthcare professional by SC injections in the anterior abdomen on each dosing 
day. Two 1.5 mL SC injections are required to deliver the investigational product. The 
injections should be administered at a distance of at least 2 cm apart and within 1 minute.
Screening visit(s) will be performed within 28 days prior to dosing, or at the discretion of the 
medical monitor, after signing the informed consent form (ICF). Screening assessments can 
be performed over multiple visits if necessary. Subjects will receive investigational product 
on Days 1, 8, 15, 29, 43, 57, 71, 85, 99, 106, 113, 127, 141, 155, 169, and 183 during the 
active treatment period. Subjects will return to the study site on Days 197, 225, 253, and 
296 during the safety follow-up period.
Subjects will be in this study for approximately 46 weeks, which includes a screening period 
of up to 28 days and a safety follow-up period of 113 days.
The study flow diagram is shown in Figure 3.1.1-1.

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Figure 3.1.1-1
Study Flow Diagram
d = day; N = number of subjects
The endpoints to be measured in this study are described in Section 2.2.
3.1.2
Treatment Regimen
A total of 42 subjects are planned for this study. Investigational product dose and treatment 
regimen for the active treatment periods is described in Table 3.1.2-1.
Table 3.1.2-1
Investigational Product Dose and Treatment Regimen
N
Dose
Treatment Regimen
Days 1 to 85 
42
(AMG 557/MEDI5872: 21
Placebo: 21)
210 mg AMG 557/MEDI5872
or placebo
Fixed SC dose (two 1.5 mL SC injections in 
the anterior abdomen, administered at a 
distance of at least 2 cm apart and within 
1 minute) on Days 1, 8, 15, 29, 43, 57, 71, 
and 85.
Days 99 to 183
42
210 mg AMG 557/MEDI5872
(or placebo on Day 106)
Fixed SC dose (two 1.5 mL SC injections in 
the anterior abdomen, administered at a 
distance of at least 2 cm apart and within 
1 minute) on Days 99, 106 a, 113, 127, 141, 
155, 169, and 183.
N = number of subjects; SC = subcutaneous
a
On Day 106, subjects who had received placebo will receive a blinded dose of AMG 557/MEDI5872, and 
subjects who received AMG 557/MEDI5872 will receive a blinded dose of placebo.

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3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
The AMG 557/MEDI5872 dose and treatment regimen for this study is based on the dose 
and schedule used in an ongoing study by Amgen in subjects with SLE with active LA
(Study 20101103). The selected dose and treatment regimen are expected to be adequately
tolerated in subjects with pSS based on a lack of dose-limiting toxicities up to 210 mg SC 
Q2W for 7 doses in subjects with SLE (Study 20060169). The selected dose and treatment 
regimen is also expected to ensure sufficient coverage of the target up to Week 28 to 
adequately test the impact of B7RP-1 blockade on the chosen PD and clinical endpoints.
A 2-compartment, nonlinear PK model with parallel linear and nonlinear (maximum 
metabolic rate [Vmax] and Michaelis-Menten constant [Km]) elimination has been developed 
based on emerging concentration data from the Phase 1 studies, which describe the PK 
profiles of single doses of AMG 557/MEDI5872 up to 140 mg SC and multiple doses of 
AMG 557/MEDI5872 up to 70 mg Q2W for 7 doses. Predicted exposures associated with 
multiple doses of 140 mg SC AMG 557/MEDI5872 or multiple doses of 210 mg SC 
AMG 557/MEDI5872 were extrapolated based on the model. In addition, PK model 
predictions have been compared with all data available as of the 18Oct2011 database 
snapshot from the multiple-ascending dose study (Study 20060169) and all data from the 
completed single-ascending dose study (Study 20060132). The PK model reasonably predicts 
the available data for both 210 mg single-dose and 140 mg multiple-dose regimens (see IB 
for further details). While full-time course profiles are available from only a subset of the 140 
and 210 mg cohorts in the multiple-dose study (Study 20060169), comparison of model 
predictions and clinical observations provides additional support for the dosing regimen. 
Pharmacokinetic-receptor occupancy modeling of serum concentrations of 
AMG 557/MEDI5872 and flow cytometric analyses of B7RP-1 occupancy on circulating 
B cells based on final data from the single-ascending dose study (Study 20060132) and 
multiple-ascending dose study (Study 20060169) indicates a 90% effective concentration of 
0.80 μg/mL (95% confidence interval [CI]: 0.31-1.3 μg/mL) and a 99% effective 
concentration of 8.8 μg/mL (95% CI: 3.5-14 μg/mL) using a simple maximum effect model. 
Pharmacokinetic modeling indicates that at serum AMG 557/MEDI5872 concentrations less 
than 2 μg/mL, B7RP-1 target-mediated (ie, nonlinear) elimination is the predominant 
AMG 557/MEDI5872 clearance pathway, suggesting that the B7RP-1 target is not saturated 
at these drug concentrations. At 2.92 μg/mL (= 9 × Km) serum AMG 557/MEDI5872 
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processes (ie, linear). This concentration likely represents target (receptor) 90% saturation in 
vivo, and takes into account compartments not measured (or accessible) using flow 
cytometric methods. The 210 mg SC dose and regimen proposed is projected to reach 
steady-state trough serum concentrations of AMG 557/MEDI5872 above the 99% effective 
concentration for approximately 35 weeks.
In order to rapidly achieve the target concentrations and to maintain this coverage for the 
duration of dosing, subjects randomized to AMG 557/MEDI5872 will receive 210 mg 
AMG 557/MEDI5872 QW for 3 weeks followed by 12 additional doses of 210 mg 
AMG 557/MEDI5872, providing treatment duration of 26 weeks. Beginning on Day 99, 
those subjects who had been randomized to placebo, will receive 210 mg 
AMG 557/MEDI5872 QW for 3 weeks followed by 5 additional doses of 210 mg 
AMG 557/MEDI5872, providing treatment duration of 13 weeks.
3.2.2
Rationale for Study Population
The study population is representative of the subset of SS subjects with pSS who have more 
systemic inflammation and, in general, would be considered for treatment with biologic 
therapies. Existing data from the literature strongly suggest that this is also the subset of 
subjects where abnormalities related to B7RP-1-ICOS activation are more pronounced
(Li et al, 2012; Szabo et al, 2013). Based on the gender distribution of pSS, it is anticipated 
that a predominantly (> 80%) female population will be recruited. Vulnerable populations 
will not be included in this study.
3.2.3
Rationale for Endpoints
The key objectives of this study are to evaluate the effect of AMG 557/MEDI5872 compared 
to placebo in reducing objective measures of overall disease activity in subjects with pSS. 
Currently, there are no validated or uniformly accepted efficacy criteria for SS. In addition, 
there have been no successful efficacy studies with immunomodulating agents in SS. The 
efficacy measures in previous treatment studies used either selected measures of glandular 
function, such as salivary flow, or composite outcome measures combining objective and 
subjective measures of disease activity. Recently, an international panel of Sjogren’s experts 
created and validated two indices to capture both the objective (ESSDAI) and subjective 
(ESSPRI) measures of SS (Seror et al, 2010; Seror et al, 2011). Although, neither of these
indices has been used as a primary efficacy measure in clinical studies, retrospective 
application of the ESSDAI to treatment studies with belimumab (Benlysta; 
Mariette et al, 2013) and rituximab (Meiners et al, 2012; Moerman et al, 2014) supports its 
use as a primary outcome measure in populations similar to this study. Unpublished data 

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from the ESSDAI development group identified the ESSDAI score of 5 as the cutoff between 
mild and moderate to severe disease, recommended the score as the lower threshold for entry 
in clinical studies, and also identified a change of at least 3 on the ESSDAI as a clinically 
significant improvement in this subpopulation.
The biomarkers to be assessed are justified on the basis that B7RP-1:ICOS interactions play a 
significant role in TFH cell differentiation. T follicular helper cells provide help to B cells in 
the germinal centers and promote their differentiation into antibody producing PB and PC. 
The ESSPRI will be used to capture the subjective aspects of pSS. Measuring changes in 
individual elements of SS and general health status will allow a more detailed analysis of the 
results and better understanding of the impact of AMG 557/MEDI5872 on various pathologic 
processes in SS.
Safety and tolerability will be evaluated by standard measures.
The exploratory biomarker endpoints reflect the expected changes based on the mechanism 
of action of AMG 557/MEDI5872.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A total of 42 subjects will be randomized in a 1:1 ratio to receive a fixed SC dose of 210 mg 
AMG 557/MEDI5872 (n = 21) or placebo (n = 21) QW for 3 weeks (Days 1 to 15) and then 
Q2W for 9 weeks (Days 29 to 85). Beginning on Day 99, all subjects (n = 42) will receive a 
fixed SC dose of 210 mg AMG 557/MEDI5872 QW (Days 99 to 113) and Q2W (Days 127 
to 183) for an additional 12 weeks.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Age 18 through 75 years at the time of signing the ICF.
2. Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act in the United States, European Union [EU] Data 
Privacy Directive in the EU) obtained from the subject/legal representative prior to 
performing any protocol-related procedures, including screening evaluations.
3. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception from signing the ICF, and 

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must agree to continue using such precautions through Day 296 of the study; cessation of 
contraception after this point should be discussed with a responsible physician. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception.
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or those who are not postmenopausal (defined as 12 months with no 
menses without an alternative medical cause).
b. A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. The 
acceptable methods of contraception are described in Table 4.1.2-1. 
4. Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use a highly effective method of contraception (see Table 4.1.2-1) from 
Day 1 through Day 296.
5. Body weight ≥ 40 kg.
6. Fulfill American-European Consensus Group (AECG) criteria for pSS (see Appendix 3).
7. ESSDAI score ≥ 6.
8. Positive anti-SS-A and/or anti-SS-B autoantibodies AND at least one of the following 
laboratory abnormalities:
a.
IgG > 13 g/L
b. RF level > upper limit of normal (ULN)
c.
Positive test for cryoglobulins
9. Willingness to undergo protocol-required minor salivary gland biopsies.
10. Meet all of the following tuberculosis (TB) criteria:
a.
No signs or symptoms suggestive of active TB upon medical history or physical 
examination
b. Negative diagnostic TB test during screening (defined as a negative interferon-
gamma release assay [IGRA] test for TB at screening) OR a confirmed indeterminate 
IGRA test for TB obtained during the screening period (those with confirmed 
indeterminate IGRA test will have repeat IGRA test at Days 99 and 197).
c.
A chest x-ray with no evidence of current active infection (eg, TB) or old active TB, 
malignancy, or clinically significant abnormalities (unless due to pSS) obtained 
during the screening period or anytime within 90 days prior to signing the ICF.
11. Immunization up to date as determined by local standard of care.

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Table 4.1.2-1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Male condom plus spermicide
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system (eg, 
Mirena®) a
•
Implants
•
Hormone shot or injection
•
Combined pill
•
Minipill
•
Patch
a
This is also considered a hormonal method.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
the investigational product or interpretation of subject safety or study results.
2. Concurrent enrollment in another clinical study involving an investigational treatment.
3. Previous treatment with AMG 557/MEDI5872.
4. Evidence of signs or symptoms of a viral, bacterial, or systemic fungal infection within 
2 weeks (14 days) prior to randomization (Day 1) according to the assessment of the 
investigator; any infection requiring IV antibiotic or antiviral treatment within 8 weeks of 
randomization (Day 1); history of herpes zoster within 3 months prior to randomization 
(Day 1).
5. History of ethanol or drug abuse within 1 year prior to signing informed consent.
6. Evidence of significant renal insufficiency, defined by estimated glomerular filtration rate
(eGFR) < 30 mL/minute/1.73m2.
7. Positive test at screening for either hepatitis B surface antigen, hepatitis B core antibody, 
hepatitis C antibody, or human immunodeficiency virus (HIV) antibody.
8. During screening and prior to randomization (Day 1), any of the following:
a.
Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 2.5 × ULN or total bilirubin > 2 × ULN (unless due to Gilbert’s disease) or 
evidence of chronic liver disease;
b. Total white blood cell count < 1,500 × 106/L;
c.
Neutrophil count < 1,000 × 106/L;
d. Platelet count < 50,000 × 106/L;
e.
Hemoglobin < 8 g/dL.
9. Poorly controlled hypertension as judged by the Principal Investigator and confirmed by 
repeat assessment during the screening period.
10. Poorly controlled diabetes (hemoglobin A1c > 8%).
11. History of malignancy, except for basal or squamous cell carcinoma of the skin or 
cervical carcinoma in situ (cervical intraepithelial neoplasia Grade 3) treated with 
documented success of curative therapy.

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12. Underlying condition (other than SS) that predisposes the subject to infections (eg, 
history of splenectomy).
13. History of anaphylaxis to any biological therapy.
14. A known history of allergy or reaction to any component of the investigational product 
formulation or history of severe reaction to any human gamma globulin therapy.
15. History of serum sickness.
16. Prior administration of any of the following:
a.
Belimumab in the past 6 months prior to randomization (Day 1);
b. Rituximab in the past 12 months or CD19+ B cells < 5/μL if rituximab treatment was 
more than 12 months prior to randomization (Day 1);
c.
Abatacept in the past 6 months prior to randomization (Day 1);
d. Tumor necrosis factor inhibitors (adalimumab, certolizumab, etanercept, golimumab, 
infliximab) in the past 3 months prior to randomization (Day 1);
e.
Tocilizumab in the past 3 months prior to randomization (Day 1);
f.
Cyclophosphamide (or any other alkylating agent) in the past 6 months prior to 
randomization (Day 1); cyclosporine (except for eye drops), tacrolimus, sirolimus, 
mycophenolate mofetil, azathioprine, or leflunomide in the past 3 months prior to 
randomization (Day 1).
17. Participation in an investigational drug or device trial within 30 days or 5 half-lives, 
whichever time period is longer, prior to randomization (Day 1).
18. Any live or attenuated vaccine within 4 weeks prior to signing the ICF (administration of 
killed vaccines is acceptable).
19. Planned or ongoing pregnancy (a negative urine pregnancy test is required during 
screening and at study visits specified in the schedule of assessments) or lactation.
20. Receiving any of the following:
a.
Corticosteroids: 
i.
> 10 mg/day oral prednisone (or equivalent);
ii. Any change or initiation of new dose of oral corticosteroids within 4 weeks prior 
to signing the ICF through randomization (Day 1);
iii. Intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to 
signing the ICF through randomization (Day 1);
iv. Any change or initiation of new dose of topical corticosteroids within 2 weeks 
prior to signing the ICF through randomization (Day 1);
b. Antimalarials: any increase or initiation of new dose of antimalarials (eg, 
chloroquine, hydroxychloroquine, quinacrine) within 12 weeks prior to signing the 
ICF through randomization (Day 1).
c.
Methotrexate: 
i.
> 20 mg/week methotrexate;
ii. Any change or initiation of new dose of methotrexate within 4 weeks prior to 
signing the ICF through randomization (Day 1);
iii. Any change in route of administration.

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d. Any increase or initiation of new dose of regularly scheduled nonsteroidal 
anti-inflammatory drugs (NSAIDs) within 2 weeks prior to signing the ICF through 
randomization (Day 1).
e.
Any increase or initiation of new doses of cevimeline or pilocarpine and cyclosporine 
eye drops (Restasis) within 2 weeks prior to signing the ICF through randomization 
(Day 1).
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IVRS/IWRS]), 
and the screening evaluations may begin to assess study eligibility (inclusion/exclusion) 
criteria. The SID number will be used to identify the subject during the screening process and 
throughout study participation, if applicable.
Subjects will be randomized at a 1:1 ratio to receive either AMG 557/MEDI5872 or placebo 
as described in Table 3.1.2-1. Randomization will be stratified by screening cellular 
immunophenotyping abnormalities (elevated TFH or elevated PB/PC vs normal values for 
both parameters).
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) and are 
rescreened will receive a new SID number. Subjects can be rescreened with medical monitor
approval.
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will 
be seen and assessed by an investigator. Adverse events will be followed up; questionnaires 
(eg, for patient-reported outcomes [PROs]) should be returned by the subject. If a subject 
withdraws from further participation in the study, then no further study visits or data 
collection should take place.

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4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occurs in the subject in question:
1. Withdrawal of consent from further treatment with investigational product or lost to 
follow-up
2. An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing
3. Any Grade ≥ 3 TEAE (based on Common Terminology Criteria for Adverse Events 
[CTCAE; Version 4.0]) that is considered to be related to investigational product by the 
investigator, unless in the opinion of the investigator, the event(s) are manifestations of 
SS (eg, within the definitions included in the ESSDAI). Isolated Grade ≥ 3 laboratory 
abnormalities without a clinical event meeting the above criteria will not automatically 
lead to discontinuation of investigational product. Grade ≥ 3 neutropenia requiring a 
therapeutic intervention to increase neutrophil counts will lead to discontinuation of 
investigational product even in the absence of any other clinical event (eg, fever) 
regardless of the relatedness to investigational product.
4. At the medical monitor’s discretion, subjects may be withdrawn if it is determined that 
eligibility criteria had been violated at the time of enrollment or subjects are
noncompliant with study procedures
5. The investigator or the medical monitor deems withdrawal as being in the subject’s best 
interest
6. Pregnancy
7. Any of the following liver function abnormalities:
a.
ALT or AST > 8 × ULN;
b. ALT or AST > 5 × ULN for more than 2 weeks;
c.
ALT or AST > 3 × ULN and bilirubin > 2 × ULN or international normalized ratio
(INR) > 1.5; see Section 5.6.2 for additional details regarding reporting of subjects 
with ALT or AST > 3 × ULN and bilirubin > 2 × ULN with unknown etiology (ie, 
Hy’s law cases);
d. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).
8. Active TB or latent TB defined as a confirmed positive IGRA test.
9. The use of any of the medications/treatments listed in Section 4.7.2 (Prohibited 
Concomitant Medications) at any time during the treatment period.
Subjects who are permanently discontinued from receiving investigational product will enter 
the follow-up period and be followed for safety and have protocol-specified assessments 
performed including follow up of any AEs unless consent is withdrawn specifically from 
further study participation (Section 4.1.5), the subject is lost to follow-up or the subject is
enrolled in another clinical study.

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4.1.7
Replacement of Subjects
Subjects who receive at least one dose of investigational product will not be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the Sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
Samples Obtained for Future Research
Samples obtained for future research will be labeled with a sample identification number. If 
the subject withdraws consent for participating in the future research, the Sponsor will locate 
the subject’s sample and destroy it. 
If the subject consents to have his/her samples used for future research, this additional 
research may not start immediately and may start at any time during the storage period. The 
subject’s sample(s) will be stored by the Sponsor with similar sample(s) from other subjects 
at a secure central laboratory. The subject’s sample(s) will not be kept for more than 25 years 
after the end of the study in which they were collected. If the subject chooses not to allow 
his/her study samples to be used for future research, the samples will be destroyed by the 
Sponsor once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the Sponsor for future research, the investigator will arrange to have it destroyed. If 
consent is withdrawn after the subject’s sample(s) have been sent to the Sponsor for future 
research, the Sponsor and the investigator will ensure that these sample(s) are destroyed 
unless the sample identification number(s) has been removed and the subject can no longer 
be linked to any sample(s). However, if the subject’s sample(s) have already been used for 
research, the Sponsor is not required to destroy results of this research. In this case only the 
remaining sample(s) will be destroyed.

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4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted at screening. Assessments should be 
performed in the order shown in the table, whenever feasible.
Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -28 to Day -1
Written informed consent/assignment of SID number
X
Subject Global Assessment of Disease Activity 
X
ESSPRI 
X
Medical history 
X
Physical examination
X
Vital signs (BP, HR, RR and temp)
X
Body height
X
Body weight 
X
Sjogren’s Classification Worksheet 
X
ESSDAI
X
Physician Global Assessment of Disease Activity
X
28-joint count
X
Safety laboratory tests (hematology, chemistry, and urinalysis)
X
Coagulation tests
X
Hemoglobin A1c
X
Serum β-hCG pregnancy test a
X
Autoantibody panel b
X
Exploratory autoantibody panel c
X
Immune panel d
X
Infectious disease panel e
X
Immunophenotyping assay
X
Chest X-ray f
X
ECG g
X
Inflammatory markers h
X
Exploratory biomarker sample (serum)
X
Optional biomarker repository sample (serum)
X
Optional biomarker repository sample (plasma)
X
Biopsy of salivary gland
X
Assessment of AEs/SAEs
X
Concomitant medications
X

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Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -28 to Day -1
Verify eligibility criteria
X
AE = adverse event; ANA = anti-nuclear antibody; PA = posteroanterior; B-2 microglobulin = beta-2 
microglobulin; βhCG = beta-human chorionic gonadotropin; BP = blood pressure; CRP = C-reactive protein; 
ECG = electrocardiogram; ENA = extractable nuclear antigens; ESR = erythrocyte sedimentation rate; ESSDAI 
= European League Against Rheumatism Sjogren’s Syndrome Disease Activity Index; ESSPRI = European 
League Against Rheumatism Sjogren’s Syndrome Patient Reported Index; HIV = human immunodeficiency 
virus; HR = heart rate; IgG = immunoglobulin G; IgM = immunoglobulin M; IGRA = interferon-gamma release 
assay; LIPS = Luciferase Immunoprecipitation Systems; RR = respiratory rate; SAE = serious adverse event; 
SID = subject identification; temp = temperature; V = visit
a
Female subjects, unless surgically sterile or 1 year postmenopausal
b
Autoantibody panel includes ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), 
rheumatoid factor (at minimum, IgG and IgM)
c
Exploratory autoantibody panel includes assessment of anti-SS-A and anti-SS-B by LIPS assay
d
Immune panel includes complements C3 and C4, cryoglobulins, quantitative immunoglobulins, and 
immunofixation electrophoresis
e
Infectious disease panel includes HIV, hepatitis B and C, IGRA
f
A PA and lateral chest x-ray will be performed at screening, if not performed within the previous 3 months
g
Standard 12-lead ECG
h
Inflammatory markers include hypergammaglobulinemia, B-2 microglobulin, ESR, and CRP
4.2.2
Active Treatment Period
Table 4.2.2-1 shows all procedures to be conducted during the active treatment period. 
Assessments should be performed in the order shown in the table, whenever feasible.
All blood, saliva, and biopsy samples should be collected prior to investigational product 
administration; the time of collection for these samples should be recorded in source 
documentation.

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Table 4.2.2-1
Schedule of Study Procedures
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Study Day / 
Procedure
1
8
(±1)
15
(±1)
29
(±3)
43
(±3)
57
(±3)
71
(±3)
85
(±3)
99 
(±3)
106 
(±1)
113 
(±1)
127 
(±3)
141 
(±3)
155 
(±3)
169 
(±3)
183 
(±3)
197
(±3)/
ETV
Subject Global Assessment of 
Disease Activity 
X
X
X
X
X
X
X
ESSPRI
X
X
X
X
X
X
X
SF-36v2 
X
X
X
X
X
X
X
PROFAD-SSI-SF
X
X
X
X
X
X
X
PGI-S
X
X
X
X
PGI-C
X
X
X
X
Physical examination 
X
X
X
X
X
X
X
X
X
Vital signs (BP, HR, RR, temp)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
Physician Global Assessment of 
Disease Activity
X
X
X
X
X
X
X
28-joint count
X
X
X
X
X
X
X
ESSDAI
X
X
X
X
X
X
X
Safety laboratory tests
(hematology, chemistry, and 
urinalysis)
X
X
X
X
X
X
X
X
X
Coagulation tests
X
X
IGRA a
X
X
Urine pregnancy test b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Autoantibody panel c
X
X
X
X
X
X
X
Exploratory autoantibody 
paneld
X
X
X
X
X
X
X
Immune panel e
X
X
X

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Table 4.2.2-1
Schedule of Study Procedures
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Study Day / 
Procedure
1
8
(±1)
15
(±1)
29
(±3)
43
(±3)
57
(±3)
71
(±3)
85
(±3)
99 
(±3)
106 
(±1)
113 
(±1)
127 
(±3)
141 
(±3)
155 
(±3)
169 
(±3)
183 
(±3)
197
(±3)/
ETV
Anti-AMG 557/MEDI5872 
antibodies sample
X
X
X
X
X
X
ECG f
X
Inflammatory markers g
X
X
X
Exploratory biomarker sample
(serum)
X
X
X
X
X
X
X
Exploratory biomarker sample 
(saliva)
X
X
X
X
X
X
X
Optional biomarker repository 
sample (serum)
X
X
X
X
X
X
X
Optional biomarker repository 
sample (plasma)
X
X
X
X
X
X
X
Optional biomarker repository 
sample (saliva)
X
X
X
X
X
X
X
Immunophenotyping assay
X
X
X
X
X
PK sample
X
X
X
X
X
X
X
X
X
X
X
PAXgene RNA
X
X
X
X
X
X
X
X
Oral evaluation
(unstimulated and stimulated 
salivary flow)
X h
X
X
X
X
X
X
Ophthalmological evaluation 
(complete dry eye evaluation) i
X h
X
X
Cell pellet for DNA 
methylation
X
X
X
Biopsy of salivary gland j
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 4.2.2-1
Schedule of Study Procedures
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
Study Day / 
Procedure
1
8
(±1)
15
(±1)
29
(±3)
43
(±3)
57
(±3)
71
(±3)
85
(±3)
99 
(±3)
106 
(±1)
113 
(±1)
127 
(±3)
141 
(±3)
155 
(±3)
169 
(±3)
183 
(±3)
197
(±3)/
ETV
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Verify eligibility criteria
X
Randomization
X
AMG 557/MEDI5872 or 
Placebo
X
X
X
X
X
X
X
X
AMG 557/MEDI5872
X
X k
X
X
X
X
X
X
AE = adverse event; ANA = anti-nuclear antibody; B-2 microglobulin = beta-2 microglobulin; BP = blood pressure; CRP = C-reactive protein; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; ENA = extractable nuclear antigens; ESR = erythrocyte sedimentation rate; ESSDAI = European League 
Against Rheumatism Sjogren’s Syndrome Disease Activity Index; ESSPRI = European League Against Rheumatism Sjogren’s Syndrome Patient Reported 
Index; ETV = Early Termination Visit; HR = heart rate; IgG = immunoglobulin G; IgM = immunoglobulin M; IGRA = interferon-gamma release assay; LIPS = 
Luciferase Immunoprecipitation Systems; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PI = Principal 
Investigator; PK = pharmacokinetic; PROFAD-SSI-SF = Profile of Fatigue and Discomfort-Sicca Symptoms Inventory-Short Form; RNA = ribonucleic acid; RR 
= respiratory rate; SAE = serious adverse event; SF-36v2 = Short Form-36 version 2; temp = temperature; V = visit
Note: All assessments should take place prior to investigational product administration.
a
In subjects with confirmed indeterminate results at screening
b
Female subjects, unless surgically sterile or 1 year postmenopausal
c
Autoantibody panel includes ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), rheumatoid factor (at minimum, IgG and IgM)
d
Exploratory autoantibody panel includes assessment of anti-SS-A and anti-SS-B by LIPS assay
e
Immune panel includes complements C3 and C4, cryoglobulins, quantitative immunoglobulins, and immunofixation electrophoresis
f
Standard 12-lead ECG
g
Inflammatory markers include hypergammaglobulinemia, B-2 microglobulin, ESR, and CRP
h
Baseline oral and ophthalmological evaluations may be performed within 28 days prior to dosing on Visit 2
i
Ophthalmological evaluation includes Schirmer’s test without anesthesia, van Bijsterveld score, and tear break-up time
j
Subjects who discontinue the study before Day 99 should only have the repeat biopsy of the salivary gland performed at the PI’s discretion
k
Blinded placebo administration for subjects who received AMG 557/MEDI5872 from Days 1 to 85

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4.2.3
Follow-up Period
Table 4.2.3-1 shows all procedures to be conducted during the follow-up period. 
Assessments should be performed in the order shown in the table, whenever feasible.
Table 4.2.3-1
Schedule of Follow-up Procedures
Visit Number
V19
V20
V21
NA
Study Days / 
Procedure
225
(±7)
253
(±7)
296
/EOS
(±7)
Unsch a
Subject Global Assessment of Disease Activity
X
X
X
X
ESSPRI
X
X
X
X
SF-36v2
X
X
X
X
PROFAD-SSI-SF
X
X
X
X
PGI-S
X
X
PGI-C
X
X
Physical examination
X
X
X
X
Vital signs (BP, HR, RR, temp)
X
X
X
X
Body weight
X
X
X
Physician Global Assessment of Disease 
Activity
X
X
X
X
28-joint count
X
X
X
X
ESSDAI
X
X
X
X
Safety laboratory tests (hematology, chemistry, 
and urinalysis)
X
X
X
X
Coagulation tests
X
Urine pregnancy test b
X
X
X
X
Autoantibody panel c
X
Exploratory autoantibody panel d
X
Immune panel e
X
X
Anti-AMG 557/MEDI5872 antibodies sample
X
X
Inflammatory markers f
X
Exploratory biomarker sample (serum)
X
X
Exploratory biomarker sample (saliva)
X
X
Optional biomarker repository sample (serum)
X
X
Optional biomarker repository sample (plasma)
X
X
Optional biomarker repository sample (saliva)
X
X
Immunophenotyping assay
X
X
PK sample
X
X
X
X
PAXgene RNA
X
X
ECG g
X
X
Oral evaluation
(unstimulated and stimulated salivary flow)
X
X
X
X

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Table 4.2.3-1
Schedule of Follow-up Procedures
Visit Number
V19
V20
V21
NA
Study Days / 
Procedure
225
(±7)
253
(±7)
296
/EOS
(±7)
Unsch a
Cell pellet collection for DNA methylation
X
Ophthalmological evaluation h
(complete dry eye evaluation)
X
X
Assessment of AEs/SAEs
X
X
X
X
Concomitant medications
X
X
X
X
AE = adverse event; ANA = anti-nuclear antibody; B-2 microglobulin = beta-2 microglobulin; BP = blood 
pressure; CRP = C-reactive protein; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EOS = End of 
Study; ENA = extractable nuclear antigens; ESR = erythrocyte sedimentation rate; ESSDAI = European League 
Against Rheumatism Sjogren’s Syndrome Disease Activity Index; ESSPRI = European League Against 
Rheumatism Sjogren’s Syndrome Patient Reported Index; HR = heart rate; IgG = immunoglobulin G; IgM = 
immunoglobulin M; LIPS = Luciferase Immunoprecipitation Systems; NA = not applicable; PGI-S = Patient 
Global Impression of Change; PGI-S = Patient Global Impression of Severity; PI = Principal Investigator; PK = 
pharmacokinetic; PROFAD-SSI-SF = Profile of Fatigue and Discomfort-Sicca Symptoms Inventory-Short 
Form; RNA = ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SF-36v2 = Short Form-36 
version 2; temp = temperature; Unsch = unscheduled; V = visit
a
Unscheduled visit assessments are to be completed at the PI’s discretion
b
Female subjects, unless surgically sterile or 1 year postmenopausal
c
Autoantibody panel includes ANA, ENA (anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), and
rheumatoid factor (at minimum, IgG and IgM)
d
Exploratory autoantibody panel includes assessment of anti-SS-A and anti-SS-B by LIPS assay
e
Immune panel includes complements C3 and C4, cryoglobulins, quantitative immunoglobulins, and 
immunofixation electrophoresis
f
Inflammatory markers include hypergammaglobulinemia, B-2 microglobulin, ESR, and CRP
g
Standard 12-lead ECG
h
Ophthalmological evaluation may be performed within 2 weeks prior to EOS, and includes Schirmer’s test 
without anesthesia, van Bijsterveld score, and tear break-up time
4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
European League Against Rheumatism Sjogren’s Syndrome Disease 
Activity Index
The ESSDAI is a validated consensus disease activity index with 12 domains (Constitutional, 
Lymphadenopathy, Glandular, Articular, Cutaneous, Pulmonary, Renal, Muscular, Peripheral 
Nervous System, Central Nervous System, Hematological, and Biological) that is able to 
capture changes in the severity of systemic manifestations of pSS. Each domain is weighted 
from 1 (Biologic domain) to 6 (Muscular domain) and has 3 or 4 levels of activity per 
domain, ranging from 0 (no activity) to 3 (high activity).

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The theoretical range of values for the ESSDAI is 0 to 123, with the final score being 
calculated as follows:
Final Score = Sum of all 12 domain scores
Domain score = Activity level × Domain weight
For example, the domain score for the Muscular domain, with a domain weight of 6 and 
levels of activity ranging from 0 to 3 (where ‘0’ indicates ‘no activity’, ‘1’ indicates ‘low 
activity’, ‘2’ indicated ‘moderate activity’, and ‘3’ indicates ‘high activity’) can range 
between 0 and 18.
Over the course of the study, the ESSDAI should be completed by the same MedImmune 
trained Principal Investigator, designated physician, or qualified site personnel whenever 
possible. If there is a change in site personnel over the course of the study, new Principal 
Investigators or site physicians/personnel must be trained prior to performing the ESSDAI. 
A copy of the ESSDAI can be found in Appendix 4.
4.3.2
Patient-reported Outcomes
Patient-reported outcomes instruments will be completed at the site on paper. 
Patient-reported outcomes assessments must be administered in a systematic way to ensure 
data integrity. The following best practice guidelines should be followed for all PRO
assessments:
•
Administer before other procedures
◦
Always administer PRO instruments before other study procedures
•
Provide the right environment
◦
Provide a quiet and private location to complete the instrument
•
No right or wrong answers
◦
Remind subjects that there are no right or wrong answers and that we are asking them 
to complete these questionnaires because we’re interested in hearing directly from 
them on how they feel
•
Help with procedural questions
◦
Make sure the subject understands how to complete the instrument. Instrument
instructions are usually self-explanatory but staff may answer questions about
procedural issues like what it means to “tick a box”
•
Avoid bias: do not clarify the meaning of questions or responses
◦
Sometimes subjects will ask center staff to clarify the meaning of a question or
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clarify items. Remind them that there are no right or wrong answers. Tell them that 
they should select the response that best answers the question as they understand it
•
No time limits
◦
Although most instruments require only a few minutes to complete, the subject
should be given as much time as is needed
•
Review for completeness
◦
Prompt review of the questionnaire for completeness will minimize missing data and 
data queries. If an item is left blank, ask the subject if they intended to leave the item 
blank. Provide an opportunity for the subject to answer if they wish
4.3.2.1
Subject Global Assessment of Disease Activity
Subjects will be asked to complete the SGA. The SGA is a single-item question which asks 
subjects consider how their illness affects them and report on how they have felt over the last 
7 days. Responses range from 0 (very well) to 100 (very poor) on a 100-mm visual analogue 
scale. The physician and subject must complete the global assessments (MDGA and SGA, 
respectively) independently of each other. A copy of the SGA can be found in Appendix 5.
4.3.2.2
Short-form 36 Version 2
The SF-36v2 [acute recall] is a 36-item, subject-completed, general health status assessment 
(Ware et al, 2007). The instrument captures information regarding 8 health domains: Physical 
Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role 
Emotional, and Mental Health. The SF-36v2 provides scores for each domain as well as two 
psychometrically-based summary scores: physical component score (PCS) and mental 
component score (MCS). The recall period for the acute version is one week (ie, “last 
week”). The instrument can be completed in approximately 10-18 minutes. A copy of the SF-
36v2 can be found in Appendix 6.
4.3.2.3
Profile of Fatigue and Discomfort-Sicca Symptoms Inventory-Short Form
The PROFAD-SSI-SF is a 19-item, subject-completed assessment of symptoms associated 
with pSS (Bowman et al, 2009). The instrument captures information on 8 domains of 
symptoms: somatic fatigue, mental fatigue, arthralgia, vascular dysfunction, oral dryness, 
ocular dryness, cutaneous and vaginal dryness. Each symptom domain is comprised of one or 
more “facets”. Patient-reported severity in the past 2 weeks is captured using an 8-point 
(0 [no/not] to 7 [as bad as imaginable]) scale. The instrument can be completed in 
approximately 5-8 minutes. A copy of the PROFAD-SSI-SF can be found in Appendix 7.

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4.3.2.4
European League Against Rheumatism Sjogren’s Syndrome Patient 
Reported Index
The ESSPRI is a 3-item, subject-completed assessment of SS symptoms (Seror et al, 2011).
The instrument captures subject-rated severity of dryness, fatigue, and pain using 0-10 
numeric rating scales anchored as no symptom (0) and maximal imaginable symptom (10). 
The recall period is stated in each question as “the last 2 weeks.” The ESSPRI total score is 
the mean of the 3 items. The instrument can be completed in approximately 1 minute. A copy 
of the ESSPRI can be found in Appendix 8.
4.3.2.5
Patient Global Impression of Change
The PGI-C is a single item designed to capture the subject’s perception of change in their 
overall symptom severity from randomization until the time of completion. Change in 
severity is captured using a 7-point scale (much better, about the same, much worse). A copy 
of the PGI-C can be found in Appendix 9.
4.3.2.6
Patient Global Impression of Severity
The PGI-S is a single item designed to capture the subject’s perception of overall symptom 
severity at the time of assessment on a 5-point categorical response scale (no symptoms, very 
severe symptoms). A copy of the PGI-S can be found in Appendix 10.
4.3.3
Medical History and Physical Examination, Electrocardiogram, 
Weight, and Vital Signs
4.3.3.1
Medical History
Complete medical history will include past and current medical conditions such as 
cardiovascular disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatological, psychiatric, genitourinary, drug and 
surgical history, or any other diseases or disorders. Medical history will be performed at 
screening and will be reviewed at Day 1; any changes in medical history since screening will 
be documented, if applicable.
4.3.3.2
Physical Examination, Height, and Weight
Physical examinations, including weight will be performed by a physician or qualified 
designee and will include examination of the following: general appearance, head, ears, eyes, 
nose, throat, neck, skin, as well as cardiovascular, respiratory, abdominal, and nervous 
systems. Each clinically significant abnormal finding will be recorded in the electronic case 
report form (eCRF). Physical examinations including weight will be performed at screening

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and during the active treatment and follow-up periods as specified in the schedule of study 
procedures (see Table 4.2.1-1, Table 4.2.2-1, Table 4.2.3-1). Height will be measured at 
screening only.
4.3.3.3
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and tympanic body temperature) will 
be obtained at screening and during the active treatment and follow-up periods as specified in 
the schedule of study procedures (see Table 4.2.1-1, Table 4.2.2-1, Table 4.2.3-1). All vital 
sign measurements will be made with the subject in a sitting position having rested in this 
position for at least 5 minutes before each reading. Vital signs will be obtained immediately 
before investigational product administration (within 15 minutes of the beginning of SC 
injection), immediately after investigational product administration, and approximately 
30 minutes after completion of investigational product administration. During the weekly 
administration periods (Days 1, 8, 15, 99, 106, and 113), vital signs will also be evaluated at
approximately 60 minutes after completion of dose administration and until stable as judged 
by the investigator.
4.3.3.4
Electrocardiogram
Electrocardiogram (ECG) recordings will be obtained at screening and during the active 
treatment and follow-up periods as specified in the schedule of study procedures (see 
Table 4.2.1-1, Table 4.2.2-1 and Table 4.2.3-1). At the specified visits, 12-lead ECGs will be 
obtained after 10 minutes of supine rest. The following variables will be reported: heart rate, 
RR, PR, QRS and QT intervals from the primary lead of the digital 12-lead ECG. The 
investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason.
4.3.4
Chest Radiograph
A chest x-ray (posteroanterior and lateral views) will be obtained during the screening period
or can be substituted with documentation of a previous chest x-ray performed anytime within 
90 days of signing the ICF. A chest x-ray that has no evidence of current active infection (eg, 
TB) or old active TB, malignancy, or clinically significant abnormalities (unless due to pSS) 
is required to meet inclusion criteria.
In addition to screening for the presence of current active infection (eg, TB) or old active TB, 
malignancy, or clinically significant abnormalities (unless due to pSS), the chest x-ray will 
be used to document the presence of significant cardiac and pulmonary disease abnormalities 
as well as to provide the initial disease activity data (pulmonary involvement) needed for the 

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ESSDAI assessment on Day 1. A formal radiologic report of the chest x-ray should be 
available at the site. The report should allow the assessment of the following:
•
No evidence of any active infection including TB
•
No evidence of old active TB
•
No evidence of malignancy
•
No evidence of other clinically significant abnormalities unless felt secondary to pSS
(these should be specified [eg, pleural effusion])
4.3.5
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. 
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed central clinical laboratory. Urine pregnancy tests may be performed at the site using 
a licensed test (dipstick). Clinically significant abnormal laboratory results, which represent a 
change which may require an intervention, should be repeated as soon as possible (preferably 
within 24 to 48 hours from receipt of results) at the discretion of the Principal Investigator.
Clinical laboratory safety tests can be repeated at the Principal Investigator’s discretion.
The following clinical laboratory tests will be performed (see Table 4.2.1-1, Table 4.2.2-1, 
Table 4.2.3-1 for the schedule of tests): 
Serum Chemistry
•
Calcium
•
Alkaline phosphatase (ALP)
•
Chloride
•
Total bilirubin and direct bilirubin
•
Magnesium
•
Creatinine
•
Potassium
•
Blood urea nitrogen
•
Sodium
•
eGFR
•
Bicarbonate
•
Glucose
•
AST
•
Albumin
•
ALT
•
Total protein
•
Cholesterol (including total, low-density 
lipoprotein, and high-density lipoprotein)
•
Uric acid
•
Triglycerides
•
Creatinine phosphokinase
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently.

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Hematology
•
White blood cell (WBC) count with differential
•
Platelet count
•
Red blood cell (RBC) count
•
Hemoglobin
•
Hematocrit
Coagulation
•
INR
•
Prothrombin time
•
Activated partial thromboplastin time
Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein
•
Microscopy including WBC/high power field 
(HPF), RBC/HPF
Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin (hCG)
•
Serum beta-hCG (at screening only)
Other Safety Tests
•
Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody
•
HIV antibody
•
IGRA
Other Tests
•
Autoantibody panel: anti-nuclear antibody, extractable nuclear antigens (anti-SS-A, anti-SS-B, anti-
Smith/anti-ribonuclear protein), RF (at minimum, IgG and IgM)
•
Exploratory autoantibody panel: anti-SS-A and anti-SS-B by Luciferase Immunoprecipitation Systems 
assay
•
Immune panel: complements C3 and C4, cryoglobulins, quantitative Igs, and immunofixation 
electrophoresis
•
Inflammatory markers: beta-2 microglobulin, ESR, CRP
•
Hemoglobin A1c

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4.3.6
Pharmacokinetic Evaluation and Methods
Serum samples for AMG 557/MEDI5872 concentration determination will be collected at 
baseline prior to investigational product administration and also during the active treatment
and follow-up periods of the study (see Table 4.2.2-1 and Table 4.2.3-1).
AMG 557/MEDI5872 serum concentrations will be measured using a validated enzyme-
linked immunosorbent assay developed at Amgen.
AMG 557/MEDI5872 plasma concentration will be measured prior to investigational product 
administration.
4.3.7
Immunogenicity Evaluation and Methods
Serum samples will be collected for the assessment of anti-AMG 557/MEDI5872 antibodies
against AMG 557/MEDI5872 during the active treatment and follow-up periods of the study 
(see Table 4.2.2-1 and Table 4.2.3-1). Serum will be measured for the presence of 
anti-AMG 557/MEDI5872 antibodies by Amgen using a validated immunoassay.
4.3.8
Biomarker Evaluation and Methods
Serum, plasma, whole blood, tissue, and saliva samples will be collected at various time 
points as outlined in Table 4.2.1-1, Table 4.2.2-1 and Table 4.2.3-1. All biomarker analyses 
will be conducted to test hypotheses associated with the mechanism of action of 
AMG 557/MEDI5872, identify subsets of subjects responsive to AMG 557/MEDI5872, and 
to characterize the gene signatures. Detailed instructions on sample collection, processing 
and shipping will be provided in a separate laboratory manual.
4.3.8.1
Biopsy of Salivary Gland
A minor salivary gland biopsy will be performed during screening, after the subject signs the 
informed consent but before receiving investigational product, and at Day 99 (see
Table 4.2.1-1 and Table 4.2.2-1) for clinical evaluation and assessment of tissue biomarkers.
Subjects who meet eligibility criteria after rescreening do not need to have a minor salivary 
gland biopsy during rescreening if a biopsy was done during their first screening period. The 
biopsy obtained during the first screening can be used as the baseline biopsy. The minor 
salivary glands are the most accessible glands located just under the mucosal surface in the
lower lip. Using sterile technique, a shallow incision 1-2 cm in length should be made on 
either side of the midline of inner lip under local anesthesia. The screening and Day 99 
biopsies will be taken from different sides of the lip. A minimum of 3 glands and a maximum 
of 6 glands should be obtained for analysis. Closure of the incision and selection of suture 
(eg, suture size and/or type [resorable vs traditional]), as well as postoperative care and 

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follow-up, should be in accordance with local medical practice and in the judgment of the 
Principal Investigator. Simple analgesics are allowed in the postoperative period, as needed.
Minor salivary gland biopsies will be analyzed for 1) the focus score (a semi-quantitative 
assessment of focal lymphocytic sialoadenitis, which is defined as the presence of ≥1 dense 
aggregate of 50 or more lymphocytes in a 4 mm2 area), 2) immunohistochemistry 
enumeration of TFH and PC (including PB) and 3) ribonucleic acid (RNA) isolation to 
evaluate gene signature biomarkers. Detailed instructions on sample collection, processing 
and shipping will be provided in a separate laboratory manual.
4.3.8.2
Immunophenotyping Assay
Blood samples for immunophenotyping (including but not limited to B-cell counts (eg,
cells/μL) and B-cell subpopulations, including PB and PC, TFH counts, and ICOS levels on 
CD4+ T cells) will be collected at specified time points specified in Table 4.2.1-1, 
Table 4.2.2-1, Table 4.2.3-1. Levels of TFH and PB/PC at screening will be used to stratify 
subjects (see Section 4.1.4 for more details). Detailed instructions on sample collection, 
processing and shipping will be provided in a separate laboratory manual.
4.3.8.3
PAXgene Ribonucleic Acid
Whole blood samples will be collected in PAXgene tubes for total RNA sample preparation. 
Ribonucleic acid will be used in the analyses of transcript expression using both Affymetrix 
U133+ microarrays and quantitative reverse-transcriptase polymerase chain reaction
technologies and stored for future analyses as specified in the exploratory biomarker analysis 
plan (EBAP). Gene signatures measuring the presence of the following cell populations will
be evaluated both pre- and post-dose and during the follow-up period at time points specified 
in Table 4.2.2-1 and Table 4.2.3-1: plasma cells, B cells, and TFH cells. Detailed instructions 
on sample collection, processing and shipping will be provided in a separate laboratory 
manual. These data will be analyzed using descriptive statistics and will not be included in 
the clinical study report (CSR).
4.3.8.4
Cell Pellet for Deoxyribonucleic Acid Methylation
The cell pellet will be collected and stored for a deoxyribonucleic acid (DNA) methylation 
assay at time points specified in Table 4.2.2-1 and Table 4.2.3-1. These samples will not be 
used for any genetic testing and will be destroyed at the end of the study. Detailed 
instructions on sample collection, processing and shipping will be provided in a separate 
laboratory manual. These data will be analyzed using descriptive statistics and will not be 
included in the CSR.

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4.3.8.5
Exploratory Biomarker Sample
Serum and saliva samples will be collected for analyses of protein biomarkers, including, but 
not limited to SS-related cytokines (B-cell activating factor, interleukin [IL]-6, IL-21) and 
SS-related exploratory autoantibodies (parotid secretory protein, carbonic anhydrase 6, 
salivary gland protein 1) at time points specified in Table 4.2.1-1, Table 4.2.2-1 and 
Table 4.2.3-1. Detailed instructions on sample collection, processing and shipping will be 
provided in a separate laboratory manual. These data will be analyzed using descriptive 
statistics and will not be included in the CSR.
4.3.8.6
Optional Biomarker Repository Samples
There is reason to believe that future scientific advancements may further the understanding 
of the pathophysiology in various disease states as they pertain to safety or efficacy. 
Collection of blood and saliva samples will allow the testing of as yet unknown hypotheses 
raised by these scientific advancements or as laboratory techniques advance. 
Deoxyribonucleic acid will not be extracted from samples collected in this study. As such, 
samples will only be used for research in pSS and not for current or future DNA testing, 
genotyping, or DNA analyses.
Sampling for biomarker repository at a given site is contingent upon the site’s Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) approval of sampling for 
exploratory biomarker assessments. If a site’s IRB/IEC does not approve the collection of 
samples for exploratory biomarker assessments, this section will not be applicable.
Samples (including serum, plasma, and saliva) for biomarker discovery and validation will 
only be collected from subjects who consent to biomarker sample collection. The subject 
may withdraw their consent to have their samples used for biomarker sample repository 
analyses at any time. Samples will be stored at MedImmune for up to a maximum of 25 years 
after the end of the main study at which time any remaining samples will be destroyed.
Detailed instructions on sample collection, processing, and shipping will be provided in a 
separate laboratory manual. These data will be analyzed using descriptive statistics and will 
not be included in the CSR.

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4.3.9
Disease Evaluation and Methods
4.3.9.1
Training
In order to maintain consistent evaluation of pSS disease activity across study sites, 
MedImmune will provide training to Principal Investigators and any designated site 
personnel who will be completing the following disease evaluation assessments:
•
ESSDAI
•
Joint count
The ESSDAI and joint count must be administered by the Principal Investigator or another 
qualified site personnel who, as per Principal Investigator discretion, are qualified to perform 
the assessments. Training will include printed training materials and formal presentations, as 
well as web-based training modules. 
Over the course of the study, investigator assessments for a given subject should be 
completed by the same MedImmune trained Principal Investigator, designated physician, or 
qualified site personnel whenever possible. If there is a change in site personnel over the 
course of the study, new Principal Investigators or site physicians/personnel must be trained 
prior to performing the ESSDAI and joint count assessments.
It is expected that the Principal Investigator will ensure their site personnel have adequate 
experience and training qualifications to perform disease assessments. Documentation of all 
training will be maintained in the site’s study file.
4.3.9.2
Sjogren’s Classification Worksheet
To ensure that the correct subject population is enrolled (subjects with pSS) during screening, 
sites will be required to complete a Sjogren’s Classification Worksheet for each screened 
subject (Table 4.2.1-1). The original copy should be maintained as a source document in the 
subject’s study file.
The worksheet is based on the AECG SS Classification Criteria, which is broken down into 
three sections: 1) Inclusion Criteria; 2) Classification Rules; and 3) Exclusion Criteria.
The AECG SS Classification Criteria contains 6 inclusion criteria, including 2 criteria that
require subjects to answer questions regarding ocular and oral dryness; objective 
confirmation of ocular involvement with ocular dying tests; histopathologic findings based 
on minor salivary gland biopsy; and objective confirmation of salivary gland involvement 
through salivary flow tests, parotid sialography, and/or salivary scintography.

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The Classification Rules provides 3 distinct definitions for diagnosing pSS based on the 
inclusion criteria. A definition for sSS is also included.
The AECG SS Classification Criteria also includes 7 exclusion criteria, including: 1) past 
head and neck radiation treatment; 2) hepatitis C infection; 3) acquired immunodeficiency 
syndrome; 4) pre-existing lymphoma; 5) sarcoidosis; 6) graft versus host disease; and 7) use 
of anticholinergic drugs (since a time shorter than 4-fold the half-life of the drug).
4.3.9.3
Physician Global Assessment of Disease Activity
A qualified investigator will complete the MDGA at the time points specified in Table 4.2.1-
1, Table 4.2.2-1, and Table 4.2.3-1. The MDGA represents the investigator’s overall 
assessment of pSS disease severity on a 0 to 10 Likert scale, with 0 indicating ‘inactive 
disease’ and 10 indicating ‘very highly active disease.’ Every attempt should be made to 
have the same investigator complete the MDGA for each subject throughout their study 
participation.
4.3.9.4
28-joint Count
A trained investigator will assess 28-joint count at the time points specified in Table 4.2.1-1, 
Table 4.2.2-1, and Table 4.2.3-1. The swollen and tender joint count is based on left and right 
shoulder, elbow, wrist, metacarpophalangeal (MCP)1, MCP2, MCP3, MCP4, MCP5, 
proximal interphalangeal (PIP)1, PIP2, PIP3, PIP4, PIP5 joints of the upper extremities, and 
left and right knee of the lower extremities. Each of the 28 joints will be evaluated for the 
presence of synovitis. Subjects will be queried at the start of the 28-joint count (prior to 
assessment of tenderness and swelling) as to whether they have experienced or are 
experiencing pain in any of the 28 joints.
4.3.9.5
Oral Evaluation
An oral evaluation, including the unstimulated whole saliva flow rate and collection, and
stimulated whole saliva flow rate and collection, will be performed at the time points 
specified in Table 4.2.2-1 and Table 4.2.3-1.
The unstimulated salivary flow assessment should be performed before the stimulated flow 
rate and collection. Subjects receiving standard of care for xerostomia at screening must 
discontinue use of pilocarpine or cevimeline for at least 12 hours and artificial saliva for at 
least 3 hours prior to the collection of saliva. Subjects should be prohibited from eating or 
drinking for at least 90 minutes prior to the collection of saliva. To minimize diurnal 
variation, every attempt should be made to collect saliva at the same time of the day as the 
Day 1 assessment across all subsequent visits.

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During the unstimulated salivary flow assessment, subjects will be asked to refrain from 
swallowing or speaking. Subjects should refrain from speaking or swallowing, with the 
exception of a single swallow, immediately prior to the initiation of the procedure. The entire 
duration of the procedure is expected to be approximately 5 minutes, during which subjects 
will be asked to allow saliva to accumulate in the oral cavity for a period of 60 seconds prior 
to emptying into a pre-weighed container; this is to be repeated a total of 5 times during the 
test.
Stimulated salivary flow rate and collection should always be performed after unstimulated 
salivary flow and collection. Subjects may be offered a single rinse with water between the 
procedures. For stimulated saliva measurements, the same procedures are followed as for the 
unstimulated collections, except that stimulus with 2% citric acid directly to both sides of the 
posterior lateral tongue will be applied for 5 seconds every 30 seconds for 2 minutes prior to 
the first stimulated collection. The weight of the collection vial is to be determined and 
recorded before and after the collection, with the difference representing the saliva volume.
4.3.9.6
Ophthalmological Evaluation
A dry eye exam will be performed by an ophthalmologist or a trained professional at the time 
points specified in Table 4.2.2-1 and Table 4.2.3-1. At a minimum, it will include a 
Schirmer’s test without local anesthesia, corneal and conjunctival staining (van Bijsterveld 
score), and the assessment of tear break-up time. These assessments will be performed 
according to local standard of care procedures. Other clinically indicated examinations may 
be performed as clinically indicated at the discretion of the ophthalmologist or a trained 
professional.
4.3.10
Estimate of Volume of Blood to Be Collected
The estimated volume of blood to be collected from each subject at each visit (and across all 
visits) from screening through Day 296 is presented in Table 4.3.10-1. If repeats of any blood 
tests are required, the volume of blood collection will increase accordingly.
Table 4.3.10-1
Estimate of Blood Volume to be Collected
Visit Day
Estimated Blood Volume (mL)
Day -28 to Day -1
65
Day 1
77
Day 8
5
Day 15
15
Day 29
54
Day 43
0

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Table 4.3.10-1
Estimate of Blood Volume to be Collected
Visit Day
Estimated Blood Volume (mL)
Day 57
54
Day 71
0
Day 85
0
Day 99
80
Day 106
5
Day 113
12
Day 127
44
Day 141
0
Day 155
34
Day 169
0
Day 183
0
Day 197/Early Termination Visit
80
Day 225
12
Day 253
12
Day 296/End of Study Visit
77
Unscheduled Visit
variable a
Total
626
a
The amount of blood taken at the unscheduled visit is estimated to be 15 mL.
4.4
Study Suspension or Termination
The Sponsor reserves the right to temporarily suspend or terminate this study at any time. 
The reasons for temporarily suspending or terminating the study may include but are not 
limited to the following: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects. Study treatment will be suspended if any of the following events occur 
in this study:
a.
Any death that that is considered to be related to investigational product by the 
investigator
b. Any Grade 4 TEAE (based on CTCAE [Version 4.0]) that is considered to be related 
to investigational product by the investigator, with the exception of anaphylactic 
reaction
c.
If 2 subjects have TEAEs in the same organ system of Grade ≥ 3 (based on CTCAE 
[Version 4]) that are considered to be related to investigational product by the 
investigator, unless in the opinion of the investigator, the events are manifestations of 
SS (eg, within the definitions included in the ESSDAI). Isolated Grade ≥ 3 laboratory 
abnormalities without a clinical event meeting the above criteria will not 
automatically trigger suspension of the study.

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Investigational product will be supplied to the site in vials with identical appearances in 
blinded, coded kits. Each kit has a unique number that is printed on all labels within the kit 
(ie, the outer carton label and the label of each vial within the carton). Each carton is labeled 
with a unique number range that corresponds to the labeled number series of the vials within 
the carton. Refer to Section 4.6.2 for information on methods for ensuring blinding.
4.5.1.1
Investigational Product Dose Preparation
The investigational product manager will select the kit assigned by the IVRS/IWRS to 
prepare the subject’s dose.
4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. AMG 557/MEDI5872 and 
placebo are supplied as frozen liquid drug product. Instructions for thawing investigational 
product are described in Section 4.5.1.3.
If there are any defects noted with the investigational product, the investigator and 
site monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.7) for further instructions.
4.5.1.3
Investigational Product Thawing Instructions
The pharmacist or qualified designee will thaw 4 vials of investigational product for each 
dose.
•
The pharmacist or qualified designee should not remove the vials from the assigned kit. 
The vials can remain in the kit during the thaw process.
Thawing
Remove the vials from the freezer and thaw in the dark in one of two ways:
1. Thaw undisturbed at room temperature (20°C to 40°C) for up to 1 hour.
2. Thaw undisturbed at refrigerated temperature (2°C to 8°C) for up to 12 hours.
During the thaw:
1. Leave vials undisturbed, except to gently swirl to check for completion of thaw. 
2. Protect from light by thawing in a darkened refrigerator or in a secondary container (ie, 
covered box)
3. Never shake vials vigorously, especially during the thawing process

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4. Carefully check the vial for cracks (see below instructions).
After Thawing
1. Once completely thawed, vials should be warmed to room temperature for up to 1 hour 
before administration.
2. Gently swirl the vial to ensure the contents are mixed to a clear, homogeneous solution.
3. Carefully check the vial for damage (eg, cracks). Vials should be free of any external 
moisture or condensation during inspection. If necessary, wipe the vial with a clean, 
lint-free wipe to remove moisture. Quarantine damaged vials and notify the investigator 
and site monitor to report compromised investigational product and obtain further 
instructions for destruction and reporting.
Storage of Thawed Investigational Product
1. Unopened vials may be kept refrigerated (2°C to 8°C), protected from light, for a 
maximum time of 7 days from the time the investigational product was removed from 
frozen storage.
2. Unopened vials may be kept at room temperature (20°C to 40°C), protected from light, 
for a maximum time of 8 hours from the time the investigational product was removed 
from frozen or refrigerated storage. Any time used for room temperature storage is also 
counted against the refrigerated storage.
3. Unopened vials may be moved between refrigerated storage and room temperature 
storage as needed within the maximum time limits for each temperature.
PLEASE NOTE:
•
Do not re-freeze the vials once set up for thaw.
•
Do not use opened and dispensed vials for subsequent dosing.
•
Storage times and temperatures must be strictly adhered to (see Table 4.5.1.3-1).
Table 4.5.1.3-1
Allowable Time and Temperatures for Investigational 
Product Thawing
Temperature
Maximum Storage Time of Vial 
Post-thaw
Timing of IP Administration
Room
20°C to 40°C (68°F to 104°F)
8 hours
IP should be administered within 
8 hours after the vial is initially 
placed at room temperature.
Refrigerated
2°C to 8°C (36°F to 46°F)
7 days
IP should be equilibrated at room 
temperature for at least 1 hour 
before administration.
IP should be administered within 
8 hours after the vial is initially 

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Table 4.5.1.3-1
Allowable Time and Temperatures for Investigational 
Product Thawing
Temperature
Maximum Storage Time of Vial 
Post-thaw
Timing of IP Administration
placed at room temperature (ie, 
from the start of equilibrium at 
room temperature).
IP = investigational product
Thawed vials of the investigational product may be maintained at 2°C to 8°C for a total of 
7 days. The investigational product not used for study administration within this time 
duration must be discarded. Once completely thawed, vials should be transferred to room 
temperature and gently swirled to ensure the vial contents are adequately mixed. Do not 
shake or refreeze investigational product after thawed. Mixing may result in the formation of 
small bubbles, which is normal. Preparation of the clinical supplies should be performed 
using aseptic techniques and under sterile conditions. Prolonged exposure of the IP to light 
should be avoided. Before administration, the thawed investigational product should be 
warmed to room temperature, if necessary, for a minimum of 1 hour, but should not be kept 
at room temperature more than 8 hours. The investigational product not used for study 
administration within this time duration must be discarded.
4.5.1.4
Dose Preparation Steps
No incompatibilities between AMG 557/MEDI5872 and plastics passing compatibility tests
have been observed.
AMG 557/MEDI5872 and placebo do not contain preservatives and any unused portion must 
be discarded. Preparation of investigational product is to be performed aseptically. Total in-
use storage time from needle puncture of the investigational product vial to start of 
administration should not exceed 4 hours at room temperature. If storage time exceeds these 
limits, a new dose must be prepared from new vials.
Each dose of investigational product will be administered by two injections 
(see Table 4.5.1.4-1) and must be prepared using plastic disposable syringes and aseptic 
technique.

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Table 4.5.1.4-1
Preparation of Investigational Product Dose
Vials Required
Dose Preparation Instructions
Syringe 
Size
4 vials (placebo or 
AMG 557/MEDI5872)
Step 1: 
•
Withdraw 0.5 mL of investigational product using a 3-mL 
syringe with a 19-gauge needle 
•
Remove the 19-gauge needle
•
Replace with another 19-gauge needle and cap 
∀
Set vial aside and do not reuse
3 mL
Step 2: 
∀
With the same syringe used in Step 1, withdraw 1 mL of 
investigational product for a total volume of 1.5 mL
∀
Remove the 19-gauge needle
•
Replace with a 25- or 27-gauge 1/2-inch needle and cap 
syringe until administration
•
Set vial aside and do not reuse
3 mL
Step 3: 
∀
Repeat Steps 1 and 2 for remaining 2 investigational product 
vials using a fresh syringe and needles for the second dose
3 mL
4.5.1.5
Treatment Administration
The first day of dosing is considered Day 1.
Each dose of AMG 557/MEDI5872 or placebo should be administered using the following 
guidelines:
•
Female subjects, unless surgically sterile or 1 year postmenopausal, must have a negative 
urine pregnancy test prior to receiving AMG 557/MEDI5872 or placebo
4.5.1.6
Monitoring of Dose Administration
Subjects should be observed for at least 1 hour following the administration of 
investigational product during the weekly treatment visits (ie, Days 1, 8, 15, 99, 106, and 
113) and at least 30 minutes following the administration of investigational product at all 
other treatment visits. Sites should follow local guidelines if they require longer observation 
periods. Treatment for injection-site reactions, hypersensitivity reactions, and/or anaphylaxis 
is at the discretion of the Principal Investigator and should reflect local standard of care.

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As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
4.5.1.7
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune, LLC
Attn: Product Complaint Department
One MedImmune Way
Gaithersburg, MD 20878 USA
4.5.2
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.3
Storage
Storage of investigational product is summarized in Table 4.5.3-1.

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Table 4.5.3-1
Storage of Investigational Product
Freezer Median Temperature
Acceptable Variation
Acceptable Range
-30°C or -70°C
-30 (±10)°C or -70 (±10)°C
-20°C to -40°C or -60°C to -80°C
Thawing temperature requirements can be found in Section 4.5.1.3.
4.5.4
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
4.5.5
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune-
authorized depot or disposed of upon authorization by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IVRS/IWRS will be used for randomization to a treatment group and assignment of 
blinded investigational product kit numbers. A subject is considered randomized into the 
study when the investigator notifies the IVRS/IWRS that the subject meets eligibility criteria 
and the IVRS/IWRS provides the assignment of blinded investigational product kit numbers 
to the subject.
Subjects will be randomized at a 1:1 ratio to receive either AMG 557/MEDI5872 or placebo 
as described in Table 3.1.2-1. Randomization will be stratified by screening cellular 
immunophenotyping abnormalities (elevated TFH or elevated PB/PC vs normal values for 
both parameters).
Investigational product (AMG 557/MEDI5872 or placebo) must be administered the same 
day the investigational product is assigned. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately.

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4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which AMG 557/MEDI5872 and placebo are identically 
labeled and indistinguishable in appearance. As such, neither the subject/legal representative 
nor any of the investigational site staff who are involved in the treatment or clinical 
evaluation of the subjects will be aware of the treatment received (International Conference 
on Harmonisation [ICH] E9).
Sponsor staff who are involved in the treatment or clinical evaluation of the subjects will also 
be unaware of the treatment received from the start of the study until all subjects have 
reached Day 99 or withdrawn from the study. After this time, Sponsor staff may be 
unblinded, as described in Section 4.6.3.2.
In the event that treatment allocation for a subject becomes known to the investigator or other 
study staff involved in the management of study subjects, the Sponsor must be notified 
immediately.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. At minimum, an attempt must be made by the investigator 
to immediately contact the medical monitor prior to unblinding. Instructions for unblinding 
an individual subject’s investigational product allocation, including the requirement to 
immediately contact the medical monitor prior to unblinding, are contained in the 
IVRS/IWRS manual. In general, unblinding should only occur if management of the medical 
emergency would be different based on the subject having received investigational product. 
In the majority of cases, the management of a medical emergency would be the same whether 
or not investigational product was received by the subject. If this was the case, the 
investigational product allocation should not be unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. Such unblinding does not on 
its own require the subject to be discontinued from investigational product.
4.6.3.2
Unblinding for the Primary Analyses
Planned analyses are described in Section 4.8.7. The primary analysis will be performed after
all subjects have completed Day 99 or have withdrawn from the study. The Sponsor staff will 

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be unblinded at the primary analysis (after Day 99). Results from the primary analysis may 
be shared with investigators and presented at public conferences. Investigators will not be 
made aware of unblinded treatment assignments for individual subjects ongoing in the 
open-label or follow-up phases of the study until these subjects have completed the study.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “prohibited” as 
listed in Section 4.7.2.
Protocol permitted medications for pSS include oral corticosteroids, anti-malarials, 
methotrexate, NSAIDs, as well as, cevimeline, pilocarpine and cyclosporine eye drops for 
dry mouth and eyes, respectively.  
Those subjects who are receiving protocol permitted medications for pSS must be maintained 
on a stable regimen (and for methotrexate, route of administration) throughout the treatment 
period.
Subjects should also receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines.
4.7.2
Prohibited Concomitant Medications
Subjects are not permitted to receive any of the following while receiving investigational 
product:
•
Belimumab
•
Rituximab
•
Abatacept

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•
Tumor necrosis factor inhibitors (adalimumab, certolizumab, etanercept, golimumab, 
infliximab)
•
Tocilizumab
•
Cyclophosphamide (or any other alkylating agent), cyclosporine (except for eye drops), 
tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, or leflunomide
•
Unstable doses of antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine)
•
Corticosteroids: > 10 mg/day oral prednisone (or equivalent) or any form of parental (IV, 
intramuscular, or intra-articular) corticosteroids
•
Methotrexate: > 20 mg/week
•
Increase in the doses of regularly scheduled NSAIDs
•
Increase in the doses of cevimeline or pilocarpine and cyclosporine eye drops (Restasis)
•
Any live or attenuated vaccine (administration of killed vaccines is acceptable) 
Other than the medications described above, use of concomitant medications including 
over-the-counter medications, herbal supplements, vitamins, etc from screening through 
Day 296/End of Study (EOS) is discouraged. Subjects must be instructed not to take any 
medications, including over-the-counter products, without first consulting with the 
investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard deviation, 
median, minimum, and maximum. Baseline values will be defined as the last assessment 
prior to the first administration of investigational product. Additional details of statistical 
analyses will be described in the statistical analysis plan.
The intent-to-treat (ITT) Population is defined as all subjects who are randomized and treated 
with investigational product and will be analyzed according to the initial randomization. 
The as-treated Population is defined as all subjects who receive any investigational product
and will be analyzed according to the actual treatment received.
Missing data will be imputed using the last-observation-carried-forward approach through 
the end of the double-blind, placebo-controlled treatment period.

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Further details will be provided in the statistical analysis plan.
4.8.2
Sample Size and Power Calculations
The planned sample size of 42 subjects (21 subjects per arm) will provide 80% power to 
detect a difference in mean change in ESSDAI of 4 (assumed standard deviation of 5; 
Moerman et al, 2014; Meiners et al, 2012) between two randomized groups at a two-sided 
0.1 level of statistical significance by using two sample t-test. This sample size also provides 
about 80% power to detect 30% relative reduction in PC from tissue under assumption of 
coefficient of variation (CV) of 0.5. It should be noted that a smaller CV has been observed 
in blood from a previous study by Amgen (Study 20060169), which could result in higher 
statistical power. The sample size was calculated by using nQuery Advisor 7.0.
4.8.3
Efficacy
4.8.3.1
Primary Analysis
Changes in ESSDAI score from baseline to Day 99 will be compared between 
AMG 557/MEDI5872 group and placebo group using an analysis of covariance (ANCOVA) 
adjusting for ESSDAI score at baseline, randomization stratum, and treatment group. The 
analysis will be conducted using the ITT Population.. The significance of treatment effect 
will be tested by using a two-sided test at significance level α of 0.1. The analysis will be 
conducted using the ITT Population.
To assess the effect of AMG 557/MEDI5872 on changes in ESSDAI over time, a 
longitudinal mixed effects analysis of variance model will be fitted for the change from 
baseline in ESSDAI, for the ITT population.
4.8.3.2
Secondary Analyses
The number and proportion of ESSDAI[3] and ESSDAI[4] responders will be summarized 
by treatment and visit. The proportion of AMG 557/MEDI5872 and placebo subjects with an 
ESSDAI[3] and ESSDAI[4] response at Day 99 will be compared using Fisher’s Exact test.
Relative change in biomarker levels in the peripheral blood and minor salivary gland tissue, 
and change in focus score, will be compared between AMG 557/MEDI5872 and placebo 
groups in a similar way to the primary endpoint, with log-transformation prior to analysis. In 
the minor salivary gland tissue, TFH and PC levels will be calculated as the number of the 
marker positive cells per unit area or among ICOS+ cells. In the peripheral blood, TFH levels
will be calculated as the percent of CD45RO+CXCR5+ICOS+PD-1+ among CD3+CD4+ 
lymphocytes and as the absolute number (eg, cells/μL) of 

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CD3+CD4+CD45RO+CXCR5+ICOS+PD-1+ lymphocytes. Also, in the peripheral blood, 
the combined PB/PC levels will be calculated as the percent of CD20dimCD27+CD38++ 
among CD19+ lymphocytes and as the absolute number (eg, cells/μL) of 
CD19+CD20dimCD27+CD38++ lymphocytes. Secondary biomarker endpoints are presented 
in Section 2.2.2.
4.8.3.3
Exploratory Analyses
Relative change in TFH, PB, and PC levels (and other exploratory immunophenotyping 
parameters) from baseline to Day 99 in peripheral blood will be log-transformed and 
compared between AMG 557/MEDI5872 and placebo groups using ANCOVA, adjusting for 
log (TFH, PB, or PC levels at baseline), randomization stratum, and treatment group. The PC 
gene signature is described by Streicher et al, 2014. The TFH gene signature is currently 
under development at MedImmune using a similar approach to the PC gene signature. The 
analysis will be conducted using the ITT Population. Exploratory biomarker endpoints are 
presented in Section 2.2.3.
A detailed description of exploratory biomarker analyses will be specified in the EBAP.
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
Treatment-emergent adverse events and TESAEs will be coded by the most updated Medical 
Dictionary for Regulatory Activities (MedDRA) version and the type, incidence, severity,
and relationship to investigational product will be summarized by MedDRA System Organ 
Class and Preferred Term. Specific AEs will be counted once for each subject for calculating 
percentages. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of relationship observed will be reported. In addition, AESIs and 
laboratory abnormalities will be summarized. The safety analyses will be conducted using 
the as-treated Population.
4.8.4.2
Analysis of Clinical Laboratory Parameters
The laboratory measurements, and the change from baseline, will be summarized by 
treatment and time point.
4.8.4.3
Other Safety and Tolerability Endpoints
Vital signs, and the change from baseline, will be summarized by dose and time point. The 
number and percentage of subjects with normal and abnormal ECG findings will be 
summarized by dose and time point.

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4.8.5
Patient-Reported Outcomes
4.8.5.1
Analysis of ESSPRI
Change in ESSPRI score from baseline to Day 99 will be compared between 
AMG 557/MEDI5872 and placebo groups using ANCOVA, adjusting for ESSPRI score at 
baseline, randomization stratum, and treatment group. The analysis will be conducted using 
the ITT Population. To assess the effect of AMG 557/MEDI5872 on changes in ESSPRI over 
time, a longitudinal mixed effects analysis of variance model will be fitted for the change 
from baseline in ESSPRI, for the ITT population.
The number and proportion of ESSPRI responders will be summarized by treatment and 
visit. The proportion of AMG 557/MEDI5872 and placebo subjects with an ESSPRI 
response at Day 99 will be compared using Fisher’s Exact test.
4.8.5.2
Analysis of PROFAD-SSI-SF
Change in the PROFAD-SSI-SF domain scores over time will be evaluated using a method 
similar to that used for the ESSPRI:
•
Change in somatic fatigue domain from baseline
•
Change in mental fatigue domain from baseline
•
Change in arthralgia domain from baseline Change in vascular dysfunction domain from 
baseline (female subjects only)
•
Change in cutaneous dryness domain from baseline
•
Change in vaginal dryness domain from baseline (female subjects only)
•
Change in ocular dryness domain from baseline
•
Change in oral dryness domain from baseline
The analysis will be conducted using the ITT Population.
4.8.5.3
Analysis of SF-36v2
Change in the following SF-36v2 scores over time will be evaluated using a method similar 
to that used for the ESSPRI:
•
Change from baseline in PCS
•
Change from baseline in MCS
•
Change from baseline in SF-36v2 domain scores

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The analysis will be conducted using the ITT Population.
4.8.5.4
Analysis of Subject Global Assessment of Disease Activity
Change in SGA score from baseline over time will be evaluated using a method similar to 
that used for the ESSPRI. 
The analysis will be conducted using the ITT Population.
4.8.5.5
Patient Global Impression of Severity
Descriptive statistics for each visit where a PGI-S assessment is completed will be calculated.
4.8.5.6
Patient Global Impression of Change
The proportion of AMG 557/MEDI5872 and placebo subjects with improvement at Day 99 
will be compared using a Chi-squared test.
The analysis will be conducted using the ITT Population.
4.8.6
Analysis of Immunogenicity/Pharmacokinetics
The number and percentage of subjects who are anti-AMG 557/MEDI5872-antibody positive 
will be summarized by dose. The impact of anti-AMG 557/MEDI5872-antibodies on PK and 
the association with TEAEs and TESAEs will be assessed.
AMG 557/MEDI5872 serum trough concentrations will be summarized by treatment group 
at each time point using descriptive statistics.
4.8.7
Planned Analyses
The primary analysis will be performed when all subjects have completed Day 99 (ie, at the 
end of the double-blind treatment phase). The primary analysis will include all assessments 
performed on the subjects prior to the data cut-off for the primary analysis.
The final analysis will be performed when all subjects have completed the treatment and 
safety follow-up periods or have withdrawn from the study.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for Good Clinical Practice (GCP) E6(R1) defines an AE as:

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Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell
increased). Abnormal laboratory values that are not, in the investigator's opinion, medically 
significant and do not require intervention should not be reported as AEs.
Adverse events may be treatment emergent (ie, occurring after initial receipt of 
investigational product) or nontreatment emergent. A non-TEAE is any new sign or 
symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above

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Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to the Sponsor. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of the investigational product.
Adverse events of special interest for this study include:
•
Hepatic function abnormality meeting the definition of Hy’s law (see Section 5.6.2).
•
New or reactivated TB infection
•
Malignancy
•
Hypersensitivity and anaphylactic reactions.
5.4
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to MedImmune 
Patient Safety. See Section 5.2 for the definition of SAEs and Appendix 2 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious”, it will be reported on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
Adverse events will be collected from time of signature of informed consent, throughout the
blinded and open-label treatment period, and including the follow-up period (through 
Day 296/EOS).
All SAEs will be recorded from the time of informed consent.

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After submitting the initial SAE report to MedImmune Patient Safety, the investigator will be 
required to follow the subject proactively and provide MedImmune Patient Safety with 
further information regarding the subject’s condition.
If at any time after completion of the study the investigator or qualified designee becomes 
aware of an SAE that is suspected to be related to investigational product, the event must be 
reported to MedImmune Patient Safety.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
The investigator is responsible for following all SAEs to resolution, until the subject returns 
to baseline status, or until the condition has stabilized, with the exception if a condition 
remains chronic, even if this extends beyond study participation.
5.5
Reporting of Serious Adverse Events
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and fax it to MedImmune Patient Safety.
MedImmune Patient Safety contact information: 
Patient Safety 
MedImmune, LLC
One MedImmune Way
Gaithersburg, MD 20878 USA
Fax: +1 301-398-4205
The Sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH guidelines and/or local regulatory requirements. The Sponsor may be 
required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit additional 
information requested by the Sponsor as soon as it becomes available.

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Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, investigators should submit a follow-up SAE Report Form 
(separate from the initial report form) with the new information. Any follow-up information 
to an SAE also needs to be provided to MedImmune Patient Safety within 24 hours of 
learning of the new information.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the SAE Report Form (see Section 5.5 for contact 
information). If the overdose results in an AE, the AE must also be recorded on the AE eCRF 
(see Section 5.4). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be reported as an SAE (see Section 5.4 and Section 5.5). MedImmune does 
not recommend specific treatment for an overdose. The investigator will use clinical 
judgment to treat any overdose.
5.6.2
Hepatic Function Abnormality
Adverse events of hepatic function abnormality of special interest to the Sponsor are defined
as any increase in ALT or AST to greater than 3 × ULN and concurrent increase in bilirubin 
to greater than 2 × ULN (ie, Hy’s law cases). Concurrent findings are those that derive from 
a single blood draw or from separate blood draws taken within 8 days of each other. In the 
event of hepatic function abnormality where the etiology is unknown, timely follow-up 
investigations and inquiries should be initiated by the investigational site, based on medical 
judgment, to make an informed decision regarding the etiology of the event.
If the underlying diagnosis for the hepatic function abnormality is known (including 
progression of pre-existing disease), the diagnosis should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains unknown, the term 
“hepatic function abnormal” should be used to report the AE/SAE.

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Hepatic function abnormality of unknown etiology, or which is considered attributable to 
investigational product, is required to be reported as “hepatic function abnormal” within 
24 hours of knowledge of the event to MedImmune Patient Safety using the SAE Report 
Form, even if the event is considered to be nonserious (see Section 5.5 for contact 
information). The investigator will review the data with the medical monitor. The 
investigator should then use clinical judgment to establish the cause based on local standard 
of care and follow the subject by conducting testing as clinically indicated.
•
If, after appropriate workup, in the opinion of the investigator, the underlying diagnosis 
for the abnormality remains unexplained, or is considered attributable to investigational 
product, dosing of the study subject should be permanently discontinued.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the Sponsor. 
5.6.3
Pregnancy
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to MedImmune Patient Safety using the 
SAE Report Form (see Section 5.5 for contact information).
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product and will be withdrawn from the study. If the subject requests to know 
which treatment she received, this information will be provided to her. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to MedImmune Patient Safety after outcome.
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to MedImmune Patient Safety using the SAE Report Form (see 
Section 5.5 for contact information). The Sponsor will endeavor to collect follow-up 
information on such pregnancies provided the partner of the study subject provides consent.
5.6.4
Adverse Events of Special Interest
The reporting period for AESIs is the period immediately following the time that informed 
consent is obtained through the end of the subject’s participation in the study. An AESI 
(serious or nonserious), regardless of the presumed relationship to the investigational 
product, is required to be reported within 24 hours of knowledge of the event to 

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MedImmune Patient Safety using the SAE Report Form (see Section 5.5 for contact 
information).
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s)
•
Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts)
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.

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6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of clinical study protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit/assessment, regardless of the number of 
doses of investigational product that was received.
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
6.4
Data Management 
Data management will be performed by Cognizant Technology Solutions according to the 
data management plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.

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The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
7.2
Subject Data Protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
Extra precautions are taken to preserve confidentiality and prevent data being linked to the 
identity of the subject. In exceptional circumstances, however, certain individuals might see 
both the data and the personal identifiers of a subject. For example, in the case of a medical 
emergency, a MedImmune medical monitor or an investigator might know a subject’s 
identity and also have access to his or her data. Also Regulatory authorities may require 
access to the relevant files, though the subject’s medical information and the files would 
remain physically separate.

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7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities.
MedImmune will provide Regulatory Authorities, IRB/IEC and Principal Investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions, where relevant.
Each Principal Investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
7.4
Informed Consent
The Principal Investigator(s) at each center will:
•
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
•
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•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated ICF before conducting any procedure 
specifically for the study
•
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
•
Ensure a copy of the signed ICF is given to the subject
•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Coordinating
Investigator and MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to IRB/IEC see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines 

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of the ICH, and any applicable regulatory requirements. The investigator will contact 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site.

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8
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Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, Manning S, et al. The CD28-related 
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inducible costimulator in the exaggerated memory B cell and plasma cell generation in 
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9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol.
Protocol Amendment 4, 24Oct2017
Text revisions resulting from this amendment are incorporated in the body of the Protocol 
Amendment 4. Major changes to the protocol are summarized below.
1. Title Page (Medical Monitor): Updated the title page of this protocol amendment to 
include the name and contact information of the new Medical Monitor, Dr. Marius 
Albulescu.
2. Protocol Synopsis (Secondary Objectives), Section 2.1.2 (Secondary Objectives): Added 
objective measures of overall disease activity to Secondary Objective 3, to include a 
secondary objective describing Secondary Endpoint 4, for which the text was amended 
and moved from Exploratory Endpoint 3 to Secondary Endpoint 4 in this protocol 
amendment (see text revision 3 below).
3. Protocol Synopsis (Study Endpoints), Section 2.2.3 (Secondary Endpoint[s]), 
Section 2.2.3 (Exploratory Endpoint[s]): Amended the definition of ESSDAI response in 
Exploratory Endpoint 3, to clarify the text, and moved Exploratory Endpoint 3 to 
Secondary Endpoint 4, to make this an endpoint of interest. Added ESSPRI response as a 
new Exploratory Endpoint 3, and MDGA as a new Exploratory Endpoint 9, as these 
endpoints were previously described in the protocol however not defined as study 
endpoints.
4. Table 4.2.3-1 (Schedule of Follow-up Procedures): Changed the window of +7 days to ±7 
days for Visit 21, Day 296/EOS, to amend a minor error in the table.
5. Section 4.6.2 (Methods for Ensuring Blinding): Rearranged and made minor edits to the 
text, to improve the readability and make the text consistent with other sections, 
respectively.
6. Section 4.6.3.1 (Unblinding in the Event of a Medical Emergency): Removed text 
specifying that subjects should be discontinued from investigational product if unblinded, 
to clarify that unblinding is not a reason to discontinue investigational product.
7. Section 4.6.3.2 (Unblinding for the Primary Analyses): Changed wording to enable 
results from the primary analysis to be presented publically before EOS, and to clarify 
that individual unblinded treatment assignments from subjects still ongoing in the study 
will not be shared with investigators until these subjects have completed the study.
8. Protocol Synopsis (Statistical Analysis Plan), Section 4.8.3.1 (Primary Analysis), Section
4.8.3.3 (Exploratory Analyses), Section 4.8.5.1 (Analysis of ESSPRI), Section 4.8.5.2 
(Analysis of PROFAD-SSI-SF), Section 4.8.5.3 (Analysis of SF-36v2), Section 4.8.5.4 
(Analysis of Subject Global Assessment of Disease Activity), Section 4.8.7 (Planned 
Analyses): Changed wording to clarify that randomization stratum will be included in the 
statistical analysis models, and that the endpoints will be analyzed over time using a 
longitudinal mixed effects model, to make minor changes in the planned statistical 
analyses.

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9. Section 4.8.3.2 (Secondary Analyses): Added text to describe the analysis of ESSDAI 
response, to make minor changes in the planned statistical analyses.
10. Section 4.8.3.2 (Secondary Analyses), and Section 4.8.3.3 (Exploratory Analyses): 
Added text to clarify that the biomarkers will be log-transformed prior to statistical 
analysis, to make minor changes in the planned statistical analyses.
11. Section 4.8.5.1 (Analysis of ESSPRI): Added text to describe further the analysis of 
ESSPRI, to make minor changes in the planned statistical analyses.
12. Section 4.8.6 (Analysis of Immunogenicity/Pharmacokinetics): Changed wording 
describing the analysis of PK data so that only trough concentrations will be analyzed, to 
make minor changes in the planned statistical analyses.
Protocol Amendment 3, 17Feb2016
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. Major changes to the protocol are summarized below.
1. Title Page (Medical Monitor): Updated the title page of this protocol amendment to 
include the name and contact information of the new Medical Monitor, Dr. Roberta 
Weiss.
2. Section 4.1.2 (Inclusion Criteria): Inclusion Criterion 1 has been changed to raise the age 
cap from 70 to 75 years to better reflect the age distribution of pSS; Inclusion Criterion 8
has been changed to lower the IgG requirement from 16g/dL to 13 g/dL, and to include a 
requirement for a positive test for cryoglobulins, to provide a broader definition of B-cell 
hyperactivity.
3. Section 4.1.3 (Exclusion Criteria): Exclusion Criterion 8 has been changed to lower the 
WBC count from 2,000 × 106/L to 1,500 × 106/L and to lower the neutrophil count
requirement from 1,500 × 106/L to 1,000 × 106/L to allow SS-associated 
leukopenia/neutropenia. Exclusion Criterion 20e has been reworded for clarification.
4. Section 4.1.6 (Discontinuation of Investigational Product): Added specific language 
about severe neutropenia to mitigate any potential risk associated with lowering the 
neutrophil count for eligibility: “Grade ≥ 3 neutropenia requiring a therapeutic 
intervention to increase neutrophil counts will lead to discontinuation of investigational 
product even in the absence of any other clinical event (eg, fever) regardless of the 
relatedness to investigational product.”
5. Section 4.2.1 (Enrollment/Screening Period); Section 4.2.2 (Active Treatment Period); 
Section 4.2.3 (Follow-up Period): Added the words “whenever feasible” to allow 
flexibility in the order in which study assessments are performed.
6. Table 4.2.1-1 (Schedule of Screening Procedures): Corrected an error in footnote “f” by 
including posteroanterior chest x-ray assessment instead of the incorrect anteroposterior 
assessment.
7. Table 4.2.2-1 (Schedule of Study Procedures): Added footnote “h” to allow baseline oral 
and ophthalmological evalutions to be performed within 28 days prior to dosing on
Visit 2 to accommodate the limited availability of ophthalmologists.

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8. Table 4.2.3-1 (Schedule of Follow-up Procedures): Modified footnote “h” to allow 
ophthalmological evalutions to be performed within 2 weeks prior to EOS to 
accommodate the limited availability of ophthalmologists.
9. Section 4.3.4 (Chest Radiograph): Corrected an error by including posteroanterior chest 
x-ray assessment instead of the incorrect anteroposterior assessment.
10. Section 4.3.9.6 (Ophthalmological Evaluation): Whereas before the ophthalmological 
evaluation was to be performed by an ophthalmologist, now it may performed by an 
ophthalmologist or a trained professional to reflect differences in local practices.
11. Table 4.5.1.4-1 (Preparation of Investigational Product Dose): Allowance has been added 
to use either a 25- or a 27-gauge needle for investigational product administration to 
accommodate differences in local practices.
Protocol Amendment 2, 28Aug2015
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Major changes to the protocol are summarized below.
1. Protocol Synopsis (Study Design), Section 3.1.1 (Overview): Added the word “multiple” 
in the description of the study for clarification; increased the approximate number of 
study sites from 10 to 15 sites.
2. Protocol Synopsis (Study Endpoints), Section 2.2.3 (Exploratory Endpoint [s]): Modified 
wording in Exploratory Endpoint 10b (second sub-bullet of the last bullet point in the 
Protocol Synopsis) for consistency with wording in other endpoints.
3. Section 4.1.3 (Exclusion Criteria): Modified Exclusion Criterion 4 in order to exclude 
subjects with only systemic fungal infections and allow subjects with topical fungal 
infections, such as fungal nail infection or oral candidiasis; modified Exclusion 
Criterion 7 to clarify that subjects who tested positive for either hepatitis B surface 
antigen, hepatitis B core antibody, hepatitis C antibody, or HIV antibody will be excluded 
from the study instead of subjects who tested positive for all 4; modified Exclusion 
Criterion 11 for clarification; modified Exclusion Criterion 13 to clarify that only subjects 
with a history of anaphylaxis to any biological therapy will be excluded from the study
and not those with a history of anaphylaxis to unrelated allergens (eg, food, iodine, IV 
contrast agents); modified Exclusion Criterion 20a (ii) to clarify that any change or 
initiation of a new dose of oral corticosteroids within 4 weeks prior to signing the ICF 
through randomization will result in exclusion from the study.
4. Section 4.1.6 (Discontinuation of Investigational Product): Added new language in the 
last paragraph to clarify that subjects will be followed up for safety and protocol-
specified assessments.
5. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples): 
Modified language under “Samples Obtained for Future Research” for clarification.
6. Table 4.2.2-1 (Schedule of Study Procedures): Removed the 3-day window from Visit 2 
as it is not needed and modified the study day window for Visits 11 and 12 for 
consistency with similar previous visits (Visits 3 and 4); added urine pregnancy testing at 

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Visits 4 and 12 for consistency with the urine pregnancy testing schedule in other visits in 
the study.
7. Section 4.3.2.6 (Patient Global Impression of Severity): Modified wording to clarify that 
the subject’s perception of overall symptom severity will be captured at the time of the 
assessment instead of completion.
8. Section 4.3.8.1 (Biopsy of Salivary Gland): Added additional language to further clarify 
the salivary gland biopsy procedures.
9. Section 4.3.9.1 (Training): Removed MDGA from the list of assessments requiring 
training as no formal training beyond the instructions provided in the study reference 
manual is necessary or will be provided.
10. Section 4.3.9.3 (Physician Global Assessment of Disease Activity): Changed wording 
from “trained” to “qualified” as no formal training for MDGA beyond the instructions 
provided in the study reference manual is necessary or will be provided.
11. Section 4.3.9.6 (Opthalmological Evaluation): Removed “with Lissamine green” to allow 
other types of stains to be used for the opthalmological evaluation procedures.
12. Table 4.3.10-1 (Estimate of Blood Volume to be Collected): Modified the footnote to 
clarify that the amount of blood taken at the unscheduled visit is only an estimated 
volume.
Administrative Change 2, 11Jun2015
1. Protocol Synopsis (Study Design), Section 3 (Study Design), Figure 3.1.1-1 (Study Flow 
Diagram), Section 4.1.2 (Inclusion Criteria), Table 4.2.3-1 (Schedule of Follow-up 
Procedures), Section 4.3.10 (Estimate of Volume of Blood to be Collected), 
Table 4.3.10-1 (Estimate of Blood Volume to Be Collected), Section 4.7.2 (Prohibited 
Concomitant Medications), Section 5.4.1 (Time Period for Collection of Adverse 
Events): Based on review of the PK modeling data, the duration of the follow-up period 
as well as the protocol-mandated duration of contraception has been increased from 
98 days to 113 days. As a result of this change, the End of Study Visit has been changed 
from Day 281 to Day 296. This change has been applied globally throughout the 
protocol. The duration of follow up is guided by the non-linear PK of 
AMG 557/MEDI5872. Population PK modeling was used to determine that the PK 
concentration in the typical subject achieved a 96.8% reduction from the Cmax value 
following the last dose of investigational product on Day 296. A 96.8% reduction in 
concentration is equivalent to that achieved using the 5 half-life standard used for drugs 
with linear PK. This corresponds to a follow-up duration of 113 days from the last dose 
of investigational product.
2. Protocol Synopsis (Study Design), Section 3 (Study Design): As a result of the changes 
mentioned above, the approximate number of weeks that the subjects will be in the study 
for has been changed from 44 weeks to 46 weeks.
3. Table 4.2.1-1 (Schedule of Screening Procedures): Corrected a typographical error by 
adding coagulation tests at the Screening visit (Visit 1) rather than the incorrect time 
point (Visit 2).

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4. Table 4.2.2-1 (Schedule of Study Procedures): Corrected a typographical error that 
included coagulation tests at Visit 2 rather than the correct time point, Screening visit 
(Visit 1).
5. Table 4.2.3-1 (Schedule of Follow-up Procedures): Added urine pregnancy test to the 
follow-up visits for females of childbearing potential to confirm the absence of pregnancy 
after the last dose of investigational product.
6. Table 4.5.1-1 (Identification of Investigational Products): Corrected a typographical error 
that incorrectly specified polysorbate 80 as an excipient in the formulation of 
AMG 557/MEDI5872 and placebo rather than the correct excipient, polysorbate 20.
Administrative Change 1, 24Feb2015
1. Section 4.1.6 (Discontinuation of Investigational Product): Added criterion for 
discontinuing investigational product in subjects who receive prohibited concomitant 
medications for consistency with language in Section 4.7.2 (Prohibited Concomitant 
Medications).
2. Table 4.2.1-1 (Schedule of Screening Procedures), Table 4.2.2-1 (Schedule of Study 
Procedures), Table 4.2.3-1 (Schedule of Follow-up Procedures): Clarified that the joint 
count assessments are “28-joint count”; removed footnote that limited joint count 
assessments in subjects with arthritis present at baseline to allow joint count assessments 
in subjects with new onset of arthritis.
3. Table 4.2.2-1 (Schedule of Study Procedures), Table 4.2.3-1 (Schedule of Follow-up 
Procedures): Specified in the footnote that the Schirmer’s test will be performed without 
anesthesia as most sites do not use anesthesia as a part of their dry eye assessment.
4. Section 4.3.9.4 (28-joint Count): Changed “joint count” to “28-joint count” for 
clarification and consistency with assessments in Table 4.2.1-1, Table 4.2.2-1, and 
Table 4.2.3-1.
5. Section 4.3.9.5 (Oral Evaluation): Corrected a typographical error that incorrectly 
specified stimulated parotid flow rate and collection rather than the correct stimulated 
whole saliva flow rate and collection.
6. Section 4.3.9.6 (Ophthalmological Evaluation): Specified that the Schirmer’s test will be 
performed without anesthesia as most sites do not use anesthesia as a part of their dry eye 
assessment.
7. Table 4.5.1-1 (Identification of Investigational Products): Removed a footnote about the 
investigational product storage conditions as the information was not as complete as that 
in Section 4.5.3 (Storage).
8. Section 4.5.1.1 (Investigational Product Dose Preparation): Corrected a typographical 
error to include selection of an investigational product kit instead of vials.
9. Section 4.5.1.3 (Investigational Product Thawing Instructions): Corrected a typographical 
error to include 4 vials of investigational product instead of 3 vials and corrected a 
typographical error that incorrectly used the word “box” rather than the corrected word 
“kit.”

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10. Section 4.5.1.4 (Dose Preparation Steps): Included “placebo” in addition to 
AMG 557/MEDI5872 in the dose preparation steps. Revised the text describing the dose 
preparation steps for clarification.
11. Table 4.5.1.4-1 (Preparation of Investigational Product Dose): Removed the original table 
and replaced it with a table describing the dose preparation steps in detail.
12. Section 4.5.4 (Definition of Temperature Excursion): Removed section as all temperature 
deviations are routinely documented.
13. Section 4.7.1 (Permitted Concomitant Medications): Added background treatments for 
pSS that are permitted in the study as a clarification of text in the section on prohibited 
concomitant medications, and corrected a typographical error that incorrectly used the 
word “excluded” rather than the corrected word “prohibited.”
Protocol Amendment 1, 26Nov2014
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Major changes to the protocol are summarized below.
1. Section 4.1.6 (Discontinuation of Investigational Product): In response to a request from 
the United States Food and Drug Administration (US FDA), Criterion 3 was added to 
specify the number and type of AEs that would trigger either discontinuing 
investigational product in an individual subject or study stopping. An individual subject 
will not receive any further investigational product if any Grade ≥ 3 TEAE (based on 
CTCAE [Version 4.0]) occurs that is considered to be related to investigational product 
by the investigator, unless in the opinion of the investigator, the event(s) are a
manifestations of SS (eg, within the definitions included in the ESSDAI). Isolated Grade 
≥ 3 laboratory abnormalities without a clinical event meeting the above criteria will not 
automatically lead to discontinuation of investigational product.
2. Table 4.2.1-1 (Schedule of Screening Procedures): Added hemoglobin A1c to screening 
procedures, as poorly controlled diabetes (hemoglobin A1c > 8%) is considered 
exclusionary. Added coagulation tests. Removed IGRA from screening procedures, as 
this is assessed as part of the infectious disease panel. 
3. Table 4.2.2-1 (Schedule of Study Procedures) and Table 4.2.3-1 (Schedule of Follow-up 
Procedures): Added time points for assessment of coagulation tests, which will be 
assessed at Day 1, Day 99, Day 197/ETV, and Day 281/EOS.
4. Section 4.3.5 (Clinical Laboratory Tests): Added creatinine phosphokinase to serum 
chemistry assessments, as subjects may have myositis. Added coagulation tests, including 
INR, prothrombin time, and activated partial thromboplastin time. Added hemoglobin 
A1c to other tests.
5. Section 4.3.9.3 (Physician Global Assessment of Disease Activity): Changed the 
description of the MDGA from “0 to 100 mm scale” to “0 to 10 Likert scale”, as the 
version of the MDGA that will be used in the study was changed.
6. Table 4.3.10-1 (Estimate of Blood Volume to be Collected): Estimated blood volumes 
were updated based on feedback received from the contract research organization and 
based on the addition of coagulation tests.

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7. Section 4.4 (Study Suspension or Termination): In response to a request from the US 
FDA, Criterion 1 was modified to specify the number and type of AEs that would trigger 
either discontinuing investigational product in an individual subject or study stopping. 
Study treatment will be suspended if any of the following events occur in the study: a) 
any death that is considered to be related to investigational product by the investigator; b) 
any Grade 4 TEAE (based on CTCAE [Version 4.0]) that is considered to be related to 
investigational product by the investigator, with the exception of anaphylactic reaction; 
and c) if 2 subjects have TEAEs in the same organ system of Grade ≥ 3 (based on 
CTCAE [Version 4.0]) that are considered to be related to investigational product by the 
investigator, unless in the opinion of the investigator, the events are manifestations of SS
(eg, within the definitions included in the ESSDAI). Isolated Grade ≥ 3 laboratory 
abnormalities without a clinical event meeting the above criteria will not automatically 
trigger suspension of the study. In these cases, study treatment will be suspended, the 
subject data will be unblinded, and the data will be reviewed by MedImmune Patient 
Safety. Based upon this review, MedImmune Patient Safety will determine if the dosing 
may resume or if the study will be terminated.
8. Section 4.6.2 (Methods for Ensuring Blinding): Clarified that Sponsor staff who are 
involved in the treatment or clinical evaluation of the subjects will also be unaware of the 
treatment received from the start of the study until all subjects have reached Day 99 or 
withdrawn from the study. After this time, Sponsor staff may be unblinded.
9. Section 4.6.3.1 (Unblinding in the Event of a Medical Emergency): Clarified that, at 
minimum, the investigator should attempt to immediately contact the medical monitor 
prior to unblinding.
10. Section 4.6.3.2 (Unblinding for the Primary Analyses): Added section to describe that the 
Sponsor staff will be unblinded at the primary analysis (after Day 99). The data from the 
primary analysis will not be communicated to contract research organization staff, 
investigator staff, or enrolled subjects, until the study is complete.
11. Section 4.7.2 (Prohibited Concomitant Medications): Clarified that subjects are not 
permitted to receive methotrexate > 20 mg/week.
12. Section 4.8.7 (Planned Analyses): Added section to describe that the primary analysis
will be performed when all subjects have completed Day 99 (ie, at the end of the 
double-blind treatment phase). The primary analysis will include all assessments 
performed on the subjects prior to the data cut-off for the primary analysis. The final 
analysis will be performed when all subjects have completed the treatment and safety 
follow-up periods or have withdrawn from the study. The analysis of the primary 
endpoint at Day 99 will not change at the final analysis, so no multiplicity adjustment 
will be applied.
13. Section 7.2 (Subject Data Protection): Removed “genetic” from the text, as there is no 
genetic testing in this study.

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Appendix 1
Signatures

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Sponsor Signature(s) 
A Phase 2a, Randomized, Placebo-controlled, Proof of Mechanism Study to Evaluate the 
Safety and Efficacy of AMG 557/MEDI5872 in Subjects with Primary Sjogren’s Syndrome
I agree to the terms of this protocol and all amendments/administrative changes.
Signature and date: 
Jorn Drappa, MD, Vice President, Clinical Development
Clinical Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 301-398-1171

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Signature of International Coordinating Investigator
A Phase 2a, Randomized, Placebo-controlled, Proof of Mechanism Study to Evaluate the 
Safety and Efficacy of AMG 557/MEDI5872 in Subjects with Primary Sjogren’s Syndrome
I, the undersigned, have reviewed this protocol and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Conference on Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the Sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the Sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the Sponsor immediately upon receipt.
Signature and date: 
Name and title: 
Address including postal code: 
  
Telephone number: 
Site/Center number (if available):
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.

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Signature of Principal or Coordinating Investigator
A Phase 2a, Randomized, Placebo-controlled, Proof of Mechanism Study to Evaluate the 
Safety and Efficacy of AMG 557/MEDI5872 in Subjects with Primary Sjogren’s Syndrome
I, the undersigned, have reviewed this protocol and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Conference on Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the Sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the Sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the Sponsor immediately upon receipt.
Signature and date:
Name and title: 
Address including postal code: 
  
Telephone number: 
Site/Center number (if available):
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.

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Appendix 2
Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grades 1 to 5 as defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death.
Grade 5 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.

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An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes non TESAEs (ie, SAEs that occur prior 
to the administration of investigational product) as well as TESAEs. A protocol-related SAE 
may occur as a result of a procedure or intervention required during the study (eg, blood 
collection, washout of an existing medication). The following guidelines should be used by 
investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).

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Appendix 3
American European Consensus Group Criteria
Source: Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, 
et al. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria 
proposed by the American-European Consensus Group. Ann Rheum Dis. 2002 
Jun;61(6):554-8.

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Appendix 4
European League Against Rheumatism Sjogren’s 
Syndrome Disease Activity Index

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Appendix 5
Subject Global Assessment of Disease Activity
Considering all the ways that your illness affects you, how have you been doing over the 
previous 7 days?
0
100
Very Well
Very Poor

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Appendix 6
Short-form 36 Version 2

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Appendix 7
Profile of Fatigue and Discomfort-Sicca Symptoms 
Inventory-Short Form
Please assess how bad at its worst each symptom has been in the last two weeks, by 
ringing one of the numbers 0 to 7.
1. The worst problem that I’ve had in the last two weeks with needing to rest, feeling tired, 
being exhausted or needing to sleep:
no need to rest at all
0
1
2
3
4
5
6
7
as bad as 
imaginable 
2. The worst problem that I’ve had in the last two weeks with it being hard to GET going,
things taking an effort or me feeling that ‘it’s a battle’:
not hard to get going at 
all
0
1
2
3
4
5
6
7
as bad as 
imaginable 
3. The worst problem that I’ve had in the last two weeks with it being hard to KEEP going,
me being easily worn out or lacking in energy:
not hard to keep going 
at all
0
1
2
3
4
5
6
7
as bad as 
imaginable 
4. The worst problem that I’ve had in the last two weeks with lack of strength in my 
muscles or feeling weak:
no lack of strength at 
all
0
1
2
3
4
5
6
7
as bad as 
imaginable 
5. The worst problem I’ve had in the last two weeks with not thinking clearly or finding it
hard to concentrate:

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no such problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
6. The worst problem I’ve had in the last two weeks with forgetting things or making 
mistakes:
no such problem at all
0
1
2
3
4
5
6
7
as bad as 
imaginable 

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VISIT 1
7. The worst problem that I’ve had in the last two weeks with discomfort in my limbs: e.g. 
discomfort, aches or pains in your big joints (hips, knees, shoulders) or in your muscles 
or aching all over
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
8. The worst problem in the last 2 weeks with discomfort or swelling of fingers or wrists:
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
9. The worst problem I’ve had in the last two weeks with uncomfortably cold hands:
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
10. The worst problem that I’ve had in the last two weeks with dry or itchy skin:
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
11. The worst problem that I’ve had in the last two weeks with vaginal dryness: e.g. 
experienced discomfort during sex due to vaginal dryness
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
12. The worst problem that I’ve had in the last two weeks with sore eyes: e.g. eyes felt 
gritty, painful eyes, burning eyes, itchy eyes or irritation in eyes
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 

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13. The worst problem that I’ve had in the last two weeks with eye irritation:e.g. eyes 
irritated by smoky atmosphere, eyes were uncomfortable in the wind, and/or eyes were 
uncomfortable in air-conditioning or low-humidity places 
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
14. The worst problem that I’ve had in the last two weeks with poor vision: (even if wearing
spectacles) e.g., blurred vision, poor vision, problem with eyes limited reading, watching 
TV or night driving, hard to see computer screen or cash machine screen 
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
VISIT 1
15. The worst problem that I’ve had in the last two weeks with difficulties in eating: e.g. 
mouth felt dry when eating, difficult to swallow foods, needed liquid to swallow food, 
food stuck to the mouth, needed to rinse away remains of food or have appreciated food 
less
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
16. The worst problem that I’ve had in the last two weeks with dry throat or nose: e.g. 
mouth felt dry when breathing, had difficulty talking with dry mouth, needed a drink to 
talk easily, nose felt dry, dry throat, air-conditioning dried my mouth
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
17. The worst problem that I’ve had in the last two weeks with bad breath: e.g. felt that 
your breath has smelt, saliva felt sticky

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no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
18. The worst problem in the last two weeks with needing fluid to wet my mouth: e.g. 
carried drink to bed, needed drink during the night, woke at night to pass urine, had 
urgent need to pass urine
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 
19. The worst problem that I’ve had in the last two weeks with other mouth problems: e.g. 
mouth ulcers, swollen salivary glands, felt as though choking because of dryness, change 
in flavours or tastes, needed to visit the dentists
no problem at 
all
0
1
2
3
4
5
6
7
as bad as imaginable 

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Appendix 8
European League Against Rheumatism Sjogren’s 
Syndrome Patient Reported Index
The total score is the mean score of the 3 scales.
1) How severe has your dryness been during the last 2 weeks?
No
dryness
Maximal imaginable
dryness
0
1
2
3
4
5
6
7
8
9
10
2) How severe has your fatigue been during the last 2 weeks?
No 
fatigue
Maximal imaginable
fatigue
0
1
2
3
4
5
6
7
8
9
10
3) How severe has your pain (joint or muscular pains in your arms or legs)
been during the last 2 weeks?
No 
pain
Maximal imaginable
pain
0
1
2
3
4
5
6
7
8
9
10

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Appendix 9
Patient Global Impression of Change
Overall, how would you rate the change in your Sjogren’s Syndrome symptoms since starting 
this study?
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse

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Appendix 10
Patient Global Impression of Severity
Overall, how would you rate the severity of your Sjogren’s Syndrome symptoms today?
No symptoms
Very mild
Mild
Moderate
Severe
Very Severe

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Appendix 11
Guidance for Abnormal Liver Function Tests 
Management
This guidance is based on the July 2009 Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation.
Section IV of the US FDA document deals with the clinical evaluation of and monitoring 
of drug-induced liver injury, and this protocol-specific guidance has adopted the 
recommendations on detection of drug-induced liver disease, confirmation of abnormal 
ALT/AST with regard to retesting, follow-up observation, advice on appropriate history 
gathering and advice on the need for obtaining additional laboratory tests and 
consultations as needed. MedImmune has adopted a conservative approach to holding 
administration of investigational product based on abnormal liver function tests (LFTs) 
until a full understanding of the event has been understood by the principle investigator
and the medical monitor. This understanding is required so that the principle investigator, 
in consultation with the medical monitor, can reach a decision as to whether dosing can 
be continued or whether it is advisable to stop investigational product permanently. The 
US FDA document acknowledges there is no published consensus on how this decision 
should be made but this protocol-specific guidance requires involvement of the medical 
monitor at any early stage of clinically significant increases in ALT/AST to provide 
additional information on accumulating clinical experience of sifalimumab as well as 
input from the investigator regarding the nature of the subject and other factors that may 
be relevant. This approach will provide the balance necessary to permit learning about the 
investigational product while maximizing safety concerns to minimize the potential for 
functional liver impairment and damage. There are 2 separate parts to the guidance to 
detect clinically significant liver injury depending on whether the subject entered the 
study with normal or mildly elevated (up to 2 × ULN) ALT/AST or on more severe 
abnormalities in subjects with ALT/AST > 2 × ULN at baseline.
For the purpose of this document, LFTs will be AST, ALT, total bilirubin, and alkaline 
phosphatase.
The decision to include subjects in this clinical trial with baseline LFT abnormalities is 
supported by the US FDA guidance.
Copies of the document “Guidance of Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation” can be located at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf

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Guidance for abnormal LFTs that develop post-screening in subjects with ALT/AST 
≤2 × ULN at screening due to liver involvement by pSS in the opinion of the 
investigator:

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ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalization ratio; 
LFT = liver function test; MTX = methotrexate; NSAID = nonsteroidal anti-inflammatory drug; pSS = primary 
Sjogren’s syndrome; PT = prothrombin time; RUQ = right upper quadrant; ULN = upper limit of normal 

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Guidance for abnormal LFTs that develop post-screening in subjects with ALT/AST 
≤2 × ULN at screening due to liver involvement by pSS in the opinion of the 
investigator:

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ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; CPK = 
creatinine phosphokinase; EBV = Epstein-Barr virus; GI = gastrointestinal; INH = isoniazid; INR = 
international normalization ratio; LFT = liver function test; MTX = methotrexate; NSAID = nonsteroidal anti-
inflammatory drug; pSS = primary Sjogren’s syndrome; PT = prothrombin time; RUQ = right upper quadrant; 
ULN = upper limit of normal

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Guidance for abnormal LFTs that develop post-screening in subjects with ALT/AST 
> 2 × ULN at screening due to liver involvement by pSS in the opinion of the 
investigator:
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; CPK = 
creatinine phosphokinase; EBV = Epstein-Barr virus; GI = gastrointestinal; INH = isoniazid; INR = 
international normalization ratio; LFT = liver function test; MTX = methotrexate; NSAID = nonsteroidal anti-
inflammatory drugs; pSS = primary Sjogren’s syndrome; PT = prothrombin time; RUQ = right upper quadrant; 
ULN = upper limit of normal